AML

In a phase 3 trial, adding the quinolone derivative vosaroxin (Qinprezo) to treatment with cytarabine did not improve overall survival in patients with relapsed or refractory acute myeloid leukemia (AML).

However, the combination did confer a survival benefit when transplant patients were excluded from the analysis and in patients age 60 and older.

Results of this trial were recently announced by Sunesis Pharmaceuticals, the company developing vosaroxin.

The results are set to be presented in more detail at an upcoming scientific conference.

The trial, known as VALOR, enrolled 711 AML patients who had relapsed or become refractory to treatment for the first time. The patients were randomized to receive cytarabine plus vosaroxin or cytarabine plus placebo. They were stratified for age, geography, and disease status.

The trial did not meet its primary endpoint of demonstrating a significant improvement in overall survival. The median overall survival was 7.5 months in the vosaroxin-cytarabine arm and 6.1 months in the placebo-cytarabine arm (hazard ratio [HR]=0.865, P=0.06).

However, there was a significant benefit in complete response rate with vosaroxin over placebo—30.1% and 16.3%, respectively (P=0.0000148).

Because transplant could confound the primary analysis, the researchers planned a predefined analysis of overall survival censoring for stem cell transplant.

In this analysis, patients receiving the vosaroxin combination had a median overall survival of 6.7 months, compared to 5.3 months for placebo and cytarabine (HR=0.809, P=0.02).

Results according to age

For age, the researchers stratified patients into those age 60 years and older and those younger than 60 years at enrollment.

For the younger patients (n=260), the median overall survival was 9.1 months in the vosaroxin-cytarabine arm and 7.9 months in the placebo-cytarabine arm (HR=1.079, not significant).

The complete response rates were 26.9% and 20.8%, respectively (P=0.24). The rate of stem cell transplant was 45.8% in this age group.

For patients aged 60 years and older (n=451), the median overall survival was 7.1 months in the vosaroxin-cytarabine arm and 5.0 months in the placebo-cytarabine arm (HR=0.755, P=0.006).

The complete response rates were 31.9% and 13.8%, respectively (P=0.0000048). The rate of stem cell transplant was 20.2% for this age group.

Adverse events and mortality

In the intent-to-treat population, grade 3 or higher non-hematologic adverse events that were more common in the vosaroxin arm were gastrointestinal and infection-related toxicities. This is consistent with events observed in previous company trials.

The rate of serious adverse events was 55.5% in the vosaroxin-cytarabine arm and 35.7% in the placebo-cytarabine arm.

All-cause mortality rates were similar between the arms. Thirty-day mortality rates were 7.9% in the vosaroxin-cytarabine arm and 6.6% in the placebo-cytarabine arm. And 60-day mortality rates were 19.7% and 19.4%, respectively.

Regulatory plans

Based on the results of the trial, Sunesis plans to submit a marketing authorization application for vosaroxin to the European Medicines Agency. The company also plans to meet with the US Food and Drug Administration (FDA) to determine the appropriate regulatory path forward.

The FDA and the European Commission have already granted orphan designation to vosaroxin for the treatment of AML. The drug has been granted fast track designation by the FDA as well, for the potential treatment of relapsed or refractory AML in combination with cytarabine.

In a phase 3 trial, adding the quinolone derivative vosaroxin (Qinprezo) to treatment with cytarabine did not improve overall survival in patients with relapsed or refractory acute myeloid leukemia (AML).

However, the combination did confer a survival benefit when transplant patients were excluded from the analysis and in patients age 60 and older.

Results of this trial were recently announced by Sunesis Pharmaceuticals, the company developing vosaroxin.

The results are set to be presented in more detail at an upcoming scientific conference.

The trial, known as VALOR, enrolled 711 AML patients who had relapsed or become refractory to treatment for the first time. The patients were randomized to receive cytarabine plus vosaroxin or cytarabine plus placebo. They were stratified for age, geography, and disease status.

The trial did not meet its primary endpoint of demonstrating a significant improvement in overall survival. The median overall survival was 7.5 months in the vosaroxin-cytarabine arm and 6.1 months in the placebo-cytarabine arm (hazard ratio [HR]=0.865, P=0.06).

However, there was a significant benefit in complete response rate with vosaroxin over placebo—30.1% and 16.3%, respectively (P=0.0000148).

Because transplant could confound the primary analysis, the researchers planned a predefined analysis of overall survival censoring for stem cell transplant.

In this analysis, patients receiving the vosaroxin combination had a median overall survival of 6.7 months, compared to 5.3 months for placebo and cytarabine (HR=0.809, P=0.02).

Results according to age

For age, the researchers stratified patients into those age 60 years and older and those younger than 60 years at enrollment.

For the younger patients (n=260), the median overall survival was 9.1 months in the vosaroxin-cytarabine arm and 7.9 months in the placebo-cytarabine arm (HR=1.079, not significant).

The complete response rates were 26.9% and 20.8%, respectively (P=0.24). The rate of stem cell transplant was 45.8% in this age group.

For patients aged 60 years and older (n=451), the median overall survival was 7.1 months in the vosaroxin-cytarabine arm and 5.0 months in the placebo-cytarabine arm (HR=0.755, P=0.006).

The complete response rates were 31.9% and 13.8%, respectively (P=0.0000048). The rate of stem cell transplant was 20.2% for this age group.

Adverse events and mortality

In the intent-to-treat population, grade 3 or higher non-hematologic adverse events that were more common in the vosaroxin arm were gastrointestinal and infection-related toxicities. This is consistent with events observed in previous company trials.

The rate of serious adverse events was 55.5% in the vosaroxin-cytarabine arm and 35.7% in the placebo-cytarabine arm.

All-cause mortality rates were similar between the arms. Thirty-day mortality rates were 7.9% in the vosaroxin-cytarabine arm and 6.6% in the placebo-cytarabine arm. And 60-day mortality rates were 19.7% and 19.4%, respectively.

Regulatory plans

Based on the results of the trial, Sunesis plans to submit a marketing authorization application for vosaroxin to the European Medicines Agency. The company also plans to meet with the US Food and Drug Administration (FDA) to determine the appropriate regulatory path forward.

The FDA and the European Commission have already granted orphan designation to vosaroxin for the treatment of AML. The drug has been granted fast track designation by the FDA as well, for the potential treatment of relapsed or refractory AML in combination with cytarabine.

In a phase 3 trial, adding the quinolone derivative vosaroxin (Qinprezo) to treatment with cytarabine did not improve overall survival in patients with relapsed or refractory acute myeloid leukemia (AML).

However, the combination did confer a survival benefit when transplant patients were excluded from the analysis and in patients age 60 and older.

Results of this trial were recently announced by Sunesis Pharmaceuticals, the company developing vosaroxin.

The results are set to be presented in more detail at an upcoming scientific conference.

The trial, known as VALOR, enrolled 711 AML patients who had relapsed or become refractory to treatment for the first time. The patients were randomized to receive cytarabine plus vosaroxin or cytarabine plus placebo. They were stratified for age, geography, and disease status.

The trial did not meet its primary endpoint of demonstrating a significant improvement in overall survival. The median overall survival was 7.5 months in the vosaroxin-cytarabine arm and 6.1 months in the placebo-cytarabine arm (hazard ratio [HR]=0.865, P=0.06).

However, there was a significant benefit in complete response rate with vosaroxin over placebo—30.1% and 16.3%, respectively (P=0.0000148).

Because transplant could confound the primary analysis, the researchers planned a predefined analysis of overall survival censoring for stem cell transplant.

In this analysis, patients receiving the vosaroxin combination had a median overall survival of 6.7 months, compared to 5.3 months for placebo and cytarabine (HR=0.809, P=0.02).

Results according to age

For age, the researchers stratified patients into those age 60 years and older and those younger than 60 years at enrollment.

For the younger patients (n=260), the median overall survival was 9.1 months in the vosaroxin-cytarabine arm and 7.9 months in the placebo-cytarabine arm (HR=1.079, not significant).

The complete response rates were 26.9% and 20.8%, respectively (P=0.24). The rate of stem cell transplant was 45.8% in this age group.

For patients aged 60 years and older (n=451), the median overall survival was 7.1 months in the vosaroxin-cytarabine arm and 5.0 months in the placebo-cytarabine arm (HR=0.755, P=0.006).

The complete response rates were 31.9% and 13.8%, respectively (P=0.0000048). The rate of stem cell transplant was 20.2% for this age group.

Adverse events and mortality

In the intent-to-treat population, grade 3 or higher non-hematologic adverse events that were more common in the vosaroxin arm were gastrointestinal and infection-related toxicities. This is consistent with events observed in previous company trials.

The rate of serious adverse events was 55.5% in the vosaroxin-cytarabine arm and 35.7% in the placebo-cytarabine arm.

All-cause mortality rates were similar between the arms. Thirty-day mortality rates were 7.9% in the vosaroxin-cytarabine arm and 6.6% in the placebo-cytarabine arm. And 60-day mortality rates were 19.7% and 19.4%, respectively.

Regulatory plans

Based on the results of the trial, Sunesis plans to submit a marketing authorization application for vosaroxin to the European Medicines Agency. The company also plans to meet with the US Food and Drug Administration (FDA) to determine the appropriate regulatory path forward.

The FDA and the European Commission have already granted orphan designation to vosaroxin for the treatment of AML. The drug has been granted fast track designation by the FDA as well, for the potential treatment of relapsed or refractory AML in combination with cytarabine.

Micrograph showing AML

Credit: Lance Liotta

Understanding the relationship between mutated and wild-type genes could lead to new therapies for acute myeloid leukemia (AML), according to researchers.

The group discovered that RUNX1/ETO, generated by the chromosomal translocation t(8;21), regulates a leukemia-propagating transcriptional network via a dynamic equilibrium with RUNX1.

But depleting RUNX1/ETO prompts the formation of a transcriptional network that promotes myeloid differentiation.

Constanze Bonifer, PhD, of the University of Birmingham in the UK, and her colleagues detailed this work in Cell Reports.

The researchers likened normal hematopoiesis to a production line, with genes acting as regulators to control each step of blood formation. When a mutation occurs in the relevant regulator genes, the finely balanced order of the production line is disrupted, with drastic consequences.

Using digital footprinting and chromatin immunoprecipitation sequencing, the team showed that RUNX1/ETO switches off hundreds of other genes, many of them regulators themselves. As a consequence of the drastically altered production line, normal blood formation cannot happen, and leukemic cells form.

