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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02746081
Recruitment Status : Active, not recruiting
First Posted : April 21, 2016
Last Update Posted : April 23, 2021
Sponsor:
Information provided by (Responsible Party):
Bayer

Tracking Information
First Submitted Date  ICMJE April 8, 2016
First Posted Date  ICMJE April 21, 2016
Last Update Posted Date April 23, 2021
Actual Study Start Date  ICMJE May 26, 2016
Actual Primary Completion Date November 8, 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: December 13, 2018)
  • 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%.
  • 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.
  • 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.
Original Primary Outcome Measures  ICMJE
 (submitted: April 18, 2016)
  • 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%.
  • Number of adverse events as a measure of safety and tolerability of BAY1436032 [ Time Frame: Up to 33 months ]
    Safety and tolerability variables will include AEs, laboratory safety tests, ECGs, and vital signs.
  • Recommended Phase II Dose (RP2D) of BAY1436032 [ Time Frame: 1 year ]
    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.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: December 13, 2018)
  • Objective response rate (partial and complete response) [ Time Frame: Up to 30 months ]
    Assessed by Response Evaluation Criteria in Solid Tumors (RECIST 1.1) or for gliomas Response Assessment in Neuro-Oncology (RANO)
  • Duration of response [ Time Frame: Up to 30 months ]
  • Progression free survival (PFS) [ Time Frame: Up to 30 months ]
    For expansion part only
  • Cmax of BAY1436032 [ Time Frame: on C1D-2 and C1D1 ]
  • AUC(0-12) of BAY1436032 [ Time Frame: on C1D-2 and C1D1 ]
  • AUC(0-24) of BAY1436032 [ Time Frame: on C1D-2 and C1D1 ]
  • C(max,md) of BAY1436032 [ Time Frame: on C1D15 ]
  • AUC(0-12)md of BAY1436032 [ Time Frame: on C1D15 ]
  • Change of 2-hydroxyglutarate (2-HG) concentration in plasma from baseline [ Time Frame: Up to 30 months ]
  • Change of 2-hydroxyglutarate (2-HG) concentration in urine from baseline [ Time Frame: Up to 30 months ]
Original Secondary Outcome Measures  ICMJE
 (submitted: April 18, 2016)
  • Tumor response evaluation based on Response Evaluation Criteria in Solid Tumors (RECIST 1.1) and Response Assessment in Neuro-Oncology (RANO) for gliomas. [ Time Frame: Up to 32 months ]
  • Maximum total drug concentration in plasma after single dose (Cmax) of BAY1436032 [ Time Frame: PK (dose escalation): C1D1 (pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, and 24h post-dose). ]
  • Maximum total drug concentration in plasma after multiple dose (Cmax, md) of BAY1436032 [ Time Frame: PK (dose escalation):C1D15 (pre-dose, 0.5, 1, 2, 3, 4, 6, 8, and 12 h post-dose). ]
  • AUC (area under the concentration versus time curve) from time 0 to 12 h after a single dose [AUC(0-12)] of BAY1436032 [ Time Frame: PK (dose escalation): C1D1 (pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, and 24h post-dose). ]
  • AUC (area under the concentration versus time curve) from time 0 to 12 h after multiple doses [AUC(0-12)md] of BAY1436032 [ Time Frame: PK (dose escalation): C1D15 (pre-dose, 0.5, 1, 2, 3, 4, 6, 8, and 12 h post-dose). ]
  • Change of 2-hydroxyglutarate (2-HG) concentration in plasma from baseline [ Time Frame: Up to 32 months ]
  • Change of 2-hydroxyglutarate (2-HG) concentration in urine from baseline [ Time Frame: Up to 32 months ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Phase I Study of BAY1436032 in IDH1-mutant Advanced Solid Tumors
Official Title  ICMJE 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
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.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Solid Tumors
Intervention  ICMJE Drug: BAY1436032
The selected starting dose of BAY1436032 is 300 mg/day (150 mg BID) to be administered orally continuously in tablet form in 21-day cycles. Adjustments to this schedule may be made if warranted by information collected during the course of the study. The maximum feasible dose of BAY1436032 is expected to be 3000 mg/day.
Study Arms  ICMJE Experimental: 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: Drug: BAY1436032
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: August 17, 2018)
81
Original Estimated Enrollment  ICMJE
 (submitted: April 18, 2016)
100
Estimated Study Completion Date  ICMJE December 31, 2021
Actual Primary Completion Date November 8, 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
  • 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 activated partial thromboplastin time (aPTT) ≤ 1.5 times ULN (patients on anticoagulation with an agent such as warfarin or heparin or rivoraxaban 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 by the 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) ≥ 1.5x10^9/L;
    • Platelet count ≥ 100x10^9/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 primary tumor or metastatic disease)
    • Estimated glomerular filtration rate (eGFR) ≥ 40 mL/min per 1.73 m^2 according to the Modification of Diet in Renal Disease Study Group (MDRD) formula
  • Minimum life expectancy of 3 months per the judgment of the investigator

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
  • Treatment with investigational or approved anti-cancer drugs 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)
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Denmark,   Germany,   Japan,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02746081
Other Study ID Numbers  ICMJE 18239
2015-003483-37 ( EudraCT Number )
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Bayer
Study Sponsor  ICMJE Bayer
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Bayer Study Director Bayer
PRS Account Bayer
Verification Date April 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP