A Phase 1b Dose Escalation/Expansion Study of Abexinostat in Combination With Pembrolizumab in Patients With Advanced Solid Tumor Malignancies

PRIMARY OBJECTIVES:

I. To determine the maximally tolerated and recommended phase 2 dose of abexinostat in
combination with anti-PD-1/PD-L1 checkpoint inhibitor (CPI). (Dose escalation)

II. To determine the objective response rate (ORR) by Response Evaluation Criteria in Solid
Tumors (RECIST) 1.1 criteria in patients treated with abexinostat in combination with CPI in
patients with prior primary (cohort A) or acquired (cohort B) resistance to prior CPI
treatment. (Dose expansion)

SECONDARY OBJECTIVES:

I. To determine the objective response rate and median duration of response (DoR) by immune
modified (i)RECIST criteria.

II. To determine the median progression-free survival (PFS).

III. To further characterize the safety profile of the treatment combination.

OUTLINE: This is a dose-escalation study of abexinostat.

Participants receive abexinostat orally (PO) twice daily (BID) on days 1-21 and pembrolizumab
intravenously (IV) on over 30 minutes day 1. Courses repeat every 21 days in the absence of
disease progression or unacceptable toxicity.

After completion of study treatment, participants are followed up for 90 days.

Inclusion Criteria:

- Has histologically confirmed locally advanced or metastatic solid tumor malignancy
with one of the following tumor types:

- Urothelial carcinoma

- Melanoma

- Non-small cell lung cancer

- Head and neck squamous cell carcinoma

- MSI-high solid tumor, with MSI-high status defined by microsatellite instability
testing by polymerase chain reaction (PCR), loss of mismatch repair proteins by
immunohistochemistry (IHC), or Clinical Laboratory Improvement Act
(CLIA)-approved next generation sequencing test.

- Measurable disease by RECIST 1.1 criteria.

- Dose Expansion only:

- Disease progression during or within 3 months of last dose of most recent line of
prior antiPD-1/PD-L1-based treatment with a pattern of progression as defined as
one of the following:

- Primary Resistance (Cohort A): Progressive disease as best response to prior
treatment with anti-PD-1/PD-L1 treatment

- Acquired Resistance (Cohort B): Stable disease > 6 months, partial response
or complete response to prior anti-PD-1/PD-L1 treatment with subsequent
disease progression during or within 3 months following last dose of
anti-PD-1/PD-L1 treatment

- A tumor biopsy is mandatory unless

- There is no safely accessible lesion, OR

- Archival metastatic tumor tissue is available with sufficient quantity that
was obtained following the last dose of most recent systemic therapy.

- Has Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.

- Serum creatinine =< 1.5 x institutional upper limit of normal (ULN) or calculated
creatinine clearance > 50 mL/min

- Serum bilirubin =< 1.5 mg/dL.

- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x
institutional ULN (patients with hepatic metastases must have AST/ALT =< 5 x ULN).

- Absolute neutrophil count (ANC) >= 1.5 x 10^9/L.

- Hemoglobin >= 8 g/dL.

- Platelet count >= 75 x 10^9/L.

- Agrees to use acceptable contraceptive methods for the duration of time on the study,
and continue to use acceptable contraceptive methods for 6 months (after the last
treatment with study treatment.

- Has provided signed informed consent before initiation of any study-specific
procedures or treatment.

- Men treated or enrolled on this protocol must agree to use adequate contraception the
duration of study participation and 3 months after completion of study drug
administration.

Exclusion Criteria:

- Has persistent clinically significant toxicities (grade >= 2; per National Cancer
Institute Common Terminology Criteria for Adverse Events [NCI CTCAE] version 4.03)
from previous anticancer therapy (excluding alopecia which is permitted and excluding
grades 2 and 3 laboratory abnormalities if they are not associated with symptoms, are
not considered clinically significant by the Investigator, and can be managed with
available medical therapies).

- Has a history of grade >= 3 (non-infectious) pneumonitis (interstitial lung disease)
or current grade >= 1 pneumonitis.

- Has a diagnosis of clinically significant immunodeficiency.

- Has received external-beam radiation or another systemic anticancer therapy within 14
days or 5 half-lives (whichever is shorter) before start of study treatment.

- Has received treatment with an investigational drug or monoclonal antibody within 28
days prior to study treatment administration. For classes of investigational agents
that are not known to have prolonged toxicities, the washout time may be decreased to
14 days at the discretion of the principal investigator.

- Has received previous treatment with a HDAC inhibitor.

- Has an additional active malignancy that may confound the assessment of the study
endpoints. Patients with the following concomitant neoplastic diagnoses are eligible:
nonmelanoma skin cancer and carcinoma in situ including transitional cell carcinoma,
anal carcinoma, and melanoma in situ).

- Has clinically significant cardiovascular disease including, but not limited to:

- Uncontrolled or any New York Heart Association class 3 or 4 congestive heart
failure

- Uncontrolled angina, history of myocardial infarction, unstable angina or stroke
within 6 months before study entry

- Clinically significant arrhythmias not controlled by medication.

- Has a history of untreated brain, or leptomeningeal, metastases (central nervous
system [CNS] imaging is not required before study entry unless there is a clinical
suspicion of CNS involvement).Subjects with previously treated brain metastases may
participate provided:

- They are stable (without evidence of progression by imaging for at least four
weeks and any neurologic symptoms have returned to baseline)

- They have no evidence of new or enlarging brain metastases (confirmed by imaging
within 28 days of the first dose of study drug)

- They are not using steroids for at least 7 days before the first dose of study
drug.

This exception does not include leptomeningeal metastases, which is excluded regardless of
clinical stability.

- Has a condition requiring systemic treatment with either corticosteroids (> 10 mg
daily prednisone equivalents) or other immunosuppressive medications within 14 days
before study treatment.

- Has uncontrolled intercurrent illness including, but not limited to:

- Uncontrolled infection

- Disseminated intravascular coagulation

- Psychiatric illness/social situations that would limit compliance with study
requirements.

- Has known history positive status for human immunodeficiency virus or chronic active
hepatitis B or hepatitis C (screening not required).

- Has any medical condition which in the opinion of the Investigator places the patient
at an unacceptably high risk for toxicities.