On April 2, 2017 Puma Biotechnology, Inc. (Nasdaq: PBYI), a biopharmaceutical company, has initiated an expanded access program (EAP) in the United States to provide its investigational therapy, PB272 (neratinib), to patients with HER2-positive breast cancer or HER2-mutated cancers (Press release, Puma Biotechnology, APR 2, 2017, View Source [SID1234518371]).

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The program will provide access to neratinib for the treatment of early stage HER2-positive breast cancer (extended adjuvant setting), HER2-positive metastatic breast cancer and HER2-mutated solid tumors. Patients must not be able to participate in any ongoing neratinib clinical trial to qualify for Puma’s expanded access program. Puma announced a Managed Access Program for neratinib outside the United States in the fourth quarter of 2016.

The U.S. Food and Drug Administration (FDA) permits expanded access to investigational drugs for treatment use for patients with serious or immediately life-threatening diseases or conditions who do not otherwise qualify for participation in a clinical trial and lack satisfactory therapeutic alternatives.

Caligor Opco LLC, which administers the Managed Access Program for neratinib, also will manage the U.S. expanded access program by providing regulatory and logistical support.

"This expanded access program reflects our commitment to make neratinib available to eligible patients who lack therapeutic treatment options," said Alan H. Auerbach, Chief Executive Officer and President of Puma. "As a specialist firm that focuses on early access to medicines, Caligor will facilitate access to neratinib for patients who may benefit from this therapy."

About the Neratinib Expanded Access Program

The neratinib EAP is a program for U.S. patients with early stage HER2-positive breast cancer (extended adjuvant setting), HER2-positive metastatic breast cancer and HER2-mutated solid tumors. This EAP is being administered on behalf of Puma by Caligor Opco LLC. U.S. healthcare professionals seeking more information about the neratinib EAP can email [email protected] for additional information. Patients who are interested in enrolling in the neratinib EAP should speak with their physician to determine if neratinib is an appropriate option. Neratinib is an investigational agent and, as such, has not been approved by the FDA or any other regulatory agencies in any markets.

About Caligor

Caligor Opco LLC, a portfolio company of Diversis Capital, LLC, is a global company that manages the regulatory, logistics and supply chain needs for global access programs as well as the sourcing, storing and distribution of comparator drugs for clinical trials. Caligor’s global access programs help to meet the medical needs of patients worldwide by providing access to medicines in situations where the drug has not yet been approved, or is otherwise commercially unavailable. In addition, through its proprietary TrialAssist program, Caligor optimizes its services by providing for labeling, QP certification, storage, distribution and destruction of clinical trial and unlicensed medicines managed in the access programs. The company serves pharmaceutical and biotechnology companies from facilities in Secaucus, New Jersey and Dartford, UK, as well as strategically situated depot locations worldwide. More information is available at View Source

On April 2, 2017 Bristol-Myers Squibb Company (NYSE:BMY) and Incyte Corporation (Nasdaq:INCY) reported the companies have agreed to advance their clinical development program evaluating the combination of epacadostat, Incyte’s investigational oral selective IDO1 enzyme inhibitor, with Opdivo (nivolumab), Bristol-Myers Squibb’s PD-1 immune checkpoint inhibitor, into phase 3 registrational studies in first-line non-small cell lung cancer across the spectrum of PD-L1 expression and first-line head and neck cancer (Press release, Bristol-Myers Squibb, APR 2, 2017, View Source [SID1234518356]). Additionally, the companies are expanding the ECHO-204 Phase 1/2 study, established under a collaboration between the companies in 2014, to include anti-PD-1/PD-L1 relapsed/refractory melanoma cohorts. The expanded clinical development program, including the phase 3 registrational studies, will be co-funded by the two companies.

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"We are pleased to build upon our existing collaboration with Incyte and advance the clinical development of epacadostat combined with Opdivo into phase 3 registrational trials," said Fouad Namouni, M.D., head of Development, Oncology, Bristol-Myers Squibb. "Incyte shares our goal of improving clinical outcomes for patients with some of the hardest-to-treat cancers, and we look forward to working together on studies evaluating the clinical outcomes of this therapeutic combination."

