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

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 onemeasurable target lesion is required in expansion cohort patients

• Patients with advanced cancer who are refractory to, have demonstratedintolerance to, or have refused access to, available standard therapies

• Glioma patients must have completed chemoradiotherapy at least 12 weeks priorto screening and their baseline scan

• Patient must be able to provide a formalin-fixed and paraffin-embedded (FFPE) tumortissue specimen prior to treatment. The specimen may have been taken at any timeduring the course of the disease and may be from the primary tumor or from ametastasis

• Patient must be able to take oral medication and comply with protocol procedures andscheduled 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 thefirst dose of study drug in women of childbearing potential. Negative results mustbe available prior to study drug administration. Pregnancy tests will be repeatedregularly during treatment

• Sexually active women and men of reproductive potential must agree to use highlyeffective contraception. This applies for the period between signing of the informedconsent and 3 months after the last administration of study drug. These proceduresshould be documented in source documents. The investigator or a designated associateis 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 ofcontraception

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

• Hysterectomy, or vasectomy of the partner (provided that partner is the solesexual partner of the woman of childbearing potential trial participant andthat the vasectomized partner has received medical assessment of the surgicalsuccess) In addition, the use of condoms for patients or their partners isrequired

• Ability to understand and the willingness to sign a written informed consent. Asigned informed consent, including consent for biomarker analyses, must be obtainedprior to any study-specific procedures

• Adequate blood clotting as defined by international normalized ratio (INR) andactivated partial thromboplastin time (aPTT) ≤ 1.5 times ULN (patients onanticoagulation with an agent such as warfarin or heparin or rivoraxaban will beallowed to participate provided that no prior evidence of underlying abnormality inthese parameters exists). For patients on warfarin, close monitoring of at leastweekly evaluations will be performed until INR is stable based on a measurement atpre-dose, as defined by the local standard of care

• Adequate bone marrow, liver, and renal functions as assessed by the followinglaboratory requirements to be conducted within 7 days prior to the first dose ofstudy 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 intrahepaticcholangiocarcinoma (IHCC) patients only, total bilirubin ≤ 2.5 times ULN isacceptable

• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 timesULN (≤ 5 times ULN for patients with impaired liver function due primary tumoror metastatic disease)

• Estimated glomerular filtration rate (eGFR) ≥ 40 mL/min per 1.73 m^2 accordingto 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 anyagent given in association with this study

• History of cardiac disease, including congestive heart failure of New York HeartAssociation (NYHA) class >II, unstable angina (anginal symptoms at rest) ornew-onset angina (within 6 months prior to study entry), myocardial infarctionwithin 6 months prior to study entry, or cardiac arrhythmias requiringanti-arrhythmic therapy except for beta-blockers and digoxin; evidence foruncontrolled coronary artery disease (e.g. angina pectoris, myocardial infarctionwithin 6 months prior to study entry, major regional wall motion abnormalities uponbaseline echocardiography or multiple-gated acquisition [MUGA] scan). Patients witha pacemaker are also excluded

• Left ventricular ejection fraction (LVEF) < 40% as measured by echocardiography orMUGA scan performed at Screening

• Uncontrolled hypertension defined as systolic blood pressure ≥ 160 mmHg or diastolicblood pressure ≥ 100 mmHg, despite medical management

• Patients who have an active clinically significant infection of the National CancerInstitute Common Terminology Criteria for Adverse Events (CTCAE) grade ≥ 2

• Previous or coexisting cancer(s) distinct in primary site or histology from thecancer evaluated in this study EXCEPT:

• Appropriately treated cervical cancer in-situ, non-melanoma skin cancers, orsuperficial bladder tumors (Ta and Tis)

• Any cancer that was curatively treated at least 3 years before entry into thisstudy

• Unresolved specific chronic toxicity of previous treatment of grade > 1 except foralopecia or hemoglobin ≤9.0 g/dL (or ≤5.6 mmol/L)

• Major surgery, significant trauma, wide-field radiotherapy, or therapy withmonoclonal antibodies within 4 weeks before the first dose of study drug

• Treatment with investigational or approved anti-cancer drugs within 4 weeks beforethe start of BAY1436032 treatment and during the study (glioma patients must havecompleted chemoradiotherapy at least 12 weeks prior to screening and their baselinescan; see inclusion criteria #2)

• Pregnant women. Women of reproductive potential must have a negative serum or urinepregnancy test performed within 7 day

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