Metastatic Cholangiocarcinoma, Unresectable Cholangiocarcinoma
Conditions
Keywords
Cholangiocarcinoma, fibroblast growth factor receptor inhibitor, FGFR, FGFR rearrangement
Brief summary
The purpose of this study is to evaluate the efficacy and safety of pemigatinib versus gemcitabine plus cisplatin chemotherapy in first-line treatment of participants with unresectable or metastatic cholangiocarcinoma with FGFR2 rearrangement.
Interventions
DRUGPemigatinib
Pemigatinib at the protocol-defined dose administered orally once daily as continuous therapy schedule (a cycle is 3 weeks).
DRUGGemcitabine
Gemcitabine 1000 mg/m\^2 administered as an intravenous infusion on Days 1 and 8 of every 3-week cycle for up to 8 cycles.
DRUGCisplatin
Cisplatin 25 mg/m\^2 administered as an intravenous infusion on Days 1 and 8 of every 3-week cycle for up to 8 cycles.
Sponsors
Incyte Corporation
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Male and female participants at least 18 years of age at the time of signing the informed consent form (ICF). * Histologically or cytologically confirmed cholangiocarcinoma that is previously untreated and considered unresectable and/or metastatic (Stage IV per the American Joint Committee on Cancer (AJCC) Cancer Staging Manual). * Radiographically measurable or evaluable disease by CT or MRI per RECIST v1.1 criteria. * Eastern Cooperative Oncology Group performance status 0 to 1. * Documented FGFR2 rearrangement. * Willingness to avoid pregnancy or fathering children.
Exclusion criteria
* Received prior anticancer systemic therapy for unresectable and/or metastatic disease (not including adjuvant/neo-adjuvant treatment completed at least 6 months prior to enrollment, and participants that have received treatment for locally advanced disease with trans-arterial chemoembolization or selective internal radiation therapy, if clear evidence of radiological progression is observed before enrollment, or enrolled as of Amendment 6 (or Amendment 5-JP2) and the participant received 1 cycle of gemcitabine plus cisplatin \[the start of study drug {Cycle 1 Day 1} must be at least 14 days and ≤ 4 weeks {28 days} from the last dose of gemcitabine plus cisplatin\]). * Child-Pugh B and C. * Toxicities related to prior therapy(ies) must be Common Terminology Criteria for Adverse Events (CTCAE) v5.0 ≤ Grade 1 at the time of screening. * Concurrent anticancer therapy, other than the therapies being tested in this study. * Participant is a candidate for potentially curative surgery. * Current evidence of clinically significant corneal (including but not limited to bullous/band keratopathy, corneal abrasion, inflammation/ulceration, and keratoconjunctivitis) or retinal disorder (including but not limited to central serous retinopathy, macular/retinal degeneration, diabetic retinopathy, retinal detachment) as confirmed by ophthalmologic examination. * Radiation therapy administered within 4 weeks of enrollment/randomization/first dose of study treatment. * Known central nervous system (CNS) metastases or history of uncontrolled seizures. * Known additional malignancy that is progressing or requires active treatment (exceptions: basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially curative therapy). * Laboratory values at screening outside the protocol-defined range. * History of calcium and phosphate hemostasis disorder or systemic mineral imbalance with ectopic calcification of soft tissues (exception: commonly observed calcifications in soft tissues, such as the skin, kidney, tendons or vessels due to injury, disease, and aging, in the absence of systemic mineral imbalance). * Significant gastrointestinal disorders that could interfere with absorption, metabolism, or excretion of pemigatinib. * Clinically significant or uncontrolled cardiac disease. * History or presence of an abnormal ECG, which, in the investigator's opinion, is clinically meaningful. * Chronic or current active infectious disease requiring systemic antibiotics or antifungal or antiviral treatment within 2 weeks prior to enrollment (participants with asymptomatic chronic infections on prophylactic treatment are allowed). Note: HIV-positive participants are allowed if all of the following criteria are met: CD4+ count ≥ 300/µL, undetectable viral load, receiving antiretroviral therapy that does not interact with study drug, and no HIV/AIDS-associated opportunistic infection in the last 12 months. * Use of any potent CYP3A4 inhibitors or inducers or moderate CYP3A4 inducers within 14 days or 5 half-lives (whichever is longer) before the first dose of study treatment. Note: Moderate CYP3A4 inhibitors are not prohibited * Known hypersensitivity or severe reaction to pemigatinib, gemcitabine, cisplatin, or their excipients. * Inadequate recovery from toxicity and/or complications from a major surgery before starting therapy.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Randomized Treatment Period: Progression-free Survival (PFS) | up to 1422 days | PFS was defined as the time from the date of randomization until the date of disease progression (according to Response Evaluation Criteria in Solid Tumors version 1.1 \[RECIST v1.1\] and assessed by an Independent Central Review \[ICR\]) or death, whichever occurs first. |
