Phase 1/2 Study of Derazantinib (ARQ 087) in Adult Subjects With Advanced Solid Tumors With FGFR Genetic Alterations

Overview

This is an open-label, Phase 1/2, dose escalation and signal finding study of derazantinib administered to subjects with advanced solid tumors with FGFR genetic alterations, including intrahepatic cholangiocarcinoma (iCCA) with FGFR2 gene fusion. The study is designed to explore the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy of derazantinib and to define a RP2D of derazantinib.

Full Title of Study: “A Phase 1/2 Study of Derazantinib in Adult Subjects With Advanced Solid Tumors With FGFR Genetic Alterations, Including Intrahepatic Cholangiocarcinoma With FGFR2 Gene Fusion”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: N/A
    • Intervention Model: Single Group Assignment
    • Primary Purpose: Treatment
    • Masking: None (Open Label)
  • Study Primary Completion Date: September 25, 2018

Interventions

  • Drug: Derazantinib
    • Subjects in this study will receive derazantinib orally at dose levels specified for their respective dose cohorts. Dosing will begin at 25 mg every other day (QOD) and will escalate until the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) is determined. Cycles will be repeated in four-week (28 day) intervals until progression of disease, unacceptable toxicity, or another discontinuation criterion is met. In the case of toxicity, dose adjustment will be permitted.

Arms, Groups and Cohorts

  • Experimental: derazantinib
    • Subjects will receive derazantinib orally at dose levels specified for their respective dose cohorts on a 28-day schedule. Subjects will receive treatment with derazantinib until progression of disease (clinical or radiological), unacceptable toxicity, or another of the discontinuation criteria is documented.

Clinical Trial Outcome Measures

Primary Measures

  • Adverse events graded by CTCAE v4.03 as a measure of the safety and tolerability profile of derazantinib
    • Time Frame: Assessed at each scheduled visit up to treatment discontinuation + 30 days with an estimated treatment duration of 4 to 24 weeks

Secondary Measures

  • Characterize the pharmacokinetic (PK) profile of derazantinib
    • Time Frame: Part 1: t=Days 1, 2, 3, and 4. Cohort 5+: t=Days 1, 2, 8, 15, 22, and 23 of Cycle 1; and t=Days 1 and 15 of subsequent cycles
    • Single dose PK parameters include the peak plasma concentration (Cmax), area under the plasma concentration vs. time curve (AUC), and half-life of derazantinib
  • Assess pharmacodynamic (PD) activity of derazantinib
    • Time Frame: Part 1 t=Days 1, 2, 3, and 4. For Cohort 5+: t=Days 1, 8, 15, 22 of Cycle 1; and t=Days 1 of Cycles 2-5. For Part 2: t=Day 1 of Cycle 1-6
    • PD parameters include changes of phosphate, glucose, and FGF 19, 21, and/or 23
  • Evaluate dose limiting toxicity (DLT) graded per CTCAE v4.03 to determine the recommended Phase 2 dosing (RP2D) regimen
    • Time Frame: Up to treatment discontinuation + 30 days with an estimated treatment duration of 4 to 24 weeks
  • Evaluate further the RP2D of derazantinib in subjects with FGFR genetic alterations, including subjects with iCCA with FGFR2 gene fusion (Part 2; Expanded Cohort, signal finding)
    • Time Frame: Up to treatment discontinuation + 30 days with an estimated treatment duration of 4 to 24 weeks
  • Evaluate tumor response assessed by RECIST v1.1 after treatment with derazantinib
    • Time Frame: Baseline and every 8 weeks or as otherwise clinically indicated

Participating in This Clinical Trial

Inclusion Criteria

1. Signed written informed consent granted 2. Men or women ≥18 years of age 3. Histologically or cytologically confirmed, locally advanced, inoperable, or metastatic solid tumors. Subjects eligible for enrollment in the Expanded Cohort must have documented and/or confirmed FGFR genetic alterations, including iCCA with FGFR2 gene fusion. 4. Failure to respond to standard therapy, or for whom standard therapy does not exist. 5. Evaluable or measurable disease 6. Archival and/or fresh biopsy tissue samples must be available prior to the first dose of the study drug 7. Life expectancy ≥ 12 weeks 8. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 9. Hemoglobin (Hgb) ≥ 9.0 g/dL 10. Absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L 11. Platelet count ≥ 100 x 10^9/L 12. Total bilirubin ≤ 1.5 × upper limit of normal (ULN) (≤ 2 x ULN for subjects with cholangiocarcinoma) 13. Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 3 × ULN (≤ 5 x ULN for subjects with liver metastases) 14. Serum creatinine ≤ 1.5 x ULN or creatinine clearance > 60 mL/min/1.73 m^2 for subjects with creatinine levels above institutional normal 15. Albumin ≥ 2.8 g/dL 16. INR 0.8 to ULN or ≤ 3 for subjects receiving anticoagulant therapy 17. Men or women of child-producing potential must agree to use double-barrier contraceptive measures, oral contraception, or avoid intercourse during the study and for 90 days after the last dose of study drug 18. Women of childbearing potential must have a negative serum pregnancy test during Screening Period and within 48 hours of the first dose of derazantinib. Exclusion Criteria:

1. Anti-cancer therapy, such as chemotherapy, immunotherapy, hormonal, targeted therapy, or investigational agents within four weeks or five times of the drug half life, whichever is longer, of the first dose of derazantinib 2. Major surgery or radiation therapy within four weeks of the first dose of derazantinib 3. Previous treatment with FGFR inhibitors 4. History of allergic reactions attributed to compounds of similar chemical or biological composition as derazantinib 5. Unable or unwilling to swallow the complete daily dose of derazantinib 6. Clinically unstable central nervous system (CNS) metastasis 7. History of myocardial infarction (MI) or congestive heart failure defined as Class II to IV per the New York Heart Association classification within 6 months of the first dose of derazantinib (MI occurring >6 months of the first dose of derazantinib will be permitted) 8. Significant GI disorder(s) that could interfere with the absorption, metabolism, or excretion of derazantinib (e.g. Crohn's disease, ulcerative colitis, extensive gastric resection) 9. History and/or current evidence of clinically relevant ectopic mineralization/calcification 10. Previous malignancy within 2 years prior to the first dose of derazantinib, except curatively treated non-melanoma skin cancer, carcinoma in-situ of the breast or cervix, or superficial bladder tumors 11. Known human immunodeficiency virus (HIV) infection 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. – Uncontrolled diabetes mellitus 13. Blood transfusion within 5 days of the blood draw being used to confirm eligibility 14. Pregnant or breastfeeding
  • Gender Eligibility: All

    Minimum Age: 18 Years

    Maximum Age: N/A

    Are Healthy Volunteers Accepted: No

    Investigator Details

    • Lead Sponsor
      • Basilea Pharmaceutica
    • Collaborator
      • ArQule
    • Provider of Information About this Clinical Study
      • Sponsor
    • Overall Official(s)
      • Stephan Braun, MD, Study Director, Basilea Pharmaceutica

    Citations Reporting on Results

    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.

    Papadopoulos KP, El-Rayes BF, Tolcher AW, Patnaik A, Rasco DW, Harvey RD, LoRusso PM, Sachdev JC, Abbadessa G, Savage RE, Hall T, Schwartz B, Wang Y, Kazakin J, Shaib WL. A Phase 1 study of ARQ 087, an oral pan-FGFR inhibitor in patients with advanced solid tumours. Br J Cancer. 2017 Nov 21;117(11):1592-1599. doi: 10.1038/bjc.2017.330. Epub 2017 Oct 3.

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