On September 27, 2015 Ignyta, Inc. (Nasdaq: RXDX), a precision oncology biotechnology company, reported that updated interim results of its Phase 1 clinical trials of entrectinib, the company’s proprietary oral tyrosine kinase inhibitor targeting solid tumors that harbor activating alterations to NTRK1, NTRK2, NTRK3, ROS1 or ALK, were presented in an oral presentation session at the 2015 European Cancer Congress (ECC 2015) in Vienna, Austria (Press release, Ignyta, SEP 27, 2015, View Source [SID:1234507570]).

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"We continue to be excited by the data from our two Phase 1 clinical trials of entrectinib, particularly in patients who would meet the anticipated eligibility criteria for our planned Phase 2 clinical trials," said Pratik Multani, M.D., Chief Medical Officer of Ignyta. "Out of the 18 patients in the two studies who met these criteria, we observed 13 responses, for an overall response rate of 72% across multiple tumor histologies. In addition, based upon an increased dataset of 92 patients, we have been able to confirm entrectinib’s acceptable safety profile for further development at the recommended phase 2 dose (RP2D). We intend to use this clinical experience as the basis for STARTRK-2, our planned, potentially registration-enabling Phase 2 clinical trial of entrectinib."

The clinical trials included the ALKA-372-001 study and the STARTRK-1 study, which is the first of the "Studies of Tumor Alterations Responsive to Targeting Receptor Kinases". Both trials were designed to determine the maximum tolerated dose (MTD) and/or recommended Phase 2 dose, as well as preliminary anti-cancer activity, of single agent entrectinib in patients with solid tumors with the relevant molecular alterations: NTRK1 (encoding TrkA), ROS1 or ALK for ALKA-372-001 and NTRK1/2/3 (encoding TrkA/TrkB/TrkC), ROS1 or ALK for STARTRK-1.

As of the August 15, 2015, data cut-off for the presentation, the findings showed:

A total of 92 patients with a range of solid tumors had been dosed across both clinical trials, with nine patients treated at or above the RP2D beyond six months and one patient beyond one year.

Entrectinib was well tolerated to date:
Across both studies, the most frequent (>10% incidence) treatment-related adverse events were fatigue, dysgeusia, paresthesia, nausea, and myalgia. Seven of these were Grade 3 in severity, consisting of fatigue (4 patients), cognitive impairment (2 patients), and diarrhea (1 patient). No Grade 4 treatment-related adverse events were observed;

Across both studies, there were only three treatment-related serious adverse events: Grade 3 cognitive impairment and Grade 3 myocarditis, both of which occurred above the RP2D, and Grade 2 fatigue. All events were reversible and resolved upon dose modification;

The fixed daily dose RP2D was determined to be 600 mg, taken orally once per day (QD);
18 patients across both clinical trials met the company’s expected Phase 2 eligibility criteria, which include:
Presence of NTRK1/2/3, ROS1 or ALK gene rearrangements, as opposed to other types of molecular alterations (e.g., SNPs, amplifications, deletions);

ALK-inhibitor and/or ROS1-inhibitor naïve; and

Treatment at or above the RP2D;

The response rate in the 18 patients who met these criteria across both studies was 72% (13 responses out of 18 treated patients, as assessed by the clinical sites). Nine of these responders remain on study treatment with durable responses of up to 21 treatment cycles. An additional 3 patients remain on study with stable disease. The responses included:

3 responses out of 4 patients with NTRK1/2/3 gene rearrangements, including patients with non-small cell lung cancer (NSCLC), colorectal cancer and salivary gland cancer, with one of the responding patients remaining on treatment at 6 months; a fourth patient with an astrocytoma remains on treatment after two months with stable disease;

6 responses, including one complete response, out of 8 patients with ROS1 gene rearrangements, all of which were in NSCLC. All of the patients who responded remain on treatment, the longest at 21 months; and

4 responses out of 6 patients with ALK gene rearrangements, including two NSCLC patients and two patients with other solid tumors; two of the 4 responders subsequently progressed.

