REFOCUS: A First-in-Human Study of Highly Selective FGFR2 Inhibitor, RLY-4008, in Patients With ICC and Other Advanced Solid Tumors

Study Overview
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Brief Summary
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This is a Phase 1/2, open-label, FIH study designed to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PDy), and antineoplastic activity of RLY-4008, a potent and highly selective FGFR2 inhibitor, in patients with unresectable or metastatic cholangiocarcinoma (CCA) and other solid tumors. The study consists of 3 parts: a dose escalation (Part 1), a dose expansion (Part 2), and an extension (Part 3).

Official Title
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A First-in-Human Study of Highly Selective FGFR2 Inhibitor, RLY-4008, in Patients With Intrahepatic Cholangiocarcinoma (ICC) and Other Advanced Solid Tumors

Conditions
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FGFR2 Gene Mutation, FGFR2 Gene Fusion/Rearrangement, FGFR2 Gene Translocation, FGFR2 Gene Activation, Intrahepatic Cholangiocarcinoma, Other Solid Tumors, Adult, FGFR2 Amplification, Cholangiocarcinoma

Intervention / Treatment
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* Drug: RLY-4008


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria Histologically or cytologically confirmed unresectable or metastatic solid tumor Documented FGFR2 gene fusion, mutation, or amplification per local testing of blood and/or tumor Patient must have measurable disease per RECIST v1.1 Patient has ECOG performance status of 0-1 Patient must have disease that is refractory to standard therapy, disease that has not adequately responded to standard therapy, disease for which standard or curative therapy does not exist, or the patient must be intolerant to or have declined standard therapy Part 2 dose expansion patients with Cholangiocarcinoma: Group 1: CCA patients with an FGFR2 fusion previously treated with an FGFRi Group 2: CCA patients with an FGFR2 fusion with prior chemotherapy but not previously treated with an FGFRi Group 6: CCA patients with an FGFR2 fusion with no prior chemotherapy and not previously treated with an FGFRi. Prior adjuvant/neo-adjuvant treatment completed >6 months before enrollment is acceptable. Up to 2 cycles of palliative chemotherapy are allowed during screening Group 7: CCA patients with an FGFR2 mutation or amplification and not previously treated with an FGFRi. Note: For Group 7, patients with confirmed diagnosis of unresectable or metastatic CCA with an FGFR2 fusion are not eligible. Part 2 dose expansion patients with other solid tumors (NOT Cholangiocarcinoma): Group 3: Non-CCA patients with an FGFR2 fusion and not previously treated with an FGFRi. Group 4: Non-CCA patients with an FGFR2 amplification and not previously treated with an FGFRi. Group 5: Non-CCA patients with an FGFR2 mutation and not previously treated with an FGFRi Part 3 extension: CCA patients with an FGFR2 fusion with prior chemotherapy but not previously treated with an FGFRi Key Exclusion Criteria Ongoing, clinically significant FGFRi-induced retinal detachment or an ongoing clinically significant corneal or retinal disorder Patient does not have adequate organ function (defined in protocol) Patient has active infection, including human immunodeficiency virus (HIV), hepatitis B virus (HBV), and/or hepatitis C virus (HCV) (defined in protocol). Patients with well-controlled HBV are eligible (defined in protocol). QT interval corrected using Fridericia's formula (QTcF) > 480 msec or history of prolonged QT syndrome, Torsades de pointes or familial history of prolonged QT syndrome Clinically significant, uncontrolled cardiovascular disease CNS metastases or primary CNS tumor that is associated with progressive neurologic symptoms

