On September 28, 2015 Syndax Pharmaceuticals, Inc. and Merck (NYSE:MRK), known as MSD outside the United States and Canada, reported the dosing of the first patients in the Phase 1b/2 clinical trial of Syndax’s entinostat in combination with Merck’s anti-PD-1 therapy KEYTRUDA (pembrolizumab) in patients with non-small cell lung cancer (NSCLC) or melanoma (Press release, Merck & Co, SEP 28, 2015, View Source [SID:1234507590]). The clinical trial, designated ENCORE 601 by Syndax and KEYNOTE 142 by Merck, is evaluating the safety, tolerability and efficacy of entinostat, an oral, small molecule that targets immune regulatory cells, combined with KEYTRUDA, an anti-programmed cell death protein 1 (anti-PD-1) antibody.

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"This is an important clinical milestone for Syndax and our collaboration with Merck that was achieved on schedule with our joint development plan," said Michael L. Meyers, M.D., Ph.D., Syndax’s Chief Development Officer. "As entinostat has been shown in preclinical models to reduce the number and inhibit the function of host immune suppressor cells, we believe that entinostat combined with KEYTRUDA could result in an improved response rate for the combination compared to either agent alone. The initiation of this trial advances our immuno-oncology program developing entinostat as a potential combination therapy in multiple cancer indications with an initial focus on tumors that have shown sensitivity to immunotherapy."

"Our collaboration with Syndax exemplifies our interest in exploring innovative therapeutic combinations with KEYTRUDA," said Eric Rubin, M.D., vice president and therapeutic area head, early-stage oncology development, Merck Research Laboratories. "We are pleased with the rapid initiation and progress being made by Syndax towards gaining a better understanding of the potential of KEYTRUDA and entinostat in these difficult-to-treat patient populations."

The ENCORE 601/KEYNOTE 142 trial is designed as a Phase 1b/2 open label clinical trial with dose escalation for entinostat, in which the Phase 1b portion will evaluate the safety and tolerability of the combination of entinostat and KEYTRUDA in patients with NSCLC, and the Phase 2 portion will assess the safety and preliminary efficacy of the combination in separate cohorts in patients with NSCLC or melanoma. The trial will be conducted in the United States and is expected to enroll up to 178 patients.

About KEYTRUDA (pembrolizumab)

KEYTRUDA is a humanized monoclonal antibody that blocks the interaction between PD-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 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.

Selected Important Safety Information for KEYTRUDA

Pneumonitis occurred in 12 (2.9%) of 411 patients, including Grade 2 or 3 cases in 8 (1.9%) and 1 (0.2%) patients, respectively, receiving KEYTRUDA. 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 patients for signs and symptoms of hypophysitis (including hypopituitarism and adrenal insufficiency). 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.

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.

Type 1 diabetes mellitus, including diabetic ketoacidosis, has occurred in patients receiving KEYTRUDA. Monitor patients for hyperglycemia and other signs and symptoms of diabetes. Administer insulin for type 1 diabetes, and withhold KEYTRUDA in cases of severe hyperglycemia until metabolic control is achieved.

Nephritis occurred in 3 (0.7%) patients, 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.

Other clinically important immune-mediated adverse reactions can occur. The following clinically significant immune-mediated adverse reactions occurred in patients treated with KEYTRUDA: exfoliative dermatitis, uveitis, arthritis, myositis, pancreatitis, hemolytic anemia, partial seizures arising in a patient with inflammatory foci in brain parenchyma, severe dermatitis including bullous pemphigoid, 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.

Infusion-related reactions, including severe and life-threatening reactions, have occurred in patients receiving KEYTRUDA. Monitor patients for signs and symptoms of infusion-related reactions including rigors, chills, wheezing, pruritus, flushing, rash, hypotension, hypoxemia, and fever. For severe or life-threatening reactions, stop infusion and permanently discontinue KEYTRUDA.

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.

KEYTRUDA was discontinued for adverse reactions in 9% of 411 patients. Adverse reactions, reported in at least two patients, that led to discontinuation of KEYTRUDA were: pneumonitis, renal failure, and pain. Serious adverse reactions occurred in 36% of patients. The most frequent serious adverse reactions, reported in 2% or more of patients, were renal failure, dyspnea, pneumonia, and cellulitis.

The most common adverse reactions (reported in at least 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 September 28, 2015 Eli Lilly and Company’s (NYSE: LLY) reported that a Phase II study of their CYRAMZA (ramucirumab) in combination with docetaxel met its primary endpoint, demonstrating a statistically significant increase in progression-free survival (PFS) for patients with locally advanced or metastatic urothelial carcinoma who failed prior platinum-based therapy (Press release, Eli Lilly, SEP 28, 2015, View Source [SID:1234507588]). Bladder cancer accounts for the vast majority of all urothelial carcinoma.

