Author: [email protected]

6-K – Report of foreign issuer [Rules 13a-16 and 15d-16]

On November 27, 2015 Can-Fite BioPharma Ltd. (NYSE MKT: CANF) (TASE:CFBI), a biotechnology company with a pipeline of proprietary small molecule drugs being developed to treat inflammatory diseases, cancer and sexual dysfunction, reported financial results for the nine months ended September 30, 2015 and updates on its drug development programs (Filing, 6-K, Can-Fite BioPharma, NOV 27, 2015, View Source [SID:1234508352]).

Clinical Development Program and Corporate Highlights Include:

● Fortifies Balance Sheet with $13.8 Million Fund Raise
During September 2015, Can-Fite closed on approximately $9 million in funding from institutional investors. As of September 30, 2015 Can-Fite had cash and cash equivalents of $14.46 million. In October the Company raised an additional $4.8 million.

● CF102 – Receives Fast Track Designation in U.S. & Orphan Drug Designation in Europe; Reports Compelling Preclinical Data and Files Patent for NASH
During, and immediately following, the third quarter of 2015, three significant events moved CF102’s clinical development forward. 1) The U.S. Food and Drug Administration (FDA) granted Fast Track Designation to CF102 as a second line treatment for hepatocellular carcinoma (HCC), the most common form of liver cancer. With Fast Track CF102 benefits from more frequent meetings and communications with the FDA to review the drug’s development plan to support approval, while also allowing the Company to submit parts of the New Drug Application (NDA) on a rolling basis for review as data becomes available. CF102 also has the FDA’s Orphan Drug Designation. 2) In October 2015, the European Medicines Agency (EMA) granted Orphan Drug Designation to CF102 for the indication of HCC, giving CF102 protocol assistances and a 10-year market exclusivity following market approval in 28 EU member states and 3 additional European Economic Area countries. Can-Fite continues to enroll and dose patients in its global Phase II liver cancer study. Approximately 78 patients are expected to be enrolled in the trial in the U.S., Europe, and Israel by June 30, 2016. 3) In November 2015, the Company reported data from a preclinical study of an animal model of non-alcoholic steatohepatitis (NASH), revealing CF102 had a statistically significant reduction in liver pathology. This data supports the development of CF102 for NASH, which represents a large and unmet medical need, with no U.S. FDA approved treatment currently available. The addressable market for the treatment of NASH in 2025 is estimated at $35-$40 billion by Deutsche Bank. Can-Fite filed a patent for CF102 in the treatment of NASH.

● CF602 – Reports Mechanism of Action Study Data for Upcoming IND Submission
In October 2015, Can-Fite reported new findings for its CF602 drug candidate showing a defined mechanism of action in erectile dysfunction similar to sildenafil (Viagra) in a rat model of diabetes mellitus. CF602 demonstrated effects on erection superior to that of Viagra in animal studies. Viagra, sold by Pfizer, generated global sales of $1.685 billion in 2014. Can-Fite plans to file an Investigational New Drug (IND) application with the FDA for CF602 in the third quarter of 2016.

● CF101 – Preparing for Phase III trials in Rheumatoid Arthritis & Psoriasis
Can-Fite is currently preparing the protocol for its Phase III trial of CF101 in the treatment of psoriasis. Protocol design is scheduled for completion by the end of 2015. Having already completed the Phase III protocol for CF101 in the treatment of rheumatoid arthritis, Can-Fite plans to submit this protocol to Institutional Review Boards (IRBs) during in the fourth quarter of 2015. Marking an important step for CF101 prior to coming to market, "piclidenoson" was accepted as the drug’s proposed generic by the World Health Organization.

● Enrolling Patients in Ongoing Phase II Glaucoma Study by Can-Fite Subsidiary OphthaliX
OphthaliX continues to enroll patients in a Phase II clinical study of CF101 for glaucoma and data release is expected during the first half of 2016.

"During and immediately following the third quarter, we achieved regulatory milestones for CF102 that we believe will significantly accelerate our liver cancer drug’s time to market. Given the lack of effective medications for liver cancer, we are pleased that Fast Track designation in the U.S. and Orphan Drug designation in Europe are designed to expedite CF102’s pathway through advanced clinical trials and into market approval. NASH, another large and unmet medical need, has just emerged as a potential new indication for CF102 based on compelling new preclinical data," stated Can-Fite CEO Dr. Pnina Fishman. "We also very encouraged by the new mechanism of action data we reported for CF602 in sexual dysfunction. These animal studies demonstrated that CF602 produced erectile effects superior to Viagra and therefore we believe it has the potential to offer value in the market. We are currently preparing CF602’s IND for the indication of sexual dysfunction."

"As we look ahead to 2016, we are preparing to commence Phase III trials for CF101 in both psoriasis and rheumatoid arthritis. With a portfolio of indications that are all advancing towards market, we were pleased to fortify our balance sheet with $13.8 million from institutional investors," Dr. Fishman added.

Research and development expenses for the nine months ended September 30, 2015 were NIS 9.58 million (U.S. $2.44 million) compared with NIS 12.44 million (U.S. $3.17 million) for the same period in 2014. Research and developments expenses for the nine months of 2015 comprised primarily of expenses associated with the Phase II study for CF102 as well as expenses for ongoing studies of CF101. The decrease is primarily due to the completion of the Phase II/III psoriasis study during the first quarter of 2015 and a decrease in the scope of the non-clinical expenses during the first nine months of 2015 as compared to the parallel period in 2014.

