On April 24, 2017 Eli Lilly and Company (NYSE: LLY) reported that following a pre-planned interim analysis for MONARCH 3, the trial met its primary endpoint of demonstrating statistically significant improvement in progression-free survival (PFS) (Press release, Eli Lilly, APR 24, 2017, View Source [SID1234518668]). In addition, improvement was shown in a key secondary endpoint of objective response rate (ORR). The Phase 3 study evaluated abemaciclib, a cyclin-dependent kinase (CDK)4 and CDK6 inhibitor, in combination with an aromatase inhibitor (letrozole or anastrozole) compared to treatment with an aromatase inhibitor alone in women with hormone-receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer. Detailed efficacy and safety results will be presented at a medical meeting in the second half of the year.

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"Today marks another important milestone in our clinical development program for abemaciclib, a drug we believe has the potential to be best in class," said Levi Garraway, M.D., Ph.D., senior vice president, global development and medical affairs, Lilly Oncology. "We are very excited about the results seen in patients with breast cancer, from single-agent activity to clinically meaningful benefit when used in combination with fulvestrant or aromatase inhibitors. Along with additional abemaciclib clinical trials in other tumor types, these data underscore Lilly’s commitment to delivering life-changing medicines to treat and cure people living with cancer around the world."

The global Phase 3, double-blind, placebo-controlled study was designed to evaluate the efficacy and safety of abemaciclib in combination with an aromatase inhibitor as initial endocrine-based therapy for postmenopausal women with advanced (locoregionally recurrent or metastatic) breast cancer who have had no prior systemic treatment for advanced disease. A total of 493 patients were randomized to receive 150 mg of abemaciclib or placebo orally twice a day without interruption, given in combination with either 1 mg of anastrozole or 2.5 mg of letrozole once daily until disease progression or unacceptable toxicity. The primary endpoint of the study was PFS, with key secondary endpoints of ORR, overall survival and safety. The adverse events were generally consistent with previous studies of abemaciclib, with the most common adverse events being diarrhea, neutropenia, fatigue, and nausea.

Following this MONARCH 3 interim analysis, Lilly intends to begin global submissions of these results in the third quarter of 2017. In addition, Lilly intends to initiate MONARCH 1 and MONARCH 2 submissions beginning in the second quarter of 2017.

Other MONARCH trials currently underway include: monarcHER, which is evaluating abemaciclib plus trastuzumab (with or without fulvestrant) in women with HR+, HER2+ locally advanced or metastatic breast cancer, and MONARCH plus, a Phase 3 study of abemaciclib in combination with endocrine therapies to support registration in China. In addition, Lilly has an ongoing Phase 3 trial evaluating abemaciclib in lung cancer. Lilly is also evaluating abemaciclib in patients with brain metastases, as well as in patients with pancreatic cancer.

Notes to Editor

About Metastatic Breast Cancer
Breast cancer is the most common cancer in women worldwide with nearly 1.7 million new cases diagnosed in 2012.1 In the U.S. this year, approximately 252,710 new cases of invasive breast cancer will be diagnosed and about 40,610 people will die from breast cancer.2 Of all early stage breast cancer cases diagnosed in the U.S., approximately 30 percent will become metastatic, spreading to other parts of the body. In addition, an estimated six to 10 percent of all new breast cancer cases are initially diagnosed as being stage IV, or metastatic.3 Metastatic breast cancer is considered incurable, but is generally treatable.

About Abemaciclib
In many cancers, uncontrolled cell growth arises from a loss of cell cycle regulation due to increased signaling from CDK4 and CDK6. Abemaciclib (LY2835219) is an investigational, oral cell cycle inhibitor, designed to block the growth of cancer cells by specifically inhibiting cyclin-dependent kinases, CDK4 and CDK6 and was most active against Cyclin D1 and CDK4 in cell-free enzymatic assays. In breast cancer, Cyclin D1/CDK4 has been shown to promote phosphorylation of the retinoblastoma protein (Rb), cell proliferation and tumor growth. In hormone receptor-positive breast cancer cell lines, sustained target inhibition by abemaciclib reduced phosphorylation of Rb, inducing cell cycle arrest.

In 2015, the U.S. Food and Drug Administration granted abemaciclib Breakthrough Therapy Designation based on data from the breast cancer cohort expansion of the company’s Phase 1 trial, JPBA, which studied the efficacy and safety of abemaciclib in women with advanced or metastatic breast cancer. In addition to its current MONARCH clinical trials evaluating abemaciclib in breast cancer, a Phase 3 trial of abemaciclib in lung cancer is also underway.

For more information on additional abemaciclib trials, a complete listing can be found on ClinicalTrials.gov (in the search box on the home page, type in "abemaciclib").

On April 21, 2017 Pfizer Inc. (NYSE:PFE) reported that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has adopted a positive opinion recommending approval of BESPONSA (inotuzumab ozogamicin) in the European Union (EU) as monotherapy for the treatment of adults with relapsed or refractory CD22-positive B-cell precursor Philadelphia chromosome negative (Ph-) acute lymphoblastic leukemia (ALL) and Philadelphia chromosome positive (Ph+) ALL, who have previously failed treatment with at least one tyrosine kinase inhibitor (TKI) (Press release, Pfizer, APR 21, 2017, View Source [SID1234518667]). The CHMP’s opinion will now be reviewed by the European Commission (EC). If approved, BESPONSA will be the first antibody drug conjugate available for patients with this type of leukemia.

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"Relapsed or refractory ALL is a rapidly progressive and often fatal disease. BESPONSA is an antibody-drug conjugate that has been designed to bind to a receptor – CD22 – that is present on the leukemia cells of most patients with ALL and deliver a potent toxin – calicheamicin – into those cells," said Mace Rothenberg, MD, chief development officer, Oncology, Pfizer Global Product Development. "The positive results of the INO-VATE 1022 Phase 3 trial provide strong evidence of the important role BESPONSA may have versus commonly used chemotherapy regimens used in this situation, and we believe BESPONSA could provide patients with relapsed or refractory ALL with a much needed treatment option."

"Approximately 10,000 new adult cases of ALL are diagnosed in Europe each year, and there is an urgent unmet need for patients with relapsed or refractory adult ALL, as the reported long term survival rates range from between less than 10 percent to approximately 20 percent1," said Professor Matthias Stelljes, Department of Medicine A/Hematology and Oncology, University of Münster, Germany. "Today’s decision by the CHMP to recommend marketing authorization of BESPONSA is an important step forward for patients in Europe, and the community looks forward to potentially having a new treatment option available."

ALL is an aggressive type of leukemia with a poor prognosis in adults.2 The current foundational treatment is intensive, long-term chemotherapy.3 ALL is uncommon in adults, representing about 15 percent of leukemias, with about 10,000 new adult cases diagnosed in Europe each year.4 Approximately 20 to 40 percent of newly diagnosed adults with ALL are cured with current treatment regimens,5 however about 20 percent of adult patients will be refractory, or resistant, to treatment, and an additional 40 to 50 percent will relapse within months or years. For patients with relapsed or refractory adult ALL, the five-year overall survival rate is less than 10 percent.6

The Marketing Authorization Application (MAA) for BESPONSA was based on results from the Phase 3 INO-VATE 1022 trial, which enrolled 326 adult patients with relapsed or refractory B-cell ALL, and compared BESPONSA to standard of care chemotherapy. The INO-VATE 1022 study had two primary endpoints, complete response with or without hematologic remission (CR/CRi) and overall survival (OS). Results from the trial were published in The New England Journal of Medicine in June 2016.

A Biologics License Application (BLA) for BESPONSA for the treatment of adult patients with relapsed or refractory B-cell precursor ALL has been accepted for filing and granted Priority Review by the U.S. Food and Drug Administration (FDA). The Prescription Drug User Fee Act (PDUFA) goal date for a decision by the FDA is in August 2017. BESPONSA received Breakthrough Therapy designation from the FDA in October 2015 for ALL.

With a growing hematology pipeline, Pfizer is committed to extending therapeutic progress in acute and chronic leukemias that leverage select pathways and mechanism of actions (MOAs). Specifically, our investigational products aim to treat some of the hardest to treat leukemias, including acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML) and mantle cell lymphoma (MCL).

About BESPONSA (Inotuzumab Ozogamicin)

BESPONSA is an investigational antibody-drug conjugate (ADC) comprised of a monoclonal antibody (mAb) targeting CD22, a cell surface antigen found on cancer cells in almost all B-ALL patients, linked to a cytotoxic agent.7 When BESPONSA binds to the CD22 antigen on B-cells, it is internalized into the cell, where the cytotoxic agent, calicheamicin, is released to destroy the cell.8 The most common adverse events (AEs) observed in clinical trials for BESPONSA were cytopenias, including febrile neutropenia. Common nonhematologic treatment-emergent AEs with BESPONSA included nausea, headache and pyrexia. Additionally, veno-occlusive liver disease (VOD) was observed more frequently in patients treated with BESPONSA, especially those who went on to receive hematopoietic stem cell transplantation.

BESPONSA originates from a collaboration between Pfizer and Celltech, now UCB. Pfizer has sole responsibility for all manufacturing and clinical development activities for this molecule.

On April 21, 2017 Bristol-Myers Squibb Company (NYSE:BMY) reported that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency has recommended the approval of Opdivo (nivolumab) for the treatment of locally advanced unresectable or metastatic urothelial carcinoma (mUC) in adults after failure of prior platinum-containing therapy (Press release, Bristol-Myers Squibb, APR 21, 2017, View Source [SID1234518666]). The CHMP recommendation will now be reviewed by the European Commission (EC), which has the authority to approve medicines for the European Union (EU).

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Opdivo is the first and only PD-1 immune checkpoint inhibitor for the treatment of patients with previously treated mUC to receive a positive CHMP opinion. Opdivo is already approved by the EC for six indications in four distinct tumor types.

"We view the CHMP recommendation of Opdivo for previously treated locally advanced or metastatic urothelial carcinoma as an important milestone for the patients. Bristol-Myers Squibb looks forward to collaborating with the European Commission as it considers this potential new indication for Opdivo," said Murdo Gordon, executive vice president and chief commercial officer, Bristol-Myers Squibb.

The CHMP adopted its positive opinion based on results from the Phase 2 clinical trial CheckMate -275 in patients with locally advanced unresectable or mUC that progressed after a platinum-containing therapy and were treated with Opdivo. The primary endpoint of CheckMate -275 was objective response rate and additional efficacy measures included durability of response and overall survival. Data from CheckMate -275 were presented at the 2016 European Society for Medical Oncology Congress in October 2016 and published online in Lancet Oncology in January 2017.

About Bladder Cancer

Bladder cancer, which typically begins in the cells that line the inside of the bladder, is the fifth most commonly diagnosed cancer in Europe, with an estimated 151,000 new cases diagnosed per year and over 52,000 deaths per year. Urothelial cancer is the most common type of bladder cancer, accounting for approximately 90% of cases. The majority of bladder cancers are diagnosed at an early stage, but rates of recurrence and progression are high, and approximately 78% of patients will experience a recurrence within five years. Survival rates vary depending on the stage, type of the cancer and when it is diagnosed. For Stage IV bladder cancer, the five-year survival rate is 15%.

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

At Bristol-Myers Squibb, patients are at the center of everything we do. Our vision for the future of cancer care is focused on researching and developing transformational Immuno-Oncology (I-O) medicines that will raise survival expectations in hard-to-treat cancers and will change the way patients live with cancer.

We are leading the scientific understanding of I-O through our extensive portfolio of investigational and approved agents, including the first combination of two I-O agents in metastatic melanoma, and our differentiated clinical development program, which is studying broad patient populations across more than 35 types of cancers with 13 clinical-stage molecules designed to target different immune system pathways. Our deep expertise and innovative clinical trial designs uniquely position us to advance the science of combinations across multiple tumors and potentially deliver the next wave of I-O combination regimens with a sense of urgency. We also continue to pioneer research that will help facilitate a deeper understanding of the role of immune biomarkers and inform which patients will benefit most from I-O therapies.

We understand making the promise of I-O a reality for the many patients who may benefit from these therapies requires not only innovation on our part but also close collaboration with leading experts in the field. Our partnerships with academia, government, advocacy and biotech companies support our collective goal of providing new treatment options to advance the standards of clinical practice.

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 60 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 50 countries, including the United States and the European Union.

U.S. FDA-APPROVED INDICATIONS FOR OPDIVO

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.

On April 21, 2017 GlycoMimetics, Inc. (NASDAQ: GLYC) reported that the company will provide an update on clinical data from its Phase 1 and 2 studies of GMI-1271 at the 2017 American Society for Clinical Oncology in Chicago (Press release, GlycoMimetics, APR 21, 2017, View Source [SID1234518662]). GMI-1271 is an antagonist of E-selectin, for which prior data has shown an emerging and differentiated efficacy profile.

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Details of the ASCO (Free ASCO Whitepaper) presentations include:

Abstract #2520

Poster discussion. DeAngelo, D.J., et al. "GMI-1271, a Novel E-Selectin Antagonist, in Combination with Chemotherapy in Relapsed/Refractory AML." Session Title: Poster Discussion Session: Developmental Therapeutics—Clinical Pharmacology and Experimental Therapeutics, Monday, June 5, 11:30 a.m.-12:45 p.m. CT.

