Clinical Trials /

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

NCT03230318

Description:

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.

Related Conditions:
  • Cholangiocarcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • 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

Clinical Trial IDs

  • ORG STUDY ID: DZB-CS-301
  • SECONDARY ID: ARQ 087-301
  • NCT ID: NCT03230318

Conditions

  • Intrahepatic Cholangiocarcinoma
  • Combined Hepatocellular and Cholangiocarcinoma

Interventions

DrugSynonymsArms
derazantinibderazantinib

Purpose

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.

Trial Arms

NameTypeDescriptionInterventions
derazantinibExperimentalOral administration
  • derazantinib

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:

               1. If central laboratory designated by Sponsor:

                  Positive FISH test; and/or

               2. 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 status based on local NGS testing performed or commissioned
             by the respective study site using a validated test. For NGS testing, no central
             laboratory will be established for the purpose of Substudy 2.

          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 109/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 ≥ 60 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. Systemic anti-cancer therapy, such as chemotherapy, immunotherapy, hormonal, targeted
             therapy, or investigational agents within four weeks of the first dose of
             derazantinib, or within five half-lives of any investigational or licensed medicinal
             product, whichever is the longer period.

          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., ponatinib, dovitinib, nintedanib,
             AZD4547, NVP-BGJ398, LY2784455, BAY1163877)

             - 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 corneal or retinal disorder, including but not limited to
             bullous/band keratopathy, keratoconjunctivitis, 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. Previous malignancy within 2 years of the first dose of derazantinib, except
             curatively treated or low grade malignancies such as non-melanoma skin cancer,
             carcinoma in-situ of the breast, cervix, and superficial bladder tumors

         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

         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)
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Substudy 1: Anti-cancer activity of derazantinib by Objective Response Rate (ORR)
Time Frame:Up to approximately 32 weeks
Safety Issue:
Description:ORR will be assessed by central radiology review as per RECIST version 1.1

Secondary Outcome Measures

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

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Basilea Pharmaceutica

Trial 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

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