Breast Cancer
Conditions
Keywords
male breast cancer, recurrent breast cancer, stage IIIB breast cancer, stage IIIC breast cancer, stage IV breast cancer, estrogen receptor-negative breast cancer, HER2-negative breast cancer, progesterone receptor-negative breast cancer, triple-negative breast cancer
Brief summary
RATIONALE: Drugs used in chemotherapy, such as bendamustine, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Erlotinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor. Giving bendamustine together with erlotinib may kill more tumor cells. PURPOSE: This phase I/II trial is studying the side effects and best dose of giving bendamustine together with erlotinib in treating patients with stage IIIB, stage IIIC, or stage IV breast cancer.
Detailed description
OBJECTIVES: Primary * To determine the phase II dose and assess the toxicity of bendamustine hydrochloride and erlotinib hydrochloride in patients with triple-receptor (estrogen receptor, progesterone receptor, and HER-2)-negative, stage IIIB, IIIC, or IV breast cancer. (Phase I) * To determine the efficacy of this regimen in these patients. (Phase II) Secondary (Correlative) * To assess the correlation between tumor EGFR expression and EGFR gene amplification and treatment efficacy and toxicity. * To assess for differences in treatment efficacy between basal-like and non-basal-like cancers. * To assess for differences in treatment efficacy between tumors with and without expression of DNA damage-response (DDR) checkpoint proteins. * To assess for differences in the activation state of DDR checkpoint proteins based on breast cancer subtype. OUTLINE: This is a multicenter, phase I dose-escalation study followed by a phase II study. Patients receive bendamustine hydrochloride IV over 30 minutes on days 1-2 and oral erlotinib hydrochloride once daily on days 5-21. Treatment repeats every 28 days for at least 6 courses in the absence of disease progression or unacceptable toxicity. Patients with no evidence of disease progression may continue with daily single-agent oral erlotinib hydrochloride on days 1-28. Treatment continues every 28 days in the absence of disease progression or unacceptable toxicity. Breast cancer tissue blocks from prior procedures are obtained for correlative studies. After a tissue microarray (TMA) and a TMA map are prepared, TMA slides are used for hematoxylin and eosin (H&E) staining, FISH, and IHC. After completion of study treatment, patients are followed every 3 months for 2 years.
Interventions
DRUGbendamustine
100 or 120 mg/m2 IV on days 1 and 2
DRUGerlotinib
100 or 150 mg po on days 5 - 21 of each 28 day cycle
DRUGMaintenance erlotinib
150 mg po daily (days 1 - 28 of 28 day cycle)
Sponsors
National Comprehensive Cancer Network
Genentech, Inc.
Ohio State University Comprehensive Cancer Center
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
DISEASE CHARACTERISTICS: * Histologically confirmed breast cancer meeting 1 of the following criteria: * Unresectable stage IIIB or IIIC disease * Stage IV disease * Must be negative for all of the following: * Estrogen receptor (\< 10%) * Progesterone receptor (\<10%) * HER-2 (negative FISH, IHC 0 - 1+, or IHC +2 with negative FISH) * Measurable or evaluable disease * No symptomatic or progressive CNS (central nervous system) metastases * Previously treated CNS metastases allowed provided all of the following criteria are met: * At least 8 weeks since prior radiation to brain or CNS metastases * No concurrent steroids * No leptomeningeal disease PATIENT CHARACTERISTICS: * Menopausal status not specified * ECOG (Eastern Cooperative Oncology Group) performance status 0-2 * Life expectancy ≥ 6 months * WBC \> 1,500/mm³ * Platelet count \> 100,000/mm³ * Creatinine clearance \> 40 mL/min * Normal electrolytes (i.e., Na, K, and Ca normal; minor deviations are allowed if they do not impact on patient safety in the clinical judgment of the treating physician) * Bilirubin ≤ 1.5 times upper limit of normal (ULN) * ALT and AST ≤ 2.5 times ULN (≤ 5 times ULN in the presence of documented liver metastases) * Alkaline phosphatase ≤ 2.5 times ULN (≤ 5 times ULN in the presence of liver or bone metastases) * Not pregnant or nursing * Fertile patients must use effective barrier contraception * No uncontrolled intercurrent illness * No active infection requiring systemic therapy * Able to swallow oral medications and with no medical problems or prior surgeries that may interfere with the absorption of oral medications including the following: * Uncontrolled nausea, vomiting, or diarrhea * Lack of the physical integrity of the upper gastrointestinal tract * Malabsorption syndrome * No known hypersensitivity to bendamustine hydrochloride, mannitol, or erlotinib hydrochloride * No prior malignancy in the past 5 years except for adequately treated basal cell or squamous cell skin carcinoma, or adequately treated stage I-II cancer for which the patient is in complete remission PRIOR CONCURRENT THERAPY: * See Disease Characteristics * Prior adjuvant or neoadjuvant chemotherapy and 1 prior chemotherapy regimen in the metastatic setting allowed provided recovered from all acute toxicities * No prior bendamustine hydrochloride or EGFR-directed therapy * No other concurrent antineoplastic treatments, including radiotherapy, chemotherapy, biological therapy, hormonal therapy, immunotherapy, gene therapy, and surgery * Intravenous bisphosphonates allowed * No concurrent antiretroviral therapy for HIV-positive patients * No other concurrent investigational agents
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum-tolerated Dose of Erlotinib Hydrochloride (Phase I) | Up to two years | 28 day cycle included intravenous erlotinib on days 15-21. |
| Dose-limiting Toxicity (Phase I) | Up to two years | — |
| Maximum-tolerated Dose of Bendamustine Hydrochloride (Phase I) | Up to two years | 28 day cycle included intravenous bendamustine on days 1 and 2. |
| Progression-free Survival at 6 Months and 12 Months (Phase II) | Up to two years | Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) | Up to two years | Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. |
| Relationship of EGFR Expression or Amplification, Basal-like Tumors, and DNA Damage-repair Checkpoint Activation With ORR, CBR, DR, and OS | up to two years | — |
| Clinical Benefit Rate (CBR) | Up to two years | — |
| Duration of Response (DR) | Up to two years | — |
| Overall Survival (OS) | from time of study enrollment until death, for up to 2 years | — |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Bendamustine and Erlotinib Bendamustine 100 or 120 mg/m2 IV on days 1 and 2 and erlotinib 100 or 150 mg po on days 5 - 21 of each 28 day cycle.