Entrectinib has demonstrated objective tumor response in the central nervous system (CNS), a frequent site of metastases and progression of advanced solid tumors.

On Wednesday, September 30, 2015, Ignyta will file a Form-8-K with the U.S. Securities and Exchange Commission (SEC) containing the materials presented at the ECC 2015. The company’s SEC filings can be found on the company’s website at www.ignyta.com and on the SEC’s website at www.sec.gov.

On September 27, 2015 Merck (NYSE:MRK), known as MSD outside the United States and Canada, reported new findings from the KEYNOTE-028 Phase 1b study, the clinical trial investigating the use of the company’s anti-PD-1 therapy, KEYTRUDA (pembrolizumab) in multiple, difficult-to-treat cancers (Press release, Merck & Co, SEP 27, 2015, View Source [SID:1234507574]). Data from this trial, to be presented at the European Cancer Congress (ECC) in Vienna, Austria, Sept. 25-29, include the first-time findings for KEYTRUDA in two gastrointestinal cancers, advanced anal cancer and advanced biliary tract cancer, and add to Merck’s growing body of clinical data for KEYTRUDA.

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KEYNOTE-028 is an ongoing multi-cohort, non-randomized Phase 1b basket trial – a trial design that allows for the study of multiple sub-populations of different tumor or histological types within one study. The study is evaluating the safety, tolerability, and anti-tumor activity of KEYTRUDA monotherapy (10 mg/kg dosed every two weeks) in more than 450 patients across 20 different types of cancer. The study was designed to evaluate patients with advanced solid tumors that express PD-L1 and which have not responded to current therapy or for which current therapy is not appropriate.

"Through innovative trials like KEYNOTE-028, we are advancing our understanding of the potential benefit of KEYTRUDA in a wide range of difficult-to-treat cancers," said Dr. Roger Dansey, senior vice president and therapeutic area head, oncology late-stage development, Merck Research Laboratories. "Merck is committed to evaluating KEYTRUDA across as many tumor types as possible and the expansion of our clinical development program over the years reflects this. We are encouraged by these early stage data, and will continue to advance KEYTRUDA in order to deliver on our goal of helping as many people with cancer as possible."

The KEYTRUDA clinical development program has rapidly expanded to encompass more than 30 tumor types in more than 130 clinical trials, of which more than 70 trials combine KEYTRUDA with other cancer treatments. Registration-enabling trials of KEYTRUDA monotherapy are currently enrolling patients in melanoma, non-small cell lung cancer (NSCLC), head and neck cancer, bladder cancer, gastric cancer, colorectal cancer, and Hodgkin Lymphoma, with further trials in planning for other cancers.

Early Findings from Advanced Squamous Cell Carcinoma (SCC) of the Anal Canal (Abstract #500)

Early findings from 25 heavily pre-treated patients with advanced anal cancer – to be presented in an oral session on Sunday, Sept. 27 by Dr. Patrick Ott, Dana-Farber Cancer Institute – demonstrated an overall response rate (ORR) of 20 percent (confirmed and unconfirmed) (95% CI, 6.8-40.7) and a disease control rate (DCR) of 64 percent (95% CI, 42.5-82.0). Five partial responses (95% CI, 6.8-40.7) were observed, and 44 percent of patients (n=11/25) had stable disease (95% CI, 24.4-65.1). Additionally, the 6-month progression-free survival (PFS) rate was 31.6 percent and the 12-month PFS rate was 19.7 percent. At the time of the analysis, response duration ranged from 0.1+ to 9.2+ months, with the median not yet reached. The median stable disease duration was 3.6 months (range, 1.8+ to 11.0+).

Adverse events were generally consistent with previously reported safety data for KEYTRUDA. Grade 3-4 investigator-assessed, treatment-related adverse events were thyroid-stimulating hormone increased (n=1), colitis (n=1), diarrhea (n=1), and general physical health deterioration (n=1). Immune-mediated adverse events were hypothyroidism (n=3) and colitis (n=1). There were no treatment-related deaths.