General and administrative expenses were NIS 6.79 million (U.S. $1.73 million) for the nine months ended September 30, 2015 compared to NIS 7.73 million (U.S. $1.97 million) for the same period in 2014. The decrease is primarily due to a reduction in salary and professional services expenses.

Financial expenses, net for the nine months ended September 30, 2015 aggregated NIS 4.70 million (U.S. $1.20 million) compared to financial income, net of NIS 3.28 million (U.S. $0.84 million) for the same period in 2014. The increase in financial expenses, net in the nine months of 2015 was mainly due to an increase in the fair value of warrants that are accounted as financial liability.

Can-Fite’s net loss for the nine months ended September 30, 2015 was NIS 20.53 million (U.S. $5.23 million) compared with a net loss of NIS 16.89 million (U.S. $4.31 million) for the same period in 2014. The increase in net loss for the nine months of 2015, was primarily attributable to an increase in finance expenses, net offset by decreases in operating expenses.

As of September 30, 2015, Can-Fite had cash and cash equivalents of NIS 56.73 million (U.S. $14.46 million) as compared to NIS 36.09 million (U.S. $9.20 million) at December 31, 2014. The increase in cash during the nine months ended September 30, 2015 is due to NIS 32.35 million ($8.25 million) received from issuance of shares and warrants, net of issuance expenses and NIS 5.14 million (U.S. $1.31 million) received from Cipher Pharmaceuticals as upfront payment for entering into the distribution agreement with Cipher, offset by operating expenses. An additional $4.3 million, net was raised in October 2015, following the end of the third quarter.

For the convenience of the reader, the reported NIS amounts have been translated into U.S. dollars, at the representative rate of exchange on September 30, 2015 (U.S. $ 1 = NIS 3.923).

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The Company’s consolidated financial results for the nine months ended September 30, 2015 are presented in accordance with International Financial Reporting Standards.

Bristol-Myers Squibb Announces Regulatory Update for Opdivo (nivolumab) in Advanced Melanoma

On November 27, 2015 Bristol-Myers Squibb Company (NYSE:BMY) reported that the U.S. Food and Drug Administration (FDA) has issued a Complete Response Letter for its supplemental Biologics License Application (sBLA) for Opdivo (nivolumab) as a single agent for the treatment of previously untreated patients, specifically those with BRAF V600 mutation positive unresectable or metastatic melanoma (Press release, Bristol-Myers Squibb, NOV 27, 2015, View Source [SID:1234508353]).

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Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

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As part of the Complete Response Letter, the FDA indicated the need for additional data in the BRAF mutated patient population. Bristol-Myers Squibb is working to evaluate the request outlined by the FDA and will continue to work closely with the agency to determine whether additional data, currently under review, adequately addresses these comments.

The sBLA submitted for Opdivo as a single agent for previously untreated metastatic melanoma was based on clinical data from the Phase 3 CheckMate -066 trial which evaluated Opdivo in treatment-naïve patients with BRAF wild-type advanced melanoma compared to dacarbazine. The FDA approved Opdivo as a single agent for the treatment of patients with BRAF wild-type unresectable or metastatic melanoma, based on CheckMate -066, on November 23, 2015. In addition to data from CheckMate -066, the Company submitted data for Opdivo in BRAF V600 mutation positive metastatic melanoma, which was the subject of the FDA’s Complete Response Letter.

A separate sBLA, which included data from CheckMate -067 evaluating Opdivo as a single agent and in combination with Yervoy (ipilimumab) in patients with previously untreated advanced melanoma, was accepted by the FDA for review in September and granted Priority Review with a target action date of January 23, 2016. Data for Opdivo monotherapy in both BRAF wild-type and BRAF V600 mutation positive advanced melanoma was included as part of this application.

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.

INDICATIONS and IMPORTANT SAFETY INFORMATION for OPDIVO (nivolumab)

INDICATIONS

OPDIVO (nivolumab) as a single agent is indicated for the treatment of patients with BRAF V600 wild-type unresectable or metastatic melanoma.

OPDIVO (nivolumab) as a single agent is indicated for the treatment of patients with unresectable or metastatic, BRAF V600 mutation-positive melanoma and disease progression following ipilimumab and 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 (nivolumab), in combination with (ipilimumab), is indicated for the treatment of patients with BRAF V600 wild-type, unresectable or metastatic melanoma. 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 (nivolumab) is indicated for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving OPDIVO.

OPDIVO (nivolumab) is indicated for the treatment of patients with advanced renal cell carcinoma (RCC) who have received prior anti-angiogenic therapy.

IMPORTANT SAFETY INFORMATION

WARNING: IMMUNE-MEDIATED ADVERSE REACTIONS

YERVOY can result in severe and fatal immune-mediated adverse reactions. These immune-mediated reactions may involve any organ system; however, the most common severe immune-mediated adverse reactions are enterocolitis, hepatitis, dermatitis (including toxic epidermal necrolysis), neuropathy, and endocrinopathy. The majority of these immune-mediated reactions initially manifested during treatment; however, a minority occurred weeks to months after discontinuation of YERVOY.

Assess patients for signs and symptoms of enterocolitis, dermatitis, neuropathy, and endocrinopathy and evaluate clinical chemistries including liver function tests (LFTs), adrenocorticotropic hormone (ACTH) level, and thyroid function tests at baseline and before each dose.

