AstraZeneca, Pharmacyclics, Inc., and Janssen Research & Development, LLC , have entered into a clinical trial collaboration to evaluate the efficacy and safety of AstraZeneca's investigational anti-PD-L1 immune checkpoint inhibitor, MEDI4736, in combination with Imbruvica (ibrutinib), an oral Bruton's tyrosine kinase inhibitor, co-developed by Pharmacyclics and Janssen and commercialized outside the US by Janssen affiliates. The study will assess the combination as a treatment for patients with hematological cancers, including diffuse large B-cell lymphoma and follicular lymphoma, which are investigational uses for both compounds.

MEDI4736 blocks the signals that help tumors avoid detection by the immune system, countering the tumor's immune-evading tactics. Ibrutinib blocks signals that tell malignant B cells (white blood cells that produce antibodies) to multiply and spread, according to information from AstraZeneca. Preclinical evidence suggests that the combination of these two agents may lead to an enhanced anti-tumou immune response.

The Phase I part of the trial is expected to establish a recommended dose regimen for the combination of MEDI4736 and ibrutinib, and the Phase IIa part of the trial will assess the safety and efficacy of the investigational combination. Under the agreement, the two-part trial will be conducted by Pharmacyclics. The financial terms of the agreement have not been disclosed.

MEDI4736 is in development as monotherapy in solid tumours. It is currently in Phase III development for patients with non-small cell lung cancer and clinical trials are due to commence in 2014 for patients with squamous cell carcinoma of the head and neck. AstraZeneca and MedImmune, its biologics research and development arm, also have a broad programme of immuno-oncology combination trials underway, including MEDI4736 + tremelimumab (CTLA-4), MEDI4736 + MEDI0680 (PD-1), MEDI4736 + MEDI6469 (OX40) and MEDI4736 + Iressa (epidermal growth factor receptor-tyrosine kinase inhibitor).

Imbruvica is an oral, once-daily therapy that inhibits a protein called Bruton’s tyrosine kinase, a key signaling molecule in the B-cell receptor signaling complex that plays an important role in the survival and spread of malignant B cells. The drug blocks signals that tell malignant B cells to multiply and spread.

Imbruvica was approved by the US Food and Drug Administration for treating chronic lymphocytic leukemia (CLL) who have received at least one prior therapy and for the treatment of CLL patients with del 17p, a genetic mutation that occurs when part of chromosome 17 has been lost. The drug is also approved for the treatment of patients with mantle cell lymphoma (MCL) who have received at least one prior therapy.

The drug is being studied alone and in combination with other treatments in several blood cancers, including CLL, MCL, Waldenstrom’s macroglobulinemia, diffuse large B-cell lymphoma, follicular lymphoma, and multiple myeloma. Last month, Imbruvica received approval in the European Union for treating relapsed or refractory MCL and CLL. Pharmacylics submitted a supplemental new drug application to the FDA for treating Waldenstrom’s macroglobulinemia, a rare type of B-cell lymphoma.

In addition to its pact with Pharmacyclics and Janssen for studying MEDI4736 in combination with Imbruvica, AstraZeneca has signed a second collaboration with Pharmacyclics that will focus on hematological cancers and will explore separate combinations of two different AstraZeneca investigational PI3 kinase pathway inhibitors with Imbruvica for the treatment of patients with relapsed or refractory diffuse large B-cell lymphomas. Preclinical evidence suggests that the combination of Imbruvia with these investigational medicines may enhance their effects.

Under the terms of the agreements, AstraZeneca and Pharmacyclics will collaborate on a non-exclusive basis and multiple Phase I and Phase IIa studies may be considered and conducted. The studies focused on solid tumors will be led by Pharmacyclics while AstraZeneca will lead those exploring hematological cancers. The Phase I element of each study is expected to establish a recommended safe and tolerable dose and schedule for the combination, and the Phase IIa element will assess its safety and efficacy in an expanded patient population.The financial terms of the agreement have not been disclosed. The results of the clinical studies will be used to determine whether further clinical development of the different combinations is warranted.

Source: AstraZeneca (Janssen and Pharmacyclics) and AstraZeneca (Pharmacyclics)