A Study of RLY-4008 in Patients with Intrahepatic Cholangiocarcinoma and Other Advanced Solid Tumors

Overview

About this study

The purpose of this study is to define the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D), safety profile, pharmacokinetics (PK), pharmacodynamics and preliminary anti-tumor activity of RLY-4008 in patients with ICC and other advanced solid tumors. 

Participation eligibility

Participant eligibility includes age, gender, type and stage of disease, and previous treatments or health concerns. Guidelines differ from study to study, and identify who can or cannot participate. There is no guarantee that every individual who qualifies and wants to participate in a trial will be enrolled. Contact the study team to discuss study eligibility and potential participation.

Inclusion Criteria:

  • Patient is willing and able to provide written informed consent for the study prior to the performance of any study-specific procedures.
  • Patient is ≥ 18 years of age.
  • 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.
  • Patient must have measurable or evaluable disease per Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1).
  • Patient has Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 to 1
  • Overall, patient has documented FGFR2 alteration in blood and/or tumor per local assessment as defined by:
    • FGFR2 fusion or other rearrangement as detected by DNA or RNA sequencing or break-apart fluorescence in situ hybridization (FISH);
    • 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 a creditable next-generation sequencing (NGS) test (e.g., FoundationOne CDx). No amplification cutoff is defined for circulating tumor DNA (ctDNA);
    • FGFR2 mutations must include one or more of the following primary oncogenic FGFR2 mutations or acquired FGFR2 resistance mutations:
    • H167_N173del, S252X, P253X, 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;
    • Other potential FGFR2-dependent tumor types may be considered for Part 1.

Part 1:

  • Patient has a histologically or cytologically confirmed diagnosis of unresectable or metastatic ICC or other unresectable or metastatic solid tumor.
  • 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 (e.g., 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:

Groups 1A/1B:

  • Patient must have a confirmed diagnosis of unresectable or metastatic ICC with FGFR2 fusion (per local assessment of blood and/or tumor) and has received prior treatment with a pan-FGFR inhibitor (e.g., pemigatinib, erdafitinib, infigratinib, futibatinib).

Groups 2A/2B:

  • Patient must have a confirmed diagnosis of unresectable or metastatic ICC with FGFR2 fusion (per local assessment of blood and/or tumor) and has NOT received prior treatment with a pan-FGFR inhibitor (e.g., pemigatinib, erdafitinib, infigratinib, futibatinib);

Group 3:

  • Patient has an unresectable or metastatic solid tumor with FGFR2 fusion (per local assessment of blood and/or tumor) other than ICC.

Group 4:

  • Patient has an unresectable or metastatic solid tumor with FGFR2 amplification (per local assessment of blood and/or tumor).

Group 5:

  • Patient has an unresectable or metastatic solid tumor with an oncogenic FGFR2 mutation (per local assessment of blood and/or tumor).
  • Patient must submit tumor tissue (archived or newly obtained biopsy) prior to study drug initiation for determination of FGFR2 status.

Exclusion Criteria:

  • Patient’s cancer has a known primary driver alteration other than FGFR2 that is amenable to approved targeted therapy (e.g., EGFR, ALK, ROS1, RET, HER2, BRAF, IDH1). Patients may be eligible after consultation with the Sponsor.
  • Patient has ongoing clinically significant FGFR inhibitor-induced retinal detachment or an ongoing clinically significant corneal or retinal disorder.
  • Patient does not have the following adequate organ function assessments within 7 days prior to the first dose of RLY-4008:
    • Platelet count ≥ 75 × 10^9 /L (platelet transfusion may be used to reach 75 × 10^9 /L but must have been administered at least 2 weeks prior to the first dose of RLY-4008) b. Absolute neutrophil count (ANC) ≥ 1 × 10^9 /L;
    • 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);
    • 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;
    • Total bilirubin < 1.5 × ULN; < 3 × ULN with direct bilirubin < 1.5 × ULN in the presence of Gilbert’s disease;
    • 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;
    • Serum phosphate < 7.0 mg/dL (2.3 mmol/L).
    • Patient has active infection, including human immunodeficiency virus (HIV), hepatitis B virus (HBV), and/or hepatitis C virus (HCV).
      • 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 (1);
      • 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 (2, 3);
      • Patients positive for HCV antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV RNA.
  • 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.
  • 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 prolongation (eg, Type II second-degree heart block or third-degree heart block).
  • Patient has 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.
  • Patient 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 < Grade 2 prior to starting RLY-4008). RLY-4008 may be started within these washout periods if considered by the Investigator to be safe and within the best interest of the patient, with prior Sponsor approval.
  • Patient received local hepatic therapy (e.g., transcatheter arterial chemoembolization [TACE] or yttrium90 [Y90]) within 4 weeks prior to C1D1.
  • Patient 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.
  • Patient has had a 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). Study centers should discuss other minor surgeries with the Sponsor.
  • Patient has a history of another primary malignancy that has been diagnosed or required therapy within the past year. The following prior malignancies are not exclusionary: completely resected basal cell and squamous cell skin cancer, curatively treated localized prostate or breast cancer, curatively treated localized thyroid cancer, and completely resected carcinoma in situ of any site. Adjuvant hormonal therapy for previously treated breast cancer, prostate cancer, or other hormone-dependent solid tumor is not exclusionary.
  • Patient is unwilling or unable to comply with scheduled visits, drug administration plan, laboratory tests, or other study procedures and study restrictions.
  • Women who are unwilling, if not post-menopausal or surgically sterile, to abstain from sexual intercourse or employ highly effective contraception during the RLY-4008 administration period and for at least 180 days (6 months) 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 (3 months) after the last dose of RLY-4008.
  • Pregnant females, as documented by a serum beta human chorionic gonadotropin (β-hCG) pregnancy test consistent with pregnancy, obtained within 7 days prior to the first dose of RLY-4008. Females with β-hCG values that are within the range for pregnancy but are not pregnant (false positives) may be enrolled with written consent of the Sponsor, after pregnancy has been ruled out. Females of nonchildbearing potential (postmenopausal for more than 1 year; bilateral tubal ligation; bilateral oophorectomy; hysterectomy) do not require a serum β-hCG test.
  • If female, patient is breastfeeding.
  • Patient has prior or ongoing clinically significant illness, medical condition, surgical history, physical finding, or laboratory abnormality that, in the Investigator’s opinion, could affect the safety of the patient; alter the absorption, distribution, metabolism, or excretion of the RLY-4008; or impair the assessment of study results.
  • Patient has documented history of and/or ongoing clinically significant ectopic mineralization/calcification.

Eligibility last updated 1/13/22. Questions regarding updates should be directed to the study team contact.

Participating Mayo Clinic locations

Study statuses change often. Please contact the study team for the most up-to-date information regarding possible participation.

Mayo Clinic Location Status Contact

Rochester, Minn.

Mayo Clinic principal investigator

Amit Mahipal, M.B.B.S.

Open for enrollment

Contact information:

Cancer Center Clinical Trials Referral Office

(855) 776-0015

Scottsdale/Phoenix, Ariz.

Mayo Clinic principal investigator

Mitesh Borad, M.D.

Open for enrollment

Contact information:

Cancer Center Clinical Trials Referral Office

(855) 776-0015

Jacksonville, Fla.

Mayo Clinic principal investigator

Hani Babiker, M.D.

Open for enrollment

Contact information:

Cancer Center Clinical Trials Referral Office

(855) 776-0015

More information

Publications

Publications are currently not available
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CLS-20504322

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