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Orteronel Plus Prednisone Improved Progression Free Survival in MenWith Chemotherapy-Naïve Metastatic Castration ResistantProstate Cancer in Phase 3 Study

On May 16, 2014 Takeda reported data from ELM-PC4, a pivotal, international, double blind, randomized Phase 3 trial showing that the investigational drug orteronel plus prednisone reduced the risk of radiographic progression free survival (rPFS), one of the study’s two primary endpoints, by 30 percent compared to placebo plus prednisone in men with chemotherapy-naïve metastatic castration resistant prostate cancer (mCRPC) [median rPFS 11.0 vs. 8.3 months (HR 0.7; 95% CI:0.5-0.8; P < 0.001)] (Press release Takeda, MAY 15, 2014, View Source [SID:1234500593]). The second primary endpoint, overall survival (OS), showed a numerical improvement in median OS of 1.9 months that was not statistically significant [median OS: 31.4 vs. 29.5 months (HR 0.9; 95% CI: 0.8-1.1; P=0.314)]. Results from the study will be presented as an oral presentation on June 1 during the Genitourinary (Prostate) Cancer session at the annual meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper).

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"The significant rPFS advantage observed for orteronel combined with prednisone in the ELM-PC4 study is consistent with the previously reported rPFS improvement observed in the ELM-PC5 study, where orteronel was also studied with prednisone in men with mCRPC who had previously received chemotherapy. We are carefully analyzing these data to fully inform future decisions in the orteronel program," said Michael Vasconcelles, M.D., Global Head, Takeda Oncology Therapeutic Area Unit. "We thank and express our gratitude to the patients, their families and the study investigators for their significant contributions to the orteronel program to date."

The abstract, titled "Phase 3, randomized, placebo-controlled trial of orteronel (TAK-700) plus prednisone in patients (pts) with chemotherapy-naïve metastatic castration-resistant prostate cancer (mCRPC) (ELM-PC 4 trial) [Abstract #5008]", compared orteronel 400 mg twice daily (BID) plus prednisone 5 mg BID to placebo plus prednisone in 1,560 men with progressive chemotherapy-naïve mCRPC (rising PSA and/or radiographic evidence of metastases) and serum testosterone < 50 ng/dL post orchiectomy or with maintained GnRH suppression. In the study, men with progressive mCRPC were randomized 1:1 to either treatment or control groups. The final analysis for rPFS was conducted at an interim analysis for OS, and the final analysis for OS was conducted at 600 deaths. The results will be presented by Ronald DeWit, MD, PhD, Erasmus MC Cancer Institute. Key secondary endpoints showed more patients experienced at least a 50 percent decrease in prostate-specific antigen and favorable circulating tumor cell (CTC) counts at 12 weeks in the treatment arm compared to the control. Common all-grade adverse events with orteronel and prednisone compared to control included nausea (36% vs. 15%), fatigue (34% vs. 20%), constipation (33% vs. 15%) and diarrhea (28% vs. 14%); 30 percent vs. 18 percent of patients in the orteronel arm and control arm, respectively, discontinued due to adverse events. No new safety signals attributed to orteronel were identified in this study.

MedImmune and Incyte announce collaboration on immuno-oncology combination clinical trial

On May 14, 2014 AstraZeneca reported that MedImmune, its global biologics research and development arm, has entered into a clinical study collaboration with biopharmaceutical company Incyte Corporation (Press release, MedImmune, MAY 14, 2014, View Source! [SID1234523898]). The Phase I/II oncology study will evaluate the efficacy and safety of MedImmune’s investigational anti-PD-L1 immune checkpoint inhibitor, MEDI4736, in combination with Incyte’s oral indoleamine dioxygenase-1 (IDO1) inhibitor, INCB24360.

Both MEDI4736 and INCB24360 are investigational compounds that are part of a new class of cancer treatments known as immunotherapies, which use the body’s own immune system to help fight cancer. MEDI4736 blocks the signals that help tumours avoid detection by the immune system, countering the tumour’s immune-evading tactics, while INCB24360 enhances the ability of immune cells to combat the tumour. Preclinical evidence suggests that the combination of these two agents may lead to an enhanced anti-tumour immune response.

Under the terms of the agreement, MedImmune and Incyte will collaborate on a non-exclusive basis on the study, to evaluate the combination in multiple solid tumours including metastatic melanoma, non-small cell lung cancer, squamous cell carcinoma of the head and neck and pancreatic cancer. The Phase I part of the trial is expected to establish a recommended dose regimen of both MEDI4736 and INCB24360 and the Phase II part of the study will assess the safety and efficacy of the combination. Results from the study will be used to determine whether further clinical development of this combination is warranted. The study will be co-funded equally by Incyte and MedImmune and conducted by Incyte.

Dr. Bahija Jallal, Executive Vice President, MedImmune, said: "Immuno-oncology is one of the most exciting areas in our industry and we are progressing our strong pipeline as rapidly as possible. Our partnership with Incyte is further evidence of our belief that combination therapies have the potential to be one of the most effective ways of treating cancer."

