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
• Last Update Posted: October 31, 2019
• 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 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.

Condition or disease	Intervention/treatment	Phase
Solid Tumor	Drug: Derazantinib	Phase 1; Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 119 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: December 10, 2012
• Actual Primary Completion Date: September 25, 2018
• Actual Study Completion Date: September 25, 2018

Arms and Interventions

Arm

Intervention/treatment

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.

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.

Outcome Measures

Primary Outcome Measures :

1. 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 Outcome Measures :

1. 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
2. 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
3. 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 ]
4. 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 ]
5. Evaluate tumor response assessed by RECIST v1.1 after treatment with derazantinib [ Time Frame: Baseline and every 8 weeks or as otherwise clinically indicated ]

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. 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

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: Stephan Braun, MD; Basilea Pharmaceutica

More Information

Publications of 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.

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
• Last Update Posted: October 31, 2019
• Last Verified: March 2019

• 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