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Doc laments increasing use of P values
Photo by Rhoda Baer
A review of the biomedical literature indicates an increase in the use of P values in recent years, but researchers say this technique can provide misleading results.
“It’s usually a suboptimal technique, and then it’s used in a biased way, so it can become very misleading,” said John Ioannidis, MD, of Stanford University in California.
He and his colleagues reviewed the use of P values and recounted their findings in JAMA.
The team used automated text-mining analysis to extract data on P values reported in 12,821,790 MEDLINE abstracts and 843,884 abstracts and full-text articles in PubMed Central from 1990 to 2015.
The researchers also assessed the reporting of P values in 151 English-language core clinical journals and specific article types as classified by PubMed.
They manually evaluated a random sample of 1000 MEDLINE abstracts for reporting of P values and other types of statistical information. And of those abstracts reporting empirical data, 100 articles were assessed in their entirety.
The data showed that reporting of P values more than doubled from 1990 to 2014—increasing from 7.3% to 15.6%.
In abstracts from core medical journals, 33% reported P values in 2014. And in the subset of randomized, controlled clinical trials, nearly 55% reported P values in 2014.
Dr Ioannidis noted that some researchers mistakenly think a P value is an estimate of how likely it is that a result is true.
“The P value does not tell you whether something is true,” he explained. “If you get a P value of 0.01, it doesn’t mean you have a 1% chance of something not being true.”
“A P value of 0.01 could mean the result is 20% likely to be true, 80% likely to be true, or 0.1% likely to be true—all with the same P value. The P value alone doesn’t tell you how true your result is.”
For an actual estimate of how likely a result is to be true or false, Dr Ioannidis said, researchers should instead use false-discovery rates or Bayes factor calculations.
He and his colleagues assessed the use of false-discovery rates, Bayes factor calculations, effect sizes, and confidence intervals in the 796 papers in their review that contained empirical data.
They found that 111 of these papers reported effect sizes, and 18 reported confidence intervals. None of the papers reported Bayes factors or false-discovery rates.
Fewer than 2% of the abstracts the team reviewed reported both an effect size and a confidence interval.
In a manual review of 99 randomly selected full-text articles, the researchers found that 55 articles reported at least 1 P value. But only 4 articles reported confidence intervals for all effect sizes, none used Bayesian methods, and 1 used false-discovery rates.
In light of these findings, Dr Ioannidis advocates more stringent approaches to analyzing data.
“The way to move forward is that P values need to be used more selectively,” he said. “When used, they need to be complemented by effect sizes and uncertainty [confidence intervals]. And it would often be a good idea to use a Bayesian approach or a false-discovery rate to answer the question, ‘How likely is this result to be true?’” 
Photo by Rhoda Baer
A review of the biomedical literature indicates an increase in the use of P values in recent years, but researchers say this technique can provide misleading results.
“It’s usually a suboptimal technique, and then it’s used in a biased way, so it can become very misleading,” said John Ioannidis, MD, of Stanford University in California.
He and his colleagues reviewed the use of P values and recounted their findings in JAMA.
The team used automated text-mining analysis to extract data on P values reported in 12,821,790 MEDLINE abstracts and 843,884 abstracts and full-text articles in PubMed Central from 1990 to 2015.
The researchers also assessed the reporting of P values in 151 English-language core clinical journals and specific article types as classified by PubMed.
They manually evaluated a random sample of 1000 MEDLINE abstracts for reporting of P values and other types of statistical information. And of those abstracts reporting empirical data, 100 articles were assessed in their entirety.
The data showed that reporting of P values more than doubled from 1990 to 2014—increasing from 7.3% to 15.6%.
In abstracts from core medical journals, 33% reported P values in 2014. And in the subset of randomized, controlled clinical trials, nearly 55% reported P values in 2014.
Dr Ioannidis noted that some researchers mistakenly think a P value is an estimate of how likely it is that a result is true.
“The P value does not tell you whether something is true,” he explained. “If you get a P value of 0.01, it doesn’t mean you have a 1% chance of something not being true.”
“A P value of 0.01 could mean the result is 20% likely to be true, 80% likely to be true, or 0.1% likely to be true—all with the same P value. The P value alone doesn’t tell you how true your result is.”
For an actual estimate of how likely a result is to be true or false, Dr Ioannidis said, researchers should instead use false-discovery rates or Bayes factor calculations.
He and his colleagues assessed the use of false-discovery rates, Bayes factor calculations, effect sizes, and confidence intervals in the 796 papers in their review that contained empirical data.
They found that 111 of these papers reported effect sizes, and 18 reported confidence intervals. None of the papers reported Bayes factors or false-discovery rates.
Fewer than 2% of the abstracts the team reviewed reported both an effect size and a confidence interval.
In a manual review of 99 randomly selected full-text articles, the researchers found that 55 articles reported at least 1 P value. But only 4 articles reported confidence intervals for all effect sizes, none used Bayesian methods, and 1 used false-discovery rates.
In light of these findings, Dr Ioannidis advocates more stringent approaches to analyzing data.
“The way to move forward is that P values need to be used more selectively,” he said. “When used, they need to be complemented by effect sizes and uncertainty [confidence intervals]. And it would often be a good idea to use a Bayesian approach or a false-discovery rate to answer the question, ‘How likely is this result to be true?’”
Photo by Rhoda Baer
A review of the biomedical literature indicates an increase in the use of P values in recent years, but researchers say this technique can provide misleading results.
“It’s usually a suboptimal technique, and then it’s used in a biased way, so it can become very misleading,” said John Ioannidis, MD, of Stanford University in California.
He and his colleagues reviewed the use of P values and recounted their findings in JAMA.
The team used automated text-mining analysis to extract data on P values reported in 12,821,790 MEDLINE abstracts and 843,884 abstracts and full-text articles in PubMed Central from 1990 to 2015.
The researchers also assessed the reporting of P values in 151 English-language core clinical journals and specific article types as classified by PubMed.
They manually evaluated a random sample of 1000 MEDLINE abstracts for reporting of P values and other types of statistical information. And of those abstracts reporting empirical data, 100 articles were assessed in their entirety.
The data showed that reporting of P values more than doubled from 1990 to 2014—increasing from 7.3% to 15.6%.
In abstracts from core medical journals, 33% reported P values in 2014. And in the subset of randomized, controlled clinical trials, nearly 55% reported P values in 2014.
Dr Ioannidis noted that some researchers mistakenly think a P value is an estimate of how likely it is that a result is true.
“The P value does not tell you whether something is true,” he explained. “If you get a P value of 0.01, it doesn’t mean you have a 1% chance of something not being true.”
“A P value of 0.01 could mean the result is 20% likely to be true, 80% likely to be true, or 0.1% likely to be true—all with the same P value. The P value alone doesn’t tell you how true your result is.”
For an actual estimate of how likely a result is to be true or false, Dr Ioannidis said, researchers should instead use false-discovery rates or Bayes factor calculations.
He and his colleagues assessed the use of false-discovery rates, Bayes factor calculations, effect sizes, and confidence intervals in the 796 papers in their review that contained empirical data.
They found that 111 of these papers reported effect sizes, and 18 reported confidence intervals. None of the papers reported Bayes factors or false-discovery rates.
Fewer than 2% of the abstracts the team reviewed reported both an effect size and a confidence interval.
In a manual review of 99 randomly selected full-text articles, the researchers found that 55 articles reported at least 1 P value. But only 4 articles reported confidence intervals for all effect sizes, none used Bayesian methods, and 1 used false-discovery rates.
In light of these findings, Dr Ioannidis advocates more stringent approaches to analyzing data.
“The way to move forward is that P values need to be used more selectively,” he said. “When used, they need to be complemented by effect sizes and uncertainty [confidence intervals]. And it would often be a good idea to use a Bayesian approach or a false-discovery rate to answer the question, ‘How likely is this result to be true?’”
Protein plays key role in B-ALL subtype
An RNA binding protein promotes the development of MLL-rearranged B-cell acute lymphoblastic leukemia (B-ALL), according to research published in The Journal of Clinical Investigation.
Researchers found an overabundance of the protein, IGF2BP3, in MLL-rearranged B-ALL.
They also identified genes that are directly regulated by IFG2BP3, and many of them turned out to be oncogenes that have already been implicated in cancers.
The overall effect of IFG2BP3 in MLL-rearranged B-ALL is to promote the proliferation of B cells by shifting the expression of a large number of genes, explained study author Jeremy Sanford, PhD, of the University of California Santa Cruz.
“This protein, IFG2BP3, has been correlated with many types of malignancies and with the worst prognoses,” he noted. “What is exciting about this study is that it goes beyond correlation and shows causation, because we demonstrated, for the first time, that aberrant expression of this protein is sufficient to induce pathology.”
This research began in the lab of Dinesh Rao, PhD, an assistant professor at the University of California Los Angeles who was studying MLL-rearranged B-ALL.
After researchers in Dr Rao’s lab identified IGF2BP3 as one of the top dysregulated genes in this malignancy, they began working with Dr Sanford’s lab to figure out which genes were being directly regulated by IGF2BP3.
Dr Sanford’s lab was among the few using individual nucleotide resolution crosslinking immunoprecipitation (iCLIP), a technique that can capture RNA molecules bound to a particular protein.
iCLIP enabled the researchers to identify IGF2BP3 binding sites in several hundred RNA transcripts in 2 B-ALL cell lines.
