On December 7, 2015 Merck (NYSE:MRK), known as MSD outside the United States and Canada, reported new study findings investigating the use of KEYTRUDA (pembrolizumab), the company’s anti-PD-1 therapy, in combination with lenalidomide and low-dose dexamethasone (two commonly used treatments for multiple myeloma) in patients whose disease has progressed after at least two lines of prior therapy, including a proteasome inhibitor and an IMiD (immune modulatory drug) (Press release, Merck & Co, DEC 7, 2015, View Source [SID:1234508450]). The initial findings from the ongoing Phase 1 KEYNOTE-023 study showed an overall response rate (ORR) of 76 percent (n=13/17), as assessed by the International Myeloma Working Group (IMWG) 2006 Criteria. These results will be presented today at the 57th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting by Jesus San Miguel, M.D., Ph.D., Clínica Universidad de Navarra, Pamplona, Spain (Abstract #505). Based in part on these data, Merck has initiated two Phase 3 studies evaluating KEYTRUDA in the treatment of multiple myeloma.

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"Many patients with multiple myeloma relapse after their initial treatment, reinforcing the need for additional treatment options," said Dr. Jesus San Miguel. "These findings highlight the potential of combining KEYTRUDA with an IMiD and dexamethasone in patients who have multiple myeloma."

"Our clinical program explores the potential for KEYTRUDA across broad patient populations, including in combination with other medicines," said Roger Dansey, M.D., senior vice president and therapeutic area head, oncology late-stage development, Merck Research Laboratories. "We are encouraged by these results, showing responses in patients who have relapsed following treatment for multiple myeloma when treated with KEYTRUDA in combination with lenalidomide and dexamethasone, and look forward to building on these data."

Results from KEYNOTE-023 Presented at ASH (Free ASH Whitepaper)

In the study with 50 heavily pre-treated patients, initial findings from 17 patients who were treated with KEYTRUDA (pembrolizumab) in combination with lenalidomide and low-dose dexamethasone demonstrated an ORR of 76 percent (n=13/17) (per IMWG 2006), including four very good partial responses (24%) and nine partial responses (53%).

Adverse events in all 50 patients were consistent with previously reported safety data for KEYTRUDA as well as lenalidomide and low-dose dexamethasone. Grade 3 or 4 treatment-related adverse events included: neutropenia (n=11), thrombocytopenia (n=4), diarrhea (n=1), fatigue (n=1), anemia (n=4), hyperglycemia (n=3) and muscle spasms (n=1). Immune-mediated adverse events included: adrenal insufficiency (n=1), hyperthyroidism (n=2), hypothyroidism (n=2), and thyroiditis (n=1). No treatment-related deaths were reported.

About the KEYTRUDA Development Program and KEYNOTE-023

Merck is conducting a broad hematological malignancy program with approximately 20 clinical trials, including four registration-enabling studies and more than 15 combinations across a variety of lymphomas, myeloma, leukemia, and other hematologic malignancies. Registration-enabling trials of KEYTRUDA are currently enrolling patients in melanoma, NSCLC, head and neck cancer, bladder cancer, gastric cancer, colorectal cancer, esophageal cancer, breast cancer, Hodgkin lymphoma, multiple myeloma and other tumors, with further trials in planning for other cancers.

KEYNOTE-023 is a global, open-label, Phase 1 study designed to evaluate KEYTRUDA treatment in combination with dexamethasone and two different doses of lenalidomide in approximately 75 patients with relapsed/refractory multiple myeloma (RRMM). Patients will receive KEYTRUDA (2 mg/kg every two weeks) in combination with lenalidomide (10 mg or 25 mg) or KEYTRUDA (200 mg fixed dose every two weeks) with lenalidomide (10 mg or 25 mg); all patients will receive 40 mg low-dose dexamethasone weekly. Primary endpoints include safety and tolerability; secondary endpoints include ORR, duration of response, progression-free survival (PFS), and overall survival (OS).

About Multiple Myeloma

Multiple myeloma is a cancer of blood plasma cells in which abnormal plasma cells multiply uncontrollably in the bone marrow and occasionally in other parts of the body. Manifestations of the disease often include bone pain and fractures, and may include kidney problems, a weakened immune system weakness, and confusion. Multiple myeloma is the second most common blood cancer. In 2015, an estimated 26,850 people are expected to be diagnosed and an estimated 11,240 people are expected to die of the disease in the U.S. alone.

About KEYTRUDA (pembrolizumab) Injection 100 mg

KEYTRUDA is a humanized monoclonal antibody that works by increasing the ability of the body’s immune system to help detect and fight tumor cells. KEYTRUDA blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes, which may affect both tumor cells and healthy cells.

