On June 17, 2017 Juno Therapeutics, Inc. (NASDAQ: JUNO), a biopharmaceutical company developing innovative cellular immunotherapies for the treatment of cancer, today reported 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 (Press release, Juno, JUN 17, 2017, View Source [SID1234519575]).

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JCAR017 is Juno’s investigative chimeric antigen receptor (CAR) T cell product candidate that targets CD19, a protein expressed on the surface of almost all B cell malignancies, and uses a defined composition of CD4 to CD8 T cells and a 4-1BB costimulatory domain, which differentiates it from other current CD19-directed CAR T product candidates. JCAR017 has been granted Breakthrough Therapy designation by the FDA for treatment of r/r aggressive large B cell NHL and PRIME designation by the European Medicines Agency for treatment of r/r diffuse large B cell lymphoma (DLBCL), a type of NHL.

"We are pleased to again present TRANSCEND data, which show compelling results in the treatment of aggressive relapsed or refractory NHL," said Sunil Agarwal, M.D., Juno’s President of Research and Development. "High rates of durable responses and the early survival data are especially exciting, as is the emerging safety profile. The majority of TRANSCEND patients experienced no cytokine release syndrome or neurotoxicity at all. While still early, these data suggest that JCAR017 could be administered on an outpatient basis."

Data were presented by Jeremy Abramson, M.D., of Massachusetts General Hospital Cancer Center, from the multicenter TRANSCEND trial (ABSTRACT #128), a Phase 1 study 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.

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).

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.

"CAR T cell therapy represents an important step forward in providing options for these highly chemotherapy refractory patients and addresses a significant unmet medical need," said Dr. Abramson. "I am particularly excited about the emerging efficacy and safety profile with JCAR017, which could ultimately prove to be optimal therapy for patients with relapsed and refractory DLBCL."

Key data and findings:
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.

About Juno’s Chimeric Antigen Receptor (CAR) and T Cell Receptor (TCR) Technologies
Juno’s CAR and TCR technologies genetically engineer T cells to recognize and kill cancer cells. Juno’s CAR T cell technology inserts a gene for a particular CAR into the T cell, enabling it to recognize cancer cells based on the expression of a specific protein located on the cell surface. Juno’s TCR technology provides the T cells with a specific T cell receptor to recognize protein fragments derived from either the surface or inside the cell. When either type of engineered T cell engages the target protein on the cancer cell, it initiates a cell-killing response against the cancer cell. JCAR014 and JCAR017 are investigational product candidates and their safety and efficacy have not been established.