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

A Phase 1/2 Study of ARQ 087 in Adult Subjects With Advanced Solid Tumors With FGFR Genetic Alterations, Including Intrahepatic Cholangiocarcinoma With FGFR2 Gene Fusion

This was an open-label, Phase 1/2, dose escalation and signal finding study of derazantinib administered to patients with advanced solid tumors (Part 1; Dose Escalation/Food-effect Cohorts) or with advanced solid tumors with FGFR genetic aberrations, including iCCA with FGFR2 gene fusion (Part 2; Expanded Cohort, signal finding).

Study Overview

• Status: Completed
• Conditions: Solid Tumor
• Intervention / Treatment: Drug: Derazantinib low dose range; Drug: Derazantinib middle dose range; Drug: Derazantinib high dose range; Drug: Derazantinib at recommended phase 2 dose (RP2D)

• Study Type: Interventional
• Enrollment (Actual): 119
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Italy
  • Milan, Italy, 20089
    • Istituto Clinico Humanitas
  • Milan, Italy, 20133
    • Istituto Nazionale Tumori (National Cancer Institute)
  • Padova, Italy, 35128
    • Instituto Oncologico Veneto, IRCCS
  • Pisa, Italy, 56126
    • Azienda Ospedaliero-Universitaria Pisana - U.O. Oncologia Medica 2 Univ.
• United States
  • Arizona
    • Scottsdale, Arizona, United States, 85258
      • Scottsdale Healthcare Research Institute
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University, Winship Cancer Institute
  • Michigan
    • Detroit, Michigan, United States, 48201
      • Karmanos Cancer Institute, Detroit
  • Nevada
    • Las Vegas, Nevada, United States, 89169
      • Comprehensive Cancer Centers of Nevada
  • New York
    • Bronx, New York, United States, 10467
      • Montefiore-Einstein Center for Cancer Care
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania Hospital
  • Texas
    • San Antonio, Texas, United States, 78229
      • START - South Texas Accelerated Research Therapeutics, LLC
  • Washington
    • Seattle, Washington, United States, 98109
      • University of Washington

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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. Patients eligible for enrollment in the Expanded Cohort must have documented and/or confirmed FGFR genetic aberrations, 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 patients with cholangiocarcinoma)
13. Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 3 × ULN (≤ 5 x ULN for patients with liver metastases)
14. Serum creatinine ≤ 1.5 x ULN or creatinine clearance > 60 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal
15. Albumin ≥ 2.8 g/dL
16. INR 0.8 to ULN or ≤ 3 for patients 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Low Dose Group; Patients who received derazantinib orally at dose levels from 25 mg every other day (QOD) - 200 mg daily (QD) on a 28-day schedule until documented progression of disease (clinical or radiological), unacceptable toxicity, or another of the discontinuation criteria.	Drug: Derazantinib low dose range; Derazantinib was administered orally at dose levels from 25 mg QOD - 200 mg QD on a 28-day schedule.
Experimental: Middle Dose Group; Patients who received derazantinib orally at dose levels from 250 mg QD - 325 mg QD on a 28-day schedule until documented progression of disease (clinical or radiological), unacceptable toxicity, or another of the discontinuation criteria.	Drug: Derazantinib middle dose range; Derazantinib was administered orally at dose levels from 250 mg QD - 325 mg QD on a 28-day schedule.
Experimental: High Dose Group; Patients who received derazantinib orally at dose levels from 400 mg QD - 425 mg QD on a 28-day schedule until documented progression of disease (clinical or radiological), unacceptable toxicity, or another of the discontinuation criteria.	Drug: Derazantinib high dose range; Derazantinib was administered orally at dose levels from 400 mg QD - 425 mg QD on a 28-day schedule.
Experimental: Expanded Cohort Group; Patients who received derazantinib orally at the recommended phase 2 dose of 300 mg QD on a 28-day schedule until documented progression of disease (clinical or radiological), unacceptable toxicity, or another of the discontinuation criteria.	Drug: Derazantinib at recommended phase 2 dose (RP2D); Derazantinib was administered orally at the recommended phase 2 dose of 300 mg QD on a 28-day schedule.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Patients With Drug-related Treatment-emergent Adverse Events (TEAEs)	Adverse events were graded for severity according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. CTCAE is classifying AEs and their associated severity from Grade 1 (Mild AE), Grade 2 (Moderate AE), Grade 3 (Severe or medically significant but not immediately life-threatening), Grade 4 (Life-threatening consequences) to Grade 5 (Death related to AE)	Adverse events were collected and reported from the time of receiving first dose of derazantinib to the end of study assessment and follow-up period (30-day post-treatment)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of Patients With an Objective Tumor Response Per RECIST 1.1	The number of patients with an objective tumor response, which included those with either a complete response (CR) or a partial response (PR) based on RECIST v1.1 guidelines which defines criteria for the radiological assessment in tumor response. The objective response rate (ORR) was defined as the proportion of patients with a CR or PR.	Assessments were performed at Baseline, and every 8 weeks during continuous drug administration until the End of Treatment visit (7 [+3] days after the last dose of derazantinib) or as otherwise clinically indicated.
Proportion of Patients With Disease Control Per RECIST 1.1	The number of patients with tumor disease control, which included those with either a complete or partial tumor response, or a stable disease (SD) based on RECIST v1.1 guidelines which defines criteria for the radiological assessment in tumor response. The disease control rate (DCR) was defined as the proportion of patients with CR, PR or SD.	Assessments were performed at Baseline, and every 8 weeks during continuous drug administration until the End of Treatment visit (7 [+3] days after the last dose of derazantinib) or as otherwise clinically indicated.
Progression-free Survival (PFS)	PFS was calculated as the time from the date of first dose until documented radiographic disease progression or death from any cause, whichever occurred first. Disease progression is measured according to a specified radiologic increase in tumor size.	Assessments were performed at Baseline, and every 8 weeks during continuous drug administration until the End of Treatment visit (7 [+3] days after the last dose of derazantinib) or as otherwise clinically indicated.

