Phase I Dose Escalation of Oral BAY1161909 in Combination With Intravenous Paclitaxel
|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|
- 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 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)].
- 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 (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). ] [ 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 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. ] [ Designated as safety issue: Yes ]C1D1 (single-dose PK without IV paclitaxel), C1D2 (multiple-dose PK without IV paclitaxel; no ED on C1D2, MD=Morning Dose ED= Evening Dose
- 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]. ] [ Designated as safety issue: Yes ]
- 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. ] [ Designated as safety issue: Yes ]
- 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. ] [ Designated as safety issue: Yes ]
- Tumor response evaluation following RECIST 1.1 criteria [ Time Frame: Up to 2 years ] [ Designated as safety issue: No ]
|Study Start Date:||May 2014|
|Estimated Study Completion Date:||February 2017|
|Estimated Primary Completion Date:||September 2016 (Final data collection date for primary outcome measure)|
Experimental: BAY1161909 + Paclitaxel
- Investigating the combination of BAY1161909 with Paclitaxel (75 mg) and (90 mg) in an intermittent dosing schedule - Expansion Cohort
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
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.
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.
Please refer to this study by its ClinicalTrials.gov identifier: NCT02138812
|Contact: Bayer Clinical Trials Contactemail@example.com|
|Contact: For more information for participation into this trial 646-776-7532 (local)||844-229-3710 (Toll free)||Bayer@emergingmed.com|
|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|
|Study Director:||Bayer Study Director||Bayer|