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Final results of the Phase II trial were presented at the European Cancer Congress (ECC2015) in Vienna, Austria (Abstract #2508) on September 27. Based on these findings, Lilly recently initiated a Phase III trial called RANGE, which has begun to enroll patients.

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"We are encouraged with these promising findings that could help lead to much-needed progress in this area – people with advanced urothelial carcinoma have limited treatment options today," said Daniel Petrylak, M.D., professor of medicine (medical oncology) and of urology at Yale University Cancer Center and the study’s principal investigator. "This is an aggressive type of cancer and unfortunately, despite available first-line therapies, most patients who have disease progression eventually succumb to their disease. Currently, there are no agents specifically approved in the U.S., nor is there a consistently-employed single standard of care in the U.S. or globally, for the treatment of second-line bladder cancer."

The three-arm trial evaluated 140 patients with advanced carcinoma of the urothelial tract (bladder, urethra, ureter, or renal pelvis) who, after a first-line platinum-based chemotherapy regimen, had relapsed up to one year following the initial treatment. Patients were randomized to receive either a combination of ramucirumab and docetaxel (n=46), docetaxel alone (n=45), or a combination of icrucumab and docetaxel (n=49). Treatment continued until disease progression or toxicity levels resulted in an interruption of treatment with one or more of the study medicines.

Median PFS, the study’s primary endpoint, was 5.4 months (HR 0.389; 95% CI: 0.389 0.235-0.643; p < 0.001) on the ramucirumab-docetaxel arm as compared to 2.8 months for patients treated with docetaxel alone, and 1.6 months for those treated with icrucumab and docetaxel. Objective response rate (ORR) results – or patients who achieved either a complete response or partial response to treatment – also favored the ramucirumab combination arm with a significantly higher confirmed ORR (24%) compared to those on the docetaxel arm (9%) and the icrucumab combination arm (12%). A statistically significant benefit in disease control rate – or patients who achieved complete response, partial response, or stable disease – was identified on the ramucirumab arm (78%) versus the docetaxel arm (58%) and the icrucumab arm (45%). While the study was not powered for overall survival (OS), results favored the ramucirumab combination arm, but were not statistically significant, with 10.4 months median OS identified on the ramucirumab arm compared to 9.2 months on the docetaxel arm and 6.7 months on the icrucumab arm.

The observed safety findings are consistent with prior Phase III studies of ramucirumab and docetaxel. The most common ( > 5% incidence) grade ≥3 adverse events occurring at a higher rate on the ramucirumab-plus-docetaxel arm compared to the docetaxel arm were fatigue (35% vs. 13%), febrile neutropenia (17% vs. 13%), pneumonia (13% vs. 9%), anemia (13% vs. 7%), sepsis (11% vs. 7%), edema (9% vs. 2%), diarrhea (7% vs. 2%), intestinal obstruction (7% vs. 2%), urinary tract infection (7% vs. 2%), hypertension (7% vs. 0%), stomatitis (7% vs. 0%), and thrombocytopenia (7% vs. 0%).

The Phase III RANGE study, which is currently enrolling patients, is a randomized, double-blind, placebo-controlled study of ramucirumab and docetaxel versus placebo and docetaxel in patients with locally advanced or unresectable metastatic urothelial carcinoma whose disease progressed on or after platinum-based chemotherapy (ClinicalTrials.gov Identifier: NCT02426125).

"We are pleased to advance this CYRAMZA regimen into Phase III clinical development and look forward to that trial’s results," said Richard Gaynor, M.D., senior vice president, product development and medical affairs for Lilly Oncology. "Our excitement with the overall clinical development of CYRAMZA continues to grow, with the RANGE trial in bladder cancer marking another tumor type in late-stage evaluation in this broad development program."

About Urothelial Carcinoma and Bladder Cancer

Urothelial carcinoma are cancers that arise in the urothelial or transitional cells that line the urinary collecting system including the bladder, which is the most common site for this type of tumor. Other potential primary sites of this cancer include the renal pelvis, ureter, and urethra.

Bladder cancer is the sixth most common and deadly cancer in the U.S.,i with an estimated 74,000 new cases and 16,000 deaths expected in 2015.ii Globally, bladder cancer ranks ninth in the top most common cancers overall, and the ninth leading cause of cancer-related death, affecting approximately 430,000 people per year and resulting in more than 165,000 deaths.i

About CYRAMZA (ramucirumab)
In the U.S., CYRAMZA (ramucirumab) is approved for use as a single agent or in combination with paclitaxel as a treatment for people with advanced or metastatic gastric (stomach) or gastroesophageal junction (GEJ) adenocarcinoma whose cancer has progressed on or after prior fluoropyrimidine- or platinum-containing chemotherapy. It is also approved in combination with docetaxel as a treatment for people with metastatic non-small cell lung cancer (NSCLC) whose cancer has progressed on or after platinum-based chemotherapy. Additionally, it is approved with FOLFIRI as a treatment for people with metastatic colorectal cancer (mCRC) whose cancer has progressed on or after therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine.

There are several additional studies underway or planned to investigate CYRAMZA as a single agent and in combination with other anti-cancer therapies for the treatment of multiple tumor types. This broad global development program has enrolled more than 7,000 patients across more than 50 trials of CYRAMZA worldwide.

CYRAMZA is an antiangiogenic therapy. It is a vascular endothelial growth factor (VEGF) Receptor 2 antagonist that specifically binds and blocks activation of VEGF Receptor 2 by blocking the binding of VEGF receptor ligands VEGF-A, VEGF-C, and VEGF-D. CYRAMZA inhibited angiogenesis in an in vivo animal model.

About Angiogenesis and VEGF Protein
Angiogenesis is the process of making new blood vessels. In a person with cancer, angiogenesis creates new blood vessels that give a tumor its own blood supply, allowing it to grow and spread.

Some tumors create proteins called VEGF. These proteins attach to the VEGF receptors of blood vessel cells causing new blood vessels to form around the tumors, enabling growth. Blocking the VEGF protein from linking to the blood vessels helps to inhibit tumor growth by slowing angiogenesis and the blood supply that feeds tumors. Of the three known VEGF receptors, VEGF Receptor 2 is linked most closely to VEGF-induced tumor angiogenesis.

INDICATIONS
Gastric Cancer
CYRAMZA, as a single agent or in combination with paclitaxel, is indicated for the treatment of patients with advanced or metastatic, gastric or gastroesophageal junction (GEJ) adenocarcinoma with disease progression on or after prior fluoropyrimidine- or platinum-containing chemotherapy.

Non-Small Cell Lung Cancer
CYRAMZA, in combination with docetaxel, is indicated for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) with disease progression on or after platinum-based chemotherapy. Patients with epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving CYRAMZA.

Colorectal Cancer
CYRAMZA, in combination with FOLFIRI (irinotecan, folinic acid, and 5-fluorouracil), is indicated for the treatment of patients with metastatic colorectal cancer (mCRC) with disease progression on or after prior therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine.

IMPORTANT SAFETY INFORMATION FOR CYRAMZA

WARNING: HEMORRHAGE, GASTROINTESTINAL PERFORATION, AND IMPAIRED WOUND HEALING

Hemorrhage: CYRAMZA increased the risk of hemorrhage and gastrointestinal hemorrhage, including severe and sometimes fatal hemorrhagic events. Permanently discontinue CYRAMZA in patients who experience severe bleeding.

Gastrointestinal Perforation: CYRAMZA can increase the risk of gastrointestinal perforation, a potentially fatal event. Permanently discontinue CYRAMZA in patients who experience a gastrointestinal perforation.

Impaired Wound Healing: Impaired wound healing can occur with antibodies inhibiting the VEGF pathway. Discontinue CYRAMZA therapy in patients with impaired wound healing. Withhold CYRAMZA prior to surgery and discontinue CYRAMZA if a patient develops wound healing complications.
Warnings and Precautions

Hemorrhage

CYRAMZA increased the risk of hemorrhage and gastrointestinal hemorrhage including severe and sometimes fatal hemorrhagic events. In study 1, which evaluated CYRAMZA as a single agent in advanced gastric cancer, the incidence of severe bleeding was 3.4% for CYRAMZA and 2.6% for placebo. In study 2, which evaluated CYRAMZA plus paclitaxel in advanced gastric cancer, the incidence of severe bleeding was 4.3% for CYRAMZA plus paclitaxel and 2.4% for placebo plus paclitaxel. Patients with gastric cancer receiving nonsteroidal anti-inflammatory drugs (NSAIDs) were excluded from enrollment in studies 1 and 2; therefore, the risk of gastric hemorrhage in CYRAMZA-treated patients with gastric tumors receiving NSAIDs is unknown. In study 3, which evaluated CYRAMZA plus docetaxel in metastatic non-small cell lung cancer (NSCLC), the incidence of severe bleeding was 2.4% for CYRAMZA plus docetaxel and 2.3% for placebo plus docetaxel. Patients with NSCLC receiving therapeutic anticoagulation or chronic therapy with NSAIDs or other antiplatelet therapy other than once-daily aspirin or with radiographic evidence of major airway or blood vessel invasion or intratumor cavitation were excluded from study 3; therefore, the risk of pulmonary hemorrhage in these groups of patients is unknown. In study 4, which evaluated CYRAMZA plus FOLFIRI in metastatic colorectal cancer, the incidence of severe bleeding was 2.5% for CYRAMZA plus FOLFIRI and 1.7% for placebo plus FOLFIRI. Permanently discontinue CYRAMZA in patients who experience severe bleeding.

