Debio 1347-101 Phase I Trial in Advanced Solid Tumours With Fibroblast Growth Factor Receptor (FGFR) Alterations

Study Overview
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Brief Summary
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This study is primarily designed to assess the safety and the tolerability of Debio1347 (CH5183284) in patients with advanced solid malignancies, whose tumours have an alteration of the Fibroblast Growth Factor Receptor (FGFR) 1, 2 or 3 genes, for whom standard treatment does not exist or is not indicated. The main objective of Part A is to identify the dose-limiting toxicities (DLTs) and estimate the maximum tolerated dose (MTD) based on the safety and tolerability of Debio1347 orally administered daily to these patients, in order to determine the recommended dose. The main objective of Part B is to evaluate the safety profile at the recommended dose, in a larger cohort of these patients.

Official Title
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A Phase I, Gene Alteration-based, Open Label, Multicenter Study of Oral Debio 1347 (CH5183284) in Patients With Advanced Solid Malignancies, Whose Tumours Have an Alteration of the FGFR 1, 2 or 3 Genes

Conditions
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Solid Tumours

Intervention / Treatment
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* Drug: Debio1347 (CH5183284)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Meets protocol-specified criteria for qualification and contraception Is willing and able to remain confined in the study unit for the entire duration of each treatment period and comply with restrictions related to food, drink and medications Voluntarily consents to participate and provides written informed consent prior to any protocol-specific procedures Exclusion Criteria: Has history or current use of over-the-counter medications, dietary supplements, or drugs (including nicotine and alcohol) outside protocol-specified parameters Has signs, symptoms or history of any condition that, per protocol or in the opinion of the investigator, might compromise: the safety or well-being of the participant or study staff the safety or well-being of the participant's offspring (such as through pregnancy or breast-feeding) the analysis of results