“Understanding how these rogue regulators operate is essential,” Dr Bonifer said. “[T]hese leukemic cells have one mutated gene and one unchanged one that would make the normal regulator. What happens in the leukemic cell is fundamentally a battle for supremacy between the two regulators, and the mutated one wins much of the time.”

“This is compounded by the normal regulator, which tries to compensate for defeat, and, in doing so, changes the output of genes that would be otherwise unaffected by the abnormal regulator. Quite simply, the result is a real mess. The cells are confused and can’t develop into mature blood cells.”

More specifically, the researchers found that the transcriptional program underlying leukemic propagation is regulated by a dynamic equilibrium between RUNX1/ETO and RUNX1 complexes.

Disrupting this equilibrium in t(8;21) cells by depleting RUNX1/ETO led to a global redistribution of transcription factor complexes within pre-existing open chromatin. And this prompted the formation of a transcriptional network that drives myeloid differentiation.

“If targeting [RUNX1/ETO] can reverse the changes it is making to the cellular production line, then it would ultimately point towards new avenues for a more precise treatment of leukemia,” said study author Olaf Heidenreich, PhD, of Newcastle University in the UK.

“Knowing that the production line can be restored to normal function gives us real hope. Of course, that is much easier to do in the lab than it is in the human body. But now we know how this works, we can look to deliver inhibitors to those mutated regulators. Creating one that works is the next step we have to overcome.”

Micrograph showing AML

Credit: Lance Liotta

Understanding the relationship between mutated and wild-type genes could lead to new therapies for acute myeloid leukemia (AML), according to researchers.

The group discovered that RUNX1/ETO, generated by the chromosomal translocation t(8;21), regulates a leukemia-propagating transcriptional network via a dynamic equilibrium with RUNX1.

But depleting RUNX1/ETO prompts the formation of a transcriptional network that promotes myeloid differentiation.

Constanze Bonifer, PhD, of the University of Birmingham in the UK, and her colleagues detailed this work in Cell Reports.

The researchers likened normal hematopoiesis to a production line, with genes acting as regulators to control each step of blood formation. When a mutation occurs in the relevant regulator genes, the finely balanced order of the production line is disrupted, with drastic consequences.

Using digital footprinting and chromatin immunoprecipitation sequencing, the team showed that RUNX1/ETO switches off hundreds of other genes, many of them regulators themselves. As a consequence of the drastically altered production line, normal blood formation cannot happen, and leukemic cells form.

“Understanding how these rogue regulators operate is essential,” Dr Bonifer said. “[T]hese leukemic cells have one mutated gene and one unchanged one that would make the normal regulator. What happens in the leukemic cell is fundamentally a battle for supremacy between the two regulators, and the mutated one wins much of the time.”

“This is compounded by the normal regulator, which tries to compensate for defeat, and, in doing so, changes the output of genes that would be otherwise unaffected by the abnormal regulator. Quite simply, the result is a real mess. The cells are confused and can’t develop into mature blood cells.”

More specifically, the researchers found that the transcriptional program underlying leukemic propagation is regulated by a dynamic equilibrium between RUNX1/ETO and RUNX1 complexes.

Disrupting this equilibrium in t(8;21) cells by depleting RUNX1/ETO led to a global redistribution of transcription factor complexes within pre-existing open chromatin. And this prompted the formation of a transcriptional network that drives myeloid differentiation.

“If targeting [RUNX1/ETO] can reverse the changes it is making to the cellular production line, then it would ultimately point towards new avenues for a more precise treatment of leukemia,” said study author Olaf Heidenreich, PhD, of Newcastle University in the UK.

“Knowing that the production line can be restored to normal function gives us real hope. Of course, that is much easier to do in the lab than it is in the human body. But now we know how this works, we can look to deliver inhibitors to those mutated regulators. Creating one that works is the next step we have to overcome.”

Micrograph showing AML

Credit: Lance Liotta

Understanding the relationship between mutated and wild-type genes could lead to new therapies for acute myeloid leukemia (AML), according to researchers.

The group discovered that RUNX1/ETO, generated by the chromosomal translocation t(8;21), regulates a leukemia-propagating transcriptional network via a dynamic equilibrium with RUNX1.

But depleting RUNX1/ETO prompts the formation of a transcriptional network that promotes myeloid differentiation.

Constanze Bonifer, PhD, of the University of Birmingham in the UK, and her colleagues detailed this work in Cell Reports.

The researchers likened normal hematopoiesis to a production line, with genes acting as regulators to control each step of blood formation. When a mutation occurs in the relevant regulator genes, the finely balanced order of the production line is disrupted, with drastic consequences.

Using digital footprinting and chromatin immunoprecipitation sequencing, the team showed that RUNX1/ETO switches off hundreds of other genes, many of them regulators themselves. As a consequence of the drastically altered production line, normal blood formation cannot happen, and leukemic cells form.

“Understanding how these rogue regulators operate is essential,” Dr Bonifer said. “[T]hese leukemic cells have one mutated gene and one unchanged one that would make the normal regulator. What happens in the leukemic cell is fundamentally a battle for supremacy between the two regulators, and the mutated one wins much of the time.”

“This is compounded by the normal regulator, which tries to compensate for defeat, and, in doing so, changes the output of genes that would be otherwise unaffected by the abnormal regulator. Quite simply, the result is a real mess. The cells are confused and can’t develop into mature blood cells.”

More specifically, the researchers found that the transcriptional program underlying leukemic propagation is regulated by a dynamic equilibrium between RUNX1/ETO and RUNX1 complexes.

Disrupting this equilibrium in t(8;21) cells by depleting RUNX1/ETO led to a global redistribution of transcription factor complexes within pre-existing open chromatin. And this prompted the formation of a transcriptional network that drives myeloid differentiation.

“If targeting [RUNX1/ETO] can reverse the changes it is making to the cellular production line, then it would ultimately point towards new avenues for a more precise treatment of leukemia,” said study author Olaf Heidenreich, PhD, of Newcastle University in the UK.

“Knowing that the production line can be restored to normal function gives us real hope. Of course, that is much easier to do in the lab than it is in the human body. But now we know how this works, we can look to deliver inhibitors to those mutated regulators. Creating one that works is the next step we have to overcome.”

DNA repair

Credit: Tom Ellenberger

Researchers say they’ve discovered “an intimate link” between RUNX genes and Fanconi anemia, a finding that also has implications for treating acute myeloid leukemia (AML).

The group found that RUNX1 and RUNX3 interact with Fanconi anemia group D2 (FANCD2), a protein involved in the repair of DNA damage.

The RUNX proteins facilitate the recruitment of FANCD2 to sites of DNA damage in both Fanconi anemia and AML.

Motomi Osato, MD, PhD, of the Cancer Science Institute of Singapore, and his colleagues recounted these findings in Cell Reports.

The researchers began by studying RUNX deficiency in mice. They found that knockdown of both RUNX1 and RUNX3 led to bone marrow failure or myeloproliferative disorders in the mice.

These clinical manifestations are seen in inherited bone marrow failure syndromes such as Fanconi anemia, which is caused by the disruption of gene products that participate in the repair of DNA interstrand crosslinks (ICLs).

With this in mind, the researchers decided to investigate RUNX function in the ICL repair pathway. And they found RUNX proteins play a critical role in the pathway by facilitating the recruitment of FANCD2 to sites of DNA damage.

To explore the clinical relevance of RUNX participation in DNA damage repair, the team conducted experiments in Kasumi-1 and SKNO-1 cells. These AML cell lines express RUNX1-ETO, which is thought to suppress the expression and/or function of RUNX1 and RUNX3 simultaneously.

The researchers showed that Kasumi-1 and SKNO-1 cells were sensitive to the ICL-inducing agent mytomycin C, and knocking down RUNX1-ETO reduced this sensitivity. Depleting RUNX1-ETO also led to increased FANCD2 recruitment to chromatin.

The team said these results suggest that RUNX1-ETO might repress FANCD2 foci formation and ICL repair in AML cells. And they predicted that RUNX dysfunction would sensitize the cells to PARP inhibitors.

So they tested 2 PARP inhibitors—olaparib and rucaparib—in Kasumi-1 cells and observed sensitivity to both drugs. Knocking down RUNX1-ETO partially reduced this sensitivity, while adding mytomycin C increased sensitivity.

“PARP inhibitors have been with us for quite some time, but nobody has realized their application for leukemia,” Dr Osato said. “Our study has shed light on the possibility of a more effective treatment using a combined therapy with PARP inhibitors, which can potentially be extended to other types of common cancers.”

The researchers are now conducting additional drug testing in xenograft models.

DNA repair

Credit: Tom Ellenberger

Researchers say they’ve discovered “an intimate link” between RUNX genes and Fanconi anemia, a finding that also has implications for treating acute myeloid leukemia (AML).

The group found that RUNX1 and RUNX3 interact with Fanconi anemia group D2 (FANCD2), a protein involved in the repair of DNA damage.

The RUNX proteins facilitate the recruitment of FANCD2 to sites of DNA damage in both Fanconi anemia and AML.

Motomi Osato, MD, PhD, of the Cancer Science Institute of Singapore, and his colleagues recounted these findings in Cell Reports.

The researchers began by studying RUNX deficiency in mice. They found that knockdown of both RUNX1 and RUNX3 led to bone marrow failure or myeloproliferative disorders in the mice.

These clinical manifestations are seen in inherited bone marrow failure syndromes such as Fanconi anemia, which is caused by the disruption of gene products that participate in the repair of DNA interstrand crosslinks (ICLs).

With this in mind, the researchers decided to investigate RUNX function in the ICL repair pathway. And they found RUNX proteins play a critical role in the pathway by facilitating the recruitment of FANCD2 to sites of DNA damage.

To explore the clinical relevance of RUNX participation in DNA damage repair, the team conducted experiments in Kasumi-1 and SKNO-1 cells. These AML cell lines express RUNX1-ETO, which is thought to suppress the expression and/or function of RUNX1 and RUNX3 simultaneously.

The researchers showed that Kasumi-1 and SKNO-1 cells were sensitive to the ICL-inducing agent mytomycin C, and knocking down RUNX1-ETO reduced this sensitivity. Depleting RUNX1-ETO also led to increased FANCD2 recruitment to chromatin.

The team said these results suggest that RUNX1-ETO might repress FANCD2 foci formation and ICL repair in AML cells. And they predicted that RUNX dysfunction would sensitize the cells to PARP inhibitors.

