Palbociclib in Estrogen Receptor Positive (ER+) Human Epidermal Growth Factor Receptor 2 Positive (HER2+) Metastatic Breast Cancer

Study Overview
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Brief Summary
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This study will determine the recommend dose of palbociclib in combination with letrozole and another medication, Ado-trastuzumab emtansine (T-DM1). Additionally, researchers will determine how well this recommended dose will improve outcomes in this type of advanced breast cancer. The study will include a safety lead-in with escalating dosing of palbociclib to determine the recommended phase II dose (RP2D) of palbociclib in this combination and an expanded phase II of palbociclib at the RP2D in combination with letrozole and Ado- trastuzumab Emtansine (T-DM1). The starting dose of palbociclib will be 75 milligrams (mg) by mouth (PO) daily for each 21 day cycle. If 0 of 3 patients at the 75mg dose level experience a dose limiting toxicity (DLT), the next 3 patients will be enrolled at the next higher dosing cohort of 100mg PO daily for each 21 day cycle. If 0 of 3 patients at the 100mg dose level experience a DLT, the next 3 patients will be enrolled at the next higher dosing cohort of 125mg PO daily for each 21 day cycle. If 0 of 3 patients at the 125mg dose level experience a DLT, 125mg PO daily of palbociclib will be the phase II recommended dose used in the phase II expanded cohort. Patients receiving the phase II recommended dose in phase I will be enrolled in phase II of the study. During safety lead-in and expanded phase II, Letrozole 2.5mg PO will be administered daily for each 21 day cycle and T-DM1 3.6 milligrams per kilograms intravenously (IV) will be administered on Day 1 of each 21 day cycle.

Official Title
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A Phase I/II Study of Palbociclib, Letrozole and T-DM1 in Trastuzumab Refractory Estrogen Receptor Positive (ER+) and HER2 Positive Metastatic Breast Cancer

Conditions
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HER2-positive Breast Cancer, Breast Cancer Metastatic

Intervention / Treatment
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* Drug: Palbociclib 75mg
* Drug: Letrozole 2.5mg
* Drug: T-DM1
* Drug: Palbociclib 100mg
* Drug: Palbociclib 125mg
* Drug: Palbociclib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Pathologically confirmed diagnosis of Estrogen Receptor (ER) positive and HER2 (human epidermal growth factor receptor 2) positive metastatic breast cancer based on local laboratory results. Prior treatment with a taxane (including paclitaxel, docetaxel and/or nanoparticle protein-bound paclitaxel). Prior treatment with trastuzumab with or without pertuzumab. Measurable or non-measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) criteria version 1.1. Eastern Cooperative Oncology Group Performance Status of 0-2 Adequate organ and marrow function Women must be post-menopausal Must be able to swallow pills Exclusion Criteria: Current or anticipated use of other investigational agents Prior therapy with a cyclin-dependent kinase 4/6 inhibitor Subject has received chemotherapy or radiotherapy within 14 days prior to Cycle 1, Day 1 of the study or has not recovered from adverse events due to agents administered more than 14 days earlier Subject has leptomeningeal disease History of allergic reactions attributed to compounds of similar chemical or biologic composition to palbociclib or other agents used in study Subject has other illness or disease that the investigator believes will interfere with study requirements.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1: Palbociclib 75 mg<br>Palbociclib 75 milligrams (mg) by mouth (PO) daily Letrozole 2.5 mg PO Daily Ado-trastuzumab Emtansine (T-DM1) 3.6 milligrams per kilograms (mg/kg) intravenous (IV) Day 1 | Drug: Palbociclib 75mg<br>* Oral Administration<br>* Other names: Ibrance;Drug: Letrozole 2.5mg<br>* Oral Adminstration<br>* Other names: Femara;Drug: T-DM1<br>* Intravenous Administration<br>* Other names: Kadcyla;|
| Experimental: Phase 1: Palbociclib 100 mg<br>Palbociclib 100 milligrams (mg) by mouth (PO) daily Letrozole 2.5 mg PO Daily Ado-trastuzumab Emtansine (T-DM1) 3.6 milligrams per kilograms (mg/kg) intravenous (IV) Day 1 | Drug: Letrozole 2.5mg<br>* Oral Adminstration<br>* Other names: Femara;Drug: T-DM1<br>* Intravenous Administration<br>* Other names: Kadcyla;Drug: Palbociclib 100mg<br>* Oral Administration<br>* Other names: Ibrance;|
| Experimental: Phase 1: Palbociclib 125 mg<br>Palbociclib 125 milligrams (mg) by mouth (PO) daily Letrozole 2.5 mg PO Daily Ado-trastuzumab Emtansine (T-DM1) 3.6 milligrams per kilograms (mg/kg) intravenous (IV) Day 1 | Drug: Letrozole 2.5mg<br>* Oral Adminstration<br>* Other names: Femara;Drug: T-DM1<br>* Intravenous Administration<br>* Other names: Kadcyla;Drug: Palbociclib 125mg<br>* Oral Administration<br>* Other names: Ibrance;|
| Experimental: Phase 2: RP2D<br>Recommended Phase 2 dose (RP2D; determined during Phase 1 Safety Run In) Palbociclib by mouth (PO) daily Letrozole 2.5 mg PO Daily Ado-trastuzumab Emtansine (T-DM1) 3.6 milligrams per kilograms (mg/kg) intravenous (IV) Day 1 | Drug: Letrozole 2.5mg<br>* Oral Adminstration<br>* Other names: Femara;Drug: T-DM1<br>* Intravenous Administration<br>* Other names: Kadcyla;Drug: Palbociclib<br>* Oral Administration<br>* Other names: Ibrance;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of Overall Response | Determine overall response rate (ORR), defined per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 | From the time of first documented complete response or appearance of one or more new lesions, until the first documented date of recurrent or progressive disease, whichever came first, assessed up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of participants with complete response (CR). | Defined per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 | Up to 5 years | 
| Proportion of participants with partial response (PR). | Defined per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 | Up to 5 years | 
| Proportion of participants with stable disease (SD). | Defined per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 | Up to 5 years | 
| Proportion of participants with Grade 3 or higher adverse event. | Defined per Common Terminology Criteria for Adverse Events (CTCAE) v4.03 | Up to 5 years | 
| Number of patients with adverse events | Determine safety and tolerability of the intervention, defined per Common Terminology Criteria for Adverse Events (CTCAE) v4.03. | Up to 5 years | 
| Number of participants with a worsening Patient Reported Outcomes of Adverse Events (PRO-AE) score | PRO-AE score defined per Patient Reported Outcome Measurement Information System (PROMIS) and Breast Cancer Prevention Trial (BCPT) Symptom Checklist. | At baseline and Day 1 of each cycle, up to 5 years (each cyle is 21 days) | 
| Peak observed plasma concentration | Defined per maximum observed concentration (Cmax) and time of Cmax (Tmax). | Cycle 1, Day 1: 0 ,2,4 and 8 hours post treatment; Cycle 1, Day 15: 0 hours post treatment (each cyle is 21 days) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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palbociclib