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

• ClinicalTrials.gov Identifier: NCT03230318
• Recruitment Status: Recruiting
• First Posted: July 26, 2017
• Last Update Posted: February 1, 2021
• Sponsor: Basilea Pharmaceutica
• Information provided by (Responsible Party): Basilea Pharmaceutica

Tracking Information

• First Submitted Date: July 24, 2017
• First Posted Date: July 26, 2017
• Last Update Posted Date: February 1, 2021
• Actual Study Start Date: November 10, 2017
• Estimated Primary Completion Date: October 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: July 29, 2019)

• Substudy 1: Anti-cancer activity of derazantinib by Objective Response Rate (ORR) [ Time Frame: Up to approximately 32 weeks ]
  ORR will be assessed by central radiology review as per RECIST version 1.1
• Substudy 2: Anti-tumor activity of derazantinib by Progression Fress Survival at 3 months (PFS 3) [ Time Frame: 3 months ]
  PFS 3 will be assessed based on survival status or central radiology review (Response Evaluation Criteria in Solid Tumors, RECIST 1.1)

Original Primary Outcome Measures (submitted: July 24, 2017)

Anti-cancer activity of ARQ 087 by Objective Response Rate (ORR) [ Time Frame: Up to approximately 32 weeks ]

ORR will be assessed by central radiology review per RECIST version 1.1

Current Secondary Outcome Measures (submitted: July 29, 2019)

• Safety of derazantinib as assessed by adverse events [ Time Frame: Up to approximately 36 weeks ]
  Adverse events will be graded using NCI CTCAE guidelines, version 4.03
• Anti-cancer activity of derazantinib by duration of response (DoR) [ Time Frame: Up to approximately 32 weeks ]
  DoR will be assessed by central radiology review per RECIST version 1.1
• Anti-cancer activity of derazantinib by progression free survival (PFS) [ Time Frame: Up to approximately 32 weeks ]
  PFS will be assessed by central radiology review per RECIST version 1.1
• Anti-cancer activity of derazantinib by overall survival (OS) [ Time Frame: Up to approximately 36 weeks ]
  OS will be calculated from the first date of receiving study drug until death
• Health-related quality of life as assessed by the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 questionnaire [ Time Frame: Up to approximately 36 weeks ]
• Health-related quality of life as assessed by the EORTC QLQ-BIL21 questionnaire [ Time Frame: Up to approximately 36 weeks ]
• Health-related quality of life as assessed by the EuroQol EQ-5D questionnaire [ Time Frame: Up to approximately 36 weeks ]
• Substudy 2: Anti-cancer activity of derazantinib by Objective Response Rate [ Time Frame: Up to approximately 32 weeks ]
  ORR will be assessed by central radiology review as per RECIST version 1.1

Original Secondary Outcome Measures (submitted: July 24, 2017)

• Safety of ARQ 087 as assessed by adverse events [ Time Frame: Up to approximately 36 weeks ]
  Adverse events will be graded using NCI CTCAE guidelines, version 4.03
• Anti-cancer activity of ARQ 087 by progression free survival (PFS) [ Time Frame: Up to approximately 32 weeks ]
  PFS will be assessed by central radiology review per RECIST version 1.1
• Anti-cancer activity of ARQ 087 by overall survival (OS) [ Time Frame: Up to approximately 36 weeks ]
  OS will be calculated from the first date of receiving study drug until death
• Anti-cancer activity of ARQ 087 by duration of response (DoR) [ Time Frame: Up to approximately 32 weeks ]
  DoR will be assessed by central radiology review per RECIST version 1.1

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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
• Brief Summary: 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.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Intrahepatic Cholangiocarcinoma
• Combined Hepatocellular and Cholangiocarcinoma

Intervention

Drug: derazantinib

derazantinib will be orally administered at 300 mg once per day one hour prior to or two hours after a meal and is supplied as 100 mg capsules.

Study Arms

Experimental: derazantinib

Oral administration

Intervention: Drug: derazantinib

• 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.

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: July 29, 2019): 143
• Original Estimated Enrollment (submitted: July 24, 2017): 100
• Estimated Study Completion Date: December 2021
• Estimated Primary Completion Date: October 2021 (Final data collection date for primary outcome measure)

Eligibility Criteria

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 (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])

4. Substudy 1: FGFR2 gene fusion status based on the following assessments:

   a) If central laboratory designated by Sponsor: Positive FISH test; and/or b) 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/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 receiving 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 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:

   1. Abstinence from heterosexual activity**

   2. 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 < 45 years of age a high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a post -menopausal state in women not using hormonal contraception or hormonal replacement therapy. In the absence of 12 months of amenorrhea, a single FSH measurement is not sufficient.

        • Abstinence (relative to heterosexual activity) can be used as the sole method of contraception if it is consistently employed as the subject's preferred and usual lifestyle and if considered acceptable by local regulatory agencies and ERCs/IRBs. Periodic abstinence (e.g., calendar, ovulation, sympto-thermal, post-ovulation methods, etc.) and withdrawal are not acceptable methods of contraception.

          • 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:

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).

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

4. 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 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)
6. Current evidence of clinically significant corneal or retinal disorder 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. 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)

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 will be 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, 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)
11. History of additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin that has undergone potentially curative therapy, and in situ cervical cancer.

12. 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
    • 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 being 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)

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Stephan Braun, MD; +41 61 606 12 25; stephan.braun@basilea.com

Contact: Frédérique Cantero, MD; +41 61 606 1329; frederique.cantero@basilea.com

• Listed Location Countries: Belgium, Canada, France, Germany, Ireland, Italy, Korea, Republic of, Spain, Switzerland, United Kingdom, United States

Administrative Information

• NCT Number: NCT03230318
• Other Study ID Numbers: DZB-CS-301; ARQ 087-301 ( Other Identifier: ArQule, Inc )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Responsible Party: Basilea Pharmaceutica
• Study Sponsor: Basilea Pharmaceutica
• Collaborators: Not Provided

Investigators

• Study Director: Stephan Braun, MD; Basilea Pharmaceutica

• PRS Account: Basilea Pharmaceutica
• Verification Date: January 2021