On March 30, 2016 OXiGENE, Inc. (Nasdaq:OXGN), a biopharmaceutical company developing vascular disrupting agents (VDAs) for the treatment of cancer, reported that the U.S. Food and Drug Administration (FDA) has granted Fast Track designation to CA4P for the treatment of platinum-resistant ovarian cancer (Press release, OXiGENE, MAR 30, 2016, View Source [SID:1234510177]).

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Companies with Fast Track designation are able to benefit from more frequent meetings and communications with the FDA regarding development plans to support product registration, and may also be eligible for priority review of New Drug Applications, which shortens FDA’s standard review timeline.

"The FDA’s granting of Fast Track status to CA4P is a significant acknowledgement of the potential for CA4P to provide a new and better treatment option for women with platinum-resistant ovarian cancer," stated William D. Schwieterman, M.D., President and Chief Executive Officer of OXiGENE. "I am pleased that we now have the opportunity to work closely with FDA to expedite our CA4P development program in ovarian cancer, as we seek to bring this promising product candidate to patients."

OXiGENE’s Fast Track application included data showing that CA4P is a novel investigational agent that has been shown in a randomized controlled trial to provide improved response rates and improved progression-free survival to patients with recurrent ovarian cancer when used in combination with bevacizumab (combination anti-vascular therapy) compared to bevacizumab alone, outcomes which were especially prominent in a subgroup of patients with platinum-resistant ovarian cancer.

On March 30, 2016 Genmab A/S (Nasdaq Copenhagen: GEN) reported that the Phase III Castor study (MMY3004) of daratumumab in combination with bortezomib and dexamethasone versus bortezomib and dexamethasone in patients with relapsed or refractory multiple myeloma met the primary endpoint of improving progression free survival (PFS) in an interim analysis (p =< 0.0001) (Press release, Genmab, MAR 30, 2016, View Source [SID:1234510176]). The planned interim analysis was conducted by an Independent Data Monitoring Committee (IDMC).

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Daratumumab showed a tolerable safety profile in the interim analysis. Based on the IDMC’s recommendation, the study will be stopped early. Patients originally assigned to the bortezomib plus dexamethasone treatment group will be offered the option of receiving daratumumab following confirmed disease progression. Patients will continue to be monitored for safety and overall survival. Further analysis of the safety and efficacy data is underway. Based on the interim data, Janssen Biotech, Inc., who licensed daratumumab from Genmab in 2012, will engage in a dialogue with health authorities about the potential for these data to serve as the basis for a regulatory submission for daratumumab in this indication.

"We are very pleased with the positive interim result in this study, which documents the therapeutic potential of daratumumab in combination with bortezomib and dexamethasone. We look forward to having the data presented at a future major medical conference," said Jan van de Winkel, Ph.D., Chief Executive Officer of Genmab.

About the study
The Phase III study includes approximately 490 patients who had relapsed or refractory multiple myeloma. Patients were randomized to receive either daratumumab combined with subcutaneous bortezomib (a type of chemotherapy, called a proteasome inhibitor) and dexamethasone (a corticosteroid), or bortezomib and dexamethasone alone. The primary endpoint of the study is progression free survival (PFS).

About multiple myeloma
Multiple myeloma is an incurable blood cancer that starts in the bone marrow and is characterized by an excess proliferation of plasma cells.1 Multiple myeloma is the third most common blood cancer in the U.S., after leukemia and lymphoma.2 Approximately 26,850 new patients were estimated to be diagnosed with multiple myeloma and approximately 11,240 people would die from the disease in the U.S. in 2015.3 Globally, it was estimated that 124,225 people would be diagnosed and 87,084 would die from the disease in 2015.4 While some patients with multiple myeloma have no symptoms at all, most patients are diagnosed due to symptoms which can include bone problems, low blood counts, calcium elevation, kidney problems or infections.5 Patients who relapse after treatment with standard therapies, including proteasome inhibitors or immunomodulatory agents, have poor prognoses and few treatment options.6

About DARZALEX (daratumumab)
DARZALEX (daratumumab) injection for intravenous infusion is indicated in the United States for the treatment of patients with multiple myeloma who have received at least three prior lines of therapy, including a proteasome inhibitor (PI) and an immunomodulatory agent, or who are double-refractory to a PI and an immunomodulatory agent.7 DARZALEX is the first monoclonal antibody (mAb) to receive U.S. Food and Drug Administration (FDA) approval to treat multiple myeloma. For more information, visit www.DARZALEX.com.

Daratumumab is a human IgG1k monoclonal antibody (mAb) that binds with high affinity to the CD38 molecule, which is highly expressed on the surface of multiple myeloma cells. It is believed to induce rapid tumor cell death through programmed cell death, or apoptosis,7,8 and multiple immune-mediated mechanisms, including complement-dependent cytotoxicity,7,8 antibody-dependent cellular phagocytosis9,10 and antibody-dependent cellular cytotoxicity.7,8 In addition, daratumumab therapy results in a reduction of immune-suppressive myeloid derived suppressor cells (MDSCs) and subsets of regulatory T cells (Tregs) and B cells (Bregs), all of which express CD38. These reductions in MDSCs, Tregs and Bregs were paralleled by increases in CD4+ and CD8+ T cell numbers in both the peripheral blood and bone marrow.7

Daratumumab is being developed by Janssen Biotech, Inc. under an exclusive worldwide license to develop, manufacture and commercialize daratumumab from Genmab. Five Phase III clinical studies with daratumumab in relapsed and frontline settings are currently ongoing, and additional studies are ongoing or planned to assess its potential in other malignant and pre-malignant diseases on which CD38 is expressed, such as smoldering myeloma and non-Hodgkin’s lymphoma.

On March 30, 2016 Bristol-Myers Squibb Company (NYSE:BMY) reported that the European Medicines Agency (EMA) validated a type II variation application, which seeks to extend the current indications for Opdivo to include the treatment of patients with classical Hodgkin lymphoma (cHL) after prior therapies (Press release, Bristol-Myers Squibb, MAR 30, 2016, View Source [SID:1234510175]). The application included CheckMate -205 data, which evaluated Opdivo in cHL patients who have received autologous stem cell transplant and brentuximab vedotin. Validation of the application confirms the submission is complete and begins the EMA’s centralized review process.

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"We are eager to continue to extend the use of Opdivo as a treatment option and potentially provide hematology with its first PD-1 inhibitor, a type of treatment that is designed to work with the PD-1 pathway and leverage the immune system to help fight classical Hodgkin lymphoma," said Jean Viallet, M.D., Oncology Global Clinical Research Lead, Bristol-Myers Squibb. "We are hopeful to build on expanding our hematology franchise and bring the science of Immuno-Oncology to these adult relapsed and refractory classical Hodgkin lymphoma patients in Europe who often have limited remaining treatment options."

CheckMate -205 is a Phase 2 study evaluating the safety and efficacy of Opdivo in patients with relapsed or refractory cHL. The results of this trial are expected to be presented at a medical meeting later this year.

About Hodgkin Lymphoma

Hodgkin lymphoma, which also is known as Hodgkin disease, is one of two main types of lymphoma, a group of cancers most often beginning in the lymph nodes. Hodgkin lymphoma is characterized by malignant lymphocytes called Reed-Sternberg cells. The other type of lymphoma is non-Hodgkin lymphoma, which is much more common. In the European Union, about 12,200 new cases and 2,600 deaths are expected each year. There remains a significant unmet need for patients who have relapsed or have become refractory to current treatments.

Bristol-Myers Squibb & Immuno-Oncology: Advancing Oncology Research

At Bristol-Myers Squibb, we have a vision for the future of cancer care that is focused on Immuno-Oncology, now considered a major treatment choice alongside surgery, radiation and chemotherapy for certain types of cancer.

We have a comprehensive clinical portfolio of investigational and approved Immuno-Oncology agents, many of which were discovered and developed by our scientists. Our ongoing Immuno-Oncology clinical program is looking at broad patient populations, across multiple solid tumors and hematologic malignancies, and lines of therapy and histologies, with the intent of powering our trials for important measures. We pioneered the research leading to the first regulatory approval for the combination of two Immuno-Oncology agents, and continue to study the role of combinations in cancer.