"We are very pleased to expand our partnership with Bristol-Myers Squibb and move the combination of epacadostat plus Opdivo forward into pivotal studies," said Steven Stein, M.D., Chief Medical Officer, Incyte. "We believe that further expanding the ECHO development program for epacadostat, including the initiation of these new Phase 3 trials, will bring us closer to our goal of providing new treatment options for patients with certain cancers."

About Epacadostat (INCB024360)

Indoleamine 2,3-dioxygenase 1 (IDO1) is a key immunosuppressive enzyme that modulates the anti-tumor immune response by promoting regulatory T cell generation and blocking effector T cell activation, thereby facilitating tumor growth by allowing cancer cells to avoid immune surveillance. Epacadostat is a first-in-class, highly potent and selective oral inhibitor of the IDO1 enzyme that is designed to reverse tumor-associated immune suppression and restore effective anti-tumor immune responses. In single-arm studies, the combination of epacadostat and immune checkpoint inhibitors has shown proof-of-concept in patients with unresectable or metastatic melanoma.

About the Opdivo Clinical Development Program

Bristol-Myers Squibb’s global development program founded on scientific expertise in the field of Immuno-Oncology includes a broad range of clinical trials studying Opdivo, across all phases, including Phase 3, in a variety of tumor types. To date, the Opdivo clinical development program has enrolled more than 25,000 patients.

About Opdivo

Opdivo is a programmed death-1 (PD-1) immune checkpoint inhibitor that is designed to uniquely harness the body’s own immune system to help restore anti-tumor immune response. By harnessing the body’s own immune system to fight cancer, Opdivo has become an important treatment option across multiple cancers.

Opdivo’s leading global development program is based on Bristol-Myers Squibb’s scientific expertise in the field of Immuno-Oncology and includes a broad range of clinical trials across all phases, including Phase 3, in a variety of tumor types. To date, the Opdivo clinical development program has enrolled more than 25,000 patients. The Opdivo trials have contributed to gaining a deeper understanding of the potential role of biomarkers in patient care, particularly regarding how patients may benefit from Opdivo across the continuum of PD-L1 expression.

In July 2014, Opdivo was the first PD-1 immune checkpoint inhibitor to receive regulatory approval anywhere in the world. Opdivo is currently approved in more than 57 countries, including the United States, the European Union and Japan. In October 2015, the company’s Opdivo and Yervoy combination regimen was the first Immuno-Oncology combination to receive regulatory approval for the treatment of metastatic melanoma and is currently approved in more than 47 countries, including the United States and the European Union.

OPDIVO AND YERVOY INDICATIONS & IMPORTANT SAFETY INFORMATION

INDICATIONS

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 the confirmatory trials.

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

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.

OPDIVO (nivolumab) is indicated for the treatment of patients with classical Hodgkin lymphoma (cHL) that has relapsed or progressed after autologous hematopoietic stem cell transplantation (HSCT) and post-transplantation brentuximab vedotin. This indication is approved under accelerated approval based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

OPDIVO (nivolumab) is indicated for the treatment of patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) with disease progression on or after platinum-based therapy.

OPDIVO (nivolumab) is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy or have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

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

OPDIVO can cause immune-mediated pneumonitis. Fatal cases have been reported. Monitor patients for signs with radiographic imaging and for symptoms of pneumonitis. Administer corticosteroids for Grade 2 or more severe pneumonitis. Permanently discontinue for Grade 3 or 4 and withhold until resolution for Grade 2. In patients receiving OPDIVO monotherapy, fatal cases of immune-mediated pneumonitis have occurred. Immune-mediated pneumonitis occurred in 3.1% (61/1994) of patients. In patients receiving OPDIVO with YERVOY, immune-mediated pneumonitis occurred in 6% (25/407) of patients.

In Checkmate 205 and 039, pneumonitis, including interstitial lung disease, occurred in 4.9% (13/263) of patients receiving OPDIVO. Immune-mediated pneumonitis occurred in 3.4% (9/263) of patients receiving OPDIVO: Grade 3 (n=1) and Grade 2 (n=8).

