A Phase II, Single Arm Study of BGJ398 in Patients With Advanced Cholangiocarcinoma

Study Overview
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Brief Summary
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This is a multi-center, open label, single arm phase II study evaluating BGJ398 (infigratinib) anti-tumor activity in advanced or metastatic cholangiocarcinoma patients with fibroblast growth factor receptor (FGFR) genetic alterations.

Detailed Description
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Adult patients with histologically or cytologically confirmed advanced or metastatic cholangiocarcinoma with FGFR2 gene fusions or translocations or other FGFR genetic alterations have been enrolled. Subjects must have received at least one prior regimen containing gemcitabine with or without cisplatin for advanced/metastatic disease. Subjects should have had evidence of progressive disease following their prior regimen or if prior treatment was discontinued due to toxicity must have continued evidence of measurable disease. Up to approximately 160 adult patients over age 18, both male and female were planned for enrollment. Three cohorts of subjects comprise the study population: Cohort 1: subjects with FGFR2 gene fusions (ie, fusions or rearrangements [formerly translocations]). Cohort 2: subjects with FGFR genetic alterations other than FGFR2 gene fusions or rearrangements. Cohort 3: subjects with FGFR2 gene fusions or rearrangements who have received a prior FGFR inhibitor. All subjects received oral BGJ398 (infigratinib), once-daily, on a three weeks on (21 days), one week off (7 days) schedule. One treatment cycle consists of 28 days. Notes: Cohort 1 was pre-specified as the primary analysis population. Results of these analyses were previously disclosed (posted 22 June 2022). There were no additional efficacy or safety endpoints to assess in Cohort 1 after primary completion (01 March 2021). Cohorts 2 and 3 were added at protocol amendment (PA) 4 to support only exploratory efficacy objectives of the study. These cohorts were ongoing the time of primary completion (01 March 2021). After interim review of the data from these cohorts (as permitted by the protocol) only limited efficacy was observed and the sponsor terminated the study early. Therefore, a formal efficacy analysis was not performed for Cohorts 2 and 3. However, baseline characteristics and safety data were analyzed.

Official Title
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A Phase II Multicenter, Single Arm Study of Oral BGJ398 in Adult Patients With Advanced or Metastatic Cholangiocarcinoma With FGFR2 Gene Fusions or Other FGFR Genetic Alterations Who Failed or Are Intolerant to Platinum-based Chemotherapy

Conditions
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Advanced Cholangiocarcinoma, FGFR2 Gene Mutation

Intervention / Treatment
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* Drug: BGJ398 (infigratinib)


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: - Adult patients with histologically or cytologically confirmed cholangiocarcinoma at the time of diagnosis. Patients with cancers of the gallbladder or ampulla of Vater are not eligible. - Patients must have received at least one prior regimen containing gemcitabine with or without cisplatin for advanced/ metastatic disease. Patient should have evidence of progressive disease following prior regimen, or if prior treatment discontinued due to toxicity must have continued evidence of measurable or evaluable disease. Exclusion criteria: Prior or current treatment with a MEK inhibitor (all Cohorts), BGJ398 (infigratinib) (all Cohorts), or selective FGFR inhibitor (Cohorts 1 and 2 only). insufficient organ function Absolute Neutrophil Count (ANC) < 1,000/mm3 [1.0 x 10^9/L] Platelets < 75,000/mm3 [75 x 10^9/L] Hemoglobin < 109.0 g/dL Total bilirubin > 1.5x upper limit of normal (ULN) Aspartate aminotransferase/glutamic oxaloacetic transaminase (AST/SGOT) and alanine aminotransferase/glutamic pyruvic transaminase (ALT/SGPT) > 2.5x ULN (AST and ALT > 5x ULN in the presence of liver metastases) Serum creatinine > 1.5x ULN and a calculated or measured creatinine clearance < 45 mL/min Inorganic phosphorus outside of normal limits Total and ionized serum calcium outside of normal limits Other protocol-defined inclusion/exclusion criteria may apply.

