A First-in-human Study of Highly Selective FGFR2 Inhibitor, RLY-4008, in Patients with Intrahepatic Cholangiocarcinoma (ICC) and Other Advanced Solid Tumors
This is an open-label, FIH study designed to evaluate the safety, tolerability, PK, pharmacodynamics, and preliminary antineoplastic activity of RLY-4008, a potent and highly selective fibroblast growth factor receptor 2 (FGFR2) inhibitor administered orally patients with unresectable or metastatic ICC and other unresectable or metastatic solid tumors. This study consists of 2 parts, a dose escalation (Part 1) and a dose expansion (Part 2).
To determine the MTD and RP2D of RLY-4008 To determine the safety and tolerability of RLY-4008
- Willing and able to provide written informed consent for the study prior to the performance of any study-specific procedures.
- 18 years of age or older
- 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
- Measurable or evaluable disease per Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1).
- Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 to 1 Disease and FGFR2 status
- Documented FGFR2 alteration in blood and/or tumor per local assessment as defined in the protocol. Part 1:
- Histologically or cytologically confirmed diagnosis of unresectable ICC or metastatic CCA or other unresectable or metastatic solid tumor.
- 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.
- 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:
- Patient will enroll based on their tumor type and prior therapy status: Cholangiocarcinoma: 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. Groups 2A: 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 NOT received prior treatment with an FGFRi. Group 6: 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 have NOT received prior anticancer systemic therapy for unresectable and/or metastatic disease. Prior adjuvant/neo-adjuvant treatment is acceptable if completed at least 6 months prior to enrollment. A single cycle of palliative chemotherapy is allowed while patients are in screening to define FGFR2 status. Group 7: patients must have a confirmed diagnosis of unresectable or metastatic CCA with FRFR2 mutation or amplification (per local assessment of blood and/or tumor). Other solid tumors NOT cholangiocarcinoma: Group 3: patient has an advanced unresectable or metastatic solid tumor with FGFR2 fusion (per local assessment of blood and/or tumor) other than CCA. Group 4: patient has an advanced unresectable or metastatic solid tumor with FGFR2 amplification (per local assessment of blood and/or tumor) other than CCA. Group 5: patient has an advanced unresectable or metastatic solid tumor with an oncogenic FGFR2 mutation (per local assessment of blood and/or tumor) other than CCA
- Must submit tumor tissue (archived or newly obtained biopsy) prior to study drug initiation for determination of FGFR2 status.
- Other criteria apply
- Patient's cancer in Part 1 and 2 (not applicable to part 3) has a known primary driver alteration other than FGFR2 that is amenable to approved targeted therapy. Patients may be eligible after consultation with the Sponsor.
- Ongoing clinically significant FGFRi-induced renal detachment or an ongoing clinically significant corneal or retinal disorder.
- Has any of the lab values identified in protocol within 14 days prior to the first dose of RLY-4008.
- Active human immunodeficiency virus (HIV) or active hepatitis B virus (HBV) and/or hepatitis C virus (HCV). Testing is not required.
- 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.
- Clinically significant, uncontrolled cardiovascular disease including congestive heart failure Gradye 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 prolongation (eg, Type II second-degree heart block or third-degree heart block).
- Central nervous system (CNS) metastases or primary CNS tumor that is associated with progressive neurologic symptoms or requires increasing doses of corticosteroids to control the CNS disease. If patient requires corticosteroids for management of CNS disease, the dose must have been stable for the 2 weeks preceding Cycle 1 Day 1 (C1D1). Patients with stable or asymptomatic CNS metastases or primary CNS can be eligible after consultation with the Sponsor.
- Received anticancer therapy (including both systemic therapy and radiotherapy, but not including immunotherapy or other antibody therapies) within 14 days or 5 half-lives (whichever is shorter) prior to the first dose of study drug. Patients who received previous immunotherapy or other antibody therapy, within 28 days (immune related toxicities must have resolved to > Received local hepatic therapy (eg, transcatheter arterial chemoembolization [TACE] or yttrium90 [Y90]) within 4 weeks prior to C1D1.
- Received neutrophil growth factor support within 14 days of the first dose of RLY-4008.
- Patient requires treatment with a prohibited medication or use with caution herbal remedy that cannot be discontinued at least 2 weeks before the start of RLY-4008 administration.
- Major surgical procedure within 14 days of the first dose of RLY-4008 (procedures such as central venous catheter placement, and tumor needle biopsy are not considered major surgical procedures).
- History of another primary malignancy that has been diagnosed or required therapy within the past year.
- Women who are unwilling, if not postmenopausal or surgically sterile, to abstain from sexual intercourse or employ highly effective contraception during the RLY-4008 administration period and for at least 30 days after the last dose of RLY-4008. Men who are unwilling, if not surgically sterile, to abstain from sexual intercourse or employ highly effective contraception during the RLY-4008 administration period and for at least 90 days after the last dose of RLY-4008. Refer to Section 5.4.2 for acceptable methods of contraception.
- Women who are breast feeding
- Other Exclusions may apply
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