So they tested 2 PARP inhibitors—olaparib and rucaparib—in Kasumi-1 cells and observed sensitivity to both drugs. Knocking down RUNX1-ETO partially reduced this sensitivity, while adding mytomycin C increased sensitivity.

“PARP inhibitors have been with us for quite some time, but nobody has realized their application for leukemia,” Dr Osato said. “Our study has shed light on the possibility of a more effective treatment using a combined therapy with PARP inhibitors, which can potentially be extended to other types of common cancers.”

The researchers are now conducting additional drug testing in xenograft models.

DNA repair

Credit: Tom Ellenberger

Researchers say they’ve discovered “an intimate link” between RUNX genes and Fanconi anemia, a finding that also has implications for treating acute myeloid leukemia (AML).

The group found that RUNX1 and RUNX3 interact with Fanconi anemia group D2 (FANCD2), a protein involved in the repair of DNA damage.

The RUNX proteins facilitate the recruitment of FANCD2 to sites of DNA damage in both Fanconi anemia and AML.

Motomi Osato, MD, PhD, of the Cancer Science Institute of Singapore, and his colleagues recounted these findings in Cell Reports.

The researchers began by studying RUNX deficiency in mice. They found that knockdown of both RUNX1 and RUNX3 led to bone marrow failure or myeloproliferative disorders in the mice.

These clinical manifestations are seen in inherited bone marrow failure syndromes such as Fanconi anemia, which is caused by the disruption of gene products that participate in the repair of DNA interstrand crosslinks (ICLs).

With this in mind, the researchers decided to investigate RUNX function in the ICL repair pathway. And they found RUNX proteins play a critical role in the pathway by facilitating the recruitment of FANCD2 to sites of DNA damage.

To explore the clinical relevance of RUNX participation in DNA damage repair, the team conducted experiments in Kasumi-1 and SKNO-1 cells. These AML cell lines express RUNX1-ETO, which is thought to suppress the expression and/or function of RUNX1 and RUNX3 simultaneously.

The researchers showed that Kasumi-1 and SKNO-1 cells were sensitive to the ICL-inducing agent mytomycin C, and knocking down RUNX1-ETO reduced this sensitivity. Depleting RUNX1-ETO also led to increased FANCD2 recruitment to chromatin.

The team said these results suggest that RUNX1-ETO might repress FANCD2 foci formation and ICL repair in AML cells. And they predicted that RUNX dysfunction would sensitize the cells to PARP inhibitors.

So they tested 2 PARP inhibitors—olaparib and rucaparib—in Kasumi-1 cells and observed sensitivity to both drugs. Knocking down RUNX1-ETO partially reduced this sensitivity, while adding mytomycin C increased sensitivity.

“PARP inhibitors have been with us for quite some time, but nobody has realized their application for leukemia,” Dr Osato said. “Our study has shed light on the possibility of a more effective treatment using a combined therapy with PARP inhibitors, which can potentially be extended to other types of common cancers.”

The researchers are now conducting additional drug testing in xenograft models.

Preparing pills for a trial

Credit: Esther Dyson

The US Food and Drug Administration (FDA) has granted fast track designation for AG-221 to treat acute myelogenous leukemia (AML) patients with mutated isocitrate dehydrogenase-2 (IDH2).

AG-221 is an IDH2 inhibitor under evaluation in a phase 1 trial of patients with advanced hematologic malignancies.

Results from this trial were presented at the 19th Congress of the European Hematology Association, which took place in Milan in June.

The FDA’s fast track drug development program is designed to expedite clinical development and submission of a new drug application (NDA) for drugs with the potential to treat serious or life-threatening conditions and address unmet medical needs.

Fast track designation facilitates meetings between the FDA and the company developing a drug to discuss all aspects of development to support approval. It also affords the developer the opportunity to submit sections of an NDA on a rolling basis as data become available, so the FDA does not have wait for the entire NDA submission before beginning its review.

AG-221 also recently received orphan designation as a treatment for AML. The FDA grants orphan status to support the development of drugs for underserved patient populations or rare disorders that affect fewer than 200,000 people in the US.

Orphan designation affords the drug’s developer certain benefits, including market exclusivity upon regulatory approval, exemption of FDA application fees, and tax credits for qualified clinical trials.

Phase 1 trial results

Thus far in the phase 1 study, AG-221 has proven active and well-tolerated in patients with AML, myelodysplastic syndromes (MDS), and chronic myelomonocytic leukemia (CMML).

The trial included 35 patients with a median age of 68 years (range, 48-81).

Twenty-seven patients had relapsed/refractory AML, 4 had relapsed/refractory MDS, 2 had untreated AML, 1 had CMML, and 1 had granulocytic sarcoma. Thirty-one patients had R140Q IDH2 mutations, and 4 had R172K IDH2 mutations.

The patients received AG-221 at doses ranging from 30 mg BID to 150 mg QD. Patients completed a median of 1 cycle of treatment (range, <1-5+) and a mean of 2 cycles.

The drug was generally well-tolerated, largely prompting grade 1 or 2 adverse events. Grade 3 or higher events included thrombocytopenia (n=3), anemia (n=1), febrile neutropenia (n=3), sepsis (n=3), diarrhea (n=1), fatigue (n=1), leukocytosis (n=2), neutropenia (n=1), and rash (n=1).

Four patients had serious events possibly related to treatment. One patient had grade 3 confusion and grade 5 respiratory failure. One patient had grade 3 leukocytosis, grade 3 anorexia, and grade 1 nausea. One patient had grade 3 diarrhea. And 1 patient had grade 3 leukocytosis.

Twenty-five patients were evaluable for response. There were 6 complete responses (CRs), 2 CRs with incomplete platelet recovery, 1 CR with incomplete hematologic recovery, and 5 partial responses. Five patients had stable disease, and 6 had progressive disease.

The most responses occurred among patients who received AG-221 at 50 mg BID, and most responses occurred in cycle 1.

Twelve of the 14 responses are ongoing. Of the 8 patients who achieved a CR or CR with incomplete platelet recovery, 5 have lasted more than 2.5 months (range, 1-4+ months). And the 5 patients with stable disease remain on study.

This study is sponsored by Agios Pharmaceuticals Inc., the company developing AG-221 in collaboration with Celgene.

Preparing pills for a trial

Credit: Esther Dyson

The US Food and Drug Administration (FDA) has granted fast track designation for AG-221 to treat acute myelogenous leukemia (AML) patients with mutated isocitrate dehydrogenase-2 (IDH2).

AG-221 is an IDH2 inhibitor under evaluation in a phase 1 trial of patients with advanced hematologic malignancies.

Results from this trial were presented at the 19th Congress of the European Hematology Association, which took place in Milan in June.

The FDA’s fast track drug development program is designed to expedite clinical development and submission of a new drug application (NDA) for drugs with the potential to treat serious or life-threatening conditions and address unmet medical needs.

Fast track designation facilitates meetings between the FDA and the company developing a drug to discuss all aspects of development to support approval. It also affords the developer the opportunity to submit sections of an NDA on a rolling basis as data become available, so the FDA does not have wait for the entire NDA submission before beginning its review.

AG-221 also recently received orphan designation as a treatment for AML. The FDA grants orphan status to support the development of drugs for underserved patient populations or rare disorders that affect fewer than 200,000 people in the US.

Orphan designation affords the drug’s developer certain benefits, including market exclusivity upon regulatory approval, exemption of FDA application fees, and tax credits for qualified clinical trials.

Phase 1 trial results

Thus far in the phase 1 study, AG-221 has proven active and well-tolerated in patients with AML, myelodysplastic syndromes (MDS), and chronic myelomonocytic leukemia (CMML).

The trial included 35 patients with a median age of 68 years (range, 48-81).

Twenty-seven patients had relapsed/refractory AML, 4 had relapsed/refractory MDS, 2 had untreated AML, 1 had CMML, and 1 had granulocytic sarcoma. Thirty-one patients had R140Q IDH2 mutations, and 4 had R172K IDH2 mutations.

The patients received AG-221 at doses ranging from 30 mg BID to 150 mg QD. Patients completed a median of 1 cycle of treatment (range, <1-5+) and a mean of 2 cycles.

The drug was generally well-tolerated, largely prompting grade 1 or 2 adverse events. Grade 3 or higher events included thrombocytopenia (n=3), anemia (n=1), febrile neutropenia (n=3), sepsis (n=3), diarrhea (n=1), fatigue (n=1), leukocytosis (n=2), neutropenia (n=1), and rash (n=1).

Four patients had serious events possibly related to treatment. One patient had grade 3 confusion and grade 5 respiratory failure. One patient had grade 3 leukocytosis, grade 3 anorexia, and grade 1 nausea. One patient had grade 3 diarrhea. And 1 patient had grade 3 leukocytosis.

Twenty-five patients were evaluable for response. There were 6 complete responses (CRs), 2 CRs with incomplete platelet recovery, 1 CR with incomplete hematologic recovery, and 5 partial responses. Five patients had stable disease, and 6 had progressive disease.

The most responses occurred among patients who received AG-221 at 50 mg BID, and most responses occurred in cycle 1.

Twelve of the 14 responses are ongoing. Of the 8 patients who achieved a CR or CR with incomplete platelet recovery, 5 have lasted more than 2.5 months (range, 1-4+ months). And the 5 patients with stable disease remain on study.

This study is sponsored by Agios Pharmaceuticals Inc., the company developing AG-221 in collaboration with Celgene.

Preparing pills for a trial

Credit: Esther Dyson

The US Food and Drug Administration (FDA) has granted fast track designation for AG-221 to treat acute myelogenous leukemia (AML) patients with mutated isocitrate dehydrogenase-2 (IDH2).

AG-221 is an IDH2 inhibitor under evaluation in a phase 1 trial of patients with advanced hematologic malignancies.

Results from this trial were presented at the 19th Congress of the European Hematology Association, which took place in Milan in June.

The FDA’s fast track drug development program is designed to expedite clinical development and submission of a new drug application (NDA) for drugs with the potential to treat serious or life-threatening conditions and address unmet medical needs.

Fast track designation facilitates meetings between the FDA and the company developing a drug to discuss all aspects of development to support approval. It also affords the developer the opportunity to submit sections of an NDA on a rolling basis as data become available, so the FDA does not have wait for the entire NDA submission before beginning its review.

AG-221 also recently received orphan designation as a treatment for AML. The FDA grants orphan status to support the development of drugs for underserved patient populations or rare disorders that affect fewer than 200,000 people in the US.

Orphan designation affords the drug’s developer certain benefits, including market exclusivity upon regulatory approval, exemption of FDA application fees, and tax credits for qualified clinical trials.

