Pevonedistat with or without Pemetrexed Disodium and Cisplatin in Treating Patients with Malignant Mesothelioma
This phase I / II trial studies the side effects and best dose of pevonedistat with or without pemetrexed disodium and cisplatin, and to see how well they work in treating patients with malignant mesothelioma. Pevonedistat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as pemetrexed disodium and cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving pevonedistat, pemetrexed disodium, and cisplatin may work better in treating patients with malignant mesothelioma.
- Patients must have a histologically confirmed diagnosis of epithelioid, sarcomatoid, or mixed-type malignant pleural or peritoneal mesothelioma that is not amenable to surgery
- Patients must have measurable disease according to the modified Response Evaluation Criteria in Solid Tumors (RECIST) criteria for pleural mesothelioma, or standard RECIST for peritoneal mesothelioma; patients must have adequate tissue sample available for molecular profiling with Memorial Sloan-Kettering (MSK)-IMPACT (archived tissue block or 15-20 unstained slides); patients will sign a separate informed document (Institutional Review Board [IRB] #12-245) to allow this to be performed
- Karnofsky performance status >= 70%
- Serum creatinine =< 1.5 x upper limit of normal (ULN)
- Albumin > 2.7 g/dL (repeat if more than 7 days before the first dose)
- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x ULN
- Total bilirubin =< upper limit of normal (ULN) except in patients with Gilbert's syndrome; patients with Gilbert's syndrome may enroll if direct bilirubin =< 1.5 x ULN of the direct bilirubin
- Absolute neutrophil count (ANC) >= 1.5 x 10^9/L
- Platelets >= 100 x 10^9/L
- Hemoglobin >= 9 g/dL
- Are postmenopausal for at least 1 year before the screening visit, OR
- Are surgically sterile, OR
- If they are of childbearing potential: * Agree to practice 1 highly effective method and 1 additional effective (barrier) method of contraception, at the same time, from the time of signing the informed consent through 4 months after the last dose of study drug (female and male condoms should not be used together), or * Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the subject; (periodic abstinence [e.g., calendar, ovulation, symptothermal, postovulation methods] withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception)
- Male patients, even if surgically sterilized (i.e., status post vasectomy), who: * Agree to practice effective barrier contraception during the entire study treatment period and through 4 months after the last dose of study drug (female and male condoms should not be used together), or * Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the subject; (periodic abstinence [e.g., calendar, ovulation, symptothermal, postovulation methods for the female partner] withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception)
- Signed informed consent
- COHORT I: Patients must have received at least one and no more than four prior systemic therapy regimens; at least one of the regimens must have included pemetrexed and a platinum
- COHORT I: Patients must have MM that harbors an NF2 mutation believed to cause functional loss of the NF2 protein as determined by any Clinical Laboratory Improvement Act (CLIA) lab certified next generation sequencing (NGS) platform or NF2 loss must be documented by CLIA certified immunohistochemistry (IHC)
- COHORT II: Patients must not have previously received treatment with chemotherapy for MM
- COHORT II: Patients must not have >= grade 2 peripheral neuropathy
- COHORT II: Patients must not have >= grade 2 hearing deficits
- Patients currently receiving anticancer therapies or who have received anticancer therapies within 3 weeks of the start of study drug including chemotherapy, biologics, targeted therapies, or immunologics
- Treatment with any investigational products within 4 weeks before the first dose of any study drug
- Any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of study procedures
- Patients currently receiving radiation therapy, or who have received radiation within 2 weeks from the start of therapy
- Patients who have had a major surgery or significant traumatic injury within 4 weeks of start of study drug, patients who have not recovered from the side effects of any major surgery (defined as requiring general anesthesia) or patients that may require major surgery during the course of the study
- Diagnosed or treated for another malignancy within 2 years before randomization or previously diagnosed with another malignancy and have any evidence of residual disease; patients with nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone resection
- Life-threatening illness unrelated to cancer
- Patients with uncontrolled coagulopathy or bleeding disorder
- Patients who have any severe and/or uncontrolled medical conditions or other conditions that could affect their participation in the study such as: * Known cardiopulmonary disease defined as: ** Unstable angina ** Congestive heart failure (New York Hear Association [NYHA] class III or IV ** Myocardial infarction (MI) within 6 months prior to first dose (patients who had ischemic heart disease such as acute chest syndrome [ACS], MI and/or revascularization greater than 6 months before screening and who are without cardiac symptoms may enroll) ** Cardiomyopathy ** Clinically significant arrhythmia: *** Polymorphic ventricular fibrillation or torsade de pointes *** Permanent atrial fibrillation [a fib], defined as continuous a fib >= 6 months *** Persistent a fib, defined as sustained a fib lasting > 7 days and/or requiring cardioversion in the 4 weeks before screening *** Grade 3 a fib defined as symptomatic and incompletely controlled medically, or controlled with device (e.g. pacemaker), or ablation *** Patients with paroxysmal a fib or < grade (Gr) 3 a fib for period of at least 6 months are permitted to enroll provided that their rate is controlled on a stable regimen *** Implantable cardioverter defibrillator ** Moderate to severe aortic and/or mitral stenosis or other valvulopathy (ongoing) ** Symptomatic pulmonary hypertension * Active infection requiring IV antibiotic, antiviral, or anti-fungal medications within 2 weeks of starting study drug * Known history of human immunodeficiency virus (HIV) seropositivity
- Known hepatitis B surface antigen seropositive or known or suspected active hepatitis C infection * Note: Patients who have isolated positive hepatitis B core antibody (i.e., in the setting of negative hepatitis B surface antigen and negative hepatitis B surface antibody) must have an undetectable hepatitis B viral load; patients who have positive hepatitis C antibody may be included if they have an undetectable hepatitis C viral load
- Known hepatic cirrhosis or severe pre-existing hepatic impairment
- Uncontrolled high blood pressure (i.e., systolic blood pressure > 180 mm Hg, diastolic blood pressure > 95 mm Hg)
- Prolonged rate corrected QT (QTc) interval >= 500 msec, calculated according to institutional guidelines
- Left ventricular ejection fraction (LVEF) < 50% as assessed by echocardiogram or radionuclide angiography
- Known central nervous system (CNS) involvement
- Female patients who are both lactating and breastfeeding or have a positive serum pregnancy test during the screening period or a positive urine pregnancy test on day 1 before first dose of study drug
- Female patients who intend to donate eggs (ova) during the course of this study or 4 months after receiving their last dose of study drug(s)
- Male patients who intend to donate sperm during the course of this study or 4 months after receiving their last dose of study drug(s)
- Patients with a currently active second malignancy requiring treatment
- Treatment with clinically significant metabolic enzyme inducers within 14 days before the first dose of the study drug; clinically significant metabolic enzyme inducers are not permitted during this study
Locations & Contacts
Trial Objectives and Outline
I. To determine the clinical benefit rate (complete response [CR] + partial response [PR] + stable disease [SD]) of single agent pevonedistat at 18 weeks in patients with previously treated malignant mesothelioma (MM) that has an NF2 mutation. (Cohort I)
II. To establish the safety of the combination of pevonedistat and pemetrexed disodium (pemetrexed)/cisplatin in patients with previously untreated MM, and determine the recommended phase II dose. (Cohort II)
I. To determine the progression-free and overall survival in both cohorts.
II. To determine the response rate of single agent pevonedistat in previously treated patients with MM, and the response rate of pevonedistat plus pemetrexed disodium (pemetrexed)/cisplatin in previously untreated patients.
III. To determine the pharmacokinetics (PK) for pevonedistat in combination with chemotherapy.
IV. To explore downstream mechanistic biomarkers of pevonedistat activity in on treatment biopsy samples from patients in cohort 1.
OUTLINE: This is a phase I, dose-escalation study of pevonedistat followed by a phase II study. Patients are assigned to 1 of 2 cohorts.
COHORT I: Patients with advanced MM previously treated with 1-2 prior chemotherapy regimens and tumors with NF2 gene mutation receive pevonedistat intravenously (IV) on days 1, 3, and 5. Cycles repeat every 21 days in the absence of disease progression or unaccepted toxicity.
COHORT II: Patients with advanced MM previously untreated with chemotherapy receive pevonedistat as in Cohort I. Patients also receive pemetrexed disodium IV and cisplatin IV on day 1. Cycles repeat every 21 days in the absence of disease progression or unaccepted toxicity.
After completion of study treatment, patients are followed up periodically.
Trial Phase & Type
Memorial Sloan Kettering Cancer Center
Marjorie G. Zauderer
Secondary IDs NCI-2017-02048
Clinicaltrials.gov ID NCT03319537