The work also revealed that IGF2BP3 enhanced the expression of MYC and other oncogenes in hematopoietic stem cells.
In experiments with mice, the researchers found that overexpression of IGF2BP3 in the bone marrow leads to proliferation of hematopoietic stem cells and B-cell progenitors, reproducing some features of MLL-rearranged B-ALL.
“Understanding its mechanism of action is important for thinking about therapeutics that might interfere with the action of this protein in disease,” Dr Sanford said.
“One possibility is an RNA-based therapeutic that could sequester the protein and keep it from binding to RNA transcripts. That would be a way to influence the expression of many genes involved in the proliferation of cancer cells.”
An RNA binding protein promotes the development of MLL-rearranged B-cell acute lymphoblastic leukemia (B-ALL), according to research published in The Journal of Clinical Investigation.
Researchers found an overabundance of the protein, IGF2BP3, in MLL-rearranged B-ALL.
They also identified genes that are directly regulated by IFG2BP3, and many of them turned out to be oncogenes that have already been implicated in cancers.
The overall effect of IFG2BP3 in MLL-rearranged B-ALL is to promote the proliferation of B cells by shifting the expression of a large number of genes, explained study author Jeremy Sanford, PhD, of the University of California Santa Cruz.
“This protein, IFG2BP3, has been correlated with many types of malignancies and with the worst prognoses,” he noted. “What is exciting about this study is that it goes beyond correlation and shows causation, because we demonstrated, for the first time, that aberrant expression of this protein is sufficient to induce pathology.”
This research began in the lab of Dinesh Rao, PhD, an assistant professor at the University of California Los Angeles who was studying MLL-rearranged B-ALL.
After researchers in Dr Rao’s lab identified IGF2BP3 as one of the top dysregulated genes in this malignancy, they began working with Dr Sanford’s lab to figure out which genes were being directly regulated by IGF2BP3.
Dr Sanford’s lab was among the few using individual nucleotide resolution crosslinking immunoprecipitation (iCLIP), a technique that can capture RNA molecules bound to a particular protein.
iCLIP enabled the researchers to identify IGF2BP3 binding sites in several hundred RNA transcripts in 2 B-ALL cell lines.
The work also revealed that IGF2BP3 enhanced the expression of MYC and other oncogenes in hematopoietic stem cells.
In experiments with mice, the researchers found that overexpression of IGF2BP3 in the bone marrow leads to proliferation of hematopoietic stem cells and B-cell progenitors, reproducing some features of MLL-rearranged B-ALL.
“Understanding its mechanism of action is important for thinking about therapeutics that might interfere with the action of this protein in disease,” Dr Sanford said.
“One possibility is an RNA-based therapeutic that could sequester the protein and keep it from binding to RNA transcripts. That would be a way to influence the expression of many genes involved in the proliferation of cancer cells.”
An RNA binding protein promotes the development of MLL-rearranged B-cell acute lymphoblastic leukemia (B-ALL), according to research published in The Journal of Clinical Investigation.
Researchers found an overabundance of the protein, IGF2BP3, in MLL-rearranged B-ALL.
They also identified genes that are directly regulated by IFG2BP3, and many of them turned out to be oncogenes that have already been implicated in cancers.
The overall effect of IFG2BP3 in MLL-rearranged B-ALL is to promote the proliferation of B cells by shifting the expression of a large number of genes, explained study author Jeremy Sanford, PhD, of the University of California Santa Cruz.
“This protein, IFG2BP3, has been correlated with many types of malignancies and with the worst prognoses,” he noted. “What is exciting about this study is that it goes beyond correlation and shows causation, because we demonstrated, for the first time, that aberrant expression of this protein is sufficient to induce pathology.”
This research began in the lab of Dinesh Rao, PhD, an assistant professor at the University of California Los Angeles who was studying MLL-rearranged B-ALL.
After researchers in Dr Rao’s lab identified IGF2BP3 as one of the top dysregulated genes in this malignancy, they began working with Dr Sanford’s lab to figure out which genes were being directly regulated by IGF2BP3.
Dr Sanford’s lab was among the few using individual nucleotide resolution crosslinking immunoprecipitation (iCLIP), a technique that can capture RNA molecules bound to a particular protein.
iCLIP enabled the researchers to identify IGF2BP3 binding sites in several hundred RNA transcripts in 2 B-ALL cell lines.
The work also revealed that IGF2BP3 enhanced the expression of MYC and other oncogenes in hematopoietic stem cells.
In experiments with mice, the researchers found that overexpression of IGF2BP3 in the bone marrow leads to proliferation of hematopoietic stem cells and B-cell progenitors, reproducing some features of MLL-rearranged B-ALL.
“Understanding its mechanism of action is important for thinking about therapeutics that might interfere with the action of this protein in disease,” Dr Sanford said.
“One possibility is an RNA-based therapeutic that could sequester the protein and keep it from binding to RNA transcripts. That would be a way to influence the expression of many genes involved in the proliferation of cancer cells.”
Idelalisib trials stopped due to AEs
Photo courtesy of
Gilead Sciences
The US Food and Drug Administration (FDA) has reported that Gilead Sciences, Inc., is stopping 6 clinical trials of idelalisib (Zydelig) due to adverse events (AEs) observed in patients receiving idelalisib in combination with other drugs.
The AEs, which include deaths, were mostly related to infections.
The trials include patients with chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma, and indolent non-Hodgkin lymphomas.
The FDA said it is reviewing the findings of these trials and will communicate new information as necessary.
A few days ago, the European Medicines Agency (EMA) announced its decision to review the safety of idelalisib due to the aforementioned AEs. The EMA said it is reviewing data from 3 idelalisib trials.
While this review is underway, the EMA advised that patients starting or already on treatment with idelalisib be carefully monitored for signs of infection. If the drug is well tolerated, treatment should not be stopped.
The FDA has not made any recommendations about treatment with idelalisib.
About idelalisib
Idelalisib is currently approved by the FDA for use in combination with rituximab to treat patients with relapsed CLL who cannot receive rituximab alone.
Idelalisib also has accelerated approval from the FDA to treat patients with relapsed follicular lymphoma who have received at least 2 prior systemic therapies and patients with relapsed small lymphocytic lymphoma who have received at least 2 prior systemic therapies.
In the European Union, idelalisib is approved for use in combination with rituximab to treat adults with CLL who have received at least 1 prior therapy or as first-line treatment in the presence of 17p deletion or TP53 mutation in CLL patients deemed unsuitable for chemo-immunotherapy.
Idelalisib is also approved in the European Union as monotherapy for adults with follicular lymphoma that is refractory to 2 prior lines of treatment.
Photo courtesy of
Gilead Sciences
The US Food and Drug Administration (FDA) has reported that Gilead Sciences, Inc., is stopping 6 clinical trials of idelalisib (Zydelig) due to adverse events (AEs) observed in patients receiving idelalisib in combination with other drugs.
The AEs, which include deaths, were mostly related to infections.
The trials include patients with chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma, and indolent non-Hodgkin lymphomas.
The FDA said it is reviewing the findings of these trials and will communicate new information as necessary.
A few days ago, the European Medicines Agency (EMA) announced its decision to review the safety of idelalisib due to the aforementioned AEs. The EMA said it is reviewing data from 3 idelalisib trials.
While this review is underway, the EMA advised that patients starting or already on treatment with idelalisib be carefully monitored for signs of infection. If the drug is well tolerated, treatment should not be stopped.
The FDA has not made any recommendations about treatment with idelalisib.
About idelalisib
Idelalisib is currently approved by the FDA for use in combination with rituximab to treat patients with relapsed CLL who cannot receive rituximab alone.
Idelalisib also has accelerated approval from the FDA to treat patients with relapsed follicular lymphoma who have received at least 2 prior systemic therapies and patients with relapsed small lymphocytic lymphoma who have received at least 2 prior systemic therapies.
In the European Union, idelalisib is approved for use in combination with rituximab to treat adults with CLL who have received at least 1 prior therapy or as first-line treatment in the presence of 17p deletion or TP53 mutation in CLL patients deemed unsuitable for chemo-immunotherapy.
Idelalisib is also approved in the European Union as monotherapy for adults with follicular lymphoma that is refractory to 2 prior lines of treatment.
Photo courtesy of
Gilead Sciences
The US Food and Drug Administration (FDA) has reported that Gilead Sciences, Inc., is stopping 6 clinical trials of idelalisib (Zydelig) due to adverse events (AEs) observed in patients receiving idelalisib in combination with other drugs.
The AEs, which include deaths, were mostly related to infections.
The trials include patients with chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma, and indolent non-Hodgkin lymphomas.
The FDA said it is reviewing the findings of these trials and will communicate new information as necessary.
A few days ago, the European Medicines Agency (EMA) announced its decision to review the safety of idelalisib due to the aforementioned AEs. The EMA said it is reviewing data from 3 idelalisib trials.
While this review is underway, the EMA advised that patients starting or already on treatment with idelalisib be carefully monitored for signs of infection. If the drug is well tolerated, treatment should not be stopped.
The FDA has not made any recommendations about treatment with idelalisib.
