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

This study is currently recruiting participants. (see Contacts and Locations)
Verified September 2014 by Bayer
Sponsor:
Information provided by (Responsible Party):
Bayer
ClinicalTrials.gov Identifier:
NCT02138812
First received: May 8, 2014
Last updated: September 3, 2014
Last verified: September 2014
  Purpose

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 Intervention Phase
Medical Oncology
Drug: BAY1161909
Drug: Paclitaxel
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: 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

Resource links provided by NLM:


Further study details as provided by Bayer:

Primary Outcome Measures:
  • Maximum tolerated dose(MTD) [ Time Frame: Up to 2 years ] [ Designated as safety issue: Yes ]
    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 MTD of oral BAY1161909 will first be determined in combination with 75 mg/m2 IV paclitaxel [MTD (75)].The MTD of oral BAY 1161909 will then be refined for the combination with 90 mg/m2 IV paclitaxel [MTD (90)]

  • Number of subjects with adverse events and serious adverse events as a measure of safety and tolerability [ Time Frame: Up to 2 years ] [ Designated as safety issue: Yes ]
  • Plasma concentration of Paclitaxel characterized by Cmax [ Time Frame: C2D1 (Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 24 (C2D2), and 48 hours (C2D3) after the start of infusion on C2D1) ] [ Designated as safety issue: Yes ]
  • Plasma concentration of BAY1161909 characterized by Cmax [ Time Frame: C1D1(Pre-dose & 0.5, 1, 2, 3, 4, 6, 8, 12 hours after morning dose on C1D1(12-hour sample to be collected before administration of evening dose)& C1D2(Pre-dose & 0.5, 1, 2, 3, 4, 6, 8, 12, 24 (C1D3),48 (C1D4),& 72 hours (C1D5) after morning dose on C1D2 ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Exploratory Outcomes -Tumor response evaluation following RECIST 1.1 criteria [ Time Frame: Up to 2 years ] [ Designated as safety issue: No ]

Estimated Enrollment: 41
Study Start Date: May 2014
Estimated Study Completion Date: September 2016
Estimated Primary Completion Date: September 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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.
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.


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
  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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 TNBC(triple negative breast cancer), 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
  • 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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02138812

Contacts
Contact: Bayer Clinical Trials Contact clinical-trials-contact@bayerhealthcare.com
Contact: For trial location information (Phone Menu Options '3' or '4') (+)1-888-84 22937

Locations
United States, Connecticut
Not yet recruiting
New Haven, Connecticut, United States, 06520
United States, Massachusetts
Not yet recruiting
Boston, Massachusetts, United States, 02215
United States, Michigan
Not yet recruiting
Detroit, Michigan, United States, 48201
United States, Tennessee
Not yet recruiting
Nashville, Tennessee, United States, 37203
United States, Texas
Recruiting
San Antonio, Texas, United States, 78229
Sponsors and Collaborators
Bayer
Investigators
Study Director: Bayer Study Director Bayer
  More Information

Additional Information:
No publications provided

Responsible Party: Bayer
ClinicalTrials.gov Identifier: NCT02138812     History of Changes
Other Study ID Numbers: 16804
Study First Received: May 8, 2014
Last Updated: September 3, 2014
Health Authority: United States: Food and Drug Administration

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

Additional relevant MeSH terms:
Paclitaxel
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on September 11, 2014