An Open-Label Safety and Tolerability Study of INCB062079 in Subjects With Advanced Hepatocellular Carcinoma and Other Malignancies

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the safety and tolerability, and determine the maximum tolerated dose of INCB062079 in subjects with advanced hepatocellular carcinoma and other malignancies.

Official Title
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A Phase 1, Open-Label, Dose-Escalation and Expansion, Safety and Tolerability Study of INCB062079 in Subjects With Advanced Hepatocellular Carcinoma and Other Malignancies

Conditions
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Hepatocellular Carcinoma (HCC), Cholangiocarcinoma, Esophageal Cancer, Nasopharyngeal Cancer, Ovarian Cancer, Solid Tumors

Intervention / Treatment
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* Drug: INCB062079


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Part 1: HCC; cholangiocarcinoma; or esophageal, nasopharyngeal, or serious ovarian cancer, regardless of FGF19/FGFR4 status; or other solid tumor malignancies with documented FGF19/FGFR4 alteration (FGF19/FGFR4 pathway activating alterations include, but are not limited to, FGFR4 amplification, FGFR4 activating mutations, and FGF19 amplification) based on local testing. Part 2: Subjects will be enrolled into 1 of 3 cohorts: Cohort A: HCC with FGF19 amplification. Cohort B: HCC without FGF19 amplification. Cohort C: cholangiocarcinoma, esophageal, nasopharyngeal or serous ovarian cancers (regardless of FGF19/FGFR4 status), or other solid tumor malignancies with documented FGF19/FGFR4 alteration. Has progressed after prior therapy and either a) there is no further effective standard anticancer therapy available (including subject refusal) or b) is intolerant to standard anticancer therapy. Life expectancy > 12 weeks. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 (Part 1) or 0-2 (Part 2). Archival tumor specimen according to protocol-defined criteria. Centrally analyzed screening C4 (bile acid synthesis precursor) results must be below 40.9 ng/mL, which is the upper limit as determined by the sponsor. Must agree to take bile acid sequestrants while taking INCB062079. Exclusion Criteria: Treatment with other investigational study drug for any indication for any reason, or receipt of anticancer medications within 28 days before first dose of study drug; subjects must have recovered from AEs due to previously administered therapies. Prior receipt of a selective FGFR4 inhibitor within the last 6 months. Laboratory parameters outside the protocol-defined ranges. History or presence of an abnormal ECG that in the investigator's opinion is clinically meaningful. Prior radiotherapy within 2 weeks of study treatment. A 1-week washout period is permitted for palliative radiation to non- central nervous system (CNS) disease with medical monitor approval. History of human immunodeficiency virus infection. Untreated brain or CNS metastases or brain/CNS metastases that have progressed. Subjects with previously treated and clinically stable brain/CNS metastases and who are off all corticosteroids for ≥ 4 weeks are eligible. Chronic or current active infectious disease requiring systemic antibiotic, antifungal, or antiviral treatment, except concomitant antiviral systemic therapy for chronic hepatitis B or C. Child-Pugh liver function Class B or C. History of clinically significant or uncontrolled cardiac disease. History of allergic reactions to INCB062079, any of the excipients of INCB062079 or similar compounds. Pregnant or nursing women or subjects expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 90 days after last dose of study drug. Any medical condition that would in the investigator's judgment interfere with full participation in the study, including administration of study medication and attending required study visits; pose a significant risk to the subject; or interfere with interpretation of study data.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1<br>Subjects with HCC, cholangiocarcinoma, or esophageal, nasopharyngeal, or serous ovarian cancers, regardless of FGF/FGFR alteration status. | Drug: INCB062079<br>* In Part 1, initial cohort dose of INCB062079 at the protocol-defined starting dose, with subsequent dose escalations based on protocol-specific criteria. The recommended dose(s) from Part 1 will be taken forward into Part 2 cohorts.<br>|
| Experimental: Part 2 Cohort A<br>Subjects with HCC with FGF19 amplification. | Drug: INCB062079<br>* In Part 1, initial cohort dose of INCB062079 at the protocol-defined starting dose, with subsequent dose escalations based on protocol-specific criteria. The recommended dose(s) from Part 1 will be taken forward into Part 2 cohorts.<br>|
| Experimental: Part 2 Cohort B<br>Subjects with HCC without FGF19 amplification. | Drug: INCB062079<br>* In Part 1, initial cohort dose of INCB062079 at the protocol-defined starting dose, with subsequent dose escalations based on protocol-specific criteria. The recommended dose(s) from Part 1 will be taken forward into Part 2 cohorts.<br>|
| Experimental: Part 2 Cohort C<br>Subjects with cholangiocarcinoma or esophageal, nasopharyngeal, or serous ovarian cancers (regardless of FGF/FGFR status), or other solid tumor malignancies with documented FGF19/FGFR4 alteration. | Drug: INCB062079<br>* In Part 1, initial cohort dose of INCB062079 at the protocol-defined starting dose, with subsequent dose escalations based on protocol-specific criteria. The recommended dose(s) from Part 1 will be taken forward into Part 2 cohorts.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and tolerability of INCB062079 as measured by assessment of adverse events (AEs) | An AE is defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related, that occurs after a subject provides informed consent. | Baseline to 30-35 days after end of treatment, up to approximately 6 months per subject. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Tumor response rates in subjects with measurable disease based on Response Evaluation Criteria in Solid Tumors (RECIST) | Subjects with hepatocellular carcinoma (HCC) will be evaluated via modified RECIST for HCC; subjects with other advanced malignancies will be evaluated using standard RECIST v1.1. | Every 2 cycles during the treatment period and every 8 weeks during the follow-up period, up to approximately 6 months per subject. | 
| Cmax of INCB062079 | Defined as maximum observed plasma concentration. | Protocol-defined time points during Cycles 1 and 2 of treatment, up to approximately 2 months per subject. | 
| Tmax of INCB062079 | Defined as time to maximum plasma concentration. | Protocol-defined time points during Cycles 1 and 2 of treatment, up to approximately 2 months per subject. | 
| Cmin of INCB062079 | Defined as minimum observed plasma concentration during the dosing interval. | Protocol-defined time points during Cycles 1 and 2 of treatment, up to approximately 2 months per subject. | 
| AUC0-t of INCB062079 | Defined as area under the single-dose plasma concentration-time curve from Hour 0 to the last quantifiable measurable plasma concentration. | Protocol-defined time points during Cycles 1 and 2 of treatment, up to approximately 2 months per subject. | 
| t½ of INCB062079 | Defined as the apparent plasma terminal phase disposition half-life. | Protocol-defined time points during Cycles 1 and 2 of treatment, up to approximately 2 months per subject. | 
| Cl/F of INCB062079 | Defined as oral dose clearance. | Protocol-defined time points during Cycles 1 and 2 of treatment, up to approximately 2 months per subject. | 
| Analysis of biomarkers | A plasma sample will be collected during screening for possible analysis of FGFR4 pathway mutations using tumor circulating DNA. | Screening visit | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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solid tumors, hepatocellular carcinoma, cholangiocarcinoma, esophageal, nasopharyngeal, serous ovarian, fibroblast growth factor (FGF), fibroblast growth factor receptor (FGFR)