http://orcid.org/0000-0002-0405-7480
While much progress has occurred in the treatment of relapsed and refractory (RR) hematologic malignancies eg. 4 new drugs were approved in 2015 for the treatment of RR multiple myeloma, unfortunately relapses remain common with progressively shorter remissions with increasing lines of therapy. In particular, frail elderly patients continue to have inferior outcomes. Therefore, there is still a dire need for safe/tolerable agents with novel mechanisms of action.
ONC201 is a first-in-class orally administered imipridone small molecule in Phase II trials [Citation1,Citation2], and here Prabhu et al. demonstrate single agent preclinical activity in hematologic malignancies [Citation3]. Even at low micromolar concentrations, dose and time dependent apoptosis was observed in leukemia, myeloma, and lymphoma cell lines. The apoptosis appeared to be p53 independent and associated with activation of the ATF4/CHOP-mediated integrated stress response (ISR) pathway. Clinically, pharmacokinetic results of phase 1 dose escalation studies have demonstrated ONC201 concentrations associated with preclinical activity can readily be attained in patients [Citation4]. Equally important, there has been a striking lack of toxicity during dose escalation Phase I and ongoing Phase II studies. Early evidence of activity in solid tumors such as high-grade glioma has already been noted [Citation5].
Given the complex genomic, epigenetic, and immunologic changes that accumulate in RR hematologic malignancies, rational combination therapy preferably based on pre-clinical supporting data, is often required to achieved sustained disease control. Prabhu et al. also demonstrate remarkable preclinical synergy both in-vitro and in-vivo with back bone therapies of hematologic disorders including cytarabine in leukemia and lymphoma, hypomethylating agents in leukemia, and proteasome inhibitors in lymphoma and myeloma – many of which also activate the ISR pathway. Preclinical synergy with lack of single agent toxicity makes ONC201 an ideal candidate for combination therapy.
These results form the basis for ongoing ONC201 single agent trials in several RR hematological malignancies, including acute leukemia (NCT02392572), lymphoma (NCT02420795), multiple myeloma (NCT02609230) and combination trial with dexamethasone in RR multiple myeloma (NCT02863991).
Disclosure statement
No potential conflict of interest was reported by the author(s).
References
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