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Patients receive oxaliplatin IV over 2 hours, irinotecan hydrochloride IV over 90 minutes, and fluorouracil IV continuously over 46 hours on days 1 and 15. Patients also receive pan FGFR kinase inhibitor BGJ398 PO QD on days 8-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Irinotecan Hydrochloride

Laboratory Biomarker Analysis

pan FGFR Kinase Inhibitor BGJ398

Pharmacological Study

Wen Wee Ma

This phase Ib/II trial studies the side effects and best dose of pan fibroblast growth factor receptor (FGFR) kinase inhibitor BGJ398 when given together with fluorouracil, irinotecan hydrochloride and oxaliplatin (combination chemotherapy) in treating patients with untreated pancreatic cancer that has spread to another place in the body. Pan FGFR kinase inhibitor BGJ398 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as fluorouracil, irinotecan hydrochloride and oxaliplatin, 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. Giving pan FGFR kinase inhibitor BGJ398 together with fluorouracil, irinotecan hydrochloride and oxaliplatin may be a better treatment for pancreatic cancer.

PRIMARY OBJECTIVES:

I. To determine dose-limiting toxicity, the maximum tolerated dose and recommended phase II dose of BGJ398 (pan FGFR kinase inhibitor BGJ398) administered in combination with modified (m)FOLFIRINOX (fluorouracil, irinotecan hydrochloride and oxaliplatin) in patients with advanced pancreatic and colorectal cancer patients. (Phase Ib)

II. To determine the 6-month overall survival rate of patients with treatment-naïve metastatic pancreatic ductal adenocarcinoma treated with BGJ398 plus mFOLFIRINOX. (Phase II)

SECONDARY OBJECTIVES:

I. To determine the pharmacokinetic profile of BGJ398, fluorouracil, oxaliplatin, irinotecan (irinotecan hydrochloride) and their metabolites when administered in combination and explore for drug-drug interactions. (Phase Ib)

II. To determine the 1-year overall survival rate, response rate, progression free survival and cancer antigen (CA)19-9 changes in treatment-naïve metastatic pancreatic cancer patients treated with BGJ398 plus mFOLFIRINOX. (Phase II)

III. To determine the safety and tolerability of BGJ398 in combination with mFOLFIRINOX in the study population.

IV. To explore plasma and tumor biomarkers associated with efficacy to the study combination.

OUTLINE: This is a phase Ib, dose-escalation study of pan FGFR kinase inhibitor BGJ398 followed by a phase II study.

Patients receive oxaliplatin intravenously (IV) over 2 hours, irinotecan hydrochloride IV over 90 minutes, and fluorouracil IV continuously over 46 hours on days 1 and 15. Patients also receive pan FGFR kinase inhibitor BGJ398 orally (PO) once daily (QD) on days 8-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 28 days and then every 4 months for up to 2 years.

Pan FGFR Kinase Inhibitor BGJ398 and Combination Chemotherapy in Treating Patients With Untreated Metastatic Pancreatic Cancer

A Phase Ib/II Study of BGJ398 in Combination Modified FOLFIRINOX in Treatment-Naïve Metastatic Pancreatic Cancer Patients

The MTD will be estimated using isotonic regression (cumulative cohort design).

The overall survival will be summarized using Kaplan-Meier methods, from which an estimate of the 6-month survival rate and corresponding standard error will be obtained using the methods proposed by Breslow and Day.

The CA19-9 expression will be reported by time as mean, median, standard deviation, and percentiles. Changes in expression will be evaluated using the paired t-test or Wilcoxon signed rank test, as appropriate.

The frequency of toxicities will be tabulated by grade across all dose levels and cycles. The frequency of toxicities will also be tabulated for the dose estimated to be the MTD and RP2D in phase Ib.

The objective tumor responses will be reported as frequencies and relative frequencies, with the response rates estimated with Clopper-Pearson 95% confidence intervals.

The progression free survival will be summarized using standard Kaplan-Meier methods, with estimates of median survival and given survival rates (i.e., 1 year) will be obtained with 95% confidence intervals.

Will be evaluated using logistic regression models and associated exact methods.

National Cancer Institute (NCI)

Roswell Park Cancer Institute

Spots Global Cancer Trial Database for pan fgfr kinase inhibitor bgj398