On September 2, 2015 Bristol-Myers Squibb Company (NYSE:BMY) reported that the U.S. Food and Drug Administration (FDA) has accepted for filing and review the supplemental Biologics License Application (sBLA) for Opdivo for the treatment of previously treated patients with non-squamous (NSQ) non-small cell lung cancer (NSCLC) (Press release, Bristol-Myers Squibb, SEP 2, 2015, View Source [SID:1234507376]). Schedule your 30 min Free 1stOncology Demo! This sBLA seeks to expand the current indication for Opdivo in patients with previously treated squamous (SQ) NSCLC. The projected FDA action date is January 2, 2016.
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The agency has also granted this application priority review, and Opdivo Breakthrough Therapy Designation for this indication, underscoring the need for new treatments for this patient population, where currently a significant unmet medical need remains. According to the FDA, the criteria for Breakthrough Therapy Designation requires preliminary clinical evidence that demonstrates the drug may have substantial improvement on at least one clinically significant endpoint over available therapy.
"We are pleased with this important step forward in the FDA’s consideration to expand the use of Opdivo to include non-squamous non-small cell lung cancer patients, as well as the Breakthrough Therapy Designation," said Michael Giordano, senior vice president, head of Development, Oncology, Bristol-Myers Squibb. "From its inception, our clinical development program for Opdivo in lung cancer has been based on our deep scientific expertise and always with the goal of helping patients achieve gains in survival. We look forward to working with the FDA to make this treatment option available to more patients."
The submission is based on CheckMate -057, a Phase 3 study that evaluated the survival of patients with NSQ NSCLC who had progressed during or after one prior platinum doublet-based chemotherapy regimen. The positive results of a separate study, Checkmate -017, formed the basis of the current lung cancer indication; study -017 evaluated the survival of patients with SQ NSCLC who had progressed during or after one prior platinum doublet-based chemotherapy regimen. In both studies Opdivo demonstrated an overall survival benefit.
About Lung Cancer
Lung cancer is the leading cause of cancer deaths globally, resulting in more than 1.5 million deaths each year according the World Health Organization. NSCLC is one of the most common types of the disease and accounts for approximately 85 percent of cases. Survival rates vary depending on the stage and type of the cancer when it is diagnosed. Globally, the five-year survival rate for Stage I NSCLC is between 47 and 50 percent; for Stage IV NSCLC, the five-year survival rate drops to two percent.
About Opdivo
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.
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. 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. In the U.S., the FDA granted its first approval for Opdivo 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. On March 4, 2015, Opdivo received its second FDA approval for the treatment of patients with metastatic squamous non-small cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapy. On July 20, the European Commission approved Nivolumab BMS for the treatment of locally advanced or metastatic SQ NSCLC after prior chemotherapy.
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%).
VAXIN CHANGES COMPANY NAME TO ALTIMMUNE; MOVE REFLECTS COMPANY’S EXPANSION BEYOND VACCINES TO INCLUDE IMMUNOTHERAPEUTICS
On September 1, 2015 Vaxin Inc., a clinical stage immunotherapy and vaccine company, reported that it has changed its corporate name to Altimmune, Inc. Vaxin was founded in 1997 to pioneer new-generation vaccine technologies and products (Press release, Altimmune, SEP 1, 2015, View Source [SID1234517080]). Since then, the company has achieved steady success, developing promising vaccine candidates for biodefense and other public health needs, as well as animal health. In a strategic growth move earlier this year, the company acquired UK-based Immune Targeting Systems (ITS) and added prominent new investors to its syndicate. The acquisition vaulted Vaxin into the immunotherapeutics sector, growing its therapeutics expertise, expanding its market, and broadening its global footprint. The new name marks the next chapter for the newly combined company.
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"The Vaxin brand has served as a superb ambassador of our vaccine product family, but the expansion of our product platform calls for a new brand," said president and CEO, Bill Enright. "The name Altimmune reflects the novel solutions we bring to the broader biotech marketplace today. Bold emphasis on the immune system is intentional; it speaks to alternative therapies that stimulate immune responses for prevention and treatment of diseases. With some of today’s most exciting research discoveries happening in this area, our new name conveys a promise to deliver essential innovation to the space."
Beyond a Vaccine Company
The company name change marks a high point for Altimmune. Last month, the company initiated a first-inman phase I clinical trial of HepTcell (FP-02.2), an immunotherapeutic compound to treat and potentially cure, people chronically infected with the hepatitis B virus (HBV). Patient enrollment has begun for the multicenter trial to be conducted at seven sites in the United Kingdom. The study aims to recruit 72 patients with chronic HBV infection. The clinical trial initiation augments rising momentum for Altimmune’s vaccine products. In its latest success, the company demonstrated in pre-clinical studies that a single intranasal vaccination with its NasoShield anthrax vaccine was non-inferior to the protection conferred by two vaccinations of the currently licensed Anthrax Vaccine Absorbed (AVA; BioThrax). Intranasal delivery is generally believed to be a superior vaccination route because the mucosal immune response has been shown to be important for protection, particularly against respiratory pathogens. Importantly, NasoShield produced protective immunity with earlier onset and greater persistence than AVA, suggesting that NasoShield may offer both rapid and long-lasting protection with just a single dose. The study results were published in the April 2015 issue of the prestigious journal, Clinical Vaccine Immunology. 2 Altimmune is headquartered in Gaithersburg, Maryland, with operating sites in the UK and France.
