Clinical Trials

Date: 2016-12-03

Type of information: Presentation of results at a congress

phase: 1

Announcement: presentation of results at the 58th American Society of Hematology (ASH) Annual Meeting

Company: Juno Therapeutics (USA - WA)

Product: JCAR014

Action mechanism:

cell therapy/immunotherapy product/gene therapy/CAR-T cell therapy. JCAR014 is a CD19-specific CAR T cell therapy.  This product uses the 4-1BB costimulatory domain and is composed of CD8+ T cells and CD4+ T cells in a defined ratio. JCAR014 was originally developed at the Fred Hutchinson Cancer Research Center.

Disease: relapsed or refractory non-Hodgkin lymphoma (NHL), chronic lymphocytic leukemia (CLL)

Therapeutic area: Cancer - Oncology

Country: USA

Trial details:

Latest news:

* On December 3, 2016, Juno Therapeutics announced in a presentation at the 58th American Society of Hematology (ASH) Annual Meeting early data for JCAR014 in patients with chronic lymphocytic leukemia (CLL) who failed treatment with ibrutinib. 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.
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.

* On June 4, 2016, Juno Therapeutics announced that data will be presented at the 52nd Annual Meeting of the American Society for Clinical Oncology (ASCO) in Chicago, including an oral presentation on JCAR014. Updated results from a randomized Phase I/II study examining JCAR014 in patients with relapsed or refractory acute lymphoblastic leukemia (ALL), non-Hodgkin lymphoma (NHL), and chronic lymphocytic leukemia (CLL) were presented by Cameron Turtle, MBBS, Ph.D., of the Fred Hutchinson Cancer Research Center.  In efficacy-evaluable ALL patients (N=34), complete remission was reported in 34/34 (100%) patients and complete molecular remission as measured by flow cytometry (CmR) was achieved in 32/34 (94%) patients. Additionally, 13/20 (65%) had a complete molecular remission as measured by the highly sensitive technique of IGH deep sequencing. In the cohort that received fludarabine/cyclophosphamide (Flu/Cy) lymphodepletion, 22/22 (100%) patients achieved a complete remission, all of which were a CmR. Median disease free survival (DFS) and overall survival (OS) have not yet been reached with patients followed for up to 18 months. Severe cytokine release syndrome (sCRS) was observed in 14/36 (39%) patients and Grade 3 or higher neurotoxicity was observed in 14/36 (39%) patients.
In patients with multiple NHL histologies (N=20), predominantly diffuse large B-cell lymphoma, who received Flu/Cy lymphodepletion followed by JCAR014 dose level 2 (2x106/kg), 16/20 (80%) had an overall response (OR), of which 10/20 (50%) experienced a complete response (CR). CRs continue in 70% of patients, ranging from 3 to 11+ months. sCRS was observed in 2/20 (10%) patients and Grade 3 or higher neurotoxicity was observed in 2/20 (10%) patients. Notably, 16/20 (80%) patients treated with Flu/Cy lymphodepletion followed by JCAR014 dose level 2 were treated in the outpatient setting, and 6/20 (30%) did not require hospitalization during the first 30 days of treatment.
A total of 13 high-risk CLL patients (complex karyotype, del17p, ibrutinib-refractory, ibrutinib-intolerant) received JCAR014 and either non-Flu/Cy (n=2) or Flu/Cy (n=11) lymphodepleting chemotherapy. In the Flu/Cy patients, OR rate was 10/11 (91%) patients, of which 5/11 (45%) patients achieved CR. CRs are ongoing in 100% of these patients with a range of 3 to 19+ months. sCRS was observed in 3/13 (23%) patients and Grade 3 or higher neurotoxicity was observed in 3/13 (23%) patients.

* On December 6, 2015, Juno Therapeutics announced, in partnership with its collaborators, that clinical data from a chimeric antigen receptor (CAR) T cell product candidate, JCAR014, demonstrated encouraging clinical responses in patients with relapsed or refractory (r/r) non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL). Results will be presented in an oral presentation at the 57th Annual Meeting of the American Society of Hematology (ASH) in Orlando. Key data will include:

⁽¹⁾The 2*10⁶/kg dose highlighted in the box above represents the dose moving forward.
⁽²⁾All patients in the Flu/Cy cohorts that achieved a CR remain in CR 2-9 months after therapy.

CR = complete response; PR = partial response
Median of 5 prior treatment regimens; 16 patients failed prior autologous and/or allogeneic transplant.
29 out of 32 patients had chemorefractory disease.

⁽¹⁾All CLL patients have been previously treated with ibrutinib.
⁽²⁾The flu/cy regimen highlighted in the box represents the conditioning regimen moving forward.
⁽³⁾All patients in CR remain in CR 2-14 months after therapy.
⁽⁴⁾The patient died 3 months after therapy of pulmonary aspergillosis.

JCAR014 (CD19-specific CAR T cells of defined subset composition) demonstrated potent anti-tumor activity and an acceptable toxicity profile in r/r adult B-cell NHL patients and CLL patients previously treated with ibrutinib.
A meaningful percentage of patients achieved a complete response in both r/r NHL and r/r CLL.
While longer follow-up is necessary to define full durability, there have been no relapses in NHL and CLL patients that achieved a complete response in this study with follow-up ranging from 2 to 14 months.
The addition of fludarabine and cyclophosphamide (flu/cy) lymphodepletion improved CAR T cell peak expansion, persistence and clinical outcomes in NHL.
Severe cytokine release syndrome and severe neurotoxicity were observed in some patients; lower doses of this defined cell product candidate appeared to correlate with lower rates of these toxicities.

 

Is general: Yes