Arterial Thromboembolic Events (ATEs)

Serious, sometimes fatal, ATEs including myocardial infarction, cardiac arrest, cerebrovascular accident, and cerebral ischemia occurred in clinical trials including 1.7% of 236 patients who received CYRAMZA as a single agent for gastric cancer in study 1. Permanently discontinue CYRAMZA in patients who experience a severe ATE.

Hypertension

An increased incidence of severe hypertension occurred in patients receiving CYRAMZA as a single agent (8%) as compared to placebo (3%), in patients receiving CYRAMZA plus paclitaxel (15%) as compared to placebo plus paclitaxel (3%), and in patients receiving CYRAMZA plus docetaxel (6%) as compared to placebo plus docetaxel (2%), and in patients receiving CYRAMZA plus FOLFIRI (11%) as compared to placebo plus FOLFIRI (3%). Control hypertension prior to initiating treatment with CYRAMZA. Monitor blood pressure every 2 weeks or more frequently as indicated during treatment. Temporarily suspend CYRAMZA for severe hypertension until medically controlled. Permanently discontinue CYRAMZA if medically significant hypertension cannot be controlled with antihypertensive therapy or in patients with hypertensive crisis or hypertensive encephalopathy.

Infusion-Related Reactions (IRRs)

Prior to the institution of premedication recommendations across clinical trials of CYRAMZA, IRRs occurred in 6 out of 37 patients (16%), including 2 severe events. The majority of IRRs across trials occurred during or following a first or second CYRAMZA infusion. Symptoms of IRRs included rigors/tremors, back pain/spasms, chest pain and/or tightness, chills, flushing, dyspnea, wheezing, hypoxia, and paresthesia. In severe cases, symptoms included bronchospasm, supraventricular tachycardia, and hypotension. Monitor patients during the infusion for signs and symptoms of IRRs in a setting with available resuscitation equipment. Immediately and permanently discontinue CYRAMZA for grade 3 or 4 IRRs.

Gastrointestinal Perforations

CYRAMZA is an antiangiogenic therapy that can increase the risk of gastrointestinal perforation, a potentially fatal event. Four of 570 patients (0.7%) who received CYRAMZA as a single agent in advanced gastric cancer clinical trials experienced gastrointestinal perforation. In study 2, the incidence of gastrointestinal perforation was 1.2% for CYRAMZA plus paclitaxel as compared to 0.3% for placebo plus paclitaxel. In study 3, the incidence of gastrointestinal perforation was 1% for CYRAMZA plus docetaxel as compared to 0.3% for placebo plus docetaxel. In study 4, the incidence of gastrointestinal perforation was 1.7% for CYRAMZA plus FOLFIRI and 0.6% for placebo plus FOLFIRI. Permanently discontinue CYRAMZA in patients who experience a gastrointestinal perforation.

Impaired Wound Healing

Impaired wound healing can occur with antibodies inhibiting the VEGF pathway. CYRAMZA has not been studied in patients with serious or nonhealing wounds. CYRAMZA, an antiangiogenic therapy, has the potential to adversely affect wound healing. Discontinue CYRAMZA therapy in patients with impaired wound healing. Withhold CYRAMZA prior to surgery. Resume CYRAMZA following the surgical intervention based on clinical judgment of adequate wound healing. If a patient develops wound healing complications during therapy, discontinue CYRAMZA until the wound is fully healed.
Clinical Deterioration in Child-Pugh B or C Cirrhosis

Clinical deterioration, manifested by new onset or worsening encephalopathy, ascites, or hepatorenal syndrome, was reported in patients with Child-Pugh B or C cirrhosis who received single-agent CYRAMZA. Use CYRAMZA in patients with Child-Pugh B or C cirrhosis only if the potential benefits of treatment are judged to outweigh the risks of clinical deterioration.
Reversible Posterior Leukoencephalopathy Syndrome (RPLS)

