A First-in-Human Study of Highly Selective FGFR2 Inhibitor, RLY-4008, in Patients With Intrahepatic Cholangiocarcinoma (ICC) and Other Advanced Solid Tumors

Recruiting

• Conditions: Bile Duct Cancer; Intrahepatic Bile Duct Carcinoma; 10019815

• Registration Number: NL-OMON54283
• Lead Sponsor: Relay Therapeutics, Inc.

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Last Update Posted: 18 June 2024

Recruitment & Eligibility

• Status: Recruiting
• Sex: Not specified
• Target Recruitment: 4

Inclusion Criteria

General Inclusion Criteria
1. Patient is willing and able to provide written informed consent for the
study prior to the performance of any study-specific procedures.
2. Patient is >= 18 years of age.
3. 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.
4. Patient must have measurable disease per Response Evaluation Criteria in
Solid Tumors, Version 1.1 (RECIST v1.1).
5. Patient has Eastern Cooperative Oncology Group (ECOG) performance status
(PS) of 0 to 1 (Appendix B).

Disease and FGFR2 status
6. Overall, patient has documented FGFR2 alteration in blood and/or tumor per
local assessment as defined by:
a. FGFR2 fusion or other rearrangement as detected by DNA or RNA sequencing or
break-apart fluorescence in situ hybridization (FISH).
b. FGFR2 amplifications must either include an amplified FGFR2 locus with copy
number >= 8 (FGFR2 probe: reference ratio >= 4 per FISH) in tumor tissue or be
defined as FGFR2 amplified by validated next-generation sequencing (NGS) test
(including but not limited to FoundationOne CDx, Tempus xT, Caris MI, or
Guardant360). No amplification cutoff is defined for circulating tumor DNA
(ctDNA).
c. FGFR2 mutations must include one or more of the following primary oncogenic
FGFR2 mutations or acquired FGFR2 resistance mutations:
o H167_N173del, S252X, P253X, F276C, Y375X, C382X, M537X, N549X, V564X,
E565X, L617X, K641X, K659X, and R664X (numbering based on mesenchymal isoform
IIIc; X represents any amino acid change except a synonymous mutation). Other
potentially oncogenic and/or resistance FGFR2 mutations may be considered but
must be approved by the Sponsor prior to enrollment.
d. Other potential FGFR2-dependent tumor types may be considered for Part 1.

Part 1:
7. Patient has a histologically or cytologically confirmed diagnosis of
unresectable or metastatic CCA or other unresectable or metastatic solid tumor.
8. Patient has documented FGFR2 genomic alteration (fusion, amplification, or
mutation) in blood and/or tumor tissue per local assessment. Patients with
other potential oncogenic FGFR2 alterations (eg, FGFR2 protein or mRNA
overexpression) and other tumor types known to exhibit an FGFR2 oncogenic
alteration may be eligible for the dose escalation (Part 1) of the study after
consultation with the Sponsor.
9. Patient agrees to provide archived tumor tissue (if available) or is willing
to undergo pretreatment tumor biopsy (if considered safe and medically
feasible) to assess FGFR2 status. If the patient does not have available
archived tumor tissue or tumor amenable to tumor biopsy, he/she may be eligible
for the study upon consultation with the Sponsor.

Part 2:
10. Patient will enroll based on their tumor type and prior therapy status:
Cholangiocarcinoma:
a. Groups 1A: patient must have a confirmed diagnosis of unresectable or
metastatic CCA with FGFR2 fusion or other rearrangement (per local assessment
of blood and/or tumor) and has been previously treated with chemotherapy and
has received prior treatment with an FGFRi.
b. Groups 2A: patient must have a confirmed diagnosis of unresectable or

Exclusion Criteria

Patients who meet one or more of the following criteria will not be considered
eligible to participate in the clinical study:
1. Patient has a cancer other than FGFR2 fusion/rearrangement positive CCA and
has a known primary driver alteration that is amenable to approved targeted
therapy (eg, EGFR, ALK, ROS1, RET, HER2, BRAF, IDH1, KRAS). Patients may be
eligible after consultation with the Sponsor.
2. Patient has ongoing clinically significant FGFRi-induced retinal detachment
or an ongoing clinically significant corneal or retinal disorder.
3. Patient does not have the following adequate organ function assessments
within 7 days prior to the first dose of RLY-4008:
a. Platelet count >=75 × 109/L (platelet transfusion may be used to reach 75 ×
109/L but must have been administered at least 2 weeks prior to the first dose
of RLY-4008)
b. Absolute neutrophil count (ANC) >= 1 × 109/L
c. Hemoglobin >= 8 g/dL (red blood cell transfusion and erythropoietin may be
used to reach 8 g/dL but must have been administered at least 2 weeks prior to
the first dose of
RLY-4008)
d. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) < 3 × the
upper limit of normal (ULN) if no hepatic metastases are present; < 5 × ULN if
hepatic
metastases are present
e. Total bilirubin < 1.5 × ULN; < 3 × ULN with direct bilirubin < 1.5 × ULN in
the presence of Gilbert*s disease
f. Estimated (including Cockcroft-Gault, Modification of Diet in Renal Disease
[MDRD], or Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI]
formulas) or measured creatinine clearance > 50 mL/min (Appendix A)
g. Serum phosphate < 7.0 mg/dL (2.3 mmol/L)
4. Patient has active infection, including human immunodeficiency virus (HIV),
hepatitis B virus (HBV) and/or hepatitis C virus (HCV).
a. Active HIV is defined by positivity for HIV 1 or HIV 2 antibodies.
HIV-positive patients are allowed if all of the following criteria are met:
CD4+ count >= 350/µL, undetectable viral load, receiving antiretroviral therapy
(ART) that does not interact with study drug (patients should be on established
ART for at least 4 weeks), and no HIV/AIDS-associated opportunistic infection
in the last 12 months.
b. Active HBV is defined by a positive HBV surface antigen (HBsAg) result.
Patients with a past or resolved HBV infection (defined as the presence of
hepatitis B core antibody [anti-HBc], absence of HBsAg, and serum HBV DNA <
1000 IU/mL) are eligible. Patients with well-controlled HBV, indicated by the
presence of HBsAg with serum HBV DNA <500 IU/mL are also eligible.
c. Patients positive for HCV antibody are eligible only if polymerase chain
reaction (PCR) is negative for HCV RNA.

5. Patient has a QT interval corrected using Fridericia*s formula (QTcF) > 480
msec. Patient has a history of prolonged QT syndrome or torsades de pointes.
Patient has a familial history of prolonged QT syndrome.
6. Patient has clinically significant, uncontrolled cardiovascular disease
including congestive heart failure Grade III or IV according to the New York
Heart Association (NYHA)
classification; myocardial infarction or unstable angina within the previous
six months; uncontrolled hypertension (Grade 3 or higher); or clinically
significant, uncontrolled
arrhythmia, including bradyarrhythmias that may cause QT prolon

Study & Design

• Study Type: Interventional
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
<p>Primary Objectives<br /><br>- To determine the MTD and RP2D of RLY-4008<br /><br>- To determine the safety and tolerability of RLY-4008<br /><br><br /><br>- Frequency, severity, timing, and relationship to RLY-4008 of any AEs and<br /><br>SAEs. All AEs and SAEs will be collected and graded according to<br /><br>NCI CTCAE, Version 5.0.<br /><br>- Dose modification (e.g., dose interruption, dose reduction, dose<br /><br>discontinuation) </p><br>