Phase 1 trial results

Thus far in the phase 1 study, AG-221 has proven active and well-tolerated in patients with AML, myelodysplastic syndromes (MDS), and chronic myelomonocytic leukemia (CMML).

The trial included 35 patients with a median age of 68 years (range, 48-81).

Twenty-seven patients had relapsed/refractory AML, 4 had relapsed/refractory MDS, 2 had untreated AML, 1 had CMML, and 1 had granulocytic sarcoma. Thirty-one patients had R140Q IDH2 mutations, and 4 had R172K IDH2 mutations.

The patients received AG-221 at doses ranging from 30 mg BID to 150 mg QD. Patients completed a median of 1 cycle of treatment (range, <1-5+) and a mean of 2 cycles.

The drug was generally well-tolerated, largely prompting grade 1 or 2 adverse events. Grade 3 or higher events included thrombocytopenia (n=3), anemia (n=1), febrile neutropenia (n=3), sepsis (n=3), diarrhea (n=1), fatigue (n=1), leukocytosis (n=2), neutropenia (n=1), and rash (n=1).

Four patients had serious events possibly related to treatment. One patient had grade 3 confusion and grade 5 respiratory failure. One patient had grade 3 leukocytosis, grade 3 anorexia, and grade 1 nausea. One patient had grade 3 diarrhea. And 1 patient had grade 3 leukocytosis.

Twenty-five patients were evaluable for response. There were 6 complete responses (CRs), 2 CRs with incomplete platelet recovery, 1 CR with incomplete hematologic recovery, and 5 partial responses. Five patients had stable disease, and 6 had progressive disease.

The most responses occurred among patients who received AG-221 at 50 mg BID, and most responses occurred in cycle 1.

Twelve of the 14 responses are ongoing. Of the 8 patients who achieved a CR or CR with incomplete platelet recovery, 5 have lasted more than 2.5 months (range, 1-4+ months). And the 5 patients with stable disease remain on study.

This study is sponsored by Agios Pharmaceuticals Inc., the company developing AG-221 in collaboration with Celgene.

Azathioprine tablets

A class of immunosuppressive agents appear to increase the risk of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) in patients with inflammatory bowel disease (IBD).

In an observational study of more than 19,000 IBD patients, past exposure to the agents—thiopurines—increased the risk of developing AML or MDS nearly 7-fold, when compared to the general population.

However, the absolute risk to an individual patient was about 1 in 10,000.

The researchers reported these results in Clinical Gastroenterology and Hepatology.

Thiopurines are an established treatment for IBD patients, but the drugs are also used to prevent rejection after a kidney transplant, to treat rheumatoid arthritis, as maintenance therapy for acute lymphocytic leukemia, and to induce remission in patients with AML.

Previous research showed that long-term use of thiopurines can increase a person’s risk of developing lymphoma.

“In order to make appropriate, informed decisions about thiopurines, patients and providers need to be well-educated about the risks and benefits of this treatment,” said study author Laurent Peyrin-Biroulet, MD, PhD, of the University Hospital of Nancy-Brabois in France.

“According to our research, the risk of myeloid disorders was not increased among the overall IBD population, compared with the general population. However, it was increased amongst those taking thiopurines. We hope these findings encourage other researchers to investigate more about the drug and its potentially harmful effects.”

The researchers analyzed 19,486 patients who were enrolled in the Cancers Et Surrisque Associé aux Maladies inflammatoires intestinales En France study from May 2004 through June 2005.

At study entry, 10,810 patients had never received thiopurines, 2810 patients had discontinued such drugs, and 5866 patients were still receiving them.

After 3 years of follow up, 5 patients were diagnosed with incident myeloid disorders—2 with AML and 3 with MDS. Four of these patients had been exposed to thiopurines—1 with ongoing treatment and 3 with past exposure.

The risk of myeloid disorders was not increased among the overall IBD population, compared with the general population. The standardized incidence ratio (SIR) was 1.80.

Similarly, the risk of myeloid disorders was not increased among IBD patients still receiving thiopurine treatment. The SIR was 1.54.

However, patients with prior exposure to thiopurines did have a significantly increased risk of myeloid disorders, with an SIR of 6.98.

The researchers noted that, although these findings provide evidence of a connection between thiopurines and myeloid disorders in IBD patients, the absolute risk to an individual patient was low.

So it seems the link between thiopurines and myeloid disorders remains complex. And physicians must balance the risk against the known benefits of thiopurines in the management of IBD.

The American Gastroenterological Association has developed a guideline-based clinical decision support tool to help providers determine when to use thiopurines in these patients.

Azathioprine tablets

A class of immunosuppressive agents appear to increase the risk of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) in patients with inflammatory bowel disease (IBD).

In an observational study of more than 19,000 IBD patients, past exposure to the agents—thiopurines—increased the risk of developing AML or MDS nearly 7-fold, when compared to the general population.

However, the absolute risk to an individual patient was about 1 in 10,000.

The researchers reported these results in Clinical Gastroenterology and Hepatology.

Thiopurines are an established treatment for IBD patients, but the drugs are also used to prevent rejection after a kidney transplant, to treat rheumatoid arthritis, as maintenance therapy for acute lymphocytic leukemia, and to induce remission in patients with AML.

Previous research showed that long-term use of thiopurines can increase a person’s risk of developing lymphoma.

“In order to make appropriate, informed decisions about thiopurines, patients and providers need to be well-educated about the risks and benefits of this treatment,” said study author Laurent Peyrin-Biroulet, MD, PhD, of the University Hospital of Nancy-Brabois in France.

“According to our research, the risk of myeloid disorders was not increased among the overall IBD population, compared with the general population. However, it was increased amongst those taking thiopurines. We hope these findings encourage other researchers to investigate more about the drug and its potentially harmful effects.”

The researchers analyzed 19,486 patients who were enrolled in the Cancers Et Surrisque Associé aux Maladies inflammatoires intestinales En France study from May 2004 through June 2005.

At study entry, 10,810 patients had never received thiopurines, 2810 patients had discontinued such drugs, and 5866 patients were still receiving them.

After 3 years of follow up, 5 patients were diagnosed with incident myeloid disorders—2 with AML and 3 with MDS. Four of these patients had been exposed to thiopurines—1 with ongoing treatment and 3 with past exposure.

The risk of myeloid disorders was not increased among the overall IBD population, compared with the general population. The standardized incidence ratio (SIR) was 1.80.

Similarly, the risk of myeloid disorders was not increased among IBD patients still receiving thiopurine treatment. The SIR was 1.54.

However, patients with prior exposure to thiopurines did have a significantly increased risk of myeloid disorders, with an SIR of 6.98.

The researchers noted that, although these findings provide evidence of a connection between thiopurines and myeloid disorders in IBD patients, the absolute risk to an individual patient was low.

So it seems the link between thiopurines and myeloid disorders remains complex. And physicians must balance the risk against the known benefits of thiopurines in the management of IBD.

The American Gastroenterological Association has developed a guideline-based clinical decision support tool to help providers determine when to use thiopurines in these patients.

Azathioprine tablets

A class of immunosuppressive agents appear to increase the risk of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) in patients with inflammatory bowel disease (IBD).

In an observational study of more than 19,000 IBD patients, past exposure to the agents—thiopurines—increased the risk of developing AML or MDS nearly 7-fold, when compared to the general population.

However, the absolute risk to an individual patient was about 1 in 10,000.

The researchers reported these results in Clinical Gastroenterology and Hepatology.

Thiopurines are an established treatment for IBD patients, but the drugs are also used to prevent rejection after a kidney transplant, to treat rheumatoid arthritis, as maintenance therapy for acute lymphocytic leukemia, and to induce remission in patients with AML.

Previous research showed that long-term use of thiopurines can increase a person’s risk of developing lymphoma.

“In order to make appropriate, informed decisions about thiopurines, patients and providers need to be well-educated about the risks and benefits of this treatment,” said study author Laurent Peyrin-Biroulet, MD, PhD, of the University Hospital of Nancy-Brabois in France.

“According to our research, the risk of myeloid disorders was not increased among the overall IBD population, compared with the general population. However, it was increased amongst those taking thiopurines. We hope these findings encourage other researchers to investigate more about the drug and its potentially harmful effects.”

The researchers analyzed 19,486 patients who were enrolled in the Cancers Et Surrisque Associé aux Maladies inflammatoires intestinales En France study from May 2004 through June 2005.

At study entry, 10,810 patients had never received thiopurines, 2810 patients had discontinued such drugs, and 5866 patients were still receiving them.

After 3 years of follow up, 5 patients were diagnosed with incident myeloid disorders—2 with AML and 3 with MDS. Four of these patients had been exposed to thiopurines—1 with ongoing treatment and 3 with past exposure.

The risk of myeloid disorders was not increased among the overall IBD population, compared with the general population. The standardized incidence ratio (SIR) was 1.80.

Similarly, the risk of myeloid disorders was not increased among IBD patients still receiving thiopurine treatment. The SIR was 1.54.

However, patients with prior exposure to thiopurines did have a significantly increased risk of myeloid disorders, with an SIR of 6.98.

The researchers noted that, although these findings provide evidence of a connection between thiopurines and myeloid disorders in IBD patients, the absolute risk to an individual patient was low.

So it seems the link between thiopurines and myeloid disorders remains complex. And physicians must balance the risk against the known benefits of thiopurines in the management of IBD.

The American Gastroenterological Association has developed a guideline-based clinical decision support tool to help providers determine when to use thiopurines in these patients.

Patient receiving chemotherapy

Credit: Rhoda Baer

Adding the Plk1 inhibitor volasertib to chemotherapy can prolong survival in older patients with previously untreated acute myeloid leukemia (AML), researchers have reported in Blood.

In a phase 2 study, AML patients aged 65 or older who were ineligible for intensive induction therapy had higher response and survival rates when they received volasertib plus low-dose cytarabine (LDAC),  compared to LDAC alone.

However, adverse events, such as febrile neutropenia and infections, were more common with volasertib.

“These clinical trial results . . . are important and have informed future research for this rare disease, where new treatment options are greatly needed,” said study author Hartmut Döhner, MD, of the University Hospital Ulm in Germany.

“The established approach to treat younger AML patients is an intensive chemotherapy regimen, [but] older patients often cannot tolerate these chemotherapy doses and have very limited treatment options.”

To test volasertib as a potential option, the researchers enrolled and treated 87 patients with previously untreated AML who were ineligible for intensive induction therapy. Their median age was 75 years.

