Cholangiocarcinoma, FGFR2 Amplification, FGFR2 Gene Activation, FGFR2 Gene Fusion/Rearrangement, FGFR2 Gene Mutation, FGFR2 Gene Translocation, Intrahepatic Cholangiocarcinoma, Other Solid Tumors, Adult
Conditions
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).
Interventions
DRUGRLY-4008
RLY-4008 is an oral inhibitor of FGFR2
Sponsors
Elevar Therapeutics
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
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
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion 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.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Part 1 and Part 4: Number of patients with adverse events and serious adverse events | 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 | 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 | 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 | Every 28-day cycle until end of treatment, approximately 24 months. |
| Part 4: Number of patients with dose reductions | Every 28-day cycle until end of treatment, approximately 24 months. |
| Part 4: Number of patients with dose discontinuations | Every 28-day cycle until end of treatment, approximately 24 months. |
Secondary
| Measure | Time frame |
|---|---|
| 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 |
| 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 |
| 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 |
| 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 |
| 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) |
| 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) |
| 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) |
| 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 |
| 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 |
| 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 |
| 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 |
| 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 |
| 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 |
| Part 2 and Part 3:Overall survival (OS) | Up to approximately 36 months. |
| 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 |
| Part 2 and Part 3:Dose intensity | Every 28-day cycle until end of treatment, approximately 24 months. |
| Part 2 and Part 3: Number of patients with dose interruptions | Every 28-day cycle until end of treatment, approximately 24 months. |
| Part 2 and Part 3: Number of patients with dose reductions | Every 28-day cycle until end of treatment, approximately 24 months. |
| Part 2 and Part 3: Number of patients with dose discontinuations | 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 | Approximately every 8 weeks during treatment and every 12 weeks after the last dose in the absence of progressive disease, approximately 36 months |
Countries
Australia, France, Germany, Hong Kong, Italy, Netherlands, Singapore, South Korea, Spain, Sweden, Taiwan, United Kingdom, United States
Outcome results
None listed