We are also investigating other immune system pathways in the treatment of cancer including CTLA-4, CD-137, KIR, SLAMF7, PD-1, GITR, CSF1R, IDO, and LAG-3. These pathways may lead to potential new treatment options – in combination or monotherapy – to help patients fight different types of cancers.

Our collaboration with academia, as well as small and large biotech companies, is responsible for researching the potential Immuno-Oncology and non-Immuno-Oncology combinations, with the goal of providing new treatment options in clinical practice.

At Bristol-Myers Squibb, we are committed to conducting research for hard-to-treat cancers.

About Opdivo

Cancer cells may exploit "regulatory" pathways, such as checkpoint pathways, to hide from the immune system and shield the tumor from immune attack. Opdivo is a PD-1 immune checkpoint inhibitor that binds to the checkpoint receptor PD-1 expressed on activated T-cells. It blocks the binding of PD-L1 and PD-L2, preventing the PD-1 pathway’s suppressive signaling on the immune system, including the interference with an anti-tumor immune response.

Opdivo’s broad global development program is based on Bristol-Myers Squibb’s understanding of the biology behind Immuno-Oncology. Our company is at the forefront of researching the potential of Immuno-Oncology in hard-to-treat cancers. This scientific expertise serves as the basis for the Opdivo development program, which includes a broad range of Phase 3 clinical trials. To date, the Opdivo clinical development program has enrolled more than 18,000 patients.

Opdivo was the first PD-1 immune checkpoint inhibitor to receive regulatory approval anywhere in the world in July 2014 and currently has regulatory approval in 48 countries, including the United States, Japan and in the European Union.

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 BRAF V600 mutation-positive unresectable or metastatic melanoma. This indication is approved under accelerated approval based on progression-free survival. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

OPDIVO (nivolumab), in combination with YERVOY (ipilimumab), is indicated for the treatment of patients with unresectable or metastatic melanoma. This indication is approved under accelerated approval based on progression-free survival. 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, 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 069 and 067, immune-mediated pneumonitis occurred in 6% (25/407) of patients receiving OPDIVO with YERVOY: Fatal (n=1), Grade 3 (n=6), Grade 2 (n=17), and Grade 1 (n=1). In Checkmate 037, 066, and 067, immune-mediated pneumonitis occurred in 1.8% (14/787) of patients receiving OPDIVO: Grade 3 (n=2) and Grade 2 (n=12). 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).