Patients received LDAC at 20 mg BID subcutaneously on days 1 through 10 (n=45) or LDAC plus volasertib at 350 mg intravenously on days 1 and 15, every 4 weeks (n=42). Overall, patient demographics and baseline disease characteristics were balanced between the treatment arms.

The response rate (complete response or complete response with incomplete blood count recovery) was more than doubled for patients receiving volasertib and LDAC compared to LDAC alone. The rates were 31% (13/42) and 13.3% (6/45), respectively (odds ratio, 2.91; P=0.052).

Responses in patients receiving volasertib and LDAC were observed across all genetic groups, including 5 of 14 patients with adverse genetics.

Remissions with the combination treatment appeared to be more durable than those observed with LDAC alone. The median relapse-free survival was 18.5 months and 10.0 months, respectively.

The median event-free survival was prolonged in patients receiving volasertib as well. Their event-free survival was 5.6 months, compared to 2.3 months for patients who received LDAC alone (hazard ratio 0.57,

P=0.021).

Patients who received volasertib also experienced improvements in overall survival. The median overall survival was 8.0 months for the volasertib arm and 5.2 months for the LDAC-alone arm (hazard ratio 0.63; P=0.047).

Patients receiving volasertib and LDAC had higher rates of adverse events than patients in the LDAC-alone arm. Events of note included grade 3 febrile neutropenia (38% vs 7%), grade 3 infections (38% vs 7%) and grade 3 gastrointestinal events (21% vs 7%).

Based on these results, researchers are now investigating volasertib in combination with LDAC in a randomized, double-blind, phase 3 trial for AML called POLO-AML-2.

Patient receiving chemotherapy

Credit: Rhoda Baer

Adding the Plk1 inhibitor volasertib to chemotherapy can prolong survival in older patients with previously untreated acute myeloid leukemia (AML), researchers have reported in Blood.

In a phase 2 study, AML patients aged 65 or older who were ineligible for intensive induction therapy had higher response and survival rates when they received volasertib plus low-dose cytarabine (LDAC),  compared to LDAC alone.

However, adverse events, such as febrile neutropenia and infections, were more common with volasertib.

“These clinical trial results . . . are important and have informed future research for this rare disease, where new treatment options are greatly needed,” said study author Hartmut Döhner, MD, of the University Hospital Ulm in Germany.

“The established approach to treat younger AML patients is an intensive chemotherapy regimen, [but] older patients often cannot tolerate these chemotherapy doses and have very limited treatment options.”

To test volasertib as a potential option, the researchers enrolled and treated 87 patients with previously untreated AML who were ineligible for intensive induction therapy. Their median age was 75 years.

Patients received LDAC at 20 mg BID subcutaneously on days 1 through 10 (n=45) or LDAC plus volasertib at 350 mg intravenously on days 1 and 15, every 4 weeks (n=42). Overall, patient demographics and baseline disease characteristics were balanced between the treatment arms.

The response rate (complete response or complete response with incomplete blood count recovery) was more than doubled for patients receiving volasertib and LDAC compared to LDAC alone. The rates were 31% (13/42) and 13.3% (6/45), respectively (odds ratio, 2.91; P=0.052).

Responses in patients receiving volasertib and LDAC were observed across all genetic groups, including 5 of 14 patients with adverse genetics.

Remissions with the combination treatment appeared to be more durable than those observed with LDAC alone. The median relapse-free survival was 18.5 months and 10.0 months, respectively.

The median event-free survival was prolonged in patients receiving volasertib as well. Their event-free survival was 5.6 months, compared to 2.3 months for patients who received LDAC alone (hazard ratio 0.57,

P=0.021).

Patients who received volasertib also experienced improvements in overall survival. The median overall survival was 8.0 months for the volasertib arm and 5.2 months for the LDAC-alone arm (hazard ratio 0.63; P=0.047).

Patients receiving volasertib and LDAC had higher rates of adverse events than patients in the LDAC-alone arm. Events of note included grade 3 febrile neutropenia (38% vs 7%), grade 3 infections (38% vs 7%) and grade 3 gastrointestinal events (21% vs 7%).

Based on these results, researchers are now investigating volasertib in combination with LDAC in a randomized, double-blind, phase 3 trial for AML called POLO-AML-2.

Patient receiving chemotherapy

Credit: Rhoda Baer

Adding the Plk1 inhibitor volasertib to chemotherapy can prolong survival in older patients with previously untreated acute myeloid leukemia (AML), researchers have reported in Blood.

In a phase 2 study, AML patients aged 65 or older who were ineligible for intensive induction therapy had higher response and survival rates when they received volasertib plus low-dose cytarabine (LDAC),  compared to LDAC alone.

However, adverse events, such as febrile neutropenia and infections, were more common with volasertib.

“These clinical trial results . . . are important and have informed future research for this rare disease, where new treatment options are greatly needed,” said study author Hartmut Döhner, MD, of the University Hospital Ulm in Germany.

“The established approach to treat younger AML patients is an intensive chemotherapy regimen, [but] older patients often cannot tolerate these chemotherapy doses and have very limited treatment options.”

To test volasertib as a potential option, the researchers enrolled and treated 87 patients with previously untreated AML who were ineligible for intensive induction therapy. Their median age was 75 years.

Patients received LDAC at 20 mg BID subcutaneously on days 1 through 10 (n=45) or LDAC plus volasertib at 350 mg intravenously on days 1 and 15, every 4 weeks (n=42). Overall, patient demographics and baseline disease characteristics were balanced between the treatment arms.

The response rate (complete response or complete response with incomplete blood count recovery) was more than doubled for patients receiving volasertib and LDAC compared to LDAC alone. The rates were 31% (13/42) and 13.3% (6/45), respectively (odds ratio, 2.91; P=0.052).

Responses in patients receiving volasertib and LDAC were observed across all genetic groups, including 5 of 14 patients with adverse genetics.

Remissions with the combination treatment appeared to be more durable than those observed with LDAC alone. The median relapse-free survival was 18.5 months and 10.0 months, respectively.

The median event-free survival was prolonged in patients receiving volasertib as well. Their event-free survival was 5.6 months, compared to 2.3 months for patients who received LDAC alone (hazard ratio 0.57,

P=0.021).

Patients who received volasertib also experienced improvements in overall survival. The median overall survival was 8.0 months for the volasertib arm and 5.2 months for the LDAC-alone arm (hazard ratio 0.63; P=0.047).

Patients receiving volasertib and LDAC had higher rates of adverse events than patients in the LDAC-alone arm. Events of note included grade 3 febrile neutropenia (38% vs 7%), grade 3 infections (38% vs 7%) and grade 3 gastrointestinal events (21% vs 7%).

Based on these results, researchers are now investigating volasertib in combination with LDAC in a randomized, double-blind, phase 3 trial for AML called POLO-AML-2.

Attendees at EHA 2014

Photo courtesy of EHA

MILAN—The IDH2 inhibitor AG-221 is well-tolerated and exhibits durable clinical activity in patients with hematologic disorders, results of a phase 1 study suggest.

The drug prompted responses in patients with myelodysplastic syndromes (MDS), acute myeloid leukemia (AML), or chronic myelomonocytic leukemia (CMML).

Fourteen of 25 patients achieved a response, and 12 of those responses are ongoing.

Most adverse events (AEs) were grade 1 or 2 in nature. However, 4 patients did have serious AEs that were possibly related to treatment.

Stéphane de Botton, MD, PhD, of Institut Gustave Roussy in Villejuif, France, presented these results at the 19th Annual Congress of the European Hematology Association (EHA) as abstract LB2434.

Dr de Botton and his colleagues enrolled 35 patients who had a median age of 68 years (range, 48-81).

Twenty-seven patients had relapsed/refractory AML, 4 had relapsed/refractory MDS, 2 had untreated AML, 1 had CMML, and 1 had granulocytic sarcoma. Thirty-one patients had R140Q IDH2 mutations, and 4 had R172K IDH2 mutations.

The patients received AG-221 at 30 mg BID (n=7), 50 mg BID (n=7), 75 mg BID (n=6), 100 mg QD (n=5), 100 mg BID (n=5), or 150 mg QD (n=5). Patients completed a median of 1 cycle of treatment (range, <1-5+) and a mean of 2 cycles.

Safety data

“AG-221 was remarkable well-tolerated, and the [maximum tolerated dose] has not been reached,” Dr de Botton said. “The majority of adverse events were grade 1 and 2.”

Eighteen patients were evaluable for safety. AEs of all grades included nausea (n=4), pyrexia (n=4), thrombocytopenia (n=4), anemia (n=3), dizziness (n=3), febrile neutropenia (n=3), peripheral edema (n=3), sepsis (n=3), cough (n=2), diarrhea (n=2), fatigue (n=2), leukocytosis (n=2), neutropenia (n=2), petechiae (n=2), and rash (n=2).

Grade 3 or higher AEs included thrombocytopenia (n=3), anemia (n=1), febrile neutropenia (n=3), sepsis (n=3), diarrhea (n=1), fatigue (n=1), leukocytosis (n=2), neutropenia (n=1), and rash (n=1). Dr de Botton noted that diarrhea and rash were not expected events.

Four patients had serious AEs possibly related to treatment. One patient had grade 3 confusion and grade 5 respiratory failure. One patient had grade 3 leukocytosis, grade 3 anorexia, and grade 1 nausea. One patient had grade 3 diarrhea. And 1 patient had grade 3 leukocytosis.

Seven patients died within 30 days of study drug termination: 4 in the 30-mg cohort, 2 in the 50-mg cohort, and 1 in the 100-mg-BID cohort.

Five deaths were due to complications of disease-related sepsis (all in cycle 1), 1 complication of a humeral fracture, and 1 complication of a stroke.

Activity and response data

The researchers observed high AG-221 accumulation after multiple doses. And results were “really very similar” between the 30-mg-BID cohort and the 100-mg-QD cohort, Dr de Botton noted.

He also said AG-221 was “very efficient” at inhibiting 2-HG in the plasma. 2-HG was inhibited up to 100% in subjects with R140Q mutations and up to 60% in subjects with R172K mutations.

Twenty-five patients were evaluable for response. The remaining 10 patients did not have day-28 marrow assessments, either due to early termination (n=7) or receiving less than 28 days of treatment although they were still on the study (n=3).

In all, there were 6 complete responses (CRs), 2 CRs with incomplete platelet recovery (CRps), 1 CR with incomplete hematologic recovery (CRi), and 5 partial responses (PRs). Five patients had stable disease (SD), and 6 had progressive disease (PD).