Ignyta Announces Entrectinib Clinical Case Report Presentation at the 2015 World Conference on Lung Cancer
On September 01, 2015 Ignyta, Inc. (Nasdaq: RXDX), a precision oncology biotechnology company, reported that an abstract relating to entrectinib, the company’s proprietary oral tyrosine kinase inhibitor targeting solid tumors that harbor activating alterations to TrkA, TrkB, TrkC, ROS1 or ALK, has been selected for a mini-oral presentation at the 16th World Conference on Lung Cancer on September 9, 2015 in Denver, Colorado (Press release, Ignyta, SEP 1, 2015, View Source [SID:1234507379]). The presentation, which will be made by Anna F. Farago, M.D., Ph.D., of the Center for Thoracic Cancers at Massachusetts General Hospital, details a clinical case study in which entrectinib therapy resulted in rapid clinical improvement accompanied by radiographic evidence of a systemic partial response and near complete resolution of multiple CNS metastases in a patient with non-small cell lung cancer harboring an NTRK1 gene rearrangement whose disease had progressed after multiple prior therapies.
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"We are honored that the International Association for the Study of Lung Cancer’s Scientific Program Committee for the 2015 World Lung Conference has selected this abstract detailing how entrectinib treatment helped a patient in our Phase 1 clinical trial of entrectinib," said Pratik Multani, M.D., M.S., Chief Medical Officer of Ignyta. "We are looking forward to sharing this case study in this prestigious scientific forum, and to discussing our Phase 1 data and our future clinical development plans for entrectinib with key scientific and clinical experts during the World Lung conference."
Details of the presentation are as follows:
Title: Clinical Response to Entrectinib in a Patient with NTRK1-Rearranged Non-Small Cell Lung Cancer (NSCLC) (ID number 2913)
Date/time: Wednesday, September 9, 2015, 6:30 PM – 8:00 PM, Mountain time
Location: Four Seasons Ballroom, F3/F4
Presenter: Anna F. Farago, M.D., Ph.D., Center for Thoracic Cancers, Massachusetts General Hospital
Session: New Kinase Targets
CEL-SCI REPORTS AUGUST PATIENT ENROLLMENT FOR ITS PHASE 3 HEAD AND NECK CANCER TRIAL
On September 1, 2015 CEL-SCI Corporation (NYSE MKT: CVM) ("CEL SCI" or the "Company") reported that in the month of August it has enrolled 19 patients in its ongoing Phase 3 trial of its investigational immunotherapy Multikine* (Leukocyte Interleukin, Injection) in patients with advanced primary squamous cell carcinoma of the oral cavity/soft palate, a type of head and neck cancer (Press release, Cel-Sci, SEP 1, 2015, View Source [SID:1234507373]). Total patient enrollment is now 540 as of August 31, 2015 in the world’s largest Phase 3 study in head and neck cancer.
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"A lower enrollment number in the month of August was expected since the majority of our clinical sites are in Europe and the month of August is known to be a primary vacation time in Europe. We expect enrollment in the fall to increase rapidly again with the goal of being completely enrolled by March of next year," stated CEL-SCI Chief Executive Officer Geert Kersten.
A total of 880 patients are expected to be enrolled, through approximately 100 clinical centers in over 20 countries.
About the Multikine Phase 3 Study
The Multikine Phase 3 study is enrolling just diagnosed, not yet treated patients with advanced primary squamous cell carcinoma of the head and neck. The objective of the study is to demonstrate a statistically significant improvement in the overall survival of enrolled patients who are treated with the Multikine treatment regimen plus standard of care ("SOC") vs. subjects who are treated with SOC only. Standard of care for these patients consists of the surgical removal of the tumor and any locally involved lymph nodes, followed by radiotherapy or concurrent radiochemotherapy.
About Multikine
Multikine (Leukocyte Interleukin, Injection) is an investigational immunotherapeutic agent that is being tested in an open-label, randomized, controlled, global pivotal Phase 3 clinical trial as a potential first-line treatment for advanced primary squamous cell carcinoma of the head and neck. Multikine is designed to be a different type of therapy in the fight against cancer: one that appears to have the potential to work with the body’s natural immune system in the fight against tumors.
Multikine is also being tested in a Phase 1 study under a Cooperative Research and Development Agreement ("CRADA") with the U.S. Naval Medical Center, San Diego, and at University of California, San Francisco (UCSF), as a potential treatment for peri-anal warts in HIV/HPV co-infected men and women. CEL-SCI has also entered into two co-development agreements with Ergomed Clinical Research Limited to further the development of Multikine for cervical dysplasia/neoplasia in women who are co-infected with HIV and HPV and for peri-anal warts in men and women who are co-infected with HIV and HPV.
RedHill Biopharma Announces Last Patient Visit in the Phase I Study With YELIVA(TM) (ABC294640) for Advanced Solid Tumors
On September 1, 2015 RedHill Biopharma Ltd. (NASDAQ:RDHL) (TASE:RDHL) ("RedHill" or the "Company"), an Israeli biopharmaceutical company primarily focused on late clinical-stage, proprietary, orally-administered, small molecule drugs for inflammatory and gastrointestinal (GI) diseases, including gastrointestinal cancers, reported that the last patient has completed the final scheduled follow-up visit in the Phase I study evaluating YELIVA (ABC294640), the Company’s orally-administered first-in-class sphingosine kinase-2 (SK2) selective inhibitor, for the treatment of advanced solid tumors (the ABC-101 study) (Press release, RedHill Biopharma, SEP 1, 2015, View Source [SID:1234507372]).
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The ABC-101 Phase I study was conducted at the Medical University of South Carolina Hollings Cancer Center and was led by Principal Investigators Melanie Thomas, MD, and Carolyn Britten, MD. The open-label, dose-escalation, pharmacokinetic (PK) and pharmacodynamic (PD) first-in-human Phase I study of YELIVA (ABC294640) enrolled 22 patients with advanced solid tumors. The patients were continuously treated with the study drug in the absence of disease progression and evaluated for an additional period of up to one year after discontinuing treatment with YELIVA (ABC294640). The primary objectives of the study were to identify the maximum tolerated dose (MTD) and the dose limiting toxicities (DLTs) and to evaluate the safety of YELIVA (ABC294640). The secondary objectives of the study were to determine the pharmacokinetic (PK) and pharmacodynamic (PD) properties of YELIVA (ABC294640) and to assess its antitumor activity.
The study was supported by grants from the National Cancer Institute (NCI) and the FDA’s Office of Orphan Products Development (OOPD). Preliminary positive data from the Phase I study was presented by Apogee Biotechnology Corporation at the November 2013 Molecular Targets and Cancer Therapeutics meeting.
The analysis of the study is currently ongoing and top-line results are expected to be announced early in the fourth quarter of 2015. A full analysis and the final Clinical Study Report (CSR) are expected by the end of the year or early 2016.
YELIVA (ABC294640) is a proprietary, first-in-class, orally-administered sphingosine kinase-2 (SK2) selective inhibitor, with anti-cancer and anti-inflammatory activities, targeting multiple oncology, inflammatory and GI indications. SK2 is an innovative molecular target for anti-cancer therapy because of its critical role in catalyzing the formation of the lipid-signaling molecule sphingosine 1-phosphate (S1P), which is known to regulate cell proliferation and activation of inflammatory pathways. By inhibiting SK2, YELIVA (ABC294640) could potentially be effective in treating multiple oncology, inflammatory and gastrointestinal indications.
Reza Fathi, Ph.D., RedHill’s Senior VP Research & Development said: "The completion of the final follow-up visit by the last patient in the Phase I study of YELIVA (ABC294640) is an important milestone for RedHill, and we look forward to completing the analysis of the study, which includes analysis of plasma S1P levels as a potential new pharmacodynamic biomarker for anti-cancer activity of a sphingolipid targeted drug."
RedHill recently initiated a Phase I/II clinical study in the U.S. evaluating YELIVA (ABC294640) in patients with refractory/relapsed diffuse large B-cell lymphoma (DLBCL), primarily patients with HIV-related DLBCL, supported by a grant from the NCI Small Business Technology Transfer (STTR) program. Additional Phase II clinical studies are planned, including a multiple myeloma study to be conducted at Duke University and supported by the NCI, and a radioprotection study to evaluate potential prevention of mucositis in cancer patients undergoing therapeutic radiotherapy. Numerous successful pre-clinical studies were conducted with YELIVA (ABC294640) in GI, inflammation, radioprotection and oncology models.
The studies with YELIVA (ABC294640) are registered on www.ClinicalTrials.gov, a web-based service by the U.S. National Institute of Health which provides public access to information on publicly and privately supported clinical studies.
About YELIVA (ABC294640):
YELIVA (ABC294640) is a first-in-class, proprietary sphingosine kinase-2 (SK2) selective inhibitor, administered orally, with anti-cancer and anti-inflammatory activities, targeting multiple potential oncology, inflammatory and gastrointestinal indications. By inhibiting the SK2 enzyme, YELIVA (ABC294640) blocks the synthesis of sphingosine 1-phosphate (S1P), a lipid that promotes cancer growth and pathological inflammation. YELIVA (ABC294640) was originally developed by U.S.-based Apogee Biotechnology Corp. and completed multiple successful pre-clinical studies in oncology, inflammation, GI, and radioprotection models, as well as the ABC-101 Phase I clinical study in cancer patients with advanced solid tumors. A Phase I/II clinical study evaluating YELIVA (ABC294640) in patients with refractory/relapsed diffuse large B-cell lymphoma (DLBCL) has been initiated in the U.S. The development of YELIVA (ABC294640) was funded to date primarily by grants and contracts from U.S. federal and state government agencies.