HER2-negative gastric adenocarcinoma harboring FGFR genetic aberrations
Conditions
Interventions
Product Name: Derazantinib
Pharmaceutical Form: Capsule, hard
CAS Number: 1821329-75-2
Other descriptive name: ARQ087•2 HCL
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration
Sponsors
Basilea Pharmaceutica International Ltd.
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Informed consent signed by the patient indicating that they understand the purpose of, and procedures required for, the study, and are willing to participate in the study, prior to any study-related procedure. 2. Male or female aged = 18 years. 3. Histologically-confirmed adenocarcinoma of the gastro-esophageal junction or stomach. 4. Negative HER2 status obtained from the most recent available tissue sample. 5. Inoperable recurrent, locally-advanced adenocarcinoma or progressing stage IV adenocarcinoma of the gastro-esophageal junction or stomach, and prior antitumor treatment as specified for each Substudy: ? Substudy 1 : Patients with radiographically-documented disease progression after either standard first- or second-line treatment, and no approved treatment alternative. ? Substudy 2: Patients with radiographically-documented disease progression after standard first-line treatment, and per Investigator assessment considered suitable to tolerate the treatment regimen. ? Substudy 3: Patients with objective radiographically-documented disease progression: - During, or within 6 months after, administration of the last cycle of adjuvant / neoadjuvant / perioperative chemotherapy (platinum plus fluoropyrimidine with or without antracycline and/or taxane and/or irinotecan) for locally advanced disease, or - During, or any time after, administration of the last cycle of first-line taxane-free chemotherapy (platinum plus fluoropyrimidine with or without antracycline) for metastatic disease or locally advanced disease. 6. Positive test for eligible FGFRfus/amp/mt status as per central testing. 7. For Substudies 1 and 3, measurable disease as defined by the Investigator using Response Evaluation Criteria in Solid Tumors 1.1 criteria (RECIST 1.1) disease per RECIST 1.1 is not required for Substudy 2. 8. ECOG PS 0 or 1. 9. Adequate organ functions, as indicated by Screening visit local laboratory values 10. Men and women of childbearing potential must agree to avoid impregnating a partner or becoming pregnant, respectively, during the study, and for at least 150 days after the last dose of study drug. Are the trial subjects under 18? no Number of subjects for this age range: 0 F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 127 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 127
Exclusion criteria
Exclusion criteria: 1. Receipt of prior cancer treatment within specific interval periods (see Exclusion criterion 1). 2. For patients enrolled in Substudy 1, prior treatment with FGFR inhibitors. 3. For patients enrolled in Substudy 2 and 3, prior treatment with - Taxanes within 6 months prior to randomization - FGFR inhibitors or pathway-targeting agents - Anti-VEGF(R) therapeutic antibody or pathway-targeting agents. 4. For patients enrolled in Substudy 3, prior treatment with anti-programmed cell death receptor-1 (PD-1) or anti-programmed death ligand-1 (PD-L1) therapeutic antibody or pathway-targeting agents. 5. Concurrent evidence of corneal or retinal disorder, including but not limited to bullous/band keratopathy, keratoconjunctivitis (unless keratoconjunctivitis sicca), corneal abrasion (unless related to trauma), inflammation/ulceration, confirmed by ophthalmological examination. 6. History of clinically significant cardiac disorders: New York Heart Association Class II to IV congestive heart failure, within 6 months of the first dose of study drug; any arterial thrombotic event, including myocardial infarction, unstable angina, cerebrovascular accident, or transient ischemic attack, within 6 months of the first dose of study drug; concurrent and clinically significant abnormalities on electrocardiogram [ECG] at Screening, including a QT interval corrected by Fridericia’s formula [QTcF]1 > 450 ms for males or > 460 ms for females. 7. Any unresolved clinically-significant Common Terminology Criteria for Adverse Events (CTCAE) Grade =2 toxicity (except for alopecia, Grade 2 platinum-therapy-related neuropathy, and/or Grade 2 anemia, from previous anti-tumor treatment and/or from medical/surgical procedures/interventions). 8. Known central nervous system (CNS) metastases. ... 18. Pregnant or breast feeding. Applicable to patients considered for enrollment in Substudy 2 or 3: 19. Concurrent uncontrolled or active infection with human immunodeficiency virus (HIV; known HIV 1/2 antibodies positive). 20. Active hepatitis B virus (HBV) and hepatitis C virus (HCV) co infection. 21. Active tuberculosis. 22. Lack of recovery from major surgery after 4 weeks, or major elective surgery is planned during the foreseeable duration of the patient's participation in the study, or placement of a central venous access device within 7 days prior to randomization. 23. Uncontrolled arterial hypertension, with a systolic blood pressure = 150 mm Hg or a diastolic blood pressure = 90 mm Hg despite standard medical management. 