AstraZeneca announced that its global biologics research and development arm, MedImmune has entered into an exclusive clinical trial collaboration with Mirati Therapeutics, Inc., an oncology company focusing on genetic and epigenetic drivers of cancer. The phase I/II study will evaluate the safety and efficacy of MedImmune’s investigational anti-PDL1 immune checkpoint inhibitor, durvalumab (MEDI4736), in combination with mocetinostat, Mirati’s investigational spectrum-selective histone deacetylase (HDAC) inhibitor.

This novel combination will initially be evaluated in patients with non-small cell lung cancer (NSCLC), with the potential to explore additional indications in the future.

Durvalumab is designed to counter the tumour’s immune-evading tactics by blocking a signal that helps tumours avoid detection, while mocetinostat selectively inhibits class I HDAC enzymes, which has the potential to enhance the positive effect of checkpoint inhibitors, such as durvalumab, on tumour immunity.

David Berman, senior vice president and head of the oncology innovative medicines unit, MedImmune, said, “The collaboration with Mirati is yet another example of our combination-focused immuno-oncology strategy and our comprehensive approach in lung cancer as a key disease area. We continue to follow the scientific evidence to explore novel combination treatments to meet unmet patient need, with durvalumab as the cornerstone.”

Charles M. Baum, president and chief executive officer, Mirati, said, “There is a growing body of evidence that mocetinostat may enhance the efficacy of immune check-point inhibitors such as PD-L1 antibodies. Mocetinostat selectively targets specific HDACs that may increase the efficacy of durvalumab in patients with non-small cell lung cancer, as well as other tumour types. We look forward to working with MedImmune on this combination to potentially improve future outcomes for patients.”

Under the terms of the agreement, Mirati will conduct and fund the initial phase I/II clinical trial, which is expected to start in 2016, and MedImmune will supply durvalumab for the trial. The parties have established a Joint Steering Committee to oversee the trial. In the event that the initial clinical trial demonstrates positive results, MedImmune will have an exclusive period of time in which to negotiate a commercial license for the combination in this indication.

Mocetinostat is an orally-bioavailable, spectrum-selective HDAC inhibitor. Mocetinostat is currently in two single-agent phase II trials evaluating the treatment of patients that carry inactivating mutations of the histone acetyltransferase genes CREBBP and EP300. One trial is in patients with bladder cancer, the other is an investigator-sponsored study in patients with diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL). The US Food and Drug Administration (FDA) granted Orphan Drug Designation to mocetinostat as a treatment for DLBCL. Additionally, there is growing evidence suggesting that class I spectrum-selective HDAC inhibitors may be able to increase the target patient population and enhance the activity of immune check-point inhibitors when these classes of agents are combined. Based on this strong scientific rationale, mocetinostat is being evaluated in combination with a PD-L1 monoclonal antibody for the treatment of NSCLC. This phase I/II study is expected to begin in 2016. Mirati retains worldwide rights to mocetinostat with the exception of certain Asian territories where the programme is partnered with Taiho Pharmaceutical Co., Ltd.

Durvalumab 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. Durvalumab blocks these signals, countering the tumour’s immune-evading tactics.

Durvalumab was accelerated into phase III clinical development in non-small cell lung cancer and head and neck cancer. The OCEANS clinical development programme will evaluate durvalumab as monotherapy and in combination with a cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) monoclonal antibody tremelimumab, in lung cancer, across the spectrum of the disease. In head and neck cancer, durvalumab is being investigated in three late stage studies (HAWK, CONDOR and EAGLE) as monotherapy and in combination with tremelimumab, looking at patients with different PD-L1 expression status who have failed on chemotherapy.

A comprehensive development programme for durvalumab is underway across multiple tumor types, including gastric, pancreatic and bladder cancer, in addition to lung and head and neck cancers.