TG02, an Oral CDK9-Inhibitor, in Combination with Carfilzomib Demonstrated Objective Responses in Carfilzomib Refractory Multiple Myeloma Patients

Introduction:TG02 is an orally-bioavailable, multikinase inhibitor where the primary mechanism of action is through CDK9-dependent depletion of oncoproteins such as Mcl-1 and MYC.  Safety and efficacy results for multiple myeloma (MM) patients (pts) enrolled in this ongoing phase 1b study are presented. CDK9 inhibition potently suppresses Mcl-1 to induce durable apoptotic responses in lymphoma (Gregory GP, Leukemia, 2015). CDK9 dependence may represent a druggable vulnerability in lymphomas and myelomas with dysregulated MYC expression, although inhibition of both CDK9 and MYC/BRD4 may be required for apoptosis (Lu H et al, Elife, 2015).

 Methods: This open-label Phase 1b study enrolled MM pts that previously received ≥2 lines of therapy. The primary objective was to determine the maximum tolerated dose (MTD) of TG02 in combination with carfilzomib (TG02/ CFZ); key secondary objectives were anti-tumor activity and safety.  TG02 was administered once daily on days 1, 4, 8, 11, 15, 18 of a 28-day schedule (BIW). The TG02 starting dose was 150 mg; TG02 dosing was escalated in 50 mg increments up to 300 mg.  CFZ was dosed according to the Prescribing Information.  Responses were assessed using standard criteria.

 Results: Fourteen pts were enrolled for dose escalation and 10 pts were enrolled for the MTD cohort expansion. Patients were heavily pretreated: median 6 previous treatments [min 3; max 15] and 92% pts received CFZ in a prior regimen. Best response to previous therapy was progressive disease in 46% pts.  The MTD was 250 mg TG02 combined with CFZ.  Two dose-limiting toxicities were observed (including Grade (Gr) 4 sepsis and Gr 4 neutropenia), both on the 300 mg cohort.  The most common drug-related adverse events (AEs) were diarrhea (Gr 1-2: 71% Gr 3: 17%), nausea (Gr 1-2: 79%), vomiting (Gr 1-2: 50%), fatigue (Gr 1-2: 38%, Gr 3: 4%), anorexia (Gr 1: 21%), anemia (Gr 1-2: 4%, Gr 3: 17%) and thrombocytopenia (Gr 3: 8%, Gr 4: 13%). Six patients (25%) discontinued treatment due to an AE.  Serious AEs occurred in 50% pts; only acute renal failure and febrile neutropenia occurred in >1 pt (8% each).  The severity of AEs was similar to single agent TG02. The incidence of diarrhea was increased in the TG02/ CFZ administration (88% vs 67%) but the incidence of other AEs was similar to single agent TG02.  Fourteen pts administered TG02 at the MTD were evaluable for response. The overall response rate (≥PR) was 27%; the clinical benefit rate (≥MR) was 45% (1 very good partial response, 2 partial response and 2 minimal response).  All responders (MR or better) were CFZ-refractory in a previous treatment regimen.  Durable stable disease was observed in 27% pts.

 Conclusions:  The safety profile of TG02 BIW/ CFZ was similar to that of TG02 alone.  The most common drug-related AEs were diarrhea, nausea, and vomiting; grade 4 AEs were infrequent. Additional measures will be taken to improve gastrointestinal tolerability.  Objective responses were observed in CFZ-refractory pts. Enrollment of CFZ-refractory pts administered TG02 on a once-weekly schedule in combination with CFZ is continuing.  Based on promising preclinical data, analysis of Mcl-1 and MYC expression and correlation to clinical outcome will be performed.