About idelalisib
Idelalisib is currently approved by the FDA for use in combination with rituximab to treat patients with relapsed CLL who cannot receive rituximab alone.
Idelalisib also has accelerated approval from the FDA to treat patients with relapsed follicular lymphoma who have received at least 2 prior systemic therapies and patients with relapsed small lymphocytic lymphoma who have received at least 2 prior systemic therapies.
In the European Union, idelalisib is approved for use in combination with rituximab to treat adults with CLL who have received at least 1 prior therapy or as first-line treatment in the presence of 17p deletion or TP53 mutation in CLL patients deemed unsuitable for chemo-immunotherapy.
Idelalisib is also approved in the European Union as monotherapy for adults with follicular lymphoma that is refractory to 2 prior lines of treatment.
Drug granted orphan designation for DLBCL
The US Food and Drug Administration (FDA) has granted orphan designation to the oncology drug candidate PNT2258 for the treatment of diffuse large B-cell lymphoma (DLBCL).
The FDA grants orphan designation to drugs intended to treat conditions affecting fewer than 200,000 patients in the US.
The designation provides the drug’s sponsor with various development incentives, including opportunities to apply for research-related tax credits and grant funding, assistance in designing clinical trials, and 7 years of US market exclusivity if the drug is approved.
About PNT2258
PNT2258 is designed to target cancers that overexpress BCL2, and BCL2 overexpression is thought to be a key driver of DLBCL.
PNT2258 consists of a single-stranded, 24-base DNAi oligonucleotide known as PNT100 that is encapsulated in lipid nanoparticles (LNPs).
The DNAi technology platform is based on a discovery that single-stranded DNA oligonucleotides can interact with genomic DNA to interfere with oncogenes. PNT100 DNAi is designed to target a genetic regulatory region associated with BCL2.
The LNPs are designed to provide enhanced serum stability and optimized pharmacokinetic properties to facilitate broad systemic distribution after intravenous infusion. Within the acidic environment found in tumors, the LNPs become positively charged and therefore more amenable to cellular uptake and cytoplasmic release of their payloads.
Trials of PNT2258
PNT2258 is being developed by ProNAi Therapeutics, Inc. The company has completed 2 trials of PNT2258 to date—a phase 1 trial of patients with solid tumors and a phase 2 trial of patients with non-Hodgkin lymphoma.
The phase 1 trial enrolled 22 patients with relapsed or refractory solid tumor malignancies. Results were published in Cancer Chemotherapy and Pharmacology in February 2014.
PNT2258 was deemed well-tolerated in this trial. There was no evidence of a systemic immune response to the LNPs or PNT100. There were no significant changes in immune-stimulatory cytokines or clinical signs of anaphylaxis following PNT2258 administration.
The phase 2 trial enrolled 13 patients with relapsed or refractory non-Hodgkin lymphoma. Results were presented at ASH 2014 (abstract 1716).
Six patients responded to PNT2258—4 with complete responses and 2 with partial responses. Five patients had stable disease, and 2 progressed. All 4 of the DLBCL patients in this trial responded—3 with complete responses and 1 with a partial response.
Adverse events reported in this trial include nausea (n=11), pain (n=9), chills (n=7), diarrhea (n=7), vomiting (n=7), fatigue (n=6), fever (n=6), headache (n=6), dyspnea (n=5), generalized aching (n=4), anorexia (n=4), back pain (n=4), sensory neuropathy (n=4), hypophosphatemia (n=4), anemia (n=3), hypokalemia (n=3), hyperuricemia (n=2), neutropenia (n=2), thrombocytopenia (n=4), and elevated AST/ALT (n=1).
ProNAi Therapeutics is now enrolling patients in “Wolverine,” a phase 2 trial evaluating PNT2258 in patients with relapsed or refractory DLBCL, and in “Brighton,” a phase 2 trial evaluating PNT2258 for the treatment of Richter’s transformation.
The US Food and Drug Administration (FDA) has granted orphan designation to the oncology drug candidate PNT2258 for the treatment of diffuse large B-cell lymphoma (DLBCL).
The FDA grants orphan designation to drugs intended to treat conditions affecting fewer than 200,000 patients in the US.
The designation provides the drug’s sponsor with various development incentives, including opportunities to apply for research-related tax credits and grant funding, assistance in designing clinical trials, and 7 years of US market exclusivity if the drug is approved.
About PNT2258
PNT2258 is designed to target cancers that overexpress BCL2, and BCL2 overexpression is thought to be a key driver of DLBCL.
PNT2258 consists of a single-stranded, 24-base DNAi oligonucleotide known as PNT100 that is encapsulated in lipid nanoparticles (LNPs).
The DNAi technology platform is based on a discovery that single-stranded DNA oligonucleotides can interact with genomic DNA to interfere with oncogenes. PNT100 DNAi is designed to target a genetic regulatory region associated with BCL2.
The LNPs are designed to provide enhanced serum stability and optimized pharmacokinetic properties to facilitate broad systemic distribution after intravenous infusion. Within the acidic environment found in tumors, the LNPs become positively charged and therefore more amenable to cellular uptake and cytoplasmic release of their payloads.
Trials of PNT2258
PNT2258 is being developed by ProNAi Therapeutics, Inc. The company has completed 2 trials of PNT2258 to date—a phase 1 trial of patients with solid tumors and a phase 2 trial of patients with non-Hodgkin lymphoma.
The phase 1 trial enrolled 22 patients with relapsed or refractory solid tumor malignancies. Results were published in Cancer Chemotherapy and Pharmacology in February 2014.
PNT2258 was deemed well-tolerated in this trial. There was no evidence of a systemic immune response to the LNPs or PNT100. There were no significant changes in immune-stimulatory cytokines or clinical signs of anaphylaxis following PNT2258 administration.
The phase 2 trial enrolled 13 patients with relapsed or refractory non-Hodgkin lymphoma. Results were presented at ASH 2014 (abstract 1716).
Six patients responded to PNT2258—4 with complete responses and 2 with partial responses. Five patients had stable disease, and 2 progressed. All 4 of the DLBCL patients in this trial responded—3 with complete responses and 1 with a partial response.
Adverse events reported in this trial include nausea (n=11), pain (n=9), chills (n=7), diarrhea (n=7), vomiting (n=7), fatigue (n=6), fever (n=6), headache (n=6), dyspnea (n=5), generalized aching (n=4), anorexia (n=4), back pain (n=4), sensory neuropathy (n=4), hypophosphatemia (n=4), anemia (n=3), hypokalemia (n=3), hyperuricemia (n=2), neutropenia (n=2), thrombocytopenia (n=4), and elevated AST/ALT (n=1).
ProNAi Therapeutics is now enrolling patients in “Wolverine,” a phase 2 trial evaluating PNT2258 in patients with relapsed or refractory DLBCL, and in “Brighton,” a phase 2 trial evaluating PNT2258 for the treatment of Richter’s transformation.
The US Food and Drug Administration (FDA) has granted orphan designation to the oncology drug candidate PNT2258 for the treatment of diffuse large B-cell lymphoma (DLBCL).
The FDA grants orphan designation to drugs intended to treat conditions affecting fewer than 200,000 patients in the US.
The designation provides the drug’s sponsor with various development incentives, including opportunities to apply for research-related tax credits and grant funding, assistance in designing clinical trials, and 7 years of US market exclusivity if the drug is approved.
About PNT2258
PNT2258 is designed to target cancers that overexpress BCL2, and BCL2 overexpression is thought to be a key driver of DLBCL.
PNT2258 consists of a single-stranded, 24-base DNAi oligonucleotide known as PNT100 that is encapsulated in lipid nanoparticles (LNPs).
The DNAi technology platform is based on a discovery that single-stranded DNA oligonucleotides can interact with genomic DNA to interfere with oncogenes. PNT100 DNAi is designed to target a genetic regulatory region associated with BCL2.
The LNPs are designed to provide enhanced serum stability and optimized pharmacokinetic properties to facilitate broad systemic distribution after intravenous infusion. Within the acidic environment found in tumors, the LNPs become positively charged and therefore more amenable to cellular uptake and cytoplasmic release of their payloads.
Trials of PNT2258
PNT2258 is being developed by ProNAi Therapeutics, Inc. The company has completed 2 trials of PNT2258 to date—a phase 1 trial of patients with solid tumors and a phase 2 trial of patients with non-Hodgkin lymphoma.
The phase 1 trial enrolled 22 patients with relapsed or refractory solid tumor malignancies. Results were published in Cancer Chemotherapy and Pharmacology in February 2014.
PNT2258 was deemed well-tolerated in this trial. There was no evidence of a systemic immune response to the LNPs or PNT100. There were no significant changes in immune-stimulatory cytokines or clinical signs of anaphylaxis following PNT2258 administration.
The phase 2 trial enrolled 13 patients with relapsed or refractory non-Hodgkin lymphoma. Results were presented at ASH 2014 (abstract 1716).
Six patients responded to PNT2258—4 with complete responses and 2 with partial responses. Five patients had stable disease, and 2 progressed. All 4 of the DLBCL patients in this trial responded—3 with complete responses and 1 with a partial response.
