Breast Cancer
Conditions
Keywords
stage IV breast cancer, recurrent breast cancer
Brief summary
RATIONALE: Monoclonal antibodies such as trastuzumab can locate tumor cells and either kill them or deliver tumor-killing substances to them without harming normal cells. Biological therapies such as erlotinib may interfere with the growth of tumor cells and slow the growth of the tumor. Combining trastuzumab with erlotinib may kill more tumor cells. PURPOSE: Phase II trial to study the effectiveness of combining trastuzumab with erlotinib as first-line therapy in treating women who have metastatic breast cancer associated with HER2/neu overexpression.
Detailed description
OBJECTIVES: * Determine the maximum tolerated dose and recommended phase II dose of erlotinib when combined with trastuzumab (Herceptin) as first-line therapy in women with metastatic breast cancer associated with HER2/neu overexpression. (Phase I closed to accrual as of 01/2004) * Determine the safety profile of this regimen in these patients. * Determine the rate and duration of objective response in patients treated with this regimen. * Determine the pharmacologic behavior of this regimen in these patients. * Determine time to disease progression and duration of survival in patients treated with this regimen. * Correlate the antitumor activity of this regimen with epidermal growth factor receptor expression in these patients. OUTLINE: This is a dose-escalation study of erlotinib. (Phase I closed to accrual as of 01/2004). Patients receive oral erlotinib once daily beginning on day 2 and trastuzumab (Herceptin) IV over 30-90 minutes (1-4 hours after erlotinib) once weekly beginning on day 1. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of erlotinib until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. Once the MTD is determined, additional patients are treated at the recommended phase II dose. Patients are followed every 2 months. PROJECTED ACCRUAL: A total of 3-18 patients will be accrued for the phase I portion (closed to accrual as of 01/2004) and 27-81 patients will be accrued for the phase II portion of this study.
Interventions
BIOLOGICALtrastuzumab
Day 1 4mg/kg IV 2 mg/kg IV weekly.
DRUGerlotinib hydrochloride
100 mg daily on Course 1 Day 2. After three weeks patients who have not experienced specific adverse events, dose will be escalated to 150 mg daily. Patients who have experienced specific adverse events dose will remain 100 mg daily or dose reduced as necessary per protocol.
Sponsors
Genentech, Inc.
Jonsson Comprehensive Cancer Center
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Women aged \> 18 years * Histologically documents metastatic breast cancer * HER2 positive using Fluorescence In Situ Hybridization (FISH) * For phase I, patients who have previously received treatment for their metastatic disease are allowed to participate. * For the phase II portion of the study, patients must have measureable disease (\> 2 cm; \> 1 cm on spiral CT scan) * Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 * A life expectancy of \> 3 months * Use of effective means of contraception
Exclusion criteria
* For Phase II, prior cytotoxic chemotherapy and/or prior Herceptin for their metastatic disease. Prior treatment in the adjuvant setting is allowed.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Objective Response Rate as Defined as Stable Disease or the Rate of Complete and Partial Responses Determined on Two Consecutive Occasions Greater Than or Equal to 4 Weeks Apart. | 5 years | Complete Response: The disappearance of all signs of cancer in response to treatment. This does not always mean the cancer has been cured. Also called complete remission. Partial Response: A decrease in the size of a tumor, or in the extent of cancer in the body, in response to treatment. Also called partial remission. |
| Recommended Dose for Phase II | treatment period | — |
Secondary
| Measure | Time frame |
|---|---|
| Duration of Objective Response | 5 years |
| Incidence of Adverse Events | 5 years |
| Serum Concentration of Herceptin at Specified Time-points. | 4 months |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Treatment Phase 1 trastuzumab: Day 1 4mg/kg IV 2 mg/kg IV weekly.
erlotinib hydrochloride: 100 mg daily on Course 1 Day 2. After three weeks patients who have not experienced specific adverse events, dose will be escalated to 150 mg daily. Patients who have experienced specific adverse events dose will remain 100 mg daily or dose reduced as necessary per protocol. | 16 |
| Treatment Phase 2 trastuzumab: Day 1 4mg/kg IV 2 mg/kg IV weekly.
