Solid Tumor
Conditions
Brief summary
The primary objective of this study is to assess the efficacy of Debio 1347 in terms of objective response rate (ORR) in participants with solid tumors harboring fibroblast growth factor receptor (FGFR)1-3 gene fusion/rearrangement.
Interventions
DRUGDebio 1347
Debio 1347 oral tablets.
Sponsors
Caris Life Sciences
Optimal Research (Just In Time sites)
Debiopharm International SA
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Cytologically or histologically confirmed advanced solid tumor * Radiographic progression on prior systemic therapy; prior localized therapy (i.e., radiation, ablation, embolization) is allowed provided radiographic progression out-of-field or in the treatment, field is shown * Locally-advanced (unresectable) or metastatic disease harboring an FGFR1-3 gene fusion/rearrangement potentially leading to a functional FGFR aberrant protein, identified through local and/or central molecular assay
Exclusion criteria
* History of hypersensitivity to any of the excipients in the Debio 1347 formulation * History and/or current evidence of ectopic mineralization/calcification, including but not limited to soft tissue, kidneys, intestine, myocardia, or lung, excepting calcified lymph nodes, lung nodules and asymptomatic vascular or cartilage/tendon calcifications * Administration of any investigational agent within 2 weeks prior to initial dosing with Debio 1347 (3 weeks for immune checkpoint inhibitors)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) as Centrally Measured by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) Criteria | Up to disease progression or end of study (up to 1 year and 9 months) | ORR was defined as the percentage of participants with a best overall response (BOR) of partial or complete response (PR or CR). BOR was defined as the best confirmed response observed from first administration of study drug until disease progression. CR was defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. PR was defined as ≥30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Disease Control Rate (DCR) as Centrally Measured by Independent Review Committee (IRC) | Up to disease progression or end of study (up to 2 years and 9 months) | DCR was defined as the percentage of participants with a BOR of confirmed CR, confirmed PR or stable disease (SD) ≥6 weeks. BOR was defined as the best confirmed response observed from first administration of study drug until disease progression. CR was defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. PR was defined as ≥30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking as reference the smallest sum diameters while on study. PD was defined as ≥ 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. |
| Progression-Free Survival (PFS) as Centrally Measured by Independent Review Committee (IRC) | From the start of the study up to disease progression or death (up to 2 years and 9 months) | PFS was defined as the time from the start date of treatment to date of the first documented progression or death due to any cause. |
| Overall Survival (OS) | Until death or loss to follow-up or end of study (up to 2 years and 9 months) | OS was defined as the time from the start date of treatment to date of death due to any cause. Participants with no documented death were censored at the last date known to be alive. |
| Duration of Response (DOR) as Centrally Measured by Independent Review Committee (IRC) | Up to disease progression or end of study (up to 2 years and 9 months) | DOR was defined as the time from the date of the initial PR or CR to date of the first documented progression or death due to any cause. CR was defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. PR was defined as ≥30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. |
| Trough Concentration at Steady State (Ctrough,ss) of Debio 1347 in Plasma | Predose and post dose up to Cycle 2 Day 28 (each cycle length = 28 days) | Geometric mean and geometric percent CV summary was estimated based on log-linear model. |
| Area Under the Plasma Concentration-Time Curve Over the Dosing Interval at Steady State (AUCtau,ss) of Debio 1347 in Plasma | Predose and post dose up to Cycle 2 Day 28 (each cycle length = 28 days) | Geometric mean and geometric percent CV summary was estimated based on log-linear model. |
| Correlation of Debio 1347 Plasma Concentration (C) and QT Interval Corrected for Heart Rate Using Fridericia's Formula (QTcF) | Pre-dose on Days 14 and 28, and 1, 3, 7 hours post-dose on Day 28 of Cycle 1; pre-dose on Days 14 and 28, and 3 hours post-dose on Day 28 of Cycle 2 (each cycle length = 28 days) | — |
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs) Assessed by National Cancer Institute Common Terminology Criteria (NCI CTCAE) v5.0 and Serious Adverse Events (SAEs) | From first dose of study drug up to 30 days post last dose (Up to 2 years and 9 months) | An AE is any untoward medical occurrence in a participant or clinical trial participant administered a medicinal product and which does not necessarily have a causal relationship with this treatment. A TEAE is defined as an AE that either starts or worsens in severity on or after the first administration of the study drug and within 30 days of the last administration of the study drug. An SAE is any untoward medical occurrence that at any dose results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect or is medically significant. |
Countries
Australia, Austria, Brazil, Bulgaria, Croatia, Czechia, Denmark, Finland, France, Greece, Netherlands, Norway, Philippines, Poland, Romania, Russia, Singapore, South Korea, Spain, Taiwan, Ukraine, United Kingdom, United States
Participant flow
Recruitment details
A total of 63 participants were enrolled at 31 investigational sites in the United States, France, Spain, Finland, Korea, Singapore, Australia, Bulgaria, Denmark, Norway, Russian Federation, Taiwan, and the United Kingdom from 22 March 2019 to 04 January 2022.
