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First-in-class small molecule ONC201 in b-cell malignancies.
Background: ONC201 is an orally active first-in-class small molecule inducer of the integrated stress response (ISR). Both preclinical tumor sensitivity profiling and mechanism of action studies indicate that B-cell malignancies, including non-Hodgkin’s lymphomas (NHL) and multiple myeloma, are among the most ONC201-sensitive tumor types. The former is based on in vitro and in vivo efficacy evaluations of over 1,000 cancer cell lines and patient samples. The mechanistic congruency is based on PERK-independent induction of the ISR by ONC201 that promotes apoptosis through induction of the ATF4/CHOP signaling axis. Malignant B cells are highly susceptible to ISR-induced apoptosis due to elevated basal ER stress levels driven by immunoglobulin and oncogenic protein production. Methods: Based on these preclinical findings, there are two clinical trials evaluating single agent ONC201 in B-cell malignances. One trial is a phase I/II study in NHL. This study includes adult patients with relapsed and/or refractory mantle cell, diffuse large B-cell, and/or transformed large cell lymphomas who have received < 5 lines of prior therapy. The phase I part of trial is a 3 + 3 dose escalation of ONC201 to establish the recommended phase II dose (RP2D) with once every 1 or 3 week administration. Currently, 3 patients have been enrolled on a once every three-week schedule. Clinical trial information: NCT02420795
Abstracts by Hun Ju Lee:
Lenalidome in combination with rituximab for relapsed or refractory mantel cell lymphoma: Updated analysis of a phase 2 trial.Meeting: 2015 ASCO Annual Meeting | Abstract No: 8542
Comparison of fludarabine (F), cyclophosphamide (C), and rituximab (R) versus FCR plus bevacizumab (B) in relapse chronic lymphocytic leukemia (CLL).Meeting: 2012 ASCO Annual Meeting | Abstract No: 6598