On February 08, 2016 OncoMed Pharmaceuticals Inc. (NASDAQ:OMED), a clinical-stage company developing novel anti-cancer stem cell and immuno-oncology therapeutics, reported updates on the tarextumab (anti-Notch 2/3, OMP-59R5) Phase 2 programs in pancreatic cancer (the "ALPINE" study) and small cell lung cancer (the "PINNACLE" study) (Press release, OncoMed, FEB 8, 2016, View Source [SID:1234509000]). OncoMed will continue the PINNACLE Phase 2 trial of tarextumab in small cell lung cancer following a review of unblinded safety and efficacy data from both the ALPINE and PINNACLE studies by the U.S. Food and Drug Administration (FDA) and the PINNACLE Data Safety Monitoring Board (DSMB). The PINNACLE study remains blinded to OncoMed, investigators and patients. OncoMed has discontinued dosing of tarextumab in the Phase 2 ALPINE clinical study.

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"After communicating with the FDA and the PINNACLE trial DSMB we have received feedback that appropriate safety monitoring is in place to continue the PINNACLE trial," said Paul J. Hastings, Chairman and Chief Executive Officer of OncoMed. "While we remain blinded to the PINNACLE trial data, differences in pancreatic and small cell lung cancer biology, combined with our understanding of the potential mechanisms of tarextumab, give us confidence to continue the PINNACLE Phase 2 clinical trial."

ALPINE Analysis

On January 25, OncoMed announced feedback received from a pre-planned DSMB analysis of the ALPINE Phase 2 clinical trial. Following receipt of that feedback, OncoMed promptly discontinued patient dosing in the ALPINE trial and proceeded to unblind the study. Subsequently, based on its own initial analysis of unblinded interim Phase 2 data, OncoMed confirmed key findings by the DSMB regarding futility of the ALPINE trial. Post-hoc, exploratory, and ongoing analyses conducted by OncoMed revealed subgroups of patients with decreased survival and a subgroup which appears to exhibit improved survival with tarextumab. OncoMed will continue to analyze the ALPINE data, and present the data at a future medical meeting.

"We have obtained a good understanding of the results from the ALPINE trial. We believe there are important differences in effects that are unique and specific to tarextumab inhibition of Notch signaling within different tumor types that may have significant impact on the drug’s anti-tumor activity. As such, we feel that there is evidence that tarextumab may behave differently in the small cell lung cancer setting than in the pancreatic cancer setting," said Jakob Dupont, M.D., Chief Medical Officer. "We are encouraged that the PINNACLE study will continue after a careful assessment in collaboration with the independent DSMB, the FDA and the investigators. We hope to make a difference for patients with small cell lung cancer who are in need of new and improved therapies. We thank our tarextumab investigators, their teams, the patients, their families, and caregivers for participating in the ALPINE and PINNACLE clinical trials. Their efforts are advancing our understanding of pancreatic and small cell lung cancer treatment."

Impact on PINNACLE

Following notification of the ALPINE DSMB’s findings, OncoMed initiated interactions with tarextumab clinical investigators, partner GlaxoSmithKline, the FDA and the PINNACLE trial’s DSMB chairperson to assess potential impact of these results on the overall development program, including the ongoing Phase 2 PINNACLE trial in small-cell lung cancer patients.

PINNACLE trial investigators received an addendum to the informed consent form that included a description of the interim analysis from ALPINE. The FDA and the PINNACLE DSMB were provided unblinded data from both Phase 2 trials, a description of OncoMed’s exploratory analysis of the ALPINE results and related trial materials for review. The independent analyses of the FDA and PINNACLE DSMB indicated that the PINNACLE trial could continue under the supervision of the PINNACLE DSMB monitoring for safety and efficacy and that appropriate safeguards are in place.