RPLS has been reported at a rate of < 0.1% in clinical studies with CYRAMZA. Confirm the diagnosis of RPLS with MRI and discontinue CYRAMZA in patients who develop RPLS. Symptoms may resolve or improve within days, although some patients with RPLS can experience ongoing neurologic sequelae or death.
Proteinuria Including Nephrotic Syndrome

In study 4, severe proteinuria occurred more frequently in patients treated with CYRAMZA plus FOLFIRI compared to patients receiving placebo plus FOLFIRI. Severe proteinuria was reported in 3% of patients treated with CYRAMZA plus FOLFIRI (including 3 cases [0.6%] of nephrotic syndrome) compared to 0.2% of patients treated with placebo plus FOLFIRI. Monitor proteinuria by urine dipstick and/or urinary protein creatinine ratio for the development of worsening of proteinuria during CYRAMZA therapy. Withhold CYRAMZA for urine protein levels that are > 2 g over 24 hours. Reinitiate CYRAMZA at a reduced dose once the urine protein level returns to < 2 g over 24 hours. Permanently discontinue CYRAMZA for urine protein levels > 3 g over 24 hours or in the setting of nephrotic syndrome.
Thyroid Dysfunction

Monitor thyroid function during treatment with CYRAMZA. In study 4, the incidence of hypothyroidism reported as an adverse event was 2.6% in the CYRAMZA plus FOLFIRI-treated patients and 0.9% in the placebo plus FOLFIRI-treated patients.
Embryofetal Toxicity

Based on its mechanism of action, CYRAMZA can cause fetal harm when administered to pregnant women. Animal models link angiogenesis, VEGF, and VEGF Receptor 2 (VEGFR2) to critical aspects of female reproduction, embryofetal development, and postnatal development. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with CYRAMZA and for at least 3 months after the last dose of CYRAMZA.
Most Common Adverse Reactions—Single Agent

The most commonly reported adverse reactions (all grades; grade 3/4) occurring in > 5% of patients receiving CYRAMZA and > 2% higher than placebo in study 1 were hypertension (16% vs 8%; 8% vs 3%), diarrhea (14% vs 9%; 1% vs 2%), headache (9% vs 3%; 0% vs 0%), and hyponatremia (6% vs 2%; 3% vs 1%).

The most common serious adverse events with CYRAMZA in study 1 were anemia (3.8%) and intestinal obstruction (2.1%). Red blood cell transfusions were given to 11% of CYRAMZA-treated patients vs 8.7% of patients who received placebo.

Clinically relevant adverse reactions reported in > 1% and < 5% of CYRAMZA-treated patients vs placebo in study 1 were: neutropenia (4.7% vs 0.9%), epistaxis (4.7% vs 0.9%), rash (4.2% vs 1.7%), intestinal obstruction (2.1% vs 0%), and arterial thromboembolic events (1.7% vs 0%).

Across clinical trials of CYRAMZA administered as a single agent, clinically relevant adverse reactions (including grade > 3) reported in CYRAMZA-treated patients included proteinuria, gastrointestinal perforation, and infusion-related reactions. In study 1, according to laboratory assessment, 8% of CYRAMZA-treated patients developed proteinuria vs 3% of placebo-treated patients. Two patients discontinued CYRAMZA due to proteinuria. The rate of gastrointestinal perforation in study 1 was 0.8% and the rate of infusion-related reactions was 0.4%.

Most Common Adverse Reactions—Combination With Paclitaxel

The most commonly reported adverse reactions (all grades; grade 3/4) occurring in > 5% of patients receiving CYRAMZA plus paclitaxel and > 2% higher than placebo plus paclitaxel in study 2 were fatigue/asthenia (57% vs 44%; 12% vs 6%), neutropenia (54% vs 31%; 41% vs 19%), diarrhea (32% vs 23%; 4% vs 2%), epistaxis (31% vs 7%; 0% vs 0%), hypertension (25% vs 6%; 15% vs 3%), peripheral edema (25% vs 14%; 2% vs 1%), stomatitis (20% vs 7%; 1% vs 1%), proteinuria (17% vs 6%; 1% vs 0%), thrombocytopenia (13% vs 6%; 2% vs 2%), hypoalbuminemia (11% vs 5%; 1% vs 1%), and gastrointestinal hemorrhage events (10% vs 6%; 4% vs 2%).

The most common serious adverse events with CYRAMZA plus paclitaxel in study 2 were neutropenia (3.7%) and febrile neutropenia (2.4%); 19% of patients treated with CYRAMZA plus paclitaxel received granulocyte colony-stimulating factors.
Adverse reactions resulting in discontinuation of any component of the CYRAMZA plus paclitaxel combination in 2% or more patients in study 2 were neutropenia (4%) and thrombocytopenia (3%).

