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

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ClinicalTrials.gov Identifier: NCT04175912
Recruitment Status : Recruiting
First Posted : November 25, 2019
Last Update Posted : February 18, 2021
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Tracking Information
First Submitted Date  ICMJE November 22, 2019
First Posted Date  ICMJE November 25, 2019
Last Update Posted Date February 18, 2021
Actual Study Start Date  ICMJE January 31, 2020
Estimated Primary Completion Date October 1, 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: November 22, 2019)
Objective response rate [ Time Frame: 3 years ]
Will assess complete or partial response by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: July 9, 2020)
  • Incidence of adverse events [ Time Frame: Up to 30 days after the last dose of treatment ]
  • Disease control rate [ Time Frame: 3 years ]
  • Clinical benefit rate [ Time Frame: 3 years ]
  • Progression-free survival [ Time Frame: 3 years ]
  • Overall survival [ Time Frame: 3 years ]
Original Secondary Outcome Measures  ICMJE
 (submitted: November 22, 2019)
  • Incidence of adverse events [ Time Frame: Up to 30 days after the last dose of treatment ]
  • Clinical benefit rate [ Time Frame: 3 years ]
  • Progression-free survival [ Time Frame: 3 years ]
  • Overall survival [ Time Frame: 3 years ]
Current Other Pre-specified Outcome Measures
 (submitted: July 9, 2020)
  • Overexpression of NEDD8, NAE1, and UBC12 [ Time Frame: 3 years ]
    Will perform immunohistochemistry on formalin-fixed paraffin-embedded (FFPE) tissue determine whether overexpression of NEDD8, NAE1, and UBC12 can predict response to treatment. Biomarker quantification will be calculated as a continuous variable (mean optical density) and also as ordered categories (ex. 0, 1+, 2+, or 3+). Biomarker quantification will then be correlated with treatment response. Descriptive statistics will primarily be generated to summarize the correlative data. Statistical significance will be determined by students' t-test for normally distributed data. If data distributions are not normal, non-parametric methods will be used (Wilcoxon rank sum test).
  • Mutation profile of cholangiocarcinomas with overexpression of the neddylation pathway [ Time Frame: 3 years ]
  • Specimen banking [ Time Frame: 3 years ]
Original Other Pre-specified Outcome Measures
 (submitted: November 22, 2019)
  • Overexpression of NEDD8, NAE1, and UBC12 [ Time Frame: 3 years ]
    Will determine whether overexpression of NEDD8, NAE1, and UBC12 predict response to treatment. Biomarker quantification will be calculated as a continuous variable (mean optical density) and also as ordered categories (ex. 0, 1+, 2+, or 3+). Biomarker quantification will then be correlated with treatment response. Descriptive statistics will primarily be generated to summarize the correlative data. Statistical significance will be determined by students' t-test for normally distributed data. If data distributions are not normal, non-parametric methods will be used (Wilcoxon rank sum test).
  • Mutation profile of cholangiocarcinomas with overexpression of the neddylation pathway [ Time Frame: 3 years ]
  • Specimen banking [ Time Frame: 3 years ]
 
Descriptive Information
Brief Title  ICMJE Testing the Combination of Pevonedistat With Chemotherapy for Bile Duct Cancer of the Liver
Official Title  ICMJE A Phase 2 Study of Pevonedistat in Combination With Carboplatin and Paclitaxel in Advanced Intrahepatic Cholangiocarcinoma
Brief Summary 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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • 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
Intervention  ICMJE
  • Drug: Carboplatin
    Given IV
    Other Names:
    • Blastocarb
    • Carboplat
    • Carboplatin Hexal
    • Carboplatino
    • Carboplatinum
    • Carbosin
    • Carbosol
    • Carbotec
    • CBDCA
    • Displata
    • Ercar
    • JM-8
    • Nealorin
    • Novoplatinum
    • Paraplatin
    • Paraplatin AQ
    • Paraplatine
    • Platinwas
    • Ribocarbo
  • Drug: Paclitaxel
    Given IV
    Other Names:
    • Anzatax
    • Asotax
    • Bristaxol
    • Praxel
    • Taxol
    • Taxol Konzentrat
  • Drug: Pevonedistat
    Given IV
    Other Names:
    • MLN4924
    • Nedd8-Activating Enzyme Inhibitor MLN4924
Study Arms  ICMJE
  • Experimental: Arm A (pevonedistat)
    Patients 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.
    Intervention: Drug: Pevonedistat
  • Experimental: Arm B (pevonedistat, paclitaxel, carboplatin)
    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.
    Interventions:
    • Drug: Carboplatin
    • Drug: Paclitaxel
    • Drug: Pevonedistat
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: November 22, 2019)
52
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE October 1, 2022
Estimated Primary Completion Date October 1, 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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. For patients who have received localized therapy (embolization, chemoembolization, radiofrequency ablation or radiation) are eligible if measurable disease is not within the treatment field or the treated disease has clearly progressed since last localized therapy
  • 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 =< 1.5 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)
  • 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 >= 350 cells/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)
  • Women of childbearing potential and sexually active males must not expect to conceive or father children by using accepted and effective method(s) of contraception or by abstaining 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
  • Male patients must not donate sperm during the course of this study or within 4 months after receiving their last dose of protocol treatment
  • Female patients must not donate eggs (ova) during the course of this study or within 4 months after receiving their last dose of protocol treatment
  • Patient must not have a prolonged rate corrected QT (QTc) interval >= 480 msec calculated according to institutional guideline
  • 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
  • Patient must not be receiving any treatment with clinically significant metabolic enzyme inducers within 14 days before the first dose of the study drug as below. 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 breast cancer resistance protein (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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04175912
Other Study ID Numbers  ICMJE NCI-2019-07769
NCI-2019-07769 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
EA2187 ( Other Identifier: ECOG-ACRIN Cancer Research Group )
EA2187 ( Other Identifier: CTEP )
U10CA180820 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page.
URL: https://grants.nih.gov/policy/sharing.htm
Responsible Party National Cancer Institute (NCI)
Study Sponsor  ICMJE National Cancer Institute (NCI)
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Dustin A Deming ECOG-ACRIN Cancer Research Group
PRS Account National Cancer Institute (NCI)
Verification Date October 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP