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

Primary Purpose

Solid Tumor

Status
Completed
Phase
Phase 1
Locations
International
Study Type
Interventional
Intervention
Derazantinib low dose range
Derazantinib middle dose range
Derazantinib high dose range
Derazantinib at recommended phase 2 dose (RP2D)
Sponsored by
Basilea Pharmaceutica
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Solid Tumor focused on measuring 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, Tumor, Tumour, derazantinib, MK-2921

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Scottsdale Healthcare Research Institute
  • Emory University, Winship Cancer Institute
  • Karmanos Cancer Institute, Detroit
  • Comprehensive Cancer Centers of Nevada
  • Montefiore-Einstein Center for Cancer Care
  • University of Pennsylvania Hospital
  • START - South Texas Accelerated Research Therapeutics, LLC
  • University of Washington
  • Istituto Clinico Humanitas
  • Istituto Nazionale Tumori (National Cancer Institute)
  • Instituto Oncologico Veneto, IRCCS
  • Azienda Ospedaliero-Universitaria Pisana - U.O. Oncologia Medica 2 Univ.

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Experimental

Experimental

Experimental

Arm Label

Low Dose Group

Middle Dose Group

High Dose Group

Expanded Cohort Group

Arm Description

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.

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.

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.

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.

Outcomes

Primary Outcome Measures

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)

Secondary Outcome Measures

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.
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.
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.

Full Information

First Posted
December 14, 2012
Last Updated
May 9, 2023
Sponsor
Basilea Pharmaceutica
Collaborators
ArQule, Inc. (a wholly owned subsidiary of Merck Sharp and Dohme, a subsidiary of Merck & Co., Inc.)
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1. Study Identification

Unique Protocol Identification Number
NCT01752920
Brief Title
Phase 1/2 Study of Derazantinib (ARQ 087) in Adult Subjects With Advanced Solid Tumors With FGFR Genetic Alterations
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 Type
Interventional

2. Study Status

Record Verification Date
May 2023
Overall Recruitment Status
Completed
Study Start Date
December 10, 2012 (Actual)
Primary Completion Date
August 28, 2018 (Actual)
Study Completion Date
August 28, 2018 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Basilea Pharmaceutica
Collaborators
ArQule, Inc. (a wholly owned subsidiary of Merck Sharp and Dohme, a subsidiary of Merck & Co., Inc.)

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Data Monitoring Committee
No

5. 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).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Solid Tumor
Keywords
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, Tumor, Tumour, derazantinib, MK-2921

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Sequential Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
119 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Low Dose Group
Arm Type
Experimental
Arm Description
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.
Arm Title
Middle Dose Group
Arm Type
Experimental
Arm Description
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.
Arm Title
High Dose Group
Arm Type
Experimental
Arm Description
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.
Arm Title
Expanded Cohort Group
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Derazantinib low dose range
Intervention Description
Derazantinib was administered orally at dose levels from 25 mg QOD - 200 mg QD on a 28-day schedule.
Intervention Type
Drug
Intervention Name(s)
Derazantinib middle dose range
Intervention Description
Derazantinib was administered orally at dose levels from 250 mg QD - 325 mg QD on a 28-day schedule.
Intervention Type
Drug
Intervention Name(s)
Derazantinib high dose range
Intervention Description
Derazantinib was administered orally at dose levels from 400 mg QD - 425 mg QD on a 28-day schedule.
Intervention Type
Drug
Intervention Name(s)
Derazantinib at recommended phase 2 dose (RP2D)
Intervention Description
Derazantinib was administered orally at the recommended phase 2 dose of 300 mg QD on a 28-day schedule.
Primary Outcome Measure Information:
Title
Number of Patients With Drug-related Treatment-emergent Adverse Events (TEAEs)
Description
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)
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)
Secondary Outcome Measure Information:
Title
Proportion of Patients With an Objective Tumor Response Per RECIST 1.1
Description
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.
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.
Title
Proportion of Patients With Disease Control Per RECIST 1.1
Description
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.
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.
Title
Progression-free Survival (PFS)
Description
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.
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.

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Marc Engelhardt, MD
Organizational Affiliation
Basilea Pharmaceutica
Official's Role
Study Director
Facility Information:
Facility Name
Scottsdale Healthcare Research Institute
City
Scottsdale
State/Province
Arizona
ZIP/Postal Code
85258
Country
United States
Facility Name
Emory University, Winship Cancer Institute
City
Atlanta
State/Province
Georgia
ZIP/Postal Code
30322
Country
United States
Facility Name
Karmanos Cancer Institute, Detroit
City
Detroit
State/Province
Michigan
ZIP/Postal Code
48201
Country
United States
Facility Name
Comprehensive Cancer Centers of Nevada
City
Las Vegas
State/Province
Nevada
ZIP/Postal Code
89169
Country
United States
Facility Name
Montefiore-Einstein Center for Cancer Care
City
Bronx
State/Province
New York
ZIP/Postal Code
10467
Country
United States
Facility Name
University of Pennsylvania Hospital
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19104
Country
United States
Facility Name
START - South Texas Accelerated Research Therapeutics, LLC
City
San Antonio
State/Province
Texas
ZIP/Postal Code
78229
Country
United States
Facility Name
University of Washington
City
Seattle
State/Province
Washington
ZIP/Postal Code
98109
Country
United States
Facility Name
Istituto Clinico Humanitas
City
Milan
ZIP/Postal Code
20089
Country
Italy
Facility Name
Istituto Nazionale Tumori (National Cancer Institute)
City
Milan
ZIP/Postal Code
20133
Country
Italy
Facility Name
Instituto Oncologico Veneto, IRCCS
City
Padova
ZIP/Postal Code
35128
Country
Italy
Facility Name
Azienda Ospedaliero-Universitaria Pisana - U.O. Oncologia Medica 2 Univ.
City
Pisa
ZIP/Postal Code
56126
Country
Italy

12. IPD Sharing Statement

Citations:
PubMed Identifier
28972963
Citation
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.
Results Reference
result
PubMed Identifier
30420614
Citation
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.
Results Reference
result
PubMed Identifier
27627808
Citation
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.
Results Reference
derived

Learn more about this trial

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

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