Clinical Trials /

Phase I Study of Oral BAY 1217389 in Combination With Intravenous Paclitaxel

NCT02366949

Description:

Determine the safety, tolerability, maximum tolerated dose (MTD), and recommended Phase 2 dose (RP2D) of oral BAY 1217389 given in combination with intravenous (IV) paclitaxel using an intermittent dosing schedule (2 days on / 5 days off) in subjects with advanced malignancies.

Related Conditions:
  • Breast Carcinoma
  • Malignant Solid Tumor
Recruiting Status:

Completed

Phase:

Phase 1

Trial Eligibility

Document

Phase I Study of Oral BAY 1217389 in Combination With Intravenous <span class="go-doc-concept go-doc-intervention">Paclitaxel</span>

Title

  • Brief Title: Phase I Study of Oral BAY 1217389 in Combination With Intravenous Paclitaxel
  • Official Title: An Open-label Randomized Two-arm Phase I Dose-escalation Study to Characterize the Safety, Tolerability, Pharmacokinetics, and Maximum Tolerated Dose of Oral BAY 1217389 in Combination With Weekly Intravenous Paclitaxel Given in an Intermittent Dosing Schedule in Subjects With Advanced Malignancies
  • Clinical Trial IDs

    NCT ID: NCT02366949

    ORG ID: 17350

    NCI ID: 2014-004821-41

    Trial Conditions

    Medical Oncology

    Trial Interventions

    Drug Synonyms Arms
    BAY 1217389 Arm 1, Arm 2
    Paclitaxel Arm 1, Arm 2

    Trial Purpose

    Determine the safety, tolerability, maximum tolerated dose (MTD), and recommended Phase 2
    dose (RP2D) of oral BAY 1217389 given in combination with intravenous (IV) paclitaxel using
    an intermittent dosing schedule (2 days on / 5 days off) in subjects with advanced
    malignancies.

    Detailed Description

    BAY 1217389 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 BAY 1217389 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 BAY 1217389 and IV paclitaxel.

    The exploratory objectives of this study are to:

    - Determine any preliminary clinical efficacy of oral BAY 1217389 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 BAY 1217389 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 BAY 1217389 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 BAY 1217389 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

    Trial Arms

    Name Type Description Interventions
    Arm 1 Experimental Experimental Treatment (combination of BAY 1217389 with paclitaxel in an intermittent dosing schedule) Expansion Cohort - Maximum tolerated dose of BAY 1217389 and Paclitaxel BAY 1217389, Paclitaxel
    Arm 2 Placebo Comparator Standard Treatment (Single-agent Paclitaxel ) BAY 1217389, Paclitaxel

    Eligibility Criteria

    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.

    Minimum Eligible Age: 18 Years

    Maximum Eligible Age: N/A

    Eligible Gender: Both

    Primary Outcome Measures

    Maximum tolerated dose (MTD)

    Number of subjects with adverse events and serious adverse events as a measure of safety and tolerability

    Plasma concentration of Paclitaxel characterized by Cmax

    Plasma concentration of BAY 1217389 characterized by Cmax

    Secondary Outcome Measures

    Trial Keywords

    Phase 1

    Solid tumors

    Breast cancer

    Paclitaxel

    MPS-1 inhibitor

    Oncology