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

• ClinicalTrials.gov Identifier: NCT01752920
• Recruitment Status: Completed
• First Posted: December 19, 2012
• Results First Posted: October 28, 2021
• Last Update Posted: March 9, 2022
• Sponsor: Basilea Pharmaceutica
• Collaborator: ArQule, Inc. (a wholly owned subsidiary of Merck Sharp and Dohme, a subsidiary of Merck & Co., Inc.)
• Information provided by (Responsible Party): Basilea Pharmaceutica

Study Description

Brief Summary:

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).

Condition or disease	Intervention/treatment	Phase
Solid Tumor	Drug: Derazantinib low dose range; Drug: Derazantinib middle dose range; Drug: Derazantinib high dose range; Drug: Derazantinib at recommended phase 2 dose (RP2D)	Phase 1; Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 119 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: December 10, 2012
• Actual Primary Completion Date: August 28, 2018
• Actual Study Completion Date: August 28, 2018

Arms and Interventions

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.

Outcome Measures

Primary Outcome Measures :

1. Number of Patients With Drug-related Treatment-emergent Adverse Events (TEAEs) [ Time Frame: 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) ]
   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)

Secondary Outcome Measures :

1. Proportion of Patients With an Objective Tumor Response Per RECIST 1.1 [ Time Frame: 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. ]

   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.

2. Proportion of Patients With Disease Control Per RECIST 1.1 [ Time Frame: 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. ]
   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.
3. Progression-free Survival (PFS) [ Time Frame: 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. ]
   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.

Eligibility Criteria

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

Criteria

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

Contacts and Locations

Locations

United States, Arizona

Scottsdale Healthcare Research Institute

Scottsdale, Arizona, United States, 85258

United States, Georgia

Emory University, Winship Cancer Institute

Atlanta, Georgia, United States, 30322

United States, Michigan

Karmanos Cancer Institute, Detroit

Detroit, Michigan, United States, 48201

United States, Nevada

Comprehensive Cancer Centers of Nevada

Las Vegas, Nevada, United States, 89169

United States, New York

Montefiore-Einstein Center for Cancer Care

Bronx, New York, United States, 10467

United States, Pennsylvania

University of Pennsylvania Hospital

Philadelphia, Pennsylvania, United States, 19104

United States, Texas

START - South Texas Accelerated Research Therapeutics, LLC

San Antonio, Texas, United States, 78229

United States, Washington

University of Washington

Seattle, Washington, United States, 98109

Italy

Istituto Clinico Humanitas

Milan, Italy, 20089

Istituto Nazionale Tumori (National Cancer Institute)

Milan, Italy, 20133

Instituto Oncologico Veneto, IRCCS

Padova, Italy, 35128

Azienda Ospedaliero-Universitaria Pisana - U.O. Oncologia Medica 2 Univ.

Pisa, Italy, 56126

Sponsors and Collaborators

Basilea Pharmaceutica

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

  Study Documents (Full-Text)

Documents provided by Basilea Pharmaceutica:

Study Protocol  [PDF] April 10, 2015

Statistical Analysis Plan  [PDF] June 15, 2018

More Information

Publications of Results:

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.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: Basilea Pharmaceutica
• ClinicalTrials.gov Identifier: NCT01752920
• Other Study ID Numbers: ARQ 087-101
• First Posted: December 19, 2012
• Results First Posted: October 28, 2021
• Last Update Posted: March 9, 2022
• Last Verified: March 2022

• Studies a U.S. FDA-regulated Drug Product: Yes

Keywords provided by Basilea Pharmaceutica:

FGFR; ARQ 087; Targeted therapy; Molecular therapy; Tyrosine kinase inhibitor; TKI; Receptor tyrosine kinase; RTK; Biomarker; Phase 1; Phase I; Solid tumor; Liver Cancer; Hepatobiliary carcinoma; Biliary tract cancer; Cholangiocarcinoma; Intrahepatic cholangiocarcinoma; FGFR inhibitor; Targeted FGFR kinase inhibitor; Pan-FGFR inhibitor; Selective FGFR inhibitor; FGFR pathway; FGFR signaling; Fibroblast growth factor; FGFR1; FGFR2; FGFR3; FGFR4; FGF; FGF19

Additional relevant MeSH terms:

Cholangiocarcinoma; Neoplasms; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type