A pivotal study of derazantinib in patients with inoperable or advanced intrahepatic cholangiocarcinoma and FGFR2 gene fusions or FGFR2 gene mutations or amplifications


NCT ID: NCT03230318
Sponsor Protocol Number: DZB-CS-301

About this study

This pivotal, open-label, single-arm study will evaluate the anti-cancer activity of ARQ 087 by Objective Response Rate (ORR) by central radiology review as per RECIST v1.1 in subjects with inoperable or advanced intrahepatic cholangiocarcinoma (iCCA) whose tumors harbor FGFR2 gene fusions (by FISH performed by the central laboratory) and who received at least one prior regimen of systemic therapy. Subjects will be dosed orally once per day at 300 mg of ARQ 087 capsules.

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.

Pre-Screening Eligibility Criteria:

  • Signed written informed consent to permit tissue analysis.
  • 18 years of age or older.
  • No medical history that is excluded per the study treatment eligibility criteria.
  • Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1.
  • Eligible for or receiving systemic therapy for inoperable or advanced iCCA.
  • Not currently eligible for curative local or surgical therapy.
  • To be enrolled in the study, once the FGFR2 genomic aberration status is determined, each prospective patient must meet all of the following inclusion criteria and none of the exclusion criteria.

Inclusion Criteria:

  • Signed written informed consent granted prior to initiation of any study-specific procedures.
  • 18 years of age or older.
  • Histologically or cytologically confirmed locally advanced, inoperable (where surgery is not indicated due to disease extension, co-morbidities, or other technical reasons), or metastatic iCCA or mixed histology tumors (combined hepatocellular-cholangiocarcinoma [cHCC-CCA]).

Substudy 1:

  • FGFR2 fusion status based on the following assessments:
    • If central laboratory designated by the Sponsor: Positive FISH test; and/or
    • If non-central laboratory: *
    • Positive FISH or NGS test: patients may be enrolled and may start dosing, but central confirmation is required.**  
    • * Using standard protocols and approved by local IRB/IEC, CLIA, or other similar agency. For enrollment of patients in the EU, assays must be fully CE-marked. ** The patient must not be enrolled if a negative FISH test is obtained from the central laboratory prior to commencing study treatment. Patients without central confirmation of an FGFR2 fusion by the central FISH test will be assessed on a case-by-case basis.
  • Negative FISH or NGS test: tissue may be submitted to the central laboratory designated by the Sponsor, and patients may only be enrolled if the central test is positive.

Substudy 2:

  • FGFR2 mutations/amplifications without any concurrent FGFR2 translocations based on NGS testing performed or commissioned by the respective study site (see Section 6.8.2 for further details).
    • Note 1: If the FGFR2 mutation/amplification status is derived from plasma-based NGS testing, a tumor block or slides prepared thereof should be submitted for subsequent correlative tissue-based NGS test at a laboratory identified by the Sponsor.
    • Note 2: If the NGS test used cannot identify FGFR2 translocations, a FISH test is mandatory to confirm that none are present.
  • Received at least one regimen of prior systemic therapy and then experienced documented radiographic progression (for Substudy 1), and have no satisfactory treatment alternatives (for Substudy 2)
  • Measurable disease by RECIST version 1.1 criteria.
  • ECOG performance status ≤ 1.
  • Adequate organ functions as indicated by the following laboratory values (based on screening visit values from the central laboratory):
    • Hematological
      • Hemoglobin (Hgb) ≥ 9.0 g/dL;
      • Absolute neutrophil count (ANC)  ≥ 1.5 × 10^9/L;
      • Platelet count ≥ 75 × 10^9/L;
      • International normalized ratio (INR) 0.8 to upper limit of normal (ULN) or ≤ 3 for patients receiving anticoagulant therapy such as warfarin or heparin.
    • Hepatic
      • Total bilirubin ≤ 2 × ULN;
      • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 ULN (≤ 5 × ULN for patients with liver metastases);
      • Albumin ≥ 2.8 g/dL.
    • Renal
      • Serum creatinine ≤ 1.5 × ULN; or
      • Creatinine clearance of ≥ 30 mL/min as estimated by the Cockcroft-Gault equation.
  • Female and male patients of child-producing potential must agree to avoid becoming pregnant or impregnating a partner, respectively, during the study*, and for at least 120 days after the last dose of derazantinib.
  • Male patients are considered not to be of child-producing potential if they have azoospermia (whether due to vasectomy or an underlying medical condition). Female patients are considered not to be of child-producing potential if they are:
    • postmenopausal†; or
    • have had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy or bilateral tubal ligation/occlusion, at least 6 weeks prior to screening; or
    • have a congenital or acquired condition that prevents childbearing.
  • Male or female patients of child-producing potential must agree to comply with one of the following until at least 120 days after the last dose of derazantinib:
    • Abstinence from heterosexual activity‡;
    • Using (or having their partner use) a highly effective method of contraception during heterosexual activity.  Highly effective methods of contraception are§:
      • an intrauterine device (IUD);
      • vasectomy of a female patient’s male partner;
      • a contraceptive rod implanted into the skin;
      • combined (estrogen- and progestogen-containing) or progestogen-only hormonal contraception associated with inhibition of ovulation (oral contraceptive pill [estrogen/progestin pill or progestin-only pill] contraceptive skin  patch/implant, vaginal contraceptive ring, or subcutaneous contraceptive injection).
  • *From the day of first study medication, or for oral contraception from 14 days before first study medication.
  • † Postmenopausal is defined as at least 12 months with no menses without an alternative medical cause; in women < 45 years of age a high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a post -menopausal state in women not using hormonal contraception or hormonal replacement therapy. In the absence of 12 months of amenorrhea, a single FSH measurement is not sufficient.
  • ‡ Abstinence (relative to heterosexual activity) can be used as the sole method of contraception if it is consistently employed as the subject’s preferred and usual lifestyle and if it is employed during the entire period of risk associated with the study treatment and if it is considered highly effective by local regulatory agencies and ERCs/IRBs. Periodic abstinence (e.g., calendar, ovulation, sympto-thermal, post-ovulation methods, etc.) and withdrawal are not highly effective methods of contraception.
  • § If a contraceptive method listed above is restricted by local regulations/guidelines, then it does not qualify as a highly effecive method of contraception for subjects participating at sites in this country/region.