Clinically relevant adverse reactions reported in > 1% and < 5% of the CYRAMZA plus paclitaxel-treated patients in study 2 were sepsis (3.1% for CYRAMZA plus paclitaxel vs 1.8% for placebo plus paclitaxel) and gastrointestinal perforations (1.2% for CYRAMZA plus paclitaxel vs 0.3% for placebo plus paclitaxel).

Most Common Adverse Reactions—Combination With Docetaxel

The most commonly reported adverse reactions (all grades; grade 3/4) occurring in > 5% of patients receiving CYRAMZA plus docetaxel and > 2% higher than placebo plus docetaxel in study 3 were neutropenia (55% vs 46%; 49% vs 40%), fatigue/asthenia (55% vs 50%; 14% vs 11%), stomatitis/mucosal inflammation (37% vs 19%; 7% vs 2%), epistaxis (19% vs 7%; < 1% vs < 1%), febrile neutropenia (16% vs 10%; 16% vs 10%), peripheral edema (16% vs 9%; 0% vs < 1%), thrombocytopenia (13% vs 5%; 3% vs < 1%), lacrimation increased (13% vs 5%; < 1% vs 0%), and hypertension (11% vs 5%; 6% vs 2%).

The most common serious adverse events with CYRAMZA plus docetaxel in study 3 were febrile neutropenia (14%), pneumonia (6%), and neutropenia (5%). The use of granulocyte colony-stimulating factors was 42% in CYRAMZA plus docetaxel-treated patients versus 37% in patients who received placebo plus docetaxel.

In patients > 65 years of age, there were 18 (8%) deaths on treatment or within 30 days of discontinuation for CYRAMZA plus docetaxel and 9 (4%) deaths for placebo plus docetaxel. In patients < 65 years of age, there were 13 (3%) deaths on treatment or within 30 days of discontinuation for CYRAMZA plus docetaxel and 26 (6%) deaths for placebo plus docetaxel.
Treatment discontinuation due to adverse reactions occurred more frequently in CYRAMZA plus docetaxel-treated patients (9%) than in placebo plus docetaxel-treated patients (5%). The most common adverse events leading to treatment discontinuation of CYRAMZA in study 3 were infusion-related reaction (0.5%) and epistaxis (0.3%).

For patients with nonsquamous histology, the overall incidence of pulmonary hemorrhage was 7% and the incidence of grade > 3 pulmonary hemorrhage was 1% for CYRAMZA plus docetaxel compared to 6% overall incidence and 1% for grade > 3 pulmonary hemorrhage for placebo plus docetaxel. For patients with squamous histology, the overall incidence of pulmonary hemorrhage was 10% and the incidence of grade > 3 pulmonary hemorrhage was 2% for CYRAMZA plus docetaxel compared to 12% overall incidence and 2% for grade ≥3 pulmonary hemorrhage for placebo plus docetaxel.

Clinically relevant adverse reactions reported in > 1% and < 5% of CYRAMZA plus docetaxel-treated patients in study 3 were hyponatremia (4.8% CYRAMZA plus docetaxel versus 2.4% for placebo plus docetaxel) and proteinuria (3.3% CYRAMZA plus docetaxel versus 0.8% placebo plus docetaxel).

Most Common Adverse Reactions—Combination With FOLFIRI

The most commonly reported adverse reactions (all grades; grade 3/4) occurring in > 5% of patients receiving CYRAMZA plus FOLFIRI and ≥2% higher than placebo plus FOLFIRI in study 4 were diarrhea (60% vs 51%; 11% vs 10%), neutropenia (59% vs 46%; 38% vs 23%), decreased appetite (37% vs 27%; 2% vs 2%), epistaxis (33% vs 15%; 0% vs 0%), stomatitis (31% vs 21%; 4% vs 2%), thrombocytopenia (28% vs 14%; 3% vs < 1%), hypertension (26% vs 9%; 11% vs 3%), peripheral edema (20% vs 9%; < 1% vs 0%), proteinuria (17% vs 5%; 3% vs < 1%), palmar-plantar erythrodysesthesia syndrome (13% vs 5%; 1% vs < 1%), gastrointestinal hemorrhage events (12% vs 7%; 2% vs 1%), hypoalbuminemia (6% vs 2%; 1% vs 0%). Twenty percent of patients treated with CYRAMZA plus FOLFIRI received granulocyte colony-stimulating factors.

The most common serious adverse events with CYRAMZA plus FOLFIRI were diarrhea (3.6%), intestinal obstruction (3.0%), and febrile neutropenia (2.8%).

