Clinical Trials

Date: 2017-12-12

Type of information: Presentation of results at a congress

phase: 1

Announcement: presentation of results at the 59th American Society of Hematology (ASH) Annual Meeting

Company: Juno Therapeutics (USA - WA)

Product: JCAR017 (lisocabtagene maraleucel)

Action mechanism:

• cell therapy/immunotherapy product/gene therapy/CAR-T cell therapy.  JCAR017 is a CD19-specific CAR T cell therapy. It uses a defined CD4:CD8 cell composition and 4-1BB as the costimulatory domain, which differentiates it from other CD19-directed CAR T product candidates in clinical development.

Disease: relapsed/refractory B cell non-Hodgkin lymphoma (NHL)

Therapeutic area: Cancer - Oncology

Country: USA

Trial details:

• TRANSCEND NHL 001 is a dose-finding study of JCAR017, which is administered following fludarabine/cyclophosphamide lymphodepletion. Patients received one of two dose levels (50 or 100 million cells). They were then evaluated for pharmacokinetics, disease response, and safety outcomes, including common CAR T side effects such as cytokine release syndrome (CRS) and neurotoxicity (NT).(NCT02631044)

Latest news:

• • On December 12, 2017,  Juno Therapeutics highlighted presentations and data from the 59th American Society of Hematology (ASH) Annual Meeting and Exposition. During ASH, Juno also announced that JCAR017 had received the United States Adopted Name (USAN) lisocabtagene maraleucel (liso-cel). Data from the TRANSCEND study of JCAR017 (liso-cel) in patients with relapsed or refractory (r/r) aggressive B-cell non-Hodgkin lymphoma (NHL) were presented in an oral session by Dr. Jeremy Abramson, M.D. of Massachusetts General Hospital. Data were based on a cutoff date of October 9, 2017 and add to those disclosed on November 1, 2017 in Abstract #581. The core group includes patients with Diffuse Large B-Cell Lymphoma (DLBCL; NOS and transformed from follicular lymphoma) who are ECOG Performance Status 0-1. The full analysis group represents all r/r patients in the DLBCL cohort, which includes patients with poor performance status (ECOG Performance Status 2) or with niche subtypes of aggressive NHL. Enrollment of the pivotal cohort is ongoing with the core group at dose level 2, one of multiple previously evaluated doses.
• Key results: In the core group at dose level 2 (DL2=100 million cells), the data showed a 3 month overall response rate (ORR) of 74% (14/19) and a 3 month complete response (CR) rate of 68% (13/19). Of patients that have reached 6 months of follow-up, 50% (7/14) were in CR. Across doses, 80% (16/20) of patients in core group with CR at 3 months stayed in CR at 6 months, and 92% (11/12) of patients in response at 6 months remained in response as of the data cutoff date.
• In the core group, 1% (1/67) experienced severe cytokine release syndrome and 15% (10/67) experienced severe neurotoxicity. 58% (39/67) had no CRS or NT of any grade. In the full group, 1% (1/91) experienced severe CRS and 12% (11/91) experienced severe NT. 60% (55/91) had no CRS or NT of any grade.
• The most common treatment-emergent adverse events (TEAEs) other than CRS and NT that occurred at ?25% in the full group included neutropenia (49%), anemia (38%), fatigue (37%), thrombocytopenia (29%), nausea (27%), and diarrhea (25%). The most common TEAEs were similar between core and full groups.
• Juno believes JCAR017’s safety profile could enable outpatient administration. A biologics license application filing is expected to be completed in the second half of 2018, with approval as early as the end of 2018.   • On December 9, 2017, Juno Therapeutics presented new translational insights on clinical outcomes with JCAR017 at the 59thAmerican Society of Hematology (ASH) Annual Meeting and Exposition. Results from these exploratory analyses suggest that patient factors may impact safety and efficacy for DLBCL patients. These factors included:
• Baseline patient characteristics, including high tumor burden and markers of inflammation, were associated with high CAR T cell expansion and increased rates of cytokine release syndrome (CRS) and neurotoxicity (NT).