Adverse events reported in this trial include nausea (n=11), pain (n=9), chills (n=7), diarrhea (n=7), vomiting (n=7), fatigue (n=6), fever (n=6), headache (n=6), dyspnea (n=5), generalized aching (n=4), anorexia (n=4), back pain (n=4), sensory neuropathy (n=4), hypophosphatemia (n=4), anemia (n=3), hypokalemia (n=3), hyperuricemia (n=2), neutropenia (n=2), thrombocytopenia (n=4), and elevated AST/ALT (n=1).
ProNAi Therapeutics is now enrolling patients in “Wolverine,” a phase 2 trial evaluating PNT2258 in patients with relapsed or refractory DLBCL, and in “Brighton,” a phase 2 trial evaluating PNT2258 for the treatment of Richter’s transformation.
Intervention helps parents cope with kids’ HSCT
Photo by Chad McNeeley
A new social-cognitive intervention can reduce stress in parents of children undergoing hematopoietic stem cell transplant (HSCT), according to research published in the Journal of Consulting and Clinical Psychology.
In the short-term, the parent social-cognitive intervention program (P-SCIP) appeared more effective than the current best-practice psychosocial care (BPC) for reducing anxiety, depression, and traumatic distress.
However, there was not much difference between P-SCIP and BPC when it came to long-term results.
Certain subgroups of parents seemed to derive more benefit from P-SCIP than other parents.
“[P]revious research from our team and others has shown that between 20% and 66% of caregivers have elevated depression and/or anxiety prior to their child’s transplant procedure,” said study author Sharon Manne, PhD, of the Rutgers Cancer Institute of New Jersey in New Brunswick.
“It was our aim in this study to develop and test an individual intervention program that targets cognitive and social processing strategies associated with caregiver adjustment and compare that to available best-practice psychosocial care.”
Interventions
This study included 218 biological or foster parents of HSCT recipients under age 19. The parents were assigned to receive P-SCIP or BPC.
P-SCIP required parents to view an interactive CD-ROM for five 60-minute sessions over a 2- to 3-week period following the child’s transplant.
The CD-ROM addressed parents’ worries about their child, coping with solvable concerns related to HSCT, coping with unchangeable problems related to HSCT, and communication and the importance of expressing feelings and needs.
Parents receiving BPC viewed a 1-hour video guide to pediatric HSCT and received a pamphlet covering common caregiver issues. The parents were also given the option of having someone watch their child for up to 5 hours and the use of walkie-talkies so the parents could communicate with their child when they were not in the room.
All participants were asked to complete an in-person survey within a month’s time of their child receiving the transplant and to complete follow-up surveys by phone or mail at 1 month, 6 months, and 1 year post-HSCT.
One hundred and ten parents were randomized to P-SCIP and 108 to BPC. Sixty-six parents completed P-SCIP through the last follow-up, as did 72 parents assigned to BPC.
Results
The researchers found that P-SCIP could reduce anxiety, depression, and—to a marginal degree—traumatic distress more than BPC.
However, the beneficial effects of P-SCIP relative to BPC were only seen at the first follow-up. The overall psychological benefits of P-SCIP were no longer evident at the 6-month or 1-year follow ups.
Still, anxiety, depression, and traumatic distress declined among all the parents over the 1-year follow-up period, which is consistent with other research on caregiver distress after pediatric HSCT.
“Our study suggests that our intervention had an impact when primary caregivers were experiencing high levels of trauma and stress—during the time of the actual transplant and hospitalization—and that the intervention was more beneficial for specific subgroups of caregivers,” Dr Manne said.
P-SCIP had a stronger effect than BPC among parents who began the study reporting higher depression and anxiety and among parents whose children developed graft-versus-host disease.
Similarly, P-SCIP had long-term effects on traumatic distress among parents who reported higher anxiety pre-HSCT and among parents whose children had graft-versus-host disease at HSCT discharge.
“Our findings suggest that screening caregivers for elevations in anxiety and targeting interventions specifically to them may prove beneficial,” Dr Manne said.
She added that a next step for this research might be to examine possible differences between mothers and fathers in the caregiver role, as most of the primary caregivers in this study were mothers.
Additionally, if this intervention is carried into the clinical setting, methods of improving intervention attendance might be considered. Utilizing phone or web-based contact that would allow the parent to remain in the room with the child during hospitalization might help the caregivers more easily access the intervention.
Photo by Chad McNeeley
A new social-cognitive intervention can reduce stress in parents of children undergoing hematopoietic stem cell transplant (HSCT), according to research published in the Journal of Consulting and Clinical Psychology.
In the short-term, the parent social-cognitive intervention program (P-SCIP) appeared more effective than the current best-practice psychosocial care (BPC) for reducing anxiety, depression, and traumatic distress.
However, there was not much difference between P-SCIP and BPC when it came to long-term results.
Certain subgroups of parents seemed to derive more benefit from P-SCIP than other parents.
“[P]revious research from our team and others has shown that between 20% and 66% of caregivers have elevated depression and/or anxiety prior to their child’s transplant procedure,” said study author Sharon Manne, PhD, of the Rutgers Cancer Institute of New Jersey in New Brunswick.
“It was our aim in this study to develop and test an individual intervention program that targets cognitive and social processing strategies associated with caregiver adjustment and compare that to available best-practice psychosocial care.”
Interventions
This study included 218 biological or foster parents of HSCT recipients under age 19. The parents were assigned to receive P-SCIP or BPC.
P-SCIP required parents to view an interactive CD-ROM for five 60-minute sessions over a 2- to 3-week period following the child’s transplant.
The CD-ROM addressed parents’ worries about their child, coping with solvable concerns related to HSCT, coping with unchangeable problems related to HSCT, and communication and the importance of expressing feelings and needs.
Parents receiving BPC viewed a 1-hour video guide to pediatric HSCT and received a pamphlet covering common caregiver issues. The parents were also given the option of having someone watch their child for up to 5 hours and the use of walkie-talkies so the parents could communicate with their child when they were not in the room.
All participants were asked to complete an in-person survey within a month’s time of their child receiving the transplant and to complete follow-up surveys by phone or mail at 1 month, 6 months, and 1 year post-HSCT.
One hundred and ten parents were randomized to P-SCIP and 108 to BPC. Sixty-six parents completed P-SCIP through the last follow-up, as did 72 parents assigned to BPC.
Results
The researchers found that P-SCIP could reduce anxiety, depression, and—to a marginal degree—traumatic distress more than BPC.
However, the beneficial effects of P-SCIP relative to BPC were only seen at the first follow-up. The overall psychological benefits of P-SCIP were no longer evident at the 6-month or 1-year follow ups.
Still, anxiety, depression, and traumatic distress declined among all the parents over the 1-year follow-up period, which is consistent with other research on caregiver distress after pediatric HSCT.
“Our study suggests that our intervention had an impact when primary caregivers were experiencing high levels of trauma and stress—during the time of the actual transplant and hospitalization—and that the intervention was more beneficial for specific subgroups of caregivers,” Dr Manne said.
P-SCIP had a stronger effect than BPC among parents who began the study reporting higher depression and anxiety and among parents whose children developed graft-versus-host disease.
Similarly, P-SCIP had long-term effects on traumatic distress among parents who reported higher anxiety pre-HSCT and among parents whose children had graft-versus-host disease at HSCT discharge.
“Our findings suggest that screening caregivers for elevations in anxiety and targeting interventions specifically to them may prove beneficial,” Dr Manne said.
She added that a next step for this research might be to examine possible differences between mothers and fathers in the caregiver role, as most of the primary caregivers in this study were mothers.
Additionally, if this intervention is carried into the clinical setting, methods of improving intervention attendance might be considered. Utilizing phone or web-based contact that would allow the parent to remain in the room with the child during hospitalization might help the caregivers more easily access the intervention.
Photo by Chad McNeeley
A new social-cognitive intervention can reduce stress in parents of children undergoing hematopoietic stem cell transplant (HSCT), according to research published in the Journal of Consulting and Clinical Psychology.
In the short-term, the parent social-cognitive intervention program (P-SCIP) appeared more effective than the current best-practice psychosocial care (BPC) for reducing anxiety, depression, and traumatic distress.
However, there was not much difference between P-SCIP and BPC when it came to long-term results.
Certain subgroups of parents seemed to derive more benefit from P-SCIP than other parents.
“[P]revious research from our team and others has shown that between 20% and 66% of caregivers have elevated depression and/or anxiety prior to their child’s transplant procedure,” said study author Sharon Manne, PhD, of the Rutgers Cancer Institute of New Jersey in New Brunswick.
“It was our aim in this study to develop and test an individual intervention program that targets cognitive and social processing strategies associated with caregiver adjustment and compare that to available best-practice psychosocial care.”
Interventions
This study included 218 biological or foster parents of HSCT recipients under age 19. The parents were assigned to receive P-SCIP or BPC.
P-SCIP required parents to view an interactive CD-ROM for five 60-minute sessions over a 2- to 3-week period following the child’s transplant.
The CD-ROM addressed parents’ worries about their child, coping with solvable concerns related to HSCT, coping with unchangeable problems related to HSCT, and communication and the importance of expressing feelings and needs.
Parents receiving BPC viewed a 1-hour video guide to pediatric HSCT and received a pamphlet covering common caregiver issues. The parents were also given the option of having someone watch their child for up to 5 hours and the use of walkie-talkies so the parents could communicate with their child when they were not in the room.
