On July 20, 2015 NIH reported that a clinical trial has shown that patients with a specific molecular subtype of diffuse large B-cell lymphoma (DLBCL) are more likely to respond to the drug ibrutinib (Imbruvica) than patients with another molecular subtype of the disease (Press release, NIH, JUL 20, 2015, View Source [SID:1234506540]). The study appeared online July 20, 2015, in Nature Medicine. Schedule your 30 min Free 1stOncology Demo! In this phase II trial, patients with the activated B-cell-like (ABC) subtype of DLBCL were more likely to respond to ibrutinib than patients with the germinal center B-cell-like (GCB) subtype of DLBCL. The trial was jointly conducted by the National Cancer Institute (NCI), which is part of the National Institutes of Health, and Pharmacyclics, Sunnyvale, California.
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Lymphomas are caused by an abnormal proliferation of white blood cells and can occur at any age. DLBCL is an aggressive form of lymphoma that grows rapidly but is potentially curable. The disease accounts for approximately 30 percent of newly diagnosed lymphomas in the United States.
Several years ago, NCI scientists identified the two primary subtypes of DLBCL based on characteristic patterns of gene activity within the lymphoma cells. The discovery of these subtypes suggested to the researchers that targeted treatments could be developed for each subtype.
Building on this work, the trial enrolled 80 patients with DLBCL that had relapsed or had not responded to prior treatment. All patients received ibrutinib. Tumor responses were seen in 25 percent of patients overall, including eight patients with complete responses and 12 with partial responses.
For the study population as a whole, after a median follow-up of 11.5 months, the median progression-free survival (the time until the disease worsened) and overall survival were 1.6 months and 6.4 months, respectively.
An analysis based on disease subtype showed that ibrutinib produced complete or partial responses in 37 percent (14 of 38) of patients with ABC DLBCL but only 5 percent (1 of 20) of patients with GCB DLBCL. Based on these results, the researchers concluded that, for future clinical trials involving ibrutinib, the ABC DLBCL gene signature could be used to identify patients who would be more likely to respond to the drug.
DLBCL originates from B cells, which play a crucial role in the body’s immune response. The target for ibrutinib, an enzyme called Bruton’s tyrosine kinase (BTK), is a key component of B-cell receptor signaling. The new study provides the first clinical evidence that ABC but not GBC tumors may produce abnormal B-cell receptor signals that promote the survival of cancer cells by activating BTK, thereby accounting for the sensitivity of ABC tumors to ibrutinib.
"Clinical trials such as this are critical for translating basic molecular findings into effective therapies," said Louis Staudt, M.D., Ph.D., NCI Center for Cancer Genomics, who co-led the study and discovered the role of B-cell receptor signaling in ABC DLBCL. Study co-leader Wyndham Wilson, M.D., Ph.D., NCI Center for Cancer Research, added, "This is the first clinical study to demonstrate the importance of precision medicine in lymphomas."
Based on this study’s results, an international phase III trial of standard chemotherapy with or without ibrutinib in patients with DLBCL, excluding the GCB subtype, is being conducted by Janssen Pharmaceuticals, Titusville, New Jersey, in collaboration with Drs. Wilson and Staudt. (ClinicalTrials.gov NCT01855750. This is the first time a phase III trial has been designed to selectively enroll patients with a particular molecular subtype of DLBCL. The study’s objective is to determine if the addition of ibrutinib to standard chemotherapy can increase the cure rate of patients with ABC DLBCL.
Ibrutinib has been approved by the U.S. Food and Drug Administration for the treatment of certain patients with several other cancers, including mantle cell lymphoma, chronic lymphocytic leukemia, and Waldenström macroglobulinemia.