bendamustine: 100 or 120 mg/m2 IV on days 1 and 2
erlotinib: 100 or 150 mg po on days 5 - 21 of each 28 day cycle
Maintenance erlotinib: 150 mg po daily (days 1 - 28 of 28 day cycle) | 11 |
| Total | 11 |
Baseline characteristics
| Characteristic | Bendamustine and Erlotinib |
|---|---|
| Age, Continuous | 53 years |
| ECOG (Eastern Cooperative Oncology Group) performance status 0 (Fully active) | 4 participants |
| ECOG (Eastern Cooperative Oncology Group) performance status 1 (Restricted) | 6 participants |
| ECOG (Eastern Cooperative Oncology Group) performance status 2 (Ambulatory and capable selfcare) | 1 participants |
| Prior chemotherapy Adjuvant only | 4 participants |
| Prior chemotherapy Both | 6 participants |
| Prior chemotherapy Metastasis/local recurrence only | 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 | 2 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 | 0 Participants |
| Race (NIH/OMB) White | 9 Participants |
| Region of Enrollment United States | 11 participants |
| Sex: Female, Male Female | 11 Participants |
| Sex: Female, Male Male | 0 Participants |
| Site of metastasis Bone | 4 participants |
| Site of metastasis Brain | 1 participants |
| Site of metastasis Chest wall/skin | 3 participants |
| Site of metastasis Liver | 3 participants |
| Site of metastasis Lung/pleura | 6 participants |
| Site of metastasis Lymph nodes | 9 participants |
| Total number of prior treatment regimens 1 prior regimen | 4 participants |
| Total number of prior treatment regimens 2 prior regimens | 7 participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 11 / 11 |
| serious Total, serious adverse events | 3 / 11 |
Outcome results
Primary
Dose-limiting Toxicity (Phase I)
Time frame: Up to two years
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Bendamustine and Erlotinib | Dose-limiting Toxicity (Phase I) | Dose level I, n=5 | 0 patients |
| Bendamustine and Erlotinib | Dose-limiting Toxicity (Phase I) | Dose level II, n=6 | 1 patients |
Primary
Maximum-tolerated Dose of Bendamustine Hydrochloride (Phase I)
28 day cycle included intravenous bendamustine on days 1 and 2.
Time frame: Up to two years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bendamustine and Erlotinib | Maximum-tolerated Dose of Bendamustine Hydrochloride (Phase I) | 120 mg/m^2 |
Primary
Maximum-tolerated Dose of Erlotinib Hydrochloride (Phase I)
28 day cycle included intravenous erlotinib on days 15-21.
Time frame: Up to two years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bendamustine and Erlotinib | Maximum-tolerated Dose of Erlotinib Hydrochloride (Phase I) | 150 mg |
Primary
Progression-free Survival at 6 Months and 12 Months (Phase II)
Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions
Time frame: Up to two years
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Bendamustine and Erlotinib | Progression-free Survival at 6 Months and 12 Months (Phase II) | 3.7 months |
Secondary
Clinical Benefit Rate (CBR)
Time frame: Up to two years
Population: The data was not collected and analyzed
Secondary
Duration of Response (DR)
Time frame: Up to two years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Bendamustine and Erlotinib | Duration of Response (DR) | 3.7 months to progression |
Secondary
Objective Response Rate (ORR)
Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.
Time frame: Up to two years
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Bendamustine and Erlotinib | Objective Response Rate (ORR) | Dose Level 1 | 0 patients |
| Bendamustine and Erlotinib | Objective Response Rate (ORR) | Dose Level 2 | 1 patients |
Secondary
Overall Survival (OS)
Time frame: from time of study enrollment until death, for up to 2 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Bendamustine and Erlotinib | Overall Survival (OS) | 10.8 months |
Secondary
Relationship of EGFR Expression or Amplification, Basal-like Tumors, and DNA Damage-repair Checkpoint Activation With ORR, CBR, DR, and OS
Time frame: up to two years
Population: Correlative studies to assess EGFR expression and gene amplification, were planned, but not collected because of early trial termination.