The most responses occurred in the 50-mg group, which had 3 CRs, 1 CRi, and 1 PR. This was followed by the 30-mg group, which had 2 CRs, 1 CRp, and 1 PR.

“The majority of responses occurred in cycle 1,” Dr de Botton noted, “except in the first cohort [30 mg], where responses occurred late, at the end of cycle 3 and cycle 4.”

Twelve of the 14 responses are ongoing. Of the 8 patients who achieved a CR or CRp, 5 have lasted more than 2.5 months (range, 1-4+ months). And the 5 patients with SD remain on study.

This study is sponsored by Celgene Corporation and Agios Pharmaceuticals Inc., the companies developing AG-221.

Attendees at EHA 2014

Photo courtesy of EHA

MILAN—The IDH2 inhibitor AG-221 is well-tolerated and exhibits durable clinical activity in patients with hematologic disorders, results of a phase 1 study suggest.

The drug prompted responses in patients with myelodysplastic syndromes (MDS), acute myeloid leukemia (AML), or chronic myelomonocytic leukemia (CMML).

Fourteen of 25 patients achieved a response, and 12 of those responses are ongoing.

Most adverse events (AEs) were grade 1 or 2 in nature. However, 4 patients did have serious AEs that were possibly related to treatment.

Stéphane de Botton, MD, PhD, of Institut Gustave Roussy in Villejuif, France, presented these results at the 19th Annual Congress of the European Hematology Association (EHA) as abstract LB2434.

Dr de Botton and his colleagues enrolled 35 patients who had a median age of 68 years (range, 48-81).

Twenty-seven patients had relapsed/refractory AML, 4 had relapsed/refractory MDS, 2 had untreated AML, 1 had CMML, and 1 had granulocytic sarcoma. Thirty-one patients had R140Q IDH2 mutations, and 4 had R172K IDH2 mutations.

The patients received AG-221 at 30 mg BID (n=7), 50 mg BID (n=7), 75 mg BID (n=6), 100 mg QD (n=5), 100 mg BID (n=5), or 150 mg QD (n=5). Patients completed a median of 1 cycle of treatment (range, <1-5+) and a mean of 2 cycles.

Safety data

“AG-221 was remarkable well-tolerated, and the [maximum tolerated dose] has not been reached,” Dr de Botton said. “The majority of adverse events were grade 1 and 2.”

Eighteen patients were evaluable for safety. AEs of all grades included nausea (n=4), pyrexia (n=4), thrombocytopenia (n=4), anemia (n=3), dizziness (n=3), febrile neutropenia (n=3), peripheral edema (n=3), sepsis (n=3), cough (n=2), diarrhea (n=2), fatigue (n=2), leukocytosis (n=2), neutropenia (n=2), petechiae (n=2), and rash (n=2).

Grade 3 or higher AEs included thrombocytopenia (n=3), anemia (n=1), febrile neutropenia (n=3), sepsis (n=3), diarrhea (n=1), fatigue (n=1), leukocytosis (n=2), neutropenia (n=1), and rash (n=1). Dr de Botton noted that diarrhea and rash were not expected events.

Four patients had serious AEs possibly related to treatment. One patient had grade 3 confusion and grade 5 respiratory failure. One patient had grade 3 leukocytosis, grade 3 anorexia, and grade 1 nausea. One patient had grade 3 diarrhea. And 1 patient had grade 3 leukocytosis.

Seven patients died within 30 days of study drug termination: 4 in the 30-mg cohort, 2 in the 50-mg cohort, and 1 in the 100-mg-BID cohort.

Five deaths were due to complications of disease-related sepsis (all in cycle 1), 1 complication of a humeral fracture, and 1 complication of a stroke.

Activity and response data

The researchers observed high AG-221 accumulation after multiple doses. And results were “really very similar” between the 30-mg-BID cohort and the 100-mg-QD cohort, Dr de Botton noted.

He also said AG-221 was “very efficient” at inhibiting 2-HG in the plasma. 2-HG was inhibited up to 100% in subjects with R140Q mutations and up to 60% in subjects with R172K mutations.

Twenty-five patients were evaluable for response. The remaining 10 patients did not have day-28 marrow assessments, either due to early termination (n=7) or receiving less than 28 days of treatment although they were still on the study (n=3).

In all, there were 6 complete responses (CRs), 2 CRs with incomplete platelet recovery (CRps), 1 CR with incomplete hematologic recovery (CRi), and 5 partial responses (PRs). Five patients had stable disease (SD), and 6 had progressive disease (PD).

The most responses occurred in the 50-mg group, which had 3 CRs, 1 CRi, and 1 PR. This was followed by the 30-mg group, which had 2 CRs, 1 CRp, and 1 PR.

“The majority of responses occurred in cycle 1,” Dr de Botton noted, “except in the first cohort [30 mg], where responses occurred late, at the end of cycle 3 and cycle 4.”

Twelve of the 14 responses are ongoing. Of the 8 patients who achieved a CR or CRp, 5 have lasted more than 2.5 months (range, 1-4+ months). And the 5 patients with SD remain on study.

This study is sponsored by Celgene Corporation and Agios Pharmaceuticals Inc., the companies developing AG-221.

Attendees at EHA 2014

Photo courtesy of EHA

MILAN—The IDH2 inhibitor AG-221 is well-tolerated and exhibits durable clinical activity in patients with hematologic disorders, results of a phase 1 study suggest.

The drug prompted responses in patients with myelodysplastic syndromes (MDS), acute myeloid leukemia (AML), or chronic myelomonocytic leukemia (CMML).

Fourteen of 25 patients achieved a response, and 12 of those responses are ongoing.

Most adverse events (AEs) were grade 1 or 2 in nature. However, 4 patients did have serious AEs that were possibly related to treatment.

Stéphane de Botton, MD, PhD, of Institut Gustave Roussy in Villejuif, France, presented these results at the 19th Annual Congress of the European Hematology Association (EHA) as abstract LB2434.

Dr de Botton and his colleagues enrolled 35 patients who had a median age of 68 years (range, 48-81).

Twenty-seven patients had relapsed/refractory AML, 4 had relapsed/refractory MDS, 2 had untreated AML, 1 had CMML, and 1 had granulocytic sarcoma. Thirty-one patients had R140Q IDH2 mutations, and 4 had R172K IDH2 mutations.

The patients received AG-221 at 30 mg BID (n=7), 50 mg BID (n=7), 75 mg BID (n=6), 100 mg QD (n=5), 100 mg BID (n=5), or 150 mg QD (n=5). Patients completed a median of 1 cycle of treatment (range, <1-5+) and a mean of 2 cycles.

Safety data

“AG-221 was remarkable well-tolerated, and the [maximum tolerated dose] has not been reached,” Dr de Botton said. “The majority of adverse events were grade 1 and 2.”

Eighteen patients were evaluable for safety. AEs of all grades included nausea (n=4), pyrexia (n=4), thrombocytopenia (n=4), anemia (n=3), dizziness (n=3), febrile neutropenia (n=3), peripheral edema (n=3), sepsis (n=3), cough (n=2), diarrhea (n=2), fatigue (n=2), leukocytosis (n=2), neutropenia (n=2), petechiae (n=2), and rash (n=2).

Grade 3 or higher AEs included thrombocytopenia (n=3), anemia (n=1), febrile neutropenia (n=3), sepsis (n=3), diarrhea (n=1), fatigue (n=1), leukocytosis (n=2), neutropenia (n=1), and rash (n=1). Dr de Botton noted that diarrhea and rash were not expected events.

Four patients had serious AEs possibly related to treatment. One patient had grade 3 confusion and grade 5 respiratory failure. One patient had grade 3 leukocytosis, grade 3 anorexia, and grade 1 nausea. One patient had grade 3 diarrhea. And 1 patient had grade 3 leukocytosis.

Seven patients died within 30 days of study drug termination: 4 in the 30-mg cohort, 2 in the 50-mg cohort, and 1 in the 100-mg-BID cohort.

Five deaths were due to complications of disease-related sepsis (all in cycle 1), 1 complication of a humeral fracture, and 1 complication of a stroke.

Activity and response data

The researchers observed high AG-221 accumulation after multiple doses. And results were “really very similar” between the 30-mg-BID cohort and the 100-mg-QD cohort, Dr de Botton noted.

He also said AG-221 was “very efficient” at inhibiting 2-HG in the plasma. 2-HG was inhibited up to 100% in subjects with R140Q mutations and up to 60% in subjects with R172K mutations.

Twenty-five patients were evaluable for response. The remaining 10 patients did not have day-28 marrow assessments, either due to early termination (n=7) or receiving less than 28 days of treatment although they were still on the study (n=3).

In all, there were 6 complete responses (CRs), 2 CRs with incomplete platelet recovery (CRps), 1 CR with incomplete hematologic recovery (CRi), and 5 partial responses (PRs). Five patients had stable disease (SD), and 6 had progressive disease (PD).

The most responses occurred in the 50-mg group, which had 3 CRs, 1 CRi, and 1 PR. This was followed by the 30-mg group, which had 2 CRs, 1 CRp, and 1 PR.

“The majority of responses occurred in cycle 1,” Dr de Botton noted, “except in the first cohort [30 mg], where responses occurred late, at the end of cycle 3 and cycle 4.”

Twelve of the 14 responses are ongoing. Of the 8 patients who achieved a CR or CRp, 5 have lasted more than 2.5 months (range, 1-4+ months). And the 5 patients with SD remain on study.

This study is sponsored by Celgene Corporation and Agios Pharmaceuticals Inc., the companies developing AG-221.

Researchers in the lab

Credit: Rhoda Baer

Researchers tested 5 anti-leukemia agents in combination with the methylation inhibitor decitabine and found that the sequential combination of decitabine and idarubicin worked synergistically to produce anti-leukemia effects.

The combination induced cell death in U937, HEL, and SKM-1 human cell lines and acute myeloid leukemia (AML) cells isolated from patients.

The researchers attributed the effects to demethylation of the Wnt/β-catenin pathway inhibitors and downregulation of the Wnt/β-catenin pathway nuclear targets.

The researchers noted that decitabine monotherapy has resulted in relatively low complete remission rates in AML and myelodysplastic syndromes (MDS). So they undertook to investigate combination therapies that would potentially improve efficacy.

Hongyan Tong, PhD, of Zhejiang University School of Medicine in Hangzhou, China, and colleagues reported their findings in the Journal of Translational Medicine.