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
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part A<br>Adaptive doses of Debio1347 (CH5183284) - (10 mg to 210 mg/day) until the recommended dose (RD) is determined. | Drug: Debio1347 (CH5183284)<br>* Debio1347 (CH5183284) tablets for oral administration<br>* Other names: CH5183284;|
| Experimental: Part B<br>Participants with various tumours receive Debio1347 (CH5183284) orally at the recommended dose established during Part A. | Drug: Debio1347 (CH5183284)<br>* Debio1347 (CH5183284) tablets for oral administration<br>* Other names: CH5183284;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part A: Percentage of Participants With Dose-Limiting Toxicities (DLTs) From Debio 1347 |  | within approximately 18 months | 
| Part B: Percentage of Participants With Treatment-Emergent Serious Adverse Events (SAEs) |  | within 2 years of starting treatment | 
| Part B: Number of Participants With Abnormal Laboratory Values and/or Adverse Events That Are Related to Treatment |  | within 2 years of starting treatment | 
| Part B: Severity of Treatment-Emergent AEs | Categories: NCI-Common Terminology Criteria for Adverse Events (CTCAE) version 4 severity criteria | within 2 years of starting treatment | 
| Part B: Severity of Laboratory Abnormalities | Categories: NCI-Common Terminology Criteria for Adverse Events (CTCAE) version 4 severity criteria | within 2 years of starting treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part A: Percentage of Participants With Treatment-Emergent Serious Adverse Events (SAEs) |  | within 2 years of starting treatment | 
| Part A: Number of Participants With Abnormal Laboratory Values and/or Adverse Events That Are Related to Treatment |  | within 2 years of starting treatment | 
| Part A: Severity of Treatment-Emergent AEs | Categories: NCI-CTCAE version 4 severity criteria | within 2 years of starting treatment | 
| Part A: Severity of Laboratory Abnormalities | Categories: NCI-CTCAE version 4 severity criteria | within 2 years of starting treatment | 
| Part A and Part B: Percentage of Participants With Treatment Discontinuations or Modifications due to AEs and Laboratory Abnormalities |  | within 2 years of starting treatment | 
| Part A and Part B: Number of Participants With Change From Baseline in Blood Pressure (BP) | Change in BP will be evaluation based on three criteria- Change to Low (decrease from pre-treatment > 20 millimeter of mercury [mmHg]), No change (change from pre-treatment within ± 20 mmHg) and Change to High (increase from pre-treatment > 20 mmHg). | within 2 years of starting treatment | 
| Part A and Part B: Number of Participants With Change From Baseline in Pulse Rate | Number of participants with change of more than 20 beats per minute from baseline will be reported. | within 2 years of starting treatment | 
| Part A and Part B: Number of Participants With Change From Baseline in Electrocardiogram (ECG) Parameters | ECG parameters will include PR, RR, QRS, QTcB and QTcF intervals. | within 2 years of starting treatment | 
| Part A and Part B: Change From Baseline in Left Ventricular Ejection Fraction (LVEF) |  | within 2 years of starting treatment | 
| Part A and Part B: Change From Baseline in Eastern Cooperative Oncology Group Performance Status (ECOG PS) |  | within 2 years of starting treatment | 
| Part A: Number of Participants With Tumour Response, According to Response Evaluation Criteria in Solid Tumours (RECIST) Version 1.1 Criteria | Includes: Best overall response, disease control, tumour size | within 2 years of starting treatment | 
| Part B: Number of Participants With Tumour Response, According to Response Evaluation Criteria in Solid Tumours (RECIST) Version 1.1 Citeria or Response Assessment in Neuro-Oncology (RANO) (for glioblastoma participants) | Includes: Best overall response, disease control, tumour size | within 2 years of starting treatment | 
| Part A and Part B: Progression-Free Survival Rate After Treatment Initiation | Categories: overall, 6 months, 1 year, 2 years | within 2 years of starting treatment | 
| Part A and Part B: Number of Participants With Changes in Ophthalmological Exams | Opthalmological exams includes visual acuity testing, slit-lamp ophthalmoscopy and indirect ophthalmoscopy. | within 2 years of starting treatment | 
| Part A: Area Under Concentration-Time Curve (AUC) Following Single- and Repeated-Dose Administration of Debio 1347 |  | Day -9, Day -2, Day 28; Ctrough on Day 8, Day 15, Day 22 of Cycle 1, and on Day 1 of Cycle 2 and Cycle 3 | 
| Part A: Concentration at the end of a Dosing Interval (Ctrough) Following Single- and Repeated-Dose Administration of Debio 1347 |  | Day -9, Day -2, Day 28; Ctrough on Day 8, Day 15, Day 22 of Cycle 1, and on Day 1 of Cycle 2 and Cycle 3 | 
| Part A: Maximum Observed Concentration (Cmax) Following Single- and Repeated-Dose Administration of Debio 1347 |  | Day -9, Day -2, Day 28; Ctrough on Day 8, Day 15, Day 22 of Cycle 1, and on Day 1 of Cycle 2 and Cycle 3 | 
| Part A: Time of Maximum Concentration (tmax) Following Single- and Repeated-Dose Administration of Debio 1347 |  | Day -9, Day -2, Day 28; Ctrough on Day 8, Day 15, Day 22 of Cycle 1, and on Day 1 of Cycle 2 and Cycle 3 | 
| Part A: Apparent Terminal Half-Life (t1/2) Following Single- and Repeated-Dose Administration of Debio 1347 |  | Day -9, Day -2, Day 28; Ctrough on Day 8, Day 15, Day 22 of Cycle 1, and on Day 1 of Cycle 2 and Cycle 3 | 
| Part A: Mean Residence Time (MRT) Following Single- and Repeated-Dose Administration of Debio 1347 |  | Day -9, Day -2, Day 28; Ctrough on Day 8, Day 15, Day 22 of Cycle 1, and on Day 1 of Cycle 2 and Cycle 3 | 
| Part A: Apparent Clearance (CL/F) Following Single- and Repeated-Dose Administration of Debio 1347 |  | Day -9, Day -2, Day 28; Ctrough on Day 8, Day 15, Day 22 of Cycle 1, and on Day 1 of Cycle 2 and Cycle 3 | 
| Part A: Apparent Volume of Distribution (Vz/F) Following Single- and Repeated-Dose Administration of Debio 1347 |  | Day -9, Day -2, Day 28; Ctrough on Day 8, Day 15, Day 22 of Cycle 1, and on Day 1 of Cycle 2 and Cycle 3 | 
| Part A: Accumulation Ratios (RAC) Following Single- and Repeated-Dose Administration of Debio 1347 |  | Day -9, Day -2, Day 28; Ctrough on Day 8, Day 15, Day 22 of Cycle 1, and on Day 1 of Cycle 2 and Cycle 3 | 
| Part A: Linearity Index (LI) Following Single- and Repeated-Dose Administration of Debio 1347 |  | Day -9, Day -2, Day 28; Ctrough on Day 8, Day 15, Day 22 of Cycle 1, and on Day 1 of Cycle 2 and Cycle 3 | 
| Part A: Peak-to-Trough fluctuation (PTF) Following Single- and Repeated-Dose Administration of Debio 1347 |  | Day -9, Day -2, Day 28; Ctrough on Day 8, Day 15, Day 22 of Cycle 1, and on Day 1 of Cycle 2 and Cycle 3 | 
| Part B: Area Under Concentration-Time Curve (AUC), Following Repeated-Dose Administration of Debio 1347 in the PK Subset |  | Day 28 | 
| Part B: Concentration at the end of a Dosing Interval (Ctrough) Following Repeated-Dose Administration of Debio 1347 in the PK Subset |  | Day 28 | 
| Part B: Maximum Observed Concentration (Cmax) Following Repeated-Dose Administration of Debio 1347 in the PK Subset |  | Day 28 | 
| Part B: Time of Maximum Concentration (tmax) Following Repeated-Dose Administration of Debio 1347 in the PK Subset |  | Day 28 | 
| Part B: Apparent Terminal Half-Life (t1/2) Following Repeated-Dose Administration of Debio 1347 in the PK Subset |  | Day 28 | 
| Part B: Mean Residence Time (MRT) Following Repeated-Dose Administration of Debio 1347 in the PK Subset |  | Day 28 | 
| Part B: Apparent clearance (CL/F) Following Repeated-Dose Administration of Debio 1347 in the PK Subset |  | Day 28 | 
| Part B: Apparent Volume of Distribution (Vz/F) Following Repeated-Dose Administration of Debio 1347 in the PK Subset |  | Day 28 | 
| Part B: Peak-to-Trough Fluctuation (PTF) Following Repeated-Dose Administration of Debio 1347 in the PK Subset |  | Day 28 | 
| Part B: Renal Clearance (CLR) Following Repeated-Dose Administration of Debio 1347 in the PK Subset |  | Day 28 | 
| Part B: Percentage of the Dose Excreted in Urine (Ae%) Following Repeated-Dose Administration of Debio 1347 in the PK Subset |  | Day 28 | 
| Part B: Ctrough in all Participants |  | Day 8, Day 15, Day 22 of Cycle 1, and Day 1 of Cycle 2 and Cycle 3 |