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NCT04526106 · CITED IN SOURCE DOCUMENTS

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

An NCI or FDA source cites this study. A citation does not establish that it applies to an individual diagnosis.

Phase
PHASE1, PHASE2
Status at capture
COMPLETED
Registry last update
2026-02-27

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 4 parts: a dose escalation (Part 1), a dose expansion (Part 2), and an extension (Part 3) and a rollover (Part 4).

Open the original ClinicalTrials.gov record → · Download preserved record

What did the study report?

Outcomes, safety and baseline populations are separate source sections. Quality-of-life measures appear under their original outcome titles.

No posted result sections were captured. Registered plans do not establish that a treatment works.

Who could take part
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: o CCA patients with an FGFR2 fusion with prior chemotherapy but not previously treated with an FGFRi * Part 4: * Patient is receiving RLY-4008 on RLY-4008-101 study and benefiting from treatment as assessed by the investigator. Key Exclusion Criteria * Parts 1, 2, and 3 * 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 * Part 4: * Patient has permanently discontinued treatment with RLY-4008 for any reason before enrolling into Part 4.
healthy Volunteers
false
minimum Age
18 Years
sex
ALL
std Ages
  1. ADULT
  2. OLDER_ADULT
Treatment arms and interventions
arm Groups
  1. description
    Multiple doses of RLY-4008 for oral administration.
    intervention Names
    1. Drug: RLY-4008
    label
    Part 1: Dose Escalation
    type
    EXPERIMENTAL
  2. description
    Oral dose of RLY-4008 as determined during Part 1 Dose Escalation.
    intervention Names
    1. Drug: RLY-4008
    label
    Part 2: Dose Expansion
    type
    EXPERIMENTAL
  3. description
    Oral dose of RLY-4008 as determined during Part 1 Dose Escalation.
    intervention Names
    1. Drug: RLY-4008
    label
    Part 3: Extension
    type
    EXPERIMENTAL
  4. description
    Oral dose of RLY-4008 as determined during Part 1 Dose Escalation.
    intervention Names
    1. Drug: RLY-4008
    label
    Part 4: Rollover
    type
    EXPERIMENTAL
interventions
  1. arm Group Labels
    1. Part 1: Dose Escalation
    2. Part 2: Dose Expansion
    3. Part 3: Extension
    4. Part 4: Rollover
    description
    RLY-4008 is an oral inhibitor of FGFR2
    name
    RLY-4008
    type
    DRUG
Study design
allocation
NON_RANDOMIZED
intervention Model
PARALLEL
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 w/ an FGFR2 fusion previously treated w/ an FGFRi treatment * Group 2: CCA patients w/ an FGFR2 fusion w/ prior chemotherapy but no prior FGFRi treatment * Group 3: Non-CCA patients w/ an FGFR2 fusion and no prior FGFRi * Group 4: Non-CCA patients w/ an FGFR2 amplification and no prior FGFRi treatment * Group 5: Non-CCA patients w/ an FGFR2 mutation and no prior FGFRi treatment * Group 6: CCA patients w/ an FGFR2 fusion with no prior chemotherapy and no prior FGFRi treatment * Group 7: CCA patients w/ an FGFR2 mutation or amplification and no prior FGFRi treatment Part 3 (Extension of Part 2, Group 2): • CCA patients w/ an FGFR2 fusion with prior chemotherapy but no prior FGFRi treatment Part 4 (Rollover): • Ongoing Parts 1, 2, and 3 patients enrolled on study and receiving RLY-4008
masking Info
masking
NONE
primary Purpose
TREATMENT
Enrollment
count
490
type
ACTUAL
Registered outcome plans (not posted results)
primary Outcomes
  1. measure
    Part 1 and Part 4: Number of patients with adverse events and serious adverse events
    time Frame
    Every cycle (4-week cycles) until study discontinuation, approximately 24 months
  2. measure
    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
  3. measure
    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
  4. measure
    Part 4: Number of patients with dose interruptions
    time Frame
    Every 28-day cycle until end of treatment, approximately 24 months.
  5. measure
    Part 4: Number of patients with dose reductions
    time Frame
    Every 28-day cycle until end of treatment, approximately 24 months.
  6. measure
    Part 4: Number of patients with dose discontinuations
    time Frame
    Every 28-day cycle until end of treatment, approximately 24 months.
secondary Outcomes
  1. measure
    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. measure
    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. measure
    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. measure
    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. measure
    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. measure
    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. measure
    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. measure
    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. measure
    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. measure
    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. measure
    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. measure
    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
Full study description
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 4 parts: a dose escalation (Part 1), a dose expansion (Part 2), and an extension (Part 3) and a rollover (Part 4).
Source references
references
  1. citation
    Ellis H, Balasooriya ER, Varkaris A, Hajian B, Wan J, Shekhar M, Gritti I, Vijay V, Albertelli L, Piot S, Lau K, Kehlmann A, Chevalier N, Nugent FW, Zhen Y, Silveira VS, Sellers WR, Corcoran RB, Juric D, Bardeesy N. Mechanisms of clinical resistance to selective FGFR2 inhibition by lirafugratinib. Ann Oncol. 2026 Jun;37(6):798-812. doi: 10.1016/j.annonc.2026.01.004. Epub 2026 Jan 20.
    pmid
    41571046
    type
    DERIVED
Source notices and limitations
    Discovery and provenance
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        sp;<a href="https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm">Drugs@FDA</a>.</p><h2>Efficacy and Safety</h2><p>Efficacy was evaluated in&nbsp;REFOCUS (NCT04526106), a multicenter, open-label, single-arm trial in 116 patients with unresectable or metastatic cholangiocarcinoma who were naïve to FGFR inhibitor treatment and
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      source event date
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      source title
      FDA approves lirafugratinib for previously treated, unresectable, locally advanced or metastatic cholangiocarcinoma

    Preserved source evidence · Not medical advice