OncoMed is conducting the PINNACLE Phase 1b/2 clinical trial of tarextumab for the treatment of small cell lung cancer. The randomized Phase 2 trial is comparing progression-free survival (PFS) outcomes for patients treated with tarextumab administered at 15 mg/kg every three weeks in combination with etoposide and cisplatin or carboplatin versus patients who receive placebo plus chemotherapy. Additionally, PFS will be assessed using a predictive biomarker for high tumor Notch3 expression. Secondary endpoints for the Phase 2 study include overall survival, overall response rate, pharmacokinetics, safety and other biomarkers. The PINNACLE study is being conducted at about 40 sites in the U.S. and is expected to enroll approximately 130 patients. Results from the Phase 2 PINNACLE trial are anticipated in 2017.

OncoMed plans to present updated PINNACLE Phase 1b data at the 16th Annual Targeted Therapies of the Treatment of Lung Cancer in Santa Monica, California taking place February 17-20, 2016.

About Tarextumab (anti-Notch2/3, OMP-59R5)

Tarextumab (anti-Notch2/3, OMP-59R5) is a fully human monoclonal antibody that targets the Notch2 and Notch3 receptors. Preclinical studies have suggested that tarextumab exhibits two mechanisms of action: (1) by downregulating Notch pathway signaling, tarextumab appears to have anti-cancer stem cell effects, and (2) tarextumab affects pericytes, impacting stromal and tumor microenvironment.

Tarextumab is part of OncoMed’s collaboration with GlaxoSmithKline (GSK). GSK has an option to obtain an exclusive license to tarextumab during certain time periods through completion of the proof-of-concept Phase 2 trials.

On February 8, 2016 Epizyme, Inc. (NASDAQ:EPZM), a clinical stage biopharmaceutical company creating novel epigenetic therapeutics for cancer patients, reported that the United States Food and Drug Administration (FDA) has granted orphan drug status to the company’s first-in-class EZH2 inhibitor, tazemetostat, for the treatment of malignant rhabdoid tumors (MRTs) (Press release, Epizyme, FEB 8, 2016, View Source [SID:1234508999]). In December 2015, the company initiated a phase 2 study in adults and a phase 1 study in children with genetically defined tumors, including MRTs. Tazemetostat is also being investigated in an ongoing five-arm phase 2 study in patients with non-Hodgkin lymphoma.

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"Malignant rhabdoid tumors are rare and aggressive cancers with poor outcomes. There have not yet been any targeted drugs developed specifically to treat these patients," said Peter Ho, M.D., Ph.D., Chief Medical Officer, Epizyme. "In an ongoing phase 1 study, tazemetostat has demonstrated encouraging clinical activity and an acceptable safety profile in patients with these severe types of cancer. We believe tazemetostat has the potential to become an important targeted therapy for patients with MRT and we are working aggressively to execute our clinical development program."

Orphan drug designation provides the sponsor of the drug with eligibility for various development incentives, including tax credits for qualified clinical testing and marketing exclusivity for a period of seven years. Therapies with orphan drug status are also not subject to a prescription drug user fee for the orphan indication.

Currently, treatment of MRT consists of surgery, chemotherapy and radiation therapy, which are associated with limited efficacy and significant treatment-related morbidity. MRT is a tumor defined by loss of INI1 protein as measured by immunohistochemistry. Other rhabdoid tumors, such as MRT of ovary, are characterized by loss of the protein SMARCA4 and have shown sensitivity to tazemetostat in preclinical models and in our phase 1 study. The orphan drug designation applies to both INI1-negative MRT as well as SMARCA4-negative MRT of ovary.

The ongoing phase 2 adult and phase 1 pediatric studies in patients with genetically-defined solid tumors include patients with rhabdoid tumors, other INI1-negative tumors, and synovial sarcoma. Interim data from Epizyme’s registration-supporting phase 2 clinical study of tazemetostat in adult patients with genetically defined solid tumors, including MRT, other INI1-negative tumors and synovial sarcoma, are anticipated to be presented at a medical conference in late 2016.

