This phase Ib trial studies the side effects and best dose of ricolinostat when given together with gemcitabine hydrochloride and cisplatin in treating patients with cholangiocarcinoma that cannot be removed by surgery or has spread to other places in the body. Ricolinostat may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as gemcitabine hydrochloride 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. Giving ricolinostat together with gemcitabine hydrochloride and cisplatin may work better in treating patients with cholangiocarcinoma that cannot be removed by surgery or has spread to other places.
PRIMARY OBJECTIVES: I. To determine the maximum tolerated dose (MTD) or a dose up to 240 mg/day, whichever is lower, of ricolinostat (ACY-1215) in combination with gemcitabine and cisplatin in patients with unresectable or metastatic cholangiocarcinoma. (Cohort I) SECONDARY OBJECTIVES: I. Characterize the safety profile of ACY-1215 in combination with gemcitabine and cisplatin in patients with unresectable or metastatic cholangiocarcinoma. (Both cohorts) II. Determine the single- and multiple-dose pharmacokinetic (PK) of ACY-1215 in combination with gemcitabine and cisplatin in patients with unresectable or metastatic cholangiocarcinoma. (Both cohorts) III. To evaluate tumor response to treatment with ACY-1215 in combination with gemcitabine and cisplatin (per Response Evaluation Criteria in Solid Tumors \[RECIST\] 1.1 criteria). (Both cohorts) IV. To assess progression-free and overall survival of patients treated with ACY-1215 in combination with gemcitabine and cisplatin. (Both cohorts) TERTIARY OBJECTIVES: I. Both blood and tissue samples will be obtained at baseline and post-treatment cycle 2 for future biomarker development, analysis, and potential blood based molecular/genomic profiling. (Both cohorts) II. Studies on Tissue pre-cycle 1 and post-cycle 2 of therapy will include: phospho extracellular signal-regulated kinases (ERK)1/2; hedgehog-signaling pathways (Gli transcription factors); BIM; histones acetylation; acetylation alpha (a)-tubulin; histone deacetylase (HDAC)6 levels; autophagy markers heat shock protein (HSP)90/70; hypoxia-inducible factor 1 (HIF1)alpha; beclin; microtubule-associated proteins 1A/1B light chain 3 (LC3); Ras homolog gene family member B (RhoB). OUTLINE: This is a dose-escalation study of ricolinostat. Patients receive cisplatin intravenously (IV) followed by gemcitabine hydrochloride IV on days 1 and 8, and ricolinostat orally (PO) on days 1-14. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 3 months for up to 1 year.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Mayo Clinic in Arizona
Scottsdale, Arizona, United States
Mayo Clinic in Florida
Jacksonville, Florida, United States
Mayo Clinic
Rochester, Minnesota, United States
MTD of ricolinostat or a dose up to 240 mg/day whichever is lower, of ACY-1215
PK blood sample
Time frame: Cycle 1, Day 1 pre-dose
MTD of ricolinostat or a dose up to 240 mg/day whichever is lower, of ACY-1215
PK blood sample
Time frame: Cycle 1, Day 8 pre-dose
MTD of ricolinostat or a dose up to 240 mg/day whichever is lower, of ACY-1215
PK blood sample
Time frame: 0.5 hr after ACY-1215 dosing
MTD of ricolinostat or a dose up to 240 mg/day whichever is lower, of ACY-1215
PK blood sample
Time frame: 24 hr after Cycle 1, Day 1 only
MTD of ricolinostat or a dose up to 240 mg/day whichever is lower, of ACY-1215
PK blood sample
Time frame: Prior to Cycle 1, Day 2 ACY-1215 dosing
MTD of ricolinostat or a dose up to 240 mg/day whichever is lower, of ACY-1215
PK blood sample
Time frame: 1 hr after ACY-1215 dosing
MTD of ricolinostat or a dose up to 240 mg/day whichever is lower, of ACY-1215
PK blood sample
Time frame: 2hr after ACY-1215 dosing
MTD of ricolinostat or a dose up to 240 mg/day whichever is lower, of ACY-1215
PK blood sample
Time frame: 4 hr after ACY-1215 dosing
MTD of ricolinostat or a dose up to 240 mg/day whichever is lower, of ACY-1215
PK blood sample
Time frame: 6-8 hr after ACY-1215 dosing
Best Response defined as the best objective status recorded using RECIST version 1.1
Responses will be summarized by simple descriptive summary statistics.
Time frame: Up to 1 year
Confirmed response is defined to be a stringent complete response, complete response, very good partial response, or partial response noted as the objective status on two consecutive evaluations using RECIST version 1.1
Will be evaluated using all cycles of treatment. 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). The number of responses may indicate further evaluation for specific tumor types in a Phase II setting.
Time frame: Up to 1 year
Incidence of adverse events evaluated via the ordinal common toxicity criteria (CTC) toxicity grading of 3+
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: Up to 1 year
Time to any hematologic nadirs (ANC, platelets, hemoglobin)
Will be summarized descriptively.
Time frame: Up to 1 year
Time to any treatment related grade 3+ toxicity
Will be summarized descriptively.
Time frame: Up to 1 year
Time to any treatment related toxicity
Will be summarized descriptively.
Time frame: Up to 1 year
Time to progression
Will be summarized descriptively.
Time frame: From registration to documentation of progression, up to 1 year
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Time to treatment failure
Will be summarized descriptively.
Time frame: From registration to documentation of progression, unacceptable toxicity, or refusal to continue participation by the patient assessed up to 1 year