Determine the safety, tolerability, maximum tolerated dose (MTD), and recommended Phase 2 dose (RP2D) of oral BAY1217389 given in combination with intravenous (IV) paclitaxel using an intermittent dosing schedule (2 days on / 5 days off) in subjects with advanced malignancies.
Completed
Phase 1
| Drug | Synonyms | Arms |
|---|---|---|
| BAY1217389 | Arm 1 | |
| Paclitaxel | Arm 1 |
BAY1217389 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.
MPS1 inhibition in combination with microtubule-interfering agents is expected to improve
therapeutic efficacy of anti-mitotic drugs and to overcome paclitaxel resistance.
The primary objectives of this study are to:
- Determine the safety, tolerability, maximum tolerated dose (MTD), and recommended Phase
2 dose (RP2D) of oral BAY1217389 given in combination with intravenous (IV) paclitaxel
using an intermittent dosing schedule (2 days on / 5 days off) in subjects with advanced
malignancies.
- Characterize the pharmacokinetics (PK) of oral BAY1217389 and IV paclitaxel.
The exploratory objectives of this study are to:
- Determine any preliminary clinical efficacy of oral BAY1217389 given in combination with
IV paclitaxel compared to paclitaxel given alone.
- Determine pharmacodynamic (PD) target modulation effects (decrease in phosphorylated
kinetochore-associated protein pKNL1 and potentially other biomarkers like activation of
the p53 system) of oral BAY1217389 in mandatory paired fresh tumor biopsies (or in
mandatory paired fresh skin punch biopsies depending on the status of the subject and
the accessibility of the tumor) taken on Day 2 of Cycle 1 (C1D2) and on C1D3.
- Evaluate the effect of oral BAY1217389 on the activation of p53 in blood samples as PD
biomarker (blood samples will be taken as a mandatory procedure to monitor PD effects on
C1D 4, C1D 3, and C1D 2).
- Evaluate the effect of BAY1217389 on levels of tumor-derived free circulating
deoxyribonucleic acid (DNA) in blood samples taken before the first dose of study
treatment and on C1D3, C1D8, and C1D15
| Name | Type | Description | Interventions |
|---|---|---|---|
| Arm 1 | Experimental | Experimental Treatment (combination of BAY1217389 with paclitaxel in an intermittent dosing schedule) Expansion Cohort - Maximum tolerated dose of BAY1217389 and Paclitaxel |
|
| Arm 2 | Placebo Comparator | Standard Treatment (Single-agent Paclitaxel ) |
|
Inclusion Criteria:
- Male or female subjects aged >/= 18 years.
- Study population:
- For the dose-escalation cohorts: Subjects with histologically or cytologically
confirmed advanced malignancies (solid tumors), refractory to any standard
therapy, have no standard therapy available
- For the expansion cohort: Subjects with advanced, histologically or cytologically
confirmed triple-negative breast cancer (TNBC), 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 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).
- 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), hepatitis B or hepatitis C infection.
| Maximum Eligible Age: | N/A |
| Minimum Eligible Age: | 18 Years |
| Eligible Gender: | All |
| Healthy Volunteers: | No |
| Measure: | Maximum tolerated dose (MTD) |
| Time Frame: | Up to 28 days (Cycle 1) |
| Safety Issue: | |
| Description: | The MTD is defined as the highest dose that can be given such that the dose-limiting toxicity (DLT) rate of the combination treatment is not more than 10% higher than the cumulative DLT rate of the standard single-agent treatment across all previous and the current cohort. |
| Phase: | Phase 1 |
| Primary Purpose: | Interventional |
| Overall Status: | Completed |
| Lead Sponsor: | Bayer |
April 7, 2020