Early Findings from Advanced Biliary Tract Cancer (Abstract #525)

Early findings from 24 heavily pre-treated patients with advanced biliary tract cancer – presented in a poster session on Saturday, Sept. 26 by Dr. Yung-Jue Bang, Seoul National University Hospital, Seoul, Korea – demonstrated an ORR of 17.4 percent (confirmed and unconfirmed) (95% CI, 5.0-38.8) (n=4/23); 17.4 percent of patients had stable disease (95% CI, 5.0-38.8) (n=4/23). As the time of the analysis, three of four responses were ongoing, and the median response duration had not yet been reached (range, 5.4+ to 9.3+ weeks).

Adverse events were generally consistent with previously reported safety data for KEYTRUDA. Grade 3-4 investigator-assessed, treatment-related adverse events were anemia (n=1), autoimmune hemolytic anemia (n=1), colitis (n=1) and dermatitis (n=1). Immune-mediated adverse events were autoimmune hemolytic anemia (n=1), colitis (n=1), hypothyroidism (n=1), and hypothyroidism (n=1). There were no treatment-related deaths.

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.

Our Focus on Cancer

Our goal is to translate breakthrough science into innovative oncology medicines to help people with cancer worldwide. At Merck Oncology, helping people fight cancer is our passion and supporting accessibility to our cancer medicines is our commitment. Our focus is on pursuing research in immuno-oncology and we are accelerating every step in the journey – from lab to clinic – to potentially bring new hope to people with cancer. For more information about our oncology clinical trials, visit www.merck.com/clinicaltrials.

On September 26, 2015 NewLink Genetics Corporation (NASDAQ:NLNK), a biopharmaceutical company at the forefront of developing and commercializing novel immuno-oncology product candidates to improve the lives of patients with cancer, reported promising early-stage clinical data from a Phase 1b study of indoximod, its wholly owned indoleamine 2,3 dioxygenase (IDO) pathway inhibitor, in combination with ipilimumab for the treatment of patients with unresectable stage 3 or 4 melanoma at the European Cancer Congress 2015 (ECC) in Vienna, Austria (Press release, NewLink Genetics, SEP 26, 2015, View Source [SID:1234507577]).

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The data reported today are from a Phase 1b safety study of nine patients to determine the safety of indoximod and to establish the dose for a Phase 2 study of indoximod in combination with ipilimumab, which is currently enrolling patients.

Indoximod is an orally available, small molecule, broad IDO pathway inhibitor that has shown the potential to interfere with multiple targets within the IDO pathway. IDO pathway inhibitors, such as indoximod, are designed to be used in combination with other therapeutic agents to maximize the body’s immune response against tumors.

Combination therapy with indoximod and ipilimumab showed encouraging clinical activity in some patients. Of the seven patients evaluable for a response, one patient had a complete response and one patient had a partial response by RECIST criteria. Five patients in the study had progressive disease, and two patients are still awaiting follow up.

"We are pleased to present data from the successful completion of our Phase 1b trial evaluating the combination of indoximod and ipilimumab in patients with advanced melanoma," said Nicholas Vahanian, M.D., President and Chief Medical Officer. "The combination was well-tolerated and did not demonstrate any regimen-limiting immune-based toxicities, abnormalities in liver function tests or other toxicities that have been reported with this class of drugs. Based on these promising clinical results, we are already enrolling patents in the Phase 2 combination study."

The Phase 2 study, currently enrolling 38 patients, will utilize a revised study design with standard of care immune checkpoint inhibition (consisting of four cycles of concomitant ipilimumab, repeat cycles of nivolumab or repeat cycles of pembrolizumab) being given in combination with indoximod. The Phase 2 dose for indoximod has been established at 1,200 mg BID (twice daily), and the primary endpoint will be preliminary efficacy as measured by median progression-free survival.

