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.