Derazantinib in Subjects With FGFR2 Gene Fusion-, Mutation- or Amplification- Positive Inoperable or Advanced Intrahepatic Cholangiocarcinoma (FIDES-01)

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.

Study Overview

• Status: Completed
• Conditions: Intrahepatic Cholangiocarcinoma; Combined Hepatocellular and Cholangiocarcinoma
• Intervention / Treatment: Drug: derazantinib

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 148
• Phase: Phase 2

Expanded Access

Available outside the clinical trial. See expanded access record.

Contacts and Locations

Study Locations

• Belgium
  • Brussels, Belgium, 1200
    • Cliniques Universitaires Saint-Luc
  • Brussels, Belgium, 1070
    • Hopital Erasme
  • Edegem, Belgium, 2650
    • Antwerp University Hospital
• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2N 4N2
      • Tom Baker Cancer Centre
  • Ontario
    • Toronto, Ontario, Canada, M5G 2M9
      • Princess Margaret Cancer Centre
• France
  • La Tronche, France, 38700
    • Chu Grenoble Alpes
  • Villejuif, France, 94805
    • Gustave Roussy
• Germany
  • Frankfurt am Main, Germany, 60590
    • Universitatsklinikum Frankfurt
  • Hamburg, Germany, 20246
    • Universitätsklinikum Hamburg-Eppendorf (UKE)
  • Hannover, Germany, 30625
    • Medizinische Hochschule Hannover (MHH)
  • Homburg, Germany, 66421
    • Universitätsklinikum des Saarlandes
  • Mainz, Germany, 55131
    • Universitätsmedizin der Johannes Gutenberg-Universität Mainz
• Ireland
  • Dublin, Ireland, D08 NHY1
    • St. James's Hospital
• Italy
  • Bologna, Italy, 40138
    • Sant'Orsola-Malpighi Hospital, University of Bologna
  • Milan, Italy, 20133
    • Fondazione IRCCS Istituto Nazionale dei Tumori
  • Monza, Italy, 20900
    • Ospedale San Gerardo
  • Padova, Italy, 35128
    • Istituto Oncologico Veneto - IRCCS
  • Pisa, Italy, 56126
    • Azienda Ospedaliero-Universitaria Pisana
  • Rozzano, Italy, 20089
    • Humanitas Cancer Center, Istituto Clinico Humanitas IRCCS
• Korea, Republic of
  • Seoul, Korea, Republic of, 3080
    • Seoul National University Hospital
  • Seoul, Korea, Republic of, 6351
    • Samsung Medical Center
  • Seoul, Korea, Republic of, 6591
    • The Catholic University of Korea, Seoul St. Mary's Hospital
• Spain
  • Barcelona, Spain, 08035
    • Vall d'Hebron University Hospital
  • Barcelona, Spain, 08908
    • Catalan Institute of Oncology
  • Madrid, Spain, 28041
    • Hospital Universitario 12 de Octubre
  • Madrid, Spain, 28007
    • Hospital General Universitario Gregorio Marañon
• Switzerland
  • Basel, Switzerland, 4031
    • Universitatsspital Basel
• United Kingdom
  • Euston, United Kingdom, NW1 2BU
    • University College London Hospitals NHS Foundation Trust
  • Glasgow, United Kingdom, G120YN
    • Beatson West Of Scotland Cancer Centre
  • Sutton, United Kingdom, SM2 5PT
    • The Royal Marsden
• United States
  • Arizona
    • Phoenix, Arizona, United States, 85054
      • Mayo Clinic
  • Florida
    • Jacksonville, Florida, United States, 32224
      • Mayo Clinic
    • Tampa, Florida, United States, 33612-9416
      • Moffitt Cancer Center
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Winship Cancer Institute of Emory University
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic
  • New York
    • New York, New York, United States, 10065-6800
      • Memorial Sloan Kettering Cancer Center - Sidney Kimmel Center for Prostate and Urologic Cancers
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Abramson Cancer Center of The University of Pennsylvania
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt-Ingram Cancer Center
  • Texas
    • Dallas, Texas, United States, 75390
      • The University of Texas Southwestern Medical Center
    • Houston, Texas, United States, 77030
      • University of Texas MD Anderson Cancer Center
  • Washington
    • Seattle, Washington, United States, 98109
      • University of Washington Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: derazantinib; Oral administration	Drug: derazantinib; Derazantinib was administered orally at 300 mg once daily