On September 27, 2015 Novartis reported results of a Phase III pivotal study showing Afinitor (everolimus) tablets reduced the risk of progression by 52% (hazard ratio [HR] = 0.48; 95% confidence interval [CI], 0.35-0.67; p<0.00001) vs placebo in patients with advanced, progressive, nonfunctional neuroendocrine tumors (NET) of gastrointestinal (GI) or lung origin (Press release, Novartis, SEP 26, 2015, View Source [SID:1234507579]). The study, RADIANT-4, will be presented at the European Cancer Congress (ECC) 2015 in Vienna, Austria, and was highlighted in the ECC press conference on Saturday, September 26[1].

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Additionally, the data show everolimus, a mammalian target of rapamycin (mTOR) inhibitor, extended median progression free survival (PFS) by 7.1 months: median PFS by central review was 11.0 months (95% CI, 9.23-13.3) in the everolimus arm and 3.9 months (95% CI, 3.58-7.43) in the placebo arm. Overall survival (OS) was a key secondary endpoint of the trial. While the OS data are not mature, the first interim analysis showed a trend favoring the everolimus arm. Additional OS analyses are planned. Another secondary endpoint was best overall response rate; the study found that 64% of patients receiving everolimus experienced at least some degree of tumor shrinkage compared to 26% of those on placebo[1].

Safety was also a secondary endpoint of the trial and adverse events (AEs) were consistent with the known safety profile of everolimus. The most common treatment-related grade 3/4 AEs (>5%) for everolimus and placebo, respectively, were stomatitis (9.0% vs 0.0%), diarrhea (7.0% vs 2.0%) and infections (7.0% vs 0.0%)[1].

"Advanced, progressive, nonfunctional NET of GI or lung origin are rare and aggressive cancers, with limited treatment options," said James Yao, MD, Professor of Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, and the study’s principal investigator. "These pivotal trial results demonstrate strong evidence for the efficacy of the mTOR inhibitor everolimus in this patient population."

NET are a rare type of cancer that originate in neuroendocrine cells found throughout the body, and are most often found in the GI tract, lungs or pancreas[5]. NET can be functional or nonfunctional: functional NET produce symptoms caused by the secretion of hormones and other substances; nonfunctional NET may produce symptoms caused by the tumor’s growth, such as intestinal blockage, pain and bleeding[5],[6],[7],[8]. At time of diagnosis, 5%-44% of patients with NET in the GI system and 28% of patients with lung NET have advanced disease, meaning the cancer has spread to other parts of the body and is more difficult to treat[5].

"These results show that everolimus has the potential to be a new, clinically meaningful therapy for patients with advanced, progressive, nonfunctional GI or lung NET, which typically have poor prognoses," said Alessandro Riva, MD, Global Head, Novartis Oncology Development and Medical Affairs. "Our work with the RADIANT clinical program demonstrates our long-term commitment to NET and has yielded important data that have led to improved outcomes for patients with different types of NET."

The results of the RADIANT-4 study-part of the largest clinical trial program in patients with advanced NET-will serve as the basis of worldwide regulatory submissions for Afinitor for the treatment of advanced, progressive, nonfunctional GI and lung NET. Afinitor is already approved in more than 95 countries worldwide for locally advanced, metastatic or unresectable progressive NET of pancreatic origin.

About RADIANT-4
RADIANT-4 (RAD001 In Advanced Neuroendocrine Tumors) is a Phase III prospective, double-blind, randomized, parallel group, placebo-controlled, multicenter study. The trial examined the efficacy and safety of everolimus plus best supportive care (BSC) vs placebo plus BSC in 302 patients with progressive, well-differentiated, nonfunctional, advanced NET of GI or lung origin. All patients received BSC during treatment, which excluded antitumor agents such as somatostatin analogues (SSAs). Patients were required to have ceased treatment with SSAs for 4 weeks before study entry. Everolimus demonstrated similar efficacy regardless of whether the patient had prior SSA therapy or not. Patients had no history or active symptoms of carcinoid syndrome, and had documented disease progression within the previous 6 months. Patients were randomized 2:1 to receive either daily everolimus 10 mg or daily placebo orally[1].