Pre-assignment details
A total of 63 participants with solid tumors harboring FGFR1-3 gene fusion/rearrangement were enrolled into one of the 3 cohorts: Cohort 1: Biliary Tract Cancer (N=30), Cohort 2: Urothelial Cancer (N=4), Cohort 3: All Other Solid Tumor Histologies (N=29) to receive Debio 1347.
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1: Debio 1347 (Biliary Tract Cancer) Participants with biliary tract cancer were included in this cohort to receive Debio 1347 80 mg tablets, orally, QD, from Day 1 to Day 28 in 28-day cycles until the occurrence of disease progression or unacceptable toxicity (up to a median duration of 20 weeks). | 30 |
| Cohort 2: Debio 1347 (Urothelial Cancer) Participants with urothelial cancer were included in this cohort to receive Debio 1347 80 mg tablets, orally, QD, from Day 1 to Day 28 in 28-day cycles until the occurrence of disease progression or unacceptable toxicity (up to a median duration of 5.86 weeks). | 4 |
| Cohort 3: Debio 1347 (All Other Solid Tumor Histologies) Participants with all other solid tumor histologies were included in this cohort to receive Debio 1347 80 mg tablets, orally, QD, from Day 1 to Day 28 in 28-day cycles until the occurrence of disease progression or unacceptable toxicity (up to a median duration of 8.14 weeks). | 29 |
| Total | 63 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 | 0 |
| Overall Study | Death | 8 | 1 | 17 |
| Overall Study | Reason not Specified | 9 | 0 | 6 |
| Overall Study | Sponsor/EthicsCommittee Decided to Terminate Study | 10 | 1 | 4 |
| Overall Study | Withdrawal of Consent | 2 | 2 | 2 |
Baseline characteristics
| Characteristic | Cohort 1: Debio 1347 (Biliary Tract Cancer) | Cohort 2: Debio 1347 (Urothelial Cancer) | Cohort 3: Debio 1347 (All Other Solid Tumor Histologies) | Total |
|---|---|---|---|---|
| Age, Continuous | 59.1 years STANDARD_DEVIATION 12.21 | 55.3 years STANDARD_DEVIATION 15.22 | 60.0 years STANDARD_DEVIATION 12.58 | 59.3 years STANDARD_DEVIATION 12.4 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 0 Participants | 1 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 29 Participants | 4 Participants | 28 Participants | 61 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 3 Participants | 1 Participants | 2 Participants | 6 Participants |
| Race/Ethnicity, Customized Black or African American | 5 Participants | 0 Participants | 0 Participants | 5 Participants |
| Race/Ethnicity, Customized Not Willing to Provide | 1 Participants | 0 Participants | 3 Participants | 4 Participants |
| Race/Ethnicity, Customized Other | 1 Participants | 0 Participants | 2 Participants | 3 Participants |
| Race/Ethnicity, Customized White | 20 Participants | 3 Participants | 22 Participants | 45 Participants |
| Sex: Female, Male Female | 16 Participants | 2 Participants | 16 Participants | 34 Participants |
| Sex: Female, Male Male | 14 Participants | 2 Participants | 13 Participants | 29 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 9 / 30 | 1 / 4 | 17 / 29 |
| other Total, other adverse events | 30 / 30 | 4 / 4 | 28 / 29 |
| serious Total, serious adverse events | 14 / 30 | 2 / 4 | 7 / 29 |
Outcome results
Primary
Objective Response Rate (ORR) as Centrally Measured by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) Criteria
ORR was defined as the percentage of participants with a best overall response (BOR) of partial or complete response (PR or CR). BOR was defined as the best confirmed response observed from first administration of study drug until disease progression. CR was defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. PR was defined as ≥30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
Time frame: Up to disease progression or end of study (up to 1 year and 9 months)
Population: ITT Population consisted of all participants who received study drug. Overall number of participants analyzed is the number of participants with measurable disease and tumor assessment at Baseline.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1: Debio 1347 (Biliary Tract Cancer) | Objective Response Rate (ORR) as Centrally Measured by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) Criteria | 6.7 percentage of participants |
| Cohort 2: Debio 1347 (Urothelial Cancer) | Objective Response Rate (ORR) as Centrally Measured by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) Criteria | 0 percentage of participants |
| Cohort 3: Debio 1347 (All Other Solid Tumor Histologies) | Objective Response Rate (ORR) as Centrally Measured by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) Criteria | 4.0 percentage of participants |
Secondary
Area Under the Plasma Concentration-Time Curve Over the Dosing Interval at Steady State (AUCtau,ss) of Debio 1347 in Plasma
Geometric mean and geometric percent CV summary was estimated based on log-linear model.