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Substudy 1: Objective Response Rate (ORR)	ORR was defined as the proportion of patients who achieved a confirmed clinical response (CR) or partial response (PR) by blinded independent central review using the internationally recognized criteria for the radiological assessment in tumor response of solid tumors (RECIST) Version 1.1	From first dose and up to 54 months
Substudy 2: Progression Free Survival at 3 Months (PFS 3)	PFS3 was defined as the proportion of patients who have progression-free survival at 3 months from the first date of receiving study drug as assessed by survival status and blinded independent central review as per RECIST 1.1.	From first dose and up to 3 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
PFS	PFS was calculated from the first date of receiving study drug until radiographic disease progression by blinded independent central review or death.	From first dose and up to 54 months
Overall Survival (OS)	OS was calculated from the first date of receiving study drug until death	From first dose and up to 54 months
Duration of Response (DoR)	DoR was calculated from the first date of documented tumor response to disease progression by blinded independent central review per RECIST version 1.1 DoR was derived only for patients who have the best overall response of CR or PR	From first dose and up to 54 months
Substudy 2: Objective Response Rate	ORR was defined as the proportion of patients who achieved a confirmed clinical response (CR) or partial response (PR) by blinded independent central review using the internationally recognized criteria for the radiological assessment in tumor response of solid tumors (RECIST) Version 1.1	From first dose and up to 54 months
Number of Patients With Grade 3-5 Treatment-emergent Adverse Events (TEAEs)	Number of patients experiencing TEAE of Grade 3 to 5 according to Common Terminology Criteria for Adverse Events (CTCAE)	TEAEs were defined as all events occurring after drug treatment began and up to 30 days after last study drug administration

Collaborators and Investigators

• Sponsor: Basilea Pharmaceutica
• Investigators: Study Director: Manuel Häckl, MD, Basilea Pharmaceutica International Ltd, Allschwil

Publications and helpful links

General Publications

• Mazzaferro V, El-Rayes BF, Droz Dit Busset M, Cotsoglou C, Harris WP, Damjanov N, Masi G, Rimassa L, Personeni N, Braiteh F, Zagonel V, Papadopoulos KP, Hall T, Wang Y, Schwartz B, Kazakin J, Bhoori S, de Braud F, Shaib WL. Derazantinib (ARQ 087) in advanced or inoperable FGFR2 gene fusion-positive intrahepatic cholangiocarcinoma. Br J Cancer. 2019 Jan;120(2):165-171. doi: 10.1038/s41416-018-0334-0. Epub 2018 Nov 13.

Study record dates

Study Major Dates

• Study Start (Actual): September 28, 2017
• Primary Completion (Actual): October 25, 2022
• Study Completion (Actual): October 25, 2022

Study Registration Dates

• First Submitted: July 24, 2017
• First Submitted That Met QC Criteria: July 24, 2017
• First Posted (Actual): July 26, 2017

Study Record Updates

• Last Update Posted (Estimated): December 19, 2023
• Last Update Submitted That Met QC Criteria: November 29, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Keywords: targeted therapy; intrahepatic cholangiocarcinoma; bile duct cancer; liver cancer; derazantinib; iCCA; biliary cancer; FGFR2 gene fusion or FGFR2 gene mutation or amplification; FGFR2 gene rearrangement; combined hepatocellular and cholangiocarcinoma; cHCC-CCA
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Digestive System Neoplasms; Liver Diseases; Liver Neoplasms; Carcinoma, Hepatocellular; Cholangiocarcinoma
• Other Study ID Numbers: DZB-CS-301; ARQ 087-301 (Other Identifier: ArQule, Inc)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No