24. History of gastrointestinal perforation and/or fistulae within 6 months prior to study entry. 25. History of clinically relevant bleeding disorders, vasculitis, or had a significant bleeding episode from the gastrointestinal tract within 3 months prior to study entry. 26. History of deep vein thrombosis, pulmonary embolism, or any other significant thromboembolism (venous port or catheter thrombosis or superficial venous thrombosis are not considered ‘significant’) during the 3 months prior to randomization. 27. The patient is receiving therapeutic anticoagulation with warfarin, low-molecular weight heparin, or similar agents. 28. The patient is receiving chronic therapy with nonsteroidal anti inflammatory agents (NSAIDs, e.g., indomethacin, ibuprofen, naproxen, or similar agents) or other anti-platelet agents (e.g., clopidogrel, ticlopidine, dipyridamole, anagrelide). Acetylsalicylic acid (aspirin) is permitted at doses up to 325 mg/day. 29.Ch
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Substudy 1 To evaluate the objective response rate (ORR) of patients with HER2neg FGFRfus/amp/mt GAC treated with derazantinib Substudy 2 To determine the RP2D of derazantinib-paclitaxel-ramucirumab in combination in patients with HER2neg FGFRfus/amp/mt GAC Substudy 3 To evaluate the ORR of patients with HER2neg FGFRfus/amp/mt GAC treated with either derazantinib, derazantinib-paclitaxel-ramucirumab, derazantinib-atezolizumab, or paclitaxel-ramucirumab;Secondary Objective: To evaluate the efficacy of the study drugs, as measured by ORR, and by disease control rate, duration of response, progression-free survival, and overall survival. To compare the ORR, DCR, DOR, PFS, and OS of patients treated with derazantinib monotherapy, derazantinib-paclitaxel-ramucirumab, and derazantinib-atezolizumab each with that of patients treated with paclitaxel-ramucirumab (derived from data from Substudy 3). To compare antitumor efficacy in patients treated with derazantinib monotherapy to that of patients treated with derazantinib-paclitaxel-ramucirumab / derazantinib-atezolizumab as well as patients treated with derazantinib-paclitaxel-ramucirumab compared to that of patients treated with paclitaxel-ramucirumab. To assess the safety and tolerability of the study drugs. To characterize the pharmacokinetic (PK) profile of derazantinib and paclitaxel when administered in combination. To evaluate changes, and assess the quality of life and symptom response from baseline;Primary end point(s): For all cohorts in Substudies 1 and 3, the primary endpoint is objective response rate (ORR), as measured by the proportion of patients with confirmed complete response (CR) or partial response (PR) by blinded independent central review (BICR) per RECIST 1.1. To determine the study population for Substudy 3, the outcomes of patients with HER2neg FGFRfus/amp/mt GAC treated with derazantinib in Substudy 1 are to be analyzed per cohort. In Substudy 2, the primary endpoint is the reco | — |
Secondary
| Measure | Time frame |
|---|---|
| Timepoint(s) of evaluation of this end point: All patients will undergo assessments for clinical safety on D1 and D15 of Cycle 1 and on D1 (+3 days) of every subsequent treatment cycle, with paclitaxel-ramucirumab-treated patients also undergoing these assessments at the treatment administration visits on D8 (+3 days) and D15 (+3 days) of every treatment cycle. Efficacy will be evaluated on C3D1 ±7 days, then every 8 weeks (±7 days) for the first 6 months, and every 12 weeks (±7 days) thereafter (see Section 5.3.3.2). AEs will be assessed continuously and at every study visit. HR-QoL questionnaires will be completed by the patient before the patient sees the physician (i.e., at the start of the visit) on D1 of every cycle;Secondary end point(s): Secondary endpoints for Substudy 1: - PFS of patients treated with derazantinib, as measured from patient enrollment to PD date by BICR - DCR, as measured by the proportion of patients with confirmed CR, PR or stable disease (SD) by BICR - DOR, as calculated from the first date of documented tumor response to disease progression by BICR (or death if no documentation of PD is obtained) - OS, as measured from patient enrollment to time of death - Safety and tolerability of study drugs, as measured by the frequency and severity of AEs (graded by CTCAE version 5.0), clinical laboratory parameters, vital signs, ECOG PS, physical examinations (including eye examinations), and ECG parameters over time Secondary endpoints for Substudy 2: - ORR, as measured by the proportion of patients with confirmed CR or PR by BICR - DCR, as measured by the proportion of patients with confirmed CR, PR or SD by BICR - DOR, as calculated from the first date of documented tumor response to disease progression by BICR (or death if no documentation of PD is obtained) - PFS of patients treated with derazantinib-paclitaxel-ramucirumab, as measured from patient enrollment to PD date by BICR - OS, as measured from patient enrollment to time of death - Saf | — |
Countries
Argentina, Australia, Belgium, Brazil, Chile, France, Germany, Italy, Korea, Republic of, Poland, Russian Federation, Spain, Turkey, United Kingdom, United States
Contacts
Public ContactSilke Friedmann
Basilea Pharmaceutica International Ltd.
Outcome results
None listed