Metastatic Breast Cancer
Conditions
Keywords
Metastatic Breast Cancer, Triple Negative, Panitumumab, Vectibix, Gemcitabine, Gemzar, Carboplatin
Brief summary
In this Phase II trial, the investigators will evaluate the combination of gemcitabine, carboplatin, and panitumumab in the treatment of patients with metastatic triple-negative breast cancer. In addition, to assess the efficacy of this combination, tumor tissue will be examined for the presence of various markers, including K-ras and PI3K-activating mutations, EGFR, PTEN, and p53. Correlation of tumor response with marker expression may define a patient subset that is particularly responsive to treatment with a panitumumab-containing combination.
Detailed description
All patients will receive a pre-emptive skin care regimen during panitumumab therapy to reduce skin toxicity. Treatment cycles will be repeated every 14 days (2 weeks). During each treatment, panitumumab will be administered first, then carboplatin, then gemcitabine. All drugs will be administered according to standard guidelines. Patients will be re-evaluated for response after completion of 3 cycles (6 weeks) of treatment. Patients with objective response or stable disease will continue treatment. Subsequent re-evaluations will occur every 6 weeks. Patients will continue treatment with all three drugs until tumor progression, or until unacceptable toxicity occurs. If patients experience toxicity caused by gemcitabine/carboplatin and are continuing to benefit from treatment, panitumumab can be continued as a single agent (at the same dose and schedule), at the discretion of the investigator, until disease progression occurs.
Interventions
DRUGPanitumumab
6 mg/kg IV on Day 1 of each 2-week treatment cycle for 3 cycles (6 weeks)
DRUGCarboplatin
AUC=2.5 IV, Day 1 of each 2-week treatment cycle for 3 cycles (6 weeks)
DRUGGemcitabine
1500 mg/m2 IV, Day 1 of each 2-week treatment cycle for 3 cycles (6 weeks)
Sponsors
Amgen
Eli Lilly and Company
SCRI Development Innovations, LLC
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
1. Female patients \>=18 years of age. 2. Histologically or cytologically confirmed diagnosis of unresectable locally advanced or stage IV breast cancer. 3. No more than 1 prior treatment regimen for metastatic breast cancer. 4. Estrogen receptor and progesterone receptor negative (defined as \<10% staining by IHC). 5. Paraffin-embedded tumor tissue (from the primary tumor or metastasis) for biomarker testing. (In the absence of paraffinembedded tissue, unstained paraffin-embedded tumor slides are acceptable). 6. Measurable disease, as defined by the Response Evaluation Criteria in Solid Tumors (RECIST version 1.1) guidelines 7. HER2 negative tumors. HER2 negativity must be confirmed by one of the following: * FISH-negative (FISH ratio \<2.2), or * IHC 0-1+, or * IHC 2-3+ AND FISH-negative (FISH ratio \<2.2) 8. Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0-1. 9. Absolute neutrophil count (ANC) \>=1.5 × 109/L; platelet count \>=100 × 109/L; hemoglobin \>=9.0 g/dL. 10. Creatinine \<=1.5 mg/dL, or creatinine clearance \>=40 mL/min (as calculated by the Cockcroft-Gault method, as follows: Female creatinine clearance = (140 - age) × (weight in kg) × 0.85 (serum creatinine × 72) 11. Adequate hepatic function, defined as follows: total bilirubin \<=1.5 x ULN; aspartate aminotransferase (AST) \<=3 × ULN (or \<= 5 x ULN if liver metastases); alanine aminotransferase (ALT) \<=3 x ULN (or \<=5 x ULN if liver metastases). 12. Magnesium level \>= the institutional lower limit of normal (LLN). 13. Women of childbearing potential must agree to use adequate contraception (per institutional standard of care) during treatment and until 6 months after the last administration of investigational products.
Exclusion criteria
1. Patients with brain metastases are not eligible. 2. History of another primary cancer, with the exception of the following: * Curatively treated in situ cervical cancer; * Curatively resected non-melanoma skin cancer; * Other primary solid tumor curatively treated with no known active disease present and no treatment administered for \>=5 years prior to study enrollment. 3. History of interstitial lung disease (e.g., pneumonitis, pulmonary fibrosis), or any evidence of interstitial lung disease on the CT scan of the chest performed at the baseline visit. 4. Prior anti-EGFR antibody therapy (e.g., cetuximab), or treatment with small-molecule EGFR inhibitors (e.g., gefitinib, erlotinib, lapatinib). 5. Radiotherapy \<=14 days prior to study enrollment. Any acute effects of radiotherapy must be resolved prior to the administration of study drugs. 6. Systemic chemotherapy, hormonal therapy, immunotherapy, or experimental or approved proteins/antibodies (e.g., bevacizumab) \<=21 days prior to study enrollment. 7. Prior therapy with gemcitabine or carboplatin in the metastatic setting is not permitted. Patients who received gemcitabine or carboplatin as part of adjuvant therapy are eligible, as long as recurrence was first documented \>12 months after the last exposure to the drug(s). 8. Major surgery within 28 days or minor surgery within 14 days of study enrollment. 9. Requirement of chronic use of immunosuppressive agents (e.g., methotrexate, cyclosporine). 10. Any investigational agent or therapy \<=30 days prior to study enrollment. 11. Uncontrolled or intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, or cardiac arrhythmia. 12. History of any medical or psychiatric condition or laboratory abnormality that, in the opinion of the investigator, may increase the risks associated with the study participation or administration of the investigational products, or that may interfere with the interpretation of the results. 13. Unwillingness or inability to comply with study requirements. 14. Women who are pregnant or breastfeeding. 15. Patients with known human immunodeficiency virus (HIV), hepatitis C virus, and/or acute or chronic hepatitis B virus infection.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival (PFS) | every 6 weeks until treatment discontinuation | Measured from Day 1 of study drug administration to disease progression - defined by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 as a 20% increase in the sum of the longest diameter of target lesions and/or appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate and Clinical Benefit Rate | every 6 weeks until treatment discontinuation | Estimated as the proportion of subjects who meet the criteria for complete or partial response (CR or PR) per Response Evaluation Criteria in Solid Tumors (RECIST) v 1.1 - for target lesions assessed by MRI: Complete Response (CR) is defined as disappearance of all target lesions; Partial Response (PR) is defined as \>=30% decrease in the sum of the longest diameter of target lesions. |
| Number of Treatment-related Toxicities Occurring in ≥10% of Patients as a Measure of Tolerability and Toxicity | every 6 weeks until discontinuation of treatment, expected average of 18 months | Assessments made through analysis of treatment-related adverse events and serious adverse events |
| Correlation of Biomarker Expressions of EGFR, K-ras, p53, PTEN Expression, and PI3K in Triple-negative Breast Cancer With Response to Treatment With the Combination of Gemcitabine, Carboplatin, and Panitumumab | 18 months | Median PFS (95% CI), months, reported by biomarker expression/mutation status for: EGFR, p53, PTEN, PIK3CA, KRAS |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Panitumumab/Gemcitabine/Carboplatin Panitumumab - 6 mg/kg IV on Day 1 of each 2-week treatment cycle for 3 cycles (6 weeks) Carboplatin - AUC=2.5 IV, Day 1 of each 2-week treatment cycle for 3 cycles (6 weeks) Gemcitabine - 1500 mg/m2 IV, Day 1 of each 2-week treatment cycle for 3 cycles (6 weeks) | 71 |
| Total | 71 |