Collaborators and Investigators

• Sponsor: Basilea Pharmaceutica
• Collaborators: ArQule, Inc. (a wholly owned subsidiary of Merck Sharp and Dohme, a subsidiary of Merck & Co., Inc.)
• Investigators: Study Director: Marc Engelhardt, MD, Basilea Pharmaceutica

Publications and helpful links

General Publications

• 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.
• 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.
• Hall TG, Yu Y, Eathiraj S, Wang Y, Savage RE, Lapierre JM, Schwartz B, Abbadessa G. Preclinical Activity of ARQ 087, a Novel Inhibitor Targeting FGFR Dysregulation. PLoS One. 2016 Sep 14;11(9):e0162594. doi: 10.1371/journal.pone.0162594. eCollection 2016.

Study record dates

Study Major Dates

• Study Start (Actual): December 10, 2012
• Primary Completion (Actual): August 28, 2018
• Study Completion (Actual): August 28, 2018

Study Registration Dates

• First Submitted: December 14, 2012
• First Submitted That Met QC Criteria: December 17, 2012
• First Posted (Estimated): December 19, 2012

Study Record Updates

• Last Update Posted (Actual): June 5, 2023
• Last Update Submitted That Met QC Criteria: May 9, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Keywords: Biomarker; Targeted therapy; Phase 1; Phase I; FGFR1; Solid tumor; Cholangiocarcinoma; Liver Cancer; FGFR4; FGF19; Phase I Clinical Trial; Tumor; FGF23; Tyrosine kinase inhibitor; TKI; FGFR; FGF21; Fibroblast growth factor; Molecular therapy; Biliary tract cancer; FGFR3; Phase 1 Clinical Trial; Tumour; FGF; FGFR2; Intrahepatic cholangiocarcinoma; ARQ 087; Receptor tyrosine kinase; RTK; Hepatobiliary carcinoma; FGFR inhibitor; Targeted FGFR kinase inhibitor; Pan-FGFR inhibitor; Selective FGFR inhibitor; FGFR pathway; FGFR signaling; FGFR mutation; FGFR gene fusion; FGFR gene translocation; FGFR genetic aberration; FGFR2 fusion; FGFR2 translocation; Clinical oncology; derazantinib; MK-2921
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Cholangiocarcinoma
• Other Study ID Numbers: ARQ 087-101

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes