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

Cholangiocarcinoma Clinical Trial

Official title:

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT04526106
• Other study ID #: RLY-4008-101
• Status: Active, not recruiting
• Phase: Phase 1/Phase 2
• Start date: September 2, 2020
• Est. completion date: October 2024

Study information

• Verified date: October 2023
• Source: Relay Therapeutics, Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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).

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 540
• Est. completion date: October 2024
• Est. primary completion date: June 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Cholangiocarcinoma
• FGFR2 Amplification
• FGFR2 Gene Activation
• FGFR2 Gene Mutation
• FGFR2 Gene Translocation
• Intrahepatic Cholangiocarcinoma

Intervention

Drug:
• RLY-4008
RLY-4008 is an oral inhibitor of FGFR2

Locations

Country	Name	City	State
Australia	St. Vincent's Hosptial Sydney	Darlinghurst
Australia	Linear Clinical Research Ltd	Nedlands
Australia	Icon Cancer Care South Brisbane	South Brisbane,
France	Institut Bergonie	Bordeaux
France	Centre Georges François Leclerc	Dijon
France	Centre Leon Berard	Lyon
France	Centre Antoine Lacassagne	Nice
France	Gustave Roussy Cancer Campus	Paris
Germany	Medizinische Hochschule Hannover	Hannover
Germany	Universitätsklinikum Heidelberg	Heidelberg
Germany	LMU Klinikum, Campus Grosshadern	Munich
Hong Kong	Queen Mary Hospital	Hong Kong
Italy	Istituto Europeo di Oncologia	Milano
Italy	Istituto Nazionale Tumori Regina Elena	Roma
Korea, Republic of	Asan Medical Center	Seoul
Korea, Republic of	Samsung Medical Center	Seoul
Korea, Republic of	Seoul National University Hospital	Seoul
Netherlands	Netherlands Cancer institute	Amsterdam
Netherlands	Erasmus MC	Rotterdam
Singapore	National Cancer Center Singapore	Singapore
Spain	Hospital Universitari Vall d'Hebron	Barcelona
Spain	START Barcelona-Hospital HM Nou Delfos	Barcelona
Spain	Hospital Universitario Fundación Jiménez Díaz- START MADRID	Madrid
Spain	Hospital Universitario HM Sanchinarro-START MADRID-CIOCC	Madrid
Spain	Clinica de Universidad de Navarra	Pamplona
Spain	Hospital Clínico Universitario de Valencia	Valencia
Sweden	Karolinska University Hospital	Stockholm
Taiwan	China Medical University Hospital	Taichung
United Kingdom	Guy's Hospital	London
United Kingdom	Sarah Cannon Research Institute UK	London
United Kingdom	University College London Hospitals NHS Foundation Trust	London
United Kingdom	The Christie NHS Foundation Trust	Manchester
United States	University of Michigan	Ann Arbor	Michigan
United States	Winship Cancer Institute, Emory University	Atlanta	Georgia
United States	The University of Alabama at Birmingham	Birmingham	Alabama
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	University of Chicago Medical Center	Chicago	Illinois
United States	Taussig Cancer Institute Cleveland Clinic	Cleveland	Ohio
United States	Texas Oncology	Dallas	Texas
United States	The University of Texas M.D. Anderson Cancer Center	Houston	Texas
United States	Mayo Clinic	Jacksonville	Florida
United States	USC Norris Comprehensive Cancer Center	Los Angeles	California
United States	Memorial Sloan Kettering Cancer Center	New York	New York
United States	Fox Chase Cancer Center	Philadelphia	Pennsylvania
United States	Mayo Clinic	Phoenix	Arizona
United States	Mayo Clinic	Rochester	Minnesota
United States	Huntsman Cancer Institute, University of Utah	Salt Lake City	Utah
United States	UCSF Helen Diller Family Comprehensive Cancer Center	San Francisco	California
United States	Virginia Mason Medical Center	Seattle	Washington
United States	Moffitt Cancer Center	Tampa	Florida

Sponsors (1)

Lead Sponsor	Collaborator
Relay Therapeutics, Inc.

Countries where clinical trial is conducted

United States,  Australia,  France,  Germany,  Hong Kong,  Italy,  Korea, Republic of,  Netherlands,  Singapore,  Spain,  Sweden,  Taiwan,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	Part 1: Number of patients with adverse events and serious adverse events		Every cycle (4-week cycles) until study discontinuation, approximately 24 months
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Part 2 and Part 3:Overall survival (OS)		Up to approximately 36 months.
Secondary	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
Secondary	Part 2 and Part 3:Dose intensity		Every 28-day cycle until end of treatment, approximately 24 months.
Secondary	Part 2 and Part 3: Number of patients with dose interruptions		Every 28-day cycle until end of treatment, approximately 24 months.
Secondary	Part 2 and Part 3: Number of patients with dose reductions		Every 28-day cycle until end of treatment, approximately 24 months.
Secondary	Part 2 and Part 3: Number of patients with dose discontinuations		Every 28-day cycle until end of treatment, approximately 24 months.
Secondary	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