Immune-Mediated Colitis

OPDIVO can cause immune-mediated colitis. Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 (of more than 5 days duration), 3, or 4 colitis. Withhold OPDIVO monotherapy for Grade 2 or 3 and permanently discontinue for Grade 4 or recurrent colitis upon re-initiation of OPDIVO. When administered with YERVOY, withhold OPDIVO and YERVOY for Grade 2 and permanently discontinue for Grade 3 or 4 or recurrent colitis. In patients receiving OPDIVO monotherapy, immune-mediated colitis occurred in 2.9% (58/1994) of patients. In patients receiving OPDIVO with YERVOY, immune-mediated colitis occurred in 26% (107/407) of patients including three fatal cases.

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

OPDIVO can cause immune-mediated hepatitis. 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 patients receiving OPDIVO monotherapy, immune-mediated hepatitis occurred in 1.8% (35/1994) of patients. In patients receiving OPDIVO with YERVOY, immune-mediated hepatitis occurred in 13% (51/407) of patients.

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 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

OPDIVO can cause immune-mediated hypophysitis, immune-mediated adrenal insufficiency, autoimmune thyroid disorders, and Type 1 diabetes mellitus. Monitor patients for signs and symptoms of hypophysitis, signs and symptoms of adrenal insufficiency, thyroid function prior to and periodically during treatment, and hyperglycemia. Administer hormone replacement as clinically indicated and 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. Withhold OPDIVO for Grade 3 and permanently discontinue for Grade 4 hyperglycemia.

In patients receiving OPDIVO monotherapy, hypophysitis occurred in 0.6% (12/1994) of patients. In patients receiving OPDIVO with YERVOY, hypophysitis occurred in 9% (36/407) of patients. In patients receiving OPDIVO monotherapy, adrenal insufficiency occurred in 1% (20/1994) of patients. In patients receiving OPDIVO with YERVOY, adrenal insufficiency occurred in 5% (21/407) of patients. In patients receiving OPDIVO monotherapy, hypothyroidism or thyroiditis resulting in hypothyroidism occurred in 9% (171/1994) of patients. Hyperthyroidism occurred in 2.7% (54/1994) of patients receiving OPDIVO monotherapy. In patients receiving OPDIVO with YERVOY, hypothyroidism or thyroiditis resulting in hypothyroidism occurred in 22% (89/407) of patients. Hyperthyroidism occurred in 8% (34/407) of patients receiving OPDIVO with YERVOY. In patients receiving OPDIVO monotherapy, diabetes occurred in 0.9% (17/1994) of patients. In patients receiving OPDIVO with YERVOY, diabetes occurred in 1.5% (6/407) of patients.

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

OPDIVO can cause immune-mediated nephritis. Monitor patients for elevated serum creatinine prior to and periodically during treatment. Administer corticosteroids for Grades 2-4 increased serum creatinine. Withhold OPDIVO for Grade 2 or 3 and permanently discontinue for Grade 4 increased serum creatinine. In patients receiving OPDIVO monotherapy, immune-mediated nephritis and renal dysfunction occurred in 1.2% (23/1994) of patients. In patients receiving OPDIVO with YERVOY, immune-mediated nephritis and renal dysfunction occurred in 2.2% (9/407) of patients.

Immune-Mediated Skin Adverse Reactions and Dermatitis

OPDIVO can cause immune-mediated rash, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), some cases with fatal outcome. Administer corticosteroids for Grade 3 or 4 rash. Withhold for Grade 3 and permanently discontinue for Grade 4 rash. For symptoms or signs of SJS or TEN, withhold OPDIVO and refer the patient for specialized care for assessment and treatment; if confirmed, permanently discontinue. In patients receiving OPDIVO monotherapy, immune-mediated rash occurred in 9% (171/1994) of patients. In patients receiving OPDIVO with YERVOY, immune-mediated rash occurred in 22.6% (92/407) of patients.

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 Encephalitis

OPDIVO can cause immune-mediated encephalitis. Evaluation of patients with neurologic symptoms may include, but not be limited to, consultation with a neurologist, brain MRI, and lumbar puncture. 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 patients receiving OPDIVO monotherapy, encephalitis occurred in 0.2% (3/1994) of patients. Fatal limbic encephalitis occurred in one patient after 7.2 months of exposure despite discontinuation of OPDIVO and administration of corticosteroids. Encephalitis occurred in one patient receiving OPDIVO with YERVOY (0.2%) after 1.7 months of exposure.

