Clinical Trials /

Phase I Study of BAY1436032 in IDH1-mutant Advanced Solid Tumors

NCT02746081

Description:

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.

Related Conditions:
  • Malignant Solid Tumor
Recruiting Status:

Active, not recruiting

Phase:

Phase 1

Trial Eligibility

Document

Phase I Study of BAY1436032 in Isocitrate Dehydrogenase-1 (<span class="go-doc-concept go-doc-biomarker">IDH1</span>)-<span class="go-doc-concept go-doc-keyword">Mutant</span> Advanced Solid Tumors

Title

  • Brief Title: Phase I Study of BAY1436032 in Isocitrate Dehydrogenase-1 (IDH1)-Mutant Advanced Solid Tumors
  • Official Title: An Open-label, Non-randomized, Multicenter Phase I Study to Determine the Maximum Tolerated or Recommended Phase II Dose of Oral Mutant IDH1 Inhibitor BAY 1436032 and to Characterize Its Safety, Tolerability, Pharmacokinetics and Preliminary Pharmacodynamic and Anti-tumor Activity in Patients With IDH1-R132X-mutant Advanced Solid Tumors
  • Clinical Trial IDs

    NCT ID: NCT02746081

    ORG ID: 18239

    NCI ID: 2015-003483-37

    Trial Conditions

    Neoplasms

    Trial Interventions

    Drug Synonyms Arms
    BAY1436032 BAY1436032

    Trial Purpose

    In patients with IDH1-R132X-mutant solid tumors treated with BAY1436032:

    1. Determine the safety, tolerability, maximum tolerated dose (MTD) or recommended phase
    II dose (RP2D) of BAY1436032;

    2. Evaluate the pharmacokinetic (PK) properties and pharmacodynamic (PD) effects of
    BAY1436032;

    3. Look for preliminary evidence of clinical efficacy in patients treated with BAY1436032.

    Detailed Description

    Trial Arms

    Name Type Description Interventions
    BAY1436032 Experimental Dose escalation part: Patients with any type of IDH1-R132X-mutant solid tumor may be eligible for enrollment. BAY1436032 tablets will be administered continuously in 21-day cycles. The selected starting dose is 300 mg/day (150 mg 2 times daily (BID)). If dose limiting toxicities (DLTs) are encountered, 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 RP2D will be chosen based on available safety, tolerability, PK, PD and clinical efficacy data. Dose expansion part: 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 representing the following IDH1-R132X-mutant tumor types: (1) anaplastic glioma; (2) glioblastoma; (3) intrahepatic cholangiocarcinoma; (4) tumor types other than those listed in Cohorts 1-3. BAY1436032

    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)

    - 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, 1 or 2

    - 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.

    - Sexually active women and men of reproductive potential must agree to use highly
    effective contraception. This applies for the period between signing of the informed
    consent and 3 months after the last administration of study drug. These procedures
    should be documented in source documents. The investigator or a designated associate
    is requested to advise the patient on how to achieve highly effective birth control.
    Highly effective contraception includes:

    - Established use of oral, injected or implanted hormonal methods of contraception

    - Placement of certain intrauterine devices (IUD) or intrauterine systems (IUS)

    - Hysterectomy, or vasectomy of the partner (provided that partner is the sole
    sexual partner of the woman of childbearing potential trial participant and that
    the vasectomized partner has received medical assessment of the surgical
    success) In addition, the use of condoms for patients or their partners is
    required

    - Ability to understand and the willingness to sign a written informed consent. A
    signed informed consent, including consent for biomarker analyses, must be obtained
    prior to any study-specific procedures.

    - Adequate blood clotting as defined by international normalized ratio (INR) and
    partial thromboplastin time (PTT) 1.5 times ULN (patients on anticoagulation with
    an agent such as Coumadin or heparin or Xarelto will be allowed to participate
    provided that no prior evidence of underlying abnormality in these parameters
    exists). For patients on warfarin, close monitoring of at least weekly evaluations
    will be performed until INR is stable based on a measurement at pre-dose, as defined
    by the local standard of care

    - Adequate bone marrow, liver, and renal functions as assessed bythe following
    laboratory requirements to be conducted within 7 days prior to the first dose of
    study drug:

    - Hemoglobin 9.0 g/dL;

    - Absolute neutrophil count (ANC) 1.5*109/L;

    - Platelet count 100*109/L.

    - Total bilirubin 1.5 times the upper limit of normal (ULN). For intrahepatic
    cholangiocarcinoma (IHCC) patients only, total bilirubin 2.5 times ULN is
    acceptable.

    - Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) 2.5 times
    ULN ( 5 times ULN for patients with impaired liver function due to metastatic
    disease)

    - Estimated glomerular filtration rate (eGFR) 50 mL/min per 1.73 m2 according to
    the Modification of Diet in Renal Disease Study Group (MDRD) formula

    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). Patients
    with a pacemaker are also excluded.

    - Left ventricle ejection fraction (LVEF) < 40% as measured by echocardiography
    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

    - Investigational drug treatment within 4 weeks before the start of BAY1436032
    treatment and during the study (glioma patients must have completed chemoradiotherapy
    at least 12 weeks prior to screening and their baseline scan; see inclusion criteria
    #2)

    - Pregnant women. Women of reproductive potential must have a negative serum or urine
    pregnancy test performed within 7 day

    - Prior treatment with any therapy targeting mutant IDH1 (including BAY1436032)

    Minimum Eligible Age: 18 Years

    Maximum Eligible Age: N/A

    Eligible Gender: Both

    Primary Outcome Measures

    Maximum tolerated dose (MTD) of BAY1436032

    Number of adverse events as a measure of safety and tolerability of BAY1436032

    Recommended Phase II Dose (RP2D) of BAY1436032

    Secondary Outcome Measures

    Tumor response evaluation based on Response Evaluation Criteria in Solid Tumors (RECIST 1.1) and Response Assessment in Neuro-Oncology (RANO) for gliomas.

    Maximum total drug concentration in plasma after single dose (Cmax) of BAY1436032

    Maximum total drug concentration in plasma after multiple dose (Cmax, md) of BAY1436032

    AUC (area under the concentration versus time curve) from time 0 to 12 h after a single dose [AUC(0-12)] of BAY1436032

    AUC (area under the concentration versus time curve) from time 0 to 12 h after multiple doses [AUC(0-12)md] of BAY1436032

    Change of 2-hydroxyglutarate(2-HG) concentration in plasma from baseline

    Change of 2-hydroxyglutarate(2-HG) concentration in urine from baseline

    Trial Keywords

    BAY1436032

    Solid tumors

    IDH1-R132X Mutation

    Cancer

    Safety

    Tolerability

    Pharmacokinetics

    Pharmacodynamics

    Efficacy