Author: [email protected]
Heron Therapeutics Resubmits SUSTOL® New Drug Application to FDA
On July 20, 2015 Heron Therapeutics, Inc. (NASDAQ:HRTX), a biotechnology company focused on improving the lives of patients by developing best-in-class medicines that address major unmet medical needs,reported that it has resubmitted its New Drug Application (NDA) for SUSTOL (granisetron) Injection, extended release, for the prevention of acute and delayed chemotherapy-induced nausea and vomiting (CINV) associated with moderately emetogenic chemotherapy (MEC) or highly emetogenic chemotherapy (HEC) regimens, to the U.S. Food and Drug Administration (FDA) (Press release, Heron Therapeutics, JUL 20, 2015, View Source;p=RssLanding&cat=news&id=2068986 [SID:1234506539]).
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Heron expects confirmation of acceptance from the FDA and a Prescription Drug User Fee Act (PDUFA) goal date within the next few weeks. The Company anticipates a six-month review by the FDA.
The NDA filing includes data from the MAGIC study, Heron’s recently completed, multi-center, placebo-controlled, Phase 3 study in patients receiving HEC agents. The MAGIC study evaluated the efficacy and safety of SUSTOL as part of a three-drug regimen with the intravenous (IV) neurokinin-1 (NK1) receptor antagonist fosaprepitant and the IV/oral corticosteroid dexamethasone for the prevention of delayed nausea and vomiting in patients receiving HEC. The MAGIC study, which was conducted entirely in the U.S. using the 2011 ASCO (Free ASCO Whitepaper) guidelines for classification of emetogenic potential, is the only Phase 3 CINV study to-date to use the currently recommended, standard-of-care, three-drug regimen for CINV prophylaxis in a HEC population as the comparator: a 5-HT3 receptor antagonist, fosaprepitant and dexamethasone.
The MAGIC study’s primary endpoint was achieved. Specifically, the percentage of patients who achieved a Complete Response was significantly higher in the SUSTOL arm compared with the comparator arm (p=0.014). Significant benefit was also observed in the reduction in episodes of nausea, which has the greatest impact on patient quality of life. Data from a previous Phase 3 study of more than 1,300 patients, which was previously submitted to the FDA, demonstrated SUSTOL’s efficacy in the prevention of acute and delayed CINV associated with MEC regimens and acute CINV associated with HEC regimens.
"The rapid resubmission of the NDA for SUSTOL, the first and only 5-HT3 receptor antagonist with extended-release technology and 5-day CINV prevention in both MEC and HEC, is a major milestone for Heron Therapeutics," commented Barry D. Quart, Pharm.D., Chief Executive Officer of Heron. "We look forward to working closely with the FDA during the SUSTOL NDA review period, as we believe SUSTOL has the potential to improve the lives of patients suffering from CINV by significantly reducing both nausea and vomiting associated with MEC or HEC regimens."
About SUSTOL for Chemotherapy-Induced Nausea and Vomiting
SUSTOL (granisetron) Injection, extended release, which utilizes Heron’s proprietary Biochronomer drug delivery technology, is Heron’s novel, long-acting formulation of granisetron for the prevention of chemotherapy-induced nausea and vomiting (CINV). Granisetron, an FDA-approved 5-hydroxytryptamine type 3 (5-HT3) receptor antagonist was selected due to its broad use by physicians based on a well-established record of safety and efficacy. SUSTOL has been shown to maintain therapeutic drug levels of granisetron for five days with a single subcutaneous injection. SUSTOL is being developed for the prevention of both acute (day 1 following the administration of chemotherapy agents) and delayed (days 2-5 following the administration of chemotherapy agents) CINV associated with moderately emetogenic chemotherapy (MEC) or highly emetogenic chemotherapy (HEC). While other 5-HT3 antagonists are approved for the prevention of CINV, SUSTOL is the first agent in the class to demonstrate efficacy in reducing the incidence of delayed CINV in patients receiving HEC, a major unmet medical need, in a randomized Phase 3 study.
Affecting 70-80% of patients undergoing chemotherapy, CINV is one of the most debilitating side effects of such treatments, often attributed as a leading cause of premature discontinuation of cancer treatment. 5-HT3 receptor antagonists have been shown to be among the most effective and preferred treatments for CINV. However, an unmet medical need exists for patients suffering from CINV during the delayed phase, which occurs on days 2-5 following the administration of chemotherapy agents. Only one 5-HT3 receptor antagonist is approved for the prevention of delayed CINV associated with MEC, and no 5-HT3 receptor antagonists are approved for prevention of delayed CINV associated with HEC.