Permanently discontinue YERVOY and initiate systemic high-dose corticosteroid therapy for severe immune-mediated reactions.

Immune-Mediated Pneumonitis

Immune-mediated pneumonitis or interstitial lung disease, including fatal cases, occurred with OPDIVO treatment. Across the clinical trial experience with solid tumors, fatal immune-mediated pneumonitis occurred with OPDIVO. In addition, in Checkmate 069, there were six patients who died without resolution of abnormal respiratory findings. Monitor patients for signs with radiographic imaging and symptoms of pneumonitis. Administer corticosteroids for Grade 2 or greater pneumonitis. Permanently discontinue for Grade 3 or 4 and withhold until resolution for Grade 2. In Checkmate 037, 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: Grade 3 (n=1) and Grade 2 (n=5). In Checkmate 066, immune-mediated pneumonitis occurred in 1.4% (3/206) of patients receiving OPDIVO and in none of the 205 patients receiving dacarbazine: Grade 2 (n=3). In Checkmate 057, immune-mediated pneumonitis, including interstitial lung disease, occurred in 3.4% (10/287) of patients: Grade 3 (n=5), Grade 2 (n=2), and Grade 1 (n=3). In Checkmate 025, pneumonitis, including interstitial lung disease, occurred in 5% (21/406) of patients receiving OPDIVO and 18% (73/397) of patients receiving everolimus. Immune-mediated pneumonitis occurred in 4.4% (18/406) of patients receiving OPDIVO: Grade 4 (n=1), Grade 3 (n=4), Grade 2 (n=12), and Grade 1 (n=1). In Checkmate 069, pneumonitis, including interstitial lung disease, occurred in 10% (9/94) of patients receiving OPDIVO in combination with YERVOY and 2.2% (1/46) of patients receiving YERVOY. Immune-mediated pneumonitis occurred in 6% (6/94) of patients receiving OPDIVO in combination with YERVOY: Grade 5 (n=1), Grade 3 (n=2) and Grade 2 (n=3).

Immune-Mediated Colitis

Immune-mediated colitis can occur with OPDIVO treatment. Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 (of more than 5 days duration), 3, or 4 colitis. As a single agent, withhold OPDIVO for Grade 2 or 3 and permanently discontinue for Grade 4 or recurrent colitis upon restarting OPDIVO. In combination with YERVOY, withhold OPDIVO for Grade 2 and permanently discontinue for Grade 3 or 4 or recurrent colitis upon restarting OPDIVO. In Checkmate 037, 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; Grade 3 (n=5) and Grade 2 (n=1). In Checkmate 066, diarrhea or colitis occurred in 28% (58/206) of patients receiving OPDIVO and 25% (52/205) of patients receiving dacarbazine. Immune-mediated colitis occurred in 4.9% (10/206) of patients receiving OPDIVO: Grade 3 (n=5) and Grade 2 (n=5). In Checkmate 057, diarrhea or colitis occurred in 17% (50/287) of patients receiving OPDIVO. Immune-mediated colitis occurred in 2.4% (7/287) of patients: Grade 3 (n=3), Grade 2 (n=2), and Grade 1 (n=2). In Checkmate 025, diarrhea or colitis occurred in 25% (100/406) of patients receiving OPDIVO and 32% (126/397) of patients receiving everolimus. Immune-mediated diarrhea or colitis occurred in 3.2% (13/406) of patients receiving OPDIVO: Grade 3 (n=5), Grade 2 (n=7), and Grade 1 (n=1). In Checkmate 069, diarrhea or colitis occurred in 57% (54/94) of patients receiving OPDIVO in combination with YERVOY and 46% (21/46) of patients receiving YERVOY. Immune-mediated colitis occurred in 33% (31/94) of patients receiving OPDIVO in combination with YERVOY: Grade 4 (n=1), Grade 3 (n=16), Grade 2 (n=9), and Grade 1 (n=5).

In a separate Phase 3 study of YERVOY 3 mg/kg, severe, life-threatening, or fatal (diarrhea of ≥7 stools above baseline, fever, ileus, peritoneal signs; Grade 3-5) immune-mediated enterocolitis occurred in 34 (7%) patients. Across all YERVOY-treated patients in that study (n=511), 5 (1%) developed intestinal perforation, 4 (0.8%) died as a result of complications, and 26 (5%) were hospitalized for severe enterocolitis.

Immune-Mediated Hepatitis

Immune-mediated hepatitis can occur with OPDIVO treatment. Monitor patients for abnormal liver tests prior to and periodically during treatment. Administer corticosteroids for Grade 2 or greater transaminase elevations. Withhold for Grade 2 and permanently discontinue for Grade 3 or 4 immune-mediated hepatitis. In Checkmate 037, 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; Grade 3 (n=2) and Grade 2 (n=1). In Checkmate 066, there was an increased incidence of liver test abnormalities in the OPDIVO-treated group as compared to the dacarbazine-treated group, with increases in ALT (25% vs. 19%), AST (24% vs. 19%), alkaline phosphatase (21% vs. 14%), and total bilirubin (13% vs. 6%). Immune-mediated hepatitis occurred in 0.9% (2/206) of patients receiving OPDIVO: Grade 3 (n=1) and Grade 2 (n=1). In Checkmate 057, one patient (0.3%) developed immune-mediated hepatitis. In Checkmate 025, there was an increased incidence of liver test abnormalities compared to baseline in AST (33% vs 39%), alkaline phosphatase (32% vs 32%), ALT (22% vs 31%), and total bilirubin (9% vs 3.5%) in the OPDIVO-treated and everolimus-treated groups, respectively. Immune-mediated hepatitis requiring systemic immunosuppression occurred in 1.5% (6/406) of patients receiving OPDIVO: Grade 3 (n=5) and Grade 2 (n=1). In Checkmate 069, immune-mediated hepatitis occurred in 15% (14/94) of patients receiving OPDIVO in combination with YERVOY: Grade 4 (n=3), Grade 3 (n=9), and Grade 2 (n=2).