The primary endpoint of RADIANT-4 was PFS by central radiology review. Secondary endpoints included safety, OS, best overall response rate (defined as complete response plus partial response) and disease control rate[1].

The safety profile of everolimus was consistent with what has been observed in previous studies of this drug. The most common treatment-related AEs included stomatitis, diarrhea, peripheral edema, fatigue, and rash. At the time of the data analysis cutoff date, the primary reasons for treatment discontinuation were disease progression (37% in the everolimus arm vs 72% in the placebo arm) and adverse events (29% in the everolimus arm vs 7% in the placebo arm). A trend towards improved survival was observed at the time of interim OS analysis [HR=0.64; 95% CI, 0.40-1.05; p=0.037], with a total of 70 deaths recorded at the time of the data cutoff (42 [20.5%] in the everolimus arm and 28 [28.6%] in the placebo arm). The result was not statistically significant, since interim analysis significance threshold was p=0.000213[1].

About Afinitor (everolimus) tablets
Afinitor (everolimus) is approved in more than 95 countries, including the United States and throughout the European Union, for locally advanced, metastatic or unresectable progressive neuroendocrine tumors of pancreatic origin. It is also approved in 121 countries including the United States and European Union for advanced renal cell carcinoma following progression on or after vascular endothelial growth factor (VEGF)-targeted therapy.

Afinitor is also approved in more than 100 countries including the United States and European Union for advanced HR+/HER2- breast cancer in combination with exemestane, after prior endocrine therapy.

Everolimus is also available from Novartis for use in certain non-oncology patient populations under the brand names Afinitor or Votubia, Certican and Zortress and is exclusively licensed to Abbott and sublicensed to Boston Scientific for use in drug-eluting stents.

Indications vary by country and not all indications are available in every country. The safety and efficacy profile of everolimus has not yet been established outside the approved indications. Because of the uncertainty of clinical trials, there is no guarantee that everolimus will become commercially available for additional indications anywhere else in the world.

Important Safety Information about Afinitor (everolimus) tablets
Afinitor/Votubia can cause serious side effects including lung or breathing problems, infections (including sepsis), and kidney failure, which can lead to death. Patients taking concomitant angiotensin-converting enzyme (ACE) inhibitors may be at an increased risk for angioedema. Mouth ulcers and mouth sores are common side effects. Afinitor/Votubia can affect blood cell counts, kidney and liver function, and blood sugar, cholesterol, and triglyceride levels. Afinitor/Votubia may cause fetal harm in pregnant women. Highly effective contraception is recommended for women of child-bearing potential while receiving Afinitor/Votubia and for up to eight weeks after ending treatment. Women taking Afinitor/Votubia should not breast feed. Fertility in women and men may be affected by treatment with Afinitor/Votubia.

The most common adverse drug reactions (incidence >=10 percent) are mouth ulcers, skin rash, feeling tired or weak, diarrhea, infections (including upper respiratory tract infection, sore throat and runny nose, sinusitis, middle ear infection and pneumonia), absence of menstrual periods, high levels of cholesterol, nausea, decreased appetite, low level of red blood cells, acne, abnormal taste, irregular menstrual periods, inflammation of lung tissue, swelling of extremities or other parts of the body, high level of blood sugar, itching, weight loss, nose bleeds, cough and headache. The most common grade 3-4 adverse drug reactions (incidence >=2 percent) are mouth ulcers, infections (including pneumonia), low level of red blood cells, absence of menstrual periods, high level of blood sugar, feeling tired or weak, diarrhea, low white blood cells, inflammation of lung tissue and spontaneous bleeding or bruising. Cases of hepatitis B reactivation, blood clots in the lung or legs, and pneumocystis jirovecii pneumonia (PJP) have been reported. Abnormalities were observed in hematology and clinical chemistry laboratory tests.

