Clinical trial NCT04526106: 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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
PHASE2
Conditions: FGFR2 Amplification
FGFR2 Gene Mutation
FGFR2 Gene Fusion/Rearrangement
FGFR2 Gene Translocation
FGFR2 Gene Activation
Intrahepatic Cholangiocarcinoma
Cholangiocarcinoma
Other Solid Tumors, Adult
Lead sponsor: Elevar Therapeutics
Sponsor class: INDUSTRY
First posted: 2020-08-25
Enrollment: 490
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
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
Primary purpose: TREATMENT

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).


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

Primary outcomes:
measure: Part 1 and Part 4: Number of patients with adverse events and serious adverse events
timeFrame: Every cycle (4-week cycles) until study discontinuation, approximately 24 months
measure: Part 1: Determination of maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) of RLY-4008
timeFrame: 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
measure: Part 2 and Part 3: Objective Response Rate (ORR) assessed by Independent Review Committee per RECIST v1.1
timeFrame: Approximately every 8 weeks during treatment and every 12 weeks after the last dose in the absence of progressive disease, approximately 36 months
measure: Part 4: Number of patients with dose interruptions
timeFrame: Every 28-day cycle until end of treatment, approximately 24 months.
measure: Part 4: Number of patients with dose reductions
timeFrame: Every 28-day cycle until end of treatment, approximately 24 months.
measure: Part 4: Number of patients with dose discontinuations
timeFrame: Every 28-day cycle until end of treatment, approximately 24 months.
Secondary outcomes:
measure: Part 1: FGFR2 gene status in plasma circulating tumor deoxyribonucleic acid (ctDNA) and tumor tissue
timeFrame: Every cycle (4-week cycles) through Cycle 3 and every other cycle thereafter until study discontinuation, approximately 24 months
measure: Part 1: Duration of Response (DOR) assessed by Investigator per RECIST v1.1
timeFrame: Approximately every 8 weeks during treatment and every 12 weeks after the last dose in the absence of progressive disease, approximately 36 months
measure: Part 1: Disease Control Rate (DCR) as assessed by Investigator per RECIST v1.1
timeFrame: Approximately every 8 weeks during treatment and every 12 weeks after the last dose in the absence of progressive disease, approximately 36 months
measure: Part 1, Part 2, and Part 3: Objective Response Rate (ORR) as assessed by Investigator per RECIST v1.1
timeFrame: Approximately every 8 weeks during treatment and every 12 weeks after the last dose in the absence of progressive disease, approximately 36 months
measure: Pharmacokinetic parameters including maximum plasma drug concentration (Cmax)
timeFrame: Approximately every 2 weeks in Cycle 1 (4-week cycle) and every cycle through Cycle 4 (4-week cycles)
measure: Pharmacokinetic parameters including area under the plasma concentration versus time curve (AUC)
timeFrame: Approximately every 2 weeks in Cycle 1 (4-week cycle) and every cycle through Cycle 4 (4-week cycles)
measure: Pharmacokinetic parameters including half-life (t1/2)
timeFrame: Approximately every 2 weeks in Cycle 1 (4-week cycle) and every cycle through Cycle 4 (4-week cycles)
measure: Part 1: Pharmacodynamic parameters including changes in fibroblast growth factor 23 (FGF-23)
timeFrame: Approximately every 2 weeks in Cycle 1 (4-week cycle) and every other cycle (4-week cycles) from Cycle 3, approximately 24 months
measure: Part 1: Pharmacodynamic parameters including changes in carcinoembryonic antigen (CEA)
timeFrame: Approximately every 2 weeks in Cycle 1 (4-week cycle) and every other cycle (4-week cycles) from Cycle 3, approximately 24 months
measure: Part 1: Pharmacodynamic parameters including changes in cancer antigen 19-9 (CA 19-9)
timeFrame: Approximately every 2 weeks in Cycle 1 (4-week cycle) and every other cycle (4-week cycles) from Cycle 3, approximately 24 months
measure: Part 2 and Part 3: Duration of response (DOR) assessed by Investigator and Independent Review Committee per RECIST v1.1
timeFrame: Approximately every 8 weeks during treatment and every 12 weeks after the last dose in the absence of progressive disease, approximately 36 months
measure: Part 2 and Part 3: Progression-free survival (PFS) assessed by Investigator and Independent Review Committee per RECIST v1.1
timeFrame: Approximately every 8 weeks during treatment and every 12 weeks after the last dose in the absence of progressive disease, approximately 36 months
measure: Part 2 and Part 3: Disease control rate (DCR) assessed by Investigator and Independent Review Committee per RECIST v1.1
