Clinical trial NCT03230318: Derazantinib in Subjects With FGFR2 Gene Fusion-, Mutation- or Amplification- Positive Inoperable or Advanced Intrahepatic Cholangiocarcinoma
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Intrahepatic Cholangiocarcinoma
Combined Hepatocellular and Cholangiocarcinoma
Keywords: iCCA
intrahepatic cholangiocarcinoma
FGFR2 gene fusion or FGFR2 gene mutation or amplification
biliary cancer
bile duct cancer
FGFR2 gene rearrangement
liver cancer
targeted therapy
combined hepatocellular and cholangiocarcinoma
cHCC-CCA
derazantinib
Lead sponsor: Basilea Pharmaceutica
Sponsor class: INDUSTRY
First posted: 2017-07-26
Enrollment: 148
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief 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.

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.

Eligibility criteria: 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)

Primary outcomes:
measure: Substudy 1: Objective Response Rate (ORR)
timeFrame: From first dose and up to 54 months
measure: Substudy 2: Progression Free Survival at 3 Months (PFS 3)
timeFrame: From first dose and up to 3 months
Secondary outcomes:
measure: PFS
timeFrame: From first dose and up to 54 months
measure: Overall Survival (OS)
timeFrame: From first dose and up to 54 months
measure: Duration of Response (DoR)
timeFrame: From first dose and up to 54 months
measure: Substudy 2: Objective Response Rate
timeFrame: From first dose and up to 54 months
measure: Number of Patients With Grade 3-5 Treatment-emergent Adverse Events (TEAEs)
timeFrame: TEAEs were defined as all events occurring after drug treatment began and up to 30 days after last study drug administration
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Mayo Clinic
state: Arizona
city: Jacksonville
country: United States
facility: Mayo Clinic
state: Florida
city: Tampa
country: United States
facility: Moffitt Cancer Center
state: Florida
city: Atlanta
country: United States
facility: Winship Cancer Institute of Emory University
state: Georgia
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center - Sidney Kimmel Center for Prostate and Urologic Cancers
state: New York
city: Philadelphia
country: United States
facility: Abramson Cancer Center of the University of Pennsylvania
state: Pennsylvania
city: Nashville
country: United States
facility: Vanderbilt-Ingram Cancer Center
state: Tennessee
city: Dallas
country: United States
facility: The University of Texas Southwestern Medical Center
state: Texas
city: Houston
country: United States
facility: University of Texas MD Anderson Cancer Center
state: Texas
city: Seattle
country: United States
facility: University of Washington Medical Center
state: Washington
city: Brussels
country: Belgium
facility: Hôpital Erasme
city: Brussels
country: Belgium
facility: Cliniques Universitaires Saint-Luc
city: Edegem
country: Belgium
facility: Antwerp University Hospital
city: Calgary
country: Canada
facility: Tom Baker Cancer Centre
state: Alberta
city: Toronto
country: Canada
facility: Princess Margaret Cancer Centre
state: Ontario
city: La Tronche
country: France
facility: CHU Grenoble Alpes
city: Villejuif
country: France
facility: Gustave Roussy
city: Frankfurt am Main
country: Germany
facility: Universitätsklinikum Frankfurt
city: Hamburg
country: Germany
facility: Universitätsklinikum Hamburg-Eppendorf (UKE)
city: Hannover
country: Germany
facility: Medizinische Hochschule Hannover (MHH)
city: Homburg
country: Germany
facility: Universitätsklinikum des Saarlandes
city: Mainz
country: Germany
facility: Universitätsmedizin der Johannes Gutenberg-Universität Mainz
city: Dublin
country: Ireland
facility: St. James's Hospital
city: Bologna
country: Italy
facility: Sant'Orsola-Malpighi Hospital, University of Bologna
city: Milan
country: Italy
facility: Fondazione IRCCS Istituto Nazionale dei Tumori
city: Monza
country: Italy
facility: Ospedale San Gerardo
city: Padova
country: Italy
facility: Istituto Oncologico Veneto - IRCCS
city: Pisa
country: Italy
facility: Azienda Ospedaliero-Universitaria Pisana
city: Rozzano
country: Italy
facility: Humanitas Cancer Center, Istituto Clinico Humanitas IRCCS
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center
city: Seoul
country: Korea, Republic of
facility: The Catholic University of Korea, Seoul St. Mary's Hospital
city: Barcelona
country: Spain
facility: Vall d'Hebrón University Hospital
city: Barcelona
country: Spain
facility: Catalan Institute of Oncology
city: Madrid
country: Spain
facility: Hospital General Universitario Gregorio Marañón
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre
city: Basel
country: Switzerland
facility: Universitätsspital Basel
city: Euston
country: United Kingdom
facility: University College London Hospitals NHS Foundation Trust
city: Glasgow
country: United Kingdom
facility: Beatson West of Scotland Cancer Centre
city: Sutton
country: United Kingdom
facility: The Royal Marsden
Study officials:
affiliation: Basilea Pharmaceutica International Ltd, Allschwil
name: Manuel Häckl, MD
role: STUDY_DIRECTOR
References:
citation: 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.