Breast Cancer
Conditions
Keywords
Breast - Female, Metastatic, HER2+
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.
Interventions
DRUGGemcitabine
The Phase I trial will start at the recommended phase II dose (RP2D) for gemcitabine but will have a de-escalation dose levels in the event that an unacceptable toxicity requires dose reduction. Dose level 0 = gemcitabine (1200 mg/m2) IV D1,8 q21 days; Dose level -1 = gemcitabine (1000 mg/m\^2) IV D1,8 q21 days; Dose level -2 = gemcitabine (850 mg/m\^2) IV D1,8 q21 days. The RP2D will be the dose level where 0-1 dose limiting toxicities (DLTs) in six patients occur.
DRUGTrastuzumab
Trastuzumab will be given using an 8 mg/kg loading dose on cycle one, day one (C1D1), followed by 6 mg/kg IV on subsequent cycles every (q) 21 days.
DRUGPertuzumab
Pertuzumab will be given using an 840 mg IV loading dose on C1D1, followed by 420 mg IV on subsequent cycles q 21 days.
Sponsors
Genentech, Inc.
H. Lee Moffitt Cancer Center and Research Institute
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Countries
United States
Participant flow
Recruitment details
Participants were enrolled at Moffitt Cancer Center October 2014 through October 2016.
Participants by arm
| Arm | Count |
|---|---|
| Dose Escalation / Phase II Treatment Single arm, non-randomized, open label phase I/II multisite Simon two stage minimax trial. Gemcitabine plus trastuzumab and pertuzumab. | 15 |
| Total | 15 |
Baseline characteristics
| Characteristic | Dose Escalation / Phase II Treatment |
|---|---|
| Age, Continuous | 58.2 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 12 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants |
| Race (NIH/OMB) White | 12 Participants |
| Region of Enrollment United States | 15 participants |
| Sex: Female, Male Female | 15 Participants |
| Sex: Female, Male Male | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 2 / 15 |
| other Total, other adverse events | 15 / 15 |
| serious Total, serious adverse events | 7 / 15 |
Outcome results
Primary
Phase II: Objective Response Rate (ORR)
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.
Time frame: Up to 36 Months
Population: All participants who have undergone 2 treatment cycles followed by a response scan and have documented best response data available.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Dose Escalation / Phase II Treatment | Phase II: Objective Response Rate (ORR) | Complete Response | 1 Participants |
| Dose Escalation / Phase II Treatment | Phase II: Objective Response Rate (ORR) | Partial Response | 1 Participants |
| Dose Escalation / Phase II Treatment | Phase II: Objective Response Rate (ORR) | Stable Disease | 8 Participants |
Primary
Phase I: Recommended Phase II Dose (RP2D)
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.
Time frame: 6 Months
Population: All participants enrolled during Phase 1
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dose Escalation / Phase II Treatment | Phase I: Recommended Phase II Dose (RP2D) | 1200 dose in mg/m^2 |
Secondary
Overall Survival (OS)
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.
Time frame: Up to 36 months
Population: All participants
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dose Escalation / Phase II Treatment | Overall Survival (OS) | 11.3545 months |
Secondary
Phase II: Progression Free Survival (PFS)
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.
Time frame: Up to 12 months
Population: All participants
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dose Escalation / Phase II Treatment | Phase II: Progression Free Survival (PFS) | 6.4883 months |