| Randomized Treatment Period: Kaplan-Meier Estimates of PFS of the Indicated Lengths of Time | up to 1422 days | PFS was defined as the time from the date of randomization until the date of disease progression (according to RECIST v1.1 and assessed by an ICR) or death, whichever occurs first. Kaplan-Meier estimates indicate the percent probability of a participant being alive at the indicated time after treatment start. |
| Transition Period: PFS | up to 1496 days | PFS was defined as the time from the date of the first dose of study drug after transition until the earliest date of progressive disease or death due to any cause. |
| Transition Period: Kaplan-Meier Estimates of PFS of the Indicated Lengths of Time | up to 1496 days | PFS was defined as the time from the date of the first dose of study drug after transition until the earliest date of progressive disease or death due to any cause. Kaplan-Meier estimates indicate the percent probability of a participant being alive at the indicated time after treatment start. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Randomized Treatment Period: Objective Response Rate (ORR) | up to 1422 days | ORR was defined as the percentage of participants with a best overall response of complete response (CR) or partial response (PR) per RECIST v1.1 as assessed by an ICR. CR: disappearance of all target and non-target lesions and no appearance of any new lesions. Any pathological lymph nodes (whether target or non-target) must have a reduction in the short axis to \<10 millimeters (mm). PR: complete disappearance or at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference the baseline sum diameters, no new lesions, and no progression of non-target lesions. |
| Transition Period: ORR | up to 1496 days | ORR was defined as the percentage of participants with a best overall response of CR or PR per RECIST v1.1 as assessed by an ICR. CR: disappearance of all target and non-target lesions and no appearance of any new lesions. Any pathological lymph nodes (whether target or non-target) must have a reduction in the short axis to \<10 mm. PR: complete disappearance or at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference the baseline sum diameters, no new lesions, and no progression of non-target lesions. |
| Randomized Treatment Period: Overall Survival | up to 1422 days | Overall survival was defined as the time from the date of randomization until death due to any cause. |
| Randomized Treatment Period: Kaplan-Meier Estimates of Overall Survival of the Indicated Lengths of Time | up to 1422 days | Overall survival was defined as the time from the date of randomization until death due to any cause. Kaplan-Meier estimates indicate the percent probability of a participant being alive at the indicated time after treatment start. |
| Randomized Treatment Period: Duration of Response (DOR) | up to 1422 days | DOR was defined as the time from the date of the first assessment of CR or PR until the date of the first disease progression by an ICR per RECIST v1.1 or death, whichever occurred first. CR: disappearance of all target and non-target lesions and no appearance of any new lesions. Any pathological lymph nodes (whether target or non-target) must have a reduction in the short axis to \<10 mm. PR: complete disappearance or at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference the baseline sum diameters, no new lesions, and no progression of non-target lesions. PD: progression of a target or non-target lesion or presence of a new lesion. |
| Randomized Treatment Period: Kaplan-Meier Estimates of DOR of the Indicated Lengths of Time | up to 1422 days | DOR was defined as the time from the date of the first assessment of CR or PR until the date of the first disease progression by an ICR per RECIST v1.1 or death, whichever occurred first. CR: disappearance of all target and non-target lesions and no appearance of any new lesions. Any pathological lymph nodes (whether target or non-target) must have a reduction in the short axis to \<10 mm. PR: complete disappearance or at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference the baseline sum diameters, no new lesions, and no progression of non-target lesions. PD: progression of a target or non-target lesion or presence of a new lesion. Kaplan-Meier estimates indicate the percent probability of a participant still having a CR or PR at the indicated time after treatment start. |
