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

Intrahepatic Cholangiocarcinoma Clinical Trial

— FIDES-01  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03230318
• Other study ID #: DZB-CS-301
• Secondary ID: ARQ 087-301
• Status: Completed
• Phase: Phase 2
• Start date: September 28, 2017
• Est. completion date: October 25, 2022

Study information

• Verified date: November 2023
• Source: Basilea Pharmaceutica
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 148
• Est. completion date: October 25, 2022
• Est. primary completion date: October 25, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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)

Related Conditions & MeSH terms

• Carcinoma, Hepatocellular
• Cholangiocarcinoma
• Combined Hepatocellular and Cholangiocarcinoma
• Intrahepatic Cholangiocarcinoma

Intervention

Drug:
• derazantinib
Derazantinib was administered orally at 300 mg once daily

Locations

Country	Name	City	State
Belgium	Cliniques Universitaires Saint-Luc	Brussels
Belgium	Hôpital Erasme	Brussels
Belgium	Antwerp University Hospital	Edegem
Canada	Tom Baker Cancer Centre	Calgary	Alberta
Canada	Princess Margaret Cancer Centre	Toronto	Ontario
France	CHU Grenoble Alpes	La Tronche
France	Gustave Roussy	Villejuif
Germany	Universitätsklinikum Frankfurt	Frankfurt am Main
Germany	Universitätsklinikum Hamburg-Eppendorf (UKE)	Hamburg
Germany	Medizinische Hochschule Hannover (MHH)	Hannover
Germany	Universitätsklinikum des Saarlandes	Homburg
Germany	Universitätsmedizin der Johannes Gutenberg-Universität Mainz	Mainz
Ireland	St. James's Hospital	Dublin
Italy	Sant'Orsola-Malpighi Hospital, University of Bologna	Bologna
Italy	Fondazione IRCCS Istituto Nazionale dei Tumori	Milan
Italy	Ospedale San Gerardo	Monza
Italy	Istituto Oncologico Veneto - IRCCS	Padova
Italy	Azienda Ospedaliero-Universitaria Pisana	Pisa
Italy	Humanitas Cancer Center, Istituto Clinico Humanitas IRCCS	Rozzano
Korea, Republic of	Samsung Medical Center	Seoul
Korea, Republic of	Seoul National University Hospital	Seoul
Korea, Republic of	The Catholic University of Korea, Seoul St. Mary's Hospital	Seoul
Spain	Catalan Institute of Oncology	Barcelona
Spain	Vall d'Hebrón University Hospital	Barcelona
Spain	Hospital General Universitario Gregorio Marañón	Madrid
Spain	Hospital Universitario 12 de Octubre	Madrid
Switzerland	Universitätsspital Basel	Basel
United Kingdom	University College London Hospitals NHS Foundation Trust	Euston
United Kingdom	Beatson West of Scotland Cancer Centre	Glasgow
United Kingdom	The Royal Marsden	Sutton
United States	Winship Cancer Institute of Emory University	Atlanta	Georgia
United States	The University of Texas Southwestern Medical Center	Dallas	Texas
United States	University of Texas MD Anderson Cancer Center	Houston	Texas
United States	Mayo Clinic	Jacksonville	Florida
United States	Vanderbilt-Ingram Cancer Center	Nashville	Tennessee
United States	Memorial Sloan Kettering Cancer Center - Sidney Kimmel Center for Prostate and Urologic Cancers	New York	New York
United States	Abramson Cancer Center of the University of Pennsylvania	Philadelphia	Pennsylvania
United States	Mayo Clinic	Phoenix	Arizona
United States	Mayo Clinic	Rochester	Minnesota
United States	University of Washington Medical Center	Seattle	Washington
United States	Moffitt Cancer Center	Tampa	Florida

Sponsors (1)

Lead Sponsor	Collaborator
Basilea Pharmaceutica

Countries where clinical trial is conducted

United States,  Belgium,  Canada,  France,  Germany,  Ireland,  Italy,  Korea, Republic of,  Spain,  Switzerland,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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	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
Secondary	Overall Survival (OS)	OS was calculated from the first date of receiving study drug until death	From first dose and up to 54 months
Secondary	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
Secondary	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
Secondary	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