KEYTRUDA is indicated in the United States at a dose of 2 mg/kg administered as an intravenous infusion over 30 minutes every three weeks for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors express PD-L1 as determined by an FDA-approved test with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving KEYTRUDA. KEYTRUDA is also indicated at the same dosing for the treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. These indications are approved under accelerated approval based on tumor response rate and durability of response. An improvement in survival or disease-related symptoms has not yet been established. Continued approval for these indications may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Selected Important Safety Information for KEYTRUDA (pembrolizumab)

Pneumonitis, including fatal cases, occurred in patients receiving KEYTRUDA. Pneumonitis occurred in 12 (2.9%) of 411 melanoma patients, including Grade 2 or 3 cases in 8 (1.9%) and 1 (0.2%) patients, respectively, receiving KEYTRUDA. Pneumonitis occurred in 19 (3.5%) of 550 patients with NSCLC, including Grade 2 (1.1%), 3 (1.3%), 4 (0.4%), or 5 (0.2%) pneumonitis in patients, receiving KEYTRUDA. Monitor patients for signs and symptoms of pneumonitis. Evaluate suspected pneumonitis with radiographic imaging. Administer corticosteroids for Grade 2 or greater pneumonitis. Withhold KEYTRUDA for Grade 2; permanently discontinue KEYTRUDA for Grade 3 or 4 or recurrent Grade 2 pneumonitis.

Colitis (including microscopic colitis) occurred in 4 (1%) of 411 patients with melanoma, including Grade 2 or 3 cases in 1 (0.2%) and 2 (0.5%) patients, respectively, receiving KEYTRUDA. Colitis occurred in 4 (0.7 %) of 550 patients with NSCLC, including Grade 2 (0.2%) or 3 (0.4%) colitis in patients receiving KEYTRUDA. Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 or greater colitis. Withhold KEYTRUDA for Grade 2 or 3; permanently discontinue KEYTRUDA for Grade 4 colitis.

Hepatitis occurred in patients receiving KEYTRUDA. Hepatitis (including autoimmune hepatitis) occurred in 2 (0.5%) of 411 patients with melanoma, including a Grade 4 case in 1 (0.2%) patient, receiving KEYTRUDA. Monitor patients for changes in liver function. Administer corticosteroids for Grade 2 or greater hepatitis and, based on severity of liver enzyme elevations, withhold or discontinue KEYTRUDA.

Hypophysitis occurred in 2 (0.5%) of 411 patients with melanoma, including a Grade 2 case in 1 and a Grade 4 case in 1 (0.2% each) patient, receiving KEYTRUDA. Hypophysitis occurred in 1 (0.2 %) of 550 patients with NSCLC, which was Grade 3 in severity. Monitor patients for signs and symptoms of hypophysitis (including hypopituitarism and adrenal insufficiency). Administer corticosteroids and hormone replacement as indicated. Withhold KEYTRUDA for Grade 2 and withhold or discontinue for Grade 3 or Grade 4 hypophysitis.

Hyperthyroidism occurred in 5 (1.2%) of 411 patients with melanoma, including Grade 2 or 3 cases in 2 (0.5%) and 1 (0.2%) patients, respectively, receiving KEYTRUDA. Hypothyroidism occurred in 34 (8.3%) of 411 patients with melanoma, including a Grade 3 case in 1 (0.2%) patient, receiving KEYTRUDA. Hyperthyroidism occurred in 10 (1.8%) of 550 patients with NSCLC, including Grade 2 (0.7%) or 3 (0.3%). Hypothyroidism occurred in 38 (6.9%) of 550 patients with NSCLC, including Grade 2 (5.5%) or 3 (0.2%). Thyroid disorders can occur at any time during treatment. Monitor patients for changes in thyroid function (at the start of treatment, periodically during treatment, and as indicated based on clinical evaluation) and for clinical signs and symptoms of thyroid disorders. Administer replacement hormones for hypothyroidism and manage hyperthyroidism with thionamides and beta-blockers as appropriate. Withhold or discontinue KEYTRUDA for Grade 3 or Grade 4 hyperthyroidism.

Type 1 diabetes mellitus, including diabetic ketoacidosis, has occurred in patients receiving KEYTRUDA. Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Administer insulin for type 1 diabetes, and withhold KEYTRUDA and administer anti-hyperglycemics in patients with severe hyperglycemia.

Nephritis occurred in patients receiving KEYTRUDA. Nephritis occurred in 3 (0.7%) patients with melanoma, consisting of one case of Grade 2 autoimmune nephritis (0.2%) and two cases of interstitial nephritis with renal failure (0.5%), one Grade 3 and one Grade 4. Monitor patients for changes in renal function. Administer corticosteroids for Grade 2 or greater nephritis. Withhold KEYTRUDA for Grade 2; permanently discontinue KEYTRUDA for Grade 3 or 4 nephritis.

Other clinically important immune-mediated adverse reactions can occur. For suspected immune-mediated adverse reactions, ensure adequate evaluation to confirm etiology or exclude other causes. Based on the severity of the adverse reaction, withhold KEYTRUDA and administer corticosteroids. Upon improvement of the adverse reaction to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Resume KEYTRUDA when the adverse reaction remains at Grade 1 or less following steroid taper. Permanently discontinue KEYTRUDA for any severe or Grade 3 immune-mediated adverse reaction that recurs and for any life-threatening immune-mediated adverse reaction.

