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Mutation causes ibrutinib resistance in CLL
Credit: Rhoda Baer
Researchers say they have identified a source of drug resistance in chronic lymphocytic leukemia (CLL).
In a letter to The New England Journal of Medicine, the team described how a mutation in Bruton’s tyrosine kinase (BTK) triggers resistance to ibrutinib, a drug that treats CLL by inhibiting BTK.
The researchers discovered this point mutation in a CLL patient enrolled in a clinical trial. The patient initially responded well to ibrutinib but stopped responding after almost 20 months.
“In a way, we are repeating, at a faster pace, the story of Gleevec [imatinib],” said study author Y. Lynn Wang, MD, PhD, of the University of Chicago in Illinois.
“That story began with development of an effective drug with few side effects, but, in many patients, the leukemia eventually found a way around it after long-term use. So researchers developed second-line drugs to overcome resistance.”
The ibrutinib study began in 2010 at Weill Cornell Medical College in New York, one of several sites for a phase 1 trial of ibrutinib. The researchers recruited 16 patients with CLL whose disease had progressed or relapsed despite multiple treatments.
Dr Wang arranged to track the progress of each patient’s leukemic cells before and during treatment and to correlate any cellular or molecular changes with each patient’s disease activity.
One of the 16 patients in the trial seemed to be unusual. This 61-year-old woman was diagnosed in 2000 at age 49. She had unsuccessfully received several different treatments before entering the study.
Within 18 months of starting ibrutinib, she showed significant improvement. At about 20 months, however, she started to decline, developing a respiratory infection that did not improve with treatment. By 21 months, it was clear she was having a relapse. The clinical team increased her dose, with no discernable effect.
Dr Wang’s team quickly began analyzing her blood samples, looking for changes that occurred between the period when she was responding well to ibrutinib and after she began to relapse.
Because complete gene sequencing would be time consuming, Dr Wang asked a graduate student working on the project, Menu Setty from Memorial Sloan-Kettering in New York, to first focus on 3 proteins that were likely candidates. One of the candidates was BTK.
And sure enough, Setty discovered a tiny but consistent change in BTK in about 90% of post-relapse cells. It was a thymidine-to-adenine mutation at nucleotide 1634 of the BTK complementary DNA, leading to a substitution of serine for cysteine at residue 481 (C481S).
When the researchers later analyzed the entire set of the patient’s genes, they found no other genetic changes that correlated with the patient’s clinical course. BTK made perfect sense as the cause for drug resistance, the researchers noted, as it’s the primary target of ibrutinib binding, and it plays a central role in rapid cell proliferation.
Dr Wang and her colleagues used structural and biochemical measures to confirm that the C481S mutation made CLL cells resistant to ibrutinib. The studies indicated that ibrutinib was 500 times less likely to bind to mutant BTK.
In an attempt to save the patient, the researchers tested alternative kinase inhibitors against the patient’s leukemic cells in the lab.
They found some kinase inhibitors remained effective against ibrutinib-resistant cells. (These studies are described in a separate manuscript that has been submitted for publication.) Unfortunately, despite this effort, the patient passed away a few weeks later, due to sepsis.
The researchers noted that the C481S mutation is one of several mechanisms that underlie resistance to ibrutinib, but this research highlights the mutation’s role in disease development and drug resistance.
Understanding the molecular and cellular mechanisms of resistance is the first step toward monitoring, early detection, and development of novel strategies to overcome drug resistance. 
Credit: Rhoda Baer
Researchers say they have identified a source of drug resistance in chronic lymphocytic leukemia (CLL).
In a letter to The New England Journal of Medicine, the team described how a mutation in Bruton’s tyrosine kinase (BTK) triggers resistance to ibrutinib, a drug that treats CLL by inhibiting BTK.
The researchers discovered this point mutation in a CLL patient enrolled in a clinical trial. The patient initially responded well to ibrutinib but stopped responding after almost 20 months.
“In a way, we are repeating, at a faster pace, the story of Gleevec [imatinib],” said study author Y. Lynn Wang, MD, PhD, of the University of Chicago in Illinois.
“That story began with development of an effective drug with few side effects, but, in many patients, the leukemia eventually found a way around it after long-term use. So researchers developed second-line drugs to overcome resistance.”
The ibrutinib study began in 2010 at Weill Cornell Medical College in New York, one of several sites for a phase 1 trial of ibrutinib. The researchers recruited 16 patients with CLL whose disease had progressed or relapsed despite multiple treatments.
Dr Wang arranged to track the progress of each patient’s leukemic cells before and during treatment and to correlate any cellular or molecular changes with each patient’s disease activity.
One of the 16 patients in the trial seemed to be unusual. This 61-year-old woman was diagnosed in 2000 at age 49. She had unsuccessfully received several different treatments before entering the study.
Within 18 months of starting ibrutinib, she showed significant improvement. At about 20 months, however, she started to decline, developing a respiratory infection that did not improve with treatment. By 21 months, it was clear she was having a relapse. The clinical team increased her dose, with no discernable effect.
Dr Wang’s team quickly began analyzing her blood samples, looking for changes that occurred between the period when she was responding well to ibrutinib and after she began to relapse.
Because complete gene sequencing would be time consuming, Dr Wang asked a graduate student working on the project, Menu Setty from Memorial Sloan-Kettering in New York, to first focus on 3 proteins that were likely candidates. One of the candidates was BTK.
And sure enough, Setty discovered a tiny but consistent change in BTK in about 90% of post-relapse cells. It was a thymidine-to-adenine mutation at nucleotide 1634 of the BTK complementary DNA, leading to a substitution of serine for cysteine at residue 481 (C481S).
When the researchers later analyzed the entire set of the patient’s genes, they found no other genetic changes that correlated with the patient’s clinical course. BTK made perfect sense as the cause for drug resistance, the researchers noted, as it’s the primary target of ibrutinib binding, and it plays a central role in rapid cell proliferation.
Dr Wang and her colleagues used structural and biochemical measures to confirm that the C481S mutation made CLL cells resistant to ibrutinib. The studies indicated that ibrutinib was 500 times less likely to bind to mutant BTK.
In an attempt to save the patient, the researchers tested alternative kinase inhibitors against the patient’s leukemic cells in the lab.
They found some kinase inhibitors remained effective against ibrutinib-resistant cells. (These studies are described in a separate manuscript that has been submitted for publication.) Unfortunately, despite this effort, the patient passed away a few weeks later, due to sepsis.
The researchers noted that the C481S mutation is one of several mechanisms that underlie resistance to ibrutinib, but this research highlights the mutation’s role in disease development and drug resistance.
Understanding the molecular and cellular mechanisms of resistance is the first step toward monitoring, early detection, and development of novel strategies to overcome drug resistance.
Credit: Rhoda Baer
Researchers say they have identified a source of drug resistance in chronic lymphocytic leukemia (CLL).
In a letter to The New England Journal of Medicine, the team described how a mutation in Bruton’s tyrosine kinase (BTK) triggers resistance to ibrutinib, a drug that treats CLL by inhibiting BTK.
The researchers discovered this point mutation in a CLL patient enrolled in a clinical trial. The patient initially responded well to ibrutinib but stopped responding after almost 20 months.
“In a way, we are repeating, at a faster pace, the story of Gleevec [imatinib],” said study author Y. Lynn Wang, MD, PhD, of the University of Chicago in Illinois.
“That story began with development of an effective drug with few side effects, but, in many patients, the leukemia eventually found a way around it after long-term use. So researchers developed second-line drugs to overcome resistance.”
The ibrutinib study began in 2010 at Weill Cornell Medical College in New York, one of several sites for a phase 1 trial of ibrutinib. The researchers recruited 16 patients with CLL whose disease had progressed or relapsed despite multiple treatments.
Dr Wang arranged to track the progress of each patient’s leukemic cells before and during treatment and to correlate any cellular or molecular changes with each patient’s disease activity.
One of the 16 patients in the trial seemed to be unusual. This 61-year-old woman was diagnosed in 2000 at age 49. She had unsuccessfully received several different treatments before entering the study.
Within 18 months of starting ibrutinib, she showed significant improvement. At about 20 months, however, she started to decline, developing a respiratory infection that did not improve with treatment. By 21 months, it was clear she was having a relapse. The clinical team increased her dose, with no discernable effect.
Dr Wang’s team quickly began analyzing her blood samples, looking for changes that occurred between the period when she was responding well to ibrutinib and after she began to relapse.
Because complete gene sequencing would be time consuming, Dr Wang asked a graduate student working on the project, Menu Setty from Memorial Sloan-Kettering in New York, to first focus on 3 proteins that were likely candidates. One of the candidates was BTK.
And sure enough, Setty discovered a tiny but consistent change in BTK in about 90% of post-relapse cells. It was a thymidine-to-adenine mutation at nucleotide 1634 of the BTK complementary DNA, leading to a substitution of serine for cysteine at residue 481 (C481S).
When the researchers later analyzed the entire set of the patient’s genes, they found no other genetic changes that correlated with the patient’s clinical course. BTK made perfect sense as the cause for drug resistance, the researchers noted, as it’s the primary target of ibrutinib binding, and it plays a central role in rapid cell proliferation.
Dr Wang and her colleagues used structural and biochemical measures to confirm that the C481S mutation made CLL cells resistant to ibrutinib. The studies indicated that ibrutinib was 500 times less likely to bind to mutant BTK.
In an attempt to save the patient, the researchers tested alternative kinase inhibitors against the patient’s leukemic cells in the lab.
They found some kinase inhibitors remained effective against ibrutinib-resistant cells. (These studies are described in a separate manuscript that has been submitted for publication.) Unfortunately, despite this effort, the patient passed away a few weeks later, due to sepsis.
The researchers noted that the C481S mutation is one of several mechanisms that underlie resistance to ibrutinib, but this research highlights the mutation’s role in disease development and drug resistance.
Understanding the molecular and cellular mechanisms of resistance is the first step toward monitoring, early detection, and development of novel strategies to overcome drug resistance.
Wealth appears to affect distribution of cancer types
Credit: Rhoda Baer
Results of a large study suggest certain malignanices are more concentrated in areas with high levels of poverty, while other cancer types arise more often in wealthy regions.
The research, conducted using data from nearly 3 million US cancer cases, also indicated that areas with higher poverty levels tended to have a lower cancer incidence but higher mortality rate than areas with lower poverty levels.
Researchers reported these findings in the journal Cancer.
Francis Boscoe, PhD, of the New York State Cancer Registry in Albany, and his colleagues conducted this research to evaluate the role of socioeconomics in cancer incidence and mortality.
So the team compared individuals living in areas with the highest poverty levels to those living in areas with the lowest poverty levels.
The researchers collected information on nearly 3 million cancer cases diagnosed between 2005 and 2009 in16 states, plus Los Angeles (an area covering 42% of the US population). Cases were divided into 1 of 4 groupings based on the poverty rate of the residential census tract at the time of diagnosis.
For all malignancies combined, there was a negligible association between cancer incidence and poverty. However, 32 of 39 cancer types showed a significant association with poverty.
Fourteen cancers were positively associated with poverty, and 18 were negatively associated. Myeloma, Hodgkin lymphoma, and non-Hodgkin lymphoma (NHL) were among the negatively associated malignancies.
The cancers most significantly associated with higher poverty levels were Kaposi sarcoma and cancers of the larynx, cervix, penis, and liver. The cancers most significantly associated with lower poverty levels were melanoma, thyroid cancer, other non-epithelial skin cancers, and testis cancer.
Overall, male malignancy rates were more sensitive to poverty level than female rates. And, in general, the race-specific cancer incidence rates differed, but the poverty gradients were similar.
For example, there was a roughly 20-fold difference in rates of melanoma between white and black individuals, but the relationship between poverty and incidence remained regardless of race.
This was not true for NHL, however. Among black individuals, the incidence of NHL increased as the poverty level increased. But among white individuals, the incidence of NHL decreased as the poverty level increased.
The researchers pointed out that—for all cancer sites, races, and sexes combined—the difference in risk between the greatest and lowest poverty category was less than 2%.
“At first glance, the effects seem to cancel one another out,” Dr Boscoe said. “But the cancers more associated with poverty have lower incidence and higher mortality, and those associated with wealth have higher incidence and lower mortality. When it comes to cancer, the poor are more likely to die of the disease, while the affluent are more likely to die with the disease.”
Dr Boscoe noted that recent gains in technology have made it much easier to link patient addresses with neighborhood characteristics, therefore making it possible to incorporate socioeconomic status into cancer surveillance.
“Our hope is that our paper will illustrate the value and necessity of doing this routinely in the future,” he concluded.
Credit: Rhoda Baer
Results of a large study suggest certain malignanices are more concentrated in areas with high levels of poverty, while other cancer types arise more often in wealthy regions.
The research, conducted using data from nearly 3 million US cancer cases, also indicated that areas with higher poverty levels tended to have a lower cancer incidence but higher mortality rate than areas with lower poverty levels.
Researchers reported these findings in the journal Cancer.
Francis Boscoe, PhD, of the New York State Cancer Registry in Albany, and his colleagues conducted this research to evaluate the role of socioeconomics in cancer incidence and mortality.
So the team compared individuals living in areas with the highest poverty levels to those living in areas with the lowest poverty levels.
The researchers collected information on nearly 3 million cancer cases diagnosed between 2005 and 2009 in16 states, plus Los Angeles (an area covering 42% of the US population). Cases were divided into 1 of 4 groupings based on the poverty rate of the residential census tract at the time of diagnosis.
For all malignancies combined, there was a negligible association between cancer incidence and poverty. However, 32 of 39 cancer types showed a significant association with poverty.
Fourteen cancers were positively associated with poverty, and 18 were negatively associated. Myeloma, Hodgkin lymphoma, and non-Hodgkin lymphoma (NHL) were among the negatively associated malignancies.
The cancers most significantly associated with higher poverty levels were Kaposi sarcoma and cancers of the larynx, cervix, penis, and liver. The cancers most significantly associated with lower poverty levels were melanoma, thyroid cancer, other non-epithelial skin cancers, and testis cancer.
Overall, male malignancy rates were more sensitive to poverty level than female rates. And, in general, the race-specific cancer incidence rates differed, but the poverty gradients were similar.
For example, there was a roughly 20-fold difference in rates of melanoma between white and black individuals, but the relationship between poverty and incidence remained regardless of race.
This was not true for NHL, however. Among black individuals, the incidence of NHL increased as the poverty level increased. But among white individuals, the incidence of NHL decreased as the poverty level increased.
The researchers pointed out that—for all cancer sites, races, and sexes combined—the difference in risk between the greatest and lowest poverty category was less than 2%.
“At first glance, the effects seem to cancel one another out,” Dr Boscoe said. “But the cancers more associated with poverty have lower incidence and higher mortality, and those associated with wealth have higher incidence and lower mortality. When it comes to cancer, the poor are more likely to die of the disease, while the affluent are more likely to die with the disease.”
Dr Boscoe noted that recent gains in technology have made it much easier to link patient addresses with neighborhood characteristics, therefore making it possible to incorporate socioeconomic status into cancer surveillance.
“Our hope is that our paper will illustrate the value and necessity of doing this routinely in the future,” he concluded.
Credit: Rhoda Baer
Results of a large study suggest certain malignanices are more concentrated in areas with high levels of poverty, while other cancer types arise more often in wealthy regions.
The research, conducted using data from nearly 3 million US cancer cases, also indicated that areas with higher poverty levels tended to have a lower cancer incidence but higher mortality rate than areas with lower poverty levels.
Researchers reported these findings in the journal Cancer.
Francis Boscoe, PhD, of the New York State Cancer Registry in Albany, and his colleagues conducted this research to evaluate the role of socioeconomics in cancer incidence and mortality.
So the team compared individuals living in areas with the highest poverty levels to those living in areas with the lowest poverty levels.
The researchers collected information on nearly 3 million cancer cases diagnosed between 2005 and 2009 in16 states, plus Los Angeles (an area covering 42% of the US population). Cases were divided into 1 of 4 groupings based on the poverty rate of the residential census tract at the time of diagnosis.
For all malignancies combined, there was a negligible association between cancer incidence and poverty. However, 32 of 39 cancer types showed a significant association with poverty.
Fourteen cancers were positively associated with poverty, and 18 were negatively associated. Myeloma, Hodgkin lymphoma, and non-Hodgkin lymphoma (NHL) were among the negatively associated malignancies.
The cancers most significantly associated with higher poverty levels were Kaposi sarcoma and cancers of the larynx, cervix, penis, and liver. The cancers most significantly associated with lower poverty levels were melanoma, thyroid cancer, other non-epithelial skin cancers, and testis cancer.
Overall, male malignancy rates were more sensitive to poverty level than female rates. And, in general, the race-specific cancer incidence rates differed, but the poverty gradients were similar.
For example, there was a roughly 20-fold difference in rates of melanoma between white and black individuals, but the relationship between poverty and incidence remained regardless of race.
This was not true for NHL, however. Among black individuals, the incidence of NHL increased as the poverty level increased. But among white individuals, the incidence of NHL decreased as the poverty level increased.
The researchers pointed out that—for all cancer sites, races, and sexes combined—the difference in risk between the greatest and lowest poverty category was less than 2%.
“At first glance, the effects seem to cancel one another out,” Dr Boscoe said. “But the cancers more associated with poverty have lower incidence and higher mortality, and those associated with wealth have higher incidence and lower mortality. When it comes to cancer, the poor are more likely to die of the disease, while the affluent are more likely to die with the disease.”
Dr Boscoe noted that recent gains in technology have made it much easier to link patient addresses with neighborhood characteristics, therefore making it possible to incorporate socioeconomic status into cancer surveillance.
“Our hope is that our paper will illustrate the value and necessity of doing this routinely in the future,” he concluded.
CHMP recommends ofatumumab for CLL
Credit: Linda Bartlett
The European Medicine Agency’s Committee for Medicinal Products for Human Use (CHMP) has issued a positive opinion for ofatumumab (Arzerra), a monoclonal antibody targeting CD20.
The CHMP is recommending that ofatumumab receive conditional approval for use in combination with chlorambucil or bendamustine to treat patients with chronic lymphocytic leukemia (CLL) who have not received prior therapy and are not eligible for fludarabine-based therapy.
The European Commission (EC) will take the CHMP’s opinion into account when deciding whether to approve ofatumumab for this indication.
Ofatumumab already has conditional approval in the Europe Union to treat CLL patients who are refractory to fludarabine and alemtuzumab.
Ofatumumab received conditional approval because the drug’s benefits appear to outweigh the risks it poses. The drug will not receive full
approval until the companies developing ofatumumab, GlaxoSmithKline and Genmab, submit results of additional research to the EC.
The CHMP’s recommendation for expanded approval is based on results from 2 trials in patients with CLL who were ineligible for fludarabine-based treatment.
The first is a phase 2 study (OMB115991) in which researchers evaluated the efficacy of ofatumumab in combination with bendamustine. The second is the phase 3 COMPLEMENT 1 study (OMB110911), a randomized trial in which researchers compared ofatumumab and chlorambucil in combination to chlorambucil alone.
Phase 2 study
Results from this single-arm study were presented at the 2013 International Workshop on CLL. Researchers enrolled 97 patients with CLL, 44 of whom were previously untreated and 53 who had relapsed. The median ages were 62.5 and 68 years, respectively.
Treatment began with acetaminophen, an antihistamine, and a glucocorticoid. Patients then received ofatumumab at 300 mg on day 1 and 1000 mg on day 8 of cycle 1. For cycles 2 through 6, they received 1000 mg on day 1 every 28 days.
Patients received bendamustine on days 1 and 2, every 28 days for up to 6 cycles. The initial dose was 90 mg/m2 for the untreated patients and 70 mg/m2 for relapsed patients.
However, patients required a dose reduction due to toxicity. The previously untreated patients were reduced to 60 mg/m2, and the relapsed patients were reduced to 50 mg/m2.
The overall response rate was 95% in the previously untreated group and 74% in the relapsed group. Complete responses occurred in 43% and 11%, respectively.
CT results showed the overall response rate was 82% in the previously untreated group and 70% in the relapsed group. Complete responses occurred in 27% and 9%, respectively. The median time to response was 0.95 months for both groups.
Grade 3 or higher adverse events occurred in 25% of patients in the previously untreated group and 38% of those in the relapsed group.
This included infusion reactions (11% and 8%, respectively), neutropenia (16% and 29%, respectively), infections (11% and 15%, respectively), rash (2% of previously untreated patients), febrile neutropenia (4% of relapsed patients), and thrombocytopenia (4% of relapsed patients).
There were no deaths in the previously untreated group, but 4 patients died in the relapsed group. Two of these deaths may have been related to study treatment. One patient died of pneumonia and hemolytic anemia 15 days after the last dose of treatment, and 1 patient died of sepsis 4 days after the last dose of treatment.
Phase 3 study
Data from the COMPLEMENT 1 study were presented at ASH 2013. Researchers compared ofatumumab plus chlorambucil to chlorambucil alone in 447 previously untreated patients with CLL who were ineligible for fludarabine-based therapy.
Patients had a median age of 69 years (range, 35 to 92). Seventy-two percent had 2 or more comorbidities, and 48% had a creatinine clearance of less than 70 mL/min.
Patients in the ofatumumab arm received the drug at 300 mg in cycle 1 on day 1, 1000 mg in cycle 1 on day 8, and 1000 mg administered on day 1 of all subsequent 28-day cycles.
In both arms, patients received chlorambucil at a dose of 10 mg/m2 orally on days 1 to 7, every 28 days. Prior to each infusion of ofatumumab, patients received acetaminophen, an antihistamine, and a glucocorticoid.
The overall response rate was 82% in the ofatumumab-chlorambucil group and 69% in the chlorambucil-alone group (P=0.001). Complete response rates were 12% and 1%, respectively.
At a median follow-up of 29 months, the median overall survival was not reached for either treatment arm. However, ofatumumab-treated patients had longer progression-free survival than patients who received chlorambucil alone—22.4 months and 13.1 months, respectively (P<0.001).
Grade 3 or higher adverse events occurred in 50% of ofatumumab-treated patients and 43% of patients who received chlorambucil alone. The most common event was neutropenia, which occurred in 26% and 14% of patients, respectively.
Grade 3 or higher infections occurred in 15% of ofatumumab-treated patients and 14% of patients who received chlorambucil alone. The most common was pneumonia, which occurred in 4% and 3%, respectively.
In the entire cohort, grade 3 or higher infusion-related events occurred in 10% of patients, but there were no fatal infusion reactions. Two percent of subjects in both arms died during treatment.
Credit: Linda Bartlett
The European Medicine Agency’s Committee for Medicinal Products for Human Use (CHMP) has issued a positive opinion for ofatumumab (Arzerra), a monoclonal antibody targeting CD20.
The CHMP is recommending that ofatumumab receive conditional approval for use in combination with chlorambucil or bendamustine to treat patients with chronic lymphocytic leukemia (CLL) who have not received prior therapy and are not eligible for fludarabine-based therapy.
The European Commission (EC) will take the CHMP’s opinion into account when deciding whether to approve ofatumumab for this indication.
Ofatumumab already has conditional approval in the Europe Union to treat CLL patients who are refractory to fludarabine and alemtuzumab.
Ofatumumab received conditional approval because the drug’s benefits appear to outweigh the risks it poses. The drug will not receive full
approval until the companies developing ofatumumab, GlaxoSmithKline and Genmab, submit results of additional research to the EC.
The CHMP’s recommendation for expanded approval is based on results from 2 trials in patients with CLL who were ineligible for fludarabine-based treatment.
The first is a phase 2 study (OMB115991) in which researchers evaluated the efficacy of ofatumumab in combination with bendamustine. The second is the phase 3 COMPLEMENT 1 study (OMB110911), a randomized trial in which researchers compared ofatumumab and chlorambucil in combination to chlorambucil alone.
Phase 2 study
Results from this single-arm study were presented at the 2013 International Workshop on CLL. Researchers enrolled 97 patients with CLL, 44 of whom were previously untreated and 53 who had relapsed. The median ages were 62.5 and 68 years, respectively.
Treatment began with acetaminophen, an antihistamine, and a glucocorticoid. Patients then received ofatumumab at 300 mg on day 1 and 1000 mg on day 8 of cycle 1. For cycles 2 through 6, they received 1000 mg on day 1 every 28 days.
Patients received bendamustine on days 1 and 2, every 28 days for up to 6 cycles. The initial dose was 90 mg/m2 for the untreated patients and 70 mg/m2 for relapsed patients.
However, patients required a dose reduction due to toxicity. The previously untreated patients were reduced to 60 mg/m2, and the relapsed patients were reduced to 50 mg/m2.
The overall response rate was 95% in the previously untreated group and 74% in the relapsed group. Complete responses occurred in 43% and 11%, respectively.
CT results showed the overall response rate was 82% in the previously untreated group and 70% in the relapsed group. Complete responses occurred in 27% and 9%, respectively. The median time to response was 0.95 months for both groups.
Grade 3 or higher adverse events occurred in 25% of patients in the previously untreated group and 38% of those in the relapsed group.
This included infusion reactions (11% and 8%, respectively), neutropenia (16% and 29%, respectively), infections (11% and 15%, respectively), rash (2% of previously untreated patients), febrile neutropenia (4% of relapsed patients), and thrombocytopenia (4% of relapsed patients).
There were no deaths in the previously untreated group, but 4 patients died in the relapsed group. Two of these deaths may have been related to study treatment. One patient died of pneumonia and hemolytic anemia 15 days after the last dose of treatment, and 1 patient died of sepsis 4 days after the last dose of treatment.
Phase 3 study
Data from the COMPLEMENT 1 study were presented at ASH 2013. Researchers compared ofatumumab plus chlorambucil to chlorambucil alone in 447 previously untreated patients with CLL who were ineligible for fludarabine-based therapy.
Patients had a median age of 69 years (range, 35 to 92). Seventy-two percent had 2 or more comorbidities, and 48% had a creatinine clearance of less than 70 mL/min.
Patients in the ofatumumab arm received the drug at 300 mg in cycle 1 on day 1, 1000 mg in cycle 1 on day 8, and 1000 mg administered on day 1 of all subsequent 28-day cycles.
In both arms, patients received chlorambucil at a dose of 10 mg/m2 orally on days 1 to 7, every 28 days. Prior to each infusion of ofatumumab, patients received acetaminophen, an antihistamine, and a glucocorticoid.
The overall response rate was 82% in the ofatumumab-chlorambucil group and 69% in the chlorambucil-alone group (P=0.001). Complete response rates were 12% and 1%, respectively.
At a median follow-up of 29 months, the median overall survival was not reached for either treatment arm. However, ofatumumab-treated patients had longer progression-free survival than patients who received chlorambucil alone—22.4 months and 13.1 months, respectively (P<0.001).
Grade 3 or higher adverse events occurred in 50% of ofatumumab-treated patients and 43% of patients who received chlorambucil alone. The most common event was neutropenia, which occurred in 26% and 14% of patients, respectively.
Grade 3 or higher infections occurred in 15% of ofatumumab-treated patients and 14% of patients who received chlorambucil alone. The most common was pneumonia, which occurred in 4% and 3%, respectively.
In the entire cohort, grade 3 or higher infusion-related events occurred in 10% of patients, but there were no fatal infusion reactions. Two percent of subjects in both arms died during treatment.
Credit: Linda Bartlett
The European Medicine Agency’s Committee for Medicinal Products for Human Use (CHMP) has issued a positive opinion for ofatumumab (Arzerra), a monoclonal antibody targeting CD20.
The CHMP is recommending that ofatumumab receive conditional approval for use in combination with chlorambucil or bendamustine to treat patients with chronic lymphocytic leukemia (CLL) who have not received prior therapy and are not eligible for fludarabine-based therapy.
The European Commission (EC) will take the CHMP’s opinion into account when deciding whether to approve ofatumumab for this indication.
Ofatumumab already has conditional approval in the Europe Union to treat CLL patients who are refractory to fludarabine and alemtuzumab.
Ofatumumab received conditional approval because the drug’s benefits appear to outweigh the risks it poses. The drug will not receive full
approval until the companies developing ofatumumab, GlaxoSmithKline and Genmab, submit results of additional research to the EC.
The CHMP’s recommendation for expanded approval is based on results from 2 trials in patients with CLL who were ineligible for fludarabine-based treatment.
The first is a phase 2 study (OMB115991) in which researchers evaluated the efficacy of ofatumumab in combination with bendamustine. The second is the phase 3 COMPLEMENT 1 study (OMB110911), a randomized trial in which researchers compared ofatumumab and chlorambucil in combination to chlorambucil alone.
Phase 2 study
Results from this single-arm study were presented at the 2013 International Workshop on CLL. Researchers enrolled 97 patients with CLL, 44 of whom were previously untreated and 53 who had relapsed. The median ages were 62.5 and 68 years, respectively.
Treatment began with acetaminophen, an antihistamine, and a glucocorticoid. Patients then received ofatumumab at 300 mg on day 1 and 1000 mg on day 8 of cycle 1. For cycles 2 through 6, they received 1000 mg on day 1 every 28 days.
Patients received bendamustine on days 1 and 2, every 28 days for up to 6 cycles. The initial dose was 90 mg/m2 for the untreated patients and 70 mg/m2 for relapsed patients.
However, patients required a dose reduction due to toxicity. The previously untreated patients were reduced to 60 mg/m2, and the relapsed patients were reduced to 50 mg/m2.
The overall response rate was 95% in the previously untreated group and 74% in the relapsed group. Complete responses occurred in 43% and 11%, respectively.
CT results showed the overall response rate was 82% in the previously untreated group and 70% in the relapsed group. Complete responses occurred in 27% and 9%, respectively. The median time to response was 0.95 months for both groups.
Grade 3 or higher adverse events occurred in 25% of patients in the previously untreated group and 38% of those in the relapsed group.
This included infusion reactions (11% and 8%, respectively), neutropenia (16% and 29%, respectively), infections (11% and 15%, respectively), rash (2% of previously untreated patients), febrile neutropenia (4% of relapsed patients), and thrombocytopenia (4% of relapsed patients).
There were no deaths in the previously untreated group, but 4 patients died in the relapsed group. Two of these deaths may have been related to study treatment. One patient died of pneumonia and hemolytic anemia 15 days after the last dose of treatment, and 1 patient died of sepsis 4 days after the last dose of treatment.
Phase 3 study
Data from the COMPLEMENT 1 study were presented at ASH 2013. Researchers compared ofatumumab plus chlorambucil to chlorambucil alone in 447 previously untreated patients with CLL who were ineligible for fludarabine-based therapy.
Patients had a median age of 69 years (range, 35 to 92). Seventy-two percent had 2 or more comorbidities, and 48% had a creatinine clearance of less than 70 mL/min.
Patients in the ofatumumab arm received the drug at 300 mg in cycle 1 on day 1, 1000 mg in cycle 1 on day 8, and 1000 mg administered on day 1 of all subsequent 28-day cycles.
In both arms, patients received chlorambucil at a dose of 10 mg/m2 orally on days 1 to 7, every 28 days. Prior to each infusion of ofatumumab, patients received acetaminophen, an antihistamine, and a glucocorticoid.