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 lymphoma, INI1-negative cancers such as malignant rhabdoid tumors and epithelioid sarcomas, certain SMARCA4-negative solid tumors, synovial sarcoma, and a range of other solid tumors.

About Tazemetostat

Epizyme is developing tazemetostat for the treatment of patients with non-Hodgkin lymphoma and for patients with INI1-negative solid tumors, certain SMARCA4-negative solid tumors and synovial sarcoma. Tazemetostat is a first-in-class small molecule inhibitor of EZH2 created by Epizyme using its proprietary product platform. In some human cancers, aberrant EZH2 enzyme activity results in dysregulation 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 compound EPZ-6438.

Additional information about this program, including clinical trial information for the adult 5-arm NHL study, can be found here: View Source

Clinical trial information for Epizyme’s ongoing phase 2 trial in adults and phase 1 trial in children with INI1-negative solid tumors, certain SMARCA4-negative solid tumors or synovial sarcoma can be found here:

View Source

View Source

On February 8, 2016 AstraZeneca and MedImmune, its global biologics research and development arm, reported publication in The Lancet Oncology of a Phase Ib study (study 006), showing antitumour activity of combination treatment with durvalumab and tremelimumab, in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC), irrespective of PD-L1 status (Press release, AstraZeneca, FEB 8, 2016, View Source [SID:1234508997]).1

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In a cohort of 26 patients treated with durvalumab 10-20 mg/kg plus tremelimumab 1 mg/kg, and followed for ≥24 weeks, the confirmed objective response rate (ORR) was 23% (95% confidence interval 9-44%).1 Comparable ORRs were seen in patients from this cohort with PD-L1 positive and negative tumours (22% and 29% respectively). Durvalumab was administered intravenously every four weeks (q4w) for 13 doses or every 2 weeks (q2w) for 26 doses, and tremelimumab was administered q4w for six doses followed by every 12 weeks (q12w) for three doses.

Data on all 56 patients treated with durvalumab 10-20 mg/kg q2w or q4w plus tremelimumab 1 mg/kg showed a manageable safety profile for an advanced NSCLC population. Thirty per cent of patients had ≥1 related Grade 3/4 adverse events (AE) and 16% discontinued treatment due to a related adverse event.

Dr Scott J. Antonia, Chair of the Department of Thoracic Oncology at Moffitt Cancer Center, Tampa, Florida, USA, said: "Combination therapy with durvalumab and tremelimumab demonstrated antitumour activity in patients with NSCLC regardless of PD-L1 status, including in patients with no evidence of tumour cell membrane PD-L1 staining. The results suggest that this combination has potential as a treatment option for patients with PD-L1 negative tumours whose needs are not addressed by currently available therapies, including immunotherapies."

With the recent introduction of checkpoint inhibitors, the presence of PD-L1 expression in a tumour is considered a significant biomarker for response to PD-L1 blockade.2 Less than half of patients with NSCLC have tumours that are PD-L1 positive,1 leaving a significant unmet medical need in the PD-L1 negative patient population.

Dr Ed Bradley, Senior Vice President, Oncology, MedImmune, said: "The newly published data are an important milestone in our scientific understanding of the patient population likely to achieve the greatest benefit from the combination of durvalumab and tremelimumab. The latest findings reinforce our belief that the combination strategy we are pursuing is key to the future success of immuno-oncology treatment."

Durvalumab is an investigational human monoclonal antibody directed against programmed death ligand-1 (PD-L1), which blocks the interactions between PD-L1 and both PD-1 and B7.1, reversing in some tumours the ability of tumour cells to avoid detection by the immune system.3 Tremelimumab inhibits the activity of cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) to boost the immune response against cancer cells.4 Preclinical data suggested that targeting both PD-L1 and CTLA-4 may have additive or synergistic effects.5

A preliminary analysis of data from Study 006 was presented at the annual meeting of the Society for Immunotherapy in Cancer (SITC) (Free SITC Whitepaper), in November 2015. The Lancet Oncology publication provides a more detailed analysis with a longer follow up period and more mature data set of confirmed responses, with a focus on those which informed the selection of durvalumab 20 mg/kg plus tremelimumab 1 mg/kg, every four weeks, for ongoing Phase III trials.1

Durvalumab and tremelimumab are pipeline products under development and, as such, are not approved by the US Food and Drug Administration, European Medicines Agency or any other regulatory agency for the uses under investigation. Information regarding these investigational products should under no circumstances be regarded as a recommendation for their use or of their safety or efficacy.

– ENDS –

NOTES TO EDITORS

About durvalumab (MEDI4736)

Durvalumab is an investigational human monoclonal antibody directed against programmed death ligand-1 (PD-L1). Signals from PD-L1 help tumours avoid detection by the immune system.2 Durvalumab blocks these signals, countering the tumour’s immune-evading tactics.3 Durvalumab is being investigated in an extensive clinical trial programme.

About tremelimumab

Tremelimumab is a fully human anti-CTLA-4 antibody. By blocking the activity of CTLA-4, tremelimumab "releases the brakes" on T cell activation and boosts the immune response against cancer cells.4,6 In animal models, CTLA-4 blockade by anti-CTLA-4 antibodies such as tremelimumab, has been shown to promote antitumour immune responses.4 In 2015, tremelimumab was granted Orphan Drug Designation by the US Food and Drug Administration as a potential treatment for malignant mesothelioma.

On February 8, 2016 CTI BioPharma Corp. (CTI BioPharma) (NASDAQ and MTA:CTIC) reported that the Company received written communication from the U.S. Food and Drug Administration (FDA) on February 4, 2016, that the FDA has placed a partial clinical hold on the clinical studies being conducted under the Company’s Investigational New Drug ("IND") application for pacritinib (Press release, CTI BioPharma, FEB 8, 2016, View Source [SID:1234508996]) .

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This clinical hold impacts part of the clinical work currently being conducted under the IND and will also affect planned clinical trials.

Under the partial clinical hold, clinical investigators may not enroll new patients or start pacritinib as initial or crossover treatment, and patients not deriving benefit after 30 weeks of pacritinib treatment should stop using pacritinib. In addition, the FDA has recommended that the Company make certain modifications of protocols, including modifying all protocols for randomized trials to disallow crossover to pacritinib, provide certain notifications, revise relevant statements in the related investigator’s brochure and informed consent documents, and take certain other actions. The Company intends to implement the FDA’s recommendations. All clinical investigators worldwide have been delivered a notice of the partial clinical hold.

The Company intends to work together with the FDA and expects to submit modifications and revisions that address the recommendations noted above. In its written notification, the FDA cited the reasons for the partial clinical hold were that there was excess mortality and other adverse events in pacritinib-treated patients compared to the control arm in the PERSIST-1 trial. The excess mortality was most evident during the non-randomized crossover period following the initial 24 weeks of randomized treatment, during which patients in the control arm could switch to pacritinib treatment. In prior correspondence, the FDA acknowledged the difficulty addressing non-significant results, and that crossover designs can confound the interpretation of safety as well as the evaluation of survival.

After submission of the required information, the FDA has indicated that it would notify the Company whether it can continue the clinical studies under the IND.

Completion of PERSIST-2 Phase 3 Trial

Additionally, CTI BioPharma announced that as of February 3, 2016, it has completed patient enrollment in the PERSIST-2 Phase 3 clinical trial of pacritinib for the treatment of patients with myelofibrosis. PERSIST-2 is evaluating pacritinib for patients with myelofibrosis whose platelet counts are less than or equal to 100,000 per microliter (≤100,000/μL). Under the FDA partial clinical hold referenced above, patients currently receiving pacritinib may continue to do so unless they are not deriving benefit after 30 weeks of pacritinib treatment, and crossover of patients from the control arm to the pacritinib arm will not be allowed.