An open-label, non-randomized, multicenter Phase I study to determine the maximum tolerated and / or recommended Phase II dose of oral mutant IDH1 (mIDH1) inhibitor BAY 1436032 and to characterize its safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary clinical efficacy in patients with mIDH1-R132X advanced acute myeloid leukemia (AML)
The goal of the pre-screening part of this clinical research study is to learn if you have a certain kind of mutation (genetic change) called IDH1. Only patients who have this mutation will be able to take part in the main part of the study. The goal of the main part of this study is to find the highest tolerable or recommended dose of BAY 1436032 that can be given to patients with advanced or refractory (has not responded to treatment) acute myeloid leukemia (AML) that has a certain kind of mutation called IDH1. The safety and tolerability of this drug will also be studied.
Disease Group: Other diseases of blood and blood-forming organs
Treatment Agent: BAY 1436032
Treatment Location: Both at MDACC & and Other Sites
Sponsor: Bayer HealthCare Pharmaceuticals Inc.
Primary objective: Determine the safety, tolerability, maximum tolerated dose (MTD) and / or recommended Phase II dose (RP2D) of BAY 1436032 in a 2 times daily (BID) dosing schedule in patients with mutant IDH1 (mIDH1)-R132X advanced AML Secondary objectives: Evaluate the pharmacokinetics (PK) of BAY 1436032 in patients with mIDH-R132X advanced AML Assess pharmacodynamic (PD) effects and evidence of clinical efficacy associated with BAY 1436032 administration in patients with mIDH1-R132X advanced AML Exploratory objectives: Assess the frequency and identity of mIDH1-R132X and other genetic alterations in biomarker specimens obtained prior to and during BAY 1436032 treatment. Evaluate potential associations between disease-associated genotypic information and clinical efficacy and / or PD effects. Evaluate further biomarkers to investigate mechanisms of resistance to BAY 1436032 treatment. Evaluate additional biomarkers to investigate the drug (i.e. mode of action-related effect and / or safety) and / or the pathomechanism of the disease.
IRB Review and Approval Date: 06/02/2017
Recruitment Status: Open
Projected Accrual: approximately 60
1) Patients with advanced AML that harbors mIDH1-R132X including
patients with myelodysplastic syndrome (MDS), myeloproliferative
neoplasms (MPN), or myelodysplastic / myeloproliferative neoplasms (MDS
/ MPN) who have converted to AML or who have developed AML secondary to
treatment of other malignancies.
2) Patients are relapsed from or refractory to at least 1 previous line of therapy, ho are intolerable to, or unable, or unwilling to receive established therapies. Patients relapsed following allogenic transplantation are also eligible
3) Male or female patients aged >/=18 years
4) Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2
5) Women must have a negative serum pregnancy test within 7 days prior to the first dose of study drug or be surgically or biologically sterile or postmenopausal. Postmenopausal women are defined as:Age >/=50 years with amenorrhea for at least 12 months or Age </=50 years with 6 months of spontaneous amenorrhea and follicle stimulating hormone level within postmenopausal range (>/= 40 mIU/mL) or Permanently sterilized women (hysterectomy, bilateral oophorectomy)
6) Women and men of reproductive potential must agree to use adequate contraception when sexually active. This applies for the time between signing of the informed consent form and 3 months after the last administration of study drug. The definition of adequate contraception will be based on the judgment of the investigator and on local requirements. Acceptable methods of contraception include, but are not limited to, (i) condoms (male or female) with or without a spermicidal agent; (ii) diaphragm or cervical cap with spermicide; (iii) intra-uterine device; (iv) hormone-based contraception. Patients must agree to utilize 2 reliable and acceptable methods of contraception simultaneously.
7) Ability to understand and the willingness to sign a written informed consent. A signed informed consent must be obtained prior to any study-specific procedures.
8) Adequate liver and renal functions as assessed by the following laboratory requirements to be conducted within 7 days before the first dose of study drug: Total bilirubin </=1.5 times the upper limit of normal (ULN) (<3 times the ULN for patients with Gilbert-Meulengracht syndrome or for patients with hyperbilirubinemia considered due to leukemic disease) Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) </=2.5 times ULN (</=5 times ULN for patients with leukemia infiltration in the liver) Estimated glomerular filtration rate (eGFR) >/=40 mL/min per 1.73 m2 according to the Modification of Diet in Renal Disease Study Group (MDRD) formula.
