Clinical trial NCT02138812: Phase I Dose Escalation of Oral BAY1161909 in Combination With Intravenous Paclitaxel
Official title: An Open-label Phase I Dose-escalation Study to Characterize the Safety, Tolerability, Pharmacokinetics, and Maximum Tolerated Dose of Oral BAY1161909 in Combination With Weekly Intravenous Paclitaxel Given in an Intermittent Dosing Schedule in Subjects With Advanced Malignancies
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Medical Oncology
Keywords: Phase 1
Solid tumors
Breast cancer
Paclitaxel
Mps-1 inhibitor
Taxanes
Lead sponsor: Bayer
Sponsor class: INDUSTRY
First posted: 2014-05-15
Enrollment: 69
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Maximum tolerated dose (MTD)
timeFrame: Up to 2 years
measure: Number of subjects with adverse events and serious adverse events as a measure of safety and tolerability.
timeFrame: Up to 2 years
measure: Plasma concentration of Paclitaxel characterized by Cmax
timeFrame: C2D1 (without oral BAY1161909): pre-dose and 0.5,1,2,3,4,6,8,12,24 (C2D2) & 48hrs (C2D3) after the start of IV infusion on C2D1. C2D8 (with oral BAY1161909): pre-dose and 0.5,1,2,3,4,6, 8,12,24 (C2D9) & 48hrs (C2D10) after the start of infusion on C2D8.
measure: Plasma concentration of BAY1161909 characterized by Cmax
timeFrame: C1D1: pre-dose & 0.5,1,2,3,4,6,8,12 hrs after the MD on C1D1 [12-hour sample to be collected before administration of the ED]. C1D2: pre-dose & 0.5,1,2,3,4,6,8,12, 24 (C1D3), 48 (C1D4), 72 (C1D5) & 144 hrs (C1D8 pre-dose) after the MD on C1D2.
measure: Plasma concentration of BAY1161909 characterized by Cmax
timeFrame: C2D8 (single-dose PK with IV paclitaxel): pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12 hours after the morning dose on C2D8 [12-hour sample to be collected before administration of the evening dose].
measure: Plasma concentration of BAY1161909 characterized by Cmax
timeFrame: C1D1 (single-dose PK cohort only): pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 24 (C1D2), 48 (C1D3), 72 (C1D4), 96 (C1D5), 168 (C1D8), 240 (C1D11) and 336 hours (before C2D1 IV paclitaxel administration) after the morning dose on C1D1.
measure: Plasma concentration of BAY1161909 characterized by Cmax
timeFrame: C1D-7 (relative bioavailability assessment subjects): pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 24 (C1D-6), and 72 (C1D-4) hours after the single dose on C1D-7.
Secondary outcomes:
Other outcomes:
measure: Tumor response evaluation following RECIST 1.1 criteria
timeFrame: Up to 2 years
Locations:
city: Santa Monica
country: United States
state: California
city: New Haven
country: United States
state: Connecticut
city: Boston
country: United States
state: Massachusetts
city: Detroit
country: United States
state: Michigan
city: Nashville
country: United States
state: Tennessee
city: San Antonio
country: United States
state: Texas
Study officials:
affiliation: Bayer
name: Bayer Study Director
role: STUDY_DIRECTOR
References: