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

NCT03590054 | Completed Phase 1 DMC FDA Drug

• 2 other identifiers: 18956NCI-2018-01395
• Study Type: interventional
• Target: 35
• Locations: 1 country
• Sites: 1

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.

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

Outcome Measures

Primary Outcomes (2)

• Maximally Tolerated Dose (MTD)

  Starting at dose level 1, if 2/3 patients have a dose-limiting toxicity (DLT), the dose will be de-escalated to dose -1. If 0/3 patients experience a DLT, 3 patients will be treated at the next dose level. If DLT attributable to the treatment is experienced in 1/3 patients, three more patients (for a total of six patients) will be treated at that dose level. If no additional DLTs are observed at the expanded dose level (i.e. 1/6 with DLT), the dose will be escalated. Escalation will terminate as soon as two or more patients experience any DLT attributable to study drugs, at a given dose level. If de-escalation is necessary, 3 patients will be enrolled on the next lower dose cohort. If 1 or less DLTs is observed in this cohort, this will be the MTD.

  Up to 21 days

• Objective Response Rate (ORR)

  Objective response rate (ORR) by RECIST 1.1 criteria in patients treated with abexinostat in combination with (CPI) immune checkpoint inhibition in patients with prior primary or acquired resistance to prior CPI treatment.

  Up to 2 years

Secondary Outcomes (5)

• Immune-modified Objective response rate (ORR)

  Up to 2 years

• Median Duration of Response (DoR)

  Up to 2 years

• Median DoR per iRECIST

  Up to 2 years

• Median Progression-Free Survival (PFS)

  Up to 2 years

• Percentage of participants reporting treatment-related Adverse Events (AE)

  Up to 2 years

Study Arms (3)

Dose Escalation: (abexinostat, pembrolizumab)

EXPERIMENTAL

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.

Drug: Abexinostat; Biological: Pembrolizumab

Cohort A: Dose Expansion (abexinostat, pembrolizumab)

EXPERIMENTAL

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.

Drug: Abexinostat; Biological: Pembrolizumab

Cohort B: Dose Expansion (abexinostat, pembrolizumab)

EXPERIMENTAL

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.

Drug: Abexinostat; Biological: Pembrolizumab

Interventions

Abexinostat DRUG

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

Also known as: PCI-24781

Cohort A: Dose Expansion (abexinostat, pembrolizumab); Cohort B: Dose Expansion (abexinostat, pembrolizumab); Dose Escalation: (abexinostat, pembrolizumab)

Pembrolizumab BIOLOGICAL

Given IV on day 1 of every 21 day cycle

Also known as: Keytruda

Cohort A: Dose Expansion (abexinostat, pembrolizumab); Cohort B: Dose Expansion (abexinostat, pembrolizumab); Dose Escalation: (abexinostat, pembrolizumab)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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:

You may not qualify if:

• 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.

Sponsors & Collaborators

• Rahul Aggarwal: lead
• Xynomic Pharmaceuticals, Inc.: collaborator

Study Sites (1)

University of California, San Francisco

San Francisco, California, 94143, United States

Location

MeSH Terms

Conditions

Melanoma; Squamous Cell Carcinoma of Head and Neck; Neoplasm Metastasis; Carcinoma, Transitional Cell; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Ureteral Neoplasms

Interventions

abexinostat; pembrolizumab

Condition Hierarchy (Ancestors)

Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Nerve Tissue; Nevi and Melanomas; Skin Neoplasms; Neoplasms by Site; Skin Diseases; Skin and Connective Tissue Diseases; Carcinoma, Squamous Cell; Carcinoma; Neoplasms, Glandular and Epithelial; Head and Neck Neoplasms; Neoplastic Processes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Lung Diseases; Respiratory Tract Diseases; Urologic Neoplasms; Urogenital Neoplasms; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Ureteral Diseases; Urologic Diseases; Male Urogenital Diseases

Study Officials

• Rahul Aggarwal, MD

  University of California, San Francisco

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Assistant Professor of Hematology/Oncology

Study Record Dates

• First Submitted: July 5, 2018
• First Posted: July 18, 2018
• Study Start: August 20, 2018
• Primary Completion: November 30, 2023
• Study Completion: November 30, 2023
• Last Updated: March 22, 2024

Record last verified: 2024-03

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)