临床试验/NCT04201145

NCT04201145撤回1 期

Phase IA-IB Open-label, Non-randomized, Neoadjuvant Treatment With Combination Pembrolizumab and Defactinib for Patients With Surgically Resectable Malignant Pleural Mesothelioma

Raphael Bueno, MD2 个研究点分布在 1 个国家开始时间: 2020年9月最近更新: 2020年11月17日

适应症

干预措施

试验速览

阶段: 1 期
状态: 撤回
发起方
试验地点: 2
主要终点: Maximum Tolerated Duration (MTD)

研究概览研究设计入排标准研究组 & 干预措施结局指标研究者研究点记录与标识符相似试验

研究概览

简要总结

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

详细描述

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.

研究设计

研究类型: Interventional
分配方式: Non Randomized
干预模型: Sequential
主要目的: Treatment
盲法: None

入排标准

年龄范围: 18 Years 至 —（Adult, Older Adult）
性别: All
接受健康志愿者: 否

入选标准

•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.
•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
•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
•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.

排除标准

•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

研究组 & 干预措施

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

干预措施: Pembrolizumab (Drug)

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

干预措施: Pembrolizumab (Drug)

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

干预措施: Defactinib (Drug)

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

干预措施: Pembrolizumab (Drug)

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

干预措施: Defactinib (Drug)

Expansion cohort

Experimental

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

干预措施: Pembrolizumab (Drug)

Expansion cohort

Experimental

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

干预措施: Defactinib (Drug)

结局指标

主要结局

Maximum Tolerated Duration (MTD)

时间窗: 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

时间窗: 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.

次要结局

Number of Participants with Dose Limiting Toxcities(56 Days)
Response Rate(56 Days)

研究者

发起方

Raphael Bueno, MD

申办方类型

Other

责任方

Sponsor Investigator

主要研究者

Raphael Bueno, MD

Sponsor Investigator

Dana-Farber Cancer Institute

研究点 (2)

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