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
Interventional Model Description: Part 1 (multiple ascending doses): • Unresectable or metastatic CCA or other unresectable or metastatic solid tumor Part 2 (RP2D determined in Part 1): Group 1: CCA patients with an FGFR2 fusion previously treated with an FGFRi Group 2: CCA patients with an FGFR2 fusion with prior chemotherapy but not previously treated with an FGFRi Group 3: Non-CCA patients with an FGFR2 fusion and not previously treated with an FGFRi Group 4: Non-CCA patients with an FGFR2 amplification and not previously treated with an FGFRi Group 5: Non-CCA patients with an FGFR2 mutation and not previously treated with an FGFRi Group 6: CCA patients with an FGFR2 fusion with no prior chemotherapy and not previously treated with an FGFRi Group 7: CCA patients with an FGFR2 mutation or amplification and not previously treated with an FGFRi Part 3 (Extension of Part 2, Group 2): • CCA patients with an FGFR2 fusion with prior chemotherapy but not previously treated with an FGFRi
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1: Dose Escalation<br>Multiple doses of RLY-4008 for oral administration. | Drug: RLY-4008<br>* RLY-4008 is an oral inhibitor of FGFR2<br>|
| Experimental: Part 2: Dose Expansion<br>Oral dose of RLY-4008 as determined during Part 1 Dose Escalation. | Drug: RLY-4008<br>* RLY-4008 is an oral inhibitor of FGFR2<br>|
| Experimental: Part 3: Extension<br>Oral dose of RLY-4008 as determined during Part 1 Dose Escalation. | Drug: RLY-4008<br>* RLY-4008 is an oral inhibitor of FGFR2<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1: Determination of maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) of RLY-4008 |  | Cycle 1 (4-week cycle) of treatment for MTD and at the end of every cycle (4-week cycles) for RP2D until study discontinuation, approximately 24 months | 
| Part 1: Number of patients with adverse events and serious adverse events |  | Every cycle (4-week cycles) until study discontinuation, approximately 24 months | 
| Part 2 and Part 3: Objective Response Rate (ORR) assessed by Independent Review Committee per RECIST v1.1 |  | Approximately every 8 weeks during treatment and every 12 weeks after the last dose in the absence of progressive disease, approximately 36 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1: FGFR2 gene status in plasma circulating tumor deoxyribonucleic acid (ctDNA) and tumor tissue |  | Every cycle (4-week cycles) through Cycle 3 and every other cycle thereafter until study discontinuation, approximately 24 months | 
| Part 1: Duration of Response (DOR) assessed by Investigator per RECIST v1.1 |  | Approximately every 8 weeks during treatment and every 12 weeks after the last dose in the absence of progressive disease, approximately 36 months | 
| Part 1: Disease Control Rate (DCR) as assessed by Investigator per RECIST v1.1 |  | Approximately every 8 weeks during treatment and every 12 weeks after the last dose in the absence of progressive disease, approximately 36 months | 
| Part 1, Part 2, and Part 3: Objective Response Rate (ORR) as assessed by Investigator per RECIST v1.1 |  | Approximately every 8 weeks during treatment and every 12 weeks after the last dose in the absence of progressive disease, approximately 36 months | 
| Pharmacokinetic parameters including maximum plasma drug concentration (Cmax) |  | Approximately every 2 weeks in Cycle 1 (4-week cycle) and every cycle through Cycle 4 (4-week cycles) | 
| Pharmacokinetic parameters including area under the plasma concentration versus time curve (AUC) |  | Approximately every 2 weeks in Cycle 1 (4-week cycle) and every cycle through Cycle 4 (4-week cycles) | 
| Pharmacokinetic parameters including half-life (t1/2) |  | Approximately every 2 weeks in Cycle 1 (4-week cycle) and every cycle through Cycle 4 (4-week cycles) | 
| Part 1: Pharmacodynamic parameters including changes in fibroblast growth factor 23 (FGF-23) |  | Approximately every 2 weeks in Cycle 1 (4-week cycle) and every other cycle (4-week cycles) from Cycle 3, approximately 24 months | 
| Part 1: Pharmacodynamic parameters including changes in carcinoembryonic antigen (CEA) |  | Approximately every 2 weeks in Cycle 1 (4-week cycle) and every other cycle (4-week cycles) from Cycle 3, approximately 24 months | 
| Part 1: Pharmacodynamic parameters including changes in cancer antigen 19-9 (CA 19-9) |  | Approximately every 2 weeks in Cycle 1 (4-week cycle) and every other cycle (4-week cycles) from Cycle 3, approximately 24 months | 
| Part 2 and Part 3: Duration of response (DOR) assessed by Investigator and Independent Review Committee per RECIST v1.1 |  | Approximately every 8 weeks during treatment and every 12 weeks after the last dose in the absence of progressive disease, approximately 36 months | 
| Part 2 and Part 3: Progression-free survival (PFS) assessed by Investigator and Independent Review Committee per RECIST v1.1 |  | Approximately every 8 weeks during treatment and every 12 weeks after the last dose in the absence of progressive disease, approximately 36 months | 
| Part 2 and Part 3: Disease control rate (DCR) assessed by Investigator and Independent Review Committee per RECIST v1.1 |  | Approximately every 8 weeks during treatment and every 12 weeks after the last dose in the absence of progressive disease, approximately 36 months | 
| Part 2 and Part 3:Overall survival (OS) |  | Up to approximately 36 months. | 
| Part 2 and Part 3:Change from baseline in quality of life as assessed by EORTC QLQ-C30 |  | Approximately every 4 weeks during treatment, approximately 24 months | 
| Part 2 and Part 3:Dose intensity |  | Every 28-day cycle until end of treatment, approximately 24 months. | 
| Part 2 and Part 3: Number of patients with dose interruptions |  | Every 28-day cycle until end of treatment, approximately 24 months. | 
| Part 2 and Part 3: Number of patients with dose reductions |  | Every 28-day cycle until end of treatment, approximately 24 months. | 
| Part 2 and Part 3: Number of patients with dose discontinuations |  | Every 28-day cycle until end of treatment, approximately 24 months. | 
| Part 2 and Part 3: Correlation between FGFR2 genotype by central tissue assessment and antitumor response, as measured by ORR |  | Approximately every 8 weeks during treatment and every 12 weeks after the last dose in the absence of progressive disease, approximately 36 months |