Solid Tumor
Conditions
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
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).
Interventions
DRUGDerazantinib low dose range
Derazantinib was administered orally at dose levels from 25 mg QOD - 200 mg QD on a 28-day schedule.
DRUGDerazantinib middle dose range
Derazantinib was administered orally at dose levels from 250 mg QD - 325 mg QD on a 28-day schedule.
DRUGDerazantinib high dose range
Derazantinib was administered orally at dose levels from 400 mg QD - 425 mg QD on a 28-day schedule.
DRUGDerazantinib 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.
Sponsors
ArQule, Inc., a subsidiary of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc. (Rahway, NJ USA)
Basilea Pharmaceutica
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With Drug-related Treatment-emergent Adverse Events (TEAEs) | 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
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Patients With an Objective Tumor Response Per RECIST 1.1 | 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. |
| Proportion of Patients With Disease Control Per RECIST 1.1 | 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. |
| Progression-free Survival (PFS) | 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. |
Countries
Italy, United States
Participant flow
Recruitment details
The study was conducted in 12 study centers, 8 in the US and 4 in Italy. 119 subjects were recruited between December 2012 and January 2017.
Pre-assignment details
A fresh core needle biopsy or fine needle aspiration could be collected during the screening period if archival tumor tissue biopsy samples were not available.
Participants by arm
| Arm | Count |
|---|---|
| Derazantinib 25 mg QOD - 200 mg QD - Low Dose Group Patients who received derazantinib orally at dose levels from 25 mg QOD - 200 mg QD on a 28-day schedule until documented progression of disease (clinical or radiological), unacceptable toxicity, or another of the discontinuation criteria. | 29 |
| Derazantinib 250 mg QOD - 325 mg QD - 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. | 13 |
| Derazantinib 400 mg QOD - 425 mg QD - 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. | 19 |
| Derazantinib 300 mg QD - 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. | 58 |
| Total | 119 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 | 5 | 10 |
| Overall Study | Clinical Disease Progression | 6 | 4 | 1 | 13 |
| Overall Study | Lack of clinical benefit | 1 | 1 | 1 | 1 |
| Overall Study | Physician Decision | 1 | 0 | 0 | 3 |
| Overall Study | Radiographic Disease Progression | 20 | 7 | 12 | 29 |
| Overall Study | Study Terminated by Sponsor | 0 | 0 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 1 | 0 | 1 |
Baseline characteristics
| Characteristic | Derazantinib 25 mg QOD - 200 mg QD - Low Dose Group | Derazantinib 250 mg QOD - 325 mg QD - Middle Dose Group | Derazantinib 400 mg QOD - 425 mg QD - High Dose Group | Derazantinib 300 mg QD - Expanded Cohort Group | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 10 Participants | 9 Participants | 11 Participants | 23 Participants | 53 Participants |
| Age, Categorical Between 18 and 65 years | 19 Participants | 4 Participants | 8 Participants | 35 Participants | 66 Participants |
| Age, Continuous | 60 years | 67 years | 66 years | 60.5 years | 63 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 1 Participants | 3 Participants | 2 Participants | 9 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 26 Participants | 12 Participants | 16 Participants | 56 Participants | 110 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants | 1 Participants | 2 Participants | 3 Participants | 9 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 1 Participants | 1 Participants | 1 Participants | 5 Participants |
| Race (NIH/OMB) White | 24 Participants | 11 Participants | 16 Participants | 54 Participants | 105 Participants |
| Sex: Female, Male Female | 17 Participants | 9 Participants | 11 Participants | 32 Participants | 69 Participants |
| Sex: Female, Male Male | 12 Participants | 4 Participants | 8 Participants | 26 Participants | 50 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 2 / 29 | 0 / 13 | 2 / 19 | 5 / 58 |
| other Total, other adverse events | 28 / 29 | 13 / 13 | 19 / 19 | 58 / 58 |
| serious Total, serious adverse events | 9 / 29 | 2 / 13 | 6 / 19 | 16 / 58 |
Outcome results
Primary
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)
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)
Population: The safety population included all subjects who received at least one dose of derazantinib.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Derazantinib 25 mg QOD - 200 mg QD - Low Dose Group | Number of Patients With Drug-related Treatment-emergent Adverse Events (TEAEs) | TEAE Grade 1 | 3 Participants |
| Derazantinib 25 mg QOD - 200 mg QD - Low Dose Group | Number of Patients With Drug-related Treatment-emergent Adverse Events (TEAEs) | TEAE Grade 2 | 14 Participants |
| Derazantinib 25 mg QOD - 200 mg QD - Low Dose Group | Number of Patients With Drug-related Treatment-emergent Adverse Events (TEAEs) | TEAE Grade 3 | 9 Participants |
| Derazantinib 25 mg QOD - 200 mg QD - Low Dose Group | Number of Patients With Drug-related Treatment-emergent Adverse Events (TEAEs) | TEAE Grade 4 | 0 Participants |
| Derazantinib 25 mg QOD - 200 mg QD - Low Dose Group | Number of Patients With Drug-related Treatment-emergent Adverse Events (TEAEs) | TEAE Grade 5 | 2 Participants |
| Derazantinib 25 mg QOD - 200 mg QD - Low Dose Group | Number of Patients With Drug-related Treatment-emergent Adverse Events (TEAEs) | no TEAE | 1 Participants |
| Derazantinib 250 mg QOD - 325 mg QD - Middle Dose Group | Number of Patients With Drug-related Treatment-emergent Adverse Events (TEAEs) | no TEAE | 0 Participants |
| Derazantinib 250 mg QOD - 325 mg QD - Middle Dose Group | Number of Patients With Drug-related Treatment-emergent Adverse Events (TEAEs) | TEAE Grade 4 | 1 Participants |
| Derazantinib 250 mg QOD - 325 mg QD - Middle Dose Group | Number of Patients With Drug-related Treatment-emergent Adverse Events (TEAEs) | TEAE Grade 1 | 1 Participants |
| Derazantinib 250 mg QOD - 325 mg QD - Middle Dose Group | Number of Patients With Drug-related Treatment-emergent Adverse Events (TEAEs) | TEAE Grade 3 | 6 Participants |
| Derazantinib 250 mg QOD - 325 mg QD - Middle Dose Group | Number of Patients With Drug-related Treatment-emergent Adverse Events (TEAEs) | TEAE Grade 2 | 5 Participants |
| Derazantinib 250 mg QOD - 325 mg QD - Middle Dose Group | Number of Patients With Drug-related Treatment-emergent Adverse Events (TEAEs) | TEAE Grade 5 | 0 Participants |
| Derazantinib 400 mg QOD - 425 mg QD - High Dose Group | Number of Patients With Drug-related Treatment-emergent Adverse Events (TEAEs) | TEAE Grade 2 | 3 Participants |
| Derazantinib 400 mg QOD - 425 mg QD - High Dose Group | Number of Patients With Drug-related Treatment-emergent Adverse Events (TEAEs) | TEAE Grade 3 | 13 Participants |
| Derazantinib 400 mg QOD - 425 mg QD - High Dose Group | Number of Patients With Drug-related Treatment-emergent Adverse Events (TEAEs) | TEAE Grade 4 | 0 Participants |
| Derazantinib 400 mg QOD - 425 mg QD - High Dose Group | Number of Patients With Drug-related Treatment-emergent Adverse Events (TEAEs) | no TEAE | 0 Participants |
| Derazantinib 400 mg QOD - 425 mg QD - High Dose Group | Number of Patients With Drug-related Treatment-emergent Adverse Events (TEAEs) | TEAE Grade 5 | 2 Participants |
| Derazantinib 400 mg QOD - 425 mg QD - High Dose Group | Number of Patients With Drug-related Treatment-emergent Adverse Events (TEAEs) | TEAE Grade 1 | 1 Participants |
| Derazantinib 300 mg QD - Expanded Cohort Group | Number of Patients With Drug-related Treatment-emergent Adverse Events (TEAEs) | TEAE Grade 5 | 5 Participants |
| Derazantinib 300 mg QD - Expanded Cohort Group | Number of Patients With Drug-related Treatment-emergent Adverse Events (TEAEs) | no TEAE | 0 Participants |
| Derazantinib 300 mg QD - Expanded Cohort Group | Number of Patients With Drug-related Treatment-emergent Adverse Events (TEAEs) | TEAE Grade 2 | 14 Participants |
| Derazantinib 300 mg QD - Expanded Cohort Group | Number of Patients With Drug-related Treatment-emergent Adverse Events (TEAEs) | TEAE Grade 4 | 4 Participants |
| Derazantinib 300 mg QD - Expanded Cohort Group | Number of Patients With Drug-related Treatment-emergent Adverse Events (TEAEs) | TEAE Grade 1 | 11 Participants |
| Derazantinib 300 mg QD - Expanded Cohort Group | Number of Patients With Drug-related Treatment-emergent Adverse Events (TEAEs) | TEAE Grade 3 | 24 Participants |
Secondary
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.
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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Derazantinib 25 mg QOD - 200 mg QD - Low Dose Group | Progression-free Survival (PFS) | 8.3 weeks |
| Derazantinib 250 mg QOD - 325 mg QD - Middle Dose Group | Progression-free Survival (PFS) | 15.3 weeks |
| Derazantinib 400 mg QOD - 425 mg QD - High Dose Group | Progression-free Survival (PFS) | 8.1 weeks |
| Derazantinib 300 mg QD - Expanded Cohort Group | Progression-free Survival (PFS) | 17.4 weeks |
Secondary
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.
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.
Population: Evaluable Population: patients who received at least one cycle of study treatment and had at least one postbaseline tumor evaluation.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Derazantinib 25 mg QOD - 200 mg QD - Low Dose Group | Proportion of Patients With an Objective Tumor Response Per RECIST 1.1 | 0 Participants |
| Derazantinib 250 mg QOD - 325 mg QD - Middle Dose Group | Proportion of Patients With an Objective Tumor Response Per RECIST 1.1 | 0 Participants |
| Derazantinib 400 mg QOD - 425 mg QD - High Dose Group | Proportion of Patients With an Objective Tumor Response Per RECIST 1.1 | 1 Participants |
| Derazantinib 300 mg QD - Expanded Cohort Group | Proportion of Patients With an Objective Tumor Response Per RECIST 1.1 | 5 Participants |
Secondary
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.
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.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Derazantinib 25 mg QOD - 200 mg QD - Low Dose Group | Proportion of Patients With Disease Control Per RECIST 1.1 | 8 Participants |
| Derazantinib 250 mg QOD - 325 mg QD - Middle Dose Group | Proportion of Patients With Disease Control Per RECIST 1.1 | 4 Participants |
| Derazantinib 400 mg QOD - 425 mg QD - High Dose Group | Proportion of Patients With Disease Control Per RECIST 1.1 | 7 Participants |
| Derazantinib 300 mg QD - Expanded Cohort Group | Proportion of Patients With Disease Control Per RECIST 1.1 | 32 Participants |