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. Across clinical trials of OPDIVO the following clinically significant immune-mediated adverse reactions occurred in <1.0% of patients receiving OPDIVO: uveitis, iritis, pancreatitis, facial and abducens nerve paresis, demyelination, polymyalgia rheumatica, autoimmune neuropathy, Guillain-Barré syndrome, hypopituitarism, systemic inflammatory response syndrome, gastritis, duodenitis, sarcoidosis, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), myositis, myocarditis, rhabdomyolysis, motor dysfunction, vasculitis, and myasthenic syndrome.

Infusion Reactions

OPDIVO can cause severe infusion reactions, which have been reported in <1.0% of patients in clinical trials. 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 patients receiving OPDIVO monotherapy, infusion-related reactions occurred in 6.4% (127/1994) of patients. In patients receiving OPDIVO with YERVOY, infusion-related reactions occurred in 2.5% (10/407) of patients.

Complications of Allogeneic HSCT after OPDIVO

Complications, including fatal events, occurred in patients who received allogeneic HSCT after OPDIVO. Outcomes were evaluated in 17 patients from Checkmate 205 and 039, who underwent allogeneic HSCT after discontinuing OPDIVO (15 with reduced-intensity conditioning, 2 with myeloablative conditioning). Thirty-five percent (6/17) of patients died from complications of allogeneic HSCT after OPDIVO. Five deaths occurred in the setting of severe or refractory GVHD. Grade 3 or higher acute GVHD was reported in 29% (5/17) of patients. Hyperacute GVHD was reported in 20% (n=2) of patients. A steroid-requiring febrile syndrome, without an identified infectious cause, was reported in 35% (n=6) of patients. Two cases of encephalitis were reported: Grade 3 (n=1) lymphocytic encephalitis without an identified infectious cause, and Grade 3 (n=1) suspected viral encephalitis. Hepatic veno-occlusive disease (VOD) occurred in one patient, who received reduced-intensity conditioned allogeneic HSCT and died of GVHD and multi-organ failure. Other cases of hepatic VOD after reduced-intensity conditioned allogeneic HSCT have also been reported in patients with lymphoma who received a PD-1 receptor blocking antibody before transplantation. Cases of fatal hyperacute GVHD have also been reported. These complications may occur despite intervening therapy between PD-1 blockade and allogeneic HSCT.

Follow patients closely for early evidence of transplant-related complications such as hyperacute GVHD, severe (Grade 3 to 4) acute GVHD, steroid-requiring febrile syndrome, hepatic VOD, and other immune-mediated adverse reactions, and intervene promptly.

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 037, serious adverse reactions occurred in 41% of patients receiving OPDIVO (n=268). 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 (n=206). 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 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 (n=313) relative to the OPDIVO arm (n=313). 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 017 and 057, serious adverse reactions occurred in 46% of patients receiving OPDIVO (n=418). The most frequent serious adverse reactions reported in at least 2% of patients receiving OPDIVO were pneumonia, pulmonary embolism, dyspnea, pyrexia, pleural effusion, pneumonitis, and respiratory failure. In Checkmate 025, serious adverse reactions occurred in 47% of patients receiving OPDIVO (n=406). The most frequent serious adverse reactions reported in ≥2% of patients were acute kidney injury, pleural effusion, pneumonia, diarrhea, and hypercalcemia. In Checkmate 205 and 039, among all patients (safety population [n=263]), adverse reactions leading to discontinuation (4.2%) or to dosing delays (23%) occurred. The most frequent serious adverse reactions reported in ≥1% of patients were infusion-related reaction, pneumonia, pleural effusion, pyrexia, rash and pneumonitis. Ten patients died from causes other than disease progression, including 6 who died from complications of allogeneic HSCT. Serious adverse reactions occurred in 21% of patients in the safety population (n=263) and 27% of patients in the subset of patients evaluated for efficacy (efficacy population [n=95]). In Checkmate 141, serious adverse reactions occurred in 49% of patients receiving OPDIVO. The most frequent serious adverse reactions reported in at least 2% of patients receiving OPDIVO were pneumonia, dyspnea, respiratory failure, respiratory tract infections, and sepsis. In Checkmate 275, serious adverse reactions occurred in 54% of patients receiving OPDIVO (n=270). The most frequent serious adverse reactions reported in at least 2% of patients receiving OPDIVO were urinary tract infection, sepsis, diarrhea, small intestine obstruction, and general physical health deterioration.