On September 28, 2015 Epizyme, Inc. (NASDAQ: EPZM) reported results from the ongoing phase 1 trial of tazemetostat, its first-in-class EZH2 inhibitor (Press release, Epizyme, SEP 26, 2015, View Source [SID:1234507562]). The data showed that tazemetostat demonstrated clinical activity in a broader group of patients with INI1-negative and SMARCA4-negative tumors than previously reported, achieved inhibition of EZH2 in tumor tissue, and had an acceptable safety profile when administered as oral monotherapy in adult patients with relapsed or refractory INI1-negative and SMARCA4-negative tumors. The data were presented at the European Cancer Congress 2015 (ECC) in Vienna, Austria by Antoine Italiano, M.D., Ph.D., of the Institut Bergonié in Bordeaux, France. Based on tazemetostat’s clinical activity observed to date and other supportive research, Epizyme will initiate a global phase 2 study in adults and a global phase 1 study in children with INI1-negative tumors and synovial sarcoma in the fourth quarter of 2015.

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INI1-negative and SMARCA4-negative tumors, such as rhabdoid tumors and epithelioid sarcoma are serious and debilitating cancers. Approximately 1,400 patients each year in the major global markets develop these tumors1, which have no established standard of care. INI1 and SMARCA4 are critical proteins of the SWI/SNF complex, which oppose the activity of EZH2. Genetic alterations or loss of function of either can result in EZH2-dependent oncogenesis in certain cancer backgrounds, thus rendering these tumors sensitive to EZH2 inhibition.

"INI1-negative tumors represent a group of devastating diseases with a very poor prognosis even for patients who can undergo a complete surgical resection. Tazemetostat has induced objective responses that are durable for some patients and has an excellent safety profile," said Dr. Italiano. "Our data provide evidence that potentially changes the landscape of clinical research in this group of tumors and could improve the treatment paradigm for these traditionally refractory diseases."

"We are excited by these data, which show clinical activity in patients with INI1-negative and SMARCA4-negative tumors. These results are consistent with preclinical data that demonstrate the important role of EZH2 in INI1- and SMARCA4-negative tumors such as malignant rhabdoid tumors where median survival after relapse is approximately nine months," said Peter Ho, M.D., Ph.D., Chief Medical Officer, Epizyme. "We are now turning our attention to initiating global registration-supporting clinical trials in adults and children with these aggressive tumors, for which new treatments are needed."

In total, 30 patients with solid tumors were enrolled into this ongoing phase 1 study, including eight patients in a food effect sub-study. Of these 30 patients, eight had INI1-negative tumors, comprised of five with malignant rhabdoid tumors and three with epithelioid sarcomas (ES). Additionally, three patients had SMARCA4-negative tumors including two patients with malignant rhabdoid tumor of the ovary, also referred to as small cell carcinoma of the ovary hypercalcemic type (SCCOHT), and one patient with thoracic sarcoma. Nineteen patients had other solid tumors that were not characterized by INI1 or SMARCA4 loss, including three patients with synovial sarcomas.

Synovial sarcomas occur in approximately 1,800 patients each year in the major markets. Synovial sarcomas are INI1-deficient rather than INI1-negative. A fusion protein that is characteristic for synovial sarcoma displaces INI1 from the SWI/SNF complex. Displacement of INI1 confers dependence of these tumors on EZH2, and hence sensitivity to an EZH2 inhibitor in preclinical models.

In addition to the 30 patients with solid tumors, 21 patients with advanced Non-Hodgkin Lymphoma (NHL) were also enrolled into this ongoing phase 1 study, and the safety data from the ECC update presentation includes these patients. The data cutoff for this presentation was August 31, 2015.

Summary of Results

A total of 11 patients with INI1-negative or SMARCA4-negative tumors have been treated. The tumor histology of these patients includes MRT, MRTO, ES and thoracic sarcoma. Nine of these 11 patients have been treated at or above the recommended phase 2 dose of 800 mg twice daily.

Six of the 11 patients experienced a reduction in tumor size as best response, with four patients experiencing tumor reduction of over 30%.