Across clinical studies with KEYTRUDA, the following clinically significant, immune-mediated adverse reactions have occurred: bullous pemphigoid and Guillain-Barré syndrome. The following clinically significant, immune-mediated adverse reactions occurred in less than 1% of patients with melanoma treated with KEYTRUDA: exfoliative dermatitis, uveitis, arthritis, myositis, pancreatitis, hemolytic anemia, and partial seizures arising in a patient with inflammatory foci in brain parenchyma. The following clinically significant, immune-mediated adverse reactions occurred in less than 1% of 550 patients with NSCLC treated with KEYTRUDA: rash, vasculitis, hemolytic anemia, serum sickness, and myasthenia gravis.

Infusion-related reactions, including severe and life-threatening reactions, have occurred in patients receiving KEYTRUDA. Monitor patients for signs and symptoms of infusion related reactions including rigors, chills, wheezing, pruritus, flushing, rash, hypotension, hypoxemia, and fever. For severe or life-threatening reactions, stop infusion and permanently discontinue KEYTRUDA.

Based on its mechanism of action, KEYTRUDA can cause fetal harm when administered to a pregnant woman. If used during pregnancy, or if the patient becomes pregnant during treatment, apprise the patient of the potential hazard to a fetus. Advise females of reproductive potential to use highly effective contraception during treatment and for 4 months after the last dose of KEYTRUDA.

Among the 411 patients with metastatic melanoma, KEYTRUDA was discontinued for adverse reactions in 9% of 411 patients. Adverse reactions, reported in at least two patients that led to discontinuation of KEYTRUDA were: pneumonitis, renal failure, and pain. Serious adverse reactions occurred in 36% of patients. The most frequent serious adverse reactions, reported in 2% or more of patients, were renal failure, dyspnea, pneumonia, and cellulitis. The most common adverse reactions (reported in at least 20% of patients) were fatigue (47%), cough (30%), nausea (30%), pruritus (30%), rash (29%), decreased appetite (26%), constipation (21%), arthralgia (20%), and diarrhea (20%).

Among the 550 patients with metastatic NSCLC, KEYTRUDA was discontinued due to adverse reactions in 14% of patients. Serious adverse reactions occurred in 38% of patients. The most frequent serious adverse reactions reported in 2% or more of patients were pleural effusion, pneumonia, dyspnea, pulmonary embolism, and pneumonitis. The most common adverse reactions (reported in at least 20% of patients) were fatigue (44%), decreased appetite (25%), dyspnea (23%), and cough (29%).

No formal pharmacokinetic drug interaction studies have been conducted with KEYTRUDA.

It is not known whether KEYTRUDA is excreted in human milk. Because many drugs are excreted in human milk, instruct women to discontinue nursing during treatment with KEYTRUDA and for 4 months after the final dose.

Safety and effectiveness of KEYTRUDA have not been established in pediatric patients.

Our Focus on Cancer

Our goal is to translate breakthrough science into innovative oncology medicines to help people with cancer worldwide. At Merck Oncology, helping people fight cancer is our passion and supporting accessibility to our cancer medicines is our commitment. Our focus is on pursuing research in immuno-oncology and we are accelerating every step in the journey – from lab to clinic – to potentially bring new hope to people with cancer. For more information about our oncology clinical trials, visit www.merck.com/clinicaltrials.

On December 7, 2015 Foundation Medicine, Inc. (NASDAQ:FMI) reported that the company and its collaborators will present 10 poster presentations at the 2015 San Antonio Breast Cancer Symposium (SABCS) Annual Meeting taking place December 8-12, 2015 in San Antonio, Texas (Press release, Foundation Medicine, DEC 7, 2015, View Source [SID:1234508449]).

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The company’s molecular information products, FoundationOne for solid tumors and FoundationOne Heme for hematologic malignancies and sarcomas, provide a comprehensive genomic profile to identify the molecular alterations in a patient’s cancer. The data to be presented at SABCS provide further supporting evidence of the clinical utility of Foundation Medicine’s assays to identify emerging treatment options and inform efforts in treating breast cancer.

The schedule for poster presentations by Foundation Medicine and/or its collaborators is as follows:

Date and Time: Thursday, December 10, 2015, from 5:00-7:00 p.m. CT
Title: Non-Amplification ERBB2 Genomic Alterations in 5,605 Cases of Refractory and Metastatic Breast Cancer: an Emerging Opportunity for anti-HER2 Targeted Therapies
Poster Display Location: P3-07-05
Session: Prognostic and Predictive Factors: Response Predictions — Biomarkers and Other Factors
Presenter: Jeffrey S. Ross MD, Chairman, Dept. of Pathology and Laboratory Medicine, Albany Medical College and Medical Director, Foundation Medicine, Inc.
Collaborators: Albany Medical College, Mayo Clinic Cancer Center, Washington University