Treatment discontinuation of any study drug due to adverse reactions occurred more frequently in CYRAMZA plus FOLFIRI-treated patients (29%) than in placebo plus FOLFIRI-treated patients (13%). The most common adverse reactions leading to discontinuation of any component of CYRAMZA plus FOLFIRI as compared to placebo plus FOLFIRI were neutropenia (12.5% versus 5.3%) and thrombocytopenia (4.2% versus 0.8%). The most common adverse reactions leading to treatment discontinuation of CYRAMZA were proteinuria (1.5%) and gastrointestinal perforation (1.7%).

Clinically relevant adverse reactions reported in > 1% and < 5% of CYRAMZA plus FOLFIRI-treated patients in study 4 consisted of gastrointestinal perforation (1.7% CYRAMZA plus FOLFIRI versus 0.6% for placebo plus FOLFIRI).

Thyroid-stimulating hormone (TSH) was evaluated in 224 patients (115 CYRAMZA plus FOLFIRI-treated patients and 109 placebo plus FOLFIRI-treated patients) with normal baseline TSH levels. Patients received periodic TSH assessments until 30 days after the last dose of study treatment. Increased TSH was observed in 53 (46%) patients treated with CYRAMZA plus FOLFIRI compared with 4 (4%) patients treated with placebo plus FOLFIRI.

Drug Interactions

No pharmacokinetic interactions were observed between ramucirumab and paclitaxel, between ramucirumab and docetaxel, or between ramucirumab and irinotecan or its active metabolite, SN-38.

Use in Specific Populations

Pregnancy: Based on its mechanism of action, CYRAMZA can cause fetal harm. Animal models link angiogenesis, VEGF, and VEGF Receptor 2 (VEGFR2) to critical aspects of female reproduction, embryofetal development, and postnatal development. There are no available data on CYRAMZA use in pregnant women to inform any drug-associated risks. No animal studies have been conducted to evaluate the effect of ramucirumab on reproduction and fetal development. Advise females of reproductive potential of the potential risk for maintaining pregnancy, risk to the fetus, and risk to newborn and pediatric development, and to use effective contraception during CYRAMZA therapy and for at least 3 months following the last dose of CYRAMZA.

Lactation: Because of the potential risk for serious adverse reactions in nursing infants from ramucirumab, advise women that breastfeeding is not recommended during treatment with CYRAMZA.

Females of Reproductive Potential: Advise females of reproductive potential that based on animal data CYRAMZA may impair fertility.

Please see full Prescribing Information for CYRAMZA, including Boxed Warnings for hemorrhage, gastrointestinal perforation, and impaired wound healing.3

On September 28, 2015 Advaxis, Inc. (NASDAQ:ADXS), a clinical-stage biotechnology company developing cancer immunotherapies, reported that the first patient was treated in a Phase 1b dose-escalation clinical study of ADXS-HER2 for the treatment of patients with metastatic HER2 expressing solid tumors (Press release, Advaxis, SEP 28, 2015, View Source [SID:1234507583]).

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The Phase 1b clinical trial is the first-in-human study of Advaxis’s lead Lm Technology immunotherapy product for HER2 expressing cancers. The dose escalation portion of the study will investigate the safety and tolerability of ADXS-HER2 as a monotherapy in approximately 18 patients diagnosed with metastatic HER2 expressing solid tumors, which include breast, gastric, esophageal and osteosarcoma. Once the maximum tolerated dose (MTD) and recommended Phase 2 dose have been identified, up to 80 patients may be enrolled in up to four HER2 expressing tumor specific cohorts in the expansion phase of the study.

"We are pleased to enroll our first patient in the dose escalation portion of this Phase 1b study of ADXS-HER2 in HER2 expressing solid tumors," said Daniel J. O’Connor, President and Chief Executive Officer of Advaxis. "With the initiation of this study, we now have three clinical constructs in development and seven ongoing clinical trials, which reinforce our long-term commitment to evaluate the potential of our immunotherapy platform across different tumor types."

Advaxis plans to establish the MTD from the Phase 1b study in pediatric patients and work with Children’s Oncology Group (COG) to potentially launch a pivotal trial in pediatric osteosarcoma in 2016. The COG, a National Cancer Institute supported clinical trials group, is the world’s largest organization devoted exclusively to childhood and adolescent cancer research.

