On May 7, 2015 Plexxikon and Merck, through a subsidiary, reported a collaborative clinical trial that will evaluate the combination of PLX3397, Plexxikon’s investigational CSF-1R inhibitor, and KEYTRUDA (pembrolizumab), Merck’s anti-PD-1 therapy, which provides the potential for a double blockade of cancer-induced immune suppression (Press release, Merck & Co, MAY 7, 2015, View Source [SID:1234503706]). The Phase 1/2 trial will enroll patients with advanced melanoma and multiple other solid tumors with the goal of determining the safety and tolerability of the combination therapy. The trial is expected to begin enrollment by mid-year.

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"We are excited to evaluate PLX3397 in combination with KEYTRUDA, as each agent is designed to attack cancer cells in different ways. Cancer cells use multiple tactics to evade host immune responses, and the combination of these two agents is being investigated to re-activate anti-tumor immunity using distinct and complementary mechanisms," stated Gideon Bollag, Ph.D, chief executive officer of Plexxikon, a member of the Daiichi Sankyo Group. "Importantly, both PLX3397 and KEYTRUDA have potential application in multiple types of cancer."

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"We are at an important juncture in the advancement of immuno-oncology, and this is why Merck is focused on this area of breakthrough science," stated Dr. Eric Rubin, therapeutic area head, oncology early-stage development, Merck Research Laboratories. "Given the promising data observed with KEYTRUDA and PLX3397, we are eager to see how combining these medicines may be complementary in increasing the immune response."

About PLX3397

PLX3397 is a novel oral small molecule that potently and selectively inhibits CSF-1R, KIT, and mutant FLT3 kinases. CSF1R and KIT regulate key components of both the tumor and its microenvironment (macrophages, osteoclasts, mast cells). In addition to melanoma and other solid tumors to be studied in this collaborative trial, PLX3397 is being evaluated in several other clinical indications, including tenosynovial giant cell tumor (TGCT), historically called pigmented villonodular synovitis (PVNS) or giant cell tumor of the tendon sheath (GCT-TS), breast cancer and glioblastoma. For more information on PLX3397 clinical trials, please visit www.clinicaltrials.gov.

About KEYTRUDA (pembrolizumab)

KEYTRUDA (pembrolizumab) is a humanized monoclonal antibody that blocks the interaction between PD-1 (programmed death receptor-1) and its ligands, PD-L1 and PD-L2. By binding to the PD-1 receptor and blocking the interaction with the receptor ligands, KEYTRUDA releases the PD-1 pathway-mediated inhibition of the immune response, including the anti-tumor immune response.

KEYTRUDA is indicated in the United States at a dose of 2 mg/kg administered as an intravenous infusion over 30 minutes every three weeks for the treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. This indication is approved under accelerated approval based on tumor response rate and durability of response. An improvement in survival or disease-related symptoms has not yet been established. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Merck is advancing a broad and fast-growing clinical development program for KEYTRUDA with more than 85 clinical trials – across more than 30 tumor types and over 14,000 patients – both as a monotherapy and in combination with other therapies.

Selected Important Safety Information for KEYTRUDA

Pneumonitis occurred in 12 (2.9%) of 411 patients with advanced melanoma receiving KEYTRUDA (the approved indication in the United States), including Grade 2 or 3 cases in 8 (1.9%) and 1 (0.2%) patients, respectively. Monitor patients for signs and symptoms of pneumonitis. Evaluate suspected pneumonitis with radiographic imaging. Administer corticosteroids for Grade 2 or greater pneumonitis. Withhold KEYTRUDA for Grade 2; permanently discontinue KEYTRUDA for Grade 3 or 4 pneumonitis.

Colitis (including microscopic colitis) occurred in 4 (1%) of 411 patients, including Grade 2 or 3 cases in 1 (0.2%) and 2 (0.5%) patients respectively, receiving KEYTRUDA. Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 or greater colitis. Withhold KEYTRUDA for Grade 2 or 3; permanently discontinue KEYTRUDA for Grade 4 colitis.

Hepatitis (including autoimmune hepatitis) occurred in 2 (0.5%) of 411 patients, including a Grade 4 case in 1 (0.2%) patient, receiving KEYTRUDA. Monitor patients for changes in liver function. Administer corticosteroids for Grade 2 or greater hepatitis and, based on severity of liver enzyme elevations, withhold or discontinue KEYTRUDA.

Hypophysitis occurred in 2 (0.5%) of 411 patients, including a Grade 2 case in 1 and a Grade 4 case in 1 (0.2% each) patient, receiving KEYTRUDA. Monitor for signs and symptoms of hypophysitis. Administer corticosteroids for Grade 2 or greater hypophysitis. Withhold KEYTRUDA for Grade 2; withhold or discontinue for Grade 3; and permanently discontinue KEYTRUDA for Grade 4 hypophysitis.

Nephritis occurred in 3 (0.7%) patients receiving KEYTRUDA, consisting of one case of Grade 2 autoimmune nephritis (0.2%) and two cases of interstitial nephritis with renal failure (0.5%), one Grade 3 and one Grade 4. Monitor patients for changes in renal function. Administer corticosteroids for Grade 2 or greater nephritis. Withhold KEYTRUDA for Grade 2; permanently discontinue KEYTRUDA for Grade 3 or 4 nephritis.