SUSTOL was the subject of a recently completed, multi-center, placebo-controlled, Phase 3 clinical study in patients receiving HEC regimens known as MAGIC. The MAGIC study evaluated the efficacy and safety of SUSTOL as part of a three-drug regimen with the intravenous (IV) neurokinin-1 (NK1) receptor antagonist fosaprepitant and the IV/oral corticosteroid dexamethasone. The MAGIC study, which was conducted entirely in the U.S. using the 2011 ASCO (Free ASCO Whitepaper) guidelines for classification of emetogenic potential, is the only Phase 3 CINV prophylaxis study in a HEC population performed to date to use the currently recommended, standard-of-care, three-drug regimen as a comparator: a 5-HT3 receptor antagonist, fosaprepitant, and dexamethasone. The study’s primary endpoint was achieved. Specifically, the percentage of patients who achieved a Complete Response in the delayed phase was significantly higher in the SUSTOL arm compared with the comparator arm (p=0.014). Heron resubmitted its New Drug Application (NDA) for SUSTOL to the U.S. Food and Drug Administration (FDA) in July 2015. SUSTOL is not approved by the FDA or any other regulatory authority.
Delcath Receives Orphan Drug Designation From FDA For Melphalan To Treat Cholangiocarcinoma
On July 20, 2015 Delcath Systems, Inc. (NASDAQ: DCTH), a specialty pharmaceutical and medical device company focused on oncology with an emphasis on the treatment of primary and metastatic liver cancers, reported that the U.S. Food and Drug Administration (FDA) Office of Orphan Products Development (OOPD) has granted Orphan Drug Designation for melphalan for the treatment of cholangiocarcinoma (Press release, Delcath Systems, JUL 20, 2015, View Source [SID:1234506537]). Schedule your 30 min Free 1stOncology Demo! The OOPD is tasked with evaluating the scientific and clinical data submissions from sponsors to identify and designate products as promising for rare diseases and to further advance scientific development of such promising medical products.
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Orphan drug designation provides certain exclusivity benefits, tax credits for certain research and a waiver of the New Drug Application user fee. Cholangiocarcinoma is recognized by the FDA as an orphan disease, usually defined as a condition that affects fewer than 200,000 people nationwide.
Intrahepatic cholangiocarcinoma (ICC), a sub-category of cholangiocarcinoma, is a tumor in the bile duct that arises within the liver. It is the second most common primary liver tumor and represents approximately 15% of new HCC cases diagnosed annually. Surgical resection, the standard of care, is not possible for an estimated 80% to 90% of patients diagnosed with ICC.
The Company recently announced the expansion of its global Phase 2 clinical study in primary liver cancer (HCC) to include an ICC cohort, which is investigating the safety and efficacy of Melphalan/HDS treatment in patients with unresectable ICC confined to the liver. The study is being conducted at the same hospitals in Europe participating in the Company’s Phase 2 HCC trial, and is expected to enroll 11 patients. The ICC cohort will evaluate tumor response (objective response rate) as measured by modified Response Evaluation Criteria in Solid Tumor (mRECIST), and will assess progression-free survival and safety. Additional analyses will be conducted to characterize the systemic exposure of melphalan administered by Melphalan/HDS, as well as to assess patient-reported clinical outcomes, or quality-of-life.
"We are pleased with the receipt of orphan drug designation for melphalan in the treatment of patients with cholangiocarcinoma as it is a key milestone that supports our broader regulatory and development strategy for our Melphalan/Hepatic Delivery System (Melphalan/HDS) as a therapy for primary and metastatic liver cancers," said Jennifer Simpson, Ph.D., M.S.N., C.R.N.P., President and Chief Executive Officer of Delcath. "ICC is a disease of significant unmet medical need and our Melphalan/HDS treatment may offer clinical benefit for ICC patients who face limited treatment options."