All participants were asked to complete an in-person survey within a month’s time of their child receiving the transplant and to complete follow-up surveys by phone or mail at 1 month, 6 months, and 1 year post-HSCT.
One hundred and ten parents were randomized to P-SCIP and 108 to BPC. Sixty-six parents completed P-SCIP through the last follow-up, as did 72 parents assigned to BPC.
Results
The researchers found that P-SCIP could reduce anxiety, depression, and—to a marginal degree—traumatic distress more than BPC.
However, the beneficial effects of P-SCIP relative to BPC were only seen at the first follow-up. The overall psychological benefits of P-SCIP were no longer evident at the 6-month or 1-year follow ups.
Still, anxiety, depression, and traumatic distress declined among all the parents over the 1-year follow-up period, which is consistent with other research on caregiver distress after pediatric HSCT.
“Our study suggests that our intervention had an impact when primary caregivers were experiencing high levels of trauma and stress—during the time of the actual transplant and hospitalization—and that the intervention was more beneficial for specific subgroups of caregivers,” Dr Manne said.
P-SCIP had a stronger effect than BPC among parents who began the study reporting higher depression and anxiety and among parents whose children developed graft-versus-host disease.
Similarly, P-SCIP had long-term effects on traumatic distress among parents who reported higher anxiety pre-HSCT and among parents whose children had graft-versus-host disease at HSCT discharge.
“Our findings suggest that screening caregivers for elevations in anxiety and targeting interventions specifically to them may prove beneficial,” Dr Manne said.
She added that a next step for this research might be to examine possible differences between mothers and fathers in the caregiver role, as most of the primary caregivers in this study were mothers.
Additionally, if this intervention is carried into the clinical setting, methods of improving intervention attendance might be considered. Utilizing phone or web-based contact that would allow the parent to remain in the room with the child during hospitalization might help the caregivers more easily access the intervention.
Gut microbes affect platelet function, thrombosis risk
Image by Andre E.X. Brown
New research indicates that gut microbes alter platelet function, which affects the risk of thrombosis and related events like heart attack and stroke.
When the nutrient choline, which is abundant in animal products like meat and egg yolk, is ingested, gut microbes play a role in breaking it down and producing the compound TMAO.
Recent studies have shown that blood TMAO levels are associated with a heightened risk of heart attack and stroke.
The new study, published in Cell, suggests that TMAO encourages hyper-reactive platelet function, thereby increasing the likelihood of thrombosis.
Researchers said this could be the mechanism by which TMAO increases the risk of heart attack and stroke. And these findings reveal a previously unrecognized mechanistic link between specific dietary nutrients, gut microbes, platelet function, and thrombosis risk.
“It is remarkable that gut microbes produce a compound that alters platelet function and thrombotic heart attack and stroke risk,” said study author Stanley Hazen, MD, PhD, of the Cleveland Clinic in Ohio.
“This new link helps explain how diet-induced TMAO generation is mechanistically linked to development of lethal adverse complications of heart disease.”
Dr Hazen and his colleagues first discovered a link between TMAO, gut microbes, and heart disease 5 years ago.
For the current study, the researchers analyzed blood levels of TMAO in more than 4000 patients and saw a significant correlation between higher TMAO and thrombosis potential. This led to the hypothesis that TMAO may directly impact platelet function.
Subsequent studies with both human platelets and animal models confirmed that TMAO makes platelets hyper-reactive, heightening thrombosis potential and accelerating clotting rates.
“We have shown that TMAO fundamentally alters calcium signaling within platelets,” Dr Hazen said. “When TMAO is elevated, platelet responsiveness to known triggers like thrombin, collagen, or ADP is heightened.”
“In general, there’s a broad range for how quickly different people will form clots. However, across the board, when TMAO is elevated, platelet responsiveness jumps to the hyper-reactive side of normal.”
Dr Hazen and his colleagues said these results suggest that lowering TMAO—via dietary manipulation, alteration in microbial community with a probiotic or prebiotic, or direct pharmacological inhibition of microbial enzymes involved in TMA production—may be a way to reduce the risk of thrombotic events.
They noted that, unlike current antiplatelet therapies, targeting TMAO would likely reduce platelet hyper-responsiveness to the normal range and not induce impairment in overall platelet function. So the intervention could attenuate pro-thrombotic tendencies without increasing the risk of bleeding complications.
Image by Andre E.X. Brown
New research indicates that gut microbes alter platelet function, which affects the risk of thrombosis and related events like heart attack and stroke.
When the nutrient choline, which is abundant in animal products like meat and egg yolk, is ingested, gut microbes play a role in breaking it down and producing the compound TMAO.
Recent studies have shown that blood TMAO levels are associated with a heightened risk of heart attack and stroke.
The new study, published in Cell, suggests that TMAO encourages hyper-reactive platelet function, thereby increasing the likelihood of thrombosis.
Researchers said this could be the mechanism by which TMAO increases the risk of heart attack and stroke. And these findings reveal a previously unrecognized mechanistic link between specific dietary nutrients, gut microbes, platelet function, and thrombosis risk.
“It is remarkable that gut microbes produce a compound that alters platelet function and thrombotic heart attack and stroke risk,” said study author Stanley Hazen, MD, PhD, of the Cleveland Clinic in Ohio.
“This new link helps explain how diet-induced TMAO generation is mechanistically linked to development of lethal adverse complications of heart disease.”
Dr Hazen and his colleagues first discovered a link between TMAO, gut microbes, and heart disease 5 years ago.
For the current study, the researchers analyzed blood levels of TMAO in more than 4000 patients and saw a significant correlation between higher TMAO and thrombosis potential. This led to the hypothesis that TMAO may directly impact platelet function.
Subsequent studies with both human platelets and animal models confirmed that TMAO makes platelets hyper-reactive, heightening thrombosis potential and accelerating clotting rates.
“We have shown that TMAO fundamentally alters calcium signaling within platelets,” Dr Hazen said. “When TMAO is elevated, platelet responsiveness to known triggers like thrombin, collagen, or ADP is heightened.”
“In general, there’s a broad range for how quickly different people will form clots. However, across the board, when TMAO is elevated, platelet responsiveness jumps to the hyper-reactive side of normal.”
Dr Hazen and his colleagues said these results suggest that lowering TMAO—via dietary manipulation, alteration in microbial community with a probiotic or prebiotic, or direct pharmacological inhibition of microbial enzymes involved in TMA production—may be a way to reduce the risk of thrombotic events.
They noted that, unlike current antiplatelet therapies, targeting TMAO would likely reduce platelet hyper-responsiveness to the normal range and not induce impairment in overall platelet function. So the intervention could attenuate pro-thrombotic tendencies without increasing the risk of bleeding complications.
Image by Andre E.X. Brown
New research indicates that gut microbes alter platelet function, which affects the risk of thrombosis and related events like heart attack and stroke.
When the nutrient choline, which is abundant in animal products like meat and egg yolk, is ingested, gut microbes play a role in breaking it down and producing the compound TMAO.
Recent studies have shown that blood TMAO levels are associated with a heightened risk of heart attack and stroke.
The new study, published in Cell, suggests that TMAO encourages hyper-reactive platelet function, thereby increasing the likelihood of thrombosis.
Researchers said this could be the mechanism by which TMAO increases the risk of heart attack and stroke. And these findings reveal a previously unrecognized mechanistic link between specific dietary nutrients, gut microbes, platelet function, and thrombosis risk.
“It is remarkable that gut microbes produce a compound that alters platelet function and thrombotic heart attack and stroke risk,” said study author Stanley Hazen, MD, PhD, of the Cleveland Clinic in Ohio.
“This new link helps explain how diet-induced TMAO generation is mechanistically linked to development of lethal adverse complications of heart disease.”
Dr Hazen and his colleagues first discovered a link between TMAO, gut microbes, and heart disease 5 years ago.
For the current study, the researchers analyzed blood levels of TMAO in more than 4000 patients and saw a significant correlation between higher TMAO and thrombosis potential. This led to the hypothesis that TMAO may directly impact platelet function.
Subsequent studies with both human platelets and animal models confirmed that TMAO makes platelets hyper-reactive, heightening thrombosis potential and accelerating clotting rates.
“We have shown that TMAO fundamentally alters calcium signaling within platelets,” Dr Hazen said. “When TMAO is elevated, platelet responsiveness to known triggers like thrombin, collagen, or ADP is heightened.”
“In general, there’s a broad range for how quickly different people will form clots. However, across the board, when TMAO is elevated, platelet responsiveness jumps to the hyper-reactive side of normal.”
Dr Hazen and his colleagues said these results suggest that lowering TMAO—via dietary manipulation, alteration in microbial community with a probiotic or prebiotic, or direct pharmacological inhibition of microbial enzymes involved in TMA production—may be a way to reduce the risk of thrombotic events.
They noted that, unlike current antiplatelet therapies, targeting TMAO would likely reduce platelet hyper-responsiveness to the normal range and not induce impairment in overall platelet function. So the intervention could attenuate pro-thrombotic tendencies without increasing the risk of bleeding complications.
