On November 24, 2015 Bristol-Myers Squibb Company (NYSE:BMY) reported that the European Commission (EC) has approved the reconciliation of indications for nivolumab under the Opdivo European Marketing Authorization Application (MAA) (Press release, Bristol-Myers Squibb, NOV 24, 2015, View Source [SID:1234508345]). In compliance with European Commission regulations, Bristol-Myers Squibb previously submitted two separate MAAs to the European Medicines Agency (EMA); one under the name Opdivo for the treatment of unresectable or metastatic melanoma in adults, and one under the name Nivolumab BMS for the treatment of locally advanced or metastatic squamous (SQ) non-small cell lung cancer (NSCLC) after prior chemotherapy. An application to reconcile these two indications was then submitted under the Opdivo brand name.

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Following approval for both of these indications by the EC earlier this year, the Company is voluntarily withdrawing the Marketing Authorization under the Nivolumab BMS brand name. This withdrawal has no impact for SQ NSCLC patients taking nivolumab since Opdivo is now approved for the treatment of SQ NSCLC, as well as for melanoma.

Mathias Hukkelhoven, Ph.D., senior vice president, head of Global Regulatory, Safety and Biometrics, Bristol-Myers Squibb, commented, "To make Opdivo available to healthcare professionals and patients in the timeliest way possible, Bristol-Myers Squibb worked with European health authorities on an innovative regulatory approach – one that was critically focused on speed to patients for both patient populations. We submitted two separate Marketing Authorization Applications for indications in advanced melanoma and squamous non-small cell lung cancer for review in parallel. As the European Commission has now granted approval for both Opdivo and Nivolumab BMS, we have reconciled these indications under the Opdivo brand name."

While different in name, Nivolumab BMS and Opdivo are the same Immuno-Oncology agent approved at the same dosing level and schedule. Nivolumab BMS is currently marketed in a few countries in the European Union. Squamous NSCLC patients presently treated with Nivolumab BMS will be automatically switched to Opdivo when Nivolumab BMS is no longer available in their country. Patients or healthcare professionals who have further questions about the withdrawal or reconciliation may contact Bristol-Myers Squibb Medical Information.

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 the first PD-1 immune checkpoint inhibitor to receive regulatory approval anywhere in the world in July 2014, and currently has regulatory approval in 40 countries including the United States, Japan, and in the European Union.

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 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 5.2% (21/406) of patients receiving OPDIVO and 18.4% (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 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 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%) 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 I 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 I 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 and 057 (n=555), adrenal insufficiency occurred in 1% of patients receiving OPDIVO. In Checkmate 025, adrenal insufficiency occurred in 2% (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% (8/268) of patients receiving OPDIVO and 1% (1/102) of patients receiving chemotherapy. 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 43/406 (10.6%) patients receiving OPDIVO, including one Grade 3 event, and in 12/397 (3.0%) patients receiving everolimus. Hypothyroidism/thyroiditis occurred in 8.1% (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 025, hyperglycemic adverse events occurred in 37/406 (9%) patients. Diabetes mellitus or diabetic ketoacidosis occurred in 1% (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 057, Grade 2 immune-mediated renal dysfunction occurred in 0.3% (1/287) of patients receiving OPDIVO. In Checkmate 025, renal injury occurred in 6.6% (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 037 (n=268), the incidence of rash was 21%; the incidence of Grade 3 or 4 rash was 0.4%. 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 7.4% (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% 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 <2% of single-agent OPDIVO-treated patients: uveitis, pancreatitis, abducens nerve paresis, demyelination, polymyalgia rheumatica, autoimmune neuropathy, 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: facial nerve paralysis, motor dysfunction, vasculitis, and myasthenic syndrome. In Checkmate 069, the following additional immune-mediated adverse reactions occurred in 1% of patients treated with OPDIVO in combination with YERVOY: Guillain-Barré syndrome and hypopituitarism. Across clinical trials of OPDIVO in combination with YERVOY, the following additional clinically significant, immune-mediated adverse reactions were identified: uveitis, sarcoidosis, duodenitis, pancreatitis, and gastritis.

Infusion Reactions

Severe infusion reactions have been reported in <1% 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, Grade 2 infusion reactions occurred in 1% (3/287) of patients receiving OPDIVO. In Checkmate 025, hypersensitivity/infusion-related reactions occurred in 6.2% (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% (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 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 at least 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 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%).

