Clinical Trials /

Testing the Combination of Pevonedistat With Chemotherapy for Bile Duct Cancer of the Liver

NCT04175912

Description:

This phase II trial studies how well pevonedistat alone or in combination with chemotherapy (paclitaxel and carboplatin) works in treating patients with bile duct cancer of the liver. Pevonedistat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as paclitaxel and carboplatin, 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. This study may help the study doctors find out how well pevonedistat shrinks bile duct cancer of the liver when given alone and when in combination with paclitaxel and carboplatin.

Related Conditions:
  • Cholangiocarcinoma
  • Hepatocellular Carcinoma
  • Intrahepatic Cholangiocarcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Testing the Combination of Pevonedistat With Chemotherapy for Bile Duct Cancer of the Liver
  • Official Title: A Phase 2 Study of Pevonedistat in Combination With Carboplatin and Paclitaxel in Advanced Intrahepatic Cholangiocarcinoma

Clinical Trial IDs

  • ORG STUDY ID: NCI-2019-07769
  • SECONDARY ID: NCI-2019-07769
  • SECONDARY ID: EA2187
  • SECONDARY ID: EA2187
  • SECONDARY ID: U10CA180820
  • NCT ID: NCT04175912

Conditions

  • Metastatic Cholangiocarcinoma
  • Metastatic Hepatocellular Carcinoma
  • Stage III Hepatocellular Carcinoma AJCC v8
  • Stage III Intrahepatic Cholangiocarcinoma AJCC v8
  • Stage IIIA Hepatocellular Carcinoma AJCC v8
  • Stage IIIA Intrahepatic Cholangiocarcinoma AJCC v8
  • Stage IIIB Hepatocellular Carcinoma AJCC v8
  • Stage IIIB Intrahepatic Cholangiocarcinoma AJCC v8
  • Stage IV Hepatocellular Carcinoma AJCC v8
  • Stage IV Intrahepatic Cholangiocarcinoma AJCC v8
  • Stage IVA Hepatocellular Carcinoma AJCC v8
  • Stage IVB Hepatocellular Carcinoma AJCC v8
  • Unresectable Cholangiocarcinoma
  • Unresectable Hepatocellular Carcinoma
  • Unresectable Intrahepatic Cholangiocarcinoma

Interventions

DrugSynonymsArms
CarboplatinBlastocarb, Carboplat, Carboplatin Hexal, Carboplatino, Carboplatinum, Carbosin, Carbosol, Carbotec, CBDCA, Displata, Ercar, JM-8, Nealorin, Novoplatinum, Paraplatin, Paraplatin AQ, Paraplatine, Platinwas, RibocarboArm B (pevonedistat, paclitaxel, carboplatin)
PaclitaxelAnzatax, Asotax, Bristaxol, Praxel, Taxol, Taxol KonzentratArm B (pevonedistat, paclitaxel, carboplatin)
PevonedistatMLN4924, Nedd8-Activating Enzyme Inhibitor MLN4924Arm A (pevonedistat)

Purpose

This phase II trial studies how well pevonedistat alone or in combination with chemotherapy (paclitaxel and carboplatin) works in treating patients with bile duct cancer of the liver. Pevonedistat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as paclitaxel and carboplatin, 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. This study may help the study doctors find out how well pevonedistat shrinks bile duct cancer of the liver when given alone and when in combination with paclitaxel and carboplatin.

Detailed Description

      PRIMARY OBJECTIVE:

      I. To determine the objective response rate of pevonedistat as a single agent and in
      combination with carboplatin and paclitaxel in patients with unresectable intrahepatic
      cholangiocarcinoma.

      SECONDARY OBJECTIVES:

      I. To evaluate the safety profile of pevonedistat alone and in combination with carboplatin
      and paclitaxel in patients with intrahepatic cholangiocarcinoma.

      II. To determine the clinical benefit rate of patients with advanced intrahepatic
      cholangiocarcinoma (ICC) treated with pevonedistat monotherapy and in combination with
      carboplatin and paclitaxel.

      III. To determine progression-free survival of patients treated with pevonedistat monotherapy
      and in combination with carboplatin and paclitaxel.

      IV. To determine overall survival of patients treated with pevonedistat monotherapy and in
      combination with carboplatin and paclitaxel.

      EXPLORATORY OBJECTIVES:

      I. To determine whether overexpression of NEDD8, NAE1, and UBC12 predict response to
      treatment.

      II. To identify the mutation profile of those cholangiocarcinomas with overexpression of the
      neddylation pathway.

      III. To bank specimens for further future investigations.

      OUTLINE: Patients are randomized to 1 of 2 arms.