Of five patients with an INI1-negative malignant rhabdoid tumor, one patient achieved a complete response (CR) at week eight and remains on study and in CR through week 65.

Of three patients with SMARCA4-negative tumors, two patients have malignant rhabdoid tumor of the ovary. One MRTO patient achieved a PR at week 8 and remains on study through week 25. A second MRTO patient remains on study with stable disease (SD) through week 26.

Of three patients with an INI1-negative epithelioid sarcoma, one patient achieved a PR of short duration and remains on study with SD through week 25. The second patient remains on study with SD through week 24.
Clinical activity was not observed in the 19 patients with other tumors, including the three patients with synovial sarcomas.
Inhibition of EZH2, as measured by post-treatment H3K27 trimethylation compared to baseline, was observed in tumor tissue of INI1-negative patients as assessed by immunohistochemistry.

The majority of adverse events observed in the study were grade 1 or grade 2 within the entire population of 51 patients with NHL and solid tumors. The most frequent adverse events regardless of attribution were asthenia, decreased appetite, thrombocytopenia, nausea, dyspnea, anemia and constipation. Five grade 3 or greater treatment-related adverse events have been observed including one each of: thrombocytopenia, neutropenia, hypertension, liver function test elevation and decreased appetite.

Solid tumor patients enrolled in this study had been heavily pre-treated, with over half of patients having received three or more prior anti-cancer therapies.

Study Design
The data presented at ECC are from the ongoing first-in-human phase 1 trial of tazemetostat in adults with relapsed or refractory B-cell lymphomas or advanced solid tumors. The primary objective of the study was to determine the recommended phase 2 dose. Secondary endpoints included safety, pharmacokinetics, pharmacodynamics and tumor response evaluated every eight weeks.
Tazemetostat is administered orally twice daily. Five cohorts were studied in the dose escalation phase: 100 mg, 200 mg, 400 mg, 800 mg and 1600 mg; and two cohorts, 800 mg and 1600 mg, were evaluated in the dose expansion phase. Patients enrolled into the food effects sub-study received tazemetostat at 400 mg.

Expanded Tazemetostat Phase 1 and Phase 2 Plans
A planned phase 2 trial studying tazemetostat in adult patients with INI1-negative solid tumors or synovial sarcoma is expected to begin in the fourth quarter of 2015. A phase 1 dose escalation study in pediatric patients with INI1-deficient solid tumors is also expected to start in the fourth quarter of 2015. The INI1-deficient tumor studies will enroll subjects in the U.S., EU and Australia.

Epizyme is already enrolling patients into an international five-arm, multi-center, phase 2 study that will assess the safety and efficacy of tazemetostat in patients with relapsed or refractory NHL, stratified by cell of origin and EZH2 mutation status.

The company plans to initiate additional trials of tazemetostat, including:

A combination study of tazemetostat with R-CHOP in patients with diffuse large B-cell lymphoma (DLBCL), including higher risk front-line patients. R-CHOP, which represents the current first-line regimen for patients with DLBCL, is comprised of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone.
A combination study of tazemetostat with a B-cell signaling agent or other emerging targeted therapy for B-cell lymphomas.
About EZH2 in Cancer
EZH2 is a histone methyltransferase (HMT) that is increasingly understood to play a potentially oncogenic role in a number of cancers. These include non-Hodgkin lymphomas, rhabdoid tumors and other INI1-deficient cancers such as epithelioid sarcomas and synovial sarcoma as well as a range of other solid tumors.

About Tazemetostat
Epizyme is developing tazemetostat for the treatment of non-Hodgkin lymphoma patients and patients with INI1-deficient solid tumors. Tazemetostat is a first-in-class small molecule inhibitor of EZH2 created by Epizyme using its proprietary product platform. In many human cancers, aberrant EZH2 enzyme activity results in misregulation of genes that control cell proliferation resulting in the rapid and unconstrained growth of tumor cells. Tazemetostat is the WHO International Non-Proprietary Name (INN) for EPZ-6438.

Additional information about this program, including clinical trial information, may be found here: View Source