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

• ClinicalTrials.gov Identifier: NCT02150967
• Recruitment Status: Completed
• First Posted: May 30, 2014
• Results First Posted: July 15, 2022
• Last Update Posted: July 15, 2022
• Sponsor: QED Therapeutics, Inc.
• Collaborator: Helsinn Healthcare SA
• Information provided by (Responsible Party): QED Therapeutics, Inc.

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Advanced Cholangiocarcinoma; FGFR2 Gene Mutation	Drug: BGJ398 (infigratinib)	Phase 2

Detailed Description:

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]) and those with other FGFR genetic alterations (ie, nonfusion; these subjects were enrolled before protocol amendment [PA] 2).

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.

Note: Cohorts 2 and 3 were added at PA 4 to support exploratory objectives of the study. These cohorts are not part of the primary efficacy analysis reported in this disclosure.

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 143 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: July 23, 2014
• Actual Primary Completion Date: March 1, 2021
• Actual Study Completion Date: February 7, 2022

Arms and Interventions

Arm	Intervention/treatment
Experimental: BGJ398 (infigratinib); To estimate the anti-tumor activity of BGJ398 (infigratinib)	Drug: BGJ398 (infigratinib); Capsule for oral use

Outcome Measures

Primary Outcome Measures :

1. Overall Response Rate (ORR) as Assessed by Blinded Independent Central Imaging Review (BICR) [ Time Frame: 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. ]

   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).

   Cohort 1 (Other FGFR alterations) was not the primary analysis population, thus efficacy results for this cohort are not reported.

Secondary Outcome Measures :

1. Overall Response Rate (ORR) as Assessed by the Investigator [ Time Frame: 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. ]

   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).

   Cohort 1 (Other FGFR alterations) was not the primary analysis population, thus efficacy results for this cohort are not reported.

2. Best Overall Response (BOR) [ Time Frame: 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. ]

   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: Primary efficacy outcome measures were prespecified only for Cohort 1 (FGFR fusions).

3. Disease Control Rate (DCR) [ Time Frame: 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. ]

   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).

   Cohort 1 (Other FGFR alterations) was not the primary analysis population, thus efficacy results for this cohort are not reported.

4. Progression-Free Survival (PFS) [ Time Frame: 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. ]

   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).

   Cohort 1 (Other FGFR alterations) was not the primary analysis population, thus efficacy results for this cohort are not reported.

5. Overall Survival (OS) [ Time Frame: 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. ]

   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).

   Cohort 1 (Other FGFR alterations) was not the primary analysis population, thus efficacy results for this cohort are not reported.

6. Duration of Response (DOR) [ Time Frame: 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. ]

   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).

   Cohort 1 (Other FGFR alterations) was not the primary analysis population, thus efficacy results for this cohort are not reported.

7. Response Onset [ Time Frame: 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 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).

   Cohort 1 (Other FGFR alterations) was not the primary analysis population, thus efficacy results for this cohort are not reported.

Other Outcome Measures:

1. Growth Modulation Index (GMI) [ Time Frame: 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. ]

   The GMI is defined as the ratio of PFS (months) during treatment with infigratinib relative to the time (months) to progression (TTP) during treatment with last prior line of therapy.

   Subjects served as their own control.

   Results are provided for both BICR and Investigator assessment.

   Note: The primary efficacy outcome measures were prespecified only for Cohort 1 (FGFR fusions).

   Cohort 1 (Other FGFR alterations) was not the primary analysis population, thus efficacy results for this cohort are not reported.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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.