Time frame: Predose and post dose up to Cycle 2 Day 28 (each cycle length = 28 days)
Population: PK Population included participants who received one or more doses of Debio 1347 and have at least one PK concentration result available. Overall number of participants analyzed is the number of participants with data available for analyses.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: Debio 1347 (Biliary Tract Cancer) | Area Under the Plasma Concentration-Time Curve Over the Dosing Interval at Steady State (AUCtau,ss) of Debio 1347 in Plasma | 23326.7 hour*nanogram (h*ng)/mL | Geometric Coefficient of Variation 70.4 |
| Cohort 2: Debio 1347 (Urothelial Cancer) | Area Under the Plasma Concentration-Time Curve Over the Dosing Interval at Steady State (AUCtau,ss) of Debio 1347 in Plasma | 13999.0 hour*nanogram (h*ng)/mL | Geometric Coefficient of Variation 39.1 |
| Cohort 3: Debio 1347 (All Other Solid Tumor Histologies) | Area Under the Plasma Concentration-Time Curve Over the Dosing Interval at Steady State (AUCtau,ss) of Debio 1347 in Plasma | 18192.1 hour*nanogram (h*ng)/mL | Geometric Coefficient of Variation 86.2 |
Secondary
Correlation of Debio 1347 Plasma Concentration (C) and QT Interval Corrected for Heart Rate Using Fridericia's Formula (QTcF)
Time frame: Pre-dose on Days 14 and 28, and 1, 3, 7 hours post-dose on Day 28 of Cycle 1; pre-dose on Days 14 and 28, and 3 hours post-dose on Day 28 of Cycle 2 (each cycle length = 28 days)
Population: The study was terminated by sponsor and thus the analysis for this outcome measure was not deemed necessary and no data was collected.
Secondary
Disease Control Rate (DCR) as Centrally Measured by Independent Review Committee (IRC)
DCR was defined as the percentage of participants with a BOR of confirmed CR, confirmed PR or stable disease (SD) ≥6 weeks. BOR was defined as the best confirmed response observed from first administration of study drug until disease progression. CR was defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. PR was defined as ≥30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking as reference the smallest sum diameters while on study. PD was defined as ≥ 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study.
Time frame: Up to disease progression or end of study (up to 2 years and 9 months)
Population: ITT population consisted of all participants who received study drug. Percentages are rounded off to the nearest single decimal point.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1: Debio 1347 (Biliary Tract Cancer) | Disease Control Rate (DCR) as Centrally Measured by Independent Review Committee (IRC) | 63.3 percentage of participants |
| Cohort 2: Debio 1347 (Urothelial Cancer) | Disease Control Rate (DCR) as Centrally Measured by Independent Review Committee (IRC) | 0 percentage of participants |
| Cohort 3: Debio 1347 (All Other Solid Tumor Histologies) | Disease Control Rate (DCR) as Centrally Measured by Independent Review Committee (IRC) | 34.5 percentage of participants |
Secondary
Duration of Response (DOR) as Centrally Measured by Independent Review Committee (IRC)
DOR was defined as the time from the date of the initial PR or CR to date of the first documented progression or death due to any cause. CR was defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. PR was defined as ≥30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
Time frame: Up to disease progression or end of study (up to 2 years and 9 months)
Population: ITT Population consisted of all participants who received study drug. Only participants with best overall response of CR or PR were analyzed for this endpoint.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 3: Debio 1347 (All Other Solid Tumor Histologies) | Duration of Response (DOR) as Centrally Measured by Independent Review Committee (IRC) | 5.55 months |
Secondary
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) Assessed by National Cancer Institute Common Terminology Criteria (NCI CTCAE) v5.0 and Serious Adverse Events (SAEs)
An AE is any untoward medical occurrence in a participant or clinical trial participant administered a medicinal product and which does not necessarily have a causal relationship with this treatment. A TEAE is defined as an AE that either starts or worsens in severity on or after the first administration of the study drug and within 30 days of the last administration of the study drug. An SAE is any untoward medical occurrence that at any dose results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect or is medically significant.
