Phase 1b Study of PD-0332991 in Combination With T-DM1(Trastuzumab-DM1)
Condition: Advanced Breast Cancer
MeSH terms: Breast Neoplasms
Study type: Interventional
Phase: Phase 1

Summary: 
      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
    

Intervention name(s): PD-0332991 and T-DM1
Intervention type(s): Drug
Intervention description(s): 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)
Other intervention name(s): KADCYLA=T-DM1; Palbociclib=PD-0332991
Intervention MeSH terms: Palbociclib; Ado-Trastuzumab Emtansine
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Breast Cancer; Advanced Breast Cancer