Pembrolizumab + Defactinib In Pleural Mesothelioma

NCT04201145 | Withdrawn Phase 1 DMC FDA Drug

• 1 other identifier: 19-736
• Study Type: interventional
• Target: N/A
• Locations: 1 country
• Sites: 2

Brief Summary

This research study is studying a new drug combination of Pembrolizumab and Defactinib followed by surgical resection possible treatment for resectable Malignant Pleural Mesothelioma (MPM). The names of the study drugs involved in this study are:

• Pembrolizumab
• Defactinib

Conditions

Malignant Pleural Mesothelioma

Keywords

Malignant Pleural Mesothelioma

Outcome Measures

Primary Outcomes (2)

• Maximum Tolerated Duration (MTD)

  standard 3+3 design to determine the maximum tolerated duration (MTD) of oral defactinib when combined with 2 cycles of pembrolizumab

  56 days

• Biomarker activity in response to the MTD of defactinib in combination with pembrolizumab

  Pre- versus post-treatment changes may be analyzed using the sign test or Wilcox on signed-rank test to assess whether the biomarker distribution has changed following treatment.

  56 days

Secondary Outcomes (2)

• Number of Participants with Dose Limiting Toxcities

  56 Days

• Response Rate

  56 Days

Study Arms (4)

Run in cohort: pembrolizumab only

EXPERIMENTAL

Treatment with pembrolizumab as a single agent for 56 days \- 2 doses during treatment cycle, intravenous, at predetermined protocol dose

Drug: Pembrolizumab

Cohort 1: pembrolizumab + defactinib 12 days

EXPERIMENTAL

Treatment with Defactinib in combination with Pembrolizumab for 12 days * Defactinib oral, twice daily, per predetermined dose for 12 days of treatment in combination * Pembrolizumab via infusion, twice per cycle, per predetermined dose

Drug: Pembrolizumab; Drug: Defactinib

Cohort 2: pembrolizumab + defactinib 35 days

EXPERIMENTAL

Treatment with defactinib in combination with pembrolizumab to 35 days * Defactinib oral, twice daily, per predetermined dose for 35 days of treatment in combination * Pembrolizumab via infusion, twice per cycle, per predetermined dose

Drug: Pembrolizumab; Drug: Defactinib

Expansion cohort

EXPERIMENTAL

Tolerated phase IA regimen will be administered in a phase IB expansion cohort

Drug: Pembrolizumab; Drug: Defactinib

Interventions

Pembrolizumab DRUG

IV, predetermined dosage, twice per cycle

Also known as: Keytruda®

Cohort 1: pembrolizumab + defactinib 12 days; Cohort 2: pembrolizumab + defactinib 35 days; Expansion cohort; Run in cohort: pembrolizumab only

Defactinib DRUG

Defactinib oral, twice daily, per predetermined dose and predetermined duration as defined by cohort

Also known as: PF-04554878

Cohort 1: pembrolizumab + defactinib 12 days; Cohort 2: pembrolizumab + defactinib 35 days; Expansion cohort

Eligibility Criteria

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

You may qualify if:

• Participant must have histologically confirmed malignant pleural mesothelioma that is not metastatic or unresectable
• Be willing and able to provide written informed consent/assent to the trial.
• Be ≥ 18 years of age on day of signing informed consent.
• Have measurable disease based on modified RECIST 1.1.
• Be willing to provide tissue from a newly obtained core or excisional biopsy of a tumor lesion. Newly-obtained is defined as a specimen obtained up to 6 weeks (42 days) prior to initiation of treatment on Day 1. Subjects for whom newly-obtained samples cannot be provided (e.g. inaccessible or subject safety concern) may submit an archived specimen only upon agreement from the Investigator Sponsor.
• Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. Evaluation of ECOG is to be performed within 7 days prior to the date of allocation/randomization.
• Demonstrate adequate organ function as defined. If screening hematology and clinical chemistry tests are performed within 10 days of Day 1, they need not be repeated at Day
• Adequate Organ Function Laboratory Values
• Absolute neutrophil count (ANC) ≥1,500 /mcL
• Platelets ≥100,000 / mcL
• Hemoglobin ≥9 g/dL or ≥5.6 mmol/L without transfusion or EPO dependency (\>2 days from assessment)
• Serum creatinine OR Measured or calculateda creatinine clearance (GFR can also be used in place of creatinine or CrCl) ≤1.5 X upper limit of normal (ULN) OR
• ≥60 mL/min for subject with creatinine levels \> 1.5 X institutional ULN
• Serum total bilirubin ≤ 1.5 X ULN OR Direct bilirubin ≤ ULN for subjects with total bilirubin levels \> 1.5 ULN
• AST (SGOT) and ALT (SGPT) ≤ 2.5 X ULN OR ≤ 5 X ULN for subjects with liver metastases

You may not qualify if:

• The subject must be excluded from participating in the trial if the subject:
• Is currently participating or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment.
• Has a diagnosis of immunodeficiency including diagnosis of infection with Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies) or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment.
• Hypersensitivity to pembrolizumab or any of its excipients.
• Hypersensitivity to defactinib.
• Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to monoclonal antibody administered more than 4 weeks earlier.
• Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to a previously administered treatment.
• Note: Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and may qualify for the study.
• Note: If subject underwent major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy.
• Has a known additional malignancy that is progressing or requires active treatment. Exceptions include in situ cervical cancer and basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy.
• History of upper gastrointestinal bleeding, ulceration, or perforation within 12 months prior to the first dose of study drug.
• Known history of Gilbert's Syndrome or any current hyperbilirubinemia of any cause.
• Known history of stroke or cerebrovascular accident within 6 months prior to the first dose of study drug.
• Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis, or has previously treated brain metastases.
• Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.

Sponsors & Collaborators

• Raphael Bueno, MD: lead
• Merck Sharp & Dohme LLC: collaborator

Study Sites (2)

Brigham and Women's Hospital

Boston, Massachusetts, 02115, United States

Location

Dana Farber Cancer Institute

Boston, Massachusetts, 02115, United States

Location

MeSH Terms

Conditions

Mesothelioma, Malignant

Interventions

pembrolizumab; defactinib

Condition Hierarchy (Ancestors)

Mesothelioma; Adenoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Mesothelial; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Pleural Neoplasms; Lung Diseases; Respiratory Tract Diseases

Study Officials

• Raphael Bueno, MD

  Brigham and Women's Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Sponsor Investigator

Study Record Dates

• First Submitted: December 13, 2019
• First Posted: December 17, 2019
• Study Start: September 1, 2020
• Primary Completion: December 31, 2021
• Study Completion: December 31, 2022
• Last Updated: November 17, 2020

Record last verified: 2020-11

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: Data can be shared no earlier than 1 year following the date of publication
• Access Criteria: Contact the Partners Innovations team at http://www.partners.org/innovation

Locations

US (2)