The overall response rate was 82% in the ofatumumab-chlorambucil group and 69% in the chlorambucil-alone group (P=0.001). Complete response rates were 12% and 1%, respectively.
At a median follow-up of 29 months, the median overall survival was not reached for either treatment arm. However, ofatumumab-treated patients had longer progression-free survival than patients who received chlorambucil alone—22.4 months and 13.1 months, respectively (P<0.001).
Grade 3 or higher adverse events occurred in 50% of ofatumumab-treated patients and 43% of patients who received chlorambucil alone. The most common event was neutropenia, which occurred in 26% and 14% of patients, respectively.
Grade 3 or higher infections occurred in 15% of ofatumumab-treated patients and 14% of patients who received chlorambucil alone. The most common was pneumonia, which occurred in 4% and 3%, respectively.
In the entire cohort, grade 3 or higher infusion-related events occurred in 10% of patients, but there were no fatal infusion reactions. Two percent of subjects in both arms died during treatment.
Guideline updates for non-Hodgkin lymphomas
At the 2014 National Comprehensive Cancer Network annual conference in Hollywood, Florida, Dr Andrew D Zelenetz, chair of the NCCN Non-Hodgkin Lymphomas Guidelines panel, presented guideline updates for non-Hodgkin lymphomas.
Click on the PDF icon at the top of this introduction to read the full article.
At the 2014 National Comprehensive Cancer Network annual conference in Hollywood, Florida, Dr Andrew D Zelenetz, chair of the NCCN Non-Hodgkin Lymphomas Guidelines panel, presented guideline updates for non-Hodgkin lymphomas.
Click on the PDF icon at the top of this introduction to read the full article.
At the 2014 National Comprehensive Cancer Network annual conference in Hollywood, Florida, Dr Andrew D Zelenetz, chair of the NCCN Non-Hodgkin Lymphomas Guidelines panel, presented guideline updates for non-Hodgkin lymphomas.
Click on the PDF icon at the top of this introduction to read the full article.
Refugees struggle to access cancer treatment
Credit: UK Department
for International Development
A new study published in The Lancet Oncology reveals a high demand for costly cancer treatment among refugees from the recent conflicts in Iraq and Syria, with host countries struggling to find the money and medicine to treat their new patients.
The findings prompted a call from study author Paul Spiegel, MD, the United Nations High Commissioner for Refugees (UNHCR) Chief Medical Expert, for schemes to improve access to affordable cancer care for refugees.
In the first study of its kind, Dr Spiegel and his colleagues examined data from funding applications made to the UNHCR Exceptional Care Committee (ECC) from refugees in Jordan and Syria whose cancer treatment costs were likely to exceed US$2000 a year.
The results indicate that cancer is an important public health problem in refugee settings, the researchers said. The study also highlights the challenges and costs national health systems and humanitarian organizations face when overwhelmed by massive influxes of refugees.
For example, in Jordan, the ECC assessed 1989 applications for treatment between 2010 and 2012. Roughly a quarter of these (511) were for cancer, with breast cancer and colorectal cancer being the most common. Around half (48%) of these cases were approved and funded.
Funding was often denied because the patient had a poor prognosis (43% of cases in 2011 and 31% in 2012) or the treatment was too costly (25% in 2011). The average amount requested from the ECC for cancer treatment was $11,540 in 2011 and $5151 in 2012. However, the amounts approved were substantially lower—$4626 in 2011 and $3501 in 2012.
“The countries in the Middle East have welcomed millions of refugees, first from Iraq and then Syria,” Dr Spiegel said. “This massive influx has strained health systems at all levels. Despite help from international organizations and donors to expand health facilities and pay for additional personnel and drugs, it has been insufficient.”
“The burden has fallen disproportionately on the host countries to absorb the costs. For example, the Jordanian Ministry of Health footed an estimated $53 million bill for medical care for refugees in the first 4 months of 2013.”
Dr Spiegel and his colleagues are therefore calling for improved cancer prevention and treatment in refugee settings through the use of innovative financing schemes; better primary care, including screening for common cancers (eg, colonoscopies and mammograms); and the development of web-based cancer registries to prevent the interruption of treatment.
“Until now, the responses to humanitarian crises have been primarily based on experiences from refugee camps in sub-Saharan Africa where infectious diseases and malnutrition have been the priority,” Dr Spiegel said. “In the 21st century, refugee situations are substantially longer and increasingly occur in middle-income countries where the levels of chronic diseases, including cancer, are higher.”
“Cancer diagnosis and care in humanitarian emergencies typifies a growing trend towards more costly chronic disease care, something that seems to have been overlooked but is of increasing importance because the number of refugees is growing.”
Credit: UK Department
for International Development
A new study published in The Lancet Oncology reveals a high demand for costly cancer treatment among refugees from the recent conflicts in Iraq and Syria, with host countries struggling to find the money and medicine to treat their new patients.
The findings prompted a call from study author Paul Spiegel, MD, the United Nations High Commissioner for Refugees (UNHCR) Chief Medical Expert, for schemes to improve access to affordable cancer care for refugees.
In the first study of its kind, Dr Spiegel and his colleagues examined data from funding applications made to the UNHCR Exceptional Care Committee (ECC) from refugees in Jordan and Syria whose cancer treatment costs were likely to exceed US$2000 a year.
The results indicate that cancer is an important public health problem in refugee settings, the researchers said. The study also highlights the challenges and costs national health systems and humanitarian organizations face when overwhelmed by massive influxes of refugees.
For example, in Jordan, the ECC assessed 1989 applications for treatment between 2010 and 2012. Roughly a quarter of these (511) were for cancer, with breast cancer and colorectal cancer being the most common. Around half (48%) of these cases were approved and funded.
Funding was often denied because the patient had a poor prognosis (43% of cases in 2011 and 31% in 2012) or the treatment was too costly (25% in 2011). The average amount requested from the ECC for cancer treatment was $11,540 in 2011 and $5151 in 2012. However, the amounts approved were substantially lower—$4626 in 2011 and $3501 in 2012.
“The countries in the Middle East have welcomed millions of refugees, first from Iraq and then Syria,” Dr Spiegel said. “This massive influx has strained health systems at all levels. Despite help from international organizations and donors to expand health facilities and pay for additional personnel and drugs, it has been insufficient.”
“The burden has fallen disproportionately on the host countries to absorb the costs. For example, the Jordanian Ministry of Health footed an estimated $53 million bill for medical care for refugees in the first 4 months of 2013.”
Dr Spiegel and his colleagues are therefore calling for improved cancer prevention and treatment in refugee settings through the use of innovative financing schemes; better primary care, including screening for common cancers (eg, colonoscopies and mammograms); and the development of web-based cancer registries to prevent the interruption of treatment.
“Until now, the responses to humanitarian crises have been primarily based on experiences from refugee camps in sub-Saharan Africa where infectious diseases and malnutrition have been the priority,” Dr Spiegel said. “In the 21st century, refugee situations are substantially longer and increasingly occur in middle-income countries where the levels of chronic diseases, including cancer, are higher.”
“Cancer diagnosis and care in humanitarian emergencies typifies a growing trend towards more costly chronic disease care, something that seems to have been overlooked but is of increasing importance because the number of refugees is growing.”
Credit: UK Department
for International Development
A new study published in The Lancet Oncology reveals a high demand for costly cancer treatment among refugees from the recent conflicts in Iraq and Syria, with host countries struggling to find the money and medicine to treat their new patients.
The findings prompted a call from study author Paul Spiegel, MD, the United Nations High Commissioner for Refugees (UNHCR) Chief Medical Expert, for schemes to improve access to affordable cancer care for refugees.
In the first study of its kind, Dr Spiegel and his colleagues examined data from funding applications made to the UNHCR Exceptional Care Committee (ECC) from refugees in Jordan and Syria whose cancer treatment costs were likely to exceed US$2000 a year.
The results indicate that cancer is an important public health problem in refugee settings, the researchers said. The study also highlights the challenges and costs national health systems and humanitarian organizations face when overwhelmed by massive influxes of refugees.
For example, in Jordan, the ECC assessed 1989 applications for treatment between 2010 and 2012. Roughly a quarter of these (511) were for cancer, with breast cancer and colorectal cancer being the most common. Around half (48%) of these cases were approved and funded.
Funding was often denied because the patient had a poor prognosis (43% of cases in 2011 and 31% in 2012) or the treatment was too costly (25% in 2011). The average amount requested from the ECC for cancer treatment was $11,540 in 2011 and $5151 in 2012. However, the amounts approved were substantially lower—$4626 in 2011 and $3501 in 2012.
“The countries in the Middle East have welcomed millions of refugees, first from Iraq and then Syria,” Dr Spiegel said. “This massive influx has strained health systems at all levels. Despite help from international organizations and donors to expand health facilities and pay for additional personnel and drugs, it has been insufficient.”
“The burden has fallen disproportionately on the host countries to absorb the costs. For example, the Jordanian Ministry of Health footed an estimated $53 million bill for medical care for refugees in the first 4 months of 2013.”
Dr Spiegel and his colleagues are therefore calling for improved cancer prevention and treatment in refugee settings through the use of innovative financing schemes; better primary care, including screening for common cancers (eg, colonoscopies and mammograms); and the development of web-based cancer registries to prevent the interruption of treatment.
“Until now, the responses to humanitarian crises have been primarily based on experiences from refugee camps in sub-Saharan Africa where infectious diseases and malnutrition have been the priority,” Dr Spiegel said. “In the 21st century, refugee situations are substantially longer and increasingly occur in middle-income countries where the levels of chronic diseases, including cancer, are higher.”
“Cancer diagnosis and care in humanitarian emergencies typifies a growing trend towards more costly chronic disease care, something that seems to have been overlooked but is of increasing importance because the number of refugees is growing.”
Drug gets orphan designation for CLL/SLL
The US Food and Drug Administration (FDA) has granted orphan designation for MOR208, an anti-CD19 monoclonal antibody, for the treatment of chronic lymphocytic leukemia (CLL) or small lymphocytic leukemia (SLL).
The European Medicines Agency (EMA) also announced a positive opinion of the orphan medicinal product application for MOR208 to treat patients with CLL/SLL.
Researchers said MOR208 showed promise in a phase 1 study of CLL/SLL patients.
Orphan drug and orphan medicinal product status are granted by the FDA and EMA to promote the development of promising therapeutics for the treatment of rare diseases affecting fewer than 200,000 people in the US annually and no more than 5 in 10,000 people in the European Union (EU).
