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

Phase 2Active Not RecruitingNCT04526106

Elevar Therapeutics490 enrolled

Overview

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).

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

490

Conditions

FGFR2 Amplification FGFR2 Gene Mutation FGFR2 Gene Fusion/Rearrangement FGFR2 Gene Translocation FGFR2 Gene Activation

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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 \&gt;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\&#39;s formula (QTcF) \&gt; 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.

Locations (48)

The University of Alabama at Birmingham

Birmingham, Alabama, United States

Mayo Clinic

Phoenix, Arizona, United States

USC Norris Comprehensive Cancer Center

Los Angeles, California, United States

UCSF Helen Diller Family Comprehensive Cancer Center

San Francisco, California, United States

Mayo Clinic

Jacksonville, Florida, United States

Outcomes

Primary Outcomes

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

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 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

Part 4: Number of patients with dose interruptions

Time frame: Every 28-day cycle until end of treatment, approximately 24 months.

Part 4: Number of patients with dose reductions

Time frame: Every 28-day cycle until end of treatment, approximately 24 months.

Part 4: Number of patients with dose discontinuations

Time frame: Every 28-day cycle until end of treatment, approximately 24 months.

Secondary Outcomes

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

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

Overview

Conditions

Interventions

Eligibility

Locations (48)

Outcomes

Primary Outcomes

Secondary Outcomes