| Transition Period: DOR | up to 1496 days | DOR was defined as the time from the date of the first assessment of CR or PR until the date of the first disease progression by an ICR per RECIST v1.1 or death, whichever occurred first. CR: disappearance of all target and non-target lesions and no appearance of any new lesions. Any pathological lymph nodes (whether target or non-target) must have a reduction in the short axis to \<10 mm. PR: complete disappearance or at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference the baseline sum diameters, no new lesions, and no progression of non-target lesions. PD: progression of a target or non-target lesion or presence of a new lesion. |
| Transition Period: Kaplan-Meier Estimates of DOR of the Indicated Lengths of Time | up to 1496 days | DOR was defined as the time from the date of the first assessment of CR or PR until the date of the first disease progression by an ICR per RECIST v1.1 or death, whichever occurred first. CR: disappearance of all target and non-target lesions and no appearance of any new lesions. Any pathological lymph nodes (whether target or non-target) must have a reduction in the short axis to \<10 mm. PR: complete disappearance or at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference the baseline sum diameters, no new lesions, and no progression of non-target lesions. PD: progression of a target or non-target lesion or presence of a new lesion. Kaplan-Meier estimates indicate the percent probability of a participant still having a CR or PR at the indicated time after treatment start. |
| Randomized Treatment Period: Disease Control Rate (DCR) | up to 1422 days | DCR was defined as the percentage of participants who achieved a best overall response of CR, PR, or SD per RECIST v1.1 as assessed by an ICR. CR: disappearance of all target and non-target lesions and no appearance of any new lesions. Any pathological lymph nodes (whether target or non-target) must have a reduction in the short axis to \<10 mm. PR: complete disappearance or at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference the baseline sum diameters, no new lesions, and no progression of non-target lesions. PD: progression of a target or non-target lesion or presence of a new lesion. SD: no change in target lesions to qualify for CR, PR, or PD. |
| Transition Period: DCR | up to 1496 days | DCR was defined as the percentage of participants who achieved a best overall response of CR, PR, or SD per RECIST v1.1 as assessed by an ICR. CR: disappearance of all target and non-target lesions and no appearance of any new lesions. Any pathological lymph nodes (whether target or non-target) must have a reduction in the short axis to \<10 mm. PR: complete disappearance or at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference the baseline sum diameters, no new lesions, and no progression of non-target lesions. PD: progression of a target or non-target lesion or presence of a new lesion. SD: no change in target lesions to qualify for CR, PR, or PD. |
| Number of Participants With Any Treatment-emergent Adverse Event (TEAE) | up to 1457 days | An adverse event (AE) is any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of study treatment. A TEAE was defined as any AE either reported for the first time or the worsening of a pre-existing event after the first dose of study drug until 30 days after the last dose of study drug for participants who did not transition to pemigatinib. For participants who transitioned to pemigatinib, the end date was 30 days after the last dose date of gemcitabine plus cisplatin or the day before the first dose of pemigatinib after transition, whichever occurred first. |
| Number of Participants With Any Treatment-related TEAE | up to 1457 days | An AE is any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of study treatment. A TEAE was defined as any AE either reported for the first time or the worsening of a pre-existing event after the first dose of study drug until 30 days after the last dose of study drug for participants who did not transition to pemigatinib. For participants who transitioned to pemigatinib, the end date was 30 days after the last dose date of gemcitabine plus cisplatin or the day before the first dose of pemigatinib after transition, whichever occurred first. |
