This phase II trial assesses the feasibility (including both safety and tolerability) of conducting Next Generation Sequencing and administering targeted therapy (infigratinib) in the preoperative setting for patients with intrahepatic cholangiocarcinoma that can be removed by surgery (resectable). Chemotherapy drugs, such as nab-paclitaxel, cisplatin, and gemcitabine, 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. Targeted therapy with infigratinib will bind to FGFR which can help stop tumor cell growth and cause tumor cell death. Giving chemotherapy and/or targeted therapy before surgery may make the tumor smaller for resection and may help prevent the cancer from coming back. If a molecular profiling test shows a genetic change called an FGFR2 fusion, patients receive both chemotherapy and targeted therapy while patients without a FGFR2 fusion just receive chemotherapy. Giving targeted therapy based on molecular profile testing results prior to attempted resection of an intrahepatic cholangiocarcinoma that has a risk for either not being able to be removed or for coming back after it has been removed may help improve treatment outcomes.
PRIMARY OBJECTIVE: I. To assess the feasibility of a novel treatment strategy that includes conducting next generation sequencing (NGS)-based treatment on a preoperative tissue biopsy and subsequent administration of infigratinib phosphate (infigratinib) to patients with FGFR2 fusions versus neoadjuvant chemotherapy consisting of gemcitabine hydrochloride (gemcitabine), cisplatin, and nab-paclitaxel to all other patients for resectable intrahepatic cholangiocarcinoma. SECONDARY OBJECTIVES: I. To evaluate the efficacy of the intervention by assessing the radiological response rate. II. To assess degree of pathologic response in the surgical specimen. III. To assess response to therapy by measuring circulating tumor deoxyribonucleic acid (CT-DNA). IV. To determine the R0 resection rate. V. To determine recurrence-free survival (RFS). VI. To determine overall survival (OS). OUTLINE: While awaiting NGS molecular profile results, all patients receive nab-paclitaxel intravenously (IV) over 30 minutes, cisplatin IV over 60 minutes, and gemcitabine IV over 30 minutes on days 1 and 8 of one 21-day cycle in the absence of disease progression or unacceptable toxicity. After obtaining NGS molecular profile results, patients who are FGFR2 fusion/translocation positive are assigned to Arm A, while patients who are FGFR2 fusion/translocation negative are assigned to Arm B. ARM A: Patients receive infigratinib orally (PO) once daily (QD) on days 1-21 of each cycle. Treatment repeats every 28 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients whose cancer is stable or improved undergo surgery to remove the tumor within 8 weeks of completing preoperative therapy per standard of care. ARM B: Patients continue receiving nab-paclitaxel IV over 30 minutes, cisplatin IV over 60 minutes, and gemcitabine IV over 30 minutes on days 1 and 8 of each cycle. Treatment repeats every 21 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity. Patients whose cancer is stable or improved undergo surgery to remove the tumor within 8 weeks of completing preoperative therapy per standard of care. After completion of study treatment, patients are followed up within 4 weeks and every 4 months for 3 years.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
SINGLE
Feasibility of Completing All Preoperative Testing and Therapy
Treatment completion is defined as completion of next generation sequencing testing and all preoperative and operative therapy. The completion of all therapy rate, along with the exact 95% binomial confidence interval will be record. If a patient is not a candidate for surgery after completion of all preoperative therapy, this will be considered an event against feasibility of this treatment strategy, at which time patients will receive further treatment as best deemed by their treating physician.
Time frame: Up to 3 years
Unacceptable Toxicity
Unacceptable toxicity is defined as any grade 3 or higher toxicities by Common Terminology Criteria for Adverse Events criteria that result in a treatment delay of \>4 weeks. The rate of unacceptable toxicity will be reported, along with the exact 95% binomial confidence interval. If the therapy cannot be completed due to a delay of \>4 weeks, this will be considered an event for this approach not being feasible.
Time frame: Up to 3 years
Safety and Tolerability
Safety and tolerability will be assessed in terms of adverse events, and serious adverse events. Summary of these events will be tabulated by the maximum reported Common Terminology Criteria for Adverse Events grade and in relation to study treatment. Both adverse Events and serious adverse events will be tabulated using frequencies and percentages.
Time frame: Up to 3 years
Radiological Response Rate by Response Evaluation Criteria in Solid Tumors
Radiological response rate will be defined as the percentage of patients who will have complete response, partial response or stable disease after the neoadjuvant therapy. The radiological response rate will be estimated, along with the exact 95% binomial confidence interval.
Time frame: Up to 3 years
Pathologic Response Rate
Pathologic response will be defined as the degree of treatment effect to preoperative therapy. This will be measured as percent of viable cancer cells and percent of necrotic cells in the surgically resected specimen. A pathologic complete response is defined as having no viable cancer cells in the surgical specimen at the time of surgery.
Time frame: Up to 3 years
Circulating Tumor Deoxyribonucleic Acid Response
Circulating tumor deoxyribonucleic acid will be collected as an exploratory secondary endpoint. The investigators will be blinded as to the results of the circulating tumor deoxyribonucleic acid assay until after the study is complete as to avoid any bias towards treatment decisions based on this exploratory endpoint.
Time frame: Up to 3 years
Recurrence-Free Survival
Recurrence-free survival is defined as the time between the date of surgery and the date of disease recurrence or death, whichever occurred first. If a patient did not have an event (i.e. disease recurrence or death) by the time of final analysis, patient will be censored at the last disease evaluation time. The Kaplan-Meier method will be used to estimate recurrence-free survival. The two-sided log-rank tests will be used to assess the differences of recurrence-free survival between groups.
Time frame: Time between the date of surgery and the date of disease recurrence or death, whichever occurred first, or assessed up to 3 years
Overall Survival
Overall survival is defined as the time from date of neoadjuvant treatment start to the date of death from any cause or to the date of last follow-up if patients are alive. If a patient is alive by the time of final analysis, the patient will be censored at the last follow-up date. The Kaplan-Meier method will be used to estimate overall survival. The two-sided log-rank tests will be used to assess the differences of overall survival between groups.
Time frame: Time from date of neoadjuvant treatment start to the date of death from any cause or to the date of last follow-up if patients are alive, or assessed up to 3 years
This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.