"Research collaborations that evaluate combinations of novel immunotherapies across a broad range of indications have the potential to accelerate our understanding of this rapidly evolving field, to identify new areas of opportunity for immunotherapies, and to more rapidly address the unmet needs of patients with a wide range of cancers," said Hervé Hoppenot, President and Chief Executive Officer of Incyte. "For these reasons, we welcome the opportunity to work with MedImmune to explore the potential of combining MEDI4736 with INCB24360."

AstraZeneca and MedImmune have recently initiated other immuno-oncology combination trials, including MEDI4736 with IRESSA and MEDI4736 with tremelimumab. Other combination trials are planned to start imminently, demonstrating the strength and rapid progression of the company’s immuno-oncology portfolio.

NOTES FOR EDITORS

About MEDI4736

MEDI4736 is an investigational human monoclonal antibody directed against programmed cell death ligand 1 (PD-L1). Signals from PD-L1 help tumours avoid detection by the immune system. MEDI4736 blocks these signals, countering the tumour’s immune-evading tactics. MEDI4736 is being developed, alongside other immunotherapies (IMTs), to empower the patient’s immune system and attack the cancer.

About INCB24360

INCB24360 is an orally bioavailable small molecule inhibitor of IDO1 that has nanomolar potency in both biochemical and cellular assays, potent activity in enhancing T lymphocyte, dendritic cell and natural killer cell responses in vitro, with a high degree of selectivity. INCB24360 has been shown to be efficacious in mouse models of cancer as a single agent and in combination with cytotoxic and immunotherapy agents, and its ability to reduce tumour growth is dependent on a functional immune system – consistent with its proposed mechanism of action. A Phase I dose-escalation trial demonstrated that INCB24360 results in greater than 90 percent inhibition of IDO1 activity at generally well-tolerated doses.

INCB24360 is currently in Phase I/II development for metastatic melanoma in combination with ipilimumab (www.clinicaltrials.gov Identifier: NCT01604889) and as monotherapy for ovarian cancer (www.clinicaltrials.gov Identifier: NCT01685255). Incyte has also established a clinical agreement to combine INCB24360 with a novel anti-PD-1 immunotherapy checkpoint inhibitor.

(Press release, AllaChem, MAY 14, 2014, View Source [SID:1234502047])

Kancera AB files patent for HDAC6 inhibitors against cancer

On May 14, 2014 Kancera reported that the company has registered a patent application (EP14167988.6) for new compounds against cancer that selectively inhibit the enzyme HDAC6 (Press release Kancera, MAY 14, 2014, View Source;releaseID=885909 [SID:1234500836]). The new patent application is based on the ability of HDAC6 inhibitors to influence mechanisms both inside and outside of the cell nucleus. It has been shown that the major biological role of HDAC6 is in the regulation of the cancer cell´s ability to migrate and form metastases.

On December 3, 2013, Kancera announced a surprising discovery of a new class of compounds against cancer that acts selectively on HDAC6. This class of compounds has now been claimed in a patent application. Furthermore, chemical synthetic routes have been developed that allow for an efficient optimization of patentable HDAC6 inhibitor analogues with further improved pharmaceutical properties.

Independent researchers have shown that inhibitors of HDAC6 have the potential to be used also for the treatment of autoimmune and neurodegenerative diseases as well as depression.

About the HDAC6 project
Histone deacetylases (HDACs) are primarily involved in removing the acetyl groups from the so-called histones and thereby affect how our genes are stored. Most HDACs are activated in the cell nucleus but HDAC6 mainly affect the cell function outside the cell nucleus. The major biological role of is in the regulation of the cancer cell´s ability to migrate and form metastases. The use of HDAC inhibitors in the treatment of cancer patients has so far yielded promising results, but has been limited due to severe side effects. For this reason, the pharmaceutical industry is now looking for more selective inhibitors of individual HDAC enzymes. Unlike other HDACs, loss of HDAC6 function is not associated with severe toxicity. Kancera´s discovery of selective HDAC6 inhibitors may provide a solution on how health care should take advantage of the anti-cancer effects of HDAC inhibitors without causing the patient severe side effects.

Investigational PD-1 Immune Checkpoint Inhibitor Nivolumab Receives U.S. FDA Breakthrough Therapy Designation for Hodgkin Lymphoma

On May 14, 2014 Bristol-Myers Squibb reported that the U.S. Food and Drug Administration (FDA) has granted the investigational PD-1 immune checkpoint inhibitor nivolumab Breakthrough Therapy Designation for the treatment of patients with Hodgkin lymphoma (HL) after failure of autologous stem cell transplant and brentuximab (Press release Bristol-Myers Squibb, MAY 14, 2014, View Source [SID:1234500524]). The designation is based on data from a cohort of patients with HL in the company’s ongoing Phase 1b study of relapsed and refractory hematological malignancies.