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

NCT03590054

Description:

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.

Related Conditions:
  • Head and Neck Squamous Cell Carcinoma
  • Melanoma
  • Non-Small Cell Lung Carcinoma
  • Urothelial Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: 18956
  • SECONDARY ID: NCI-2018-01395
  • NCT ID: NCT03590054

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

Interventions

DrugSynonymsArms
AbexinostatTreatment (abexinostat, pembrolizumab)
PembrolizumabTreatment (abexinostat, pembrolizumab)

Purpose

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.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (abexinostat, pembrolizumab)ExperimentalParticipants receive abexinostat PO BID on days 1-21 and pembrolizumab IV on over 30 minutes day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
  • Abexinostat

Eligibility Criteria

        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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximally Tolerated Dose
Time Frame:Up to 21 days
Safety Issue:
Description: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.

Secondary Outcome Measures

Measure:Immune-modified ORR
Time Frame:Up to 2 years
Safety Issue:
Description:Objective response rate (ORR) by iRECIST. The criteria are identical to those of RECIST 1.1 but have been adapted to account for instances where an increase in tumor burden, or the appearance of new lesions, does not reflect true tumor progression. iRECIST requires the confirmation of progression and uses the terms iUPD (unconfirmed progression) and iCPD (confirmed progression).
Measure:Median Duration of Response (DoR)
Time Frame:Up to 2 years
Safety Issue:
Description:The duration of overall response is measured from the time measurement criteria are met for CR (complete response) or PR (partial response), whichever is first recorded, until the first date that recurrent or progressive disease is objectively documented.
Measure:Median DoR per iRECIST
Time Frame:Up to 2 years
Safety Issue:
Description:The duration of overall response is measured from the time measurement criteria are met for CR (complete response) or PR (partial response), whichever is first recorded, until the first date that recurrent or progressive disease is objectively documented. The criteria are identical to those of RECIST 1.1 but have been adapted to account for instances where an increase in tumor burden, or the appearance of new lesions, does not reflect true tumor progression. iRECIST requires the confirmation of progression and uses the terms iUPD (unconfirmed progression) and iCPD (confirmed progression).
Measure:Median Progression-Free Survival (PFS)
Time Frame:Up to 2 years
Safety Issue:
Description:PFS is defined as the time from the date of initiation of study treatment to the date measurement criteria are first met for radiographic PD or death from any cause, whichever occurs first.
Measure:Incidence of Adverse Events (AE)
Time Frame:Up to 2 years
Safety Issue:
Description:The incidences and percentages of patients experiencing each AE preferred term will be summarized by NCI-CTCAE version 4.03 grade.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Rahul Aggarwal

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