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

Study Description

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Brief Summary:

This is an open-label, Phase 1/2, dose escalation and signal finding study of ARQ 087 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 ARQ 087 and to define a RP2D of ARQ 087.

Condition or disease	Intervention/treatment	Phase
Solid Tumor	Drug: ARQ 087	Phase 1; Phase 2

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	109 participants
Intervention Model:	Single Group 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
Study Start Date :	December 2012
Estimated Primary Completion Date :	June 2018
Estimated Study Completion Date :	December 2018

Arms and Interventions

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Arm

Intervention/treatment

Experimental: ARQ 087; Subjects will receive ARQ 087 orally at dose levels specified for their respective dose cohorts on a 28-day schedule. Subjects will receive treatment with ARQ 087 until progression of disease (clinical or radiological), unacceptable toxicity, or another of the discontinuation criteria is documented.

Drug: ARQ 087; Subjects in this study will receive ARQ 087 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

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Primary Outcome Measures :

1. Adverse events graded by CTCAE v4.03 as a measure of the safety and tolerability profile of ARQ 087 [ 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 ARQ 087 [ 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 ARQ 087
2. Assess pharmacodynamic (PD) activity of ARQ 087 [ 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 ARQ 087 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 ARQ 087 [ Time Frame: Baseline and every 8 weeks or as otherwise clinically indicated ]

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Senior)
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 ARQ 087.

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 ARQ 087
2. Major surgery or radiation therapy within four weeks of the first dose of ARQ 087
3. Previous treatment with FGFR inhibitors
4. History of allergic reactions attributed to compounds of similar chemical or biological composition as ARQ 087
5. Unable or unwilling to swallow the complete daily dose of ARQ 087
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 ARQ 087 (MI occurring >6 months of the first dose of ARQ 087 will be permitted)
8. Significant GI disorder(s) that could interfere with the absorption, metabolism, or excretion of ARQ 087 (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 ARQ 087, 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

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Locations

United States, Arizona
Scottsdale, Arizona, United States, 85258
United States, Georgia
Atlanta, Georgia, United States, 30322
United States, Michigan
Detroit, Michigan, United States, 48201
United States, Nevada
Las Vegas, Nevada, United States, 89169
United States, New York
Bronx, New York, United States, 10467
United States, Pennsylvania
Philadelphia, Pennsylvania, United States, 19104
United States, Texas
San Antonio, Texas, United States, 78229
United States, Washington
Seattle, Washington, United States, 98109
Italy
Milan, Italy, 20133
Padova, Italy, 35128
Pisa, Italy, 56126
Rozzano, Milan, Italy, 20089

Sponsors and Collaborators

ArQule

More Information

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

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:	ArQule
ClinicalTrials.gov Identifier:	NCT01752920 History of Changes
Other Study ID Numbers:	ARQ 087-101
First Posted:	December 19, 2012
Last Update Posted:	January 12, 2018
Last Verified:	January 2018

Keywords provided by ArQule:

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