In a separate Phase 3 study of YERVOY 3 mg/kg, severe, life-threatening, or fatal hepatotoxicity (AST or ALT elevations >5x the ULN or total bilirubin elevations >3x the ULN; Grade 3-5) occurred in 8 (2%) patients, with fatal hepatic failure in 0.2% and hospitalization in 0.4%.

Immune-Mediated Dermatitis

In a separate Phase 3 study of YERVOY 3 mg/kg, severe, life-threatening, or fatal immune-mediated dermatitis (eg, Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash complicated by full thickness dermal ulceration, or necrotic, bullous, or hemorrhagic manifestations; Grade 3-5) occurred in 13 (2.5%) patients. 1 (0.2%) patient died as a result of toxic epidermal necrolysis. 1 additional patient required hospitalization for severe dermatitis.

Immune-Mediated Neuropathies

In a separate Phase 3 study of YERVOY 3 mg/kg, 1 case of fatal Guillain-Barré syndrome and 1 case of severe (Grade 3) peripheral motor neuropathy were reported.

Immune-Mediated Endocrinopathies

Hypophysitis, adrenal insufficiency, thyroid disorders, and type 1 diabetes mellitus can occur with OPDIVO treatment. Monitor patients for signs and symptoms of hypophysitis, signs and symptoms of adrenal insufficiency during and after treatment, thyroid function prior to and periodically during treatment, and hyperglycemia. Administer corticosteroids for Grade 2 or greater hypophysitis. Withhold for Grade 2 or 3 and permanently discontinue for Grade 4 hypophysitis. Administer corticosteroids for Grade 3 or 4 adrenal insufficiency. Withhold for Grade 2 and permanently discontinue for Grade 3 or 4 adrenal insufficiency. Administer hormone-replacement therapy for hypothyroidism. Initiate medical management for control of hyperthyroidism. Administer insulin for type 1 diabetes. Withhold OPDIVO for Grade 3 and permanently discontinue for Grade 4 hyperglycemia.

In Checkmate 025, hypophysitis occurred in 0.5% (2/406) of patients receiving OPDIVO: Grade 3 (n=1) and Grade 1 (n=1). In Checkmate 069, hypophysitis occurred in 13% (12/94) of patients receiving OPDIVO in combination with YERVOY: Grade 3 (n=2) and Grade 2 (n=10). In Checkmate 037, 066, 057, <1.0% of OPDIVO-treated patients developed adrenal insufficiency. In Checkmate 025, adrenal insufficiency occurred in 2.0% (8/406) of patients receiving OPDIVO: Grade 3 (n=3), Grade 2 (n=4), and Grade 1 (n=1). In Checkmate 069, adrenal insufficiency occurred in 9% (8/94) of patients receiving OPDIVO in combination with YERVOY: Grade 3 (n=3), Grade 2 (n=4), and Grade 1 (n=1). In Checkmate 037, 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 3.0% (8/268) of patients receiving OPDIVO and 1.0% (1/102) of patients receiving chemotherapy. In Checkmate 066, hypothyroidism occurred in 7% (14/206) of patients receiving OPDIVO (Grade 3 (n=1)) and 0.9% (2/205) of patients receiving dacarbazine. Hyperthyroidism occurred in 4.4% (9/206) of patients receiving OPDIVO (Grade 3 (n=1)) and 0.9% (2/205) of patients receiving dacarbazine. In Checkmate 057, Grade 1 or 2 hypothyroidism, including thyroiditis, occurred in 7% (20/287) and elevated TSH occurred in 17% of patients receiving OPDIVO. Grade 1 or 2 hyperthyroidism occurred in 1.4% (4/287) of patients. In Checkmate 025, thyroid disease occurred in 11% (43/406) of patients receiving OPDIVO, including one Grade 3 event, and in 3.0% (12/397) of patients receiving everolimus. Hypothyroidism/thyroiditis occurred in 8% (33/406) of patients receiving OPDIVO: Grade 3 (n=2), Grade 2 (n=17), and Grade 1 (n=14). Hyperthyroidism occurred in 2.5% (10/406) of patients receiving OPDIVO: Grade 2 (n=5) and Grade 1 (n=5). In Checkmate 069, hypothyroidism occurred in 19% (18/94) of patients receiving OPDIVO in combination with YERVOY. All were Grade 1 or 2 in severity except for one patient who experienced Grade 3 autoimmune thyroiditis. Grade 1 hyperthyroidism occurred in 2.1% (2/94) of patients receiving OPDIVO in combination with YERVOY. In Checkmate 066, diabetes mellitus or diabetic ketoacidosis occurred in 1.0% (2/206) of patients receiving OPDIVO and none of the 205 receiving dacarbazine; Grade 3 diabetic ketoacidosis (n=1) and Grade 2 diabetes mellitus (n=1). In Checkmate 025, hyperglycemic adverse events occurred in 9% (37/406) patients. Diabetes mellitus or diabetic ketoacidosis occurred in 1.5% (6/406) of patients receiving OPDIVO: Grade 3 (n=3), Grade 2 (n=2), and Grade 1 (n=1).