timeFrame: Approximately every 8 weeks during treatment and every 12 weeks after the last dose in the absence of progressive disease, approximately 36 months
measure: Part 2 and Part 3:Overall survival (OS)
timeFrame: Up to approximately 36 months.
measure: Part 2 and Part 3:Change from baseline in quality of life as assessed by EORTC QLQ-C30
timeFrame: Approximately every 4 weeks during treatment, approximately 24 months
measure: Part 2 and Part 3:Dose intensity
timeFrame: Every 28-day cycle until end of treatment, approximately 24 months.
measure: Part 2 and Part 3: Number of patients with dose interruptions
timeFrame: Every 28-day cycle until end of treatment, approximately 24 months.
measure: Part 2 and Part 3: Number of patients with dose reductions
timeFrame: Every 28-day cycle until end of treatment, approximately 24 months.
measure: Part 2 and Part 3: Number of patients with dose discontinuations
timeFrame: Every 28-day cycle until end of treatment, approximately 24 months.
measure: Part 2 and Part 3: Correlation between FGFR2 genotype by central tissue assessment and antitumor response, as measured by ORR
timeFrame: Approximately every 8 weeks during treatment and every 12 weeks after the last dose in the absence of progressive disease, approximately 36 months
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: The University of Alabama at Birmingham
state: Alabama
city: Phoenix
country: United States
facility: Mayo Clinic
state: Arizona
city: Los Angeles
country: United States
facility: USC Norris Comprehensive Cancer Center
state: California
city: San Francisco
country: United States
facility: UCSF Helen Diller Family Comprehensive Cancer Center
state: California
city: Jacksonville
country: United States
facility: Mayo Clinic
state: Florida
city: Tampa
country: United States
facility: Moffitt Cancer Center
state: Florida
city: Atlanta
country: United States
facility: Winship Cancer Institute, Emory University
state: Georgia
city: Chicago
country: United States
facility: University of Chicago Medical Center
state: Illinois
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: Cleveland
country: United States
facility: Taussig Cancer Institute Cleveland Clinic
state: Ohio
city: Philadelphia
country: United States
facility: Fox Chase Cancer Center
state: Pennsylvania
city: Dallas
country: United States
facility: Texas Oncology
state: Texas
city: Houston
country: United States
facility: The University of Texas M.D. Anderson Cancer Center
state: Texas
city: Salt Lake City
country: United States
facility: Huntsman Cancer Institute, University of Utah
state: Utah
city: Seattle
country: United States
facility: Virginia Mason Medical Center
state: Washington
city: Darlinghurst
country: Australia
facility: St. Vincent's Hosptial Sydney
city: Nedlands
country: Australia
facility: Linear Clinical Research Ltd
city: South Brisbane,
country: Australia
facility: Icon Cancer Care South Brisbane
city: Bordeaux
country: France
facility: Institut Bergonie
city: Dijon
country: France
facility: Centre Georges François Leclerc
city: Lyon
country: France
facility: Centre Leon Berard
city: Paris
country: France
facility: Gustave Roussy Cancer Campus
city: Hannover
country: Germany
facility: Medizinische Hochschule Hannover
city: Heidelberg
country: Germany
facility: Universitätsklinikum Heidelberg
city: Munich
country: Germany
facility: LMU Klinikum, Campus Grosshadern
city: Hong Kong
country: Hong Kong
facility: Queen Mary Hospital
city: Milano
country: Italy
facility: Istituto Europeo di Oncologia
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center
city: Amsterdam
country: Netherlands
facility: Netherlands Cancer institute
city: Rotterdam
country: Netherlands
facility: Erasmus MC
city: Singapore
country: Singapore
facility: National Cancer Center Singapore
city: Barcelona
country: Spain
facility: START Barcelona-Hospital HM Nou Delfos
city: Barcelona
country: Spain
facility: Hospital Universitari Vall d'Hebron
city: Madrid
country: Spain
facility: Hospital Universitario Fundación Jiménez Díaz- START MADRID
city: Madrid
country: Spain
facility: Hospital Universitario HM Sanchinarro-START MADRID-CIOCC
city: Pamplona
country: Spain
facility: Clinica de Universidad de Navarra
city: Valencia
country: Spain
facility: Hospital Clínico Universitario de Valencia
city: Stockholm
country: Sweden
facility: Karolinska University Hospital
city: Taichung
country: Taiwan
facility: China Medical University Hospital
city: London
country: United Kingdom
facility: Guy's Hospital
city: London
country: United Kingdom
facility: Sarah Cannon Research Institute UK
city: London
country: United Kingdom
facility: University College London Hospitals NHS Foundation Trust
city: Manchester
country: United Kingdom
facility: The Christie NHS Foundation Trust
Study officials:
References: