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Pembrolizumab + Defactinib In Pleural Mesothelioma

Primary Purpose

Malignant Pleural Mesothelioma

Status
Withdrawn
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Pembrolizumab
Defactinib
Sponsored by
Raphael Bueno, MD
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Malignant Pleural Mesothelioma focused on measuring Malignant Pleural Mesothelioma

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • 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
    • International Normalized Ratio (INR) or Prothrombin Time (PT)-Activated Partial Thromboplastin Time (aPTT) ≤1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants

      ≤1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants

    • Creatinine clearance should be calculated per institutional standard.
  • Female subjects of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a negative serum pregnancy test will be required.
  • Female and male subjects of childbearing potential must be willing to use an adequate method of contraception

    • Contraception, for the course of the study through 120 days after the last dose of study medication.
    • Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.

Exclusion Criteria:

  • 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.
  • Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis. Has an active infection requiring systemic therapy.
  • Has a known history of active TB (Bacillus Tuberculosis)
  • Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.
  • Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
  • Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment.
  • Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.
  • Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected).
  • Has received a live vaccine within 30 days of planned start of study therapy.

    -- Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines, and are not allowed.

  • Has a known history of myocarditis

Sites / Locations

  • Brigham and Women's Hospital
  • Dana Farber Cancer Institute

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Experimental

Experimental

Experimental

Arm Label

Run in cohort: pembrolizumab only

Cohort 1: pembrolizumab + defactinib 12 days

Cohort 2: pembrolizumab + defactinib 35 days

Expansion cohort

Arm Description

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

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

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

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

Outcomes

Primary Outcome Measures

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
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.

Secondary Outcome Measures

Number of Participants with Dose Limiting Toxcities
NCI-CTCAE version 5.0
Response Rate
Modified RECIST criteria for mesothelioma

Full Information

First Posted
December 13, 2019
Last Updated
November 16, 2020
Sponsor
Raphael Bueno, MD
Collaborators
Merck Sharp & Dohme LLC
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1. Study Identification

Unique Protocol Identification Number
NCT04201145
Brief Title
Pembrolizumab + Defactinib In Pleural Mesothelioma
Official Title
Phase IA-IB Open-label, Non-randomized, Neoadjuvant Treatment With Combination Pembrolizumab and Defactinib for Patients With Surgically Resectable Malignant Pleural Mesothelioma
Study Type
Interventional

2. Study Status

Record Verification Date
November 2020
Overall Recruitment Status
Withdrawn
Why Stopped
Funding complications coupled with competing scientific objectives
Study Start Date
September 2020 (Anticipated)
Primary Completion Date
December 31, 2021 (Anticipated)
Study Completion Date
December 31, 2022 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Raphael Bueno, MD
Collaborators
Merck Sharp & Dohme LLC

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

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
Detailed Description
The research study procedures include screening for eligibility and study treatment including evaluations and follow up visits. The names of the study drugs involved in this study are: Pembrolizumab Defactinib The Investigators are looking for the highest dose of the study drug that can be administered safely without severe or unmanageable side effects in participants that have Malignant Pleural Mesothelioma (MPM), not everyone who participates in this research study will receive the same dose of the study drug. The dose given will depend on the number of participants who have been enrolled prior and how well the dose was tolerated. The dose of the study drug, pembrolizumab, will not change no matter when the participant is enrolled into the study. The order in which the participant is enrolled to the study will determine the cohort assigned to: Run-In Cohort: Pembrolizumab only followed by surgery Cohort 1: Pembrolizumab and defactinib followed by surgery Cohort 2: Pembrolizumab and defactinib followed by surgery Expansion Cohort: Pembrolizumab and defactinib at the maximum dose as determined from the previous cohorts (Cohorts 1 and 2) The U.S. Food and Drug Administration (FDA) has not approved defactinib as a treatment for any disease. The U.S. Food and Drug Administration (FDA) has not approved pembrolizumab for this specific disease but it has been approved for other uses.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Malignant Pleural Mesothelioma
Keywords
Malignant Pleural Mesothelioma

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Sequential Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
0 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Run in cohort: pembrolizumab only
Arm Type
Experimental
Arm Description
Treatment with pembrolizumab as a single agent for 56 days - 2 doses during treatment cycle, intravenous, at predetermined protocol dose
Arm Title
Cohort 1: pembrolizumab + defactinib 12 days
Arm Type
Experimental
Arm Description
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
Arm Title
Cohort 2: pembrolizumab + defactinib 35 days
Arm Type
Experimental
Arm Description
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
Arm Title
Expansion cohort
Arm Type
Experimental
Arm Description
Tolerated phase IA regimen will be administered in a phase IB expansion cohort
Intervention Type
Drug
Intervention Name(s)
Pembrolizumab
Other Intervention Name(s)
Keytruda®
Intervention Description
IV, predetermined dosage, twice per cycle
Intervention Type
Drug
Intervention Name(s)
Defactinib
Other Intervention Name(s)
PF-04554878
Intervention Description
Defactinib oral, twice daily, per predetermined dose and predetermined duration as defined by cohort
Primary Outcome Measure Information:
Title
Maximum Tolerated Duration (MTD)
Description
standard 3+3 design to determine the maximum tolerated duration (MTD) of oral defactinib when combined with 2 cycles of pembrolizumab
Time Frame
56 days
Title
Biomarker activity in response to the MTD of defactinib in combination with pembrolizumab
Description
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.
Time Frame
56 days
Secondary Outcome Measure Information:
Title
Number of Participants with Dose Limiting Toxcities
Description
NCI-CTCAE version 5.0
Time Frame
56 Days
Title
Response Rate
Description
Modified RECIST criteria for mesothelioma
Time Frame
56 Days

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: 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 International Normalized Ratio (INR) or Prothrombin Time (PT)-Activated Partial Thromboplastin Time (aPTT) ≤1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants ≤1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants Creatinine clearance should be calculated per institutional standard. Female subjects of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a negative serum pregnancy test will be required. Female and male subjects of childbearing potential must be willing to use an adequate method of contraception Contraception, for the course of the study through 120 days after the last dose of study medication. Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject. Exclusion Criteria: 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. Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis. Has an active infection requiring systemic therapy. Has a known history of active TB (Bacillus Tuberculosis) Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial. Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected). Has received a live vaccine within 30 days of planned start of study therapy. -- Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines, and are not allowed. Has a known history of myocarditis
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Raphael Bueno, MD
Organizational Affiliation
Brigham and Women's Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
Brigham and Women's Hospital
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02115
Country
United States
Facility Name
Dana Farber Cancer Institute
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02115
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing Plan Description
The Dana-Farber / Harvard Cancer Center encourages and supports the responsible and ethical sharing of data from clinical trials. De-identified participant data from the final research dataset used in the published manuscript may only be shared under the terms of a Data Use Agreement. Requests may be directed to Sponsor Investigator or designee. The protocol and statistical analysis plan will be made available on Clinicaltrials.gov only as required by federal regulation or as a condition of awards and agreements supporting the research.
IPD Sharing Time Frame
Data can be shared no earlier than 1 year following the date of publication
IPD Sharing Access Criteria
Contact the Partners Innovations team at http://www.partners.org/innovation

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Pembrolizumab + Defactinib In Pleural Mesothelioma

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