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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04526106
Recruitment Status : Recruiting
First Posted : August 25, 2020
Last Update Posted : October 25, 2023
Sponsor:
Information provided by (Responsible Party):
Relay Therapeutics, Inc.

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).

Condition or disease Intervention/treatment Phase
FGFR2 Amplification FGFR2 Gene Mutation FGFR2 Gene Fusion/Rearrangement FGFR2 Gene Translocation FGFR2 Gene Activation Intrahepatic Cholangiocarcinoma Cholangiocarcinoma Other Solid Tumors, Adult Drug: RLY-4008 Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 550 participants
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
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
Actual Study Start Date : September 2, 2020
Estimated Primary Completion Date : June 2024
Estimated Study Completion Date : October 2024


Arm Intervention/treatment
Experimental: Part 1: Dose Escalation
Multiple doses of RLY-4008 for oral administration.
Drug: RLY-4008
RLY-4008 is an oral inhibitor of FGFR2

Experimental: Part 2: Dose Expansion
Oral dose of RLY-4008 as determined during Part 1 Dose Escalation.
Drug: RLY-4008
RLY-4008 is an oral inhibitor of FGFR2

Experimental: Part 3: Extension
Oral dose of RLY-4008 as determined during Part 1 Dose Escalation.
Drug: RLY-4008
RLY-4008 is an oral inhibitor of FGFR2




Primary Outcome Measures :
  1. 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 ]
  2. 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 ]
  3. 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 ]

Secondary Outcome Measures :
  1. 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 ]
  2. 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 ]
  3. 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 ]
  4. 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 ]
  5. 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) ]
  6. 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) ]
  7. 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) ]
  8. 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 ]
  9. 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 ]
  10. 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 ]
  11. 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 ]
  12. 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 ]
  13. 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 ]
  14. Part 2 and Part 3:Overall survival (OS) [ Time Frame: Up to approximately 36 months. ]
  15. 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 ]
  16. Part 2 and Part 3:Dose intensity [ Time Frame: Every 28-day cycle until end of treatment, approximately 24 months. ]
  17. Part 2 and Part 3: Number of patients with dose interruptions [ Time Frame: Every 28-day cycle until end of treatment, approximately 24 months. ]
  18. Part 2 and Part 3: Number of patients with dose reductions [ Time Frame: Every 28-day cycle until end of treatment, approximately 24 months. ]
  19. Part 2 and Part 3: Number of patients with dose discontinuations [ Time Frame: Every 28-day cycle until end of treatment, approximately 24 months. ]
  20. 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 ]


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04526106


Contacts
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Contact: Relay Therapeutics, Inc. 339-230-7475 ClinicalTrials@relaytx.com

Locations
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Sponsors and Collaborators
Relay Therapeutics, Inc.
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Responsible Party: Relay Therapeutics, Inc.
ClinicalTrials.gov Identifier: NCT04526106    
Other Study ID Numbers: RLY-4008-101
First Posted: August 25, 2020    Key Record Dates
Last Update Posted: October 25, 2023
Last Verified: October 2023
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Cholangiocarcinoma
Neoplasms
Adenocarcinoma
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type