Please see U.S. Full Prescribing Information for OPDIVO and YERVOY including Boxed WARNING for YERVOY regarding immune-mediated adverse reactions.

On November 24, 2015 The U.S. Food and Drug Administration reported that it approved Portrazza (necitumumab) in combination with two forms of chemotherapy to treat patients with advanced (metastatic) squamous non-small cell lung cancer (NSCLC) who have not previously received medication specifically for treating their advanced lung cancer (Press release, , NOV 24, 2015, View Source [SID:1234508346]).
Lung cancer is the leading cause of cancer death in the United States, with an estimated 221,200 new diagnoses and 158,040 deaths in 2015. The most common type of lung cancer, non-small cell lung cancer, is further divided into two main types named for the kinds of cells found in the cancer – squamous cell and non-squamous cell (which includes adenocarcinoma).

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"Lung cancer tumors can be varied, so treatment options need to be tailored to the specific type of lung cancer in the patient," said Richard Pazdur, M.D., director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. "Today’s approval provides certain patients with squamous cell lung cancer a new option that may extend survival."

Portrazza is a monoclonal antibody that blocks activity of EGFR, a protein commonly found on squamous NSCLC tumors.

The safety and efficacy of Portrazza were evaluated in a multicenter, randomized, open-label clinical study of 1,093 participants with advanced squamous NSCLC who received the chemotherapies gemcitabine and cisplatin with or without Portrazza. Those taking Portrazza plus gemcitabine and cisplatin lived longer on average (11.5 months) compared to those only taking gemcitabine and cisplatin (9.9 months). Portrazza was not found to be an effective treatment in patients with non-squamous NSCLC.

The most common side effects of Portrazza are skin rash and magnesium deficiency (hypomagnesemia), which can cause muscular weakness, seizure, irregular heartbeats and can be fatal. Portrazza includes a boxed warning to alert health care providers of serious risks of treatment with Portrazza, including cardiac arrest and sudden death, as well as hypomagnesemia.

Portrazza is marketed by Eli Lilly and Company, based in Indianapolis, Indiana.

On November 23, 2015 DelMar Pharmaceuticals, Inc. (OTCQX: DMPI) ("DelMar" and the "Company"), a biopharmaceutical company focused on the development and commercialization of new cancer therapies, reported updated data from the fully enrolled 14-patient expansion cohort of the Company’s ongoing Phase II clinical study of VAL-083 (dianhydrogalactitol) in refractory glioblastoma multiforme (GBM) that is being conducted at Sarah Cannon Research Institute, Mayo Clinic, and UCSF Medical Center (Press release, DelMar Pharmaceuticals, NOV 23, 2015, View Source [SID:1234508323]).

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The data were presented at the 20th Annual Scientific Meeting and Education Day of the Society for Neuro-Oncology (SNO) in San Antonio, Texas, held November 19-22, in a poster entitled, "Phase I/II study of Dianhydrogalactitol (VAL-083) In Patients With Recurrent Malignant Glioma." Interested parties can access the poster here.

DelMar will host a conference call and live webcast for investors, analysts and other interested parties today at 4:30 p.m. Eastern Time / 1:30 p.m. Pacific Time to provide a business update and discuss these new data.

"The interim survival data from the Phase II expansion cohort is highly promising and consistent with our observations from the Phase I dose-escalation portion of the trial," stated Jeffrey Bacha, DelMar’s chairman & CEO. "A Kaplan Meyer survival estimate, based on these preliminary interim data, projects a greater than 9-month median survival in refractory GBM patients whose tumors have recurred following both front-line therapy with temozolomide and second-line bevacizumab (Avastin) treatment."

"These results continue to support the potential of VAL-083 to address the significant unmet medical need for these patients who currently have no approved therapeutic options," said Mr. Bacha.

"The Phase II portion of the VAL-083 study in patients with recurrent GBM enrolled very quickly. This rapid enrollment, combined with the enthusiasm we have seen from clinical investigators, is a clear demonstration of the overwhelming unmet medical need for new therapies in the treatment of GBM," stated Mr. Bacha.

"The data from the Phase II cohort of our clinical study continue to show that VAL-083 is well-tolerated at the 40 mg/m2 dosing regimen. This dose previously demonstrated the potential to improve survival outcomes in post-bevacizumab refractory GBM," Mr. Bacha continued. "The expanded Phase II data set support 40 mg/m2 as the appropriate dose for advancement into registration-directed Phase II/III clinical trials with VAL-083 in patients with recurrent GBM."

"Additionally, we have continued to demonstrate that the cytotoxic mechanism of VAL-083 is distinct from other chemotherapies used in the treatment of cancer. We can leverage this new understanding of how VAL-083 attacks the tumor with clinical trial data from previously conducted Phase I and Phase II NCI-sponsored clinical trials that validates VAL-083’s clinical activity against a range of tumor-types to address modern unmet medical needs in the treatment of cancer," added Mr. Bacha.

"In the case of GBM, we have shown that the anti-tumor activity of VAL-083 is independent of MGMT, the resistance mechanism which causes the majority of GBM patients to fail currently available cytotoxic chemotherapy," said Mr. Bacha.

"Taken together with historical and recently demonstrated clinical activity, these results suggest that VAL-083’s distinct anti-cancer mechanism has the potential to overcome chemo-resistance and surpass the standard of care in the treatment of GBM," Mr. Bacha concluded.

DelMar is conducting an open-label, single-arm Phase I/II dose-escalation study with VAL-083 in patients with histologically-confirmed GBM, previously treated with radiation who have failed both front-line therapy temozolomide and second-line Avastin (bevacizumab), and, in most cases, one or more salvage therapies. The study utilized 3+3 dose-escalation design. Patients received VAL-083 on days 1, 2, 3 of a 21-day cycle (ClinicalTrials.gov Identifier NCT01478178) at Sarah Cannon Research Institute, Mayo Clinic, and UCSF Medical Center.

In the Phase I dose-escalation portion of the study, VAL-083 was well tolerated at doses up to 40mg/m2 using a regimen of daily x 3 every 21 days. The 40 mg/m2/d dose exhibited a favorable safety profile, with a trend toward improved survival versus lower doses. Following determination of the maximum tolerated dose (MTD) at 40 mg/m2/d, a 14-patient Phase II expansion cohort was rapidly enrolled at a dose of 40 mg/m2/d on day 1, 2, 3 of a 21 day cycle.

Update on Status of Phase II Expansion Cohort

14 patients have been enrolled in the Phase II expansion cohort and all patients have received at least one cycle of treatment to date.

Safety observations in the Phase II expansion cohort to date are consistent with the Phase I dose-escalation cohort. Generally, observed myelosuppression is mild (Grade 1), with the exception of one patient.

One subject previously treated with CCNU developed Grade 4 thrombocytopenia suggesting patients with prior nitrosourea treatment who may exhibit higher susceptibility to thrombocytopenia. The inclusion criteria were modified to account for this observation.

A Kaplan Meyer survival estimate based on interim analysis of patients enrolled in the Phase II expansion cohort is consistent with observations made in the Phase I dose-escalation portion of the study. This preliminary interim analysis suggests a potentially meaningful survival benefit in this population following treatment with VAL-083 at doses >30 mg/m2/d in comparison to published reports for the same refractory GBM population.

GBM is the most common and deadly form of brain cancer. Standard front-line treatment following surgical resection is temozolomide chemotherapy combined with radiation treatment followed by maintenance therapy with temozolomide. Temozolomide is often ineffective in the majority of GBM patients by O6-methylguanine-DNA-methyltransferase (MGMT), a naturally occurring DNA-repair enzyme causing resistance to treatment. Bevacizumab (Avastin) has been approved as second-line therapy for patients failing front-line therapy; however, data presented at the SNO2015 meeting suggest that bevacizumab treatment does not prolong survival for refractory GBM patients. DelMar has demonstrated that VAL-083’s anti-tumor activity is unaffected by the expression of MGMT, a DNA repair enzyme that is implicated in chemotherapy resistance and poor outcomes in GBM patients following standard front-line treatment with temozolomide.

Taken together with historical and recently demonstrated clinical activity, these data suggest a distinct anti-cancer mechanism for VAL-083 which has the potential to overcome chemo-resistance and surpass the standard of care in the treatment of GBM.

The poster on the clinical trial data presented at SNO may be found on DelMar’s website under View Source

CONFERENCE CALL DETAILS
DelMar is hosting a conference call today at 4:30 p.m. Eastern Time / 1:30 p.m. Pacific Time. For both "listen-only" participants and those who wish to take part in the question and answer portion of the call, the telephone Dial-in Number is (844) 303-8663 (toll-free) with Conference ID 81768802. A link to the webcast and slides will be available on the IR Calendar of the Investors section of the Company’s website at www.delmarpharma.com, and will be archived for 30 days.

About VAL-083
VAL-083 is a "first-in-class," small-molecule chemotherapeutic. In more than 40 Phase I and II clinical studies sponsored by the U.S. National Cancer Institute, VAL-083 demonstrated clinical activity against a range of cancers including lung, brain, cervical, ovarian tumors and leukemia both as a single-agent and in combination with other treatments. VAL-083 is approved in China for the treatment of chronic myelogenous leukemia (CML) and lung cancer, and has received orphan drug designation in Europe and the U.S. for the treatment of malignant gliomas.

VAL-083 is a bi-functional DNA N7 cross-linking agent that crosses the blood-brain barrier that has demonstrated historical clinical activity against a range of cancers, including GBM, in prior NCI-sponsored clinical trials. DelMar has demonstrated that VAL-083 induces phosphorylation of H2AX, a hallmark of double-strand DNA breaks, leading to cell cycle arrest in the late G2/S phase. H2AX is a histone involved in the CHK2 checkpoint activation pathway, a key component of the body’s immune response to DNA damage that activates down-stream signaling ultimately resulting in apoptosis (cancer cell death). Additionally, the cytotoxic activity of VAL-083 appears to be less dependent on wild type p53 in comparison to other chemotherapeutic agents. Alteration in p53 has been correlated with poor patient outcomes in GBM. In particular, gain-of-function mutant p53 is strongly associated with a poor prognosis for overall survival in patients with glioblastoma, potentially by increasing expression of MGMT, a DNA repair enzyme that is implicated in chemotherapy resistance to temozolomide and poor outcomes in GBM patients.

DelMar has previously demonstrated that VAL-083’s anti-tumor activity is unaffected by the expression of MGMT. Taken together with historical and recently demonstrated clinical activity, these data suggest a distinct anti-cancer mechanism for VAL-083 which has the potential to overcome chemo-resistance and surpass the standard of care in the treatment of GBM.

DelMar recently announced the completion of enrollment in a Phase II clinical trial of VAL-083 in refractory GBM. Patients have been enrolled at five clinical centers in the United States: Mayo Clinic (Rochester, MN); UCSF (San Francisco, CA) and three centers associated with the Sarah Cannon Cancer Research Institute (Nashville, TN, Sarasota, FL and Denver, CO).

In the Phase I dose-escalation portion of the study, VAL-083 was well tolerated at doses up to 40mg/m2 using a regimen of daily x 3 every 21 days. Adverse events were typically mild to moderate; no treatment-related serious adverse events reported at doses up to 40 mg/m2. Dose limiting toxicity (DLT) defined by thrombocytopenia (low platelet counts) was observed in two of six (33%) of patients at 50 mg/m2. Generally, DLT-related symptoms resolved rapidly and spontaneously without concomitant treatment, although one patient who presented with hemorrhoids received a platelet transfusion as a precautionary measure.

Sub-group analysis of data from the Phase I dose-escalation portion of the study suggested a dose-dependent and clinically meaningful survival benefit following treatment with VAL-083 in GBM patients whose tumors had progressed following standard treatment with temozolomide, radiotherapy, bevacizumab and a range of salvage therapies.

Patients in a low dose (<5mg/m2) sub-group had a median survival of approximately five (5) months versus median survival of approximately nine (9) months for patients in the therapeutic dose (30mg/m2 & 40mg/m2) sub-group following initiation of VAL-083 treatment. DelMar reported increased survival at 6, 9 and 12 months following initiation of treatment with VAL-083 in the therapeutic dose sub-group compared to the low dose sub-group.

On November 23, 2015 NewLink Genetics Corporation (NLNK), a biopharmaceutical company at the forefront of discovering, developing and commercializing novel immuno-oncology product candidates, including both cellular immunotherapy and checkpoint inhibitor platforms, to improve the lives of patients with cancer, reported a trial update from a Phase 1b/2 study of indoximod in combination with temozolomide presented on November 20 at the 20th Annual Scientific Meeting of the Society for Neuro-Oncology in San Antonio, Texas (Press release, NewLink Genetics, NOV 23, 2015, View Source [SID:1234508326]).

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Indoleamine 2,3-dioxygenase (IDO) is a key immuno-modulatory enzyme that allows tumors to thwart the host immune response and therefore is an important research target. IDO is expressed in a large proportion of solid tumors, including 50-90% of glioblastoma tumors. Indoximod is NewLink Genetics’ proprietary product candidate that has shown the potential to interfere with multiple targets within the IDO pathway and thereby to unleash the immune system to fight cancer.