Time frame: From first dose of study drug up to 30 days post last dose (Up to 2 years and 9 months)
Population: Safety Population consisted of all participants who received study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort 1: Debio 1347 (Biliary Tract Cancer) | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) Assessed by National Cancer Institute Common Terminology Criteria (NCI CTCAE) v5.0 and Serious Adverse Events (SAEs) | TEAEs | 30 Participants |
| Cohort 1: Debio 1347 (Biliary Tract Cancer) | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) Assessed by National Cancer Institute Common Terminology Criteria (NCI CTCAE) v5.0 and Serious Adverse Events (SAEs) | Serious TEAEs | 14 Participants |
| Cohort 2: Debio 1347 (Urothelial Cancer) | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) Assessed by National Cancer Institute Common Terminology Criteria (NCI CTCAE) v5.0 and Serious Adverse Events (SAEs) | TEAEs | 4 Participants |
| Cohort 2: Debio 1347 (Urothelial Cancer) | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) Assessed by National Cancer Institute Common Terminology Criteria (NCI CTCAE) v5.0 and Serious Adverse Events (SAEs) | Serious TEAEs | 2 Participants |
| Cohort 3: Debio 1347 (All Other Solid Tumor Histologies) | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) Assessed by National Cancer Institute Common Terminology Criteria (NCI CTCAE) v5.0 and Serious Adverse Events (SAEs) | TEAEs | 28 Participants |
| Cohort 3: Debio 1347 (All Other Solid Tumor Histologies) | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) Assessed by National Cancer Institute Common Terminology Criteria (NCI CTCAE) v5.0 and Serious Adverse Events (SAEs) | Serious TEAEs | 7 Participants |
Secondary
Overall Survival (OS)
OS was defined as the time from the start date of treatment to date of death due to any cause. Participants with no documented death were censored at the last date known to be alive.
Time frame: Until death or loss to follow-up or end of study (up to 2 years and 9 months)
Population: ITT population consisted of all participants who received study drug.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1: Debio 1347 (Biliary Tract Cancer) | Overall Survival (OS) | NA months |
| Cohort 2: Debio 1347 (Urothelial Cancer) | Overall Survival (OS) | NA months |
| Cohort 3: Debio 1347 (All Other Solid Tumor Histologies) | Overall Survival (OS) | 7.13 months |
Secondary
Progression-Free Survival (PFS) as Centrally Measured by Independent Review Committee (IRC)
PFS was defined as the time from the start date of treatment to date of the first documented progression or death due to any cause.
Time frame: From the start of the study up to disease progression or death (up to 2 years and 9 months)
Population: ITT population consisted of all participants who received study drug.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1: Debio 1347 (Biliary Tract Cancer) | Progression-Free Survival (PFS) as Centrally Measured by Independent Review Committee (IRC) | 3.68 months |
| Cohort 2: Debio 1347 (Urothelial Cancer) | Progression-Free Survival (PFS) as Centrally Measured by Independent Review Committee (IRC) | 1.77 months |
| Cohort 3: Debio 1347 (All Other Solid Tumor Histologies) | Progression-Free Survival (PFS) as Centrally Measured by Independent Review Committee (IRC) | 1.84 months |
Secondary
Trough Concentration at Steady State (Ctrough,ss) of Debio 1347 in Plasma
Geometric mean and geometric percent CV summary was estimated based on log-linear model.
Time frame: Predose and post dose up to Cycle 2 Day 28 (each cycle length = 28 days)
Population: Pharmacokinetic (PK) Population included participants who received one or more doses of Debio 1347 and have at least one PK concentration result available. Overall number of participants analyzed is the number of participants with data available for analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: Debio 1347 (Biliary Tract Cancer) | Trough Concentration at Steady State (Ctrough,ss) of Debio 1347 in Plasma | 619.6 nanogram per millilitre (ng/mL) | Geometric Coefficient of Variation 100 |
| Cohort 2: Debio 1347 (Urothelial Cancer) | Trough Concentration at Steady State (Ctrough,ss) of Debio 1347 in Plasma | 306.8 nanogram per millilitre (ng/mL) | Geometric Coefficient of Variation 43.4 |
| Cohort 3: Debio 1347 (All Other Solid Tumor Histologies) | Trough Concentration at Steady State (Ctrough,ss) of Debio 1347 in Plasma | 463.2 nanogram per millilitre (ng/mL) | Geometric Coefficient of Variation 127.3 |