A Phase I/II Open-Label Multicenter Study Of The Cyclin Kinase Inhibitor AT7519M Alone and In Combination With Bortezomib In Patients With Previously Treated Multiple Myeloma
Authors: Raje Noopur , Hari Parameswaran N. , Landau Heather , Richardson Paul G. , Rosenblatt Jacalyn , Couture Nicole , Lyons John F. , Langford Gillian , Yule Murray 
Published: October 2019

Background

The benefits of targeting the cyclins and RNAPII transcription in multiple myeloma (MM) was previously demonstrated using the cyclin kinase inhibitor AT7519 in preclinical studies. Predicated upon this work, a phase I/II trial was undertaken in relapsed refractory MM patients

Purpose

To identify the optimum dose of the AT7519M both as a single agent (Part one) and in combination with Bortezomib (Part two) in patients with MM.

Methods

In Part one nine patients with relapsed or refractory MM were treated with AT7519M alone using a twice weekly regimen (days one, four, eight and eleven) of a 21 day cycle. The starting dose of AT7519M was 21 mg/m2 per dose during Cycle one, and provided treatment was well tolerated the dose was escalated to 27 mg/m2 per dose for Cycle two onwards. In the second part of the study the safety and tolerability of the combination of AT7519M (dose levels 14 and 21 mg/m2 per dose) with Bortezomib (dose levels 1 and 1.3 mg/m2 per dose) were explored in an escalating fashion using a “3 + 3” design. In order to be eligible patients must have measurable MM, and initially must have had progressed through at least two previous lines of therapy or following a protocol amendment, been refractory to Bortezomib, as defined by progression on a Bortezomib-containing regimen within six weeks of starting the study. Patients with significantly abnormal liver or renal function (creatinine clearance < 30 ml/min) or significant underlying neuropathy were excluded.

Results

The median number of cycles of treatment administered in the first part of the study (9 patients) was two (range two to four) and the best response to treatment was stable disease. Two patients discontinued treatment as a result of toxicity – one as a result of a persistent elevation in serum creatinine and the second as a consequence of Grade 3 fatigue. Two patients did not undergo a dose escalation to 27 mg/m2 as planned because of poor tolerability of the 21 mg/m2 dose (fatigue) or progressive disease. Pharmacokinetic analysis of the two dose levels revealed overlapping exposure and further evaluation of the 27 mg/m2 dose was not performed.

In the second part of the study, three patients per cohort, 9 patients in total, were treated at escalating AT7519/Bortezomib dose levels of 14 mg/m2/1 mg/m2; 21 mg/m2/1 mg/m2 21 mg/m2/1.3 mg/m2. The median number of previous regimens was 5 (range 2 – 6). Based on the investigator assessments at least one objective response was seen at each dose level (MR x1, PR x 2, VGPR x 1). The median number of cycles received was three (range one to 9; ongoing). There were no dose-limiting toxicities. The most commonly reported adverse events to date have been haematological in nature. There have been two adverse events ≥Grade 3 in severity (neutropenia, and dyspnea) considered to be at least possibly related to treatment.

Conclusions

Treatment with AT7519M was well tolerated in this patient population and full doses of this agent and Bortezomib were successfully achieved in combination. The maximum tolerated dose was 21 mg/m2 AT7519M and 1.3 mg/m2 Bortezomib. Although no significant efficacy was seen following treatment with AT7519M alone in this heavily pretreated patient population, the combination of AT7519M with Bortezomib achieved significant (33% ≥ PR) responses in a proportion of patients who were either pre-treated with or refractory to treatment with Bortezomib.

Disclosures:

Raje: Celgene, Millenium, Onyx, Amgen: Consultancy; Acetylon, Eli Lilly: Research Funding. Richardson:Millennium: The Takeda Oncology Company: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity’s Board of Directors or advisory committees; Johnson & Johnson: Membership on an entity’s Board of Directors or advisory committees; Britsol-Myers Squibb: Membership on an entity’s Board of Directors or advisory committees. Lyons:Astex Pharmaceuticals Inc.: Employment. Langford:Astex: Employment. Yule:Astex: Consultancy.