An Open-label, Non-randomized, Multicenter Phase I Study to Determine the Maximum Tolerated or Recommended Phase II Dose of Oral Mutant IDH1 Inhibitor BAY1436032 and to Characterize Its Safety, Tolerability, Pharmacokinetics and Preliminary Pharmacodynamic and Anti-tumor Activity in Patients With IDH1-R132X-mutant Advanced Solid Tumors
Overview
- Phase
- Phase 1
- Intervention
- BAY1436032
- Conditions
- Solid Tumors
- Sponsor
- Bayer
- Enrollment
- 81
- Primary Endpoint
- Recommended Phase II Dose (RP2D) of BAY1436032
- Status
- Completed
- Last Updated
- last year
Overview
Brief Summary
The primary objective of this study is:
- Determine the safety, tolerability, maximum tolerated dose (MTD) or recommended Phase II dose (RP2D) of BAY 1436032 in patients with isocitrate dehydrogenase-1 (IDH1)-R132X-mutant advanced solid tumors.
The secondary objectives of this study are:
- Evaluate the pharmacokinetics (PK) of BAY1436032 in patients with IDH1-R132X-mutant advanced solid tumors.
- Evaluate the effect of a standard high-fat, high calorie meal on the PK of BAY1436032.
- Assess pharmacodynamic (PD) effects and evidence of clinical efficacy associated with BAY1436032 administration in patients with IDH1-R132X-mutant advanced solid tumors.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Male or female patients ≥ 18 years of age
- •Patients with a histologically confirmed solid tumor:
- •Tumor must harbor an IDH1-R132X mutation
- •Disease must be evaluable as per RECIST 1.1 or RANO (for gliomas). At least one measurable target lesion is required in expansion cohort patients
- •Patients with advanced cancer who are refractory to, have demonstrated intolerance to, or have refused access to, available standard therapies
- •Glioma patients must have completed chemoradiotherapy at least 12 weeks prior to screening and their baseline scan
- •Patient must be able to provide a formalin-fixed and paraffin-embedded (FFPE) tumor tissue specimen prior to treatment. The specimen may have been taken at any time during the course of the disease and may be from the primary tumor or from a metastasis
- •Patient must be able to take oral medication and comply with protocol procedures and scheduled visits
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
- •Negative serum or urine pregnancy test must be obtained within 7 days prior to the first dose of study drug in women of childbearing potential. Negative results must be available prior to study drug administration. Pregnancy tests will be repeated regularly during treatment
Exclusion Criteria
- •Known hypersensitivity to the study drug or excipients of the preparation or any agent given in association with this study
- •History of cardiac disease, including congestive heart failure of New York Heart Association (NYHA) class \>II, unstable angina (anginal symptoms at rest) or new-onset angina (within 6 months prior to study entry), myocardial infarction within 6 months prior to study entry, or cardiac arrhythmias requiring anti-arrhythmic therapy except for beta-blockers and digoxin; evidence for uncontrolled coronary artery disease (e.g. angina pectoris, myocardial infarction within 6 months prior to study entry, major regional wall motion abnormalities upon baseline echocardiography or multiple-gated acquisition \[MUGA\] scan). Patients with a pacemaker are also excluded
- •Left ventricular ejection fraction (LVEF) \< 40% as measured by echocardiography or MUGA scan performed at Screening
- •Uncontrolled hypertension defined as systolic blood pressure ≥ 160 mmHg or diastolic blood pressure ≥ 100 mmHg, despite medical management
- •Patients who have an active clinically significant infection of the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) grade ≥ 2
- •Previous or coexisting cancer(s) distinct in primary site or histology from the cancer evaluated in this study EXCEPT:
- •Appropriately treated cervical cancer in-situ, non-melanoma skin cancers, or superficial bladder tumors (Ta and Tis)
- •Any cancer that was curatively treated at least 3 years before entry into this study
- •Unresolved specific chronic toxicity of previous treatment of grade \> 1 except for alopecia or hemoglobin ≤9.0 g/dL (or ≤5.6 mmol/L)
- •Major surgery, significant trauma, wide-field radiotherapy, or therapy with monoclonal antibodies within 4 weeks before the first dose of study drug
Arms & Interventions
BAY1436032
Dose escalation: Patients with any type of IDH1-R132X-mutant solid tumor may be eligible for enrollment. A minimum of 3 patients per cohort will be treated. If dose limiting toxicities (DLTs) occur, Bayesian dose-DLT modeling will be performed to help guide dosing decisions and to identify the maximum tolerated dose (MTD). If the MTD is not reached, a recommended phase II dose (RP2D) will be chosen based on available safety, tolerability, PK, PD and clinical efficacy data. Dose expansion: The dose and schedule that was determined to be most appropriate in the dose escalation part of the study, which may be the MTD and / or the RP2D, will be used. Cohorts will consist of patients with the following IDH-R132X-mutant tumor types: (1) anaplastic glioma; (2) glioblastoma; (3) intrahepatic cholangiocarcinoma; (4) tumor types other than those in Cohorts 1-3.
Intervention: BAY1436032
Outcomes
Primary Outcomes
Recommended Phase II Dose (RP2D) of BAY1436032
Time Frame: Up to 20 months
If the MTD is not reached, the primary variable will be the RP2D, defined based on all available safety, PK, PD, biomarker, and efficacy data collected after the start of BAY1436032 treatment.
Number of participants with adverse events as a measure of safety and tolerability of BAY1436032
Time Frame: Up to 30 months
Safety and tolerability variables will include AEs, laboratory safety tests, ECGs, and vital signs.
Maximum tolerated dose (MTD) of BAY1436032
Time Frame: 21 days
MTD is defined as the maximum dose at which the predicted incidence of DLTs during Cycle 1 (DLT evaluation period) is ≤25%.
Secondary Outcomes
- Objective response rate (partial and complete response)(Up to 30 months)
- Duration of response(Up to 30 months)
- AUC(0-24) of BAY1436032(on C1D-2 and C1D1)
- Change of 2-hydroxyglutarate (2-HG) concentration in plasma from baseline(Up to 30 months)
- Progression free survival (PFS)(Up to 30 months)
- Cmax of BAY1436032(on C1D-2 and C1D1)
- AUC(0-12) of BAY1436032(on C1D-2 and C1D1)
- C(max,md) of BAY1436032(on C1D15)
- AUC(0-12)md of BAY1436032(on C1D15)
- Change of 2-hydroxyglutarate (2-HG) concentration in urine from baseline(Up to 30 months)