Baseline characteristics
| Characteristic | Panitumumab/Gemcitabine/Carboplatin |
|---|---|
| Age, Continuous | 54 Years |
| Region of Enrollment United States | 71 participants |
| Sex: Female, Male Female | 71 Participants |
| Sex: Female, Male Male | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 70 / 71 |
| serious Total, serious adverse events | 10 / 71 |
Outcome results
Primary
Progression-free Survival (PFS)
Measured from Day 1 of study drug administration to disease progression - defined by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 as a 20% increase in the sum of the longest diameter of target lesions and/or appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions
Time frame: every 6 weeks until treatment discontinuation
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Panitumumab/Gemcitabine/Carboplatin | Progression-free Survival (PFS) | 4.4 Months |
Secondary
Correlation of Biomarker Expressions of EGFR, K-ras, p53, PTEN Expression, and PI3K in Triple-negative Breast Cancer With Response to Treatment With the Combination of Gemcitabine, Carboplatin, and Panitumumab
Median PFS (95% CI), months, reported by biomarker expression/mutation status for: EGFR, p53, PTEN, PIK3CA, KRAS
Time frame: 18 months
Population: Excludes patients in the following categories due to insufficient data: PTEN status unknown, PIK3CA Status unknown and KRAS no mutation
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Panitumumab/Gemcitabine/Carboplatin | Correlation of Biomarker Expressions of EGFR, K-ras, p53, PTEN Expression, and PI3K in Triple-negative Breast Cancer With Response to Treatment With the Combination of Gemcitabine, Carboplatin, and Panitumumab | 4.57 months |
| EGFR Amplified | Correlation of Biomarker Expressions of EGFR, K-ras, p53, PTEN Expression, and PI3K in Triple-negative Breast Cancer With Response to Treatment With the Combination of Gemcitabine, Carboplatin, and Panitumumab | 3.42 months |
| p53 Normal | Correlation of Biomarker Expressions of EGFR, K-ras, p53, PTEN Expression, and PI3K in Triple-negative Breast Cancer With Response to Treatment With the Combination of Gemcitabine, Carboplatin, and Panitumumab | 4.16 months |
| p53 Loss | Correlation of Biomarker Expressions of EGFR, K-ras, p53, PTEN Expression, and PI3K in Triple-negative Breast Cancer With Response to Treatment With the Combination of Gemcitabine, Carboplatin, and Panitumumab | 5.32 months |
| PTEN Normal | Correlation of Biomarker Expressions of EGFR, K-ras, p53, PTEN Expression, and PI3K in Triple-negative Breast Cancer With Response to Treatment With the Combination of Gemcitabine, Carboplatin, and Panitumumab | 4.4 months |
| PTEN Loss | Correlation of Biomarker Expressions of EGFR, K-ras, p53, PTEN Expression, and PI3K in Triple-negative Breast Cancer With Response to Treatment With the Combination of Gemcitabine, Carboplatin, and Panitumumab | 2.91 months |
| PIK3CA No Mutation | Correlation of Biomarker Expressions of EGFR, K-ras, p53, PTEN Expression, and PI3K in Triple-negative Breast Cancer With Response to Treatment With the Combination of Gemcitabine, Carboplatin, and Panitumumab | 4.37 months |
| PIK3CA Mutation(s) | Correlation of Biomarker Expressions of EGFR, K-ras, p53, PTEN Expression, and PI3K in Triple-negative Breast Cancer With Response to Treatment With the Combination of Gemcitabine, Carboplatin, and Panitumumab | 4.73 months |
Secondary
Number of Treatment-related Toxicities Occurring in ≥10% of Patients as a Measure of Tolerability and Toxicity
Assessments made through analysis of treatment-related adverse events and serious adverse events
Time frame: every 6 weeks until discontinuation of treatment, expected average of 18 months
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Panitumumab/Gemcitabine/Carboplatin | Number of Treatment-related Toxicities Occurring in ≥10% of Patients as a Measure of Tolerability and Toxicity | Fatigue | 37 participants |
| Panitumumab/Gemcitabine/Carboplatin | Number of Treatment-related Toxicities Occurring in ≥10% of Patients as a Measure of Tolerability and Toxicity | Nausea/vomiting | 36 participants |
