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Derazantinib in Subjects With FGFR2 Gene Fusion-, Mutation- or Amplification- Positive Inoperable or Advanced Intrahepatic Cholangiocarcinoma

This pivotal, open-label, single-arm study will evaluate the anti-cancer activity of derazantinib 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) or FGFR2 gene mutations or amplifications (based on NGS testing performed or commissioned by the respective study center) and who received at least one prior regimen of systemic therapy. Subjects will be dosed orally once per day at 300 mg of derazantinib capsules.
Phase II
Mol. targeted/Immunotherapy/Biologics
ARQ 087
Goff, Laura
Vanderbilt University


18 Years
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 gene fusion status based on the following assessments:

If central laboratory designated by Sponsor: Positive FISH test; and/or

If non-central laboratory: i) Positive FISH or NGS test: patients may be enrolled and may start dosing, but central confirmation is required* ii) 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 *Using standard protocols and approved by local IRB/EC, by CLIA or other similar agency. Substudy 2: FGFR2 mutation status based on local NGS testing performed or commissioned by the respective study site using a validated test. For NGS testing, no central laboratory will be established for the purpose of Substudy 2.

Received at least one regimen of prior systemic therapy and then experienced documented radiographic progression

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).


Hemoglobin (Hgb) ? 9.0 g/dL

Absolute neutrophil count (ANC) ? 1.5 x 109/L

Platelet count ? 75 x 109/L

International normalized ratio (INR) 0.8 to upper limit of normal (ULN) or ? 3 for subjects receiving anticoagulant therapy such as Coumadin or heparin


Total bilirubin ? 2 x ULN

AST and ALT ? 3 ULN (? 5 x ULN for subjects with liver metastases)

Albumin ? 2.8 g/dL


Serum creatinine ? 1.5 x ULN

Creatinine clearance of ? 60 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, use double-barrier contraceptive measures, oral contraception, or avoidance of intercourse, during the study*, and until at least 120 for 90 days after the last dose of derazantinib. *From the day of first study medication, or for oral contraception from 14 days before first study medication. 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) an acceptable method of contraception during heterosexual activity. Acceptable methods of contraception are***:

any ONE of:

an intrauterine device (IUD)

vasectomy of a female patient's male partner

a contraceptive rod implanted into the skin.

any TWO in combination of:

diaphragm with spermicide (cannot be used in conjunction with cervical cap/spermicide)

cervical cap with spermicide (nulliparous women only)

contraceptive sponge (nulliparous women only)

male condom or female condom (cannot be used together)

hormonal contraceptive (oral contraceptive pill [estrogen/progestin pill or progestin-only pill], contraceptive skin patch, vaginal contraceptive ring, or subcutaneous contraceptive injection) *Postmenopausal is defined as at least 12 months with no menses without an alternative medical cause; in women
If a contraceptive method listed above is restricted by local regulations/guidelines, then it does not qualify as an acceptable method of contraception for subjects participating at sites in this country/region.

Exclusion Criteria:

Systemic anti-cancer therapy, such as chemotherapy, immunotherapy, hormonal, targeted therapy, or investigational agents within four weeks of the first dose of derazantinib, or within five half-lives of any investigational or licensed medicinal product, whichever is the longer period.

Major surgery, locoregional therapy, or radiation therapy within four weeks of the first dose of derazantinib

Previous treatment with any FGFR inhibitor (e.g., ponatinib, dovitinib, nintedanib, AZD4547, NVP-BGJ398, LY2784455, BAY1163877)

Subjects who received less than four weeks of therapy and were unable to continue therapy due to toxicity will be allowed to participate

Unable or unwilling to swallow the complete daily dose of derazantinib capsules

Clinically unstable central nervous system (CNS) metastases (to be eligible, subjects 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, anti-epileptics, or other symptom-relieving medications)

Current evidence of corneal or retinal disorder, including but not limited to bullous/band keratopathy, keratoconjunctivitis, 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 subjects 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 will be permitted)

QTcF >450 msec (males or females)

Serum electrolyte abnormalities defined as follows:

Hyperphosphataemia: Serum phosphate > institutional ULN

Hyperkalemia: > 6.0 mmol/L

Hypercalcemia: corrected serum calcium
Hypocalcemia: corrected serum calcium > 3.1 mmol/L (> 12.5 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)

Previous malignancy within 2 years of the first dose of derazantinib, except curatively treated or low grade malignancies such as non-melanoma skin cancer, carcinoma in-situ of the breast, cervix, and superficial bladder tumors

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

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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