Contacts and Locations

Locations

United States, Arizona

QED Investigative Site

Phoenix, Arizona, United States, 85054

United States, California

QED Investigative Site

Los Angeles, California, United States, 90033

QED Investigative Site

Los Angeles, California, United States, 90095

QED Investigative Site

San Francisco, California, United States, 94158

United States, Massachusetts

QED Investigative Site

Boston, Massachusetts, United States, 02114

United States, Michigan

QED Investigative Site

Detroit, Michigan, United States, 48201

United States, New York

QED Investigative Site

New York, New York, United States, 10016

QED Investigative Site

New York, New York, United States, 10029

QED Investigative Site

New York, New York, United States, 10065

United States, Ohio

QED Investigative Site

Columbus, Ohio, United States, 43221

United States, Texas

QED Investigative Site

Houston, Texas, United States, 77030-4009

Belgium

QED Investigative Site

Brussels, Belgium, 1200

QED Investigative Site

Leuven, Belgium, 3000

Germany

QED Investigative Site

Koeln, Nordrhein-Westfalen, Germany, 50937

QED Investigative Site

Heidelberg, Germany, 69120

QED Investigative Site

Tuebingen, Germany

Italy

QED Investigative Site

Ancona, AN, Italy, 60126

QED Investigative Site

Milano, MI, Italy, 20132

QED Investigative Site

Roma, RM, Italy, 00168

Korea, Republic of

QED Investigative Site

Seoul, Korea, Korea, Republic of, 03080

QED Investigative Site

Seoul, Korea, Korea, Republic of, 06351

Russian Federation

QED Investigative Site

Moscow, Russian Federation, 125367

QED Investigative Site

Volzhskiy, Russian Federation, 404133

Singapore

QED Investigative Site

Singapore, Singapore, 119228

QED Investigative Site

Singapore, Singapore, 169610

Spain

QED Investigative Site

Barcelona, Spain, 8035

QED Investigative Site

Barcelona, Spain, 8908

QED Investigative Site

Madrid, Spain, 28050

Taiwan

QED Investigative Site

Taipei, Taiwan ROC, Taiwan, 10041

QED Investigative Site

Zhunan, Taiwan, 35053

Thailand

QED Investigative Site

Khon Kaen, THA, Thailand, 40002

QED Investigative Site

Bangkok, Thailand, 10330

QED Investigative Site

Bangkok, Thailand, 10400

United Kingdom

QED Investigative Site

Bebington, United Kingdom, CH63 4JY

QED Investigative Site

Birmingham, United Kingdom, B15 2TH

QED Investigative Site

Manchester, United Kingdom, M20 4BX

QED Investigative Site

Nottingham, United Kingdom, NG5 1PB

Sponsors and Collaborators

QED Therapeutics, Inc.

Helsinn Healthcare SA

Investigators

• Study Director: QED Therapeutics; QED Therapeutics

  Study Documents (Full-Text)

Documents provided by QED Therapeutics, Inc.:

Study Protocol  [PDF] January 15, 2020

Statistical Analysis Plan  [PDF] May 13, 2020

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Javle M, Roychowdhury S, Kelley RK, Sadeghi S, Macarulla T, Weiss KH, Waldschmidt DT, Goyal L, Borbath I, El-Khoueiry A, Borad MJ, Yong WP, Philip PA, Bitzer M, Tanasanvimon S, Li A, Pande A, Soifer HS, Shepherd SP, Moran S, Zhu AX, Bekaii-Saab TS, Abou-Alfa GK. Infigratinib (BGJ398) in previously treated patients with advanced or metastatic cholangiocarcinoma with FGFR2 fusions or rearrangements: mature results from a multicentre, open-label, single-arm, phase 2 study. Lancet Gastroenterol Hepatol. 2021 Oct;6(10):803-815. doi: 10.1016/S2468-1253(21)00196-5. Epub 2021 Aug 3.

Javle M, Lowery M, Shroff RT, Weiss KH, Springfeld C, Borad MJ, Ramanathan RK, Goyal L, Sadeghi S, Macarulla T, El-Khoueiry A, Kelley RK, Borbath I, Choo SP, Oh DY, Philip PA, Chen LT, Reungwetwattana T, Van Cutsem E, Yeh KH, Ciombor K, Finn RS, Patel A, Sen S, Porter D, Isaacs R, Zhu AX, Abou-Alfa GK, Bekaii-Saab T. Phase II Study of BGJ398 in Patients With FGFR-Altered Advanced Cholangiocarcinoma. J Clin Oncol. 2018 Jan 20;36(3):276-282. doi: 10.1200/JCO.2017.75.5009. Epub 2017 Nov 28.

Borad MJ, Gores GJ, Roberts LR. Fibroblast growth factor receptor 2 fusions as a target for treating cholangiocarcinoma. Curr Opin Gastroenterol. 2015 May;31(3):264-8. doi: 10.1097/MOG.0000000000000171.

• Responsible Party: QED Therapeutics, Inc.
• ClinicalTrials.gov Identifier: NCT02150967
• Other Study ID Numbers: CBGJ398X2204; 2013-005085-19 ( EudraCT Number )
• First Posted: May 30, 2014
• Results First Posted: July 15, 2022
• Last Update Posted: July 15, 2022
• Last Verified: June 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by QED Therapeutics, Inc.:

cholangiocarcinoma,; FGFR2 gene fusion,; FGFR genetic alteration

Additional relevant MeSH terms:

Cholangiocarcinoma; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Infigratinib; Antineoplastic Agents