The update presented is from a Phase 1b/2 study of indoximod in combination with temozolomide in patients with advanced glioblastoma who have previously demonstrated that their tumors are refractory to temozolomide. The completed Phase 1b portion of the study, which enrolled 12 patients, continues to show that the combination has an acceptable safety profile, confirming data previously presented. This Phase 1b portion of the study also demonstrated preliminary efficacy of the combination therapy. A six-month progression free survival (PFS) rate of 25% was observed, which compares favorably to the historical rate of 15% for refractory glioblastoma. In addition, the patient previously reported as having achieved a radiographically confirmed partial response (PR) remains on study treatment and has thus far demonstrated a durable response of greater than eight months, with an overall survival on trial of 20 months.

The Phase 2 portion of the study, which aims to determine the preliminary efficacy of the combination therapy, has enrolled 40 of a planned 132 patients as of the data cutoff. Nine of the 40 patients have been enrolled for more than six months and seven are evaluable as to outcome. One of these seven patients has demonstrated a radiographically confirmed PR after previously being refractory to treatment with temozolomide. The objective response occurred after having stable disease on treatment for six months. Of note, the onsets of the two partial responses, one in Phase 1b and one in Phase 2, were delayed, suggesting a possible immunotherapy-based mechanism of response.

"It is encouraging to see some promising early signs of activity of this combination of an immunotherapy with standard chemotherapy in recurrent GBM, which is a disease with huge unmet need," said Howard Colman, MD, PhD, Associate Professor of Neurosurgery and Director of Medical Neuro-Oncology at the Huntsman Cancer Institute at the University of Utah and an author of the study.

"I am particularly impressed with the potential early signals of an immune-mediated effect, as evidenced by the delayed onset and durability of the responses observed," said Olivier Rixe, MD, PhD, Professor of Medicine and Associate Director for Clinical Research at the University of New Mexico Comprehensive Cancer Center and an author of the study. "This is one of the first clinical trials testing an immune checkpoint inhibitor in glioblastoma. It shows that indoximod is the first such therapy to produce an objective response in glioblastoma."

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"We are pleased with the preliminary safety and efficacy data on the combination of indoximod and temozolomide in glioblastoma obtained so far in this study," said Nicholas Vahanian, M.D., President and Chief Medical Officer. "We look forward to learning more about indoximod in our clinical studies in glioblastoma and four other cancer types, as well as about our six other immuno-oncology products currently in clinical testing."

On November 23, 2015 Hanmi Pharmaceutical Co., Ltd. and ZAI Lab Limited reported that they have executed a collaboration and license agreement under which ZAI Lab will acquire exclusive rights in China (including Hong Kong and Macau) to develop, manufacture and commercialize HM61713, a novel, third-generation EGFR targeted therapy for the treatment of EGFR mutation positive lung cancer.

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HM61713 is a novel, third-generation, irreversible EGFR mutant-selective tyrosine kinase inhibitor (TKI) developed to specifically target tumors with T790M mutations. At the ASCO (Free ASCO Whitepaper) Annual Meeting 2015, interim results of the Phase I/II clinical trial were presented and showed strong efficacy signals, combined with a favorable safety profile. In July this year, Hanmi and Boehringer Ingelheim entered into an exclusive license and collaboration agreement for the development and global commercialization rights, except South Korea, China and Hong Kong, of HM61713 (BI1482694).

"We are delighted to partner with Hanmi, a leader in novel drug R&D in Asia and globally," said Samantha Du, Chairman and CEO of ZAI Lab, "NSCLC is a huge unmet need in China with the world’s largest patient population. Our collaboration with Hanmi is aimed at bringing this late stage and potentially revolutionary drug quickly to the Chinese patients. We also look forward to building and continuing our strategic collaboration with Hanmi."

The agreement with ZAI Lab reflects the fact that the population of NSCLC patient in China which HM61713 targets, takes more than a half of total NSCLC patient in the world. According to the Global Data, 46% of the total NSCLC patient in the world this year is in China and by 2020, the Chinese patient population would rapidly increase up to 62% of the total.

Dr. Gwan Sun Lee, CEO of Hanmi said, "Through our collaboration with ZAI Lab with well-built, experienced R&D capability, the possibility to develop HM61713 as a first-in-class drug in China is now open. We look forward to providing innovative treatment options to Chinese patients suffering from lung cancer."