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Kura Oncology Doses First Patient in Phase 2 Study of Tipifarnib in Lower Risk Myelodysplastic Syndromes

On June 16, 2016 Kura Oncology, Inc. (NASDAQ:KURA), a clinical stage biopharmaceutical company, reported the first patient has been dosed in a Phase 2 clinical trial of tipifarnib in patients with lower risk myelodysplastic syndromes (MDS) (Press release, Kura Oncology, JUN 16, 2016, View Source [SID:1234513434]).

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"We believe there is a significant unmet need for therapies targeting MDS," said Antonio Gualberto, M.D., Ph.D., Chief Medical Officer of Kura Oncology. "We were encouraged by data from a previous Phase 2 trial of tipifarnib conducted by Johnson & Johnson that showed modest activity of this agent in the overall population of patients with intermediate to high risk MDS. Using translational medicine methodologies, we identified potential predictive biomarkers of this activity, and one key goal of this study is to validate the ability of those biomarkers to identify the patients most likely to benefit from tipifarnib."

"Patients with MDS, a group of diverse bone marrow disorders, suffer from a dearth of treatment options and the development of new drugs is vital to combat the disease," said Joseph G. Jurcic, M.D., Professor of Medicine and principal investigator at Columbia University Medical Center. "The analyses from previous studies provide a strong rationale for evaluating tipifarnib in this indication."

MDS is a group of hematopoietic stem cell malignancies with significant morbidity and mortality. MDS is characterized by ineffective blood cell production, or hematopoiesis, leading to low blood cell counts, or cytopenias, and a high risk of progression to acute myeloid leukemia. MDS is estimated to have an annual incidence of approximately 13,000 patients in the United States. These patients generally have a poor prognosis due to the low response rate to available treatment options.

The trial is designed to enroll approximately 58 patients and will evaluate tipifarnib as a treatment for patients with lower risk myelodysplastic syndromes. Patient samples will be analyzed for the presence or absence of various biomarkers potentially relevant to the activity of tipifarnib. Additional information about this clinical trial is available at clinicaltrials.gov using the identifier: NCT02779777.

About Tipifarnib

Kura Oncology’s lead program, tipifarnib, is an inhibitor of farnesylation, a key cell signaling process implicated in cancer initiation and development. In extensive clinical trials, tipifarnib has shown a well-established safety profile and compelling and durable anti-cancer activity in certain patient subsets. Preclinical and clinical data suggest that, in the appropriate context, tipifarnib has the potential to provide significant benefit to cancer patients with limited treatment options. Leveraging advances in next-generation sequencing as well as emerging information about cancer genetics and tumor biology, Kura Oncology will seek to identify patients most likely to benefit from tipifarnib. Kura Oncology holds an exclusive license to develop and commercialize tipifarnib in the field of oncology, under an agreement with Janssen Pharmaceutica NV.

Tri-Institutional Therapeutics Discovery Institute, Inc. Expands Partnership with Takeda Pharmaceutical Company, Ltd.

On June 16, 2016 Memorial Sloan Kettering Cancer Center, The Rockefeller University and Weill Cornell Medicine reported that they will expand the focus of the successful Tri-Institutional Therapeutics Discovery Institute, Inc. (Tri-I TDI), a partnership established in 2013 to expedite early-stage drug discovery of innovative new therapies (Press release, Takeda, JUN 16, 2016, View Source [SID:1234513420]). Under this expansion, Tri-I TDI will extend its current relationship with its industry partner, Takeda Pharmaceutical Company, Ltd. (TSE:4502) from the realm of small molecule discovery into the new research area of antibody drug discovery. All three institutions will benefit from Tri-I TDI’s expansion.

"We are thrilled at the prospect of growing our strong Tri-I TDI partnership, where we continue to tackle important health questions and improve drug development efficiency. Through our current work, we’ve established a streamlined process to apply our breakthrough research into clinical application and look forward to adding antibody knowledge into our expanding range of capabilities" said Dr. Augustine Choi, interim dean of Weill Cornell Medicine.

"TDI has already had an important impact by providing an opportunity for our scientists, and those of our collaborating institutions, to develop small molecules that might lead to new drugs," said Dr. Marc Tessier-Lavigne, president of The Rockefeller University. "With the addition of its antibody program, TDI will go even further, jumpstarting the development of an additional type of therapy for poorly treated diseases."

"What began as a novel partnership between academia and industry has now become a powerful voice in medical research," said Memorial Sloan Kettering President and CEO Dr. Craig B. Thompson. "Our collaboration has provided more efficient paths to translate laboratory discoveries into bedside treatments that lead to improved patient care and well being. This partnership is a great example of how collaboration and open partnerships are the future of medical research."