CheckMate -025, a Pivotal Phase III Opdivo (nivolumab) Renal Cell Cancer Trial, Stopped Early
On July 20, 2015 Bristol-Myers Squibb Company (NYSE:BMY)reported that an open-label, randomized Phase III study evaluating Opdivo (nivolumab) versus everolimus in previously-treated patients with advanced or metastatic renal cell carcinoma (RCC) was stopped early because an assessment conducted by the independent Data Monitoring Committee (DMC) concluded that the study met its endpoint, demonstrating superior overall survival in patients receiving Opdivo compared to the control arm (Press release, Bristol-Myers Squibb, JUL 20, 2015, View Source [SID:1234506536]). Schedule your 30 min Free 1stOncology Demo! The company looks forward to sharing these data with health authorities soon.
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"The results of CheckMate -025 mark the first time an Immuno-Oncology agent has demonstrated a survival advantage in advanced renal cell carcinoma, a patient group that currently has limited treatment options," said Michael Giordano, senior vice president, Head of Development, Oncology, Bristol-Myers Squibb. "Through our Opdivo clinical development program, we aim to redefine treatment expectations for patients with advanced RCC by providing improved survival."
CheckMate -025 investigators are being informed of the decision to stop the comparative portion of the trial. Bristol-Myers Squibb is working to ensure that eligible patients will be informed of the opportunity to continue or start treatment with Opdivo in an open-label extension as part of the company’s commitment to providing patient access to Opdivo, and characterizing long-term survival. The company will complete a full evaluation of the final CheckMate -025 data and work with investigators on the future presentation and publication of the results.
About CheckMate -025
CheckMate -025 is a Phase III, open-label, randomized study of Opdivo versus everolimus in previously-treated patients with advanced or metastatic clear-cell renal cell carcinoma. The trial randomized 821 patients to receive either nivolumab 3 mg/kg intravenously every two weeks or everolimus 10 mg tablets by mouth daily until documented disease progression or unacceptable toxicity. The primary endpoint is overall survival. Secondary endpoints include objective response rate and progression-free survival.
About Renal Cell Carcinoma
Renal cell carcinoma (RCC) is the most common type of kidney cancer in adults, accounting for more than 100,000 deaths worldwide each year. Clear-cell RCC is the most prevalent type of RCC and constitutes 80 percent to 90 percent of all cases. RCC is approximately twice as common in men as in women, with the highest rates of the disease in North America and Europe. Globally, the five-year survival rate for those diagnosed with metastatic, or advanced kidney cancer, is 12.1 percent.
Immuno-Oncology at Bristol-Myers Squibb
Surgery, radiation, cytotoxic or targeted therapies have represented the mainstay of cancer treatment over the last several decades, but long-term survival and a positive quality of life have remained elusive for many patients with advanced disease.
To address this unmet medical need, Bristol-Myers Squibb is leading research in an innovative field of cancer research and treatment known as Immuno-Oncology, which involves agents whose primary mechanism is to work directly with the body’s immune system to fight cancer. The company is exploring a variety of compounds and immunotherapeutic approaches for patients with different types of cancer, including researching the potential of combining Immuno-Oncology agents that target different pathways in the treatment of cancer.
Bristol-Myers Squibb is committed to advancing the science of Immuno-Oncology, with the goal of changing survival expectations and the way patients live with cancer.
About Opdivo
Opdivo is a programmed death-1 (PD-1) immune checkpoint inhibitor that has received approval from the U.S. Food and Drug Administration (FDA) as a monotherapy in two cancer indications. On March 4, 2015, Opdivo received FDA approval for the treatment of patients with metastatic squamous non-small cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapy.