Hyperthyroidism occurred in 5 (1.2%) of 411 patients, including Grade 2 or 3 cases in 2 (0.5%) and 1 (0.2%) patients respectively, receiving KEYTRUDA. Hypothyroidism occurred in 34 (8.3%) of 411 patients, including a Grade 3 case in 1 (0.2%) patient, receiving KEYTRUDA. Thyroid disorders can occur at any time during treatment. Monitor patients for changes in thyroid function (at the start of treatment, periodically during treatment, and as indicated based on clinical evaluation) and for clinical signs and symptoms of thyroid disorders. Administer corticosteroids for Grade 3 or greater hyperthyroidism. Withhold KEYTRUDA for Grade 3; permanently discontinue KEYTRUDA for Grade 4 hyperthyroidism. Isolated hypothyroidism may be managed with replacement therapy without treatment interruption and without corticosteroids.

Other clinically important immune-mediated adverse reactions can occur. The following clinically significant, immune-mediated adverse reactions occurred in less than 1% of patients treated with KEYTRUDA: exfoliative dermatitis, uveitis, arthritis, myositis, pancreatitis, hemolytic anemia, partial seizures arising in a patient with inflammatory foci in brain parenchyma, adrenal insufficiency, myasthenic syndrome, optic neuritis, and rhabdomyolysis.

For suspected immune-mediated adverse reactions, ensure adequate evaluation to confirm etiology or exclude other causes. Based on the severity of the adverse reaction, withhold KEYTRUDA and administer corticosteroids. Upon improvement of the adverse reaction to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Restart KEYTRUDA if the adverse reaction remains at Grade 1 or less. Permanently discontinue KEYTRUDA for any severe or Grade 3 immune-mediated adverse reaction that recurs and for any life-threatening immune-mediated adverse reaction.

Based on its mechanism of action, KEYTRUDA may cause fetal harm when administered to a pregnant woman. If used during pregnancy, or if the patient becomes pregnant during treatment, apprise the patient of the potential hazard to a fetus. Advise females of reproductive potential to use highly effective contraception during treatment and for 4 months after the last dose of KEYTRUDA.

For the treatment of advanced melanoma, KEYTRUDA was discontinued for adverse reactions in 6% of 89 patients who received the recommended dose of 2 mg/kg and 9% of 411 patients across all doses studied. Serious adverse reactions occurred in 36% of patients receiving KEYTRUDA. The most frequent serious adverse drug reactions reported in 2% or more of patients were renal failure, dyspnea, pneumonia, and cellulitis.

The most common adverse reactions (reported in ≥20% of patients) were fatigue (47%), cough (30%), nausea (30%), pruritus (30%), rash (29%), decreased appetite (26%), constipation (21%), arthralgia (20%), and diarrhea (20%).

The recommended dose of KEYTRUDA is 2 mg/kg administered as an intravenous infusion over 30 minutes every three weeks until disease progression or unacceptable toxicity. No formal pharmacokinetic drug interaction studies have been conducted with KEYTRUDA. It is not known whether KEYTRUDA is excreted in human milk. Because many drugs are excreted in human milk, instruct women to discontinue nursing during treatment with KEYTRUDA. Safety and effectiveness of KEYTRUDA have not been established in pediatric patients.

On May 7, 2015 Roche reported that the US Food and Drug Administration (FDA) has granted breakthrough therapy designation for venetoclax (RG7601, GDC-0199/ABT-199), an investigational medicine being developed in partnership with AbbVie, for the treatment of people who have relapsed or refractory chronic lymphocytic leukemia (CLL) with a genetic abnormality known as 17p deletion (Press release, Hoffmann-La Roche , MAY 7, 2015, View Source [SID:1234503676]). Breakthrough therapy designation is designed to accelerate the development and review of medicines intended to treat serious and life-threatening diseases with evidence showing that the medicines may provide a substantial improvement over current treatment options.

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"People who have relapsed or refractory CLL with a 17p deletion typically have a poor prognosis, and do not respond to many currently available treatment options," said Sandra Horning, MD, Roche’s Chief Medical Officer and Head of Global Clinical Development. "We are pleased that the FDA has granted venetoclax Breakthrough Therapy designation and hope this regulatory pathway will help us bring venetoclax to people with this difficult-to-treat disease soon."

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About CLL and 17p deletion
CLL is a slow-growing cancer of the blood and bone marrow that is generally considered incurable, and is one of the most common adult leukemias worldwide.1,2 Most cases of CLL (95 percent) start in white blood cells called B-cells.1 In certain cases of CLL, a part of chromosome 17 is lost and along with it an important gene that controls apoptosis called p53.3 The 17p deletion is found in 3 to 10 percent of previously untreated cases and approximately 30 to 50 percent of relapsed or refractory cases.4 People with 17p deletion CLL have poor results with conventional chemotherapy regimens and a median life expectancy of less than three years.5

About venetoclax
Venetoclax (RG7601, GDC-0199/ABT-199) is an investigational small molecule designed to selectively bind and inhibit Bcl-2 proteins, an important regulator of a process called programmed cell death, or apoptosis. These proteins are thought to impact how certain blood cancers form, develop and become resistant to treatment. Bcl-2 proteins are expressed at high levels in CLL, non-Hodgkin’s lymphoma (NHL) and in other cancers caused by blood cells called B-cells. Venetoclax is being developed in collaboration with AbbVie and currently being studied in Phase II and Phase III studies for CLL and in Phase I and II studies for several other blood cancers.