Negative cancer trials have long-term impact
for a clinical trial
Photo by Esther Dyson
Cancer trials with negative results don’t make an immediate splash in the scientific literature, but they do have a long-term impact on research, according to a study published in JAMA Oncology.
Researchers found that first reports of positive phase 3 cancer trials were twice as likely as first reports of negative phase 3 cancer trials
to be cited in scientific journals.
But over time, when all articles associated with the trials were considered, the scientific impact of negative trials and positive trials was about the same.
“Negative trials aren’t scientific failures,” said study author Joseph Unger, PhD, of the Fred Hutchinson Cancer Research Center in Seattle, Washington.
“We found that they have a positive, lasting impact on cancer research.”
Dr Unger and his colleagues analyzed every randomized, phase 3 cancer trial completed by the cooperative group SWOG from 1984 to 2014. This amounted to 94 studies involving 46,424 patients.
Of those 94 studies, 26 were positive, meaning that the treatment tested performed measurably better than the standard treatment at the time.
Analyses revealed that primary manuscripts first announcing these encouraging results were published in journals with higher impact factors and were cited twice as often as primary manuscripts of negative trials.
The mean 2-year impact factor of the journals was 28 for positive trials and 18 for negative trials (P=0.007). And the mean number of citations per year was 43 for positive trials and 21 for negative trials (P=0.03).
However, when the researchers looked at the number of citations from all primary and secondary manuscripts, they did not see a significant difference between positive and negative trials. The mean number of citations per year was 55 and 45, respectively (P=0.53).
“Negative trials matter because they tell us what doesn’t work, which can be as important as what does,” said study author Dawn Hershman, MD, of Columbia University Medical Center in New York, New York.
“Negative trials are also critical for secondary research, which mines existing trial data to answer new questions in cancer care and prevention. Negative trials are used frequently in secondary research and add great value to the scientific community.”
for a clinical trial
Photo by Esther Dyson
Cancer trials with negative results don’t make an immediate splash in the scientific literature, but they do have a long-term impact on research, according to a study published in JAMA Oncology.
Researchers found that first reports of positive phase 3 cancer trials were twice as likely as first reports of negative phase 3 cancer trials
to be cited in scientific journals.
But over time, when all articles associated with the trials were considered, the scientific impact of negative trials and positive trials was about the same.
“Negative trials aren’t scientific failures,” said study author Joseph Unger, PhD, of the Fred Hutchinson Cancer Research Center in Seattle, Washington.
“We found that they have a positive, lasting impact on cancer research.”
Dr Unger and his colleagues analyzed every randomized, phase 3 cancer trial completed by the cooperative group SWOG from 1984 to 2014. This amounted to 94 studies involving 46,424 patients.
Of those 94 studies, 26 were positive, meaning that the treatment tested performed measurably better than the standard treatment at the time.
Analyses revealed that primary manuscripts first announcing these encouraging results were published in journals with higher impact factors and were cited twice as often as primary manuscripts of negative trials.
The mean 2-year impact factor of the journals was 28 for positive trials and 18 for negative trials (P=0.007). And the mean number of citations per year was 43 for positive trials and 21 for negative trials (P=0.03).
However, when the researchers looked at the number of citations from all primary and secondary manuscripts, they did not see a significant difference between positive and negative trials. The mean number of citations per year was 55 and 45, respectively (P=0.53).
“Negative trials matter because they tell us what doesn’t work, which can be as important as what does,” said study author Dawn Hershman, MD, of Columbia University Medical Center in New York, New York.
“Negative trials are also critical for secondary research, which mines existing trial data to answer new questions in cancer care and prevention. Negative trials are used frequently in secondary research and add great value to the scientific community.”
for a clinical trial
Photo by Esther Dyson
Cancer trials with negative results don’t make an immediate splash in the scientific literature, but they do have a long-term impact on research, according to a study published in JAMA Oncology.
Researchers found that first reports of positive phase 3 cancer trials were twice as likely as first reports of negative phase 3 cancer trials
to be cited in scientific journals.
But over time, when all articles associated with the trials were considered, the scientific impact of negative trials and positive trials was about the same.
“Negative trials aren’t scientific failures,” said study author Joseph Unger, PhD, of the Fred Hutchinson Cancer Research Center in Seattle, Washington.
“We found that they have a positive, lasting impact on cancer research.”
Dr Unger and his colleagues analyzed every randomized, phase 3 cancer trial completed by the cooperative group SWOG from 1984 to 2014. This amounted to 94 studies involving 46,424 patients.
Of those 94 studies, 26 were positive, meaning that the treatment tested performed measurably better than the standard treatment at the time.
Analyses revealed that primary manuscripts first announcing these encouraging results were published in journals with higher impact factors and were cited twice as often as primary manuscripts of negative trials.
The mean 2-year impact factor of the journals was 28 for positive trials and 18 for negative trials (P=0.007). And the mean number of citations per year was 43 for positive trials and 21 for negative trials (P=0.03).
However, when the researchers looked at the number of citations from all primary and secondary manuscripts, they did not see a significant difference between positive and negative trials. The mean number of citations per year was 55 and 45, respectively (P=0.53).
“Negative trials matter because they tell us what doesn’t work, which can be as important as what does,” said study author Dawn Hershman, MD, of Columbia University Medical Center in New York, New York.
“Negative trials are also critical for secondary research, which mines existing trial data to answer new questions in cancer care and prevention. Negative trials are used frequently in secondary research and add great value to the scientific community.”
AEs prompt EMA review of idelalisib
Photo courtesy of
Gilead Sciences, Inc.
The European Medicines Agency (EMA) is reviewing the safety of idelalisib (Zydelig), a drug approved to treat chronic lymphocytic leukemia (CLL) and follicular lymphoma in the European Union (EU).
The European Commission (EC) requested the review because of serious adverse events (AEs), including deaths, reported in 3 clinical trials investigating idelalisib in combination with other drugs.
The AEs were mostly infection-related.
The EMA is reviewing data from these studies to assess whether the findings have any consequences for the authorized uses of idelalisib.
In the meantime, the EMA advises that patients starting or already on treatment with idelalisib be carefully monitored for signs of infections. If the drug is well tolerated, treatment should not be stopped.
The EMA is considering whether any other immediate measures are necessary during the review period. The agency said it will communicate further and keep doctors and patients informed as appropriate.
About idelalisib
In the EU, idelalisib is approved for use in combination with rituximab to treat adults with CLL who have received at least 1 prior therapy or as first-line treatment in the presence of 17p deletion or TP53 mutation in CLL patients unsuitable for chemo-immunotherapy.
Idelalisib is also approved as monotherapy for adults with follicular lymphoma that is refractory to 2 prior lines of treatment.
About the trials
The trials in which patients have experienced serious AEs involve patients with CLL and indolent non-Hodgkin lymphoma (NHL).
In one trial (NCT01732926), researchers are evaluating idelalisib in combination with bendamustine and rituximab for previously treated indolent NHL.
In another (NCT01732913), researchers are testing idelalisib in combination with rituximab for previously treated indolent NHL.
And in the third (NCT01980888), researchers are evaluating idelalisib in combination with bendamustine and rituximab in patients with previously untreated CLL.
The EMA noted that these studies are investigating combinations of drugs that are currently not approved in the EU and include patients with disease characteristics different from those covered by the approved indications for idelalisib.
About the review
The EMA has begun the review of idelalisib at the request of the EC, under Article 20 of Directive 2001/83/EC.
The review is being carried out by the EMA’s Pharmacovigilance Risk Assessment Committee, the committee responsible for the evaluation of safety issues for human medicines, which will make a set of recommendations.
Those recommendations will then be forwarded to the Committee for Medicinal Products for Human Use, which is responsible for questions concerning medicines for human use and will adopt a final opinion on the safety of idelalisib.
The final stage of the review procedure is the EC’s adoption of a legally binding decision that is applicable in all EU member states.
Photo courtesy of
Gilead Sciences, Inc.
The European Medicines Agency (EMA) is reviewing the safety of idelalisib (Zydelig), a drug approved to treat chronic lymphocytic leukemia (CLL) and follicular lymphoma in the European Union (EU).
The European Commission (EC) requested the review because of serious adverse events (AEs), including deaths, reported in 3 clinical trials investigating idelalisib in combination with other drugs.
The AEs were mostly infection-related.
The EMA is reviewing data from these studies to assess whether the findings have any consequences for the authorized uses of idelalisib.
In the meantime, the EMA advises that patients starting or already on treatment with idelalisib be carefully monitored for signs of infections. If the drug is well tolerated, treatment should not be stopped.
The EMA is considering whether any other immediate measures are necessary during the review period. The agency said it will communicate further and keep doctors and patients informed as appropriate.
About idelalisib
In the EU, idelalisib is approved for use in combination with rituximab to treat adults with CLL who have received at least 1 prior therapy or as first-line treatment in the presence of 17p deletion or TP53 mutation in CLL patients unsuitable for chemo-immunotherapy.
Idelalisib is also approved as monotherapy for adults with follicular lymphoma that is refractory to 2 prior lines of treatment.
About the trials
The trials in which patients have experienced serious AEs involve patients with CLL and indolent non-Hodgkin lymphoma (NHL).
In one trial (NCT01732926), researchers are evaluating idelalisib in combination with bendamustine and rituximab for previously treated indolent NHL.
