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FDA Actions & Updates

The latest approvals, designations, and new indications from the U.S. Food and Drug Administration for oncology drugs.

Thursday, April 09, 2015

The Food and Drug Administration has given Cometriq (cabozantinib) Fast Track status for the treatment of patients with advanced renal cell carcinoma (RCC) who have received one prior therapy.


Cabozantinib, made by Exelixis, inhibits the activity of multiple tyrosine kinases including MET, VEGFRs, and RET. Cabozantinib is being investigated in the ongoing Phase III METEOR pivotal pivotal trial in patients with metastatic RCC who have had disease progression following treatment with at least one VEGFR tyrosine kinase inhibitor. Patients are randomized 1:1 to receive 60 mg of cabozantinib daily or 10 mg of everolimus daily.


The primary endpoint of the trial is progression-free survival, and secondary endpoints are overall survival and objective response rate. The company notes in a news release that “top-line” results from the trial are expected to be released in the second quarter of this year, and that the drug is also being investigated in a Phase III trial called CELESTIAL in second-line hepatocellular carcinoma (HCC).


Until relatively recently, treatments for metastatic RCC was considered limited to immunotherapy such as interleukin-2 and interferon. But with the introduction of targeted therapies for RCC about 10 years ago, four new therapies became available in the last five years, but with efficacy results that were generally the same. Moreover, there have been only modest improvements in progression-free survival in patients refractory to sunitinib, the commonly used first-line therapy.


Cometriq is already approved for treatment of progressive, metastatic medullary thyroid cancer.


The drug has serious and sometimes fatal side effects: gastrointestinal perforations and fistulas; severe and sometimes fatal hemorrhage; increased thrombotic events including heart attacks; wound complications;

increased hypertension; osteonecrosis of the jaw; palmar-plantar erythrodysesthesia syndrome; and kidney problems. Other adverse effects include reversible posterior leukoencephalopathy syndrome, diarrhea, stomatitis, palmar-plantar erythrodysesthesia syndrome (PPES), decreased weight, decreased appetite, nausea, fatigue, oral pain, hair color changes, dysgeusia, hypertension, abdominal pain, and constipation.


The most common laboratory abnormalities are increased AST, increased ALT, lymphopenia, increased alkaline phosphatase, hypocalcemia, neutropenia, thrombocytopenia, hypophosphatemia, and hyperbilirubinemia.

Tuesday, April 07, 2015

The Food and Drug Administration has granted Breakthrough Therapy Designation to rucaparib as monotherapy for patients with advanced ovarian cancer who have received at least two lines of prior platinum-containing therapy, and who have BRCA-mutated tumors (including both germline BRCA [gBRCA] and somatic BRCA [sBRCA] mutations.


Rucaparib, made by Clovis Oncology, is an oral, potent inhibitor of PARP1 and PARP2 being developed for the treatment of platinum-sensitive ovarian cancer, specifically in patients with tumors with BRCA mutations and other DNA repair deficiencies beyond BRCA—i.e., “BRCA-like” or “BRCAness.”


The Breakthrough Therapy designation was granted based on interim efficacy and safety results from two ongoing Phase II studies of rucaparib in ovarian cancer, including a Phase II study in women with gBRCA mutations, and the ARIEL2 treatment study.


A news release from the company noted that a clinical data update from the ARIEL2 study presented last week at the Annual Meeting on Women’s Cancer demonstrated that seventy percent (16 of 23) of evaluable BRCA-mutant patients achieved a RECIST and/or CA-125 response, and 65% (15 of 23) achieved a RECIST response. Responses were observed in both germline and somatic BRCA-mutant tumors.


“Women with ovarian cancer are in need of better therapeutic options, and there is great focus on the potential of PARP inhibitors; data presented to date in mutant BRCA patients treated with rucaparib are very encouraging, as is the Breakthrough Therapy designation conferred by the FDA,” Robert L. Coleman, MD, one of the two principal investigators of the ARIEL2 study said in a news release. He is Professor & Deputy Chairman and Vice Chair of  Clinical Research and the Ann Rife Cox Chair in Gynecology in the Department of Gynecologic Oncology and Reproductive Medicine at the University of Texas MD Anderson Cancer Center.


