Clinical Trials /

Pevonedistat Alone and in Combination With Chemotherapy in Patients With Mesothelioma

NCT03319537

Description:

The purpose of this study is to test any good and bad effects of activity pevonedistat taken alone, and also to test the safety of pevonedistat in combination with standard chemotherapy, pemetrexed/cisplatin.

Related Conditions:
  • Malignant Mesothelioma
  • Malignant Pleural Mesothelioma
  • Peritoneal Malignant Mesothelioma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Pevonedistat Alone and in Combination With Chemotherapy in Patients With Mesothelioma
  • Official Title: Pevonedistat as a Single Agent and in Combination With Chemotherapy in Patients With Malignant Mesothelioma

Clinical Trial IDs

  • ORG STUDY ID: 17-361
  • NCT ID: NCT03319537

Conditions

  • Mesothelioma

Interventions

DrugSynonymsArms
pevonedistatPevonedistat
Pemetrexed and cisplatinpevonedistat in combination with pemetrexed and cisplatin

Purpose

The purpose of this study is to test any good and bad effects of activity pevonedistat taken alone, and also to test the safety of pevonedistat in combination with standard chemotherapy, pemetrexed/cisplatin.

Trial Arms

NameTypeDescriptionInterventions
PevonedistatExperimental
  • pevonedistat
pevonedistat in combination with pemetrexed and cisplatinExperimental
  • pevonedistat
  • Pemetrexed and cisplatin

Eligibility Criteria

        Inclusion Criteria:

        Both cohorts:

          -  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 RECIST criteria for
             pleural mesothelioma, or standard RECIST for peritoneal mesothelioma. Patients must
             have adequate tissue sample available for molecular profiling with MSK-IMPACT
             (archived tissue block or 15-20 unstained slides). Patients will sign a separate
             informed document (IRB #12-245) to allow this to be performed.

          -  Patients must be at least 18 years of age.

          -  Karnofsky performance status ≥ 70%.

          -  Adequate renal function: serum creatinine ≤ 1.5 x ULN.

          -  Clinical laboratory values within the following parameters (repeat if more than 7 days
             before the first dose):

             °Albumin > 2.7 g/dL

          -  Patients must have adequate hepatic function as defined by:

               -  AST and 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.

          -  Patients must have adequate bone marrow function as defined by:

               -  Absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L

               -  Platelets ≥ 100 x 10^9/L

               -  Hemoglobin ≥ 9 g/dL.

          -  Female patients who

               -  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 1:

          -  Patients must have received at least one and no more than two prior systemic therapy
             regimens. At least one of the regimens must have included pemetrexed and a platinum.

          -  Patients must have MM that harbors an NF2 mutation believed to cause functional loss
             of the NF2 protein as determined by any CLIA lab certified NGS platform or NF2 loss
             must be documented by CLIA certified IHC.

        Cohort 2:

          -  Patients must not have previously received treatment with chemotherapy for MM.

          -  Patients must not have ≥ grade 2 peripheral neuropathy.

          -  Patients must not have > grade 2 hearing deficits.

        Exclusion Criteria:

          -  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 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 < 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 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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:number of patients who have a clinical benefit rate (CBR) (cohort 1)
Time Frame:at 18 weeks post initiation of treatment
Safety Issue:
Description:The CBR is defined as the proportion of patients CR, PR or SD at 18 weeks based on RECIST criteria.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Memorial Sloan Kettering Cancer Center

Trial Keywords

  • Pevonedistat
  • Pemetrexed
  • Cisplatin
  • 17-361

Last Updated

October 20, 2017