Orphan drug designation includes benefits such as a 7-year period of marketing exclusivity in the US and 10 years of market exclusivity in the EU after approval. Other potential advantages come in the form of protocol assistance, the ability to apply for research funding, tax credits for certain research expenses, and fee waivers for the regulatory procedures.
MOR208 development, results
MOR208 is a humanized monoclonal antibody that targets the antigen CD19 for treatment of B-cell malignancies and autoimmune diseases. The development program for MOR208 is currently in phase 2 development in CLL, B-cell acute lymphoblastic leukemia, and non-Hodgkin lymphoma.
The drug is being developed by MorphoSys AG. The development program was in-licensed from Xencor in 2010.
Researchers evaluated MOR208 (formerly known as XmAb5574) in a phase 1 study of patients with CLL/SLL and reported their results at the 2012 ASH Annual Meeting (abstract 2894). The study was sponsored by Xencor.
The study included 27 patients with relapsed or refractory CLL/SLL. The median patient age was 66 years (range, 40-84), and patients were generally high-risk. The median number of prior therapies was 4 (range, 1-14).
Patients received MOR208 at a range of doses—0.3 mg/kg, 1 mg/kg, 3 mg/kg, 6 mg/kg, 9 mg/kg, and 12 mg/kg. MOR208 was administered as an intravenous infusion on days 1, 4, 8, 15, and 22 of cycle 1, and on days 1, 8, 15, and 22 of cycle 2.
Dose escalation continued without dose-limiting toxicities until the highest dose level. At this dose, 1 patient experienced grade 4 neutropenia associated with febrile neutropenia, and the patient was taken off treatment.
All 27 patients experienced adverse events, but the majority of them were grade 1-2. The most common events were infusion reactions. These occurred in 67% (n=18) of patients and were all grade 1 or 2.
Nineteen percent of patients (n=5) experienced grade 3-4 treatment-related adverse events, including neutropenia (n=3), thrombocytopenia (n=2), increased aspartate aminotransferase (n=1), febrile neutropenia (n=1), and tumor lysis syndrome (n=1). Four of these patients were on the 12 mg/kg dose, but 1 patient who experienced neutropenia was receiving 1 mg/kg.
Eleven percent of patients experienced a partial response according to IWCLL 2008 criteria. Responses occurred at the 6 mg/kg, 9 mg/kg, and 12 mg/kg dose levels.
All objective responses occurred in patients categorized as CLL as opposed to SLL, and none of the patients with lymph nodes greater than 5 cm responded. Two patients had progressed at the 8-week evaluation point.
The US Food and Drug Administration (FDA) has granted orphan designation for MOR208, an anti-CD19 monoclonal antibody, for the treatment of chronic lymphocytic leukemia (CLL) or small lymphocytic leukemia (SLL).
The European Medicines Agency (EMA) also announced a positive opinion of the orphan medicinal product application for MOR208 to treat patients with CLL/SLL.
Researchers said MOR208 showed promise in a phase 1 study of CLL/SLL patients.
Orphan drug and orphan medicinal product status are granted by the FDA and EMA to promote the development of promising therapeutics for the treatment of rare diseases affecting fewer than 200,000 people in the US annually and no more than 5 in 10,000 people in the European Union (EU).
Orphan drug designation includes benefits such as a 7-year period of marketing exclusivity in the US and 10 years of market exclusivity in the EU after approval. Other potential advantages come in the form of protocol assistance, the ability to apply for research funding, tax credits for certain research expenses, and fee waivers for the regulatory procedures.
MOR208 development, results
MOR208 is a humanized monoclonal antibody that targets the antigen CD19 for treatment of B-cell malignancies and autoimmune diseases. The development program for MOR208 is currently in phase 2 development in CLL, B-cell acute lymphoblastic leukemia, and non-Hodgkin lymphoma.
The drug is being developed by MorphoSys AG. The development program was in-licensed from Xencor in 2010.
Researchers evaluated MOR208 (formerly known as XmAb5574) in a phase 1 study of patients with CLL/SLL and reported their results at the 2012 ASH Annual Meeting (abstract 2894). The study was sponsored by Xencor.
The study included 27 patients with relapsed or refractory CLL/SLL. The median patient age was 66 years (range, 40-84), and patients were generally high-risk. The median number of prior therapies was 4 (range, 1-14).
Patients received MOR208 at a range of doses—0.3 mg/kg, 1 mg/kg, 3 mg/kg, 6 mg/kg, 9 mg/kg, and 12 mg/kg. MOR208 was administered as an intravenous infusion on days 1, 4, 8, 15, and 22 of cycle 1, and on days 1, 8, 15, and 22 of cycle 2.
Dose escalation continued without dose-limiting toxicities until the highest dose level. At this dose, 1 patient experienced grade 4 neutropenia associated with febrile neutropenia, and the patient was taken off treatment.
All 27 patients experienced adverse events, but the majority of them were grade 1-2. The most common events were infusion reactions. These occurred in 67% (n=18) of patients and were all grade 1 or 2.
Nineteen percent of patients (n=5) experienced grade 3-4 treatment-related adverse events, including neutropenia (n=3), thrombocytopenia (n=2), increased aspartate aminotransferase (n=1), febrile neutropenia (n=1), and tumor lysis syndrome (n=1). Four of these patients were on the 12 mg/kg dose, but 1 patient who experienced neutropenia was receiving 1 mg/kg.
Eleven percent of patients experienced a partial response according to IWCLL 2008 criteria. Responses occurred at the 6 mg/kg, 9 mg/kg, and 12 mg/kg dose levels.
All objective responses occurred in patients categorized as CLL as opposed to SLL, and none of the patients with lymph nodes greater than 5 cm responded. Two patients had progressed at the 8-week evaluation point.
The US Food and Drug Administration (FDA) has granted orphan designation for MOR208, an anti-CD19 monoclonal antibody, for the treatment of chronic lymphocytic leukemia (CLL) or small lymphocytic leukemia (SLL).
The European Medicines Agency (EMA) also announced a positive opinion of the orphan medicinal product application for MOR208 to treat patients with CLL/SLL.
Researchers said MOR208 showed promise in a phase 1 study of CLL/SLL patients.
Orphan drug and orphan medicinal product status are granted by the FDA and EMA to promote the development of promising therapeutics for the treatment of rare diseases affecting fewer than 200,000 people in the US annually and no more than 5 in 10,000 people in the European Union (EU).
Orphan drug designation includes benefits such as a 7-year period of marketing exclusivity in the US and 10 years of market exclusivity in the EU after approval. Other potential advantages come in the form of protocol assistance, the ability to apply for research funding, tax credits for certain research expenses, and fee waivers for the regulatory procedures.
MOR208 development, results
MOR208 is a humanized monoclonal antibody that targets the antigen CD19 for treatment of B-cell malignancies and autoimmune diseases. The development program for MOR208 is currently in phase 2 development in CLL, B-cell acute lymphoblastic leukemia, and non-Hodgkin lymphoma.
The drug is being developed by MorphoSys AG. The development program was in-licensed from Xencor in 2010.
Researchers evaluated MOR208 (formerly known as XmAb5574) in a phase 1 study of patients with CLL/SLL and reported their results at the 2012 ASH Annual Meeting (abstract 2894). The study was sponsored by Xencor.
The study included 27 patients with relapsed or refractory CLL/SLL. The median patient age was 66 years (range, 40-84), and patients were generally high-risk. The median number of prior therapies was 4 (range, 1-14).
Patients received MOR208 at a range of doses—0.3 mg/kg, 1 mg/kg, 3 mg/kg, 6 mg/kg, 9 mg/kg, and 12 mg/kg. MOR208 was administered as an intravenous infusion on days 1, 4, 8, 15, and 22 of cycle 1, and on days 1, 8, 15, and 22 of cycle 2.
Dose escalation continued without dose-limiting toxicities until the highest dose level. At this dose, 1 patient experienced grade 4 neutropenia associated with febrile neutropenia, and the patient was taken off treatment.
All 27 patients experienced adverse events, but the majority of them were grade 1-2. The most common events were infusion reactions. These occurred in 67% (n=18) of patients and were all grade 1 or 2.
Nineteen percent of patients (n=5) experienced grade 3-4 treatment-related adverse events, including neutropenia (n=3), thrombocytopenia (n=2), increased aspartate aminotransferase (n=1), febrile neutropenia (n=1), and tumor lysis syndrome (n=1). Four of these patients were on the 12 mg/kg dose, but 1 patient who experienced neutropenia was receiving 1 mg/kg.
Eleven percent of patients experienced a partial response according to IWCLL 2008 criteria. Responses occurred at the 6 mg/kg, 9 mg/kg, and 12 mg/kg dose levels.
All objective responses occurred in patients categorized as CLL as opposed to SLL, and none of the patients with lymph nodes greater than 5 cm responded. Two patients had progressed at the 8-week evaluation point.
Chemists discover true structure of anticancer agent
Credit: NIH
Chemists say they have determined the correct structure of a compound that has shown activity against lymphoma and a range of other cancers.
Their research, published in Angewandte Chemie, focused on a compound called TIC10.
The team showed that TIC10’s structure differs subtly from a version described by another group last year, and the previous structure associated with TIC10 actually describes a molecule that lacks TIC10’s anticancer activity.
The newly identified structure describes a molecule with potent anticancer effects in animals, representing a new family of biologically active structures that can now be explored for possible therapeutic uses.
“This new structure should generate much interest in the cancer research community,” said study author Kim D. Janda, PhD, of The Scripps Research Institute in La Jolla, California.
Antitumor potential
TIC10 was first described in Science Translational Medicine in early 2013. The authors identified the compound, within a library of thousands of molecules maintained by the National Cancer Institute (NCI), for its ability to boost cells’ production of the natural antitumor protein TRAIL. (TIC10 stands for TRAIL-inducing compound #10.)
As a small molecule, TIC10 would be easier to deliver in a therapy than the TRAIL protein itself. The paper’s authors reported that TIC10 was orally active and dramatically shrank a variety of tumors in mice.
Tumors can develop resistance to TRAIL, but Dr Janda had been studying compounds that defeat this resistance. The news about TIC10 therefore got his attention.
“I thought, ‘They have this molecule for upregulating TRAIL, and we have these molecules that can overcome tumor-cell TRAIL resistance—the combination could be important,’” he said.
The original publication on TIC10 included a figure showing its predicted structure. So Dr Janda asked one of his postdoctoral researchers, Jonathan Lockner, to make TIC10 using that information.