erlotinib hydrochloride: 100 mg daily on Course 1 Day 2. After three weeks patients who have not experienced specific adverse events, dose will be escalated to 150 mg daily. Patients who have experienced specific adverse events dose will remain 100 mg daily or dose reduced as necessary per protocol. | 11 |
| Total | 27 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 1 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 3 |
Baseline characteristics
| Characteristic | Treatment Phase 1 | Treatment Phase 2 | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 2 Participants | 2 Participants | 4 Participants |
| Age, Categorical Between 18 and 65 years | 14 Participants | 9 Participants | 23 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 2 Participants | 4 Participants |
| Race (NIH/OMB) White | 11 Participants | 7 Participants | 18 Participants |
| Region of Enrollment United States | 16 participants | 11 participants | 27 participants |
| Sex: Female, Male Female | 16 Participants | 11 Participants | 27 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 22 / 27 |
| serious Total, serious adverse events | 16 / 27 |
Outcome results
Primary
Recommended Dose for Phase II
Time frame: treatment period
Population: patients who have not experienced specific adverse events, dose will be escalated to 150 mg daily. Patients who have experienced specific adverse events dose will remain 100 mg daily or dose reduced as necessary per protocol.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Treatment Phase 1 Plus Phase 2 | Recommended Dose for Phase II | 50 dose mg/day | 6 participants receiving each dose |
| Treatment Phase 1 Plus Phase 2 | Recommended Dose for Phase II | 100 dose mg/day | 3 participants receiving each dose |
| Treatment Phase 1 Plus Phase 2 | Recommended Dose for Phase II | 150 dose mg/day | 5 participants receiving each dose |
Primary
The Objective Response Rate as Defined as Stable Disease or the Rate of Complete and Partial Responses Determined on Two Consecutive Occasions Greater Than or Equal to 4 Weeks Apart.
Complete Response: The disappearance of all signs of cancer in response to treatment. This does not always mean the cancer has been cured. Also called complete remission. Partial Response: A decrease in the size of a tumor, or in the extent of cancer in the body, in response to treatment. Also called partial remission.
Time frame: 5 years
Population: 12 patients with measurable disease and no prior trastuzumab in the metastatic setting considered evaluable at the recommended phase II dose level. 2 from phase 1 and 10 from phase 2 Excluded : 14 from Phase I: no measureable disease or previous trastuzumab. Phase II: Withdrawn due to disease complications
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Treatment Phase 1 Plus Phase 2 | The Objective Response Rate as Defined as Stable Disease or the Rate of Complete and Partial Responses Determined on Two Consecutive Occasions Greater Than or Equal to 4 Weeks Apart. | Partial Response | 4 participants |
| Treatment Phase 1 Plus Phase 2 | The Objective Response Rate as Defined as Stable Disease or the Rate of Complete and Partial Responses Determined on Two Consecutive Occasions Greater Than or Equal to 4 Weeks Apart. | Stable Disease | 1 participants |
Secondary
Duration of Objective Response
Time frame: 5 years
Population: Subjects that achieved objective response (4). All were from phase II.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Treatment Phase 1 Plus Phase 2 | Duration of Objective Response | greater than 6 months | 4 participants |
| Treatment Phase 1 Plus Phase 2 | Duration of Objective Response | greater than 2 years | 2 participants |
Secondary
Incidence of Adverse Events
Time frame: 5 years
Population: subjects evaluated for Serious Adverse Events (SAEs)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment Phase 1 Plus Phase 2 | Incidence of Adverse Events | 16 participants affected by SAEs |
Secondary
Serum Concentration of Herceptin at Specified Time-points.
Time frame: 4 months
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Treatment Phase 1 Plus Phase 2 | Serum Concentration of Herceptin at Specified Time-points. | Day 7 peak | 98.4 mcg/mL |
| Treatment Phase 1 Plus Phase 2 | Serum Concentration of Herceptin at Specified Time-points. | Day 7 trough | 46 mcg/mL |
| Treatment Phase 1 Plus Phase 2 | Serum Concentration of Herceptin at Specified Time-points. | Day 14 peak | 86 mcg/mL |
| Treatment Phase 1 Plus Phase 2 | Serum Concentration of Herceptin at Specified Time-points. | Day 14 trough | 46.9 mcg/mL |
| Treatment Phase 1 Plus Phase 2 | Serum Concentration of Herceptin at Specified Time-points. | Day 21 peak | 88.3 mcg/mL |
| Treatment Phase 1 Plus Phase 2 | Serum Concentration of Herceptin at Specified Time-points. | Day 21 trough | 50.8 mcg/mL |