The researchers chose 5 agents to combine, either simultaneously or sequentially, with decitabine—idarubicin, daunorubicin, aclarubicin, thalidomide, and homoharringtonine—and analyzed their effect on leukemia proliferation in the various AML cell lines mentioned above.

Using the U937 cell line first, the researchers found that when decitabine was combined simulataneously or sequentially with homharringtonine, aclarubicin, thalidomide, and daunorubicin, there was no synergistic effect. The confidence interval (CI) values of various doses were almost all over 0.8.

This was also true for the simultaneous combination of decitabine with idarubicin.

However, when they combined decitabine sequentially with idarubicin, the CI values on all 5 doses were under 0.8, indicating synergism.

In addition, when they administered decitabine twice in the sequence, the CI values were lower than a single administration.

They then confirmed the results in other AML cell lines (HEL and SKM-1) and in cells from AML patients.

Next, they confirmed the synergism of the sequential combination of decitabine and idarubicin in an AML mouse model and found that the combination inhibited tumor growth.

Tumor growth was inhibited significantly on days 4 (P<0.01), days 6 -16 (P<0.001), and started to wane by day 18 (P<0.05) after treatment.

The investigators determined that apoptosis was responsible for the combination’s decrease in leukemic cell viability. The apoptosis rates with the combination therapy were significantly increased in the U937, HEL, and SKM-1 cell lines compared with controls, (all P< 0.001).

In addition, the researchers observed that the tumor cells after treatment showed typical apoptosis characteristics, such as the absence of microvilli on cell membrane, nuclear and cell membrane blebbing, chromosome condensation, and the formation of apoptotic bodies.

The investigators used microarray expression to ascertain the differential gene expression profile of decitabine and idarubicin and found that the Wnt pathway was one of the major pathways disturbed.

Sequential treatment significantly upregulated the Wnt antagonist genes SFRP1, HDPR1, and DKK3. This in turn resulted in increased expression of these genes at the mRNA and protein levels.

In addition, treatment with idarubicin after decitabine caused significant down regulation of the expression of c-Myc, β-catenin, and cyclinD1 genes compared to treatment with decitabine or idarubicin alone.

The investigators concluded that the findings suggest clinical potential in sequential administration of decitabine and idarubicin in AML and high-risk MDS.

Researchers in the lab

Credit: Rhoda Baer

Researchers tested 5 anti-leukemia agents in combination with the methylation inhibitor decitabine and found that the sequential combination of decitabine and idarubicin worked synergistically to produce anti-leukemia effects.

The combination induced cell death in U937, HEL, and SKM-1 human cell lines and acute myeloid leukemia (AML) cells isolated from patients.

The researchers attributed the effects to demethylation of the Wnt/β-catenin pathway inhibitors and downregulation of the Wnt/β-catenin pathway nuclear targets.

The researchers noted that decitabine monotherapy has resulted in relatively low complete remission rates in AML and myelodysplastic syndromes (MDS). So they undertook to investigate combination therapies that would potentially improve efficacy.

Hongyan Tong, PhD, of Zhejiang University School of Medicine in Hangzhou, China, and colleagues reported their findings in the Journal of Translational Medicine.

The researchers chose 5 agents to combine, either simultaneously or sequentially, with decitabine—idarubicin, daunorubicin, aclarubicin, thalidomide, and homoharringtonine—and analyzed their effect on leukemia proliferation in the various AML cell lines mentioned above.

Using the U937 cell line first, the researchers found that when decitabine was combined simulataneously or sequentially with homharringtonine, aclarubicin, thalidomide, and daunorubicin, there was no synergistic effect. The confidence interval (CI) values of various doses were almost all over 0.8.

This was also true for the simultaneous combination of decitabine with idarubicin.

However, when they combined decitabine sequentially with idarubicin, the CI values on all 5 doses were under 0.8, indicating synergism.

In addition, when they administered decitabine twice in the sequence, the CI values were lower than a single administration.

They then confirmed the results in other AML cell lines (HEL and SKM-1) and in cells from AML patients.

Next, they confirmed the synergism of the sequential combination of decitabine and idarubicin in an AML mouse model and found that the combination inhibited tumor growth.

Tumor growth was inhibited significantly on days 4 (P<0.01), days 6 -16 (P<0.001), and started to wane by day 18 (P<0.05) after treatment.

The investigators determined that apoptosis was responsible for the combination’s decrease in leukemic cell viability. The apoptosis rates with the combination therapy were significantly increased in the U937, HEL, and SKM-1 cell lines compared with controls, (all P< 0.001).

In addition, the researchers observed that the tumor cells after treatment showed typical apoptosis characteristics, such as the absence of microvilli on cell membrane, nuclear and cell membrane blebbing, chromosome condensation, and the formation of apoptotic bodies.

The investigators used microarray expression to ascertain the differential gene expression profile of decitabine and idarubicin and found that the Wnt pathway was one of the major pathways disturbed.

Sequential treatment significantly upregulated the Wnt antagonist genes SFRP1, HDPR1, and DKK3. This in turn resulted in increased expression of these genes at the mRNA and protein levels.

In addition, treatment with idarubicin after decitabine caused significant down regulation of the expression of c-Myc, β-catenin, and cyclinD1 genes compared to treatment with decitabine or idarubicin alone.

The investigators concluded that the findings suggest clinical potential in sequential administration of decitabine and idarubicin in AML and high-risk MDS.

Researchers in the lab

Credit: Rhoda Baer

Researchers tested 5 anti-leukemia agents in combination with the methylation inhibitor decitabine and found that the sequential combination of decitabine and idarubicin worked synergistically to produce anti-leukemia effects.

The combination induced cell death in U937, HEL, and SKM-1 human cell lines and acute myeloid leukemia (AML) cells isolated from patients.

The researchers attributed the effects to demethylation of the Wnt/β-catenin pathway inhibitors and downregulation of the Wnt/β-catenin pathway nuclear targets.

The researchers noted that decitabine monotherapy has resulted in relatively low complete remission rates in AML and myelodysplastic syndromes (MDS). So they undertook to investigate combination therapies that would potentially improve efficacy.

Hongyan Tong, PhD, of Zhejiang University School of Medicine in Hangzhou, China, and colleagues reported their findings in the Journal of Translational Medicine.

The researchers chose 5 agents to combine, either simultaneously or sequentially, with decitabine—idarubicin, daunorubicin, aclarubicin, thalidomide, and homoharringtonine—and analyzed their effect on leukemia proliferation in the various AML cell lines mentioned above.

Using the U937 cell line first, the researchers found that when decitabine was combined simulataneously or sequentially with homharringtonine, aclarubicin, thalidomide, and daunorubicin, there was no synergistic effect. The confidence interval (CI) values of various doses were almost all over 0.8.

This was also true for the simultaneous combination of decitabine with idarubicin.

However, when they combined decitabine sequentially with idarubicin, the CI values on all 5 doses were under 0.8, indicating synergism.

In addition, when they administered decitabine twice in the sequence, the CI values were lower than a single administration.

They then confirmed the results in other AML cell lines (HEL and SKM-1) and in cells from AML patients.

Next, they confirmed the synergism of the sequential combination of decitabine and idarubicin in an AML mouse model and found that the combination inhibited tumor growth.

Tumor growth was inhibited significantly on days 4 (P<0.01), days 6 -16 (P<0.001), and started to wane by day 18 (P<0.05) after treatment.

The investigators determined that apoptosis was responsible for the combination’s decrease in leukemic cell viability. The apoptosis rates with the combination therapy were significantly increased in the U937, HEL, and SKM-1 cell lines compared with controls, (all P< 0.001).

In addition, the researchers observed that the tumor cells after treatment showed typical apoptosis characteristics, such as the absence of microvilli on cell membrane, nuclear and cell membrane blebbing, chromosome condensation, and the formation of apoptotic bodies.

The investigators used microarray expression to ascertain the differential gene expression profile of decitabine and idarubicin and found that the Wnt pathway was one of the major pathways disturbed.

Sequential treatment significantly upregulated the Wnt antagonist genes SFRP1, HDPR1, and DKK3. This in turn resulted in increased expression of these genes at the mRNA and protein levels.

In addition, treatment with idarubicin after decitabine caused significant down regulation of the expression of c-Myc, β-catenin, and cyclinD1 genes compared to treatment with decitabine or idarubicin alone.

The investigators concluded that the findings suggest clinical potential in sequential administration of decitabine and idarubicin in AML and high-risk MDS.

Micrograph showing AML cells

Credit: Lance Liotta

New research has revealed a mechanism of drug resistance in acute myeloid leukemia (AML) that may also occur in other cancers.

Investigators found evidence suggesting that glioma-associated protein 1 (GLI1) and the UDP glucuronosyltransferase (UGT1A) family of enzymes drive resistance to 2 drugs—ribavirin and cytarabine—in AML.

But the researchers were able to overcome this resistance by genetic or pharmacologic inhibition of GLI1.

They described this research in a letter to Nature.

“By studying drug-resistant cancer cells from AML patients and head and neck tumors, we found that a gene called GLI1 is dramatically overactive in these cells,” said study author Hiba Zahreddine, a doctoral student at the University of Montreal in Canada.

“[W[e were then able to show that this results in a specific chemical change to the drugs that prevents their toxicity toward the cancer cells,” said author Kathy Borden, PhD, of the University of Montreal’s Institute for Research in Immunology and Cancer.

Specifically, the investigators found that UGT1A enzymes add glucuronic acid to the drugs, thereby modifying their activity. And GLI1 alone is sufficient to drive UGT1A-dependent glucuronidation of ribavirin and cytarabine, which fuels drug resistance.

Fortunately, the researchers found that inhibiting GLI1, either genetically or with pharmacologic inhibitors, could force cancer cells to revert to a treatment-sensitive state.

The team therefore hopes that using GLI1 inhibitors in combination with ribavirin, cytarabine, or other therapies can overcome treatment resistance in patients with AML. The investigators have received approval from Health Canada to conduct a new clinical trial to test this theory.

“If this new approach is successful, it could have very broad applications, since the mode of action of ribavirin suggests that it could be effective against up to 30% of all cancers, including some types of breast, prostate, colon, stomach, and head and neck cancers, in addition to AML,” said Morris Goodman, co-founder and Chairman of the Board of Pharmascience Inc., the company that manufactured the ribavirin for this research.

Micrograph showing AML cells

Credit: Lance Liotta

New research has revealed a mechanism of drug resistance in acute myeloid leukemia (AML) that may also occur in other cancers.