"As we look ahead to what’s next, beyond small molecule drug discovery, this flagship collaboration will continue to push the boundaries of what’s possible in medical research," said Andrew Plump, Takeda’s chief medical and scientific officer. "We at Takeda understand the value of, and connection between, innovation and external collaboration. This is why we are so pleased to continue our relationship with the Tri-I TDI and help expand its mission to move toward novel research frontiers such as antibody drug discovery."

Takeda and M2Gen Collaborate with ORIEN to Speed Clinical Development and Discovery of Cancer Treatments Through Health Informatics

On June 16, 2016 Takeda Pharmaceutical Company Limited (TSE: 4502) and M2Gen, a healthcare informatics solutions company, reported that it has established a new collaboration to generate broad genomic data from consenting cancer patients (Press release, Takeda, JUN 16, 2016, View Source [SID:1234513412]). Under the agreement, Takeda will help build the Oncology Research Information Exchange Network (ORIEN) AvatarTM Research Program based on the Total Cancer Care Protocol, a prospective observational study enrolling patients with various cancers, and access information generated under this program.

Understanding and mapping the genetic profiles of patients with various types of cancer has the potential to speed new treatment discovery and development for millions of cancer patients worldwide. The data provided through M2Gen’s ORIEN Avatar Research Program has the potential to enable ORIEN cancer centers to more rapidly find and enroll patients with specific biomarkers into Takeda clinical studies, among others. In addition, the genomic data will accompany clinical information such as stage of disease, demographics and treatment history, further enhancing translational medicine efforts. This collaborative approach, which brings together leading pharmaceutical companies, cancer research centers and patients, may allow for more effective and efficient development of treatments across many different cancers.

"One of the biggest challenges in oncology research is identifying the right cohort of patients for enrollment into clinical trials," said Phil Rowlands, Interim Head, Oncology Therapeutic Area Unit, Takeda. "Our innovative partnership with M2Gen has the potential to enable us to more quickly and precisely enroll patients at sites with a strong commitment to high quality translational medicine."

Through the agreement, Takeda will have access to patient de-identified information generated through the ORIEN Avatar Program, representing ORIEN’s growing network of participating cancer centers. These 12 institutions, all leaders in cancer care, treat diverse populations of patients, who can elect to join the Total Cancer Care Protocol to potentially gain access to groundbreaking therapies and clinical trials. Patients who consent to participate in the protocol agree to be followed throughout their lifetime. ORIEN Avatar is focused on the use of rich clinical and molecular data to anticipate patient need, especially for novel cancer treatments through clinical trials open at ORIEN institutions.

"Our health informatics solutions allow us to share clinically meaningful data across the entire cancer care and research community – from patients to healthcare providers to the companies developing novel medicines," said William S. Dalton, Ph.D., M.D., Founder and CEO, M2Gen.

"We are excited to welcome Takeda as one of the founding partners for our ORIEN Avatar program and look forward to working together to open new doors in oncology research," said Michael A. Caligiuri, M.D., Director, The Ohio State University Comprehensive Cancer Center and CEO, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute.

This agreement is partially developed on the experience of Takeda and M2Gen, which previously partnered in 2014 to identify patients for several Phase 2 studies in gastric and pancreatic cancer. This pilot program demonstrated M2Gen’s capability to identify patients who might benefit from enrollment in the clinical trials and to facilitate rapid trial enrollment. Through ongoing collaborative learning, Takeda and M2Gen see the continued potential for success in scientific and clinical trial development and in meeting patient needs.

Merck’s KEYTRUDA® (pembrolizumab) Demonstrates Superior Progression-Free and Overall Survival Compared to Chemotherapy as First-Line Treatment in Patients with Advanced Non-Small Cell Lung Cancer

On June 16, 2016 Merck (NYSE:MRK), known as MSD outside the United States and Canada, reported that the KEYNOTE-024 trial investigating the use of KEYTRUDA (pembrolizumab), in patients with previously untreated advanced non-small cell lung cancer (NSCLC) whose tumors expressed high levels of PD-L1 (tumor proportion score of 50 percent or more), met its primary endpoint (Press release, Merck & Co, JUN 16, 2016, View Source [SID:1234513410]).

In this trial, KEYTRUDA was superior compared to chemotherapy for both the primary endpoint of progression-free survival (PFS), and the secondary endpoint of overall survival (OS). Based on these results, an independent Data Monitoring Committee (DMC) has recommended that the trial be stopped, and that patients receiving chemotherapy in KEYNOTE-024 be offered the opportunity to receive KEYTRUDA.