| Transition Period: Number of Participants With Any TEAE | up to 1531 days | An AE is any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of study treatment. A TEAE for the Crossover Evaluable Population was any AE either reported for the first time or for a worsened pre-existing event after the first dose of pemigatinib after switch and until 30 days after the last dose of pemigatinib. |
| Transition Period: Number of Participants With Any Treatment-related TEAE | up to 1531 days | An AE is any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of study treatment. A TEAE for the Crossover Evaluable Population was any AE either reported for the first time or for a worsened pre-existing event after the first dose of pemigatinib after switch and until 30 days after the last dose of pemigatinib. |
| Randomized Treatment Period: Change From Baseline (CFB) in European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-30) Scores at Early Termination | Baseline; up to 1422 days | The EORTC QLQ-C30 is a 30-item scale composed of both multi-item scales and single-item measures. These include 5 functional scales (physical functioning, role, cognitive functioning, emotional functioning, and social functioning), 3 symptom scales (fatigue, pain, and nausea/vomiting), a global health status scale, and 6 single items (constipation, diarrhea, sleep, dyspnea, appetite, financial). All scales and single-item measures range in score from 0 to 100. A high scale score represents a higher response level. Therefore, a high score for a functional scale represents a high/healthy level of functioning and a high score for the global health status/QoL represents a high QoL. A high score for a symptom scale/item represents a high level of symptomatology/problems. Change from Baseline was calculated as the post-Baseline value minus the Baseline value. |
| Randomized Treatment Period: Change From Baseline (CFB) in the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Including 21 Questions Specific to the Biliary System (EORTC QLQ-BIL21) at Early Termination | Baseline; up to 1422 days | The EORTC QLQ-BIL21 assessed QoL across 8 scales: eating, jaundice, tiredness, pain, anxiety, treatment side effects, drains, and weight loss. The raw score of each scale is the mean of the item values that contribute to the scale, and the standardized score is a linear transformation of the raw score so that the range is from 0 to 100. A high score for a symptom scale represents a high level of symptomatology/problems. The BIL21 questionnaire was only be administered to participants for whom the questionnaire is validated in that language. Change from Baseline was calculated as the post-Baseline value minus the Baseline value. |
| Randomized Treatment Period: Number of Participants With the Indicated Responses on the European Quality of Life 5 Dimensions (3 Levels) Questionnaire (EQ-5D [3L]) | Baseline; up to 1422 days | The EQ-5D (3L) is the descriptive system that comprises 5 dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension has 3 levels: no problems, some problems, extreme problems. |
Countries
Austria, Belgium, Canada, China, Denmark, Finland, France, Germany, Ireland, Israel, Italy, Japan, Netherlands, Norway, Spain, Sweden, Switzerland, United Kingdom, United States
Contacts
STUDY_DIRECTORPeter Langmuir, MD
Incyte Corporation
Participant flow
Pre-assignment details
This study was conducted at 79 study centers in 14 countries.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Customized | 58.3 years STANDARD_DEVIATION 12.76 |
| Race/Ethnicity, Customized Asian | 28 Participants |
| Race/Ethnicity, Customized Asian - Indian | 0 Participants |
| Race/Ethnicity, Customized Black or African American | 8 Participants |
| Race/Ethnicity, Customized Captured as "Hispanic" in the Database | 1 Participants |
| Race/Ethnicity, Customized Captured as "Other" in Database | 1 Participants |
| Race/Ethnicity, Customized Egyptian | 1 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 7 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 127 Participants |
| Race/Ethnicity, Customized Not Reported | 6 Participants |
| Race/Ethnicity, Customized Unknown | 2 Participants |
| Race/Ethnicity, Customized White | 60 Participants |
| Sex: Female, Male Female | 97 Participants |
| Sex: Female, Male Male | 33 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 51 / 83 | 47 / 84 | 27 / 42 |
| other Total, other adverse events | 83 / 83 | 72 / 73 | 42 / 42 |
| serious Total, serious adverse events | 23 / 83 | 17 / 73 | 9 / 42 |
Outcome results
None listed