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

Summary

Participation Requirements

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 cohor...

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: To evaluate and assess Dose Limiting Toxicities (DLT). To determine the toxicity profile. To determine the clinical response rate. To determine the duration of response. To evaluate baseline HER2 positivity biomarkers by analyzing pretreatment tumor Ki67, phospho-RB, cleaved caspase 3, phospho-histone H3, cycline E, MCM7, HER2, p27Kip1. 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. To evaluate pharmacokinetic (PK) parameters for PD-0332991 and T-DM1 including Cmax, AUC, t1/2

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