"We believe that the KEYNOTE-024 results have the potential to change the therapeutic paradigm in first-line treatment of non-small-cell lung cancer," said Dr. Roger M. Perlmutter, president, Merck Research Laboratories. "We look forward to sharing these data with the medical community and with regulatory authorities around the world."

The safety profile of KEYTRUDA in this trial was consistent with that observed in previously reported studies in patients with advanced NSCLC. Results from KEYNOTE-024 will be presented at an upcoming medical meeting.

Merck currently has the largest immuno-oncology clinical development program across the industry and is advancing five registration-enabling studies for NSCLC with KEYTRUDA as a monotherapy and in combination.

About KEYNOTE-024

KEYNOTE-024 is a randomized, pivotal, phase 3 study (ClinicalTrials.gov, NCT02142738) evaluating KEYTRUDA (pembrolizumab) monotherapy compared to standard of care (SOC) platinum-based chemotherapies in the treatment of patients with advanced NSCLC. Patients enrolled were those who had received no prior systemic chemotherapy treatment for their advanced disease and whose tumors expressed high levels of PD-L1 (defined as a tumor proportion score of 50 percent or more) as determined by a central laboratory using an immunohistochemistry assay. The study randomized 305 patients to receive KEYTRUDA (200 mg every three weeks) or SOC platinum-based chemotherapies: paclitaxel+carboplatin, pemetrexed+carboplatin, pemetrexed+cisplatin, gemcitabine+carboplatin, or gemcitabine+cisplatin. Pemetrexed maintenance therapy was permitted for patients with non-squamous histologies. In addition, patients randomized to the control had the option of crossing over to pembrolizumab upon disease progression. The primary endpoint is PFS; secondary endpoints are OS and overall response rate (ORR).

About KEYTRUDA (pembrolizumab) Injection 100 mg

KEYTRUDA is a humanized monoclonal antibody that works by increasing the ability of the body’s immune system to help detect and fight tumor cells. KEYTRUDA blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes which may affect both tumor cells and healthy cells.

KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic melanoma.

KEYTRUDA is also indicated for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors express PD-L1 as determined by an FDA-approved test with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving KEYTRUDA. 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.

KEYTRUDA is administered at a dose of 2 mg/kg as an intravenous infusion over 30 minutes every three weeks for the approved indications.

Selected Important Safety Information for KEYTRUDA (pembrolizumab)

Immune-mediated pneumonitis occurred in 19 (3.5%) of 550 patients, including Grade 2 (1.1%), 3 (1.3%), 4 (0.4%), or 5 (0.2%) pneumonitis and occurred more frequently in patients with a history of asthma/chronic obstructive pulmonary disease (5.4%) or prior thoracic radiation (6.0%). 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 or recurrent Grade 2 pneumonitis.

Immune-mediated colitis occurred in 4 (0.7%) of 550 patients, including Grade 2 (0.2%) or 3 (0.4%) colitis. 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.

Immune-mediated hepatitis occurred in patients 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 1 (0.2%) of 550 patients, which was Grade 3 in severity. Monitor patients for signs and symptoms of hypophysitis (including hypopituitarism and adrenal insufficiency). Administer corticosteroids and hormone replacement as clinically indicated. Withhold KEYTRUDA for Grade 2; withhold or discontinue for Grade 3 or 4 hypophysitis.

Hyperthyroidism occurred in 10 (1.8%) of 550 patients, including Grade 2 (0.7%) or 3 (0.3%) hyperthyroidism. Hypothyroidism occurred in 38 (6.9%) of 550 patients, including Grade 2 (5.5%) or 3 (0.2%) hypothyroidism. 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 replacement hormones for hypothyroidism and manage hyperthyroidism with thionamides and beta-blockers as appropriate. Withhold or discontinue KEYTRUDA (pembrolizumab) for Grade 3 or 4 hyperthyroidism.

Type 1 diabetes mellitus, including diabetic ketoacidosis, occurred in 3 (0.1%) of 2117 patients. Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Administer insulin for type 1 diabetes, and withhold KEYTRUDA and administer anti-hyperglycemics in patients with severe hyperglycemia.

Immune-mediated nephritis occurred in patients receiving KEYTRUDA. Monitor patients for changes in renal function. Administer corticosteroids for Grade 2 or greater nephritis. Withhold KEYTRUDA (pembrolizumab) for Grade 2; permanently discontinue KEYTRUDA for Grade 3 or 4 nephritis.

