Phase I Dose Escalation Study With an Allosteric AKT 1/2 Inhibitor in Patients

Study Overview
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Brief Summary
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This is the first study where BAY1125976 is given to humans. Patients (all comers) will receive the study drug treatment in a dose-escalation scheme (no placebo group) to determine the safety, tolerability and maximum tolerated dose (MTD) of BAY1125976. The relative bioavailability of liquid service formulation and tablets will be determined. After the MTD is defined breast cancer patients with and without AKT1 mutation will be treated. The study will also assess the pharmacokinetics, biomarker status, pharmacodynamic parameters and tumor response of BAY1125976. BAY1125976 will be given daily as single oral application. Treatment will be stopped if the tumor continues to grow, if side effects, which the patient cannot tolerate, occur or if the patient decides to exit treatment.

Official Title
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A Phase I, Multi-center, Non-randomized, Open-label, Dose Escalation Design Study to Characterize Safety, Tolerability, Pharmacokinetics and Maximum Tolerated Dose of BAY 1125976 in Subjects With Advanced Solid Tumors

Conditions
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Neoplasms

Intervention / Treatment
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* Drug: BAY1125976
* Drug: BAY1125976
* Drug: BAY1125976


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: For dose escalation cohorts: Subjects with advanced, histologically or cytologically confirmed solid tumors are eligible. Subjects' tumors (all comers) must be refractory to standard treatment with no standard therapy available, or subjects actively refuse any treatment, which would be regarded standard. In addition, the investigator must judge the experimental treatment as clinically and ethically acceptable For expansion cohort only: Subjects with histologically or cytologically proven metastatic breast cancer (with and without AKT1 E17K (G49A) mutation) or subjects with known AKT1 E17K (G49A) mutation in any other advanced solid tumor with at least one line of chemotherapy in the metastatic setting and not amenable to surgery with curative intent Subjects must have measurable disease (Response evaluation criteria in solid tumors (RECIST 1.1) Eastern Cooperative Oncology Group (ECOG) Performance Status 0 - 2 Bone marrow, liver and renal functions as assessed by adequate laboratory methods to be conducted within 7 days prior to starting study treatment Subjects must provide tumor biopsies before treatment Recovery to CTCAE (Common Terminology Criteria for Adverse Events Version 4.03) Grade 0 or Grade 1 or recovery to baseline preceding the prior treatment of any previous drug / procedure-related toxicity (except alopecia, anemia, and hypothyroidism) Exclusion Criteria: History of cardiac disease including congestive heart failure > New York Heart Association (NYHA) Class II Subjects with type 1 or type 2 diabetes mellitus Subjects with fasting glucose >125 mg/dL in 2 independent measurements or glycated hemoglobin (HbA1c) ≥ 7% Moderate and severe hepatic impairment, i.e. Child-Pugh B or C Active infections of CTCAE (Common Terminology Criteria for Adverse Events Version 4.03) Grade >2 or infections of CTCAE Grade 2 not responding to therapy Symptomatic metastatic brain or meningeal tumors unless the patient is > 3 months from definitive therapy, has a negative imaging study within 4 weeks of study entry and is clinically stable with respect to the tumor at the time of study entry. Subjects undergoing renal dialysis Previous or concurrent cancer that is distinct in primary site or histology from the cancer being evaluated in this study except cervical carcinoma in situ, treated basal cell carcinoma, superficial bladder tumors (Ta, Tis & T1) or any cancer curatively treated > 3 years prior to study entry Autologous bone marrow transplant or stem cell rescue within 4 months of study entry Treatment with oral steroids (dose ≥ 10 mg/day of methylprednisolone or equivalent) Clinically relevant findings in the ECG such as a second- or third-degree AV block, prolongation of the QRS complex over 120 msec or of the QTcF-interval over 450 msec Acute toxic effects of previous anticancer chemotherapy or immunotherapy have to be normalized to CTCAE Grade equal or lower than 1 (excluding alopecia)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BAY1125976 [once daily, dose-esc.]<br>Oral administration once daily. Starting dose is 10 mg and will be escalated depending on any dose-limiting toxicities | Drug: BAY1125976<br>* Oral administration once daily. Starting dose is 10 mg and will be escalated depending on any dose-limiting toxicities<br>|
| Experimental: BAY1125976 [twice daily, dose-esc.]<br>Oral administration twice daily. Starting dose is 40mg twice daily and will be escalated depending on any dose-limiting toxicities | Drug: BAY1125976<br>* Oral administration twice daily. Starting dose is 40mg twice daily and will be escalated depending on any dose-limiting toxicities<br>|
| Experimental: BAY1125976 [MTD]<br>Oral administration of the defined MTD which shows optimal safety, PK profile, PD target inhibition and preliminary efficacy (once daily or twice daily) in different patient groups | Drug: BAY1125976<br>* Oral administration of the defined MTD which shows optimal safety, PK profile, PD target inhibition and preliminary efficacy (once daily or twice daily) in different patient groups<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with adverse events as a measure of safety and tolerability |  | up to 2 years | 
| Maximum tolerated dose (MTD) of BAY1125976 |  | up to 2 years | 
| Area under the plasma concentration vs time curve from zero to infinity after single (first) dose |  | at pre-dose and 0.5, 1, 2, 4, 6, 8, 12 and 24 hours post-dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Food effect assessment | The effect of a high-fat, high-calorie meal on the pharmacokinetic parameters of BAY1125976 will be determined in 6 - 9 subjects in the MTD dose level or a lower dose level receiving the tablet for the cohort of the dose escalation part. | up to 2 years | 
| Tumor response will be evaluated based on Response Evaluation Criteria in Solid Tumors (RECIST) definitions |  | up to 2 years |