Abexinostat in Combination With Pembrolizumab in Patients With Advanced Solid Tumor Malignancies

NCT ID: NCT03590054

Last Updated: 2024-03-22

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 35 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2018-08-20
• Study Completion Date: 2023-11-30

Brief Summary

This phase I trial studies the best dose and side effects of abexinostat and how well it works with given together with pembrolizumab in treating participants with microsatellite instability (MSI) solid tumors that have spread to other places in the body. Abexinostat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as pembrolizumab, may interfere with the ability of tumor cells to grow and spread. Giving abexinostat and pembrolizumab may work better in treating participants with solid tumors.

Detailed Description

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.

Conditions

Stage III Cutaneous Melanoma; Stage IV Cutaneous Melanoma; Locally Advanced Melanoma; Locally Advanced Solid Neoplasm; Metastatic Head and Neck Squamous Cell Carcinoma; Metastatic Malignant Solid Neoplasm; Metastatic Melanoma; Metastatic Urothelial Carcinoma; Non-Small Cell Lung Carcinoma; Stage IB Lung Cancer AJCC v7; Stage III Cutaneous Squamous Cell Carcinoma of the Head and Neck AJCC v8; Stage III Lung Cancer AJCC v8; Stage III Ureter Cancer AJCC v8; Stage IIIA Lung Cancer AJCC v8; Stage IIIB Lung Cancer AJCC v8; Stage IIIC Lung Cancer AJCC v8; Stage IV Cutaneous Squamous Cell Carcinoma of the Head and Neck AJCC v8; Stage IV Lung Cancer AJCC v8; Stage IV Ureter Cancer AJCC v8; Stage IVA Lung Cancer AJCC v8; Stage IVB Lung Cancer AJCC v8

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Dose Escalation: (abexinostat, pembrolizumab)

Participants receive abexinostat PO BID on days -7 to -4 of the lead-in period, and days 1-4, 8-11 of each treatment cycle and pembrolizumab over 30 minutes on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Group Type: EXPERIMENTAL

Abexinostat

Intervention Type: DRUG

Given orally (PO) twice a day (BID) days 1-4, 8-11 of every 21 day cycle

Pembrolizumab

Intervention Type: BIOLOGICAL

Given IV on day 1 of every 21 day cycle

Cohort A: Dose Expansion (abexinostat, pembrolizumab)

Participants with primary resistance to prior anti-PD-1/PD-L1 will receive abexinostat PO BID on days -7 to -4 of the lead-in period, and days 1-4, 8-11 of each treatment cycle and pembrolizumab over 30 minutes on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Group Type: EXPERIMENTAL

Abexinostat

Intervention Type: DRUG

Given orally (PO) twice a day (BID) days 1-4, 8-11 of every 21 day cycle

Pembrolizumab

Intervention Type: BIOLOGICAL

Given IV on day 1 of every 21 day cycle

Cohort B: Dose Expansion (abexinostat, pembrolizumab)

Participants with acquired resistance, defined as treatment duration on prior CPI for greater than 6 months with evidence of clinical benefit (tumor regression or disease stabilization) with subsequent disease progression will receive abexinostat PO BID on days -7 to -4 of the lead-in period, and days 1-4, 8-11 of each treatment cycle and pembrolizumab over 30 minutes on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Group Type: EXPERIMENTAL

Abexinostat

Intervention Type: DRUG

Given orally (PO) twice a day (BID) days 1-4, 8-11 of every 21 day cycle

Pembrolizumab

Intervention Type: BIOLOGICAL

Given IV on day 1 of every 21 day cycle

Interventions

Abexinostat

Given orally (PO) twice a day (BID) days 1-4, 8-11 of every 21 day cycle

Intervention Type: DRUG

Pembrolizumab

Given IV on day 1 of every 21 day cycle

Intervention Type: BIOLOGICAL

Other Intervention Names

PCI-24781; Keytruda

Eligibility Criteria

Inclusion Criteria

• Patient >= 18 years of age at the time of study enrollment.
• 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
• Small cell lung cancer
• Non-pulmonary squamous cell carcinoma
• 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 Amendments (CLIA)-approved next generation sequencing test.
• Gastric and gastro-esophageal junction adenocarcinoma
• Merkel cell carcinoma
• Thymic carcinoma
• Mesothelioma
• 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 anti-PD-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, 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.
• Has adequate baseline organ function, as demonstrated by the following:

• Serum creatinine =< 1.5 x institutional upper limit of normal (ULN) or calculated creatinine clearance > 50 mL/min
• Total bilirubin =< 1.5 x institutional upper limit of normal (ULN)
• 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 5) 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 (non-infectious) pneumonitis/interstitial lung disease that required steroids or current pneumonitis/ interstitial lung disease
• 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 histone deacetylase (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.
• Use of prohibited medication within 7 days or 5 half-lives, whichever is shorter, prior to first dose of study drug

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Xynomic Pharmaceuticals, Inc.

INDUSTRY

Sponsor Role: collaborator

Rahul Aggarwal

OTHER

Sponsor Role: lead

Responsible Party

Rahul Aggarwal

Assistant Professor of Hematology/Oncology

Responsibility Role: SPONSOR_INVESTIGATOR

Principal Investigators

Rahul Aggarwal, MD

Role: PRINCIPAL_INVESTIGATOR

University of California, San Francisco

Locations

University of California, San Francisco

San Francisco, California, United States

Countries

United States

Other Identifiers

NCI-2018-01395

Identifier Type: REGISTRY

Identifier Source: secondary_id

18956

Identifier Type: -

Identifier Source: org_study_id