Common Adverse Reactions

In Checkmate 037, the most common adverse reaction (≥20%) reported with OPDIVO (n=268) was rash (21%). In Checkmate 066, the most common adverse reactions (≥20%) reported with OPDIVO (n=206) vs dacarbazine (n=205) were fatigue (49% vs 39%), musculoskeletal pain (32% vs 25%), rash (28% vs 12%), and pruritus (23% vs 12%). In Checkmate 067, the most common (≥20%) adverse reactions in the OPDIVO plus YERVOY arm (n=313) 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 (n=313) arm were fatigue (53%), rash (40%), diarrhea (31%), and nausea (28%). In Checkmate 017 and 057, the most common adverse reactions (≥20%) in patients receiving OPDIVO (n=418) were fatigue, musculoskeletal pain, cough, dyspnea, and decreased appetite. In Checkmate 025, the most common adverse reactions (≥20%) reported in patients receiving OPDIVO (n=406) vs everolimus (n=397) 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 205 and 039, among all patients (safety population [n=263]) and the subset of patients in the efficacy population (n=95), respectively, the most common adverse reactions (≥20%) were fatigue (32% and 43%), upper respiratory tract infection (28% and 48%), pyrexia (24% and 35%), diarrhea (23% and 30%), and cough (22% and 35%). In the subset of patients in the efficacy population (n=95), the most common adverse reactions also included rash (31%), musculoskeletal pain (27%), pruritus (25%), nausea (23%), arthralgia (21%), and peripheral neuropathy (21%). In Checkmate 141, the most common adverse reactions (≥10%) in patients receiving OPDIVO were cough and dyspnea at a higher incidence than investigator’s choice. In Checkmate 275, the most common adverse reactions (≥ 20%) reported in patients receiving OPDIVO (n=270) were fatigue (46%), musculoskeletal pain (30%), nausea (22%), and decreased appetite (22%).

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%).

Checkmate Trials and Patient Populations

Checkmate 067 – advanced melanoma alone or in combination with YERVOY; Checkmate 037 and 066 – advanced melanoma; Checkmate 017 – squamous non-small cell lung cancer (NSCLC); Checkmate 057 – non-squamous NSCLC; Checkmate 025 – renal cell carcinoma; Checkmate 205/039 – classical Hodgkin lymphoma; Checkmate 141 – squamous cell carcinoma of the head and neck; Checkmate 275 – urothelial carcinoma.

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

About the Bristol-Myers Squibb and Ono Pharmaceutical Collaboration

In 2011, through a collaboration agreement with Ono Pharmaceutical Co., 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 2014, Ono and Bristol-Myers Squibb 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 April 1, 2017 Infinity Pharmaceuticals, Inc. (NASDAQ: INFI) reported updated Phase 1 clinical data for IPI-549, an orally administered immuno-oncology development candidate that selectively inhibits phosphoinositide-3-kinase gamma (PI3K-gamma) (Press release, Infinity Pharmaceuticals, APR 1, 2017, View Source [SID1234518360]).

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These Phase 1 clinical dose-escalation data demonstrated that IPI-549 was well tolerated both as a monotherapy and in combination with Opdivo (nivolumab), a PD-1 immune checkpoint inhibitor. Additionally, data from the more advanced monotherapy module of the study showed IPI-549 has a favorable pharmacokinetic (PK) and pharmacodynamic (PD) profile that supports once daily (QD) dosing. The data included 15 evaluable patients who received IPI-549 as a monotherapy and six evaluable patients who received IPI-549 in combination with Opdivo. The data were presented at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2017 taking place in Washington, D.C., April 1 – 5. IPI-549 is believed to be the only selective PI3K-gamma inhibitor in clinical development.

