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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT02138812
Recruitment Status : Completed
First Posted : May 15, 2014
Last Update Posted : January 3, 2018
Information provided by (Responsible Party):

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.

Condition or disease Intervention/treatment Phase
Medical Oncology Drug: BAY1161909 Drug: Paclitaxel Phase 1

Detailed Description:

BAY 1161909 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 BAY 1161909 when given at different dose levels and schedules with paclitaxel?
  • What dose level and schedule of BAY 1161909 should be tested in future clinical research studies?
  • How much BAY 1161909 and paclitaxel is in the blood at specific times after administration?
  • Does the treatment with BAY 1161909 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.

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 69 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : May 9, 2014
Actual Primary Completion Date : April 28, 2017
Actual Study Completion Date : September 11, 2017

Resource links provided by the National Library of Medicine

Drug Information available for: Paclitaxel
U.S. FDA Resources

Arm Intervention/treatment
Experimental: BAY1161909 + Paclitaxel
- Investigating the combination of BAY1161909 with Paclitaxel (75 mg) and (90 mg) in an intermittent dosing schedule - Expansion Cohort
Drug: BAY1161909

Given orally, with a starting dose of 0.75 mg twice daily, on 14 day cycle - D1, D2, D8, D9 and 28 day cycle - D8, D9 D15 and D16 of a 28 day cycle.

FOR PK COHORT ONLY:Given orally at morning dose only on C1D1

Drug: Paclitaxel
  • Paclitaxel will be given once per week (intravenous) IV at 75 mg/m2 on D1, D8, and D15 of a 28 day cycle
  • Paclitaxel will be given once per week (intravenous) IV at 90 mg/m2 on D1, D8, and D15 of a 28 day cycle
Drug: Paclitaxel

After MTD(75) + BAY1161909 is established:

BAY1161909 will then be refined for the combination with 90 mg/m2 IV paclitaxel MTD(90) following the same dosing schedules as noted in Arm 1 for both drugs.

Primary Outcome Measures :
  1. Maximum tolerated dose(MTD) [ Time Frame: Up to 2 years ]
    MTD is defined as the highest dose of oral BAY1161909 (administered in combination with or without IV paclitaxel) that can be given such that not more than 30% of the subjects experience a dose-limiting toxicity (DLT) during Cycles 1 and 2. The safety profile of oral BAY1161909 will first be determined in combination with 75 mg/m2 IV paclitaxel [MTD (75)]. Starting in >Cohort 7 (12 mg BID BAY1161909) the MTD of oral BAY 1161909 will then be refined for the combination with 90 mg/m2 IV paclitaxel [MTD (90)].

  2. Number of subjects with adverse events and serious adverse events as a measure of safety and tolerability. [ Time Frame: Up to 2 years ]
  3. Plasma concentration of Paclitaxel characterized by Cmax [ Time Frame: C2D1 (without oral BAY 1161909):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 BAY 1161909): pre-dose and 0.5,1,2,3,4,6, 8,12,24 (C2D9) & 48hrs (C2D10) after the start of infusion on C2D8). ]
  4. Plasma concentration of BAY1161909 characterized by Cmax [ Time Frame: 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. ]
    C1D1 (single-dose PK without IV paclitaxel), C1D2 (multiple-dose PK without IV paclitaxel; no ED on C1D2, MD=Morning Dose ED= Evening Dose

  5. Plasma concentration of BAY1161909 characterized by Cmax [ Time Frame: 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]. ]
  6. Plasma concentration of BAY1161909 characterized by Cmax [ Time Frame: 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. ]
  7. Plasma concentration of BAY1161909 characterized by Cmax [ Time Frame: 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. ]

Other Outcome Measures:
  1. Tumor response evaluation following RECIST 1.1 criteria [ Time Frame: Up to 2 years ]

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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 TNBC (triple negative breast cancer)
  • 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT02138812

United States, California
Santa Monica, California, United States, 90403
United States, Connecticut
New Haven, Connecticut, United States, 06520
United States, Massachusetts
Boston, Massachusetts, United States, 02215
United States, Michigan
Detroit, Michigan, United States, 48201
United States, Tennessee
Nashville, Tennessee, United States, 37203
United States, Texas
San Antonio, Texas, United States, 78229
Sponsors and Collaborators
Study Director: Bayer Study Director Bayer

Additional Information:
Responsible Party: Bayer Identifier: NCT02138812     History of Changes
Other Study ID Numbers: 16804
First Posted: May 15, 2014    Key Record Dates
Last Update Posted: January 3, 2018
Last Verified: January 2018

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Bayer:
Phase 1
Solid tumors
Breast cancer
MPS-1 inhibitor

Additional relevant MeSH terms:
Albumin-Bound Paclitaxel
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action