In a separate Phase 3 study of YERVOY 3 mg/kg, severe to life-threatening immune-mediated endocrinopathies (requiring hospitalization, urgent medical intervention, or interfering with activities of daily living; Grade 3-4) occurred in 9 (1.8%) patients. All 9 patients had hypopituitarism, and some had additional concomitant endocrinopathies such as adrenal insufficiency, hypogonadism, and hypothyroidism. 6 of the 9 patients were hospitalized for severe endocrinopathies.

Immune-Mediated Nephritis and Renal Dysfunction

Immune-mediated nephritis can occur with OPDIVO treatment. Monitor patients for elevated serum creatinine prior to and periodically during treatment. For Grade 2 or 3 increased serum creatinine, withhold and administer corticosteroids; if worsening or no improvement occurs, permanently discontinue. Administer corticosteroids for Grade 4 serum creatinine elevation and permanently discontinue. In Checkmate 037, 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 Checkmate 066, there was an increased incidence of elevated creatinine in the OPDIVO-treated group as compared to the dacarbazine-treated group (11% vs. 10%). Grade 3 immune-mediated renal dysfunction occurred in 0.5% (1/206) of patients. In Checkmate 057, Grade 2 immune-mediated renal dysfunction occurred in 0.3% (1/287) of patients receiving OPDIVO. In Checkmate 025, renal injury occurred in 7% (27/406) of patients receiving OPDIVO and 3.0% (12/397) of patients receiving everolimus. Immune-mediated nephritis and renal dysfunction occurred in 3.2% (13/406) of patients receiving OPDIVO: Grade 5 (n=1), Grade 4 (n=1), Grade 3 (n=5), and Grade 2 (n=6). In Checkmate 069, Grade 2 or higher immune-mediated nephritis or renal dysfunction occurred in 2.1% (2/94) of patients. One patient died without resolution of renal dysfunction.

Immune-Mediated Rash

Immune-mediated rash can occur with OPDIVO treatment. Severe rash (including rare cases of fatal toxic epidermal necrolysis) occurred in the clinical program of OPDIVO. Monitor patients for rash. Administer corticosteroids for Grade 3 or 4 rash. Withhold for Grade 3 and permanently discontinue for Grade 4. In Checkmate 057, immune-mediated rash occurred in 6% (17/287) of patients receiving OPDIVO including four Grade 3 cases. In Checkmate 025, rash occurred in 28% (112/406) of patients receiving OPDIVO and 36% (143/397) of patients receiving everolimus. Immune-mediated rash, defined as a rash treated with systemic or topical corticosteroids, occurred in 7% (30/406) of patients receiving OPDIVO: Grade 3 (n=4), Grade 2 (n=7), and Grade 1 (n=19). In Checkmate 069, immune-mediated rash occurred in 37% (35/94) of patients receiving OPDIVO in combination with YERVOY: Grade 3 (n=6), Grade 2 (n=10), and Grade 1 (n=19).

Immune-Mediated Encephalitis

Immune-mediated encephalitis can occur with OPDIVO treatment. Withhold OPDIVO in patients with new-onset moderate to severe neurologic signs or symptoms and evaluate to rule out other causes. If other etiologies are ruled out, administer corticosteroids and permanently discontinue OPDIVO for immune-mediated encephalitis. Across clinical trials of 8490 patients receiving OPDIVO as a single agent or in combination with YERVOY, <1.0% of patients were identified as having encephalitis. In Checkmate 057, fatal limbic encephalitis occurred in one patient (0.3%) receiving OPDIVO.

Other Immune-Mediated Adverse Reactions

Based on the severity of adverse reaction, permanently discontinue or withhold treatment, administer high-dose corticosteroids, and, if appropriate, initiate hormone-replacement therapy. The following clinically significant immune-mediated adverse reactions occurred in <1.0% of OPDIVO-treated patients: uveitis, pancreatitis, facial and abducens nerve paresis, demyelination, polymyalgia rheumatica, autoimmune neuropathy, Guillain-Barre syndrome, hypopituitarism and systemic inflammatory response syndrome. Across clinical trials of OPDIVO administered as a single agent at doses 3 mg/kg and 10 mg/kg, additional clinically significant, immune-mediated adverse reactions were identified: motor dysfunction, vasculitis, and myasthenic syndrome. Across clinical trials of OPDIVO in combination with YERVOY, the following additional clinically significant, immune-mediated adverse reactions were identified: sarcoidosis, duodenitis, and gastritis.

Infusion Reactions

Severe infusion reactions have been reported in <1.0% of patients in clinical trials of OPDIVO as a single agent. Discontinue OPDIVO in patients with Grade 3 or 4 infusion reactions. Interrupt or slow the rate of infusion in patients with Grade 1 or 2. In Checkmate 057 and 066, Grade 2 infusion reactions occurred in 1.0% (5/493) of patients receiving OPDIVO. In Checkmate 025, hypersensitivity/infusion-related reactions occurred in 6% (25/406) of patients receiving OPDIVO and 1.0% (4/397) of patients receiving everolimus. In Checkmate 069, Grade 2 infusion reactions occurred in 3.2% (3/94) of patients receiving OPDIVO in combination with YERVOY.