Date and Time: Thursday, December 10, 2015, from 5:00-7:00 p.m. CT
Title: Evolution of Genomic Alterations on Endocrine Therapy and mTOR Inhibition in Estrogen Receptor (ER)-Positive Breast Cancer
Poster Display Location: P3-05-06
Session: 3 – Tumor Cell and Molecular Biology: Endocrine Therapy and Resistance
Presenter: Suleiman Alfred Massarweh, MD Associate Professor of Medicine(Oncology) at the Stanford University Medical Center
Collaborators: Stanford University Medical School, Stanford Cancer Institute, University of Kentucky, Markey Cancer Center

Date and Time: Friday, December 11, 2015, from 5:00-7:00 p.m. CT
Title: Lapatinib Reverses Endocrine Resistance in Select Patients with HER 2 negative, Hormone Positive Metastatic Breast Cancer
Poster Display Location: P5-14-06
Session: 5 – Advanced Endocrine Therapy
Presenter: Priyanka Sharma, MD, Associate Professor of Medicine at University of Kansas
Collaborators: University of Kansas Medical Center, Hays Medical Center, Truman Medical Center

Date and Time: Friday, December 11, 2015, from 5:00 -7:00 p.m. CT
Title: Individualized molecular analyses guide efforts in breast cancer with comprehensive genomic profiling of tissue and plasma tumor DNA
Poster Display Location: PD6-08
Session: Translational Genomics
Presenter: Heather Parsons, MD, MPH Instructor in Medicine, Harvard Medical School at Dana Farber Cancer Institute
Collaborators: Dana-Farber Cancer Institute, Johns Hopkins Medical Institutions (JHMI)

Date and Time: Saturday, December 12, 2015, from 7:30-9:00 a.m. CT
Title: Comprehensive Genomic Profiling of Clinically Advanced Mucinous Carcinoma of the Breast
Poster Display Location: P6-03-12
Session: Tumor Cell and Molecular Biology: Genomics
Presenter: Jeffrey S. Ross MD, Chairman, Dept. of Pathology and Laboratory Medicine, Albany Medical College and Medical Director, Foundation Medicine, Inc.
Collaborators: Albany Medical College

Date and Time: Saturday, December 12, 2015, from 7:30-9:00 a.m. CT
Title: Clinicopathologic Characterization and Comprehensive Genomic Profiling (CGP) of Advanced Breast Cancer Patients with Fibroblast Growth Factor Receptor (FGFR) Alterations
Poster Display Location: P6-07-06
Session: 6 – Tumor Cell and Molecular Biology: Genetics — Somatic Changes
Presenter: Ricardo Alvarez, MD, MSc , Director of Cancer Research & Breast Medical Oncologist, Southeastern Regional Medical Center, CTCA
Collaborators: Cancer Treatment Centers of America

Date and Time: Saturday, December 12, 2015, from 7:30-9:00 a.m. CT
Title: EGFR Genomic Alterations in 5,605 Cases of Refractory and Metastatic Breast Cancer
Poster Display Location: P6-03-02
Session: 6 – Tumor Cell and Molecular Biology: Genetics — Somatic Changes
Presenter: Siraj M. Ali MD, PhD, Director Clinical Development, Foundation Medicine
Collaborators: Houston Methodist Hospital

On December 7, 2015 ARIAD Pharmaceuticals, Inc. (NASDAQ:ARIA) reported the initiation of a randomized Phase 3 trial of Iclusig (ponatinib) in second-line patients with chronic myeloid leukemia (CML) in the chronic phase (CP) (Press release, Ariad, DEC 7, 2015, View Source;p=RssLanding&cat=news&id=2120512 [SID:1234508447]). The OPTIC-2L (Optimizing Ponatinib Treatment In CML, Second Line) trial is designed to investigate the efficacy and safety of ponatinib, administered at two starting doses, compared with nilotinib, in patients who are resistant to front-line treatment with imatinib. The primary endpoint of the OPTIC-2L study, now open for patient enrollment, is major molecular response (MMR) by 12 months. Approximately 600 patients are expected to be enrolled at clinical sites in Europe, Asia, Latin America and Canada.

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"Physicians treating CML patients will be extremely interested in the outcome of this clinical trial in which ponatinib — at two different doses — will be compared to nilotinib in patients resistant to imatinib," stated Dr. D. Selleslag, Department of Hematology, St-Jan Bruges-Ostend Hospital in Belgium. "By comparing ponatinib to nilotinib in the second-line setting, we will garner valuable, randomized clinical data to better understand the potential utilization of ponatinib in this broad patient population."

Major Design Features of the Trial

This study is designed to demonstrate superiority of ponatinib over nilotinib and will enroll patients with CP-CML who have become resistant to imatinib and have received no other tyrosine kinase inhibitor. These patients will be randomized to receive once-daily administration of ponatinib at a starting dose of either 30 mg (cohort A) or 15 mg (cohort B), or 400 mg of nilotinib administered twice daily (cohort C). Patients will be randomized in a ratio of 1:2:1 respectively. Upon reaching MMR, patients in cohort A will have their daily dose of ponatinib reduced to 15 mg and patients in cohort B will have their dose reduced to 10 mg.

The primary endpoint of the trial is MMR by 12 months for each cohort. Secondary endpoints include rate of vascular occlusive events in each cohort, rates of adverse events and rates of serious adverse events.

"The OPTIC-2L trial is the first direct randomized comparison of ponatinib to an approved BCR-ABL tyrosine kinase inhibitor following imatinib therapy. We expect this trial to provide important head-to-head data regarding the efficacy and safety of treating patients with ponatinib versus nilotinib in the second-line," said Frank G. Haluska, M.D., Ph.D., senior vice president of clinical research and development and chief medical officer at ARIAD. "The trial will examine lower ponatinib starting and maintenance doses than presently approved, along with a direct comparison to nilotinib, from which we may be able to obtain regulatory authorizations that would provide patients with more treatment options in an earlier line of therapy."

Patients will be enrolled at up to 90 cancer centers in Europe, Asia, Latin America and Canada. For more information about the trial, patients and physicians should call the U.S. toll-free number 855-552-7423, the EU toll-free number 800 00027423, or the international number +1 617-503-7423 or email ARIAD at [email protected].

About Iclusig (ponatinib) tablets

Iclusig is approved in the U.S., EU, Australia, Switzerland, Israel and Canada.

In the U.S., Iclusig is a kinase inhibitor indicated for the:

Treatment of adult patients with T315I-positive chronic myeloid leukemia (chronic phase, accelerated phase, or blast phase) or T315I-positive Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL).
Treatment of adult patients with chronic phase, accelerated phase, or blast phase chronic myeloid leukemia or Ph+ ALL for whom no other tyrosine kinase inhibitor (TKI) therapy is indicated.
These indications are based upon response rate. There are no trials verifying an improvement in disease-related symptoms or increased survival with Iclusig.

IMPORTANT SAFETY INFORMATION, INCLUDING THE BOXED WARNING

WARNING: VASCULAR OCCLUSION, HEART FAILURE, and HEPATOTOXICITY

See full prescribing information for complete boxed warning

Vascular Occlusion: Arterial and venous thrombosis and occlusions have occurred in at least 27% of Iclusig treated patients, including fatal myocardial infarction, stroke, stenosis of large arterial vessels of the brain, severe peripheral vascular disease, and the need for urgent revascularization procedures. Patients with and without cardiovascular risk factors, including patients less than 50 years old, experienced these events. Monitor for evidence of thromboembolism and vascular occlusion. Interrupt or stop Iclusig immediately for vascular occlusion. A benefit risk consideration should guide a decision to restart Iclusig therapy.
Heart Failure, including fatalities, occurred in 8% of Iclusig-treated patients. Monitor cardiac function. Interrupt or stop Iclusig for new or worsening heart failure.

Hepatotoxicity, liver failure and death have occurred in Iclusig-treated patients. Monitor hepatic function. Interrupt Iclusig if hepatotoxicity is suspected.

Vascular Occlusion: Arterial and venous thrombosis and occlusions, including fatal myocardial infarction, stroke, stenosis of large arterial vessels of the brain, severe peripheral vascular disease, and the need for urgent revascularization procedures have occurred in at least 27% of Iclusig-treated patients from the phase 1 and phase 2 trials. Iclusig can also cause recurrent or multi-site vascular occlusion. Overall, 20% of Iclusig-treated patients experienced an arterial occlusion and thrombosis event of any grade. Fatal and life-threatening vascular occlusion has occurred within 2 weeks of starting Iclusig treatment and in patients treated with average daily dose intensities as low as 15 mg per day. The median time to onset of the first vascular occlusion event was 5 months. Patients with and without cardiovascular risk factors have experienced vascular occlusion although these events were more frequent with increasing age and in patients with prior history of ischemia, hypertension, diabetes, or hyperlipidemia. Interrupt or stop Iclusig immediately in patients who develop vascular occlusion events.

Heart Failure: Fatal and serious heart failure or left ventricular dysfunction occurred in 5% of Iclusig-treated patients (22/449). Eight percent of patients (35/449) experienced any grade of heart failure or left ventricular dysfunction. Monitor patients for signs or symptoms consistent with heart failure and treat as clinically indicated, including interruption of Iclusig. Consider discontinuation of Iclusig in patients who develop serious heart failure.

Hepatotoxicity: Iclusig can cause hepatotoxicity, including liver failure and death. Fulminant hepatic failure leading to death occurred in an Iclusig-treated patient within one week of starting Iclusig. Two additional fatal cases of acute liver failure also occurred. The fatal cases occurred in patients with blast phase CML (BP-CML) or Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL). Severe hepatotoxicity occurred in all disease cohorts. Iclusig treatment may result in elevation in ALT, AST, or both. Monitor liver function tests at baseline, then at least monthly or as clinically indicated. Interrupt, reduce or discontinue Iclusig as clinically indicated.

Hypertension: Treatment-emergent hypertension (defined as systolic BP≥140 mm Hg or diastolic BP≥90 mm Hg on at least one occasion) occurred in 67% of patients (300/449). Eight patients treated with Iclusig (2%) experienced treatment-emergent symptomatic hypertension as a serious adverse reaction, including one patient (<1%) with hypertensive crisis. Patients may require urgent clinical intervention for hypertension associated with confusion, headache, chest pain, or shortness of breath. In 131 patients with Stage 1 hypertension at baseline, 61% (80/131) developed Stage 2 hypertension. Monitor and manage blood pressure elevations during Iclusig use and treat hypertension to normalize blood pressure. Interrupt, dose reduce, or stop Iclusig if hypertension is not medically controlled. In the event of significant worsening, labile or treatment-resistant hypertension, interrupt treatment and consider evaluating for renal artery stenosis.

Pancreatitis: Clinical pancreatitis occurred in 6% (28/449) of patients (5% Grade 3) treated with Iclusig. Pancreatitis resulted in discontinuation or treatment interruption in 6% of patients (25/449). The incidence of treatment-emergent lipase elevation was 41%. Check serum lipase every 2 weeks for the first 2 months and then monthly thereafter or as clinically indicated. Consider additional serum lipase monitoring in patients with a history of pancreatitis or alcohol abuse. Dose interruption or reduction may be required. In cases where lipase elevations are accompanied by abdominal symptoms, interrupt treatment with Iclusig and evaluate patients for pancreatitis. Do not consider restarting Iclusig until patients have complete resolution of symptoms and lipase levels are less than 1.5 x ULN.

Neuropathy: Peripheral and cranial neuropathy have occurred in Iclusig-treated patients. Overall, 13% (59/449) of Iclusig-treated patients experienced a peripheral neuropathy event of any grade (2%, grade 3/4). In clinical trials, the most common peripheral neuropathies reported were peripheral neuropathy (4%, 18/449), paresthesia (4%, 17/449), hypoesthesia (2%, 11/449), and hyperesthesia (1%, 5/449). Cranial neuropathy developed in 1% (6/449) of Iclusig-treated patients (<1% grade 3/4). Of the patients who developed neuropathy, 31% (20/65) developed neuropathy during the first month of treatment. Monitor patients for symptoms of neuropathy, such as hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic pain or weakness. Consider interrupting Iclusig and evaluate if neuropathy is suspected.

Ocular Toxicity: Serious ocular toxicities leading to blindness or blurred vision have occurred in Iclusig-treated patients. Retinal toxicities including macular edema, retinal vein occlusion, and retinal hemorrhage occurred in 3% of Iclusig-treated patients. Conjunctival or corneal irritation, dry eye, or eye pain occurred in 13% of patients. Visual blurring occurred in 6% of the patients. Other ocular toxicities include cataracts, glaucoma, iritis, iridocyclitis, and ulcerative keratitis. Conduct comprehensive eye exams at baseline and periodically during treatment.

Hemorrhage: Serious bleeding events, including fatalities, occurred in 5% (22/449) of patients treated with Iclusig. Hemorrhagic events occurred in 24% of patients. The incidence of serious bleeding events was higher in patients with accelerated phase CML (AP-CML), BP-CML, and Ph+ ALL. Most hemorrhagic events, but not all occurred in patients with grade 4 thrombocytopenia. Interrupt Iclusig for serious or severe hemorrhage and evaluate.

Fluid Retention: Serious fluid retention events occurred in 3% (13/449) of patients treated with Iclusig. One instance of brain edema was fatal. In total, fluid retention occurred in 23% of the patients. The most common fluid retention events were peripheral edema (16%), pleural effusion (7%), and pericardial effusion (3%). Monitor patients for fluid retention and manage patients as clinically indicated. Interrupt, reduce, or discontinue Iclusig as clinically indicated.

Cardiac Arrhythmias: Symptomatic bradyarrhythmias that led to a requirement for pacemaker implantation occurred in 1% (3/449) of Iclusig-treated patients. Advise patients to report signs and symptoms suggestive of slow heart rate (fainting, dizziness, or chest pain). Supraventricular tachyarrhythmias occurred in 5% (25/449) of Iclusig-treated patients. Atrial fibrillation was the most common supraventricular tachyarrhythmia and occurred in 20 patients. For 13 patients, the event led to hospitalization. Advise patients to report signs and symptoms of rapid heart rate (palpitations, dizziness). Interrupt Iclusig and evaluate.

Myelosuppression: Severe (grade 3 or 4) myelosuppression occurred in 48% (215/449) of patients treated with Iclusig. The incidence of these events was greater in patients with AP-CML, BP-CML and Ph+ ALL than in patients with CP-CML. Obtain complete blood counts every 2 weeks for the first 3 months and then monthly or as clinically indicated, and adjust the dose as recommended.