In the U.S., Opdivo is also indicated for the treatment of patients with unresectable or metastatic melanoma and disease progression following Yervoy (ipilimumab) and, if BRAF V600 mutation positive, a BRAF inhibitor. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. Opdivo became the first PD-1 immune checkpoint inhibitor to receive regulatory approval anywhere in the world on July 4, 2014 when Ono Pharmaceutical Co. announced that it received manufacturing and marketing approval in Japan for the treatment of patients with unresectable melanoma. Bristol-Myers Squibb has a broad, global development program to study Opdivo in multiple tumor types consisting of more than 50 trials – as monotherapy or in combination with other therapies – in which more than 8,000 patients have been enrolled worldwide.
IMPORTANT SAFETY INFORMATION
Immune-Mediated Pneumonitis
Severe pneumonitis or interstitial lung disease, including fatal cases, occurred with OPDIVO treatment. Across the clinical trial experience in 691 patients with solid tumors, fatal immune-mediated pneumonitis occurred in 0.7% (5/691) of patients receiving OPDIVO; no cases occurred in Trial 1 or Trial 3. In Trial 1, pneumonitis, including interstitial lung disease, occurred in 3.4% (9/268) of patients receiving OPDIVO and none of the 102 patients receiving chemotherapy. Immune-mediated pneumonitis occurred in 2.2% (6/268) of patients receiving OPDIVO; one with Grade 3 and five with Grade 2. In Trial 3, immune-mediated pneumonitis occurred in 6% (7/117) of patients receiving OPDIVO, including, five Grade 3 and two Grade 2 cases. Monitor patients for signs and symptoms of pneumonitis. Administer corticosteroids for Grade 2 or greater pneumonitis. Permanently discontinue OPDIVO for Grade 3 or 4 and withhold OPDIVO until resolution for Grade 2.
Immune-Mediated Colitis
In Trial 1, diarrhea or colitis occurred in 21% (57/268) of patients receiving OPDIVO and 18% (18/102) of patients receiving chemotherapy. Immune-mediated colitis occurred in 2.2% (6/268) of patients receiving OPDIVO; five with Grade 3 and one with Grade 2. In Trial 3, diarrhea occurred in 21% (24/117) of patients receiving OPDIVO. Grade 3 immune-mediated colitis occurred in 0.9% (1/117) of patients. Monitor patients for immune-mediated colitis. Administer corticosteroids for Grade 2 (of more than 5 days duration), 3, or 4 colitis. Withhold OPDIVO for Grade 2 or 3. Permanently discontinue OPDIVO for Grade 4 colitis or recurrent colitis upon restarting OPDIVO.
Immune-Mediated Hepatitis
In Trial 1, there was an increased incidence of liver test abnormalities in the OPDIVO-treated group as compared to the chemotherapy-treated group, with increases in AST (28% vs 12%), alkaline phosphatase (22% vs 13%), ALT (16% vs 5%), and total bilirubin (9% vs 0). Immune-mediated hepatitis occurred in 1.1% (3/268) of patients receiving OPDIVO; two with Grade 3 and one with Grade 2. In Trial 3, the incidences of increased liver test values were AST (16%), alkaline phosphatase (14%), ALT (12%), and total bilirubin (2.7%). Monitor patients for abnormal liver tests prior to and periodically during treatment. Administer corticosteroids for Grade 2 or greater transaminase elevations. Withhold OPDIVO for Grade 2 and permanently discontinue OPDIVO for Grade 3 or 4 immune-mediated hepatitis.
Immune-Mediated Nephritis and Renal Dysfunction
In Trial 1, there was an increased incidence of elevated creatinine in the OPDIVO-treated group as compared to the chemotherapy-treated group (13% vs 9%). Grade 2 or 3 immune-mediated nephritis or renal dysfunction occurred in 0.7% (2/268) of patients. In Trial 3, the incidence of elevated creatinine was 22%. Immune-mediated renal dysfunction (Grade 2) occurred in 0.9% (1/117) of patients. Monitor patients for elevated serum creatinine prior to and periodically during treatment. For Grade 2 or 3 serum creatinine elevation, withhold OPDIVO and administer corticosteroids; if worsening or no improvement occurs, permanently discontinue OPDIVO. Administer corticosteroids for Grade 4 serum creatinine elevation and permanently discontinue OPDIVO.
Immune-Mediated Hypothyroidism and Hyperthyroidism
In Trial 1, Grade 1 or 2 hypothyroidism occurred in 8% (21/268) of patients receiving OPDIVO and none of the 102 patients receiving chemotherapy. Grade 1 or 2 hyperthyroidism occurred in 3% (8/268) of patients receiving OPDIVO and 1% (1/102) of patients receiving chemotherapy. In Trial 3, hypothyroidism occurred in 4.3% (5/117) of patients receiving OPDIVO. Hyperthyroidism occurred in 1.7% (2/117) of patients, including one Grade 2 case. Monitor thyroid function prior to and periodically during treatment. Administer hormone replacement therapy for hypothyroidism. Initiate medical management for control of hyperthyroidism.
Other Immune-Mediated Adverse Reactions
In Trial 1 and 3 (n=385), the following clinically significant immune-mediated adverse reactions occurred in <2% of OPDIVO-treated patients: adrenal insufficiency, uveitis, pancreatitis, facial and abducens nerve paresis, demyeliniation, autoimmune neuropathy, motor dysfunction, and vasculitis. Across clinical trials of OPDIVO administered at doses 3 mg/kg and 10 mg/kg, additional clinically significant, immune-mediated adverse reactions were identified: hypophysitis, diabetic ketoacidosis, hypopituitarism, Guillain-Barré syndrome, and myasthenic syndrome. Based on the severity of adverse reaction, withhold OPDIVO, administer high-dose corticosteroids, and, if appropriate, initiate hormone- replacement therapy.
Embryofetal Toxicity
Based on its mechanism of action, OPDIVO can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with OPDIVO and for at least 5 months after the last dose of OPDIVO.
Lactation
It is not known whether OPDIVO is present in human milk. Because many drugs, including antibodies, are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from OPDIVO, advise women to discontinue breastfeeding during treatment.
Serious Adverse Reactions
In Trial 1, serious adverse reactions occurred in 41% of patients receiving OPDIVO. Grade 3 and 4 adverse reactions occurred in 42% of patients receiving OPDIVO. The most frequent Grade 3 and 4 adverse drug reactions reported in 2% to <5% of patients receiving OPDIVO were abdominal pain, hyponatremia, increased aspartate aminotransferase, and increased lipase.
In Trial 3, serious adverse reactions occurred in 59% of patients receiving OPDIVO. The most frequent serious adverse drug reactions reported in ≥2% of patients were dyspnea, pneumonia, chronic obstructive pulmonary disease exacerbation, pneumonitis, hypercalcemia, pleural effusion, hemoptysis, and pain.
Common Adverse Reactions
The most common adverse reactions (≥20%) reported with OPDIVO in Trial 1 were rash (21%) and in Trial 3 were fatigue (50%), dyspnea (38%), musculoskeletal pain (36%), decreased appetite (35%), cough (32%), nausea (29%), and constipation (24%).
BioMarin Provides Program Update for Talazoparib in Metastatic Breast Cancer
On July 20, 2015 BioMarin Pharmaceutical Inc. (Nasdaq:BMRN) reported an update on the ABRAZO Phase 2 study of its poly ADP-ribose polymerase (PARP) inhibitor, talazoparib (formerly referred to as BMN 673) for the treatment of patients with deleterious germline BRCA 1 or BRCA 2 mutations and locally advanced and/or metastatic breast cancer (Press release, BioMarin, JUL 20, 2015, View Source [SID:1234506535]). Schedule your 30 min Free 1stOncology Demo! The company announced that the ABRAZO Phase 2 trial has met the study’s protocol-specified threshold for documented tumor reduction (using the RECIST response rate criteria) in order to warrant expanding enrollment in the study from 70 to 140 patients. The ABRAZO study includes two cohorts of patients with BRCA mutated metastatic breast cancer. The first cohort consists of patients who have initially responded to a platinum-containing regimen then progressed, while the second cohort consists of patients who have received more than two prior chemotherapy regimens for metastatic disease. The protocol-specified expansion criteria requires that a minimum of five responses per cohort, of up to 35 patients, be observed in order to expand the study. The minimum of 5 responses was seen prior to full enrollment in each cohort.
