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Rare Diseases

Cholangiocarcinoma

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Carcinoma

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Bile Duct Cancer

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Jackson-Weiss Syndrome

Pfeiffer Syndrome

Antineoplastic Agents

All Drugs and Chemicals

Infigratinib

To estimate the anti-tumor activity of BGJ398 (infigratinib)

BGJ398 (infigratinib)

QED Therapeutics

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.

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.

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

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

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) (disclosed 22 June 2022).

Due to early termination of the study, no formal efficacy analyses were performed for Cohorts 2 and 3.

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.

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.

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)

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.

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.

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.

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.

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.

Helsinn Healthcare SA

QED Therapeutics, Inc.

Adverse events (AEs) were assessed by the investigator according to CTCAE v4.03 and coded using MedDRA v21.0.

Unless otherwise specified, treatment-emergent AEs are reported. AEs were considered treatment-emergent if they occurred on or after the first dose through the date of last dose +30 days.

Infigratinib 125 mg once daily (3 wk on/1 wk off treatment)

Cohort 1: FGFR2 Fusions

Cohort 2: Other FGFR Genetic Alterations

Cohort 3: FGFR2 Fusions and Prior FGFR Inhibitor

Total

Age, Categorical

Age, Continuous

Sex: Female, Male

Race (NIH/OMB)

North America

Europe

South Korea

Singapore

Taiwan

Thailand

Region of Enrollment

Functional status was assessed at baseline using the Eastern Cooperative Oncology Group Performance Scale (ECOG PS), defined as follows:

0. Fully active, able to carry out all pre-disease performance without restriction.

1. Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature.
2. Ambulatory and capable of all selfcare but unable to carry out any work activities; up and about more than 50% of waking hours.
3. Capable of only limited selfcare; confined to bed or chair more than 50% of waking hours.
4. Completely disabled.

ECOG PS

Primary site of cancer

Non-Liver Metastatic Site

Bone

Lung

Node

Other

Data represent the number of patients in the FAS with at least one metastatic site. Note that for some patients, metastases may have been reported at more than one site.

Time from initial diagnosis to first dose day

The date of most recent recurrence/progression is based on medical history which may not have been available for all patients.

Time from the most recent recurrence/progression to the first dose day

Histological Grade

The AJCC staging manual (7th edition) for intrahepatic cholangiocarcinoma was used for cancer staging at baseline, defined as follows:

Stage I: solitary tumor without vascular invasion. Stage II: solitary tumor with vascular invasion or multiple tumors with or without vascular invasion.

Stage III: tumor perforating the visceral peritoneum or involving local hepatic structure by direct invasion.

Stage IV: tumor with periductal invasion, or any tumor with regional lymph node metastasis present, or any tumor with or without lymph node metastasis but metastasized to a distant site.

Stage at Time of Study Entry

Full Analysis Set (FAS), defined as all subjects who had received at least 1 dose of infigratinib.

David van Veenhuyzen, Vice President, Clinical Development

Full Analysis Set (FAS), defined as all subjects in Cohort 1 who had received at least one dose of infigratinib.

Overall Response Rate (ORR) as Assessed by Blinded Independent Central Imaging Review (BICR)

Cohort 1: FGFR2 Fusion/Rearrangements

Overall Response Rate (ORR) as Assessed by the Investigator

BOR by BICR

BOR by Investigator

Best Overall Response (BOR)

DCR by BICR

DCR by Investigator

Disease Control Rate (DCR)

PFS by BICR

PFS by Investigator

Progression-Free Survival (PFS)

Overall Survival (OS)

DOR by BICR

DOR by Investigator

Full Analysis Set (FAS), defined as all subjects in Cohort 1 who had received at least one dose of infigratinib. Conducted in a subgroup of subjects who were confirmed responders (CR or PR) as assessed by BICR (N = 25) or by the Investigator (N = 35).

Duration of Response (DOR)

Response onset by BICR

Response onset by Investigator

Response Onset

Full Analysis Set (FAS), defined as all subjects in Cohort 1 who had received at least one dose of infigratinib. Conducted in a subgroup of subjects with both a PFS measure while on infigratinib and available TTP for their last prior line of therapy (N = 103).

Growth Modulation Index (GMI)

After Second-Line Therapy (Prior to Infigratinib Treatment)

Third or Later-Line Therapy (Infigratinib)

Post-hoc subgroup assessment of efficacy in those subjects who were receiving infigratinib as a third or later line of treatment.

Investigator-assessed ORR was obtained from subjects' medical histories to provide a baseline evaluation of their response after historical second-line antineoplastic treatment prior to infigratinib treatment. Investigator-assessed ORR was then calculated in the same subjects after third- or later-line infigratinib therapy.

ORR is defined as the percentage (%) of patients with CR or PR, per RECIST (v1.1).

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 (22 June 2022).

No formal efficacy analyses were performed for Cohorts 2 and 3.

Full Analysis Set (FAS), defined as all subjects in Cohort 1 who had received at least one dose of infigratinib Conducted in a subgroup of subjects who were receiving infigratinib as a third or later line of treatment (N = 59).

Retrospective Analysis of Post-second-line Antineoplastic Treatment Outcomes on ORR

Post-hoc subgroup assessment of efficacy in those subjects who were receiving infigratinib as a third or later line of treatment.

Investigator-assessed PFS was obtained from subjects' medical histories to provide a baseline evaluation of their response after historical second-line antineoplastic treatment prior to infigratinib treatment. Investigator-assessed PFS was then calculated in the same subjects after third- or later-line infigratinib therapy.

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.

Full Analysis Set (FAS), defined as all subjects in Cohort 1 who had received at least one dose of infigratinib. Conducted in a subgroup of subjects who were receiving infigratinib as a third or later line of treatment (N=59).

Retrospective Analysis of Post-second-line Antineoplastic Treatment Outcomes on PFS

Post-hoc subgroup assessment of efficacy in those subjects who were receiving infigratinib as a third or later line of treatment.

Investigator-assessed BOR was obtained from subjects' medical histories to provide a baseline evaluation of their response after historical second-line antineoplastic treatment prior to infigratinib treatment. Investigator-assessed BOR was then calculated in the same subjects after third- or later-line infigratinib therapy.

The endpoint is summarized for the rate of BOR of PD, SD, PR, and CR.

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.

Full Analysis Set (FAS), defined as all subjects in Cohort 1 who had received at least one dose of infigratinib Conducted in a subgroup of subjects who were receiving infigratinib as a third or later line of treatment (N=59).

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
A Phase II, Single Arm Study of BGJ398 in Patients With Advanced Cholangiocarcinoma	NCT02150967	Advanced Cholan... FGFR2 Gene Muta...	BGJ398 (infigra...	18 Years -	QED Therapeutics, Inc.
A Phase II, Single Arm Study of BGJ398 in Patients With Advanced Cholangiocarcinoma	NCT02150967	Advanced Cholan... FGFR2 Gene Muta...	BGJ398 (infigra...	18 Years -	QED Therapeutics, Inc.
A Phase II, Single Arm Study of BGJ398 in Patients With Advanced Cholangiocarcinoma	NCT02150967	Advanced Cholan... FGFR2 Gene Muta...	BGJ398 (infigra...	18 Years -	QED Therapeutics, Inc.

Spots Global Cancer Trial Database for fgfr genetic alteration