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. Chemotherapy drugs, 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.
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
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
40
Anchorage Associates in Radiation Medicine
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Alaska Oncology and Hematology LLC
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Alaska Women's Cancer Care
Anchorage, Alaska, United States
Objective Response
Response was evaluated using the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1). Objective response includes complete response (CR) and partial response (PR). CR is defined as disappearance of all target and non-target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \< 10 mm. PR is defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.
Time frame: Every 3 months for the first year and every 6 months for years 2-3
Clinical Benefit
Clinical benefit was evaluated using the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1), including complete response (CR), partial response (PR) and stable disease (SD) that lasted greater than or equal to 24 weeks. CR is defined as disappearance of all target and non-target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \< 10 mm. PR is defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. SD is defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease, taking as reference the smallest sum diameters while on study.
Time frame: Every 3 months for the first year and every 6 months for years 2-3
Progression-free Survival (PFS)
PFS was defined as the time from randomization to progression or death, whichever came first; patients alive without evidence of disease progression were censored at the date of last disease assessment. Patients who died without documented progression and the death occurred \> 6 weeks of last disease assessment will be censored at the date of last disease assessment that showed progression-free. Progression was evaluated using the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1), defined as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions is also considered as progression.
Time frame: Every 3 months for the first year and every 6 months for years 2-3
Overall Survival (OS)
OS was defined as the time from randomization to death from any cause, and patients still living were censored at the date last known alive.
Time frame: Every 3 months for the first year and every 6 months for years 2-3
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