Clinical Trial Results from the Subgroup of Lymphoma/CLL in a Phase 1 Study of ARQ 092, a Novel Pan AKT-Inhibitor
Authors: Harb Wael , Saleh Mansoor N. , Papadopoulos Kyriakos P , Chai Feng , Larmar Maria , Abbadessa Giovanni , Schwartz Brian , Tolcher Anthony 
Published: November 2019

Abstract
Background: ARQ 092 is an oral allosteric, potent and selective AKT inhibitor with in vitro and in vivo activity in solid and hematological tumors. ARQ 092-101, the first clinical trial of ARQ 092, has enrolled more than 100 subjects with advanced solid tumors or recurrent malignant lymphoma. As reported previously, the dose escalation portion of the study has been completed and two dosing schedules (intermittent and weekly), are recommended for phase 2 studies. The recommended phase 2 dose (RP2D) for the intermittent dosing schedule is 200 mg once daily (QD) (one week on, one week off) and for the weekly dosing schedule is 300 mg twice daily (BID) (one day on, six days off). [1, 2] Enrollment in an expansion cohort at RP2Ds is ongoing. Here we report the results from 11 subjects with lymphoma/CLL.
Material and Methods: Subjects with lymphoma/CLL have been enrolled and treated in the dose escalation and expansion cohorts with intermittent or weekly dosing schedule at the RP2Ds. Tumor responses for subjects with lymphoma were evaluated based on the Revised Response Criteria for Malignant Lymphoma. Adverse events were evaluated based on the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Blood samples were collected for PK analysis. Archival or biopsy tumor tissue samples were collected for genetic analysis.
Results: As of 15 Jun 2015, 11 subjects with lymphoma/CLL (73% male; median age 78 years; 5 follicular, 3 mantle cell, 2 diffuse large B cell, 1 CLL; 4 in dose escalation cohorts, 7 in expansion cohort) have been enrolled and treated at initial doses of 120 to 270 mg QD intermittently (n=7) or 300 mg BID weekly (n=4). All subjects have received at least one prior systemic therapy (median 2, range 1-6).
Median duration on study treatment for all 11 subjects was 8 weeks (range 1 to 30 weeks).
One subject with CLL and two with follicular lymphoma experienced durable partial responses, respectively with times to response of 8, 8 and 24 weeks and response durations of 16, 8+, and 2+ weeks. The two follicular PR subjects, one of whom had an AKT1 (E17K) mutation, remain on study treatment. In addition, one subject with follicular and one with mantle cell lymphoma experienced stable diseases. Four subjects experienced progressive diseases and two were not evaluable for tumor responses due to early consent withdrawal and clinical disease progression.
Table 1. Common drug-related adverse events (≥10%) included macula-papular rash 45%, hyperglycemia 36%, mucosal inflammation 18% and stomatitis 18%. Response Follicular N=5 CLL N=1 Mantle cell N=3 Diffuse large B cell N=2 Total N=11 PR 2 1 3 SD 1 1 2 PD 1 2 1 4 NE 1 1 2 ORR 40% 100% 0% 0% 27% DCR 60% 100% 33% 0% 45%
Conclusions: The safety profile of lymphoma subjects is consistent with subjects with solid tumors enrolled in this study. Preliminary signs of single agent activity have been documented with 3 PRs in heavily pretreated lymphoma/CLL including one with AKT1 (E17K) mutation.
[1] First-in-human study with ARQ 092, a novel pan AKT-inhibitor: Results from the advanced solid tumors cohorts. M. Saleh et al., Abstract LB-197, AACR 104th Annual Meeting, 6-10 Apr 2013. Washington, D.C. U.S.
[2] First-in-human study with ARQ 092, a novel pan AKT-inhibitor, in subjects with advanced solid tumors or recurrent malignant lymphoma. M. Saleh et al., Abstract 320, EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics , 18-21 Nov 2014, Barcelona, Spain

Disclosures
Harb: Onyx Pharmaceuticals: Consultancy. Chai:ArQule, Inc.: Employment. Larmar:ArQule, Inc.: Employment. Abbadessa:ArQule, Inc.: Employment. Schwartz:ArQule, Inc.: Employment.