Phase I Dose Escalation of Oral BAY1161909 in Combination With Intravenous Paclitaxel

NCT ID: NCT02138812

Last Updated: 2018-10-12

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE1
• Total Enrollment: 69 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2014-05-09
• Study Completion Date: 2017-10-02

Brief Summary

Determine the safety, tolerability, maximum tolerated dose (MTD), and recommended Phase II dose (RP2D) of BAY1161909 in combination with paclitaxel in subjects with advanced malignancies.

Detailed Description

BAY1161909 is a potent and highly selective inhibitor of monopolar spindle 1 (Mps1) kinase activity. Human Mps1 is a serine threonine kinase which functions as a core component of the spindle assembly checkpoint (SAC), a key surveillance mechanism that monitors the attachment of spindle microtubules to the kinetochores of the chromosomes during pro-metaphase and halts the transitions to anaphase until all chromosomes are bi-oriented, fully attached, and correctly tensed at the metaphase plate. Mps1 is expressed in the mitosis phase of the cell cycle in proliferating cells. Overexpression of Mps1 has been observed in several cancer cell lines and tumor types including lung and breast cancers.

Established anti-mitotic drugs such as vinca alkaloids, taxanes, or epothilones activate the SAC either by destabilizing or stabilizing spindle microtubules resulting in mitotic arrest. Prolonged arrest in mitosis forces a cell either into a mitotic exit without cytokinesis or into a mitotic catastrophe leading to cell death. In contrast, Mps1 inhibitors inactivate the SAC and accelerate progression of cells through mitosis eventually resulting in severe chromosomal missegregation, mitotic catastrophe, and cell death. Consequently, Mps1 inhibition leads to failure of cells to arrest in mitosis in response to anti-mitotic drugs. Thus, the combination of microtubule-interfering agents and Mps1 inhibition strongly increases chromosomal segregation errors and cell death and therefore, constitutes an efficient strategy for selectively eliminating tumor cells.

This study will attempt to answer the following questions:

• What are the side effects of BAY1161909 when given at different dose levels and schedules with paclitaxel?
• What dose level and schedule of BAY1161909 should be tested in future clinical research studies?
• How much BAY1161909 and paclitaxel is in the blood at specific times after administration?
• Does the treatment with BAY1161909 with paclitaxel show any effect on the tumor growth?
• Are there specific biomarkers that might be able to explain why some patients respond to treatment and others do not.

Conditions

Medical Oncology

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

BAY1161909 + Paclitaxel

Participants received oral doses of BAY1161909 starting from 0.75 mg twice daily, from C1D1 onwards in a 2 days on/5 days off dosing schedule as single agent treatment in Cycle 1 (14 days), and from C2D8 onwards in a 2 days on/5 days off dosing schedule in combination with weekly intravenous paclitaxel on D1, D8, and D15 of the 28-day cycles. For single-dose Pharmacokinetic (PK) cohort: in Cycle 1, participants received a single oral dose of 6 mg BAY1161909 on C1D1 with no BAY1161909 dosing for the remainder of Cycle 1.

Group Type: EXPERIMENTAL

BAY1161909

Intervention Type: DRUG

Given orally, with a starting dose of 0.75 mg twice daily from C1D1 onwards in a 2 days on/5 days off dosing schedule as single agent treatment in Cycle 1 (14 days), and from C2D8 onwards in a 2 days on/5 days off dosing schedule in 28-day cycles. For single-dose PK cohort: a single oral dose on C1D1

Paclitaxel

Intervention Type: DRUG

75 mg/m\^2 (initial dose escalation) or 90 mg/m\^2 (second dose escalation), weekly intravenously (IV) infusion on D1, D8, and D15 of the 28-day cycles from C2D1

Interventions

BAY1161909

Given orally, with a starting dose of 0.75 mg twice daily from C1D1 onwards in a 2 days on/5 days off dosing schedule as single agent treatment in Cycle 1 (14 days), and from C2D8 onwards in a 2 days on/5 days off dosing schedule in 28-day cycles. For single-dose PK cohort: a single oral dose on C1D1

Intervention Type: DRUG

Paclitaxel

75 mg/m\^2 (initial dose escalation) or 90 mg/m\^2 (second dose escalation), weekly intravenously (IV) infusion on D1, D8, and D15 of the 28-day cycles from C2D1

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• Male or female subjects aged =/> 18 years
• Subjects with advanced, histologically or cytologically confirmed advanced malignancies (solid tumors), refractory to any standard therapy, have no standard therapy available, or subjects actively refused any standard treatment and / or if, in the judgment of the investigator, experimental treatment is clinically and ethically acceptable.
• For the expansion cohort: women with histologically or cytologically confirmed triple negative breast cancer (TNBC)
• Subjects must have evaluable or measurable disease according to Response Evaluation Criteria In Solid Tumors (RECIST) 1.1
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1
• Life expectancy of at least 12 weeks
• Adequate bone marrow, liver, and renal functions

Exclusion Criteria

• Known hypersensitivity to the study drugs or excipients of the preparations or any agent given in association with this study
• Evidence of peripheral neuropathy of Grade > 2
• History of cardiac disease: congestive heart failure New York Heart Association (NYHA) class > II, unstable angina (anginal symptoms at rest), new-onset angina (within the past 3 months before study entry), myocardial infarction within the past 3 months before study entry, or cardiac arrhythmias requiring anti-arrhythmic therapy (beta blockers, calcium channel blockers, and digoxin are permitted)
• Prior treatment with more than 3 lines of cytostatic therapies for metastatic disease unless specifically agreed between investigator and sponsor. Subjects with a history of any prior Grade =/> 3 toxicity associated with taxane treatment will be excluded.
• Uncontrolled hypertension defined as systolic blood pressure >150 mmHg or diastolic blood pressure >90 mmHg, despite optimal medical management
• Moderate or severe hepatic impairment, i.e. Child-Pugh class B or C
• History of human immunodeficiency virus (HIV) infection.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Bayer

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Bayer Study Director

Role: STUDY_DIRECTOR

Bayer

Locations

Santa Monica, California, United States

New Haven, Connecticut, United States

Boston, Massachusetts, United States

Detroit, Michigan, United States

Nashville, Tennessee, United States

San Antonio, Texas, United States

Countries

United States

Related Links

https://clinicaltrials.bayer.com/

Click here to find results for studies related to Bayer products.

Other Identifiers

16804

Identifier Type: -

Identifier Source: org_study_id