Clinical Trials /

Phase 1b Study of PD-0332991 in Combination With T-DM1(Trastuzumab-DM1)

NCT01976169

Description:

Standard of care: Treatment with Trastuzumab Experimental: 21-Day Cycle of Combination therapy with T-DM1 intravenously on Day 1 and oral PD-0332991 on Days 5-18 Study Design and Methodology: This is a phase 1B inter-patient dose escalation study of PD-0332991 in combination with T-DM1 in patients with recurrent or metastatic HER2-positive breast cancer after prior trastuzumab or other HER2-directed therapies. The subjects will be administered T-DM1 by intravenous infusion at 3.6 mg/kg for 90 minutes on day 1 of each 21 day cycle. Infusion timing may vary from 30-90 minutes depending on how well the subject tolerates the treatment. A standard 3+3 trial design will be used for PD-0332991 dose escalation cohorts.The dosing of PD-0332991 will be divided into 3 cohorts, the subjects will receive PD-0332991 on days 5-18 of each 21 day cycle. Cohort 1 : PD-0332991 - 100 mg daily (oral) Cohort 2 : PD-0332991 - 150 mg daily (oral) Cohort 3 : PD-0332991 - 200 mg daily (oral) The 3+3 design entails that if one patient out of the first three patients has a DLT, up to three additional patients will be entered at that dose level Treatment cycles will continue until disease progression or withdrawal from study.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

<span class="go-doc-concept go-doc-intervention">Phase 1b</span> Study of <span class="go-doc-concept go-doc-intervention">PD-0332991</span> in Combination With <span class="go-doc-concept go-doc-intervention">T-DM1</span>(<span class="go-doc-concept go-doc-intervention">Trastuzumab</span>-DM1)

Title

  • Brief Title: Phase 1b Study of PD-0332991 in Combination With T-DM1(Trastuzumab-DM1)
  • Official Title: Phase 1B Study of PD-0332991 in Combination With T-DM1 in the Treatment of Patients With Advanced HER2 (Human Epidermal Growth Factor Receptor 2)-Positive Breast Cancer
  • Clinical Trial IDs

    NCT ID: NCT01976169

    ORG ID: 042013-042

    Trial Conditions

    Advanced Breast Cancer

    Trial Interventions

    Drug Synonyms Arms
    PD-0332991 and T-DM1 KADCYLA=T-DM1, Palbociclib=PD-0332991 PD-0332991 and T-DM1

    Trial Purpose

    Standard of care:

    Treatment with Trastuzumab

    Experimental:

    21-Day Cycle of Combination therapy with T-DM1 intravenously on Day 1 and oral PD-0332991 on
    Days 5-18

    Study Design and Methodology:

    This is a phase 1B inter-patient dose escalation study of PD-0332991 in combination with
    T-DM1 in patients with recurrent or metastatic HER2-positive breast cancer after prior
    trastuzumab or other HER2-directed therapies.

    The subjects will be administered T-DM1 by intravenous infusion at 3.6 mg/kg for 90 minutes
    on day 1 of each 21 day cycle. Infusion timing may vary from 30-90 minutes depending on how
    well the subject tolerates the treatment.

    A standard 3+3 trial design will be used for PD-0332991 dose escalation cohorts.The dosing
    of PD-0332991 will be divided into 3 cohorts, the subjects will receive PD-0332991 on days
    5-18 of each 21 day cycle.

    Cohort 1 : PD-0332991 - 100 mg daily (oral) Cohort 2 : PD-0332991 - 150 mg daily (oral)
    Cohort 3 : PD-0332991 - 200 mg daily (oral)

    The 3+3 design entails that if one patient out of the first three patients has a DLT, up to
    three additional patients will be entered at that dose level

    Treatment cycles will continue until disease progression or withdrawal from study.

    Detailed Description

    This is a phase 1B inter-patient dose escalation study of PD-0332991 in combination with
    T--DM1 in patients with recurrent or metastatic HER2-positive breast cancer after prior
    trastuzumab or other HER2-directed therapies. A standard 3+3 trial design will be used for
    PD-0332991 dose escalation cohorts. The 3+3 design entails that if one patient out of the
    first three patients has a dose-limiting toxicity (DLT), three additional patients will be
    entered at that dose level. The PD-0332991 dose levels will start at 100 mg po daily; the
    second cohort will receive 150mg po daily; the third cohort 200mg po daily. Patients receive
    PD-0332991 on days 5-18 of each 21 day cycle. T-DM1 will be given intravenously at 3.6 mg/kg
    on day 1 of each 21 day cycle.

    Toxicity will be assessed using the Common Terminology Criteria of Adverse Events (CTCAE)
    version 4.0 grading scale. Dose- limiting toxicity-DLT is defined as any drug-related grade
    3 non-hematologic toxicity or grade 4 hematologic toxicity lasting >28 days after the last
    day of therapy. If two patients experience drug-related DLT, the maximal tolerated dose
    (MTD) for the combination in HER2-positive breast cancer patients has been exceeded,
    enrollment to that dose will stop, and the next lower dose will be designated the MTD. An
    additional 15 patients will be treated at the MTD or the maximal 200mg po daily PD-0332991
    dose in combination with T-DM1 to confirm safety. Treatment cycles will continue until
    disease progression or withdrawal from study.

    Study End-points:

    1. To evaluate and assess Dose Limiting Toxicities (DLT).

    2. To determine the toxicity profile.

    3. To determine the clinical response rate.

    4. To determine the duration of response.

    5. To evaluate baseline HER2 positivity biomarkers by analyzing pretreatment tumor Ki67,
    phospho-RB, cleaved caspase 3, phospho-histone H3, cycline E, MCM7, HER2, p27Kip1.

    6. To evaluate post-treatment Ki67, phospho-RB, cleaved caspase 3, phospho-histone H3,
    cyclin E, MCM7, HER2, p27Kip1, Rb, p16ink4c, CDK4, CDK6 in order to establish biomarker
    response to treatment.

    7. To evaluate pharmacokinetic (PK) parameters for PD-0332991 and T-DM1 including Cmax,
    AUC, t1/2

    Trial Arms

    Name Type Description Interventions
    PD-0332991 and T-DM1 Experimental The subjects will be administered T-DM1 by intravenous infusion at 3.6 mg/kg for 90 minutes on day 1 of each 21 day cycle. Infusion timing may vary from 30-90 minutes depending on how well the subject tolerates the treatment. A standard 3+3 trial design will be used for PD-0332991 dose escalation cohorts.The dosing of PD-0332991 will be divided into 3 cohorts, the subjects will receive PD-0332991 on days 5-18 of each 21 day cycle. Cohort 1 : PD-0332991 - 100 mg daily (oral) Cohort 2 : PD-0332991 - 150 mg daily (oral) Cohort 3 : PD-0332991 - 200 mg daily (oral) PD-0332991 and T-DM1

    Eligibility Criteria

    Inclusion Criteria:

    - 1.All subjects must be informed about the study and have signed a current IRB
    (Institutional Review Board) approved informed consent.

    2. All subjects must have recurrent or metastatic HER2-positive breast cancer.
    diagnosed by biopsy.

    3. All subjects must have previously received trastuzumab or other HER2 targeted
    therapies.

    4.Tumor must be HER2-positive and RB-proficient. RB (Retinoblastoma
    protein)-proficiency is determined by tumor biopsy demonstrating RB normal and
    p16in4a low by immunohistochemistry. RB proficiency means that there is an intact RB
    pathway indicative of responsiveness to PD-0332991. RB staining is scored on an
    absent (no nuclear staining), weak (nuclear staining less than observed in
    endothelial cells and stromal cells surrounding the tumor), positive (nuclear
    staining at or above surrounding tissue) (0, 0.5, 1 respectively). P16ink4a is a
    routine clinical stain that is scored using absent, weak, positive, strong (0,1,2,3
    respectively). Tumors will be scored using [p16]/[RB], where a score of less than 3
    is required for inclusion. RB loss is expected to occur in less than 15% of cases.

    5. Subjects must have a performance status of 2 on the ECOG (Eastern Cooperative
    Oncology Group)Performance scale.

    6. Subjects must have bilirubin <1.5 mg/dl, transaminases <2.5x upper limit of
    normal, albumin >3gm/dl, creatinine <1.3mg/dl, adequate cardiac reserve (EF>50%), ANC
    (Absolute neutrophil count) >1,000/mcL (microliter), and Platelets >100,000/mcL.

    7. Must be willing to be treated at the University of Texas Southwestern Hospital,
    University of Pennsylvania and affiliated clinics.

    8. Subjects must be willing to use an approved form of birth control while on this
    study and for 90 days after completion.

    9. Age > 18 years. 10. Subject must be able to swallow capsules and have no surgical
    or anatomic condition that will preclude the subject from swallowing and absorbing
    oral medications on an ongoing basis.

    Exclusion Criteria:

    - 1. Chemotherapy, radiotherapy or hormonal therapy within 3 weeks ( 6 weeks for
    nitrosoureas, mitomycin C or bevacizumab), or who have not recovered from the adverse
    events to < grade 2 due to previous agents administered more than 4 weeks prior to
    Study Day 1.

    2. Subjects less than 4 weeks post major surgery. 3. Known active CNS metastases or
    carcinomatous meningitis. Subjects with CNS (Central Nervous System) metastases
    including brain metastases who have completed a course of radiotherapy are eligible
    for the study provided they are clinically stable. However, oral corticosteroids for
    control of CNS symptoms are not allowed.

    4. Known documented or suspected hypersensitivity to the components of the study
    drug(s) or analogs.

    5. Uncontrolled systemic illness, including but not limited to ongoing or active
    infection.

    6. Symptomatic congestive heart failure, unstable angina pectoris, stroke or
    myocardial infarction within 3 months.

    7. Baseline neuropathy >grade 1. 8. Known positive for human immunodeficiency virus
    (HIV). Baseline HIV screening is not required.

    9. Pregnant or breast-feeding subjects. 10. Subjects who are unable or unwilling to
    abide by the study protocol or to cooperate fully with the investigator or designee.

    Minimum Eligible Age: 18 Years

    Maximum Eligible Age: 90 Years

    Eligible Gender: Both

    Primary Outcome Measures

    Maximum Tolerated Dose (MTD)

    Dose Limiting Toxicities (DLT)

    Secondary Outcome Measures

    Trial Keywords

    Breast Cancer

    Advanced Breast Cancer