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The ABRAZO study is the first study treating BRCA breast cancer patients with a PARP inhibitor monotherapy that has demonstrated activity in patients who are in a salvage setting defined as having failed at least two prior chemotherapy regimens for metastatic disease. In addition, this is the first reported data showing tumor reduction from a PARP inhibitor in BRCA breast cancer patients previously treated with a platinum regimen. The trial, now targeting enrollment of a total of 140 patients, is expected to be fully enrolled in the first quarter of 2016 with results expected by year end 2016. These interim results of the ABRAZO study are planned to be presented at an upcoming medical meeting in 2016.
"We are pleased to have met our protocol-specified criteria in the ABRAZO Phase 2 trial allowing us to expand enrollment and complete the study," said Hank Fuchs, M.D., Chief Medical Officer at BioMarin. "If successful, single agent efficacy in a salvage setting potentially could support registration, adoption and use by patients who have exhausted therapeutic options. We also are thrilled to have seen anti-tumor activity in patients previously treated with platinum regimens. This is an unprecedented finding in BRCA metastatic breast cancer, which may provide a further treatment option for these patients."
The company also updated guidance for completion of enrollment of the pivotal EMBRACA study, which the company now estimates to be in the first half of 2016. EMBRACA is a Phase 3, open-label, 2:1 randomized trial to compare the safety and efficacy of oral PARP inhibitor talazoparib versus protocol-specific physician’s choice in patients who have locally advanced and/or metastatic breast cancer with germline BRCA mutations. Prior guidance had been for enrollment of 430 patients by year end 2015. Since study initiation, a newly completed review of published data suggests that the median progression-free survival (PFS) is lower than originally estimated for the control arm in this patient population, and that fewer than the originally estimated 430 patients may need to be enrolled in order to achieve the targeted hazard ratio.
ABRAZO Trial Design
This is a Phase 2, 2-Stage, 2-Cohort Study of oral PARP inhibitor talazoparib (BMN 673) in patients with locally advanced and/or metastatic breast cancer with germline BRCA mutations.
The purpose of this study is to evaluate the safety and efficacy of talazoparib (BMN 673) in patients with locally advanced or metastatic breast cancer with a deleterious germline BRCA 1 or BRCA 2 mutation. Subjects will be assigned to either Cohort 1 or 2 based on prior chemotherapy for metastatic disease:
Cohort 1) Subjects who have previously responded (PR or CR) to a platinum-containing regimen for metastatic disease with disease progression > 8 weeks following the last dose of platinum
Cohort 2) Subjects who have received more than two prior chemotherapy regimens for metastatic disease and no prior platinum therapy for metastatic disease
EMBRACA Trial Design
This is a Phase 3, open-label, 2:1 randomized trial to compare the safety and efficacy of oral PARP inhibitor talazoparib (BMN 673) versus protocol-specific physician’s choice in patients who have locally advanced and/or metastatic breast cancer with germline BRCA mutations.
The primary objective of the study is to compare progression-free survival (PFS) of subjects treated with talazoparib (BMN 673) as a monotherapy relative to those treated with protocol-specific physician’s choice. The secondary objectives are to evaluate objective response rate (ORR) and overall survival (OS). Exploratory objectives are to evaluate duration of response (DOR) and health-related quality of life.
About Hereditary Breast Cancer with BRCA Mutation
BRCA1 and BRCA2 are human genes that belong to a class of genes known as tumor suppressors. Mutation of these genes has been linked to hereditary breast and ovarian cancer. A woman’s risk of developing breast and/or ovarian cancer is greatly increased if she inherits a deleterious (harmful) BRCA1 or BRCA2 mutation. Men with these mutations also have an increased risk of breast cancer. Both men and women who have harmful BRCA1 or BRCA2 mutations may be at increased risk of other cancers.
Source: National Cancer Institute at the National Institutes of Health View Source