• Data showed an approximately 8-fold increased risk for CRS and NT in patients with high baseline tumor burden. Baseline markers of inflammation were associated with more durable responses; with respect to tumor burden the association was less pronounced.
• In a separate analysis, Howard Stern, M.D., Ph.D. of Juno Therapeutics, presented findings from ASH Abstract #194, examining JCAR017 infiltration into tumor tissue and exploring potential mechanisms of resistance and relapse. Results showed that JCAR017 CD4 and CD8 CAR T cells infiltrated tumors post-treatment. CAR T cell infiltration trended higher in patients who achieved a response. At disease progression, CAR T cells were rare or absent in tumor tissue despite the presence of CD19 and persistence of peripheral blood CAR T cells in most patients. There does not yet appear to be a singular resistance pathway upregulated in the tumor at the time of progression, but well-known pathways such as PD-L1 and IDO were upregulated in different patients. These data suggest that combinations with other immunotherapies may be beneficial to further improve outcomes with JCAR017 therapy. Juno and Celgene are conducting an ongoing combination trial with JCAR017 and durvalumab, an anti-PD-L1 antibody.
• • On June 17, 2017, Juno Therapeutics presented data from the TRANSCEND trial of JCAR017 in relapsed and refractory (r/r) aggressive B cell non-Hodgkin lymphoma (NHL) at the 2017 International Conference on Malignant Lymphoma in Lugano, Switzerland. Data were presented by Jeremy Abramson, M.D., of Massachusetts General Hospital Cancer Center, from the multicenter TRANSCEND trial (ABSTRACT #128), that has treated a total of 67 patients with r/r aggressive B cell NHL, including those with DLBCL or follicular lymphoma grade 3B, as of a data cutoff date of May 4, 2017.
• Notably, the TRANSCEND NHL 001 protocol includes patients with forms of B cell NHL that would exclude them from trials of other CAR T product candidates, including those with ECOG 2 performance status, central nervous system (CNS) involvement of their lymphoma, and those relapsed after allogeneic bone marrow transplant.
• Data for the DLBCL cohort were presented in two groups: core and full. The core analysis group (N=44) includes patients that represent the population that Juno plans to move forward into a pivotal trial in the second half of 2017. The core group includes patients with DLBCL (de novo and transformed from follicular lymphoma) that are ECOG Performance Status 0-1. The full analysis group includes all r/r patients in the DLBCL cohort (N=55), including 11 patients with poor performance status or niche subtypes of aggressive NHL. Both the core and full groups received conforming product, with at least one month follow-up, and with a data cutoff date of May 4, 2017, for this presentation.
• Core Group (N=44): Combining data across dose levels: Overall response rate (ORR) is 86% (38/44) and the complete response (CR) is 59% (26/44). Three-month ORR is 66% (21/32) and CR is 50% (16/32). Of patients in response at three months, 90% (9/10) continue in response at six months.
• Early data suggest a dose response relationship at three months:
• Dose level 1 (50 million cells) ORR is 58% (11/19) and CR is 42% (8/19).
• Dose level 2 (100 million cells) ORR is 78% (7/9) and CR is 56% (5/9).
• 97% (37/38) of responding patients are alive and in follow-up as of May 4, 2017.
• 2% (1/44) experienced severe CRS and 18% (8/44) experienced severe NT.
• 66% (29/44) did not experience any CRS or NT. No deaths were reported from CRS or NT.
• There was one Grade 5 adverse event of diffuse alveolar damage, which the investigator assessed as possibly related to fludarabine, cyclophosphamide, and JCAR017 treatment, occurring on day 23 in an 82-year-old subject who refused mechanical ventilation for progressive respiratory failure while neutropenic on growth factors and broad spectrum antibiotics and antifungals. This patient had no CRS and Grade 3 neurotoxicity resolution before the Grade 5 event.
• Full Dataset (N=55): Combining data across dose levels:
• Best ORR is 76% (41/54) and CR is 52% (28/54).
• Three-month ORR is 51% (21/41) and CR is 39% (16/41). 2% (1/55) experienced severe CRS and 16% (9/55) experienced severe NT. 60% (33/55) did not experience any CRS or NT. No deaths reported from CRS or NT.
• Early data do not suggest a dose toxicity relationship at the doses tested:
• Severe CRS rate is 3% (1/30) at dose level 1 and 0% (0/19) at dose level 2.
• Severe NT rate is 20% (6/30) at dose level 1 and 11% (2/19) at dose level 2.
• 11% (6/55) received tocilizumab and 24% (13/55) received dexamethasone. The most frequently reported treatment-emergent adverse events were neutropenia (35%), CRS (35%), and fatigue (31%). Manufacturing: Product was available for 98% (86/88) of patients apheresed. TRANSCEND patients receive product made at JuMP, Juno’s manufacturing facility in Bothell, Washington. Juno expects commercial production will be accomplished in less than 21 days, and Juno is investing in manufacturing infrastructure to enable a smooth prescribing experience with a reliable delivery time at market entry. • On June 5, 2017, Juno Therapeutics announced updated data from the TRANSCEND trial of JCAR017 in relapsed and refractory (r/r) aggressive B cell non-Hodgkin lymphoma (NHL) in a presentation at the 2017 Annual Meeting of the American Society for Clinical Oncology (ASCO). The data presented  by principal investigator Jeremy Abramson, M.D., of Massachusetts General Hospital Cancer Center, were from the multicenter TRANSCEND trial (ASCO Abstract #7513), a Phase 1 study that has treated 71 patients with r/r aggressive B cell NHL, including those with diffuse large B cell lymphoma (DLBCL), follicular lymphoma grade 3B, or mantle cell lymphoma (MCL).
• Two analysis groups were presented for the DLBCL cohort, core and full. The core analysis (N=44) includes patients that represent the population that will move forward into the upcoming pivotal trial, which will begin in the second half of 2017. This includes patients with DLBCL (de novo and transformed from follicular lymphoma) that are ECOG Performance Status 0-1. The full analysis represents all r/r patients in the DLBCL cohort (N=55), including the 11 patients with poor performance status or niche subtypes of aggressive NHL. Both analysis groups are with conforming product, with at least one month follow up, and with a data cutoff date of May 4, 2017, for this presentation.
• Core Group: Combining data across dose levels:
• Overall response rate (ORR) is 86% (38/44) and the complete response (CR) is 59% (26/44).
• Three-month ORR is 66% (21/32) and CR is 50% (16/32). Of three-month responders followed up at least six months, 90% (9/10) remain in response.
• Early data suggest a dose response relationship at three months:
• Dose level 1 (50 million cells) ORR is 58% (11/19) and CR is 42% (8/19).
• Dose level 2 (100 million cells) ORR is 78% (7/9) and CR is 56% (5/9).
• 97% (37/38) of responding patients are alive and in follow up as of May 4, 2017.
• 2% (1/44) experienced severe CRS and 18% (8/44) experienced severe NT.
• 66% (29/44) did not experience any CRS or NT. No deaths were reported from CRS or NT.
• There was one Grade 5 adverse event of diffuse alveolar damage, which the investigator assessed as related to fludarabine, cyclophosphamide, and JCAR017 treatment, occurring on day 23 in an 82-year-old subject who refused mechanical ventilation for progressive respiratory failure while neutropenic on growth factors and broad spectrum antibiotics and antifungals.
• Full Dataset: Combining data across dose levels:
• Best ORR is 76% (41/54) and CR is 52% (28/54).
• Three-month ORR is 51% (21/41) and CR is 39% (16/41). 2% (1/55) experienced severe CRS and 16% (9/55) experienced severe NT. 60% (33/55) did not experience any CRS or NT. No deaths reported from CRS or NT.
• Early data do not suggest a dose toxicity relationship at the doses tested:
• Severe CRS rate is 3% (1/30) at dose level 1 and 0% (0/19) at dose level 2.
• Severe NT rate is 20% (6/30) at dose level 1 and 11% (2/19) at dose level 2.
