Malignant Pleural MesotheliomaPhase 1NCT04201145
Pembrolizumab + Defactinib In Pleural Mesothelioma
A Phase 1 study testing Pembrolizumab and Defactinib in people with Malignant Pleural Mesothelioma, run by Raphael Bueno, MD at 2 sites in United States.
Trial 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 Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Malignant Pleural Mesothelioma
- What is being tested?
- Pembrolizumab and Defactinib
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 0 participants
- Where
- 2 sitesUnited States
- Study dates
- Sep 2020to 31 Dec 2022
- Phase
- Phase 1
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
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- 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.
Who cannot join
- 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.
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- 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
Trial locations and contacts
2 sites in 1 country.
United States2 sites
Brigham and Women's Hospital
Boston, Massachusetts, 02115
Dana Farber Cancer Institute
Boston, Massachusetts, 02115
About this study
Official title: Phase IA-IB Open-label, Non-randomized, Neoadjuvant Treatment With Combination Pembrolizumab and Defactinib for Patients With Surgically Resectable Malignant Pleural Mesothelioma
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
Read the 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.
- Conditions
- Malignant Pleural Mesothelioma
- Being tested
- Pembrolizumab, Defactinib
- Keywords
- Malignant Pleural Mesothelioma
- Medical subject headings
- Mesothelioma, Malignant
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
PembrolizumabDrug
Also called Keytruda®
IV, predetermined dosage, twice per cycle
DefactinibDrug
Also called PF-04554878
Defactinib oral, twice daily, per predetermined dose and predetermined duration as defined by cohort
| Study group | Role | What they receive |
|---|---|---|
| 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 Receives: 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 Receives: 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 Receives: Drug: Pembrolizumab; Drug: Defactinib |
| Expansion cohort | Experimental | Tolerated phase IA regimen will be administered in a phase IB expansion cohort Receives: Drug: Pembrolizumab; Drug: Defactinib |
What is being measured
The primary outcome is the main question the study is designed to answer.
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
Measured: 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.
Measured: 56 days
Secondary outcomes (2)
Number of Participants with Dose Limiting Toxcities
NCI-CTCAE version 5.0
Measured: 56 Days
Response Rate
Modified RECIST criteria for mesothelioma
Measured: 56 Days
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted17 Dec 2019
- Study startSep 2020 (estimated)
- Primary completion31 Dec 2021 (estimated)
- Study completion31 Dec 2022 (estimated)
Why it stopped: Funding complications coupled with competing scientific objectives
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Malignant Pleural MesotheliomaStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Sequential
- Masking
- None (open label)
- Enrolment
- 0 participants (actual)
Sponsor and investigators
- Lead sponsor
- Raphael Bueno, MD
- Sponsor type
- University, hospital or other
- Collaborators
- Merck Sharp & Dohme LLC
- Responsible party
- Sponsor-investigator, Raphael Bueno, MD, Dana-Farber Cancer Institute
- Investigators
- Raphael Bueno, MD, Principal investigator, Brigham and Women's Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04201145
- Sponsor's protocol ID
- 19-736
- Status last verified
- Nov 2020
- First submitted
- 13 Dec 2019
- Last updated
- 17 Nov 2020
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes: 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.
Study at a glance
From the registry record, last updated by the sponsor on 17 Nov 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Phase IA-IB Open-label, Non-randomized, Neoadjuvant Treatment With Combination Pembrolizumab and Defactinib for Patients With Surgically Resectable Malignant Pleural Mesothelioma
- ClinicalTrials.gov ID
- NCT04201145
- Acronym / sponsor ID
- 19-736
- Conditions
- Malignant Pleural Mesothelioma
- Keywords
- Malignant Pleural Mesothelioma
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- WithdrawnReason stopped: Funding complications coupled with competing scientific objectives
- Enrolment
- 0 participants (actual)
- Lead sponsor
- Raphael Bueno, MDUniversity, hospital or other
- Collaborators
- Merck Sharp & Dohme LLC
- Study start
- Sep 2020 (estimated)
- Primary completion
- 31 Dec 2021 (estimated)
- Study completion
- 31 Dec 2022 (estimated)
- First posted
- 17 Dec 2019 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Sequential
- Masking
- None (open label)
- Number of arms
- 4
| Arm | Type | Receives |
|---|---|---|
| Run in cohort: pembrolizumab only | Experimental | Drug: PembrolizumabTreatment with pembrolizumab as a single agent for 56 days - 2 doses during treatment cycle, intravenous, at predetermined protocol dose |
| Cohort 1: pembrolizumab + defactinib 12 days | Experimental | Drug: Pembrolizumab, Drug: DefactinibTreatment 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 |
| Cohort 2: pembrolizumab + defactinib 35 days | Experimental | Drug: Pembrolizumab, Drug: DefactinibTreatment 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 |
| Expansion cohort | Experimental | Drug: Pembrolizumab, Drug: DefactinibTolerated phase IA regimen will be administered in a phase IB expansion cohort |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (22 listed)
- 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.
Key exclusion criteria (25 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| PembrolizumabAlso: Keytruda®IV, predetermined dosage, twice per cycle | Drug | Cohort 1: pembrolizumab + defactinib 12 days, Cohort 2: pembrolizumab + defactinib 35 days, Expansion cohort, Run in cohort: pembrolizumab only |
| DefactinibAlso: PF-04554878Defactinib oral, twice daily, per predetermined dose and predetermined duration as defined by cohort | Drug | Cohort 1: pembrolizumab + defactinib 12 days, Cohort 2: pembrolizumab + defactinib 35 days, Expansion cohort |
Primary outcome
Maximum Tolerated Duration (MTD)
Time frame: 56 days
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
Time frame: 56 days
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.
2 secondary outcomes
Number of Participants with Dose Limiting Toxcities
Time frame: 56 Days
Response Rate
Time frame: 56 Days
Results and safety
The study was withdrawn before enrolling participants, so there are no results.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 17 Nov 2020.
- Individual participant dataSharing planned: Yes. 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.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Raphael Bueno, MD principal investigator
Brigham and Women's Hospital
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Pembrolizumab and Defactinib in people with Malignant Pleural Mesothelioma, run by Raphael Bueno, MD at 2 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 22 inclusion and 25 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: withdrawn, as of the sponsor's last update on 17 Nov 2020. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study was withdrawn before enrolling participants, so there are no results.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Maximum Tolerated Duration (MTD) (time frame: 56 days). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 17 Nov 2020.