On December 3, 2016 Juno Therapeutics, Inc. (NASDAQ: JUNO), a biopharmaceutical company developing innovative cellular immunotherapies for the treatment of cancer, reported a presentation at the 58th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting encouraging early data for JCAR014 in patients with chronic lymphocytic leukemia (CLL) who failed treatment with ibrutinib (Press release, Juno, DEC 3, 2016, View Source [SID1234516883]). Insights from studies of the translational product, JCAR014, are being applied to the development of JCAR017 for the treatment of B-cell malignancies. Both JCAR014 and JCAR017 use a 4-1BB co-stimulatory domain and defined 1:1 cell ratio of CD4:CD8 T cells.

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"The responses and durability we’ve seen in this study are notable and demonstrate the potential for further investigation of JCAR017 for patients with relapsed/refractory high-risk CLL," said Mark J. Gilbert, M.D., Juno’s Chief Medical Officer. "This is especially important, given recent data that show these patients, who progress early on ibrutinib, have poor clinical outcomes with a median survival of approximately three months. In addition, emerging response criteria, such as undetectable disease in the bone marrow at the molecular level by deep sequencing, appear to correlate with long-term response duration."

The Phase I study (ASH Abstract #56), conducted by Cameron Turtle, MBBS, Ph.D., of the Fred Hutchinson Cancer Research Center, evaluated 24 heavily pre-treated patients, all of whom had failed ibrutinib, the standard-of-care treatment for CLL. Patients had received a median of five previous therapies, including three who failed prior allogeneic stem cell transplants. Patients received lymphodepletion with either fludarabine/cyclophosphamide (flu/cy) (N=21) or non-flu/cy (N=3) prior to infusion of JCAR014.

Key data for the flu/cy cohort include:
Two of 24 (8%) patients developed grade 3-5 severe cytokine release syndrome (sCRS) and 6/24 (25%) patients developed grade 3-5 severe neurotoxicity. The most frequent severe Treatment Emergent Adverse Events were febrile neutropenia (75%), CRS (29%), fever (17%), lung infection (13%), encephalopathy (13%), and hypotension (13%). There was one treatment-related mortality (4%) in the trial in a patient who received flu/cy lymphodepletion, with both grade 5 CRS and cerebral edema.

Of 17 efficacy-evaluable patients with bone marrow disease at the start of the trial and treated with flu/cy and the two lowest doses of JCAR014, 15/17 (88%) had a complete marrow response by flow cytometry. Fourteen of the complete bone marrow response patients had a response assessment by the more sensitive method of IgH deep sequencing, with 7/14 (50%) having no detectable disease. All seven of these patients are alive and progression free with follow-up ranging from 3 to 26 months. The complete marrow response by flow cytometry was similar in patients documented to be ibrutinib-refractory at 86% (12/14).

In patients with PET-avid disease at baseline and treated with flu/cy and the two lowest doses of JCAR014, 8/11 (73%) had a partial response (PR) or complete response (CR) at four weeks, with 7/11 (64%) having a CR.

In patients evaluated for efficacy at four weeks using IWCLL criteria and treated with flu/cy and the two lowest doses of JCAR014, 14/19 (74%) had a PR or CR, with 4/19 (21%) being a CR. All patients with either a CR or PR remain alive, with follow-up ranging from 3 to 26 months. There is no obvious early difference in time to progression between a CR and PR by IWCLL criteria. The response data were similar in patients documented to be ibrutinib-refractory, with overall response rate of 69% (11/16) and a CR rate of 25% (4/16).

Plans to study JCAR014 in combination with ibrutinib in CLL are underway, with a cohort expected to begin enrollment in early 2017. Juno is evaluating the use of this data with JCAR014 as a monotherapy and in combination with ibrutinib in support of a potential Juno-sponsored trial with JCAR017 in CLL.