"While tremendous progress has been made in the field of immuno-oncology, additional treatment options are needed for patients who relapse or do not respond to currently available therapies," stated Anthony Tolcher, M.D., FRCP(C), clinical director at South Texas Accelerated Research Therapeutics, an investigator for the Phase 1 study. "The emerging profile of IPI-549 is very encouraging and supports continued investigation as a monotherapy and in combination with other therapeutics, including Opdivo. I look forward to my continued participation in this study, particularly as we seek to explore the activity of IPI-549 in the planned expansion modules."

"Our preclinical research demonstrates that IPI-549 could offer a unique approach within immuno-oncology by reprogramming macrophages from a pro-tumor to an anti-tumor phenotype, thereby activating anti-tumor T cells," commented Jeffery Kutok, M.D., Ph.D., chief scientific officer at Infinity. "These data reported today are promising and represent a significant de-risking for our clinical program. We look forward to completing the dose-escalation modules of this study, and in the second half of 2017, we expect to initiate the expansion modules where we will continue to evaluate safety and also assess the activity of IPI-549 alone and in combination with Opdivo."

The Phase 1 study includes dose-escalation and expansion modules to evaluate IPI-549 as a monotherapy and in combination with Opdivo. Patient enrollment is complete in five monotherapy does-escalation cohorts with doses of IPI-549 ranging from 10 mg QD to 40 mg QD. Patient enrollment is also complete in two combination dose-escalation cohorts to evaluate IPI-549 20 mg and 30 mg QD in combination with Opdivo.

Infinity expects to complete the monotherapy dose-escalation phase of the study in the first half of 2017 and initiate the monotherapy expansion module in the second half of the year. The company also expects to complete the dose-escalation phase evaluating IPI-549 in combination with Opdivo and subsequently initiate a combination expansion module in the second half of 2017. The combination expansion module will include patients with non-small cell lung cancer (NSCLC), melanoma, and squamous cell carcinoma of the head and neck (SCCHN) whose tumors show initial resistance or subsequently develop resistance to immune checkpoint therapy. There is a great need for additional treatment options for the growing number of patients living with these cancers, which account for more than 17 percent of all new cancer cases in the U.S.1,2

The updated Phase 1 clinical data presented in the educational session today will be further detailed in a poster being presented during a poster session taking place at the AACR (Free AACR Whitepaper) Annual Meeting 2017 on Tuesday, April 4, from 8:00 a.m. – 12:00 p.m. ET. Details of the presentation are as follows:
Title: IPI-549-01 – A Phase 1/1b, First-in-Human Study of IPI-549, a PI3K-Gamma Inhibitor, as Monotherapy and in Combination with Nivolumab in Patients with Advanced Solid Tumors
Abstract number: CT089
Lead Author: Anthony Tolcher, M.D., FRCP(C), clinical director at South Texas Accelerated Research Therapeutics
Location: Convention Center, Halls A-C, Poster Section 33

Details of Today’s Presentation
In a presentation entitled "Reprogramming Tumor-Associated Macrophages by Targeting PI3K-Gamma through a Small Molecule Approach," Jeffery Kutok, M.D., Ph.D., chief scientific officer at Infinity, discussed the preclinical rationale for targeting PI3K-gamma previously reported in two publications in Nature3,4 and summarized updated clinical data from the Phase 1 study of IPI-549 in patients with advanced solid tumors. The clinical data reported today from a March 20, 2017, data cutoff included 15 evaluable patients who received monotherapy doses of IPI-549 ranging from 10 mg to 40 mg QD and six evaluable patients who received IPI-549 20 mg QD in combination with Opdivo.

Summary of Updated Phase 1 Data
The updated data from the monotherapy dose-escalation module demonstrated that IPI-549 treatment was well tolerated. Among the 15 evaluable patients, no dose limiting toxicities or serious drug-related side effects occurred, and no side effects led to treatment discontinuation or dose reduction. The PK and PD properties of IPI-549 appeared favorable, with near-complete and sustained inhibition of PI3K-gamma at doses at or above 20 mg QD, supporting once daily dosing of IPI-549. Of the 15 evaluable patients, six have remained on treatment for at least 24 weeks, and three patients have remained on treatment for more than 32 weeks. The monotherapy dose-escalation module is ongoing to determine the optimal dose for the monotherapy expansion cohort.

Preliminary data from the combination dose-escalation module evaluating 20 mg IPI-549 in combination with Opdivo demonstrated that the treatment regimen was well tolerated. Among the six evaluable patients, no dose limiting toxicities or serious drug-related side effects occurred and no side effects led to treatment discontinuation. Additionally, combination treatment did not result in new or unexpected side effects relative to the known safety profile of each treatment when administered as monotherapy. The PK profile of IPI-549 in combination with Opdivo appeared favorable and suggested that Opdivo does not affect the PK properties of IPI-549. The combination dose-escalation module is ongoing to determine the optimal dose for the combination expansion module.

Summary of Preclinical Research
Preclinical research has demonstrated that PI3K-gamma is highly expressed in tumor-associated macrophages and that blockade of PI3K-gamma signaling by treatment with IPI-549 results in reprogramming macrophages. This reprogramming shifted macrophages in the tumor microenvironment from the M2, or pro-tumor phenotype, to the M1, or anti-tumor phenotype and increased the number and activity of anti-tumor T cells that attack the tumor and also increased the production of pro-inflammatory cytokines.

Preclinical data from multiple solid tumor models demonstrated that IPI-549 was active as a monotherapy and that IPI-549 administered in combination with checkpoint inhibition led to enhanced activity compared to either treatment alone. Additionally, preclinical data demonstrated that M2, pro-tumor macrophages are associated with resistance to checkpoint inhibitor monotherapy and treatment with IPI-549 in combination with checkpoint inhibitors is able to overcome this resistance by reprogramming macrophages from the M2, pro-tumor phenotype to the M1, anti-tumor phenotype. Taken together, these preclinical data demonstrate that PI3K-gamma plays a key role in the immuno-suppressive tumor microenvironment, help to further elucidate the mechanism of action for IPI-549 and provide a strong rationale for the ongoing Phase 1 study of IPI-549.

Additional Discussion on PI3K-Gamma at AACR (Free AACR Whitepaper) Annual Meeting 2017
Judith A. Varner, Ph.D., professor in the departments of Pathology and Medicine at UC San Diego School of Medicine and the senior author of one of the two articles on PI3K-gamma published in Nature3 in November 2016, will discuss the importance of targeting PI3K-gamma to control cancer immune suppression during a scientific session at the AACR (Free AACR Whitepaper) Annual Meeting 2017 on Monday, April 3, from 6:15 p.m. – 6:45 p.m. ET.

Session: Joint Cancer Immunology (CIMM)/Tumor Microenvironment (TME) Working Groups Evening Scientific Session at the AACR (Free AACR Whitepaper) Annual Meeting 2017 on.
Presentation Title: Targeting the molecular switch controlling immune suppression for cancer therapy.
Location: Independence Ballroom A-D, Meeting Level 4, Marriott Marquis
About the IPI-549 and the Ongoing Phase 1 Study
IPI-549 is an investigational, orally administered immuno-oncology development candidate that selectively inhibits PI3K-gamma. In preclinical studies, IPI-549 reprograms macrophages from a pro-tumor to an anti-tumor phenotype and is able to overcome resistance to checkpoint inhibition.3,4 As such, IPI-549 may have the potential to treat a broad range of solid tumors and represents a potentially complementary approach to restoring anti-tumor immunity in combination with other immunotherapies such as checkpoint inhibitors.

A Phase 1 study of IPI-549 in patients with advanced solid tumors is ongoing to explore the activity, safety, tolerability, pharmacokinetics and pharmacodynamics of IPI-549 as a monotherapy and in combination with Opdivo (nivolumab), a PD-1 immune checkpoint inhibitor, in patients with advanced solid tumors.5 The study includes monotherapy and combination dose-escalation phases, in addition to a monotherapy expansion module and a combination expansion module. The expansion module evaluating IPI-549 plus Opdivo will include patients with non-small cell lung cancer (NSCLC), melanoma and squamous cell carcinoma of the head and neck (SCCHN). Patients enrolled in the combination expansion module represent a difficult-to-treat population, as they must have demonstrated initial resistance or subsequently develop resistance to an anti-PD-1 or anti-PD-L1 therapy immediately prior to enrolling in the study. Overall, the study is expected to enroll approximately 175 patients.

IPI-549 is an investigational compound and its safety and efficacy has not been evaluated by the U.S. Food and Drug Administration or any other health authority.