Other clinically important immune-mediated adverse reactions can occur. 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 to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Based on limited data from clinical studies in patients whose immune-related adverse reactions could not be controlled with corticosteroid use, administration of other systemic immunosuppressants can be considered. Resume KEYTRUDA when the adverse reaction remains at Grade 1 or less following corticosteroid taper. Permanently discontinue KEYTRUDA for any Grade 3 immune-mediated adverse reaction that recurs and for any life-threatening immune-mediated adverse reaction.

The following clinically significant, immune-mediated adverse reactions occurred in less than 1% of 550 patients: rash, vasculitis, hemolytic anemia, serum sickness, and myasthenia gravis.

Severe and life-threatening infusion-related reactions have been reported in 3 (0.1%) of 2117 patients. Monitor patients for signs and symptoms of infusion-related reactions including rigors, chills, wheezing, pruritus, flushing, rash, hypotension, hypoxemia, and fever. For Grade 3 or 4 reactions, stop infusion and permanently discontinue KEYTRUDA.

Based on its mechanism of action, KEYTRUDA can 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 due to adverse reactions in 14% of 550 patients. Serious adverse reactions occurred in 38% of patients. The most frequent serious adverse reactions reported in at least 2% of patients were pleural effusion, pneumonia, dyspnea, pulmonary embolism, and pneumonitis. The most common adverse reactions (reported in at least 20% of patients) were fatigue (44%), cough (29%), decreased appetite (25%), and dyspnea (23%).

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 and for 4 months after the final dose.

Safety and effectiveness of KEYTRUDA (pembrolizumab) 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.

As part of our focus on cancer, Merck is committed to exploring the potential of immuno-oncology with one of the fastest-growing development programs in the industry. We are currently executing an expansive research program that includes more than 270 clinical trials evaluating our anti-PD-1 therapy across more than 30 tumor types. We also continue to strengthen our immuno-oncology portfolio through strategic acquisitions and are prioritizing the development of several promising immunotherapeutic candidates with the potential to improve the treatment of advanced cancers.

For more information about our oncology clinical trials, visit www.merck.com/clinicaltrials.a

Medivation’s Pidilizumab Shows Potential Clinical Benefit and Safety in Children With Diffuse Intrinsic Pontine Glioma (DIPG)

On June 16, 2016 Medivation, Inc. (NASDAQ: MDVN) reported results from a Phase I/II study of pidilizumab, an investigational antibody with immune-mediated anti-tumor effects, that demonstrated potential clinical benefit in pediatric patients with diffuse intrinsic pontine glioma (DIPG) (Press release, Medivation, JUN 16, 2016, View Source [SID:1234513409]).

The study, which was exploratory in nature, was designed to assess the safety and tolerability of pidilizumab, as well as key clinical outcomes, such as event-free and overall survival, in this pediatric population. Preliminary data were presented this week in an oral symposium at the International Symposium on Pediatric Neuro-Oncology (ISPNO) by the study’s lead investigator Iris Fried, M.D., Attending Physician, Pediatric Hemato-oncology, Hadassah Medical Center, Jerusalem, Israel.

Diffuse intrinsic pontine glioma (DIPG) is a rare and aggressive pediatric cancer which is responsible for the highest brain tumor mortality in children.1 Approximately 300-400 pediatric brain stem tumors are diagnosed per year in the United States, approximately 75%-80% of which are DIPGs.2 Children with DIPG experience a median overall survival between 9-12 months and a two-year survival rate of less than 10%.1

Data from nine pediatric patients with DIPG who were treated with pidilizumab following completion of standard radiation therapy were presented. The median age of the study population was 6.5 years (range: 3-19 years): eight patients had intermediate risk features and one patient had high risk features. The reported mean event-free and overall survival estimates were 12 and 15.6 months, respectively. Three patients with DIPG remained progression-free at 16.3, 22, and 24 months following diagnosis, with one patient experiencing a partial response. Adverse events of any grade reported in at least one treatment cycle include neutropenia, fatigue, loss of appetite, hypertension, nausea, and lymphopenia; only neutropenia and hypertension were reported as grade 3 adverse events. The study continues to enroll patients.

"Separate studies have revealed the potential of pidilizumab in hematological malignancies, and these results, while in a small cohort in a rare disease, suggest its potential activity in other conditions," said David Hung, M.D., Founder, President and Chief Executive Officer of Medivation. "We are especially encouraged by these results in a devastating disease that typically leads to such rapid and certain mortality, and we remain committed to advancing the clinical development of pidilizumab as we continue to characterize its unique and differentiated mechanism of action."

Despite more than 30 years of clinical research, there have been no improvements in clinical outcomes and there are no approved treatments for DIPG.1,2