9) Adequate blood clotting function as assessed by the following laboratory requirements to be conducted within 7 days before the first dose of study drug International normalized ratio (INR) </=1.5 Activated partial thromboplastin time (aPTT) </= 1.5 times ULN
1) Known hypersensitivity to the study drug or excipients of the
preparation or any agent given in association with this study
2) Extramedullary disease only
3) History of cardiac disease, including congestive heart failure of New York Heart Association (NYHA) class >II,(20) 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 multigated acquisition (MUGA) scan]
4) Left ventricular ejection fraction (LVEF) <40% as measured by echocardiography or MUGA scan performed during general screening
5) Uncontrolled hypertension defined as systolic blood pressure >/= 160 mmHg or diastolic blood pressure >/=100 mmHg, despite medical management
6) Known history of human immunodeficiency virus infection
7) Known chronic or active hepatitis B or C, requiring antiviral therapy
8) Patients who have an active and uncontrolled infection requiring intravenous antibiotics, antivirals or antifungals
9) Clinical symptoms suggesting active central nervous system (CNS) leukemia or known CNS leukemia
10) Uncontrolled seizure disorder
11) History of organ allograft with the exception of allogenic bone marrow transplant or stem cell rescue provided that it occurred 3 months prior to the first dose of study drug and immunosuppressive therapy was completed prior to the first dose of study drug.
12) Active graft-versus-host disease of Glucksberg Grade >/=II(22) or requiring systemic immunosuppressive therapy
13) 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) and in-situ prostate carcinoma if Gleason score </=6 and prostate-specific antigen <10 ng/mL. Any cancer that was curatively treated at least 3 years before entry into this study
14) Unresolved chronic toxicity of previous treatment of Grade >2, except for alopecia
15) Patients on dialysis
16) Prior treatment with any therapy targeting mIDH1
17) Previous assignment to treatment during this study
18) Non-palliative radiation therapy planned to occur after the start of study treatment
19) Less than 2 weeks or 5 half-lives (whichever is longer) elapsed from the last dose of prior cytotoxic chemotherapy, biologic agents such as bortezomib, thalidomide, lenalidomide, or investigational drug treatment and initiation of BAY 1436032 treatment except the following: Medications typically used to treat AML, such as low-dose cytarabine, decitabine, and azacitidine may be given up to 1 week before the first dose of BAY 1436032 Glucocorticoids may be administered up to 1 day before the first dose of BAY 1436032. Hydroxyurea may be administered prior to and during BAY 1436032 treatment.At least 6 weeks must have elapsed between prior therapy with nitrosoureas, mitomycin C, and liposomal doxorubicin. Intrathecal therapy consisting of liposomal cytarabine or triple therapy with methotrexate (up to 15 mg), cytarabine (up to 40 mg), and corticosteroids (up to 4 mg dexamethasone) may be administered up to 2 weeks or 1 week before the first dose of BAY 1436032, respectively.
20) Major surgery, significant trauma, wide-field radiotherapy, or therapy with monoclonal antibodies within 4 weeks before the first dose of study drug
21) Use of biologic response modifiers, such as granulocyte colony-stimulating factor (G-CSF), within 3 weeks before the first dose of study drug. G-CSF and other hematopoietic growth factors may be used in the management of acute toxicity such as febrile neutropenia when clinically indicated or at the discretion of the investigator; however they may not be substituted for a required dose reduction. Patients taking chronic erythropoietin consistent with institutional guidelines can be included.
22) Previous (within 2 weeks) or concomitant participation in another clinical study with investigational medicinal products. Toxic effects of previous investigational drug treatment have to recover to Grade </= 2.
23) Substance abuse, medical, psychological, or social conditions that in the opinion of the investigator may interfere with the patient’s participation in the study or evaluation of the study results.
24) Refusal to stop breastfeeding. Breastfeeding must be discontinued before the start of treatment, during treatment, and for at least 3 months after the end of treatment with BAY 1436032.
25) Strong CYP2C8 inhibitors (e.g. gemfibrozil) and inducers (e.g. rifampin) are prohibited from 2 weeks before the first dose of study drug until discontinuation from the study.
26) CYP2C8 substrates (e.g. repaglinide, rosiglitazone, and paclitaxel) are prohibited from 2 weeks before the first dose of study drug until discontinuation from the study.
Information and next steps
Other diseases of blood and blood-forming organs
Phase I/Phase II
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