Phase I/IIa Trial of Gemcitabine Plus Trastuzumab and Pertuzumab in Previously Treated Metastatic HER2+ Breast Cancer

Phase 1

Completed

Brief Summary: The purpose of this study is to evaluate the safety and activity of gemcitabine plus trastuzumab and pertuzumab in patients with metastatic human epidermal growth factor receptor 2 (HER2)+ breast cancer who have progressed on at least one prior line of chemotherapy plus HER2 targeted agent such as T-DM1, trastuzumab, or lapatinib.

Recruitment & Eligibility

Inclusion Criteria

Adult males or females (aged 18 or older) with histologically confirmed, metastatic human epidermal growth factor receptor 2 (HER2)+ (by immunohistochemistry (IHC) 3+ or fluorescence in situ hydridization (FISH) ratio ≥ 2.0) breast cancer
Have progressed on at least one prior line of chemotherapy plus HER2 directed therapy such as trastuzumab and/or pertuzumab in the metastatic setting. T-DM1 would count as a line of therapy and patients previously treated with T-DM1 are eligible.
Have not been treated with gemcitabine in the metastatic setting
Measurable disease per Response Evaluation in Solid Tumors (RECIST) 1.1 criteria
Eastern Cooperative Oncology Group (ECOG) performance status 2≤
Left Ventricular Ejection Fraction (LVEF) ≥ 50% at baseline as determined by either echocardiogram (ECHO) or multiple gated acquisition scan (MUGA)
Adequate bone marrow function as indicated by the following: absolute neutrophil count (ANC) >1500/µL; Platelets ≥100,000/µL; Hemoglobin >10 g/dL
Adequate renal function, as indicated by creatinine ≤1.5x upper limit of normal (ULN)
Adequate liver function, as indicated by bilirubin ≤1.5x ULN, aspartic transaminase (AST) or alanine transaminase (ALT) <2x ULN unless related to metastatic breast cancer to the liver (in which case AST/ALT < 5x ULN is allowed).
Signed informed consent
Adequate birth control in sexually active women of childbearing potential

Exclusion Criteria

Active uncontrolled infection or major concurrent illness which in the opinion of the investigator would render the participant unsafe to proceed with the study
Uncontrolled central nervous system (CNS) metastases. Treated, non-progressing CNS disease (documented by brain magnetic resonance imaging [MRI]) off corticosteroids for at least 1 month potential participants are eligible.
Women who are pregnant or lactating
Prior chemotherapy within the last 3 weeks (last 6 weeks for nitrosureas/mitomycin)
Prior radiation therapy within the last 4 weeks; prior radiation therapy to indicator lesion (unless objective disease recurrence or progression within the radiation portal has been documented since completion of radiation)
Other concomitant active malignancies
History of significant cardiac disease, cardiac risk factors or uncontrolled arrhythmias
Ejection fraction <50% or below the lower limit of the institutional normal range, whichever is lower
Hypersensitivity to any of the study medications
Untreated psychiatric conditions preventing informed consent

Arm && Interventions

Group	Intervention	Description
Dose Escalation / Phase II Treatment	Gemcitabine	Single arm, non-randomized, open label phase I/II multisite Simon two stage minimax trial. Gemcitabine plus trastuzumab and pertuzumab.
Dose Escalation / Phase II Treatment	Pertuzumab	Single arm, non-randomized, open label phase I/II multisite Simon two stage minimax trial. Gemcitabine plus trastuzumab and pertuzumab.
Dose Escalation / Phase II Treatment	Trastuzumab	Single arm, non-randomized, open label phase I/II multisite Simon two stage minimax trial. Gemcitabine plus trastuzumab and pertuzumab.

Primary Outcome Measures

Name	Time	Method
Phase I: Recommended Phase II Dose (RP2D)	6 Months	The RP2D dose in mg/m\^2 of gemcitabine along with standard doses of pertuzumab (840 mg loading/420 mg maintenance) and Herceptin (8 mg/kg loading, 6 mg/kg maintenance). Safety data to be described using Common Terminology Criteria for Adverse Events (CTCAE) 4.0 terminology. Any participant who receives any dose of the study treatment will be evaluated for the safety/toxicity endpoints in the trial.
Phase II: Objective Response Rate (ORR)	Up to 36 Months	Objective Response Rate: Response according to Response Evaluation in Solid Tumors (RECIST) 1.1 for the combination of gemcitabine+trastuzumab+pertuzumab at the recommended phase II dose. Complete Response (CR): Disappearance of all evidence of tumor for at least two cycles of therapy. Tumor markers must be normal. Partial Response (PR): At least a 30% decrease in the sum of the longest diameter of target lesions, taking a reference the baseline sum longest diameter. Stable Disease (SD): Neither sufficient shrinkage to qualify for partial response nor sufficient increase to qualify for progressive disease, taking as reference the smallest sum longest diameter since the treatment started. Progressive Disease (PD): At least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter recorded since the beginning of treatment or the appearance of one or more new lesions.

Secondary Outcome Measures

Name	Time	Method
Phase II: Progression Free Survival (PFS)	Up to 12 months	Median progression free survival (in months) for all participants evaluable for response. The time-to-event data will be summarized using Kaplan-Meir curve method for all patients who are evaluable for the ORR endpoint. Progressive disease (PD): At least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter recorded since the beginning of treatment or the appearance of one or more new lesions.
Overall Survival (OS)	Up to 36 months	Median overall survival (in months) for all participants evaluable for response. The length of time from the start of treatment that participants are still alive.