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

Study Overview
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Brief Summary
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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).

Official Title
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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

Conditions
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Solid Tumor

Intervention / Treatment
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* Drug: Derazantinib low dose range
* Drug: Derazantinib middle dose range
* Drug: Derazantinib high dose range
* Drug: Derazantinib at recommended phase 2 dose (RP2D)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed written informed consent granted Men or women ≥18 years of age 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. Failure to respond to standard therapy, or for whom standard therapy does not exist. Evaluable or measurable disease Archival and/or fresh biopsy tissue samples must be available prior to the first dose of the study drug Life expectancy ≥ 12 weeks Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 Hemoglobin (Hgb) ≥ 9.0 g/dL Absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L Platelet count ≥ 100 x 10^9/L Total bilirubin ≤ 1.5 × upper limit of normal (ULN) (≤ 2 x ULN for patients with cholangiocarcinoma) Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 3 × ULN (≤ 5 x ULN for patients with liver metastases) Serum creatinine ≤ 1.5 x ULN or creatinine clearance > 60 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal Albumin ≥ 2.8 g/dL INR 0.8 to ULN or ≤ 3 for patients receiving anticoagulant therapy 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 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: 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 Major surgery or radiation therapy within four weeks of the first dose of derazantinib Previous treatment with FGFR inhibitors History of allergic reactions attributed to compounds of similar chemical or biological composition as derazantinib Unable or unwilling to swallow the complete daily dose of derazantinib Clinically unstable central nervous system (CNS) metastasis 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) 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) History and/or current evidence of clinically relevant ectopic mineralization/calcification 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 Known human immunodeficiency virus (HIV) infection 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 Blood transfusion within 5 days of the blood draw being used to confirm eligibility Pregnant or breastfeeding

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Low Dose Group<br>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<br>* Derazantinib was administered orally at dose levels from 25 mg QOD - 200 mg QD on a 28-day schedule.<br>|
| Experimental: Middle Dose Group<br>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<br>* Derazantinib was administered orally at dose levels from 250 mg QD - 325 mg QD on a 28-day schedule.<br>|
| Experimental: High Dose Group<br>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<br>* Derazantinib was administered orally at dose levels from 400 mg QD - 425 mg QD on a 28-day schedule.<br>|
| Experimental: Expanded Cohort Group<br>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)<br>* Derazantinib was administered orally at the recommended phase 2 dose of 300 mg QD on a 28-day schedule.<br>|

What is the study measuring?
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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. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Tumor, 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, FGF21, FGF23, FGFR mutation, FGFR gene fusion, FGFR gene translocation, FGFR genetic aberration, FGFR2 fusion, FGFR2 translocation, Phase 1 Clinical Trial, Phase I Clinical Trial, Clinical oncology, Tumour, derazantinib, MK-2921