Presenter: Daniel J. DeAngelo, MD, PhD, Dana Farber Cancer Institute Director of Clinical and Translational Research, Adult Leukemia, and Institute Physician ; Harvard Medical School Associate Professor of Medicine

Abstract #2560

Poster. DeAngelo, D.J. et al. "GMI-1271, a Novel E-Selectin Antagonist, Combined with Induction Chemotherapy in Elderly Patients with Untreated AML." Session Title: Poster Session: Developmental Therapeutics—Clinical Pharmacology and Experimental Therapeutics. Monday, June 5, 8:00-11:30 a.m. CT.

Presenter: Dr. DeAngelo

The ASCO (Free ASCO Whitepaper) Annual Meeting 2017 takes place from June 2 to 5, at McCormick Place in Chicago. Meeting abstracts are available at ASCO (Free ASCO Whitepaper)’s website.

On April 21, 2017 Tiziana Life Sciences plc (AIM: TILS, the "Company"), a clinical stage biotechnology company developing targeted drugs for cancer and autoimmune diseases, reported that a research article detailing the use of the Company’s lead compound, milciclib, has been published in the prestigious, peer-reviewed journal Cancer Chemotherapy and Pharmacology, entitled: "Phase I Dose-Escalation Study of Milciclib, A Novel Inhibitor of Cyclin Dependent Kinases (CDKs), in Combination with Gemcitabine in Patients with Refractory Solid Tumors"[1] (Press release, Tiziana Life Sciences, APR 21, 2017, View Source [SID1234518663]).

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In this phase I clinical trial, 16 patients with advanced metastatic tumours, refractory to existing cancer therapies, were enrolled. The treatment regimen consisted of oral treatment with milciclib once daily for 7 days on/7 days off in a 4-week cycle with concomitant gemcitabine administered intravenously once weekly for 4 weeks. This combination treatment regimen showed positive clinical responses in approximately 36% of patients, including gemcitabine refractory patients. One patient with non-small cell lung carcinoma (NSCLC), showed partial response and four patients (one each with thyroid, prostatic, pancreatic carcinoma and peritoneal mesothelioma) showed long-term disease stabilisation for up to 14 months. In previous clinical studies, oral treatment with milciclib, was found be safe and well tolerated in patients with thymoma and thymic cancers.

Gabriele Cerrone, Chairman of Tiziana Life Sciences, commented: "Following the generation of encouraging phase I clinical data with milciclib, reported in this important publication, we are rapidly moving forward with further evaluation of the drug as an oral treatment in phase IIa clinical trials for patients with refractory hepatocellular carcinoma (HCC), which is a significant unmet medical need. It is noteworthy that the combination treatment regimen used in the phase I study also exhibited positive clinical activity in patients who were previously resistant to treatment with gemcitabine, a drug widely used as a partner in combination therapies for treatment of refractory cancers. This suggests that milciclib may have therapeutic potential in combination with other existing therapies."

[1] Aspeslagh, S., Shailubhai, K., Bahleda, R. et al. Cancer Chemother Pharmacol (2017). doi:10.1007/s00280-017-3303-z

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About Milciclib

Milciclib (PHA-848125AC) is a small molecule inhibitor of several cyclin dependent kinases (CDKs) such as CDK1, CDK4, CDK5 and CDK7. CDKs are serine threonine kinases that play crucial roles in progression of the cell cycle from G1 to S phase. Overexpression of CDKs and other downstream signalling pathways that regulate cell cycles have been frequently found to be associated with development of resistance towards chemotherapies. Oral treatment with milciclib was found to be effective in reducing tumour growth in animal models of HCC, possibly through downregulation of miR-221 and miR-222. In a phase I study, oral treatment with milciclib was found to be well-tolerated and the drug showed promising clinical responses in patients with advanced solid malignancies such as in thymic carcinoma, pancreatic carcinoma and colon cancer.


About Gemcitabine

Gemcitabine, a well-known nucleoside analogue sold under the brand name Gemzar, is a widely used chemotherapeutic drug used either as a monotherapy or in combination with other anti-cancer agents for treatment of a wide range of solid tumours. Synergism between CDK inhibitors and gemcitabine has been shown in animal studies as well as in a phase I trial with cancer patients.

About Cancer Chemotherapy and Pharmacology

Cancer Chemotherapy and Pharmacology is a journal addressing a wide range of pharmacologic and oncologic concerns on both experimental and clinical levels. Primary focus in this rapid publication medium is on new anticancer agents, their experimental screening, preclinical toxicology and pharmacology, single and combined drug administration modalities, and clinical phase I, II and III trials. It is essential reading for pharmacologists and oncologists. The journal is published by Springer, which is part of Springer Nature, a global publisher that serves and supports the research community.