Although the original TIC10 research team had seemingly confirmed the predicted structure with mass spectrometry, no one had published a thorough characterization of the TIC10 molecule.
“There were no nuclear magnetic resonance data or X-ray crystallography data, and there was definitely no procedure for the synthesis,” Dr Lockner said. “My background was chemistry, though, so I was able to find a way to synthesize it starting from simple compounds.”
Surprising inactivity
There was just one problem with Dr Lockner’s newly synthesized “TIC10.” When tested, it failed to induce TRAIL expression in cells, even at high doses.
“Of course, I was nervous,” Dr Lockner said. “As a chemist, you never want to make a mistake and give biologists the wrong material.”
To try and verify they had the right material, Dr Janda’s team obtained a sample of TIC10 directly from the NCI.
“When we got that sample and tested it, we saw that it had the expected TRAIL-upregulating effect,” said Nicholas Jacob, a graduate student in the Janda Lab and coauthor of the new paper.
“That prompted us to look more closely at the structures of these 2 compounds.”
The researchers spent months characterizing their own synthesized material and the NCI material, using an array of sophisticated structural analysis tools. They also tested the 2 compounds’ biological effects.
The team eventually concluded that the TIC10 compound from the NCI library does boost TRAIL production in cells and remains promising as the basis for anticancer therapies, but it does not have the structure that was originally published.
The right structure
The originally published structure has a core made of 3 carbon-nitrogen rings in a straight line and does not induce TRAIL activity. The correct, TRAIL-inducing structure differs subtly, with an end ring that sticks out at an angle.
In chemists’ parlance, the 2 compounds are constitutional isomers: a linear imidazolinopyrimidinone and an angular imidazolinopyrimidinone.
And Dr Lockner found that the angular, TRAIL-inducing structure was easier to synthesize than the one originally described.
Now, with the correct molecule in hand and a solid understanding of its structure and synthesis, Dr Janda and his team are moving forward with their original plan to study TIC10 in combination with TRAIL-resistance-thwarting molecules as an anticancer therapy.
The therapeutic implications of TIC10 may even go beyond cancer, according to the researchers. The angular core of the TRAIL-inducing molecule Dr Janda’s team discovered is a novel type of a biologically active structure, or pharmacophore, from which chemists may now be able to build a new class of candidate drugs, possibly for a variety of ailments.
Credit: NIH
Chemists say they have determined the correct structure of a compound that has shown activity against lymphoma and a range of other cancers.
Their research, published in Angewandte Chemie, focused on a compound called TIC10.
The team showed that TIC10’s structure differs subtly from a version described by another group last year, and the previous structure associated with TIC10 actually describes a molecule that lacks TIC10’s anticancer activity.
The newly identified structure describes a molecule with potent anticancer effects in animals, representing a new family of biologically active structures that can now be explored for possible therapeutic uses.
“This new structure should generate much interest in the cancer research community,” said study author Kim D. Janda, PhD, of The Scripps Research Institute in La Jolla, California.
Antitumor potential
TIC10 was first described in Science Translational Medicine in early 2013. The authors identified the compound, within a library of thousands of molecules maintained by the National Cancer Institute (NCI), for its ability to boost cells’ production of the natural antitumor protein TRAIL. (TIC10 stands for TRAIL-inducing compound #10.)
As a small molecule, TIC10 would be easier to deliver in a therapy than the TRAIL protein itself. The paper’s authors reported that TIC10 was orally active and dramatically shrank a variety of tumors in mice.
Tumors can develop resistance to TRAIL, but Dr Janda had been studying compounds that defeat this resistance. The news about TIC10 therefore got his attention.
“I thought, ‘They have this molecule for upregulating TRAIL, and we have these molecules that can overcome tumor-cell TRAIL resistance—the combination could be important,’” he said.
The original publication on TIC10 included a figure showing its predicted structure. So Dr Janda asked one of his postdoctoral researchers, Jonathan Lockner, to make TIC10 using that information.
Although the original TIC10 research team had seemingly confirmed the predicted structure with mass spectrometry, no one had published a thorough characterization of the TIC10 molecule.
“There were no nuclear magnetic resonance data or X-ray crystallography data, and there was definitely no procedure for the synthesis,” Dr Lockner said. “My background was chemistry, though, so I was able to find a way to synthesize it starting from simple compounds.”
Surprising inactivity
There was just one problem with Dr Lockner’s newly synthesized “TIC10.” When tested, it failed to induce TRAIL expression in cells, even at high doses.
“Of course, I was nervous,” Dr Lockner said. “As a chemist, you never want to make a mistake and give biologists the wrong material.”
To try and verify they had the right material, Dr Janda’s team obtained a sample of TIC10 directly from the NCI.
“When we got that sample and tested it, we saw that it had the expected TRAIL-upregulating effect,” said Nicholas Jacob, a graduate student in the Janda Lab and coauthor of the new paper.
“That prompted us to look more closely at the structures of these 2 compounds.”
The researchers spent months characterizing their own synthesized material and the NCI material, using an array of sophisticated structural analysis tools. They also tested the 2 compounds’ biological effects.
The team eventually concluded that the TIC10 compound from the NCI library does boost TRAIL production in cells and remains promising as the basis for anticancer therapies, but it does not have the structure that was originally published.
The right structure
The originally published structure has a core made of 3 carbon-nitrogen rings in a straight line and does not induce TRAIL activity. The correct, TRAIL-inducing structure differs subtly, with an end ring that sticks out at an angle.
In chemists’ parlance, the 2 compounds are constitutional isomers: a linear imidazolinopyrimidinone and an angular imidazolinopyrimidinone.
And Dr Lockner found that the angular, TRAIL-inducing structure was easier to synthesize than the one originally described.
Now, with the correct molecule in hand and a solid understanding of its structure and synthesis, Dr Janda and his team are moving forward with their original plan to study TIC10 in combination with TRAIL-resistance-thwarting molecules as an anticancer therapy.
The therapeutic implications of TIC10 may even go beyond cancer, according to the researchers. The angular core of the TRAIL-inducing molecule Dr Janda’s team discovered is a novel type of a biologically active structure, or pharmacophore, from which chemists may now be able to build a new class of candidate drugs, possibly for a variety of ailments.
Credit: NIH
Chemists say they have determined the correct structure of a compound that has shown activity against lymphoma and a range of other cancers.
Their research, published in Angewandte Chemie, focused on a compound called TIC10.
The team showed that TIC10’s structure differs subtly from a version described by another group last year, and the previous structure associated with TIC10 actually describes a molecule that lacks TIC10’s anticancer activity.
The newly identified structure describes a molecule with potent anticancer effects in animals, representing a new family of biologically active structures that can now be explored for possible therapeutic uses.
“This new structure should generate much interest in the cancer research community,” said study author Kim D. Janda, PhD, of The Scripps Research Institute in La Jolla, California.
Antitumor potential
TIC10 was first described in Science Translational Medicine in early 2013. The authors identified the compound, within a library of thousands of molecules maintained by the National Cancer Institute (NCI), for its ability to boost cells’ production of the natural antitumor protein TRAIL. (TIC10 stands for TRAIL-inducing compound #10.)
As a small molecule, TIC10 would be easier to deliver in a therapy than the TRAIL protein itself. The paper’s authors reported that TIC10 was orally active and dramatically shrank a variety of tumors in mice.
Tumors can develop resistance to TRAIL, but Dr Janda had been studying compounds that defeat this resistance. The news about TIC10 therefore got his attention.
“I thought, ‘They have this molecule for upregulating TRAIL, and we have these molecules that can overcome tumor-cell TRAIL resistance—the combination could be important,’” he said.
The original publication on TIC10 included a figure showing its predicted structure. So Dr Janda asked one of his postdoctoral researchers, Jonathan Lockner, to make TIC10 using that information.
Although the original TIC10 research team had seemingly confirmed the predicted structure with mass spectrometry, no one had published a thorough characterization of the TIC10 molecule.
“There were no nuclear magnetic resonance data or X-ray crystallography data, and there was definitely no procedure for the synthesis,” Dr Lockner said. “My background was chemistry, though, so I was able to find a way to synthesize it starting from simple compounds.”
Surprising inactivity
There was just one problem with Dr Lockner’s newly synthesized “TIC10.” When tested, it failed to induce TRAIL expression in cells, even at high doses.
“Of course, I was nervous,” Dr Lockner said. “As a chemist, you never want to make a mistake and give biologists the wrong material.”
To try and verify they had the right material, Dr Janda’s team obtained a sample of TIC10 directly from the NCI.
“When we got that sample and tested it, we saw that it had the expected TRAIL-upregulating effect,” said Nicholas Jacob, a graduate student in the Janda Lab and coauthor of the new paper.
“That prompted us to look more closely at the structures of these 2 compounds.”
The researchers spent months characterizing their own synthesized material and the NCI material, using an array of sophisticated structural analysis tools. They also tested the 2 compounds’ biological effects.
The team eventually concluded that the TIC10 compound from the NCI library does boost TRAIL production in cells and remains promising as the basis for anticancer therapies, but it does not have the structure that was originally published.
The right structure
The originally published structure has a core made of 3 carbon-nitrogen rings in a straight line and does not induce TRAIL activity. The correct, TRAIL-inducing structure differs subtly, with an end ring that sticks out at an angle.
In chemists’ parlance, the 2 compounds are constitutional isomers: a linear imidazolinopyrimidinone and an angular imidazolinopyrimidinone.
And Dr Lockner found that the angular, TRAIL-inducing structure was easier to synthesize than the one originally described.
Now, with the correct molecule in hand and a solid understanding of its structure and synthesis, Dr Janda and his team are moving forward with their original plan to study TIC10 in combination with TRAIL-resistance-thwarting molecules as an anticancer therapy.
The therapeutic implications of TIC10 may even go beyond cancer, according to the researchers. The angular core of the TRAIL-inducing molecule Dr Janda’s team discovered is a novel type of a biologically active structure, or pharmacophore, from which chemists may now be able to build a new class of candidate drugs, possibly for a variety of ailments.
Drug gains orphan designation for DLBCL
The US Food and Drug Administration (FDA) has granted orphan designation to selinexor (KPT-330) for the treatment of diffuse large B-cell lymphoma (DLBCL).
The drug elicited responses in patients with non-Hodgkin lymphoma (NHL), including DLBCL, in an ongoing phase 1 study.
Selinexor is a selective inhibitor of nuclear transport that functions by binding to the nuclear export protein XPO1 (also called CRM1). This leads to the accumulation of tumor suppressor proteins in the cell nucleus, which is thought to cause apoptosis in cancer cells while largely sparing normal cells.
The FDA grants orphan designation to promote the development of drugs that target conditions affecting 200,000 or fewer US patients annually and are expected to provide significant therapeutic advantage over existing treatments.
Selinexor’s orphan designation for DLBCL qualifies the drug’s developer, Karyopharm Therapeutics, Inc., for benefits that apply across all stages of development, including an accelerated approval process, 7 years of market exclusivity following marketing approval, tax credits on US clinical trials, eligibility for orphan drug grants, and a waiver of certain administrative fees.
The FDA has also granted selinexor orphan status for the treatment of acute myeloid leukemia.
Phase 1 study
Researchers evaluated selinexor in an ongoing phase 1 study of patients with NHL or chronic lymphocytic leukemia (CLL) and presented results at the 2013 ASH Annual Meeting (abstract 90).
At that time, the study included 18 patients with NHL or CLL. They had a median age of 66.5 years and had received a median of 4.5 prior treatment regimens.
Patients received selinexor at 6 different dose levels. There were no clinically significant cumulative toxicities or cases of major organ dysfunction, and the maximum-tolerated dose was not reached. Researchers continued dosing at 35 mg/m2 twice weekly.
Ten patients experienced drug-related grade 3/4 adverse events, including thrombocytopenia without bleeding (n=6), neutropenia (n=5), dehydration (n=1), syncope (n=1), hypotension (n=1), and fatigue (n=1).
The most common grade 1/2 events were anorexia (n=10), fatigue (n=9), diarrhea (n=6), vomiting (n=6), neutropenia (n=5), malaise (n=3), anemia (n=3), and weight loss (n=3).
Response was evaluable in 15 patients. Eighty percent of patients, all of whom had progressive disease on study entry, experienced tumor shrinkage or disease stabilization on selinexor. The other 20% of patients progressed.
Of 3 patients with DLBCL, 1 progressed, 1 had stable disease, and 1 achieved 93% tumor shrinkage.
“We are encouraged by the response data in patients with DLBCL who have received selinexor in our ongoing phase 1 clinical trial in advanced hematological malignancies,” said Michael G. Kauffman, MD, PhD, Karyopharm’s Chief Executive Officer.
“We plan to present updated clinical data for selinexor across multiple indications, including DLBCL, at ASCO 2014.”
The US Food and Drug Administration (FDA) has granted orphan designation to selinexor (KPT-330) for the treatment of diffuse large B-cell lymphoma (DLBCL).
The drug elicited responses in patients with non-Hodgkin lymphoma (NHL), including DLBCL, in an ongoing phase 1 study.
Selinexor is a selective inhibitor of nuclear transport that functions by binding to the nuclear export protein XPO1 (also called CRM1). This leads to the accumulation of tumor suppressor proteins in the cell nucleus, which is thought to cause apoptosis in cancer cells while largely sparing normal cells.
The FDA grants orphan designation to promote the development of drugs that target conditions affecting 200,000 or fewer US patients annually and are expected to provide significant therapeutic advantage over existing treatments.
Selinexor’s orphan designation for DLBCL qualifies the drug’s developer, Karyopharm Therapeutics, Inc., for benefits that apply across all stages of development, including an accelerated approval process, 7 years of market exclusivity following marketing approval, tax credits on US clinical trials, eligibility for orphan drug grants, and a waiver of certain administrative fees.
The FDA has also granted selinexor orphan status for the treatment of acute myeloid leukemia.
Phase 1 study
Researchers evaluated selinexor in an ongoing phase 1 study of patients with NHL or chronic lymphocytic leukemia (CLL) and presented results at the 2013 ASH Annual Meeting (abstract 90).
At that time, the study included 18 patients with NHL or CLL. They had a median age of 66.5 years and had received a median of 4.5 prior treatment regimens.
Patients received selinexor at 6 different dose levels. There were no clinically significant cumulative toxicities or cases of major organ dysfunction, and the maximum-tolerated dose was not reached. Researchers continued dosing at 35 mg/m2 twice weekly.
Ten patients experienced drug-related grade 3/4 adverse events, including thrombocytopenia without bleeding (n=6), neutropenia (n=5), dehydration (n=1), syncope (n=1), hypotension (n=1), and fatigue (n=1).
The most common grade 1/2 events were anorexia (n=10), fatigue (n=9), diarrhea (n=6), vomiting (n=6), neutropenia (n=5), malaise (n=3), anemia (n=3), and weight loss (n=3).
Response was evaluable in 15 patients. Eighty percent of patients, all of whom had progressive disease on study entry, experienced tumor shrinkage or disease stabilization on selinexor. The other 20% of patients progressed.
Of 3 patients with DLBCL, 1 progressed, 1 had stable disease, and 1 achieved 93% tumor shrinkage.
“We are encouraged by the response data in patients with DLBCL who have received selinexor in our ongoing phase 1 clinical trial in advanced hematological malignancies,” said Michael G. Kauffman, MD, PhD, Karyopharm’s Chief Executive Officer.
“We plan to present updated clinical data for selinexor across multiple indications, including DLBCL, at ASCO 2014.”
The US Food and Drug Administration (FDA) has granted orphan designation to selinexor (KPT-330) for the treatment of diffuse large B-cell lymphoma (DLBCL).
The drug elicited responses in patients with non-Hodgkin lymphoma (NHL), including DLBCL, in an ongoing phase 1 study.
Selinexor is a selective inhibitor of nuclear transport that functions by binding to the nuclear export protein XPO1 (also called CRM1). This leads to the accumulation of tumor suppressor proteins in the cell nucleus, which is thought to cause apoptosis in cancer cells while largely sparing normal cells.
The FDA grants orphan designation to promote the development of drugs that target conditions affecting 200,000 or fewer US patients annually and are expected to provide significant therapeutic advantage over existing treatments.
Selinexor’s orphan designation for DLBCL qualifies the drug’s developer, Karyopharm Therapeutics, Inc., for benefits that apply across all stages of development, including an accelerated approval process, 7 years of market exclusivity following marketing approval, tax credits on US clinical trials, eligibility for orphan drug grants, and a waiver of certain administrative fees.
The FDA has also granted selinexor orphan status for the treatment of acute myeloid leukemia.
Phase 1 study
Researchers evaluated selinexor in an ongoing phase 1 study of patients with NHL or chronic lymphocytic leukemia (CLL) and presented results at the 2013 ASH Annual Meeting (abstract 90).
At that time, the study included 18 patients with NHL or CLL. They had a median age of 66.5 years and had received a median of 4.5 prior treatment regimens.
Patients received selinexor at 6 different dose levels. There were no clinically significant cumulative toxicities or cases of major organ dysfunction, and the maximum-tolerated dose was not reached. Researchers continued dosing at 35 mg/m2 twice weekly.
Ten patients experienced drug-related grade 3/4 adverse events, including thrombocytopenia without bleeding (n=6), neutropenia (n=5), dehydration (n=1), syncope (n=1), hypotension (n=1), and fatigue (n=1).
The most common grade 1/2 events were anorexia (n=10), fatigue (n=9), diarrhea (n=6), vomiting (n=6), neutropenia (n=5), malaise (n=3), anemia (n=3), and weight loss (n=3).
Response was evaluable in 15 patients. Eighty percent of patients, all of whom had progressive disease on study entry, experienced tumor shrinkage or disease stabilization on selinexor. The other 20% of patients progressed.
Of 3 patients with DLBCL, 1 progressed, 1 had stable disease, and 1 achieved 93% tumor shrinkage.
“We are encouraged by the response data in patients with DLBCL who have received selinexor in our ongoing phase 1 clinical trial in advanced hematological malignancies,” said Michael G. Kauffman, MD, PhD, Karyopharm’s Chief Executive Officer.
“We plan to present updated clinical data for selinexor across multiple indications, including DLBCL, at ASCO 2014.”
Cancer trial publications often omit minority accrual rates
Credit: Rhoda Baer
A review of clinical trial data from 2012 suggests Hispanic patients are underrepresented in US cancer studies, and many trial publications fail to provide information on patients’ racial/ethnic backgrounds.
Researchers analyzed 159 reports of phase 2 and 3 trials and found that roughly 21% included information on the number of minority patients enrolled.
About 8% of the publications included data on the number of Hispanic patients enrolled.
And from this data, the investigators found the accrual rate for Hispanic patients was about 4%.
According to the researchers, this lack of information and low representation inhibits physicians’ ability to provide optimal treatment to Hispanic cancer patients and patients belonging to other minority groups.
“We have a major responsibility to ensure adequate representation,” said study author Ian M. Thompson Jr, MD, of The University of Texas Health Science Center at San Antonio.
“How else will we know how best to treat our patients, and how else are we going to reduce the health disparities in [the Hispanic] population?”
Dr Thompson and his colleagues have a particular interest in the Hispanic population because 58% of San Antonio residents are Hispanic, as are 68% of residents in South Texas as a whole.
So the investigators wanted to determine Hispanic accrual rates in randomized trials of cancer patients. The team evaluated data from phase 2 and 3 cancer trials published in 2012. They focused on studies that were considered likely to change the standard of care and were published in “high-impact” journals.
The researchers identified 159 trials—68 phase 2 studies and 91 phase 3 studies. They discovered that 33 of the trial publications—about 21%—disclosed data on minority accrual. And 13 publications—about 8%—included data on the accrual of Hispanic cancer patients.
Of the 4154 patients enrolled on those 13 trials, 162 were Hispanic, which translates to an overall accrual rate of 3.9%. The enrollment of Hispanic patients ranged from 1 patient (0.5%) in a phase 2 trial of lung cancer to 17 patients (26%) in a phase 2 study of acute lymphoblastic leukemia.
“Fundamentally, in the most recent published cancer clinical trials, either the number and proportion of Hispanics are not reported or are far below their actual representation in the national population,” Dr Thompson summarized.
“For institutions like ours that serve a ‘minority-majority’ population, it’s a major responsibility for us to ensure adequate representation so that we can tell our patients how they can best be treated and how we can reduce the disparities of this rapidly growing population.”
Dr Thompson and his colleagues described this research in the Journal of Clinical Oncology.
Credit: Rhoda Baer
A review of clinical trial data from 2012 suggests Hispanic patients are underrepresented in US cancer studies, and many trial publications fail to provide information on patients’ racial/ethnic backgrounds.
Researchers analyzed 159 reports of phase 2 and 3 trials and found that roughly 21% included information on the number of minority patients enrolled.