In another (NCT01732913), researchers are testing idelalisib in combination with rituximab for previously treated indolent NHL.
And in the third (NCT01980888), researchers are evaluating idelalisib in combination with bendamustine and rituximab in patients with previously untreated CLL.
The EMA noted that these studies are investigating combinations of drugs that are currently not approved in the EU and include patients with disease characteristics different from those covered by the approved indications for idelalisib.
About the review
The EMA has begun the review of idelalisib at the request of the EC, under Article 20 of Directive 2001/83/EC.
The review is being carried out by the EMA’s Pharmacovigilance Risk Assessment Committee, the committee responsible for the evaluation of safety issues for human medicines, which will make a set of recommendations.
Those recommendations will then be forwarded to the Committee for Medicinal Products for Human Use, which is responsible for questions concerning medicines for human use and will adopt a final opinion on the safety of idelalisib.
The final stage of the review procedure is the EC’s adoption of a legally binding decision that is applicable in all EU member states.
Photo courtesy of
Gilead Sciences, Inc.
The European Medicines Agency (EMA) is reviewing the safety of idelalisib (Zydelig), a drug approved to treat chronic lymphocytic leukemia (CLL) and follicular lymphoma in the European Union (EU).
The European Commission (EC) requested the review because of serious adverse events (AEs), including deaths, reported in 3 clinical trials investigating idelalisib in combination with other drugs.
The AEs were mostly infection-related.
The EMA is reviewing data from these studies to assess whether the findings have any consequences for the authorized uses of idelalisib.
In the meantime, the EMA advises that patients starting or already on treatment with idelalisib be carefully monitored for signs of infections. If the drug is well tolerated, treatment should not be stopped.
The EMA is considering whether any other immediate measures are necessary during the review period. The agency said it will communicate further and keep doctors and patients informed as appropriate.
About idelalisib
In the EU, idelalisib is approved for use in combination with rituximab to treat adults with CLL who have received at least 1 prior therapy or as first-line treatment in the presence of 17p deletion or TP53 mutation in CLL patients unsuitable for chemo-immunotherapy.
Idelalisib is also approved as monotherapy for adults with follicular lymphoma that is refractory to 2 prior lines of treatment.
About the trials
The trials in which patients have experienced serious AEs involve patients with CLL and indolent non-Hodgkin lymphoma (NHL).
In one trial (NCT01732926), researchers are evaluating idelalisib in combination with bendamustine and rituximab for previously treated indolent NHL.
In another (NCT01732913), researchers are testing idelalisib in combination with rituximab for previously treated indolent NHL.
And in the third (NCT01980888), researchers are evaluating idelalisib in combination with bendamustine and rituximab in patients with previously untreated CLL.
The EMA noted that these studies are investigating combinations of drugs that are currently not approved in the EU and include patients with disease characteristics different from those covered by the approved indications for idelalisib.
About the review
The EMA has begun the review of idelalisib at the request of the EC, under Article 20 of Directive 2001/83/EC.
The review is being carried out by the EMA’s Pharmacovigilance Risk Assessment Committee, the committee responsible for the evaluation of safety issues for human medicines, which will make a set of recommendations.
Those recommendations will then be forwarded to the Committee for Medicinal Products for Human Use, which is responsible for questions concerning medicines for human use and will adopt a final opinion on the safety of idelalisib.
The final stage of the review procedure is the EC’s adoption of a legally binding decision that is applicable in all EU member states.
Class of drugs could treat B-cell malignancies
A class of drugs targeting a protein found in the endoplasmic reticulum could be effective against B-cell malignancies, according to a study published in Cancer Research.
The protein, STING, plays a critical role in producing type I interferons that help regulate the immune system.
Previous research suggested that STING agonists can improve immune responses when used in cancer immunotherapy or as vaccine adjuvants.
However, the way B cells respond to STING agonists was not well understood.
Chih-Chi Andrew Hu, PhD, of The Wistar Institute in Philadelphia, Pennsylvania, and his colleagues conducted a study to gain some insight.
The researchers found that normal B cells respond to STING agonists by undergoing mitochondria-mediated apoptosis, and STING agonists induce apoptosis in
malignant B cells through binding to STING.
STING agonists proved cytotoxic to B-cell leukemia, lymphoma, and multiple myeloma in vitro. But the drugs did not induce apoptosis in solid tumor malignancies or normal T cells.
The research also revealed that the IRE-1/XBP-1 stress response pathway is required for normal STING function. And B-cell leukemia, lymphoma, and myeloma require the IRE-1/XBP-1 pathway to be activated for survival.
Stimulation by STING agonists suppressed the IRE-1/XBP-1 pathway, which increased the level of apoptosis in malignant B cells.
The researchers confirmed these results in animal models, as treatment with STING agonists led to regression of chronic lymphocytic leukemia and multiple myeloma in mice.
“This specific cytotoxicity toward B cells strongly supports the use of STING agonists in the treatment of B-cell hematologic malignancies,” said Chih-Hang Anthony Tang, MD, PhD, of The Wistar Institute.
“We also believe that cytotoxicity in normal B cells can be managed with the administration of intravenous immunoglobulin that can help maintain normal levels of antibodies while treatment is being administered. This is something we plan on studying further.”
The Wistar Institute’s business development team is looking for a development partner for the advancement of novel STING agonists in treating B-cell hematologic malignancies.
A class of drugs targeting a protein found in the endoplasmic reticulum could be effective against B-cell malignancies, according to a study published in Cancer Research.
The protein, STING, plays a critical role in producing type I interferons that help regulate the immune system.
Previous research suggested that STING agonists can improve immune responses when used in cancer immunotherapy or as vaccine adjuvants.
However, the way B cells respond to STING agonists was not well understood.
Chih-Chi Andrew Hu, PhD, of The Wistar Institute in Philadelphia, Pennsylvania, and his colleagues conducted a study to gain some insight.
The researchers found that normal B cells respond to STING agonists by undergoing mitochondria-mediated apoptosis, and STING agonists induce apoptosis in
malignant B cells through binding to STING.
STING agonists proved cytotoxic to B-cell leukemia, lymphoma, and multiple myeloma in vitro. But the drugs did not induce apoptosis in solid tumor malignancies or normal T cells.
The research also revealed that the IRE-1/XBP-1 stress response pathway is required for normal STING function. And B-cell leukemia, lymphoma, and myeloma require the IRE-1/XBP-1 pathway to be activated for survival.
Stimulation by STING agonists suppressed the IRE-1/XBP-1 pathway, which increased the level of apoptosis in malignant B cells.
The researchers confirmed these results in animal models, as treatment with STING agonists led to regression of chronic lymphocytic leukemia and multiple myeloma in mice.
“This specific cytotoxicity toward B cells strongly supports the use of STING agonists in the treatment of B-cell hematologic malignancies,” said Chih-Hang Anthony Tang, MD, PhD, of The Wistar Institute.
“We also believe that cytotoxicity in normal B cells can be managed with the administration of intravenous immunoglobulin that can help maintain normal levels of antibodies while treatment is being administered. This is something we plan on studying further.”
The Wistar Institute’s business development team is looking for a development partner for the advancement of novel STING agonists in treating B-cell hematologic malignancies.
A class of drugs targeting a protein found in the endoplasmic reticulum could be effective against B-cell malignancies, according to a study published in Cancer Research.
The protein, STING, plays a critical role in producing type I interferons that help regulate the immune system.
Previous research suggested that STING agonists can improve immune responses when used in cancer immunotherapy or as vaccine adjuvants.
However, the way B cells respond to STING agonists was not well understood.
Chih-Chi Andrew Hu, PhD, of The Wistar Institute in Philadelphia, Pennsylvania, and his colleagues conducted a study to gain some insight.
The researchers found that normal B cells respond to STING agonists by undergoing mitochondria-mediated apoptosis, and STING agonists induce apoptosis in
malignant B cells through binding to STING.
STING agonists proved cytotoxic to B-cell leukemia, lymphoma, and multiple myeloma in vitro. But the drugs did not induce apoptosis in solid tumor malignancies or normal T cells.
The research also revealed that the IRE-1/XBP-1 stress response pathway is required for normal STING function. And B-cell leukemia, lymphoma, and myeloma require the IRE-1/XBP-1 pathway to be activated for survival.
Stimulation by STING agonists suppressed the IRE-1/XBP-1 pathway, which increased the level of apoptosis in malignant B cells.
The researchers confirmed these results in animal models, as treatment with STING agonists led to regression of chronic lymphocytic leukemia and multiple myeloma in mice.
“This specific cytotoxicity toward B cells strongly supports the use of STING agonists in the treatment of B-cell hematologic malignancies,” said Chih-Hang Anthony Tang, MD, PhD, of The Wistar Institute.
“We also believe that cytotoxicity in normal B cells can be managed with the administration of intravenous immunoglobulin that can help maintain normal levels of antibodies while treatment is being administered. This is something we plan on studying further.”
The Wistar Institute’s business development team is looking for a development partner for the advancement of novel STING agonists in treating B-cell hematologic malignancies.
Allele associated with poor outcome in CLL
A form of the CYP3A7 gene is associated with poor outcomes in chronic lymphocytic leukemia (CLL) and other cancers, according to a study published in Cancer Research.