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. When administered with YERVOY, withhold OPDIVO for Grade 2 and permanently discontinue for Grade 3 or 4 or recurrent colitis upon restarting OPDIVO. In Checkmate 069 and 067, diarrhea or colitis occurred in 56% (228/407) of patients receiving OPDIVO with YERVOY. Immune-mediated colitis occurred in 26% (107/407) of patients: Grade 4 (n=2), Grade 3 (n=60), Grade 2 (n=32), and Grade 1 (n=13). In Checkmate 037, 066, and 067, diarrhea or colitis occurred in 31% (242/787) of patients receiving OPDIVO. Immune-mediated colitis occurred in 4.1% (32/787) of patients: Grade 3 (n=20), Grade 2 (n=10), and Grade 1 (n=2). 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 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 069 and 067, immune-mediated hepatitis occurred in 13% (51/407) of patients receiving OPDIVO with YERVOY: Grade 4 (n=8), Grade 3 (n=37), Grade 2 (n=5), and Grade 1 (n=1). In Checkmate 037, 066, and 067, immune-mediated hepatitis occurred in 2.3% (18/787) of patients receiving OPDIVO: Grade 4 (n=3), Grade 3 (n=11), and Grade 2 (n=4). 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 and everolimus arms, 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 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 069 and 067, hypophysitis occurred in 9% (36/407) of patients receiving OPDIVO with YERVOY: Grade 3 (n=8), Grade 2 (n=25), and Grade 1 (n=3). In Checkmate 037, 066, and 067, hypophysitis occurred in 0.9% (7/787) of patients receiving OPDIVO: Grade 3 (n=2), Grade 2 (n=3), and Grade 1 (n=2). 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 and 067, adrenal insufficiency occurred in 5% (21/407) of patients receiving OPDIVO with YERVOY: Grade 4 (n=1), Grade 3 (n=7), Grade 2 (n=11), and Grade 1 (n=2). In Checkmate 037, 066, and 067, adrenal insufficiency occurred in 1% (8/787) of patients receiving OPDIVO: Grade 3 (n=2), Grade 2 (n=5), and Grade 1 (n=1). In Checkmate 057, 0.3% (1/287) 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 and 067, hypothyroidism or thyroiditis occurred in 22% (89/407) of patients receiving OPDIVO with YERVOY: Grade 3 (n=6), Grade 2 (n=47), and Grade 1 (n=36). Hyperthyroidism occurred in 8% (34/407) of patients: Grade 3 (n=4), Grade 2 (n=17), and Grade 1 (n=13). In Checkmate 037, 066, and 067, hypothyroidism or thyroiditis occurred in 9% (73/787) of patients receiving OPDIVO: Grade 3 (n=1), Grade 2 (n=37), Grade 1 (n=35). Hyperthyroidism occurred in 4.4% (35/787) of patients receiving OPDIVO: Grade 3 (n=1), Grade 2 (n=12), and Grade 1 (n=22). In Checkmate 057, Grade 1 or 2 hypothyroidism, including thyroiditis, occurred in 7% (20/287) and elevated thyroid stimulating hormone 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 and 067, diabetes mellitus or diabetic ketoacidosis occurred in 1.5% (6/407) of patients: Grade 4 (n=3), Grade 3 (n=1), Grade 2 (n=1), and Grade 1 (n=1). In Checkmate 037, 066, and 067, diabetes mellitus or diabetic ketoacidosis occurred in 0.8% (6/787) of patients receiving OPDIVO: Grade 3 (n=2), Grade 2 (n=3), and Grade 1 (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 069 and 067, immune-mediated nephritis and renal dysfunction occurred in 2.2% (9/407) of patients: Grade 4 (n=4), Grade 3 (n=3), and Grade 2 (n=2). In Checkmate 037, 066, and 067, nephritis and renal dysfunction of any grade occurred in 5% (40/787) of patients receiving OPDIVO. Immune-mediated nephritis and renal dysfunction occurred in 0.8% (6/787) of patients: Grade 3 (n=4) and Grade 2 (n=2). 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).

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 069 and 067, immune-mediated rash occurred in 22.6% (92/407) of patients receiving OPDIVO with YERVOY: Grade 3 (n=15), Grade 2 (n=31), and Grade 1 (n=46). In Checkmate 037, 066, and 067, immune-mediated rash occurred in 9% (72/787) of patients receiving OPDIVO: Grade 3 (n=7), Grade 2 (n=15), and Grade 1 (n=50). 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).

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. In Checkmate 067, encephalitis was identified in one patient (0.2%) receiving OPDIVO with YERVOY. 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. In < 1.0% of patients receiving OPDIVO, the following clinically significant, immune-mediated adverse reactions occurred: uveitis, pancreatitis, facial and abducens nerve paresis, demyelination, polymyalgia rheumatica, autoimmune neuropathy, Guillain-Barré syndrome, hypopituitarism, systemic inflammatory response syndrome, gastritis, duodenitis, and sarcoidosis. Across clinical trials of OPDIVO as a single agent administered at doses of 3 mg/kg and 10 mg/kg, additional clinically significant, immune-mediated adverse reactions were identified: motor dysfunction, vasculitis, and myasthenic syndrome.

Infusion Reactions

Severe infusion reactions have been reported in <1.0% of patients in clinical trials of OPDIVO. 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 069 and 067, infusion- related reactions occurred in 2.5% (10/407) of patients receiving OPDIVO with YERVOY: Grade 2 (n=6) and Grade 1 (n=4). In Checkmate 037, 066, and 067, Grade 2 infusion related reactions occurred in 2.7% (21/787) of patients receiving OPDIVO: Grade 3 (n=2), Grade 2 (n=8), and Grade 1 (n=11). In Checkmate 057, Grade 2 infusion reactions requiring corticosteroids occurred in 1.0% (3/287) 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.

