This phase I trial studies the side effects and best dose of gemcitabine and cisplatin when given together with ivosidenib or pemigatinib in treating patients with cholangiocarcinoma that cannot be removed with surgery (unresectable) or has spread to other places in the body (metastatic). Chemotherapy drugs, such as gemcitabine 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. Ivosidenib and pemigatinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving gemcitabine and cisplatin with ivosidenib or pemigatinib may work better in treating patients with cholangiocarcinoma compared to gemcitabine and cisplatin alone.
PRIMARY OBJECTIVE: I. To evaluate the safety, tolerability, maximum tolerated dose (MTD) and/or recommended phase 2 dose, gemcitabine and cisplatin in combination with either ivosidenib or pemigatinib. SECONDARY OBJECTIVES: I. To evaluate median and progression free survival (PFS) for 6 months per investigator assessment. II. To evaluate the rate of overall survival (OS) in patients treated with gemcitabine and cisplatin in combination with either ivosidenib or pemigatinib. III. To describe the overall toxicity and adverse events profile associated with gemcitabine and cisplatin in combination with either ivosidenib or pemigatinib. IV. To determine the best response profile per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria in patients treated with gemcitabine and cisplatin in combination with either ivosidenib or pemigatinib. CORRELATIVE RESEARCH OBJECTIVE: I. To measure plasma 2-hydroxglutarate (2-HG) levels =\< 21 days prior to registration and at cycle 4 day 1 (+/- 2 days). OUTLINE: This is a dose de-escalation study. Patients are assigned to 1 of 2 arms. ARM A (IDH1 GENE MUTATION): Patients receive ivosidenib orally (PO) on days 1-21, cisplatin intravenously (IV) on days 1 and 8, and gemcitabine IV on days 1 and 8. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. ARM B (FGFR2 GENE ALTERATION): Patients receive pemigatinib PO on days 1-21, cisplatin IV on days 1 and 8, and gemcitabine IV on days 1 and 8. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 30 days and then every 6 months for up to 3 years.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
8
Mayo Clinic in Arizona
Scottsdale, Arizona, United States
Emory University Hospital/Winship Cancer Institute
Atlanta, Georgia, United States
Mayo Clinic in Rochester
Rochester, Minnesota, United States
University of Nebraska Medical Center
Omaha, Nebraska, United States
Spartanburg Regional Medical Center
Forest City, North Carolina, United States
M D Anderson Cancer Center
Houston, Texas, United States
Aurora Cancer Care-Milwaukee West
Wauwatosa, Wisconsin, United States
Number of Participants With Significant Toxicities
A significant toxicity is defined as a Dose Limiting Toxicity that is possibly, probably, or definitely related to treatment. DLTs will be evaluated starting in the first cycle of combination treatment and up to 3 weeks of combination treatment. Toxicities will be assessed using the CTEP Active Version of the CTCAE. All patients meeting the eligibility criteria who have signed a consent form and have begun combination treatment will be considered evaluable for significant toxicity. Patients, who do not experience a DLT but withdraw from protocol therapy prior to 3 weeks, will not be evaluable for the primary endpoint. Incidence of significant toxicity at 3 weeks will be estimated separately by arm and will be defined as the number of patients with significant toxicity within 3 weeks of combination treatment divided by the total number of evaluable patients.
Time frame: 3 weeks
Overall Survival
Overall survival is defined to be the length of time from start of study therapy to death due to any cause. All patients meeting the eligibility criteria that have signed a consent form and begun treatment will be considered evaluable for estimation of the survival distribution. The distribution of overall survival for both arms of the study will be estimated separately using the Kaplan-Meier method.
Time frame: 27 months
Progression Free Survival
Progression free survival time is defined as the time from the start of study therapy to documentation of disease progression. Patients who die without documentation of progression will be considered to have had tumor progression at the time of death. Patients who are still alive and have not progressed will be censored for progression at the time of the last disease evaluation. The time-to-progression distribution will be estimated separately for both arms, using the Kaplan-Meier method.
Time frame: 24 months
Number of Patients Experiencing Adverse Events
The number and severity of all adverse events (overall, by dose-level, and by tumor group) will be tabulated and summarized in this patient population. The grade 3+ adverse events will also be described and summarized in a similar fashion.
Time frame: 16 months
Number of Participants Experiencing Toxicities
The term toxicity is defined as adverse events that are classified as either possibly, probably, or definitely related to study treatment. Non-hematologic toxicities will be evaluated via the ordinal Common Terminology Criteria (CTC) standard toxicity grading. Hematologic toxicity measures of thrombocytopenia, neutropenia, and leukopenia will be assessed using continuous variables as the outcome measures (primarily nadir) as well as categorization via CTC standard toxicity grading. Overall toxicity incidence as well as toxicity profiles by dose level, patient and tumor site will be explored and summarized. Frequency distributions, graphical techniques and other descriptive measures will form the basis of these analyses.
Time frame: 16 months
Best Response
Best Response is defined to be the best objective status recorded from the start of the treatment until disease progression/recurrence (taking as reference for progressive disease the smallest measurements recorded since the treatment started). The patient's best response assignment will depend on the achievement of both measurement and confirmation criteria. Response Evaluation Criteria in Solid Tumors 1.1 criteria will be used for tumor evaluation and patients will be re-evaluated every prior to treatment in cycle 3 and then in odd subsequent cycles. Responses will be summarized by simple descriptive summary statistics delineating complete and partial responses as well as stable and progressive disease in this patient population (overall and by tumor group).
Time frame: 15 months
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