Tumor Lysis Syndrome: Two patients (<1%) with advanced disease (AP-CML, BP-CML, or Ph+ ALL) treated with Iclusig developed serious tumor lysis syndrome. Hyperuricemia occurred in 7% (30/449) of patients overall; the majority had CP-CML (19 patients). Due to the potential for tumor lysis syndrome in patients with advanced disease, ensure adequate hydration and treat high uric acid levels prior to initiating therapy with Iclusig.

Compromised Wound Healing and Gastrointestinal Perforation: Since Iclusig may compromise wound healing, interrupt Iclusig for at least 1 week prior to major surgery. Serious gastrointestinal perforation (fistula) occurred in one patient 38 days post-cholecystectomy.

Embryo-Fetal Toxicity: Iclusig can cause fetal harm. If Iclusig is used during pregnancy, or if the patient becomes pregnant while taking Iclusig, the patient should be apprised of the potential hazard to the fetus. Advise women to avoid pregnancy while taking Iclusig.

Most common non-hematologic adverse reactions: (≥20%) were hypertension, rash, abdominal pain, fatigue, headache, dry skin, constipation, arthralgia, nausea, and pyrexia. Hematologic adverse reactions included thrombocytopenia, anemia, neutropenia, lymphopenia, and leukopenia.

Please see the full U.S. Prescribing Information for Iclusig, including the Boxed Warning, for additional important safety information.

On December 7, 2015 Kite Pharma, Inc. (Nasdaq:KITE) reported that it has initiated a phase 1/2 clinical study of KTE-C19 (ZUMA-4) for the treatment of pediatric and young adult patients with r/r ALL (Press release, Kite Pharma, DEC 7, 2015, View Source [SID:1234508442]). KTE-C19 is an investigational therapy in which a patient’s T cells are genetically modified to express a chimeric antigen receptor designed to target the antigen CD19, a protein expressed on the cell surface of B cell lymphomas and leukemias.

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"With the commencement of ZUMA-4, Kite has achieved its goal of initiating four company-sponsored trials this year for its lead product candidate, KTE-C19," said David Chang, M.D., Ph.D., Kite’s Executive Vice President, Research and Development, and Chief Medical Officer. "Our ZUMA trials are investigating critical needs in non-Hodgkin lymphoma (NHL) and ALL in patients with advanced, relapsed or refractory disease who have few or no other treatment options."

"We are enthusiastic about the possibility that KTE-C19 could safely put children and young adults who have persistent ALL despite multiple prior standard therapies into complete remissions," said internationally recognized leukemia expert Leonard S. Sender, M.D., Medical Director and Division Chief, and ZUMA-4 trial investigator, at Children’s Hospital of Orange Country. "Kite has done an outstanding job advancing immunotherapy for testing in multiple multi-center trials, and we are thrilled to offer this trial to our young patients and their families."

ZUMA-4 will proceed as a single-arm, open-label, multi-center study in patients with ALL whose disease is refractory to or has relapsed following standard chemotherapy or hematopoietic stem cell transplantation. The phase 1 portion of ZUMA-4 will assess the safety of KTE-C19, and the phase 2 portion will assess efficacy and safety. The study will target to enroll a total of 75 patients. Additional details about this study will be available on ClinicalTrials.gov.

On December 7, 2015 Roche (SIX: RO, ROG; OTCQX: RHHBY) reported follow-up results from the pivotal phase III GADOLIN study in people with indolent non-Hodgkin lymphoma (iNHL) who relapsed during or within six months after treatment with a MabThera/Rituxan (rituximab)-based regimen (Press release, Hoffmann-La Roche , DEC 7, 2015, View Source [SID:1234508440]). In a subgroup analysis of people with follicular lymphoma, the most common type of iNHL, treatment with Gazyva/Gazyvaro (obinutuzumab) plus bendamustine provided significantly greater depth of remission at end of induction compared to bendamustine alone, as measured by minimal residual disease (MRD)-negativity (82% vs 43%, respectively; p<0.0001)1. MRD assessment was an exploratory analysis.

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"Building on the significant progression-free survival benefit previously reported in the GADOLIN study, these follow-up data show that Gazyva/Gazyvaro-based treatment achieves significant rates of deep remission, known as minimal residual disease negativity, at the end of induction treatment," said Sandra Horning, MD, Roche’s Chief Medical Officer and Head of Global Product Development. "This achievement is particularly impressive in this difficult-to-treat patient population with follicular lymphoma, for whom treatment options are limited."

An additional analysis of the overall study population in the GADOLIN trial showed that a greater proportion of patients in the Gazyva/Gazyvaro arm reported a meaningful improvement in health-related quality of life (HRQoL) compared to those treated with bendamustine alone. HRQoL was a secondary endpoint in the study. This finding suggests that increased progression-free survival (PFS) does not appear to come at the expense of an increase in treatment-related toxicity that adversely impacts a patient’s quality of life.