Embryofetal Toxicity

Based on their mechanisms of action, OPDIVO and YERVOY 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 an OPDIVO- or YERVOY- containing regimen and for at least 5 months after the last dose of OPDIVO.

Lactation

It is not known whether OPDIVO or YERVOY 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-containing regimen, advise women to discontinue breastfeeding during treatment. Advise women to discontinue nursing during treatment with YERVOY and for 3 months following the final dose.

Serious Adverse Reactions

In Checkmate 037, 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 Checkmate 066, serious adverse reactions occurred in 36% of patients receiving OPDIVO. Grade 3 and 4 adverse reactions occurred in 41% of patients receiving OPDIVO. The most frequent Grade 3 and 4 adverse reactions reported in ≥2% of patients receiving OPDIVO were gamma-glutamyltransferase increase (3.9%) and diarrhea (3.4%). In Checkmate 057, serious adverse reactions occurred in 47% of patients receiving OPDIVO. The most frequent serious adverse reactions reported in ≥2% of patients were pneumonia, pulmonary embolism, dyspnea, pleural effusion, and respiratory failure. In Checkmate 025, serious adverse reactions occurred in 47% of patients receiving OPDIVO. The most frequent serious adverse reactions reported in ≥2% of patients were acute kidney injury, pleural effusion, pneumonia, diarrhea, and hypercalcemia. In Checkmate 069, serious adverse reactions occurred in 62% of patients receiving OPDIVO; the most frequent serious adverse events with OPDIVO in combination with YERVOY, as compared to YERVOY alone, were colitis (17% vs 9%), diarrhea (9% vs 7%), pyrexia (6% vs 7%), and pneumonitis (5% vs 0).

Common Adverse Reactions

In Checkmate 037, the most common adverse reaction (≥20%) reported with OPDIVO was rash (21%). In Checkmate 066, the most common adverse reactions (≥20%) reported with OPDIVO vs dacarbazine were fatigue (49% vs 39%), musculoskeletal pain (32% vs 25%), rash (28% vs 12%), and pruritus (23% vs 12%). In Checkmate 057, the most common adverse reactions (≥20%) reported with OPDIVO were fatigue (49%), musculoskeletal pain (36%), cough (30%), decreased appetite (29%), and constipation (23%). In Checkmate 025, the most common adverse reactions (≥20%) reported in patients receiving OPDIVO vs everolimus were asthenic conditions (56% vs 57%), cough (34% vs 38%), nausea (28% vs 29%), rash (28% vs 36%), dyspnea (27% vs 31%), diarrhea (25% vs 32%), constipation (23% vs 18%), decreased appetite (23% vs 30%), back pain (21% vs 16%), and arthralgia (20% vs 14%). In Checkmate 069, the most common adverse reactions (≥20%) reported in patients receiving OPDIVO in combination with YERVOY vs YERVOY alone were rash (67% vs 57%), pruritus (37% vs 26%), headache (24% vs 20%), vomiting (23% vs 15%), and colitis (22% vs 11%).

In a separate Phase 3 study of YERVOY 3 mg/kg, the most common adverse reactions (≥5%) in patients who received YERVOY at 3 mg/kg were fatigue (41%), diarrhea (32%), pruritus (31%), rash (29%), and colitis (8%).

FDA Grants Fast Track Designation to Cellceutix’s Brilacidin-OM for Oral Mucositis

On November 25, 2015 Cellceutix Corporation (OTC: CTIX) (the "Company"), a clinical stage biopharmaceutical company developing innovative therapies with oncology, dermatology, anti-inflammatory and antibiotic applications, reported that the U.S. Food and Drug Administration (FDA) has granted Fast Track Designation for Brilacidin-OM, an oral rinse formulation of the Company’s novel defensin-mimetic Brilacidin, for the prevention of oral mucositis (Press release, Innovation Pharmaceuticals, NOV 25, 2015, View Source [SID1234536591]). Oral mucositis, a common and often debilitating inflammation and ulceration that occurs in the mouth as a side-effect of certain cancer treatments, afflicts approximately 450,000 patients each year in the United States and can affect the course and outcome of cancer therapy. There are no FDA approved drugs for the prevention of oral mucositis.

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In an ongoing Phase 2 trial, Brilacidin-OM is being evaluated for its safety and efficacy in preventing oral mucositis in patients undergoing chemoradiation for the treatment of head and neck cancer. Seven clinical sites and two satellite sites are currently enrolling patients in the trial, with additional sites expected to open enrollment in the coming weeks.

The FDA established the Fast Track Designation process to facilitate the development, and expedite the review of, drugs that have the potential to treat serious and life threatening conditions and fill an unmet medical need. Drugs developed under the Fast Track program are afforded increased access to the FDA and could qualify for other programs to expedite development, including priority review and accelerated approval.