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BGJ398 (infigratinib)<br>To estimate the anti-tumor activity of BGJ398 (infigratinib) | Drug: BGJ398 (infigratinib)<br>* Capsule for oral use<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR) as Assessed by Blinded Independent Central Imaging Review (BICR) | ORR is defined as the percentage (%) of subjects with a best overall response of Complete Response (CR) or Partial Response (PR), as per Response Evaluation Criteria in Solid Tumors (RECIST), Version 1.1, evaluated by computed tomography (CT) or magnetic resonance imaging (MRI) scans every 28 days. RECIST (v1.1) response criteria were as follows: CR: disappearance of all target lesions. Any pathological lymph node (whether target or non-target) must have reduction in short axis to <10 mm. PR: at least a 30% decrease from baseline in the sum of diameters of all target lesions. Note: The primary efficacy outcome measures were prespecified only for Cohort 1 (FGFR fusions). Results were previously disclosed (22 June 2022). There are no additional efficacy endpoints to assess for Cohort 1, thus efficacy data were not re-analyzed for the final analysis. Due to early termination of the study, no formal efficacy analyses were performed for Cohorts 2 and 3. | Analysis was conducted when all subjects in Cohort 1 had the opportunity to be followed for at least 10 months after their initial exposure to infigratinib. Data cutoff 01 March 2021. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR) as Assessed by the Investigator | ORR is defined as the percentage (%) of subjects with a best overall response of CR or PR, evaluated by CT or MRI scans every 28 days. RECIST (v1.1) response criteria were as follows: CR: disappearance of all target lesions. Any pathological lymph node (whether target or non-target) must have reduction in short axis to <10 mm. PR: at least a 30% decrease from baseline in the sum of diameters of all target lesions. Note: The primary efficacy outcome measures were prespecified only for Cohort 1 (FGFR fusions) only. These results were previously disclosed (22 June 2022). There are no additional efficacy endpoints to assess for Cohort 1, thus efficacy data were not re-analyzed for the final analysis. Due to early termination of the study, no formal efficacy analyses were performed for Cohorts 2 and 3. | Analysis conducted when all subjects in Cohort 1 had the opportunity to be followed for at least 10 months after their initial exposure to infigratinib. Data cutoff for the primary analysis was 01 March 2021. | 
| Best Overall Response (BOR) | BOR is defined as the best overall response a subject achieved during the study before any subsequent antineoplastic therapy. The endpoint is summarized for the rate of BOR of CR, PR, progressive disease (PD), and stable disease (SD), evaluated by CT or MRI scans every 28 days. RECIST (v1.1) response criteria were as follows: CR: disappearance of all target lesions. Any pathological lymph node (whether target or non-target) must have reduction in short axis to <10 mm. PR: at least a 30% decrease from baseline in the sum of diameters of all target lesions. PD: at least a 20% increase in the sum of diameters of all target lesions from that of the smallest sum on study and an absolute increase in target lesion of at least 5mm. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum of diameters while on study. Note: The primary efficacy outcome measures were prespecified only for Cohort 1 (FGFR fusion) | Analysis conducted when all subjects in Cohort 1 had the opportunity to be followed for at least 10 months after their initial exposure to infigratinib. Data cutoff 01 March 2021. | 
| Disease Control Rate (DCR) | DCR is the percentage (%) of subjects with a BOR of CR, PR, or SD, evaluated by CT or MRI scans every 28 days. Results are based on both BICR and on Investigator assessment. RECIST (v1.1) response criteria were as follows: CR: disappearance of all target lesions. Any pathological lymph node (whether target or non-target) must have reduction in short axis to <10 mm. PR: at least a 30% decrease from baseline in the sum of diameters of all target lesions. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum of diameters while on study. Note: The primary efficacy outcome measures were prespecified only for Cohort 1 (FGFR fusions) (disclosed 22 June 2022). There are no additional efficacy endpoints to assess for Cohort 1, thus efficacy data were not re-analyzed for the final analysis. Due to early termination of the study, no formal efficacy analyses were performed for Cohorts 2 and 3. | Analysis conducted when all subjects in Cohort 1 had the opportunity to be followed for at least 10 months after their initial exposure to infigratinib. Data cutoff 01 March 2021. | 
| Progression-Free Survival (PFS) | PFS was calculated as the number of months from the first dose of study drug to the first documented progression or death due to any cause, whichever occurred earlier. Subjects without an assessment of progression or death were censored at the last adequate tumor assessment. For subjects who had an event after ≥2 missed visits, the subject was censored at the last adequate tumor assessment before the missing visit. Disease progression was assessed per RECIST (v1.1) and defined as at least a 20% increase in the sum of diameters of all target lesions from that of the smallest sum on study and an absolute increase in target lesion of at least 5mm. Results are based on both BICR and on Investigator assessment. Note: The primary efficacy outcome measures were prespecified only for Cohort 1 (FGFR fusions) (disclosed 22 June 2022). Due to early termination of the study, no formal efficacy analyses were performed for Cohorts 2 and 3. | Analysis conducted when all subjects in Cohort 1 had the opportunity to be followed for at least 10 months after their initial exposure to infigratinib. Data cutoff 01 March 2021. | 
| Overall Survival (OS) | OS was defined as the time (months) from the date of start of treatment to the date of death due to any cause. Note: The primary efficacy outcome measures were prespecified only for Cohort 1 (FGFR fusions) (disclosed 22 June 2022). Due to early termination of the study, no formal efficacy analyses were performed for Cohorts 2 and 3. | Analysis conducted when all subjects in Cohort 1 had the opportunity to be followed for at least 10 months after their initial exposure to infigratinib. Data cutoff 01 March 2021. | 
| Duration of Response (DOR) | DOR is defined as the time (months) from the initial response to the time of the event; defined as the first documented progression or death due to any cause, whichever was earlier. Note that results are based on a subgroup of subjects with confirmed responses (CR or PR) as assessed by BICR or by the Investigator. RECIST (v1.1) response criteria was as follows: CR: disappearance of all target lesions. Any pathological lymph node (whether target or non-target) must have reduction in short axis to <10 mm. PR: at least a 30% decrease from baseline in the sum of diameters of all target lesions. Note: The primary efficacy outcome measures were prespecified only for Cohort 1 (FGFR fusions) (disclosed 22 June 2022). Due to early termination of the study, no formal efficacy analyses were performed for Cohorts 2 and 3. | Analysis conducted when all subjects in Cohort 1 had the opportunity to be followed for at least 10 months after their initial exposure to infigratinib. Data cutoff 01 March 2021. | 
| Response Onset | Response onset was defined as the time (months) from the first study treatment administration date to the initial response. Note that results are based on a subgroup of subjects with confirmed responses (CR or PR) as assessed by BICR or by the Investigator. RECIST (v1.1) response criteria was as follows: CR: disappearance of all target lesions. Any pathological lymph node (whether target or non-target) must have reduction in short axis to <10 mm. PR: at least a 30% decrease from baseline in the sum of diameters of all target lesions. Note: The primary efficacy outcome measures were prespecified only for Cohort 1 (FGFR fusions) (disclosed 22 June 2022). Due to early termination of the study, no formal efficacy analyses were performed for Cohorts 2 and 3. | Analysis conducted when all subjects in Cohort 1 had the opportunity to be followed for at least 10 months after their initial exposure to infigratinib. Data cutoff 01 March 2021. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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cholangiocarcinoma,, FGFR2 gene fusion,, FGFR genetic alteration