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.

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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])

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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.

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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.

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.

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On May 14, 2014 Bristol-Myers Squibb reported from a Phase1b study evaluating the safety and efficacy of its investigational PD-1 immune checkpoint inhibitor nivolumab as a single agent in patients with advanced non-small cell lung cancer (NSCLC) who were previously treated (Study -003) and a Phase 1b study evaluating nivolumab as a single agent in chemotherapy-naïve patients (CheckMate -012) (Press release Bristol-Myers Squibb, MAY 14, 2014, View Source [SID:1234500525]). In Study -003, the two-year survival rate was 24% across doses (n=129) for previously-treated patients who received nivolumab as a single agent and highest at 45% in patients who received the 3 mg/kg dose (n=37). In CheckMate -012, the overall response rate (ORR) was 50% in PD-L1 positive tumors and 0% in PD-L1 negative tumors for chemotherapy-naïve patients who received nivolumab as a single agent (n=20). The types of treatment-related serious adverse events (SAEs) in CheckMate -012 were consistent with those in other nivolumab trials with 15% of patients experiencing grade 3-4 treatment-related SAEs. These data will be presented at the 50th Annual Meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) taking place in Chicago May 30-June 3.

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Results from Phase 1b Single Agent Study in Previously-Treated Patients (Study -003)

Study -003 is a Phase 1b dose escalation study (n=306) evaluating the safety, antitumor activity and pharmacokinetics of nivolumab as a single agent in previously-treated patients with advanced melanoma (n=107), NSCLC (n=129), renal cell carcinoma (n=34), castration-resistant prostate cancer (n=17) or colorectal cancer (n=19). Based on an amendment to the protocol, patients were followed for survival. Eligible patients were administered nivolumab as an intravenous infusion every two weeks of each eight-week treatment cycle. Cohorts of three to six patients per dose level (0.1, 0.3, 1.0, 3.0 or 10 mg/kg) were enrolled sequentially. Patients continued treatment ≤2 years (12 cycles), unless they experienced complete response, unacceptable toxicity, progressive disease or withdrew consent.

Efficacy and safety results from this study were initially presented at ASCO (Free ASCO Whitepaper) and published in the New England Journal of Medicine in 2012. Updated results from the lung cancer cohort, including those shown below, will be presented at ASCO (Free ASCO Whitepaper) on May 31 at 1:15 p.m. CDT (Abstract #8112).

Data to be presented at the 2014 ASCO (Free ASCO Whitepaper) annual meeting, with all patients having greater than or equal to one year of follow up, demonstrated a spectrum, frequency and severity of treatment-related adverse events (AEs) that were consistent with those initially reported in the study at ASCO (Free ASCO Whitepaper) in 2012. Common drug-related AEs included fatigue, decreased appetite, diarrhea, nausea, constipation, cough and dyspnea. Drug-related select AEs with potential immunologic etiologies, defined as adverse events that may require more frequent monitoring and/or unique intervention, included rash, diarrhea and pruritus. These data support the ongoing evaluation of nivolumab as a single agent at the 3 mg/kg dose in patients with previously treated advanced NSCLC in the Phase 3 CheckMate -017 and CheckMate -057 studies.

Results from Phase 1b Study of Chemotherapy-Naïve Patients (CheckMate -012)

CheckMate -012 is a multi-arm Phase 1b trial evaluating the safety and tolerability of nivolumab in patients with chemotherapy-naïve advanced NSCLC, as either a single agent or as part of a regimen with other agents, including in combination with Yervoy (ipilimumab), at different doses and schedules. Secondary outcomes include ORR and progression free survival (PFS). Results from patients who received nivolumab as a single agent, including those shown below, will be presented at ASCO (Free ASCO Whitepaper) on June 3 at 11:30 a.m. CDT (Abstract #8024).

In patients who received nivolumab 3 mg/kg as a single agent (n=20), the objective response rate (ORR) was 50% in patients whose tumors were PD-L1 positive and 0% for tumors that were PD-L1 negative. Responses were observed in both squamous and non-squamous histological subtypes. Median duration of response has not been reach after a median of 15 months of follow up.

After a median of 15 months of follow up, grade 3/4 treatment-related SAEs were reported in 3 patients (15%) and included AST (5%) or ALT (5%) elevations, cardiac failure and hyperglycemia (5%). No pneumonitis (any grade) was observed. These data support the ongoing evaluation of nivolumab as a single agent at the 3 mg/kg dose in the first-line treatment of advanced NSCLC patients in the Phase 3 CheckMate -026 study.

Data from additional arms of CheckMate -012, including nivolumab as part of a regimen with chemotherapy doublets and erlotinib, is also to be presented at ASCO (Free ASCO Whitepaper) 2014 (Abstract #8113, #8022).