      ARM A: Patients receive pevonedistat intravenously (IV) over 60 minutes on days 1, 3, and 5.
      Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

      ARM B: Patients receive pevonedistat IV over 1 hour on days 1, 3, and 5, paclitaxel IV over 3
      hours on day 1, and carboplatin IV over 15-60 minutes on day 1. Cycles repeat every 21 days
      in the absence of disease progression or unacceptable toxicity. Starting cycle 5, patients
      may receive pevonedistat monotherapy at the discretion of treating physician.

      After completion of study treatment, patients are followed up at 30 days after last dose of
      study treatment, then every 3 months for the first year and every 6 months for years 2-3.
    

Trial Arms

NameTypeDescriptionInterventions
Arm A (pevonedistat)ExperimentalPatients receive pevonedistat IV over 60 minutes on days 1, 3, and 5. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.
  • Pevonedistat
Arm B (pevonedistat, paclitaxel, carboplatin)ExperimentalPatients receive pevonedistat IV over 1 hour on days 1, 3, and 5, paclitaxel IV over 3 hours on day 1, and carboplatin IV over 15-60 minutes on day 1. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Starting cycle 5, patients may receive pevonedistat monotherapy at the discretion of treating physician.
  • Carboplatin
  • Paclitaxel
  • Pevonedistat

Eligibility Criteria

        Inclusion Criteria:

          -  Patient must have an Eastern Cooperative Oncology Group (ECOG) performance status 0-1

          -  Patient must have a life expectancy >= 12 weeks

          -  Patient must have histologically confirmed intrahepatic cholangiocarcinoma or biphasic
             hepatocellular carcinoma and cholangiocarcinoma that is metastatic or unresectable and
             who have progressed on or been intolerant of one prior line of systemic gemcitabine
             containing chemotherapy regimen.

               -  NOTE: Prior immunotherapy or targeted therapies are allowed and will not be
                  considered a line of therapy unless administered with cytotoxic chemotherapy

          -  Patient must have measurable disease

          -  Women of childbearing potential and sexually active males must use accepted and
             effective method(s) of contraception or to abstain from sexual intercourse for the
             duration of their participation in the study and continue for at least 4 months after
             the last dose of protocol treatment

          -  Leukocytes >= 3,000/mcL (obtained within 14 days prior to randomization)

          -  Absolute neutrophil count >= 1,500/mcL (obtained within 14 days prior to
             randomization)

          -  Platelets >= 100,000/mcL (obtained within 14 days prior to randomization)

          -  Total bilirubin =< institutional upper limit of normal (ULN) except in patients with
             Gilbert's syndrome. Patients with Gilbert's syndrome may enroll if direct bilirubin =<
             x ULN of the direct bilirubin (obtained within 14 days prior to randomization)

          -  Hemoglobin >= 9 g/dL (obtained within 14 days prior to randomization)

          -  Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase
             [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
             =< 2.5 x institutional ULN (obtained within 14 days prior to randomization)

          -  Creatinine =< institutional ULN, OR glomerular filtration rate (GFR) >= 40 mL/min/1.73
             m^2 (obtained within 14 days prior to randomization)

          -  Prolonged rate corrected QT (QTc) interval >= 500 msec calculated according to
             institutional guidelines

          -  Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral
             therapy with undetectable viral load within 6 months are eligible for this trial.
             Known HIV positive patients who meet the following criteria will be considered
             eligible:

               -  CD4 count >= 350cells/mm^3

               -  Undetectable viral load

               -  Maintained on modern therapeutic regimens utilizing non-CYP interactive agents
                  (i.e. excluding ritonavir)

               -  No history of acquired immunodeficiency syndrome (AIDS)-defining opportunistic
                  infections

          -  For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral
             load must be undetectable on suppressive therapy, if indicated

          -  Patients with a history of hepatitis C virus (HCV) infection must have been treated
             and cured. For patients with HCV infection who are currently on treatment, they are
             eligible if they have an undetectable HCV viral load

          -  Patients who received prior platinum or taxane chemotherapy are eligible

          -  Patients with a prior or concurrent malignancy whose natural history or treatment does
             not have the potential to interfere with the safety or efficacy assessment of the
             investigational regimen are eligible for this trial

          -  Patients with known history or current symptoms of cardiac disease, or history of
             treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac
             function using the New York Heart Association Functional Classification. To be
             eligible for this trial, patients should be class 2B or better. In addition, patients
             with any of the known cardiopulmonary disease, defined as follows, would be ineligible
             for this trial:

               -  Unstable angina

               -  Congestive heart failure (New York Heart Association [NYHA] class III or IV;);

               -  Myocardial infarction within 6 months prior to randomization (patients who had
                  ischemic heart disease such as acute coronary syndrome [ACS], myocardial
                  infarction, and/or revascularization greater than 6 months before randomization
                  and who are without cardiac symptoms may enroll)

               -  Symptomatic cardiomyopathy

               -  Clinically symptomatic pulmonary hypertension requiring pharmacologic therapy

               -  Clinically significant arrhythmia, defined as:

               -  History of polymorphic ventricular fibrillation or torsade de pointes,

               -  Permanent atrial fibrillation, defined as continuous atrial fibrillation for >= 6
                  months,

               -  Persistent atrial fibrillation, defined as sustained atrial fibrillation lasting
                  > 7 days and/or requiring cardioversion in the 4 weeks before randomization,

               -  Grade 3 atrial fibrillation defined as symptomatic and incompletely controlled
                  medically, or controlled with device (e.g., pacemaker), or ablation

               -  Patients with paroxysmal atrial fibrillation or grade < 3 atrial fibrillation for
                  period of at least 6 months are permitted to enroll provided that their rate is
                  controlled on a stable regimen

          -  Patients must have the ability to understand and the willingness to sign a written
             informed consent document

          -  Participants with impaired decision-making capacity (IDMC) who have a legally
             authorized representative (LAR) or caregiver and/or family member available will also
             be considered eligible

        Exclusion Criteria:

          -  Patients must not have had major surgery within 14 days before randomization. Patients
             with surgery planned during study period are ineligible

          -  Women must not be pregnant or breast-feeding due to the potential harm to an unborn
             fetus and possible risk for adverse events in nursing infants with the treatment
             regimens being used. Patients must also not expect to conceive or father children from
             the time of registration, while on study treatment, and until at least 4 months after
             the last dose of study treatment. All females of childbearing potential must have a
             blood test or urine study within 14 days prior to randomization to rule out pregnancy.
             A female of childbearing potential is any woman, regardless of sexual orientation or
             whether they have undergone tubal ligation, who meets the following criteria: 1) has
             achieved menarche at some point, 2) has not undergone a hysterectomy or bilateral
             oophorectomy; or 3) has not been naturally postmenopausal (amenorrhea following cancer
             therapy does not rule out childbearing potential) for at least 24 consecutive months
             (i.e., has had menses at any time in the preceding 24 consecutive months)

          -  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) are ineligible

          -  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) are ineligible

          -  Patients who have not recovered from adverse events due to prior anti-cancer therapy
             (i.e. have residual toxicities > grade 1) are ineligible with the exception of
             alopecia

          -  Patients with persistent >= grade 2 diarrhea lasting more than 3 days within 14 weeks
             of randomization are ineligible

          -  Patients with known central nervous system (CNS) involvement are ineligible

          -  Patients must not be receiving any other investigational agents

          -  Patients must not have received chemotherapy or radiotherapy within 2 weeks prior to
             randomization. Prior treatment with radiation therapy involving >= 25% of
             hematopoietically active bone marrow will be ineligible

          -  Patients must not have received immunotherapy within 8 weeks prior to randomization

          -  Patients must not have a history of allergic reactions attributed to compounds of
             similar chemical or biologic composition to pevonedistat, carboplatin, or paclitaxel

          -  Patients receiving any 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 the study. Patients must not be
             receiving any medications or substances that are strong inducers of CYP3A4/5 (i.e.
             phenytoin, rifampin, St. Johns wort) or inhibitors of BCRP (i.e. cyclosporine).
             Because the lists of these agents are constantly changing, it is important to
             regularly consult a frequently-updated medical reference. As part of
             enrollment/informed consent procedures, the patient will be counseled on the risk of
             interactions with other agents, and what to do if a new medication need to be
             prescribed or if the patient is considering a new over-the-counter medicine or herbal
             product. Inhibitors of CYP3A4/5 are allowed

          -  Patients must not have uncontrolled intercurrent illness

          -  Patients must not have uncontrolled coagulopathy or bleeding disorder

          -  Patients must not have active, uncontrolled infection or severe infectious disease
             such as severe pneumonia, meningitis, or septicemia

          -  Patients with known moderate chronic obstructive pulmonary disease, interstitial lung
             disease, and pulmonary fibrosis are ineligible

          -  Patients must not have psychiatric illness/social situations that would limit
             compliance with study requirements

          -  Participants must not have had prior pevonedistat treatment
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Objective response rate
Time Frame:3 years
Safety Issue:
Description:Will assess complete or partial response by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.

Secondary Outcome Measures

Measure:Incidence of adverse events
Time Frame:Up to 30 days after the last dose of treatment
Safety Issue:
Description:
Measure:Clinical benefit rate
Time Frame:3 years
Safety Issue:
Description:
Measure:Progression-free survival
Time Frame:3 years
Safety Issue:
Description:
Measure:Overall survival
Time Frame:3 years
Safety Issue:
Description:

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

Last Updated

February 12, 2020