This Phase 1b study builds upon efficacy and safety data from Phase 1 clinical studies of ADXS-HER2 conducted in dogs with osteosarcoma, which may have important translational relevance for human patients with osteosarcoma and other HER2 expressing cancers. Preliminary data from a Phase 1 clinical trial in canine osteosarcoma presented at the 2014 American College of Veterinary Internal Medicine (ACVIM) Forum suggested ADXS-HER2 safely delayed or prevented the development of metastatic disease and prolonged overall survival in pet dogs with osteosarcoma when administered after amputation and chemotherapy. Results from this trial led to ADXS-HER2 being considered by the U.S. Department of Agriculture (USDA) for expedited approval to treat canine osteosarcoma. Furthermore, preliminary data from a second ongoing canine Phase 1/2 trial presented at the 2015 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting suggested that ADXS-HER2 in combination with palliative radiation delayed tumor progression and prolonged overall survival in pet dogs with spontaneous osteosarcoma that are not candidates for primary tumor removal (amputation).

"The Phase 1 safety and efficacy data with ADXS-HER2 in canine osteosarcoma supports our clinical development of ADXS-HER2 in HER2 expressing solid tumors," said David J. Mauro, M.D., Ph.D., Executive Vice President and Chief Medical Officer of Advaxis. "We look forward to translating this canine evidence into the first human trial of ADXS-HER2 in metastatic HER2 expressing solid tumors."

About HER2 Expressing Solid Tumor Cancers

Human epidermal growth factor receptor 2 (HER2) is overexpressed in a percentage of solid tumors such as breast, gastric, bladder, brain, pancreatic, ovarian and bone cancer (osteosarcoma). The American Cancer Society estimates that in 2015 in the United States alone there will be 231,840 new cases of invasive breast cancer; 24,590 new cases of gastric cancer; 74,000 new cases of bladder cancer; 22,850 new cases of brain/spinal cancer; 48,960 new cases of pancreatic cancer; 21,290 new cases of ovarian cancer; and 800 new cases of osteosarcoma. HER2 expression is associated with more aggressive disease, increased risk of relapse and decreased overall survival, and is an important target for immunotherapy.

About ADXS-HER2

ADXS-HER2 is an Lm Technology immunotherapy product candidate being developed by Advaxis to target HER2 expressing cancers. ADXS-HER2 has received orphan drug designation by the U.S. Food and Drug Administration (FDA) for the treatment of osteosarcoma. Advaxis is developing ADXS-HER2 for both human and animal-health, and has seen encouraging data in canine osteosarcoma, which is considered a model for human osteosarcoma. Advaxis has licensed ADXS-HER2 and three other immunotherapy constructs to Aratana Therapeutics, Inc. for the development of pet therapeutics.

On September 28, 2015 Takeda Pharmaceutical Company Limited ("Takeda") (TSE: 4502) reported New Drug Application approval of "Leuplin PRO for injection kit 22.5 mg" (generic name: leuprorelin acetate), which is the 24 week depot of "Leuplin", a treatment for prostate cancer and premenopausal breast cancer, from the Japanese Ministry of Health, Labour and Welfare (Press release, Takeda, SEP 28, 2015, View Source [SID:1234507582]).

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Created and developed by Takeda, Leuplin is an LH-RH agonist that consistently stimulates the pituitary gland, resulting in suppressed production of male/female hormones. Leuplin is used as a treatment for hormone-dependent diseases such as prostate cancer and premenopausal breast cancer, and it is currently available in the United States, Europe, and Asia.

Leuprorelin acetate was initially approved as a once-daily injection administration in the United States in 1985, but Takeda has applied multiple innovations, based on its expertise in drug formulation technology, to turn it into a sustained-release microcapsule depot formulation, enabling it to maintain stable blood concentration levels over a long period of time. At present, both 4 week and 12 week formulations are marketed in Japan.

This approval is based on the results of two clinical phase III multicenter, randomized, open label, comparative studies evaluating safety, efficacy, pharmacokinetics, hormone dynamics, and other factors in patients with prostate cancer and those with premenopausal breast cancer. Leuplin PRO becomes the world’s first product to obtain approval for the treatment of premenopausal breast cancer for 24 week depot.

By delivering this new treatment for both prostate cancer and premenopausal breast cancer, Takeda looks forward to further contributing to meeting the needs of patients and healthcare professionals.

Product Name Leuplin PRO for injection kit 22.5 mg
Generic Name leuprorelin acetate
Indications Prostate cancer and premenopausal breast cancer
Dosage and administration The usual adult dose is 22.5mg of Leuprorelin Acetate which is subcutaneously administrated once every 24 weeks.

When using Leuplin PRO, it should be used after suspending it completely by transferring the whole quantity of the vehicle into the powder part, by pressing the plunger rod, with the injection needle held upward, with caution against foaming.