Trastuzumab and Trastuzumab-MCC-DM1 Administered Intravenously and GDC-0941 Administered Orally to Patients With HER2-Positive Metastatic Breast Cancer Who Have Progressed on Previous Trastuzumab-Based Therapy

Study Overview
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Brief Summary
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This multicenter, Phase Ib study is an open label, dose escalation, three-arm study evaluating the safety, tolerability, pharmacokinetics, and activity of oral (PO) GDC 0941 administered in combination with either intravenous (IV) infusion of T-DM1 or IV infusion of trastuzumab.

Official Title
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A Phase Ib, Open-Label Study of the Safety, Tolerability, Pharmacokinetics, and Activity of Trastuzumab and Trastuzumab-MCC-DM1 Administered Intravenously and GDC-0941 Administered Orally to Patients With HER2-Positive Metastatic Breast Cancer Who Have Progressed on Previous Trastuzumab-Based Therapy

Conditions
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Metastatic Breast Cancer

Intervention / Treatment
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* Drug: GDC-0941
* Drug: Trastuzumab
* Drug: trastuzumab-MCC-DM1


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically documented locally advanced or metastatic breast cancer that has progressed on at least one trastuzumab-based regimen in the metastatic or locally advanced setting HER2-positive disease documented by one of the following results using FDA-approved testing methods: FISH-positive, chromogenic in situ hybridization (CISH)-positive, or IHC 3 + by local laboratory assessment Life expectancy >= 90 days Agreement to use an effective form of contraception for the duration of the study Exclusion Criteria: History of Grade >= 3 hypersensitivity reaction to trastuzumab, or Grade >= 1 with the most recent trastuzumab infusion before study entry, or continued requirement for prolonged trastuzumab infusions to prevent hypersensitivity reactions History of intolerance to trastuzumab and/or adverse events related to trastuzumab that resulted in trastuzumab being permanently discontinued Prior anti-cancer therapy (e.g., biologic or other targeted therapy, chemotherapy, hormonal therapy) within 2 weeks prior to Day 1 Prior investigational anti-cancer therapy within 4 weeks prior to Day 1 Grade >= 2 peripheral neuropathy History of Grade >= 3 hyperglycemia (fasting) History of Type 1 or Type 2 diabetes requiring daily medication History of clinically significant cardiac or pulmonary dysfunction History of malabsorption syndrome or other condition that would interfere with enteral absorption Clinically significant history of liver disease, including cirrhosis, current alcohol abuse, or current known active infection with HIV, hepatitis B virus, or hepatitis C virus Any condition requiring anticoagulants, such as warfarin, heparin, or thrombolytic agents Any condition requiring > 2 grams of acetaminophen daily Need for current chronic corticosteroid therapy Pregnancy, lactation, or breast-feeding Current severe, uncontrolled systemic disease (e.g., clinically significant cardiovascular, pulmonary, or metabolic disease) Major surgical procedure or significant traumatic injury within 28 days prior to Day 1, or anticipation of the need for major surgery during the course of study treatment Symptomatic hypercalcemia requiring continued use of bisphosphonate therapy Known brain metastases that are untreated, symptomatic, or require therapy to control symptoms

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

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: A<br> | Drug: GDC-0941<br>* Oral repeating dose<br>Drug: trastuzumab-MCC-DM1<br>* Intravenous repeating dose<br>|
| Experimental: B<br> | Drug: GDC-0941<br>* Oral repeating dose<br>Drug: trastuzumab-MCC-DM1<br>* Intravenous repeating dose<br>|
| Experimental: C<br> | Drug: GDC-0941<br>* Oral repeating dose<br>Drug: Trastuzumab<br>* Intravenous repeating dose<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in cardiac function |  | Through study completion or early study discontinuation | 
| Changes in vital signs, physical findings, and clinical laboratory results during and following administration of study drugs that result in dose modification, dose delay, or discontinuation of T-DM1 and/or GDC 0941 |  | Through study completion or early study discontinuation | 
| Incidence, nature, and severity of adverse events |  | Through study completion or early study discontinuation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PK parameters of T-DM1 and GDC-0941 (total exposure, maximum serum concentration, and minimum concentration) |  | Through study completion or early study discontinuation | 
| Progression-free survival (PFS) |  | From study treatment initiation to the first occurrence of disease progression or death on study | 
| Objective response based on investigator assessment |  | Confirmed response >/= 4 weeks after initial documentation of response | 
| Duration of response |  | Time from initial complete or partial response to the time of disease progression or death on study | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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TDM-1, HER2, HER2+, HER2+ Breast Cancer, HER-2, MBC, Trastuzumab emtansine