A Phase 1/2 Study of HDAC Inhibitor, Mocetinostat, in Combination With PD-L1 Inhibitor, Durvalumab, in Advanced or Metastatic Solid Tumors and Non Small Cell Lung Cancer

Description

Advanced tumors evade host immune responses by down regulation of major histocompatibility complex (MHC) molecules and tumor antigens and by creating an immune suppressive microenvironment around the tumor. Histone deacetylases (HDACs) have been implicated in the epigenetic regulation of innate and adaptive immunity. Increasing evidence supports the proposal that spectrum-selective inhibitors of class I HDACs can reverse immune evasion and elicit antitumor host response through immunostimulatory mechanisms. The immunomodulatory properties of class I HDAC inhibitors are reported to be mediated through multiple mechanisms including: 1) induction of programmed cell death ligand 1 (PD-L1) expression on the tumor cell surface, 2) induction of tumor associated antigens (TAAs) and MHC Class I and Class II molecules on tumor cells, 3) induction of immunogenic cell death via activation and cross presentation of tumor antigens by antigen presenting cells (APCs), 4) enhanced function of T effector cells, and 5) decreased function of immunosuppressive cell subsets including T regulatory (Treg) cells and myeloid-derived suppressor cells (MDSCs). In addition, HDAC inhibitors are associated with anticancer effects through inhibiting cell cycle progression and inducing apoptosis in tumor. The combination of a class I HDAC inhibitor with an anticancer immunotherapy has the potential to enhance activity over that observed with either agent alone. Mocetinostat is a spectrum-selective Class I/IV HDAC inhibitor specifically targeting HDACs 1, 2, 3 and 11. Class I and IV HDACs are of particular interest from an immunostimulatory and immune priming perspective. Durvalumab is a human monoclonal antibody (MAb) that inhibits binding of PD-L1 to programmed cell death 1 (PD-1) and CD80 expressed on host immune effector cells, preventing immune suppression signaling. Durvalumab is being developed as a potential anticancer therapy for patients with advanced solid tumors or hematological malignancies. In this study, the treatment regimen will begin with a 7-Day Lead-in Period of mocetinostat followed by start of the combination regimen of mocetinostat and durvalumab. The Recommended Phase 2 Dose (RP2D) of mocetinostat will be established in the Phase 1 dose escalation segment, followed by evaluation of the clinical activity of the combination regimen in patients having NSCLC.

Tumor PD-L1 expression will be determined by the PD-L1 (SP263) CDx assay. No/low PD-L1 expression is defined as positivity < 25% of tumor cells; high PD-L1 expression is defined as positivity ≥25% of tumor cells. Tumor samples used to establish PD-L1 expression for eligibility must have been collected after the most recent systemic therapy.

The sample sizes for the populations to be enrolled in the Phase 2 portion of the study are based on two-stage Simon Optimal Designs.

• Cohorts 1, 3 and 4: Stage 1 of enrollment will include 9 patients. If at least 1 patient having objective response is observed, 8 additional patients will be enrolled, for a total sample size of 17 patients. If at least 3 objective responses are observed, further investigation may be warranted.
• Cohort 2: Stage 1 of enrollment will include 17 patients. If at least 6 patients having objective response are observed, 27 additional patients will be enrolled, for a total sample size of 44 patients. If at least 17 objective responses are observed, further investigation may be warranted.

The populations included in Cohorts 3 and 4, who have had progression of disease during or following treatment with a checkpoint inhibitor, represent a potential unmet medical need. For this reason, if results in Stage 2 of enrollment are of high interest, enrollment may be expanded to as many as 100 patients total in each cohort to narrow the 95% Confidence Interval (CI) around the ORR point estimate and more fully characterize the secondary endpoints in the population of interest.

Disease response and progression as documented by the investigator in the Case Report Form (CRF) will be the basis for patient management and study expansion decision making. Unconfirmed objective responses recorded in the CRF may be used as the initial basis for expansion of study enrollment; however, follow-up evaluations on patients with unconfirmed responses must continue to support the decision to continue to the full number of patients to be included in the next stage. Central radiology review for disease response and progression may be added to the study during Stage 2. If this occurs, central review of all radiologic assessments performed in the study will be expected (including retrospective review of patients enrolled in Stage 1), and central radiology review for disease response will be the basis for the primary statistical analyses to estimate the objective response rate and its confidence interval, as well as the duration of response and PFS.

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