About 8% of the publications included data on the number of Hispanic patients enrolled.
And from this data, the investigators found the accrual rate for Hispanic patients was about 4%.
According to the researchers, this lack of information and low representation inhibits physicians’ ability to provide optimal treatment to Hispanic cancer patients and patients belonging to other minority groups.
“We have a major responsibility to ensure adequate representation,” said study author Ian M. Thompson Jr, MD, of The University of Texas Health Science Center at San Antonio.
“How else will we know how best to treat our patients, and how else are we going to reduce the health disparities in [the Hispanic] population?”
Dr Thompson and his colleagues have a particular interest in the Hispanic population because 58% of San Antonio residents are Hispanic, as are 68% of residents in South Texas as a whole.
So the investigators wanted to determine Hispanic accrual rates in randomized trials of cancer patients. The team evaluated data from phase 2 and 3 cancer trials published in 2012. They focused on studies that were considered likely to change the standard of care and were published in “high-impact” journals.
The researchers identified 159 trials—68 phase 2 studies and 91 phase 3 studies. They discovered that 33 of the trial publications—about 21%—disclosed data on minority accrual. And 13 publications—about 8%—included data on the accrual of Hispanic cancer patients.
Of the 4154 patients enrolled on those 13 trials, 162 were Hispanic, which translates to an overall accrual rate of 3.9%. The enrollment of Hispanic patients ranged from 1 patient (0.5%) in a phase 2 trial of lung cancer to 17 patients (26%) in a phase 2 study of acute lymphoblastic leukemia.
“Fundamentally, in the most recent published cancer clinical trials, either the number and proportion of Hispanics are not reported or are far below their actual representation in the national population,” Dr Thompson summarized.
“For institutions like ours that serve a ‘minority-majority’ population, it’s a major responsibility for us to ensure adequate representation so that we can tell our patients how they can best be treated and how we can reduce the disparities of this rapidly growing population.”
Dr Thompson and his colleagues described this research in the Journal of Clinical Oncology.
Credit: Rhoda Baer
A review of clinical trial data from 2012 suggests Hispanic patients are underrepresented in US cancer studies, and many trial publications fail to provide information on patients’ racial/ethnic backgrounds.
Researchers analyzed 159 reports of phase 2 and 3 trials and found that roughly 21% included information on the number of minority patients enrolled.
About 8% of the publications included data on the number of Hispanic patients enrolled.
And from this data, the investigators found the accrual rate for Hispanic patients was about 4%.
According to the researchers, this lack of information and low representation inhibits physicians’ ability to provide optimal treatment to Hispanic cancer patients and patients belonging to other minority groups.
“We have a major responsibility to ensure adequate representation,” said study author Ian M. Thompson Jr, MD, of The University of Texas Health Science Center at San Antonio.
“How else will we know how best to treat our patients, and how else are we going to reduce the health disparities in [the Hispanic] population?”
Dr Thompson and his colleagues have a particular interest in the Hispanic population because 58% of San Antonio residents are Hispanic, as are 68% of residents in South Texas as a whole.
So the investigators wanted to determine Hispanic accrual rates in randomized trials of cancer patients. The team evaluated data from phase 2 and 3 cancer trials published in 2012. They focused on studies that were considered likely to change the standard of care and were published in “high-impact” journals.
The researchers identified 159 trials—68 phase 2 studies and 91 phase 3 studies. They discovered that 33 of the trial publications—about 21%—disclosed data on minority accrual. And 13 publications—about 8%—included data on the accrual of Hispanic cancer patients.
Of the 4154 patients enrolled on those 13 trials, 162 were Hispanic, which translates to an overall accrual rate of 3.9%. The enrollment of Hispanic patients ranged from 1 patient (0.5%) in a phase 2 trial of lung cancer to 17 patients (26%) in a phase 2 study of acute lymphoblastic leukemia.
“Fundamentally, in the most recent published cancer clinical trials, either the number and proportion of Hispanics are not reported or are far below their actual representation in the national population,” Dr Thompson summarized.
“For institutions like ours that serve a ‘minority-majority’ population, it’s a major responsibility for us to ensure adequate representation so that we can tell our patients how they can best be treated and how we can reduce the disparities of this rapidly growing population.”
Dr Thompson and his colleagues described this research in the Journal of Clinical Oncology.
Inhibitor gets breakthrough designation for HL
The US Food and Drug Administration (FDA) has granted breakthrough therapy designation for the investigational PD-1 immune checkpoint inhibitor nivolumab to treat Hodgkin lymphoma (HL) in patients who have failed autologous stem cell transplant and treatment with brentuximab vedotin.
The FDA’s decision is based on data from a cohort of HL patients in an ongoing phase 1b study of patients with relapsed or refractory hematologic malignancies.
According to the FDA, breakthrough designation is intended to expedite the development and review of drugs for serious or life-threatening conditions.
For a treatment to receive this designation, there must be preliminary clinical evidence that demonstrates the drug may offer substantial improvement over currently available therapy on at least 1 clinically significant endpoint.
Nivolumab is an investigational agent that binds to the checkpoint receptor PD-1 expressed on activated T cells. Researchers are investigating whether, by blocking this pathway, nivolumab would enable the immune system to resume its ability to recognize, attack, and destroy cancer cells.
Nivolumab is under investigation in multiple tumor types as monotherapy or in combination with other therapies. There are 35 trials of the agent underway, in which more than 7000 patients have been enrolled.
The breakthrough designation for nivolumab in HL is based on results of a 2-part phase 1 study, which have not been made public.
The researchers planned to enroll 100 patients with relapsed or refractory hematologic malignancies on this study. For the dose-escalation portion, the team planned to treat successive cohorts of patients using a 6+3 escalation design.
Patients would receive 1 mg/kg or 3 mg/kg of intravenous nivolumab every 2 weeks (although the first dose would be followed by a 3-week evaluation period) for 2 years, with the potential for an additional year of therapy for patients who progress.
Then, the researchers would enroll 5 cohorts of 16 patients representing the following tumor sites: HL/primary mediastinal B-cell lymphoma, multiple myeloma, B-cell lymphoma, T-cell lymphoma, and chronic myelogenous leukemia.
These patients would receive nivolumab at the maximum-tolerated dose identified in the first part of the study.
A poster describing the study plan was presented at the 2013 ASCO Annual Meeting (abstract TPS3113). The study is funded by Bristol-Myers Squibb, the company developing nivolumab.
The US Food and Drug Administration (FDA) has granted breakthrough therapy designation for the investigational PD-1 immune checkpoint inhibitor nivolumab to treat Hodgkin lymphoma (HL) in patients who have failed autologous stem cell transplant and treatment with brentuximab vedotin.
The FDA’s decision is based on data from a cohort of HL patients in an ongoing phase 1b study of patients with relapsed or refractory hematologic malignancies.
According to the FDA, breakthrough designation is intended to expedite the development and review of drugs for serious or life-threatening conditions.
For a treatment to receive this designation, there must be preliminary clinical evidence that demonstrates the drug may offer substantial improvement over currently available therapy on at least 1 clinically significant endpoint.
Nivolumab is an investigational agent that binds to the checkpoint receptor PD-1 expressed on activated T cells. Researchers are investigating whether, by blocking this pathway, nivolumab would enable the immune system to resume its ability to recognize, attack, and destroy cancer cells.
Nivolumab is under investigation in multiple tumor types as monotherapy or in combination with other therapies. There are 35 trials of the agent underway, in which more than 7000 patients have been enrolled.
The breakthrough designation for nivolumab in HL is based on results of a 2-part phase 1 study, which have not been made public.
The researchers planned to enroll 100 patients with relapsed or refractory hematologic malignancies on this study. For the dose-escalation portion, the team planned to treat successive cohorts of patients using a 6+3 escalation design.
Patients would receive 1 mg/kg or 3 mg/kg of intravenous nivolumab every 2 weeks (although the first dose would be followed by a 3-week evaluation period) for 2 years, with the potential for an additional year of therapy for patients who progress.
Then, the researchers would enroll 5 cohorts of 16 patients representing the following tumor sites: HL/primary mediastinal B-cell lymphoma, multiple myeloma, B-cell lymphoma, T-cell lymphoma, and chronic myelogenous leukemia.
These patients would receive nivolumab at the maximum-tolerated dose identified in the first part of the study.
A poster describing the study plan was presented at the 2013 ASCO Annual Meeting (abstract TPS3113). The study is funded by Bristol-Myers Squibb, the company developing nivolumab.
The US Food and Drug Administration (FDA) has granted breakthrough therapy designation for the investigational PD-1 immune checkpoint inhibitor nivolumab to treat Hodgkin lymphoma (HL) in patients who have failed autologous stem cell transplant and treatment with brentuximab vedotin.
The FDA’s decision is based on data from a cohort of HL patients in an ongoing phase 1b study of patients with relapsed or refractory hematologic malignancies.
According to the FDA, breakthrough designation is intended to expedite the development and review of drugs for serious or life-threatening conditions.
For a treatment to receive this designation, there must be preliminary clinical evidence that demonstrates the drug may offer substantial improvement over currently available therapy on at least 1 clinically significant endpoint.
Nivolumab is an investigational agent that binds to the checkpoint receptor PD-1 expressed on activated T cells. Researchers are investigating whether, by blocking this pathway, nivolumab would enable the immune system to resume its ability to recognize, attack, and destroy cancer cells.
Nivolumab is under investigation in multiple tumor types as monotherapy or in combination with other therapies. There are 35 trials of the agent underway, in which more than 7000 patients have been enrolled.
The breakthrough designation for nivolumab in HL is based on results of a 2-part phase 1 study, which have not been made public.
The researchers planned to enroll 100 patients with relapsed or refractory hematologic malignancies on this study. For the dose-escalation portion, the team planned to treat successive cohorts of patients using a 6+3 escalation design.
Patients would receive 1 mg/kg or 3 mg/kg of intravenous nivolumab every 2 weeks (although the first dose would be followed by a 3-week evaluation period) for 2 years, with the potential for an additional year of therapy for patients who progress.
Then, the researchers would enroll 5 cohorts of 16 patients representing the following tumor sites: HL/primary mediastinal B-cell lymphoma, multiple myeloma, B-cell lymphoma, T-cell lymphoma, and chronic myelogenous leukemia.
These patients would receive nivolumab at the maximum-tolerated dose identified in the first part of the study.
A poster describing the study plan was presented at the 2013 ASCO Annual Meeting (abstract TPS3113). The study is funded by Bristol-Myers Squibb, the company developing nivolumab.