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

• ClinicalTrials.gov Identifier: NCT04526106
• Recruitment Status: Active, not recruiting
• First Posted: August 25, 2020
• Last Update Posted: March 5, 2024
• Sponsor: Relay Therapeutics, Inc.
• Information provided by (Responsible Party): Relay Therapeutics, Inc.

Tracking Information

• First Submitted Date: August 7, 2020
• First Posted Date: August 25, 2020
• Last Update Posted Date: March 5, 2024
• Actual Study Start Date: September 2, 2020
• Estimated Primary Completion Date: June 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: March 28, 2023)

• Part 1: Determination of maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) of RLY-4008 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: Approximately every 8 weeks during treatment and every 12 weeks after the last dose in the absence of progressive disease, approximately 36 months ]

Original Primary Outcome Measures (submitted: August 20, 2020)

• Determination of maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) of RLY-4008 [ Time Frame: 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 ]
• Number of patients with adverse events and serious adverse events [ Time Frame: Every cycle (4-week cycles) until study discontinuation, approximately 24 months ]

Current Secondary Outcome Measures (submitted: March 28, 2023)

• Part 1: FGFR2 gene status in plasma circulating tumor deoxyribonucleic acid (ctDNA) and tumor tissue [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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) [ Time Frame: Up to approximately 36 months. ]
• Part 2 and Part 3:Change from baseline in quality of life as assessed by EORTC QLQ-C30 [ Time Frame: Approximately every 4 weeks during treatment, approximately 24 months ]
• Part 2 and Part 3:Dose intensity [ Time Frame: Every 28-day cycle until end of treatment, approximately 24 months. ]
• Part 2 and Part 3: Number of patients with dose interruptions [ Time Frame: Every 28-day cycle until end of treatment, approximately 24 months. ]
• Part 2 and Part 3: Number of patients with dose reductions [ Time Frame: Every 28-day cycle until end of treatment, approximately 24 months. ]
• Part 2 and Part 3: Number of patients with dose discontinuations [ Time Frame: 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 [ Time Frame: Approximately every 8 weeks during treatment and every 12 weeks after the last dose in the absence of progressive disease, approximately 36 months ]

Original Secondary Outcome Measures (submitted: August 20, 2020)

• FGFR2 gene status in plasma circulating tumor deoxyribonucleic acid (ctDNA) and tumor tissue [ Time Frame: Every cycle (4-week cycles) through Cycle 3 and every other cycle thereafter until study discontinuation, approximately 24 months ]
• Overall response rate (ORR) as assessed by RECIST v1.1 [ Time Frame: Approximately every 8 weeks during treatment and every 12 weeks after the last dose in the absence of progressive disease, approximately 36 months ]
• Duration of Response (DOR) as assessed by RECIST v1.1 [ Time Frame: Approximately every 8 weeks during treatment and every 12 weeks after the last dose in the absence of progressive disease, approximately 36 months ]
• Disease Control Rate (DCR) as assessed by RECIST v1.1 [ Time Frame: 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) [ Time Frame: Approximately every 2 weeks in Cycle 1 (4-week cycle) and every cycle though Cycle 4 (4-week cycles) ]
• Pharmacokinetic parameters including area under the plasma concentration versus time curve from time 0 to 24 hours postdose (AUC0-24) [ Time Frame: Approximately every 2 weeks in Cycle 1 (4-week cycle) and every cycle though Cycle 4 (4-week cycles) ]
• Pharmacokinetic parameters including terminal elimination half-life (t1/2) [ Time Frame: Approximately every 2 weeks in Cycle 1 (4-week cycle) and every cycle though Cycle 4 (4-week cycles) ]
• Pharmacodynamic parameters including changes in fibroblast growth factor 23 (FGF-23) [ Time Frame: Approximately every 2 weeks in Cycle 1 (4-week cycle) and every other cycle (4-week cycles) from Cycle 3, approximately 24 months ]
• Pharmacodynamic parameters including changes in carcinoembryonic antigen (CEA) [ Time Frame: Approximately every 2 weeks in Cycle 1 (4-week cycle) and every other cycle (4-week cycles) from Cycle 3, approximately 24 months ]
• Pharmacodynamic parameters including changes in cancer antigen 19-9 (CA 19-9) [ Time Frame: Approximately every 2 weeks in Cycle 1 (4-week cycle) and every other cycle (4-week cycles) from Cycle 3, approximately 24 months ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: REFOCUS: A First-in-Human Study of Highly Selective FGFR2 Inhibitor, RLY-4008, in Patients With ICC and Other Advanced Solid Tumors
• 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
• Brief 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).
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 1; Phase 2

Study Design

Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Intervention 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)
Primary Purpose: Treatment

Condition

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

Intervention

Drug: RLY-4008

RLY-4008 is an oral inhibitor of FGFR2

Study Arms

• Experimental: Part 1: Dose Escalation
  Multiple doses of RLY-4008 for oral administration.
  Intervention: Drug: RLY-4008
• Experimental: Part 2: Dose Expansion
  Oral dose of RLY-4008 as determined during Part 1 Dose Escalation.
  Intervention: Drug: RLY-4008
• Experimental: Part 3: Extension
  Oral dose of RLY-4008 as determined during Part 1 Dose Escalation.
  Intervention: Drug: RLY-4008

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Active, not recruiting
• Estimated Enrollment (submitted: March 1, 2024): 540
• Original Estimated Enrollment (submitted: August 20, 2020): 125
• Estimated Study Completion Date: October 2024
• Estimated Primary Completion Date: June 2024 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, France, Germany, Hong Kong, Italy, Korea, Republic of, Netherlands, Singapore, Spain, Sweden, Taiwan, United Kingdom, United States

Administrative Information

• NCT Number: NCT04526106
• Other Study ID Numbers: RLY-4008-101
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Relay Therapeutics, Inc.
• Original Responsible Party: Same as current
• Current Study Sponsor: Relay Therapeutics, Inc.
• Original Study Sponsor: Same as current
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: Relay Therapeutics, Inc.
• Verification Date: October 2023