Embryo-fetal 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 an 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 067, serious adverse reactions (73% and 37%), adverse reactions leading to permanent discontinuation (43% and 14%) or to dosing delays (55% and 28%), and Grade 3 or 4 adverse reactions (72% and 44%) all occurred more frequently in the OPDIVO plus YERVOY arm relative to the OPDIVO arm. The most frequent (≥10%) serious adverse reactions in the OPDIVO plus YERVOY arm and the OPDIVO arm, respectively, were diarrhea (13% and 2.6%), colitis (10% and 1.6%), and pyrexia (10% and 0.6%). 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.

Common Adverse Reactions

In Checkmate 067, the most common (≥20%) adverse reactions in the OPDIVO plus YERVOY arm were fatigue (59%), rash (53%), diarrhea (52%), nausea (40%), pyrexia (37%), vomiting (28%), and dyspnea (20%). The most common (≥20%) adverse reactions in the OPDIVO arm were fatigue (53%), rash (40%), diarrhea (31%), and nausea (28%). 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 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, including Boxed WARNING regarding immune-mediated adverse reactions for YERVOY.

Please see U.S. Full Prescribing Information for OPDIVO.

About the Bristol-Myers Squibb and Ono Pharmaceutical Co., Ltd. Collaboration

In 2011, through a collaboration agreement with Ono Pharmaceutical Co., Ltd (Ono), Bristol-Myers Squibb expanded its territorial rights to develop and commercialize Opdivo globally except in Japan, South Korea and Taiwan, where Ono had retained all rights to the compound at the time. On July 23, 2014, Bristol-Myers Squibb and Ono further expanded the companies’ strategic collaboration agreement to jointly develop and commercialize multiple immunotherapies – as single agents and combination regimens – for patients with cancer in Japan, South Korea and Taiwan.

On March 30, 2016 Adaptimmune Therapeutics plc (Nasdaq:ADAP), a leader in the use of TCR engineered T-cell therapy to treat cancer, reported that the U.S. Food and Drug Administration (FDA)’s Office of Orphan Products Development has granted orphan drug designation for the company’s affinity enhanced T-cell therapy targeting NY-ESO for the treatment of soft tissue sarcoma, a solid tumor cancer (Press release, Adaptimmune, MAR 30, 2016, View Source [SID:1234510164]).

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Adaptimmune is developing its NY-ESO therapy in certain soft tissue sarcomas: the company expects to initiate pivotal studies in synovial sarcoma around year end 2016, and will explore development in myxoid round cell liposarcoma.

"Soft tissue sarcomas are among the most aggressive forms of cancers, often affecting a young patient population and, for patients with metastatic and recurrent disease, therapeutic options are limited," said Dr. Rafael Amado, Adaptimmune’s Chief Medical Officer. "We are pleased that the FDA recognizes the significance of the unmet medical need in these rare cancers, and we look forward to working with them further to expeditiously advance our T-cell therapy targeting NY-ESO through clinical development in this disease."

There are approximately 50 different types of soft tissue sarcomas. The American Cancer Society estimates that, in 2016, about 12,310 new soft tissue sarcomas will be diagnosed (6,980 cases in males and 5,330 cases in females) in the United States, and approximately 4,990 Americans (2,680 males and 2,310 females) are expected to die of soft tissue sarcomas.

Adaptimmune’s affinity enhanced T-cell therapeutic candidates are novel cancer immunotherapies that have been engineered to target and destroy cancer cells by strengthening a patient’s natural T-cell response. T-cells are a type of white blood cell that play a central role in a person’s immune response. Adaptimmune’s goal is to harness the power of the T-cell and, through its multiple therapeutic candidates, significantly impact cancer treatment and clinical outcomes of patients with solid and hematologic cancers.

About Orphan Drug Designation
The status of orphan drug designation is granted by the FDA’s Office of Orphan Products Development for drugs that are intended for the safe and effective treatment of rare conditions that affect fewer than 200,000 people in the United States. Orphan drug designation qualifies a company for several benefits under the Orphan Drug Act of 1983 that apply across all stages of drug development. The benefits include seven years of market exclusivity following marketing approval, eligibility for orphan drug grants, and waiver of the Prescription Drug User Fee for the marketing application.

About Soft Tissue Sarcoma
Soft tissue sarcomas can develop from soft tissues including fat, muscle, nerves, fibrous tissues, blood vessels, or deep skin tissues. There are approximately 50 types of soft tissue sarcomas, including synovial sarcoma, a cancer of the connective tissue around the joints. Soft tissue sarcomas can develop at almost any anatomic site, such as the extremities, trunk or thorax, abdomen and retroperitoneum, pelvis and the head and neck region. The more common soft tissue sarcomas originate from muscle, nerve tissue, fat, or deep skin tissue. For a number of sarcomas, such as synovial sarcoma, the tissue origin is not well characterized. Surgical resection is the standard therapy for localized disease and radiation therapy (preoperative or postoperative) is added in selected cases.

On March 30, 2016 Tokai Pharmaceuticals Inc. (NASDAQ: TKAI), a biopharmaceutical company focused on developing and commercializing innovative therapies for prostate cancer and other hormonally driven diseases, reported that it has begun dosing patients in an expansion arm of ARMOR2, the company’s ongoing Phase 2 clinical trial of galeterone, to further explore the safety and clinical activity of galeterone in metastatic castration-resistant prostate cancer (mCRPC) patients whose disease progressed during treatment with Xtandi (enzalutamide) (Press release, Tokai Pharmaceuticals, MAR 30, 2016, View Source [SID:1234510131]).

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Tokai has expanded this arm of ARMOR2 following a compelling prostate-specific antigen (PSA) response observed in an enzalutamide-refractory patient enrolled in an initial nine-patient cohort of the study. This patient, who has been on galeterone treatment for over two years, experienced a greater than 90 percent reduction in his PSA levels after approximately seven months on study, and this patient’s PSA has remained at undetectable levels for over one year. Galeterone has been generally well-tolerated in this patient to date. Because no other enzalutamide-refractory or Zytiga (abiraterone acetate)-refractory patient enrolled in ARMOR2 was treated for more than six months, this expansion arm is designed to evaluate whether, in patients who have developed acquired resistance to enzalutamide, longer-term administration of galeterone is required in order to demonstrate clinical benefit with galeterone. In this expansion, Tokai plans to assess reduction in PSA levels and safety in up to 21 additional enzalutamide-refractory patients.

"The optimal sequencing of oral treatments for mCRPC patients remains a challenge for the field, with few enzalutamide-refractory patients experiencing prolonged benefit from subsequent therapies," said Mary-Ellen Taplin, M.D., Director of Clinical Research, Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute and principal investigator of the ARMOR2 trial. "The evaluation of long-term administration of galeterone in patients with acquired resistance to enzalutamide may provide meaningful insights into drug sequencing strategies and, if successful, could provide additional treatment options for these patients."

This expansion arm of ARMOR2 is part of Tokai’s previously announced plan to expand its clinical development program to explore the potential role of galeterone in a broader population of patients with mCRPC. In parallel, Tokai is preparing to initiate a new Phase 2 clinical trial in the middle of this year to evaluate galeterone in men with mCRPC whose disease has progressed rapidly following treatment with enzalutamide or abiraterone. At the same time, the company continues to advance ARMOR3-SV, its pivotal Phase 3 trial of galeterone in patients with AR-V7 positive mCRPC, which is now being conducted at more than 100 centers in the United States, Canada, Australia and Western Europe.

About Galeterone
Galeterone is an oral small molecule that utilizes the established pathways, including CYP17 enzyme and androgen receptor inhibition, of the current second-generation hormonal therapies abiraterone and enzalutamide. Galeterone also introduces a distinct third mechanism – androgen receptor degradation – that decreases the sensitivity of androgen receptors to androgen activity, thus leading to reductions in tumor growth. Tokai is developing galeterone for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC). ARMOR3-SV, the company’s pivotal Phase 3 study of galeterone in treatment-naive mCRPC patients whose prostate tumors express the AR-V7 splice variant, is evaluating whether administration of galeterone results in a statistically significant increase in radiographic progression-free survival as compared to enzalutamide. Tokai is also evaluating galeterone in mCRPC patients who have shown resistance following treatment with second-generation hormonal agents. Tokai has worldwide development and commercialization rights to galeterone.