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

A Pivotal Study of Derazantinib in Patients With Inoperable or Advanced Intrahepatic Cholangiocarcinoma and FGFR2 Gene Fusions or FGFR2 Gene Mutations or Amplifications

This Phase II, open-label, single-arm study evaluated the anti-cancer activity of derazantinib in subjects with inoperable or advanced intrahepatic cholangiocarcinoma (iCCA) who received at least one prior regimen of systemic therapy. Patients received an oral once-daily total dose of 300 mg derazantinib capsules.

This was a multi-center, open-label, single arm study which evaluated the anti-cancer activity of derazantinib in adult patients with inoperable or advanced iCCA in the following study population:

Patients with inoperable or advanced iCCA and with fibroblast growth factor receptor 2 (FGFR2) fusions (Substudy 1) or FGFR2 mutations/amplifications (Substudy 2), treated with at least one prior regimen of systemic therapy.

Derazantinib was supplied as 100 mg capsules. A dose of 300 mg once-daily (three capsules of 100 mg each) of derazantinib was administered orally to patients, 1 hour before, or 2 hours after, a meal.

Key Inclusion Criteria:

1. Signed written informed consent granted prior to initiation of any study-specific procedures

2. 18 years of age or older

3. Histologically or cytologically confirmed locally advanced, inoperable, or metastatic iCCA or mixed histology tumors

4. Substudy 1:

   FGFR2 fusion status based on the following assessments:

   a) If central laboratory was designated by Sponsor: Positive FISH test; and/or b) If non-central laboratory: i) Positive FISH or NGS test: patients were potentially enrolled and started dosing, but central confirmation was required* ii) Negative FISH or NGS test: tissue was submitted to the central laboratory designated by the Sponsor, and patients were only enrolled in case the central test was positive

   *By used standard protocols and approved by local IRB/EC, by CLIA or other similar agency.

   Substudy 2:

   FGFR2 mutation/amplification status based on local NGS testing performed or commissioned by the respective study site.

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

6. Measurable disease by RECIST version 1.1 criteria

7. ECOG performance status ≤ 1

8. 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 x 10^9/L
     • Platelet count ≥ 75 x 109/L
     • International normalized ratio (INR) 0.8 to upper limit of normal (ULN) or ≤ 3 for subjects who received anticoagulant therapy such as Coumadin or heparin

   • Hepatic

     • Total bilirubin ≤ 2 x ULN
     • AST and ALT ≤ 3 ULN (≤ 5 x ULN for subjects with liver metastases)
     • Albumin ≥ 2.8 g/dL

   • Renal

     • Serum creatinine ≤ 1.5 x ULN
     • Creatinine clearance of ≥ 30 mL/min as estimated by the Cockcroft-Gault equation

9. Female and male patients of child-producing potential must had agreed to avoid becoming pregnant or impregnating a partner, respectively, used double-barrier contraceptive measures, oral contraception, or had to avoid of intercourse, during the study, and until at least 120 for 90 days after the last dose of derazantinib.

Male or female patients of child-producing potential must had agreed to comply with one of the following until at least 120 days after the last dose of derazantinib:

1. Abstinence from heterosexual activity
2. Using (or having their partner use) an acceptable method of contraception during heterosexual activity.

Key Exclusion Criteria:

1. 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

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

3. Previous treatment with any FGFR inhibitor (e.g., Balversa® [erdafitinib], Pemazyre® [pemigatinib], infigratinib, rogaratinib, futibatinib, lenvatinib, ponatinib, dovitinib, nintedanib, AZD4547, LY2784455).

4. Patients who were unable or unwilling to swallow the complete daily dose of derazantinib capsules

5. Clinically unstable central nervous system (CNS) metastases (to be eligible, subjects must had stable disease ≥ 3 months, confirmed by magnetic resonance imaging (MRI) or computed tomography (CT) scan, and/or had CNS metastases well controlled by low-dose steroids, anti-epileptics, or other symptom-relieving medications)

6. Evidence of clinically significant corneal or retinal disorder which was 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.

7. 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 had to be treated and disorders/complications should had been resolved within 2 weeks prior to the first dose of derazantinib)

8. 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 was permitted)
   • QTcF >450 msec (males or females)

9. Serum electrolyte abnormalities defined as follows:

   • Hyperphosphataemia: Serum phosphate > institutional ULN
   • Hyperkalemia: > 6.0 mmol/L
   • Hypokalemia: < 3.0 mmol/L
   • Hypercalcemia: corrected serum calcium < 1.75 mmol/L (< 7.0 mg/dL)
   • Hypocalcemia: corrected serum calcium > 3.1 mmol/L (> 12.5 mg/dL)
   • Hypomagnesemia: < 0.4 mmol/L (< 0.9 mg/dL)

10. Significant gastrointestinal disorder(s) that could had, in the opinion of the Investigator, interfered with the absorption, metabolism, or excretion of derazantinib (e.g., Crohn's disease, ulcerative colitis, extensive gastric resection)

11. History of additional malignancy that was progressing or required active treatment. Exceptions included basal cell carcinoma of the skin, squamous cell carcinoma of the skin that had undergone potentially curative therapy, and in situ cervical cancer.

12. 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 on therapeutic oral or IV medication at the time of first dose of study drug administration

13. Blood or albumin transfusion within 5 days of the blood draw which has been used to confirm eligibility

14. Pregnant or breast feeding

15. Known hypsersensitivity to derazantinib, or to any of the study drug excipients (starch, lactose, crospovidone, magnesium stearate)