“I am very enthusiastic about the substantive progress made by Clovis with both rucaparib and its patient selection tool that appears to be moving beyond BRCA to efficiently identify responder versus non-responder populations. Continuing successful development of this drug and its companion diagnostic will be a huge advance for women with this disease. Importantly, these data suggest that the majority of women tested might benefit from rucaparib treatment. We hope that the ARIEL2 extension study in around 300 women, and the randomized ARIEL3 trial in 540 women, will offer definitive support both for rucaparib and the companion diagnostic.”


The new data also found that rucaparib is well tolerated: At the recommended Phase II dose of 600 mg BID, the most common treatment-related adverse events reported in 15 percent or more of all 121 patients were nausea, fatigue, transient ALT/AST elevations, dysgeusia, constipation, anemia/low hemoglobin, decreased appetite, vomiting, and diarrhea. Almost all were Grades 1 or 2: the only common grade 3/4 toxicity was anemia or low hemoglobin.


The release from the company notes that another update of rucaparib clinical data, including outcomes data on the complete Part One ARIEL2 patient population, will be presented in an oral presentation at the American Society of Clinical Oncology Annual Meeting.


The aim of ARIEL (Assessment of Rucaparib in Ovarian Cancer Trial) is to accurately and prospectively identify patients with tumor genomics associated with benefit from rucaparib therapy. The global ARIEL2 study, initiated in Q4 2013, has completed enrollment of 206 ovarian cancer patients with relapsed, platinum-sensitive disease. The single-arm, open-label Phase II study is designed to prospectively test molecular features that predict sensitivity to rucaparib using DNA sequencing to evaluate each patient’s tumor.


ARIEL2 was recently expanded into a registration study (the ARIEL2 extension), which will include an additional approximately 300 women with recurrent disease after at least three prior lines of chemotherapy, and data from this study are planned to serve as the basis of a New Drug Application (NDA) filing for the treatment of ovarian cancer next year.


The global ARIEL3 pivotal study is currently enrolling a total of 540 patients, in a randomized, double-blind Phase III study that compares the effects of rucaparib versus placebo. The study will evaluate whether maintenance rucaparib treatment in platinum-sensitive, high-grade ovarian cancer patients can extend the period of time for which a response to a prior chemotherapy is maintained. Efficacy is assessed in a pre-specified step-down manner, first in tumor BRCA-mutant patients, then in a larger group of patients with the BRCA-like signature, and finally in all randomized patients. Clovis notes that it expects to complete enrollment within the next year.


In addition to the ARIEL program in ovarian cancer, the company is also exploring rucaparib in other solid tumor types with significant BRCA and BRCA-like populations including breast, gastroesophageal, and pancreatic.

Friday, April 03, 2015

The Food and Drug Administration has granted Orphan Drug designation to IMO-8400, an antagonist of the endosomal Toll-like receptors (TLRs) 7, 8 and 9, to treat patients with diffuse large B-cell lymphoma (DLBCL).


A news release from the manufacturer, Idera Pharmaceuticals, notes that the company is conducting a clinical trial of IMO-8400 in patients with relapsed or refractory DLBCL harboring MYD88 L265P oncogenic mutation.


Preclinical trials have shown that in B-cell lymphomas characterized by the MYD88 L265P oncogenic mutation, including DLBCL, TLR signaling is over-activated, allowing tumor cell survival and proliferation.


The new trial's objectives are to evaluate the safety, tolerability, and clinical activity of the three dose-escalation groups of IMO-8400 administered subcutaneously.


"We continue to advance our efforts in DLBCL, as well as our ongoing clinical trial in Waldenstrom's macroglobulinemia, which we expect to complete and have full data available in the fourth quarter of this year," said Idera’s Interim Chief Medical Officer, James J. O'Leary, MD.

Tuesday, March 31, 2015

The U.S. Food and Drug Administration has approved Jadenu (deferasirox) tablets for the treatment of patients as young as 2 with chronic iron overload due to blood transfusions, and for the treatment of patients as young as 10 with chronic iron overload in non-transfusion-dependent thalassemia syndrome (NTDT).


Jadenu is a new oral formulation of Exjade (also deferasirox) tablets for oral suspension. Exjade is a dispersible tablet that must be mixed in liquid and taken on an empty stomach, whereas Jadenu oral tablets can be swallowed whole, with or without a light meal. Long-term daily chelation therapy is often required for patients with myelodysplastic syndromes, sickle cell disease, or thalassemia who need repeated blood transfusions.


Jadenu is being approved under the FDA’s accelerated approval program, which allows approval of a drug to treat a serious or life-threatening disease based on clinical data showing the drug has an effect on a surrogate endpoint reasonably likely to predict clinical benefit to patients. This program provides earlier patient access to promising new drugs while the company conducts confirmatory clinical trials. Continued approval for these indications for Jadenu may be contingent upon verification and description of clinical benefit in confirmatory trials.


This FDA approval for Jadenu is based on equivalence to Exjade as demonstrated in pharmacokinetic studies of healthy volunteers. There are ongoing studies to find out how Jadenu works over a longer period of time.


The most common side effects for deferasirox are: nausea, vomiting, stomach pain, diarrhea, rash, and increased kidney laboratory values. Other serious reactions for deferasirox (since it has been marketed) have included neutropenia, agranulocytosis, worsening anemia, thrombocytopenia, serious allergic reactions (including swelling of throat), severe skin reactions (including Stevens Johnson syndrome and erythema multiforme), decreased hearing, and vision changes.


Jadenu is not intended for use by patients with pre-existing severe kidney and liver problems; high-risk myelodysplastic syndromes; advanced cancer; low platelet counts; or an allergy to Jadenu.


Jadenu is marketed by Novartis.

Monday, March 30, 2015

The U.S. Food and Drug Administration has approved a label update for Zytiga (abiraterone acetate) plus prednisone for patients with metastatic castration-resistant prostate cancer who have not received chemotherapy. The updated label includes the final analysis data from the Phase III randomized, double-blind, placebo-controlled COU-AA-302 study to evaluate the drug’s efficacy. The updated data from that study were presented at the European Society for Medical Oncology 2014 Congress last year, and were recently published in The Lancet Oncology (OT 3/25/15 issue).


“This analysis adds to the robust body of clinical data supporting Zytiga as an important treatment option for men with metastatic castration-resistant prostate cancer," the study’s lead investigator, Charles Ryan, MD, Professor of Clinical Medicine and Urology at the University of California, San Francisco, said in a news release 


The updated data showed Zytiga plus prednisone significantly prolonged median overall survival (34.7 months), compared with placebo plus prednisone in patients (30.3 months), after a follow up of 49.2-months. Additionally, there were no notable changes in the safety profile of Zytiga reported in the final analysis, since the previously reported interim analyses.


Zytiga works by blocking CYP17-mediated androgen production—which fuels prostate cancer growth—at three sources: in the testes, adrenals and the prostate tumor tissue. Initial approval of the drug for the treatment of patients with metastatic castration-resistant prostate cancer was based on data from a second interim analysis of the COU-AA-302 study, which included 1,088 men with metastatic castration-resistant prostate cancer who had not received prior chemotherapy (OT 5/25/11 issue).


Zytiga is not indicated for use in women. The most common adverse reactions (>10%) are fatigue, joint swelling or discomfort, edema, hot flush, diarrhea, vomiting, cough, hypertension, dyspnea, urinary tract infection, and contusion. The most common laboratory abnormalities (>20%) are anemia, elevated alkaline phosphatase, hypertriglyceridemia, lymphopenia, hypercholesterolemia, hyperglycemia, elevated AST, hypophosphatemia, elevated ALT, and hypokalemia.


Zytiga is marketed by Janssen.

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