• 11% (6/55) received tocilizumab and 24% (13/55) received dexamethasone.
• The most frequently reported treatment-emergent adverse events were neutropenia (35%), CRS (35%), and fatigue (31%).
• • On December 5, 2016, Juno Therapeutics announced preliminary clinical data for JCAR017 in patients with relapsed or refractory (r/r) aggressive non-Hodgkin lymphoma (NHL) in a presentation at the 58th American Society of Hematology (ASH) Annual Meeting. In the multi-center Phase I trial (ASH Abstract #4192), led by principal investigator Jeremy Abramson of Massachusetts General Hospital Cancer Center, patients with r/r diffuse large B cell lymphoma (DLBCL), follicular lymphoma grade 3B or mantle cell lymphoma (MCL) were treated with fludarabine/cyclophosphamide (flu/cy) lymphodepletion and JCAR017. Key data include:
• ¤ In 22 safety-evaluable patients (19 r/r DLBCL, 1 follicular lymphoma grade 3B, and 2 MCL patients) treated at dose level 1, single-dose schedule, no severe cytokine release syndrome (sCRS) was observed. Grade 3-4 neurotoxicity was observed in 3/22 (14%) patients, all of whom received the steroid dexamethasone for neurotoxicity. A single patient received tocilizumab for early onset grade 2 CRS. The most frequently reported treatment-emergent adverse events were neutropenia (100%), decreased appetite (36%) and fatigue (32%).
• ¤ In 20 efficacy-evaluable patients with r/r DLBCL (N=19) and follicular lymphoma grade 3B (N=1) treated at dose level 1 (5x 10⁷ cells), single-dose schedule, the overall response was 16/20 (80%) and complete response (CR) was 12/20 (60%) patients.
• ¤ For DLBCL patients treated more than three months prior to the data cut-off date, 8/19 (42%) patients continue to experience an ongoing response.
• ¤ In dose level 2 (1x10⁸ cells), 2/2 (100%) patients evaluable for efficacy have a complete response, and no patients evaluable for safety to date (N=3) have had sCRS or grade 3-4 neurotoxicity.
• In addition, multiple patients had persistent cells at relapse, suggesting the potential for combination therapy to improve long-term outcomes. One of these patients subsequently achieved a second complete response after endogenous re-expansion of persistent T cells without second infusion. The Phase I TRANSCEND trial continues, enrolling more patients at dose levels 1 and 2. Juno intends to initiate a pivotal trial in the U.S. in patients with r/r DLBCL in 2017.
• • On June 4, 2016, Juno Therapeutics announced that a poster  on JCAR017 will be presented at the 52nd Annual Meeting of the American Society for Clinical Oncology (ASCO) in Chicago. Rebecca Gardner, M.D., of Seattle Children’s, announced results from Seattle Children’s Phase I study of JCAR017 in pediatric and young adults with CD19+ r/r ALL (n=42) demonstrating 39/42 (93%) patients experienced a complete remission, all of which were a CmR by flow cytometry. In patients who received the Flu/Cy preconditioning regimen, 14/14 (100%) achieved a complete remission and a CmR. sCRS was observed in 10/42 (24%) patients and Grade 3 or higher neurotoxicity was observed in 10/42 (24%) patients.
• • On June 29, 2015, Juno Therapeutics announced the FDA accepted the Company's investigational new drug (IND) application for JCAR017 for patients with relapsed/refractory (r/r) B cell non-Hodgkin lymphoma, or NHL. The IND enables Juno to initiate a multi-center Phase I trial exploring JCAR017 for r/r NHL, scheduled to begin in 2015, with the potential to advance to a registration trial in 2016. In collaboration with Seattle Children's Research Institute, Juno continues to investigate JCAR017 in pediatric patients with r/r acute lymphoblastic leukemia (ALL). Results of a Phase I study to date demonstrated 91 percent of patients achieved a complete remission, all of which were documented by flow cytometry. Adverse events were consistent with what has been previously reported. The results were presented in an oral presentation at the American Association for Cancer Research (AACR) Annual Meeting 2015 in Philadelphia.

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