Investigators found evidence suggesting that glioma-associated protein 1 (GLI1) and the UDP glucuronosyltransferase (UGT1A) family of enzymes drive resistance to 2 drugs—ribavirin and cytarabine—in AML.

But the researchers were able to overcome this resistance by genetic or pharmacologic inhibition of GLI1.

They described this research in a letter to Nature.

“By studying drug-resistant cancer cells from AML patients and head and neck tumors, we found that a gene called GLI1 is dramatically overactive in these cells,” said study author Hiba Zahreddine, a doctoral student at the University of Montreal in Canada.

“[W[e were then able to show that this results in a specific chemical change to the drugs that prevents their toxicity toward the cancer cells,” said author Kathy Borden, PhD, of the University of Montreal’s Institute for Research in Immunology and Cancer.

Specifically, the investigators found that UGT1A enzymes add glucuronic acid to the drugs, thereby modifying their activity. And GLI1 alone is sufficient to drive UGT1A-dependent glucuronidation of ribavirin and cytarabine, which fuels drug resistance.

Fortunately, the researchers found that inhibiting GLI1, either genetically or with pharmacologic inhibitors, could force cancer cells to revert to a treatment-sensitive state.

The team therefore hopes that using GLI1 inhibitors in combination with ribavirin, cytarabine, or other therapies can overcome treatment resistance in patients with AML. The investigators have received approval from Health Canada to conduct a new clinical trial to test this theory.

“If this new approach is successful, it could have very broad applications, since the mode of action of ribavirin suggests that it could be effective against up to 30% of all cancers, including some types of breast, prostate, colon, stomach, and head and neck cancers, in addition to AML,” said Morris Goodman, co-founder and Chairman of the Board of Pharmascience Inc., the company that manufactured the ribavirin for this research.

Micrograph showing AML cells

Credit: Lance Liotta

New research has revealed a mechanism of drug resistance in acute myeloid leukemia (AML) that may also occur in other cancers.

Investigators found evidence suggesting that glioma-associated protein 1 (GLI1) and the UDP glucuronosyltransferase (UGT1A) family of enzymes drive resistance to 2 drugs—ribavirin and cytarabine—in AML.

But the researchers were able to overcome this resistance by genetic or pharmacologic inhibition of GLI1.

They described this research in a letter to Nature.

“By studying drug-resistant cancer cells from AML patients and head and neck tumors, we found that a gene called GLI1 is dramatically overactive in these cells,” said study author Hiba Zahreddine, a doctoral student at the University of Montreal in Canada.

“[W[e were then able to show that this results in a specific chemical change to the drugs that prevents their toxicity toward the cancer cells,” said author Kathy Borden, PhD, of the University of Montreal’s Institute for Research in Immunology and Cancer.

Specifically, the investigators found that UGT1A enzymes add glucuronic acid to the drugs, thereby modifying their activity. And GLI1 alone is sufficient to drive UGT1A-dependent glucuronidation of ribavirin and cytarabine, which fuels drug resistance.

Fortunately, the researchers found that inhibiting GLI1, either genetically or with pharmacologic inhibitors, could force cancer cells to revert to a treatment-sensitive state.

The team therefore hopes that using GLI1 inhibitors in combination with ribavirin, cytarabine, or other therapies can overcome treatment resistance in patients with AML. The investigators have received approval from Health Canada to conduct a new clinical trial to test this theory.

“If this new approach is successful, it could have very broad applications, since the mode of action of ribavirin suggests that it could be effective against up to 30% of all cancers, including some types of breast, prostate, colon, stomach, and head and neck cancers, in addition to AML,” said Morris Goodman, co-founder and Chairman of the Board of Pharmascience Inc., the company that manufactured the ribavirin for this research.

Micrograph showing AML

The US Food and Drug Administration (FDA) has granted selinexor (KPT-330) orphan designation for the treatment of acute myeloid leukemia (AML).

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 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.

Promising early results

Selinexor has shown promising results in a phase 1 trial of older patients with relapsed or refractory AML. The study, which was sponsored by Karyopharm, was published in Blood.

Researchers enrolled 16 patients with relapsed or refractory AML. The median age was 71 years, and the median number of prior therapeutic regimens was 2.

Patients received 8 to 10 doses of selinexor on a 4-week cycle across 2 dose levels, 16.8 mg/m² to 23 mg/m² (with additional cohorts ongoing).

The researchers reported no dose-limiting toxicity, no clinically significant cumulative toxicities, and no major organ dysfunction.

However, 4 patients experienced drug-related grade 3/4 adverse events, including hypotension (n=1), increased AST (n=1), hypokalemia (n=1), nausea (n=1), headache (n=1), and fatigue (n=1).

The most common grade 1/2 toxicities were nausea (9/17; 53%), anorexia (8/17; 47%), vomiting (6/17; 35%), fatigue (5/17; 29%), weight loss (5/17; 29%), and diarrhea (3/17; 18%). But these events were manageable.

Fourteen of the patients were evaluable for response. Two (14%) achieved a complete response with full hematologic recovery, and 2 (14%) achieved a complete response without hematologic recovery. Four patients (29%) had stable disease for more than 30 days, and 6 (43%) experienced progression.

Other trials of selinexor in AML

Karyopharm’s development plans for selinexor in AML include a number of additional studies.

In a phase 2 trial, researchers will evaluate selinexor monotherapy in older patients with AML. The study will enroll patients 60 years of age or older with relapsed or refractory AML who are ineligible for intensive chemotherapy and/or transplant.

In another study, researchers will evaluate selinexor in combination with decitabine for patients with relapsed, refractory, or newly diagnosed AML. The study will enroll up to 42 patients aged 60 or older who are ineligible for intensive chemotherapy.

Lastly, researchers are planning a study of selinexor in pediatric leukemia patients. The goal of this study is to determine the oral dosing, toxicity, and preliminary clinical activity of selinexor in pediatric patients. It will enroll up to 28 children with relapsed or refractory AML or acute lymphoblastic leukemia.

Micrograph showing AML

The US Food and Drug Administration (FDA) has granted selinexor (KPT-330) orphan designation for the treatment of acute myeloid leukemia (AML).

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 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.

Promising early results

Selinexor has shown promising results in a phase 1 trial of older patients with relapsed or refractory AML. The study, which was sponsored by Karyopharm, was published in Blood.

Researchers enrolled 16 patients with relapsed or refractory AML. The median age was 71 years, and the median number of prior therapeutic regimens was 2.

Patients received 8 to 10 doses of selinexor on a 4-week cycle across 2 dose levels, 16.8 mg/m² to 23 mg/m² (with additional cohorts ongoing).

The researchers reported no dose-limiting toxicity, no clinically significant cumulative toxicities, and no major organ dysfunction.

However, 4 patients experienced drug-related grade 3/4 adverse events, including hypotension (n=1), increased AST (n=1), hypokalemia (n=1), nausea (n=1), headache (n=1), and fatigue (n=1).

The most common grade 1/2 toxicities were nausea (9/17; 53%), anorexia (8/17; 47%), vomiting (6/17; 35%), fatigue (5/17; 29%), weight loss (5/17; 29%), and diarrhea (3/17; 18%). But these events were manageable.

Fourteen of the patients were evaluable for response. Two (14%) achieved a complete response with full hematologic recovery, and 2 (14%) achieved a complete response without hematologic recovery. Four patients (29%) had stable disease for more than 30 days, and 6 (43%) experienced progression.

Other trials of selinexor in AML

Karyopharm’s development plans for selinexor in AML include a number of additional studies.

In a phase 2 trial, researchers will evaluate selinexor monotherapy in older patients with AML. The study will enroll patients 60 years of age or older with relapsed or refractory AML who are ineligible for intensive chemotherapy and/or transplant.

In another study, researchers will evaluate selinexor in combination with decitabine for patients with relapsed, refractory, or newly diagnosed AML. The study will enroll up to 42 patients aged 60 or older who are ineligible for intensive chemotherapy.

Lastly, researchers are planning a study of selinexor in pediatric leukemia patients. The goal of this study is to determine the oral dosing, toxicity, and preliminary clinical activity of selinexor in pediatric patients. It will enroll up to 28 children with relapsed or refractory AML or acute lymphoblastic leukemia.

Micrograph showing AML

The US Food and Drug Administration (FDA) has granted selinexor (KPT-330) orphan designation for the treatment of acute myeloid leukemia (AML).

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 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.

Promising early results

Selinexor has shown promising results in a phase 1 trial of older patients with relapsed or refractory AML. The study, which was sponsored by Karyopharm, was published in Blood.

Researchers enrolled 16 patients with relapsed or refractory AML. The median age was 71 years, and the median number of prior therapeutic regimens was 2.

Patients received 8 to 10 doses of selinexor on a 4-week cycle across 2 dose levels, 16.8 mg/m² to 23 mg/m² (with additional cohorts ongoing).

The researchers reported no dose-limiting toxicity, no clinically significant cumulative toxicities, and no major organ dysfunction.

However, 4 patients experienced drug-related grade 3/4 adverse events, including hypotension (n=1), increased AST (n=1), hypokalemia (n=1), nausea (n=1), headache (n=1), and fatigue (n=1).

The most common grade 1/2 toxicities were nausea (9/17; 53%), anorexia (8/17; 47%), vomiting (6/17; 35%), fatigue (5/17; 29%), weight loss (5/17; 29%), and diarrhea (3/17; 18%). But these events were manageable.

Fourteen of the patients were evaluable for response. Two (14%) achieved a complete response with full hematologic recovery, and 2 (14%) achieved a complete response without hematologic recovery. Four patients (29%) had stable disease for more than 30 days, and 6 (43%) experienced progression.

Other trials of selinexor in AML

Karyopharm’s development plans for selinexor in AML include a number of additional studies.

In a phase 2 trial, researchers will evaluate selinexor monotherapy in older patients with AML. The study will enroll patients 60 years of age or older with relapsed or refractory AML who are ineligible for intensive chemotherapy and/or transplant.

In another study, researchers will evaluate selinexor in combination with decitabine for patients with relapsed, refractory, or newly diagnosed AML. The study will enroll up to 42 patients aged 60 or older who are ineligible for intensive chemotherapy.

Lastly, researchers are planning a study of selinexor in pediatric leukemia patients. The goal of this study is to determine the oral dosing, toxicity, and preliminary clinical activity of selinexor in pediatric patients. It will enroll up to 28 children with relapsed or refractory AML or acute lymphoblastic leukemia.