| Panitumumab/Gemcitabine/Carboplatin | Number of Treatment-related Toxicities Occurring in ≥10% of Patients as a Measure of Tolerability and Toxicity | Dry skin | 21 participants |
| Panitumumab/Gemcitabine/Carboplatin | Number of Treatment-related Toxicities Occurring in ≥10% of Patients as a Measure of Tolerability and Toxicity | Hypomagnesemia | 18 participants |
| Panitumumab/Gemcitabine/Carboplatin | Number of Treatment-related Toxicities Occurring in ≥10% of Patients as a Measure of Tolerability and Toxicity | Mucositis/stomatitis | 16 participants |
| Panitumumab/Gemcitabine/Carboplatin | Number of Treatment-related Toxicities Occurring in ≥10% of Patients as a Measure of Tolerability and Toxicity | Constipation | 15 participants |
| Panitumumab/Gemcitabine/Carboplatin | Number of Treatment-related Toxicities Occurring in ≥10% of Patients as a Measure of Tolerability and Toxicity | Dyspnea | 12 participants |
| Panitumumab/Gemcitabine/Carboplatin | Number of Treatment-related Toxicities Occurring in ≥10% of Patients as a Measure of Tolerability and Toxicity | Pruritis | 12 participants |
| Panitumumab/Gemcitabine/Carboplatin | Number of Treatment-related Toxicities Occurring in ≥10% of Patients as a Measure of Tolerability and Toxicity | Anorexia | 10 participants |
| Panitumumab/Gemcitabine/Carboplatin | Number of Treatment-related Toxicities Occurring in ≥10% of Patients as a Measure of Tolerability and Toxicity | Diarrhea | 9 participants |
| Panitumumab/Gemcitabine/Carboplatin | Number of Treatment-related Toxicities Occurring in ≥10% of Patients as a Measure of Tolerability and Toxicity | AST/ALT increased | 9 participants |
| Panitumumab/Gemcitabine/Carboplatin | Number of Treatment-related Toxicities Occurring in ≥10% of Patients as a Measure of Tolerability and Toxicity | Alopecia | 7 participants |
| Panitumumab/Gemcitabine/Carboplatin | Number of Treatment-related Toxicities Occurring in ≥10% of Patients as a Measure of Tolerability and Toxicity | Dyspepsia | 7 participants |
| Panitumumab/Gemcitabine/Carboplatin | Number of Treatment-related Toxicities Occurring in ≥10% of Patients as a Measure of Tolerability and Toxicity | Myalgia | 7 participants |
| Panitumumab/Gemcitabine/Carboplatin | Number of Treatment-related Toxicities Occurring in ≥10% of Patients as a Measure of Tolerability and Toxicity | Neutropenia | 32 participants |
| Panitumumab/Gemcitabine/Carboplatin | Number of Treatment-related Toxicities Occurring in ≥10% of Patients as a Measure of Tolerability and Toxicity | Thrombocytopenia | 32 participants |
| Panitumumab/Gemcitabine/Carboplatin | Number of Treatment-related Toxicities Occurring in ≥10% of Patients as a Measure of Tolerability and Toxicity | Leukopenia | 25 participants |
| Panitumumab/Gemcitabine/Carboplatin | Number of Treatment-related Toxicities Occurring in ≥10% of Patients as a Measure of Tolerability and Toxicity | Anemia | 20 participants |
| Panitumumab/Gemcitabine/Carboplatin | Number of Treatment-related Toxicities Occurring in ≥10% of Patients as a Measure of Tolerability and Toxicity | Rash | 50 participants |
Secondary
Objective Response Rate and Clinical Benefit Rate
Estimated as the proportion of subjects who meet the criteria for complete or partial response (CR or PR) per Response Evaluation Criteria in Solid Tumors (RECIST) v 1.1 - for target lesions assessed by MRI: Complete Response (CR) is defined as disappearance of all target lesions; Partial Response (PR) is defined as \>=30% decrease in the sum of the longest diameter of target lesions.
Time frame: every 6 weeks until treatment discontinuation
Population: All evaluable patients per RECIST v 1.1
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Panitumumab/Gemcitabine/Carboplatin | Objective Response Rate and Clinical Benefit Rate | Clinical benefit rate (CR + PR + SD>6 months) | 32 Participants |
| Panitumumab/Gemcitabine/Carboplatin | Objective Response Rate and Clinical Benefit Rate | Objective response rate (CR + PR) | 30 Participants |