Data from the GADOLIN MRD subgroup analysis will be presented in a poster session today, Monday December 7 by Dr. Kirsten Mundt, Senior Scientist, Roche at the 57th American Society of Hematology (ASH) (Free ASH Whitepaper), in Orlando, Florida. Data from the GADOLIN HRQoL analysis was also presented on Saturday, December 5, during a poster session by Dr. Peter Trask, Principal Scientist, Genentech and Professor Bruce Cheson from the Georgetown University Hospital, Washington DC, USA.

The FDA has accepted for priority review a supplemental Biologics License Application (sBLA) for Gazyva/Gazyvaro in the treatment of people with follicular lymphoma who relapsed after or are refractory to a MabThera/Rituxan-containing regimen. Marketing applications have also been submitted to other global regulatory authorities, including the EMA, for approval consideration in the treatment of people with follicular lymphoma who did not respond or who progressed during or up to six months after treatment with MabThera/Rituxan or a MabThera/Rituxan-containing regimen.

About the GADOLIN study
GADOLIN is a phase III open-label, multicentre, randomised two-arm study evaluating Gazyva/Gazyvaro plus bendamustine followed by Gazyva/Gazyvaro alone for up to two years, compared to bendamustine alone. GADOLIN included 413 patients with iNHL whose disease progressed during or within six months of prior MabThera/Rituxan-based therapy. The primary endpoint of the study is progression-free survival (PFS) as assessed by an independent review committee (IRC), with secondary endpoints including PFS as assessed by investigator review, response rate (RR), best response and overall survival (OS). GADOLIN data presented at the annual meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) in June this year showed the median PFS (mPFS) was not reached in the Gazyva/Gazyvaro-based treatment group versus 14.9 months with bendamustine alone (HR=0.55, p=0.0001) as assessed by IRC. The median PFS with Gazyva/Gazyvaro-based treatment was more than double that with bendamustine alone (29.2 months versus 14.0 months (HR=0.52, p<0.0001) as assessed by investigator review. No unexpected safety signals were identified in the Gazyva/Gazyvaro-based treatment arm. Grade 3-4 adverse events that occurred in at least two percent of patients in the Gazyva/Gazyvaro-treated group or bendamustine alone group included low white blood cell count (33% versus 26.3%), low blood platelet count (10.8% versus 16.2%), infusion-related reactions (10.8% versus 5.6%), low red blood cell count (7.7% versus 10.1%), low white blood cell count with fever (4.6% versus 3.5%), nausea (1% versus 3%), fatigue (1.5% versus 2.5%), diarrhoea (1% versus 2.5%), vomiting (2.1% versus 1%), respectively.

The MRD data from the subgroup analysis of people with follicular lymphoma will be presented at a poster presentation today, Monday 7 December, from 6:00-8:00 PM ET [Abstract #3978].

About Gazyva/Gazyvaro (obinutuzumab)
Gazyva/Gazyvaro is an engineered monoclonal antibody designed to attach to CD20, a protein found only on B-cells. Gazyva/Gazyvaro is designed to attack and destroy targeted B-cells both directly and together with the body’s immune system. Gazyva/Gazyvaro is currently approved in more than 60 countries in combination with chlorambucil, for people with previously untreated chronic lymphocytic leukaemia. The approval was based on the CLL11 study, showing significant improvements with Gazyva/Gazyvaro plus chlorambucil across multiple clinical endpoints, including PFS, overall response rate (ORR), complete response rate (CR), and minimal residual disease (MRD) when compared head-to-head with MabThera/Rituxan plus chlorambucil. Gazyva is marketed as Gazyvaro in the EU and Switzerland.

Gazyva/Gazyvaro is being studied in a large clinical programme, including the Phase III GOYA and GALLIUM studies. GOYA is comparing Gazyva/Gazyvaro head-to-head with MabThera/Rituxan plus CHOP chemotherapy in first line diffuse large B-cell lymphoma (DLBCL) and GALLIUM is comparing Gazyva/Gazyvaro plus chemotherapy followed by Gazyva/Gazyvaro maintenance head-to-head with MabThera/Rituxan plus chemotherapy followed by MabThera/Rituxan maintenance in first line indolent non-Hodgkin Lymphoma (iNHL). Additional combination studies investigating Gazyva/Gazyvaro with other approved or investigational medicines, including cancer immunotherapies and small molecule inhibitors, are planned or underway across a range of blood cancers.

About non-Hodgkin lymphoma
There are two main types of lymphoma: Hodgkin lymphoma and non-Hodgkin lymphoma (NHL). NHL represents approximately 85 percent of all lymphomas diagnosed2. Approximately 200,000 people die each year from NHL worldwide and approximately one person is newly diagnosed every 90 seconds2. There are more than 60 different types of NHL that fall under two subsets, aggressive and indolent (slow growing). The most common type of indolent NHL is follicular lymphoma (FL), found in about 25 percent of all NHL patients3. Most cases of NHL start in B-lymphocytes, cells that are part of the body’s immune system and help to defend the body against infections. B-cell lymphoma develops when these cells become cancerous and begin to multiply and collect in the lymphatic system such as in lymph nodes, lymphatic tissues or the spleen.