A phase 1 trial of the HDAC inhibitor AR-42 in patients with multiple myeloma and T- and B-cell lymphomas

Abstract

Histone deacetylase inhibitors (HDACi) have proven activity in hematologic malignancies, and their FDA approval in multiple myeloma (MM) and T-cell lymphoma highlights the need for further development of this drug class. We investigated AR-42, an oral pan-HDACi, in a first-in-man phase 1 dose escalation clinical trial. Overall, treatment was well tolerated, no DLTs were evident, and the MTD was defined as 40 mg dosed three times weekly for three weeks of a 28-day cycle. One patient each with MM and mantle cell lymphoma demonstrated disease control for 19 and 27 months (ongoing), respectively. Treatment was associated with reduction of serum CD44, a transmembrane glycoprotein associated with steroid and immunomodulatory drug resistance in MM. Our findings indicate that AR-42 is safe and that further investigation of AR-42 in combination regimens for the treatment of patients with lymphoma and MM is warranted.

Trial registration: https://ichgcp.net/clinical-trials-registry/NCT01129193.

Keywords: Histone deacetylase inhibitor; lymphoma; multiple myeloma; pharmacokinetics; phase 1.

Conflict of interest statement

Declarations of Interest

The authors report no relevant conflicts of interest. Ohio State University holds the patent on the investigational drug AR-42 (US 10/597,022). The Office for Technology Licensing and Commercialization licensed AR-42 to Arno Therapeutics Inc. using the institution’s standard terms and conditions and approval process, in which no author participated.

AR-42 was generated at Ohio State University by Ching-Shih Chen PhD. Both the inventor and the university have the potential to benefit financially from AR-42 if the compound has clinical activity. None of the clinical investigators involved in this trial have personal potential to financially gain from the success of this program. To assure absence of conflict in assessment of response and attribution of toxicity, response and toxicity attribution were reviewed by CTEP prior to reporting results to mitigate institutional conflict of interest. Safety issues relative to dose increases and attribution of response were monitored by the Ohio State University Data Safety Monitoring Committee, Ohio State Phase 1 Data Safety Monitoring review committee, and the OSU Cancer Center IRB.

Figures

Figure 1

Top 10 most frequent adverse events during cycle 1 for all patients

Figure 2

Multiple myeloma patient response