Exclusion Criteria:

  • Receipt of treatment before the first dose of study drug (Cycle 1 Day 1) within an interval shorter than the following, as applicable:
    • One chemotherapy or biological (e.g., antibody) cycle interval;
    • Five half-lives of any small-molecule investigational or licensed medicinal product;
    • Two weeks, for any investigational medicinal product with an unknown half-life;
    • Four weeks of curative radiotherapy;
    • Seven days of palliative radiotherapy;
    • 28 days of radiotherapy.
  • Major surgery or locoregional therapy within 4 weeks of the first dose of derazantinib.
  • Previous treatment with any FGFR inhibitor (e.g., Balversa® [erdafitinib], Pemazyre® [pemigatinib], infigratinib, rogaratinib, futibatinib, lenvatinib, ponatinib, dovitinib, nintedanib, AZD4547, LY2784455).
  • Unable or unwilling to swallow the complete daily dose of derazantinib capsules.
  • Clinically unstable central nervous system (CNS) metastases (to be eligible, patients must have stable disease  ≥ 3 months, confirmed by magnetic resonance imaging (MRI) or computed tomography (CT) scan, and/or have CNS metastases. well controlled by low-dose steroids, antiepileptics, or other symptom-relieving medications).
  • Current evidence of clinically signficant corneal or retinal disorder likely to increase the risk of eye toxicity including, but not limited to, bullous/band keratopathy, keratoconjunctivitis (unless keratoconjunctivitis sicca), corneal abrasion, inflammation/ulceration, confirmed by ophthalmologic examination.
  • Concurrent uncontrolled or active hepatobiliary disorders, untreated or ongoing complications after laparoscopic procedures or stent placement, including but not limited to active cholangitis, biloma or abscess (to be eligible, the patients have to be treated and disorders/complications should be resolved within 2 weeks prior to the first dose of derazantinib).
  • History of significant cardiac disorders:
    • Myocardial infarction (MI) or congestive heart failure defined as Class II to IV per the New York Heart Association (NYHA) classification within 6 months of the first dose of derazantinib (MI that occurred > 6 months prior to the first dose of derazantinib are permitted);
    • QTcF > 450 msec for men and QTcF > 460 msec for women.
  • Serum electrolyte abnormalities defined as follows:
    • Hyperphosphatemia: serum phosphate > institutional ULN;
    • Hyperkalemia: serum potassium > institutional ULN;
    • Hypokalemia: serum potassium < institutional lower limit of normal (LLN);
    • Hypercalcemia: corrected serum calcium > 3.1 mmol/L (> 12.5 mg/dL);
    • Hypocalcemia: corrected serum calcium < 1.75 mmol/L (< 7.0 mg/dL);
    • Hypomagnesemia: < 0.4 mmol/L (< 0.9 mg/dL).
  • Significant gastrointestinal disorder(s) that could, in the opinion of the Investigator, interfere with the absorption, metabolism, or excretion of derazantinib (e.g., Crohn’s disease, ulcerative colitis, extensive gastric resection).
  • History of additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin that has undergone potentially curative therapy, and in situ cervical cancer.
  • Concurrent uncontrolled illness not related to cancer, including but not limited to:
    • Psychiatric illness/substance abuse/social situation that would limit compliance with study requirements;
    • Known uncontrolled human immunodeficiency virus (HIV) infection.
    • Severe bacterial, fungal, viral, and/or parasitic infections under treatment with therapeutic oral or intravenous (IV) medication at the time of first dose of study drug administration.
  • Blood or albumin transfusion within 5 days of the blood draw being used to confirm eligibility.
  • Pregnant or breast feeding.
  • Known hypsersensitivity to derazantinib, or to any of the study drug excipients (starch, lactose, crospovidone, magnesium stearate).

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