"Hundreds of thousands of patients suffer from oral mucositis each year, including many of the approximately 60,000 patients diagnosed with head and neck cancer, with no drug available to help prevent it," commented Leo Ehrlich, Chief Executive Officer at Cellceutix. "We are very optimistic about our defensin-mimetic franchise given the strong antibacterial properties of Brilacidin-IV shown in clinical trials for ABSSSI and lab studies demonstrating the anti-inflammatory and anti-biofilm properties of Brilacidin-OM, which we hope to validate in the Phase 2 trial in oral mucositis patients. The Fast Track Designation provides us a greater opportunity to interact with the FDA and the possibility of other programs to assist in hastening the development of Brilacidin-OM. With the Orphan Drug Designation for drug Kevetrin to treat retinoblastoma, an FDA meeting being scheduled at the beginning of 2016 for our planned Phase 2 trial of Kevetrin for ovarian cancer, which is also being developed under an Orphan Drug Designation, and now this Fast Track Designation for Brilacidin-OM, it’s been a solid month of developments with the FDA for our oncology pipeline."

10-K – Annual report [Section 13 and 15(d), not S-K Item 405]

(Filing, 10-K, Varian Medical Systems, NOV 25, 2015, View Source [SID:1234508351])

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Pfizer Receives European Approval to Expand Use of XALKORI® (crizotinib) to First-Line Treatment of Adults with ALK-Positive Advanced Non-Small Cell Lung Cancer

On November 25, 2015 Pfizer Inc. (NYSE:PFE) reported that the European Commission has approved a label update to expand use of XALKORI (crizotinib) to first-line treatment of adults with anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer (NSCLC) (Press release, Pfizer, NOV 25, 2015, View Source [SID:1234508364]). The Summary of Product Characteristics also has been updated to include efficacy data from PROFILE 1014, which demonstrated that XALKORI significantly prolonged progression-free survival (PFS) in previously untreated patients with ALK-positive advanced nonsquamous NSCLC when compared to standard platinum-based chemotherapy regimens.1

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"The European Commission’s decision to approve XALKORI in the first-line setting reinforces XALKORI’s role as a standard of care for patients with ALK-positive advanced NSCLC," said Andreas Penk, MD, regional president Oncology Europe, Africa and the Middle East, Head Greater China and Asia-Pacific Oncology Regions. "This milestone further underscores the importance of early and routine biomarker testing in patients with advanced NSCLC so that these patients can be identified and treated appropriately."

The European Commission’s approval of XALKORI follows the positive opinion issued by the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency, and is supported by the results from PROFILE 1014, a Phase 3 global, randomized, open-label, two-arm study evaluating the efficacy and safety of XALKORI in patients previously untreated for ALK-positive advanced nonsquamous NSCLC.1

XALKORI was the first ALK inhibitor approved by regulatory authorities in the United States (U.S.), EU, China and Japan, and it is now approved in more than 85 countries. XALKORI is widely recognized as a standard of care for patients with ALK-positive advanced NSCLC. To date, more than 20,000 patients have been treated with XALKORI worldwide.2

XALKORI is an oral, ALK inhibitor.3 By inhibiting the ALK fusion protein, XALKORI blocks signaling in a number of cell pathways that are believed to be critical for the growth and survival of tumor cells, which may lead to growth inhibition or regression of tumors.4,5

About Non-Small Cell Lung Cancer

Worldwide, lung cancer is the leading cause of cancer death in both men and women.6 NSCLC accounts for about 85 percent of lung cancer cases and remains difficult to treat, particularly in the metastatic setting.7 Approximately 57 percent of NSCLC patients are diagnosed late with metastatic, or advanced, disease where the five-year survival rate is only 5 percent.8

XALKORI (crizotinib) Indication and Important Safety Information (as per U.S. Prescribing Information)

XALKORI is a kinase inhibitor indicated for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors are anaplastic lymphoma kinase (ALK)-positive as detected by an FDA-approved test.

Hepatotoxicity: Drug-induced hepatotoxicity with fatal outcome occurred in 0.1% of patients treated with XALKORI across clinical trials (n=1669). Transaminase elevations generally occurred within the first 2 months. Monitor with liver function tests including ALT and total bilirubin every 2 weeks during the first 2 months of treatment, then once a month and as clinically indicated, with more frequent repeat testing for increased liver transaminases, alkaline phosphatase, or total bilirubin in patients who develop transaminase elevations. Permanently discontinue for ALT/AST elevation >3 times ULN with concurrent total bilirubin elevation >1.5 times ULN (in the absence of cholestasis or hemolysis); otherwise, temporarily suspend and dose-reduce XALKORI as indicated.

Interstitial Lung Disease (Pneumonitis): Severe, life-threatening, or fatal interstitial lung disease (ILD)/pneumonitis can occur. Across clinical trials (n=1669), 2.9% of XALKORI-treated patients had any grade ILD, 1.1% had Grade 3/4, and 0.5% had fatal ILD. These cases generally occurred within 3 months after initiation of treatment. Monitor for pulmonary symptoms indicative of ILD/pneumonitis. Exclude other potential causes and permanently discontinue XALKORI in patients with drug-related ILD/pneumonitis.

QT Interval Prolongation: QTc prolongation can occur. Across clinical trials (n=1560), 2.1% of patients had QTcF (corrected QT by the Fridericia method) ≥500 ms and 5.0% had an increase from baseline QTcF ≥60 ms by automated machine-read evaluation of ECG. Avoid use in patients with congenital long QT syndrome. Consider periodic monitoring with ECGs and electrolytes in patients with congestive heart failure, bradyarrhythmias, electrolyte abnormalities, or who are taking medications that prolong the QT interval. Permanently discontinue XALKORI in patients who develop QTc >500 ms or ≥60 ms change from baseline with Torsade de pointes, polymorphic ventricular tachycardia, or signs/symptoms of serious arrhythmia. Withhold XALKORI in patients who develop QTc >500 ms on at least 2 separate ECGs until recovery to a QTc ≤480 ms, then resume at a reduced dose.

Bradycardia: Symptomatic bradycardia can occur. Across clinical trials, bradycardia occurred in 12.3% of patients treated with XALKORI (N=1669). Avoid use in combination with other agents known to cause bradycardia. Monitor heart rate and blood pressure regularly. In cases of symptomatic bradycardia that is not life-threatening, hold XALKORI until recovery to asymptomatic bradycardia or to a heart rate of ≥60 bpm, re-evaluate the use of concomitant medications, and adjust the dose of XALKORI. Permanently discontinue for life-threatening bradycardia due to XALKORI; however, if associated with concomitant medications known to cause bradycardia or hypotension, hold XALKORI until recovery to asymptomatic bradycardia or to a heart rate of ≥60 bpm. If concomitant medications can be adjusted or discontinued, restart XALKORI at 250 mg once daily with frequent monitoring.

Severe Visual Loss: Across clinical trials, the incidence of Grade 4 visual field defect with vision loss was 0.2% (N=1669). Discontinue XALKORI in patients with new onset of severe visual loss (best corrected vision less than 20/200 in one or both eyes). Perform an ophthalmological evaluation. There is insufficient information to characterize the risks of resumption of XALKORI in patients with a severe visual loss; a decision to resume should consider the potential benefits to the patient.

Vision Disorders: Most commonly visual impairment, photopsia, blurred vision or vitreous floaters, occurred in 62% of 1669 patients. The majority (95%) of these patients had Grade 1 visual adverse reactions. 0.8% of patients had Grade 3 and 0.2% had Grade 4 visual impairment. The majority of patients on the XALKORI arms in Studies 1 and 2 (>50%) reported visual disturbances which occurred at a frequency of 4-7 days each week, lasted up to 1 minute, and had mild or no impact on daily activities.

Embryofetal Toxicity: XALKORI can cause fetal harm when administered to a pregnant woman. Advise of the potential risk to the fetus. Advise females of reproductive potential and males with female partners of reproductive potential to use effective contraception during treatment and for at least 45 days (females) or 90 days (males) respectively, following the final dose of XALKORI.

Adverse Reactions: Safety was evaluated in a phase 3 study in previously untreated patients with ALK-positive metastatic NSCLC randomized to XALKORI (n=171) or chemotherapy (n=169). Serious adverse events were reported in 34% of patients treated with XALKORI, the most frequent were dyspnea (4.1%) and pulmonary embolism (2.9%). Fatal adverse events in XALKORI-treated patients occurred in 2.3% of patients, consisting of septic shock, acute respiratory failure, and diabetic ketoacidosis. Common adverse reactions (all grades) occurring in ≥25% and more commonly (≥5%) in patients treated with XALKORI vs chemotherapy were vision disorder (71% vs 10%), diarrhea (61% vs 13%), edema (49% vs 12%), vomiting (46% vs 36%), constipation (43% vs 30%), upper respiratory infection (32% vs 12%), dysgeusia (26% vs 5%), and abdominal pain (26% vs 12%). Grade 3/4 reactions occurring at a ≥2% higher incidence with XALKORI vs chemotherapy were QT prolongation (2% vs 0%), and constipation (2% vs 0%). In patients treated with XALKORI vs chemotherapy, the following occurred: elevation of ALT (any grade [79% vs 33%] or Grade 3/4 [15% vs 2%]); elevation of AST (any grade [66% vs 28%] or Grade 3/4 [8% vs 1%]); neutropenia (any grade [52% vs 59%] or Grade 3/4 [11% vs 16%]); lymphopenia (any grade [48% vs 53%] or Grade 3/4 [7% vs 13%]); hypophosphatemia (any grade [32% vs 21%] or Grade 3/4 [10% vs 6%]). In patients treated with XALKORI vs chemotherapy, renal cysts occurred (5% vs 1%). Nausea (56%) decreased appetite (30%), fatigue (29%), and neuropathy (21%) also occurred in patients taking XALKORI.

Drug Interactions: Exercise caution with concomitant use of moderate CYP3A inhibitors. Avoid grapefruit or grapefruit juice which may increase plasma concentrations of crizotinib. Avoid concomitant use of strong CYP3A inducers and inhibitors. Avoid concomitant use of CYP3A substrates with narrow therapeutic range in patients taking XALKORI. If concomitant use of CYP3A substrates with narrow therapeutic range is required in patients taking XALKORI, dose reductions of the CYP3A substrates may be required due to adverse reactions.

Lactation: Because of the potential for adverse reactions in breastfed infants, advise females not to breast feed during treatment with XALKORI and for 45 days after the final dose.

Hepatic Impairment: XALKORI has not been studied in patients with hepatic impairment. As crizotinib is extensively metabolized in the liver, hepatic impairment is likely to increase plasma crizotinib concentrations. Use caution in patients with hepatic impairment.

Renal Impairment: Administer XALKORI at a starting dose of 250 mg taken orally once daily in patients with severe renal impairment (CLcr <30 mL/min) not requiring dialysis. No starting dose adjustment is needed for patients with mild and moderate renal impairment.