Among patients with CLL, breast cancer, or lung cancer, those with the CYP3A7*1C allele were more likely than those without it to experience disease progression or death.
Researchers believe this may be related to how patients metabolize treatment.
“The CYP3A7 gene encodes an enzyme that breaks down all sorts of naturally occurring substances—such as sex steroids like estrogen and testosterone—as well as a wide range of drugs that are used in the treatment of cancer,” said Olivia Fletcher, PhD, of The Institute of Cancer Research in London, UK.
“The CYP3A7 gene is normally turned on in an embryo and then turned off shortly after a baby is born, but individuals who have 1 or more copies of the CYP3A7*1C form of the gene turn on their CYP3A7 gene in adult life.”
“We found that individuals with breast cancer, lung cancer, or CLL who carry 1 or more copies of the CYP3A7*1C allele tend to have worse outcomes. One possibility is that these patients break down the drugs that they are given to treat their cancer too fast. However, further independent studies that replicate our findings in larger numbers of patients and rule out biases are needed before we could recommend any changes to the treatment that cancer patients with the CYP3A7*1C allele receive.”
To assess the impact of the CYP3A7*1C allele on patient outcomes, Dr Fletcher and her colleagues analyzed DNA samples from 1008 breast cancer patients, 1142 patients with lung cancer, and 356 patients with CLL.
The team looked for the presence of the single nucleotide polymorphism (SNP) rs45446698. Dr Fletcher explained that rs45446698 is 1 of 7 SNPs that cluster together to form the CYP3A7*1C allele.
The researchers found that, among CLL patients, rs45446698 (and, therefore, the CYP3A7*1C allele) was associated with a 62% increased risk of disease progression (P=0.03).
Among breast cancer patients, rs45446698 was associated with a 74% increased risk of breast cancer mortality (P=0.03). And among the lung cancer patients, the SNP was associated with a 43% increased risk of death from any cause (P=0.009).
The researchers also found borderline evidence of a statistical interaction between the CYP3A7*1C allele, treatment of patients with a cytotoxic agent that is a CYP3A substrate, and clinical outcome (P=0.06).
“Even though we did not see a statistically significant difference when stratifying patients by treatment with a CYP3A7 substrate, the fact that we see the same effect in 3 very different cancer types suggests to me that it is more likely to be something to do with treatment than the disease itself,” Dr Fletcher said.
“However, we are looking at ways of replicating these results in additional cohorts of patients and types of cancer, as well as overcoming the limitations of this study.”
Dr Fletcher explained that the main limitation of this study is that the researchers used samples and clinical information collected for other studies. So they did not have the same clinical information for each patient, and the samples were collected at different time points and for patients treated with various drugs.
She also noted that the researchers were not able to determine how quickly the patients broke down their treatments.
This study was supported by Sanofi-Aventis, Breast Cancer Now, Bloodwise, Cancer Research UK, the Medical Research Council, the Cridlan Trust, and the Helen Rollason Cancer Charity. The authors’ institutions received funding from the National Health Service of the United Kingdom.
A form of the CYP3A7 gene is associated with poor outcomes in chronic lymphocytic leukemia (CLL) and other cancers, according to a study published in Cancer Research.
Among patients with CLL, breast cancer, or lung cancer, those with the CYP3A7*1C allele were more likely than those without it to experience disease progression or death.
Researchers believe this may be related to how patients metabolize treatment.
“The CYP3A7 gene encodes an enzyme that breaks down all sorts of naturally occurring substances—such as sex steroids like estrogen and testosterone—as well as a wide range of drugs that are used in the treatment of cancer,” said Olivia Fletcher, PhD, of The Institute of Cancer Research in London, UK.
“The CYP3A7 gene is normally turned on in an embryo and then turned off shortly after a baby is born, but individuals who have 1 or more copies of the CYP3A7*1C form of the gene turn on their CYP3A7 gene in adult life.”
“We found that individuals with breast cancer, lung cancer, or CLL who carry 1 or more copies of the CYP3A7*1C allele tend to have worse outcomes. One possibility is that these patients break down the drugs that they are given to treat their cancer too fast. However, further independent studies that replicate our findings in larger numbers of patients and rule out biases are needed before we could recommend any changes to the treatment that cancer patients with the CYP3A7*1C allele receive.”
To assess the impact of the CYP3A7*1C allele on patient outcomes, Dr Fletcher and her colleagues analyzed DNA samples from 1008 breast cancer patients, 1142 patients with lung cancer, and 356 patients with CLL.
The team looked for the presence of the single nucleotide polymorphism (SNP) rs45446698. Dr Fletcher explained that rs45446698 is 1 of 7 SNPs that cluster together to form the CYP3A7*1C allele.
The researchers found that, among CLL patients, rs45446698 (and, therefore, the CYP3A7*1C allele) was associated with a 62% increased risk of disease progression (P=0.03).
Among breast cancer patients, rs45446698 was associated with a 74% increased risk of breast cancer mortality (P=0.03). And among the lung cancer patients, the SNP was associated with a 43% increased risk of death from any cause (P=0.009).
The researchers also found borderline evidence of a statistical interaction between the CYP3A7*1C allele, treatment of patients with a cytotoxic agent that is a CYP3A substrate, and clinical outcome (P=0.06).
“Even though we did not see a statistically significant difference when stratifying patients by treatment with a CYP3A7 substrate, the fact that we see the same effect in 3 very different cancer types suggests to me that it is more likely to be something to do with treatment than the disease itself,” Dr Fletcher said.
“However, we are looking at ways of replicating these results in additional cohorts of patients and types of cancer, as well as overcoming the limitations of this study.”
Dr Fletcher explained that the main limitation of this study is that the researchers used samples and clinical information collected for other studies. So they did not have the same clinical information for each patient, and the samples were collected at different time points and for patients treated with various drugs.
She also noted that the researchers were not able to determine how quickly the patients broke down their treatments.
This study was supported by Sanofi-Aventis, Breast Cancer Now, Bloodwise, Cancer Research UK, the Medical Research Council, the Cridlan Trust, and the Helen Rollason Cancer Charity. The authors’ institutions received funding from the National Health Service of the United Kingdom.
A form of the CYP3A7 gene is associated with poor outcomes in chronic lymphocytic leukemia (CLL) and other cancers, according to a study published in Cancer Research.
Among patients with CLL, breast cancer, or lung cancer, those with the CYP3A7*1C allele were more likely than those without it to experience disease progression or death.
Researchers believe this may be related to how patients metabolize treatment.
“The CYP3A7 gene encodes an enzyme that breaks down all sorts of naturally occurring substances—such as sex steroids like estrogen and testosterone—as well as a wide range of drugs that are used in the treatment of cancer,” said Olivia Fletcher, PhD, of The Institute of Cancer Research in London, UK.
“The CYP3A7 gene is normally turned on in an embryo and then turned off shortly after a baby is born, but individuals who have 1 or more copies of the CYP3A7*1C form of the gene turn on their CYP3A7 gene in adult life.”
“We found that individuals with breast cancer, lung cancer, or CLL who carry 1 or more copies of the CYP3A7*1C allele tend to have worse outcomes. One possibility is that these patients break down the drugs that they are given to treat their cancer too fast. However, further independent studies that replicate our findings in larger numbers of patients and rule out biases are needed before we could recommend any changes to the treatment that cancer patients with the CYP3A7*1C allele receive.”
To assess the impact of the CYP3A7*1C allele on patient outcomes, Dr Fletcher and her colleagues analyzed DNA samples from 1008 breast cancer patients, 1142 patients with lung cancer, and 356 patients with CLL.
The team looked for the presence of the single nucleotide polymorphism (SNP) rs45446698. Dr Fletcher explained that rs45446698 is 1 of 7 SNPs that cluster together to form the CYP3A7*1C allele.
The researchers found that, among CLL patients, rs45446698 (and, therefore, the CYP3A7*1C allele) was associated with a 62% increased risk of disease progression (P=0.03).
Among breast cancer patients, rs45446698 was associated with a 74% increased risk of breast cancer mortality (P=0.03). And among the lung cancer patients, the SNP was associated with a 43% increased risk of death from any cause (P=0.009).
The researchers also found borderline evidence of a statistical interaction between the CYP3A7*1C allele, treatment of patients with a cytotoxic agent that is a CYP3A substrate, and clinical outcome (P=0.06).
“Even though we did not see a statistically significant difference when stratifying patients by treatment with a CYP3A7 substrate, the fact that we see the same effect in 3 very different cancer types suggests to me that it is more likely to be something to do with treatment than the disease itself,” Dr Fletcher said.
“However, we are looking at ways of replicating these results in additional cohorts of patients and types of cancer, as well as overcoming the limitations of this study.”
Dr Fletcher explained that the main limitation of this study is that the researchers used samples and clinical information collected for other studies. So they did not have the same clinical information for each patient, and the samples were collected at different time points and for patients treated with various drugs.
She also noted that the researchers were not able to determine how quickly the patients broke down their treatments.
This study was supported by Sanofi-Aventis, Breast Cancer Now, Bloodwise, Cancer Research UK, the Medical Research Council, the Cridlan Trust, and the Helen Rollason Cancer Charity. The authors’ institutions received funding from the National Health Service of the United Kingdom.