Breast Cancer
Conditions
Keywords
ER negative, PgR negative, HER2 negative, cisplatin, carboplatinum, platinum, p63, p73
Brief summary
The purpose of this research study is to : * Determine how effective cisplatin or carboplatin is in slowing the time it takes for ER negative (estrogen-receptor-negative), PR negative (progesterone receptor-negative), HER2 negative (human epidermal growth factor receptor 2) breast cancer to progress. Cisplatin and carboplatin are anti-cancer chemotherapy drugs that stop cancer cells from growing abnormally and is used to treat other cancers. * Evaluate a new biomarker to help determine which breast cancers are most likely to respond to cisplatin chemotherapy The hypothesis is that Triple Negative metastatic breast cancer may be particularly sensitive to platinum, and that a subgroup of those patients may have a marker in their tumors that predicts response.
Detailed description
This study is a Phase 2 study designed to evaluate cisplatin/carboplatin as first or second line therapy in metastatic triple negative (ER negative, PR negative, Her2 Negative) breast cancer and to evaluate the expression of p63/p73 as a biomarker to predict response. * Participants will be given a cisplatin or carboplatin infusion intravenously on the first day of each treatment cycle. Each treatment cycle will last 3 weeks. Treating physician will select agent up to 41 patients in each cohort. Final primary endpoint analysis will use combined cis/carbo results. * During all treatment cycles participants will have a physical exam (including weight and vital signs) and they will be asked general questions about their health and any medications they may be taking, as well as specific questions about any side effects they may be experiencing while receiving study treatment. * During every treatment cycle participants will have standard blood tests to check blood counts, liver and kidney function, and a blood marker for you particular type of cancer. * CT scans will be taken of the participants tumor every 2 to 3 cycles to assess the response of the tumor to cisplatin. * Participants will be in this study for as long as they tolerate the study treatment and their disease does not get any worse. * Participants will be required to have a sample of their original tumor sent to Massachusetts General Hospital for correlative studies, or a sample from a metastatic diagnostic biopsy. * Patients with accessible tumor will be asked to provide an optional metastatic tumor biopsy for correlative studies.
Interventions
DRUGCisplatin
Given intravenously on the first day of each 3-week treatment cycle at 75mg/m2. Participants may continue to receive study treatment as long as their disease does not worsen and they do not experience serious side effects.
DRUGcarboplatin
Given intravenously on the first day of each 3-week treatment cycle at AUC 6. Participants may continue to receive study treatment as long as their disease does not worsen and they do not experience serious side effects.
Sponsors
Beth Israel Deaconess Medical Center
Dana-Farber Cancer Institute
North Shore Medical Center
Massachusetts General Hospital
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
* Histologically confirmed invasive breast cancer with stage IV disease, according to AJCC 6th edition (American Joint Committee on Cancer), either biopsy proven or with unequivocal evidence of metastatic disease by physical examination or radiological study * All tumors must be ER-, PGR- and HER2-negative * 18 years of age or older * Paraffin tissue block is required from the primary tumor tissue or from diagnostic metastatic biopsy at time of relapse * Measurable disease by RECIST * Performance status of 0,1 or 2 by ECOG criteria (Eastern Cooperative Oncology Group) * Life expectancy greater than 12 weeks * Normal organ and bone marrow function documented within 14 days prior to enrollment as defined by the protocol
Exclusion criteria
* More than 1 prior chemotherapy for the treatment of recurrent or metastatic breast cancer * Prior treatment with cisplatin, carboplatin, or other platinum chemotherapy agents * Active brain metastases or unevaluated neurological symptoms suggestive of brain metastases * Intercurrent illness or other major medical condition or comorbid condition that might affect study participation * Significant history of uncontrolled cardiac disease such as uncontrolled hypertension, unstable angina, recent myocardial infarction, uncontrolled congestive heart failure, cardiomyopathy either symptomatic or asymptomatic but with decreased ejection fraction \<45% * Renal dysfunction for which cisplatin dose would either require dose modification or would be considered unsafe * Pregnant or nursing women * History or other malignancy that was not treated with curative intent
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate | 3 years | Objective response rate (ORR) (complete response \[CR\]+ partial response \[PR\]) by RECIST (Response Evaluation Criteria In Solid Tumors). Complete Response (CR): Disappearance of all target lesions Partial Response (PR): At least a 30% decrease in the sum of the LD (longest diameter) of target lesions, taking as reference the baseline sum LD Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started Progressive Disease (PD): At least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions |
| Response Rate Categorized by p63/p73 Ratio | 3 years | Response rate categorized by pre-specified ΔNp63/TAp73 expression ratio cutoff in the primary tumors from this patient cohort as a bio-marker to predict response to cisplatin or carboplatin. Response is defined as partial or completed response as determined by RECIST. Expression ratio was measured using quantitative RT-PCR (Reverse transcription polymerase chain reaction). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate Categorized by Subgroup | 3 years | The number of participants achieving an objective response (as determined by RECIST) categorized by treatment cohort and whether the treatment was first or second line treatment. First line treatment means that the drug used was the first drug used for the treatment of the primary cancer. Second line treatment means that a first line treatment failed to produce the desired response, so a new drug was used for treatment. |
| Progression Free Survival and Overall Survival | 5 years | Median progression free survival and overall survival (progression determined using RECIST) during a median follow-up time of 50 months. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Single Arm Cisplatin or carboplatin (1 arm, 2 cohorts)
Cisplatin: Given intravenously on the first day of each 3-week treatment cycle at 75mg/m2. Participants may continue to receive study treatment as long as their disease does not worsen and they do not experience serious side effects.
carboplatin: Given intravenously on the first day of each 3-week treatment cycle at AUC 6. Participants may continue to receive study treatment as long as their disease does not worsen and they do not experience serious side effects. | 86 |
| Total | 86 |
Baseline characteristics
| Characteristic | Single Arm |
|---|---|
| Age, Continuous | 52 years |
| Age, Customized < 40 | 13 Participants |
| Age, Customized 40-65 | 63 Participants |
| Age, Customized > 65 | 10 Participants |
| ECOG PS 0 | 55 Participants |
| ECOG PS 1 | 20 Participants |
| ECOG PS 2 | 5 Participants |
| ECOG PS Not reported | 6 Participants |
| Prior chemotherapy Adjuvant/neoadjuvant | 74 participants |
| Prior chemotherapy Anthracycline | 65 participants |
| Prior chemotherapy Taxane | 67 participants |
| Race/Ethnicity, Customized African American | 7 Participants |
| Race/Ethnicity, Customized Asian | 4 Participants |
| Race/Ethnicity, Customized > one or other | 6 Participants |
| Race/Ethnicity, Customized White | 69 Participants |
| Region of Enrollment United States | 86 Participants |
| Sex: Female, Male Female | 86 Participants |
| Sex: Female, Male Male | 0 Participants |
| Site of metastases Bone | 25 participants |
| Site of metastases Brain | 4 participants |
| Site of metastases Liver | 25 participants |
| Site of metastases Lung | 44 participants |
| Site of metastases Lymph nodes | 54 participants |
| Site of metastases Skin | 16 participants |
| Stage at initial diagnosis of breast cancer 1 | 10 Participants |
| Stage at initial diagnosis of breast cancer 2 | 32 Participants |
| Stage at initial diagnosis of breast cancer 3 | 37 Participants |
| Stage at initial diagnosis of breast cancer 4 | 7 Participants |
| Treatment cohort Carboplatin (cohort 2) | 43 Participants |
| Treatment cohort Cisplatin (cohort 1) | 43 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 75 / 86 |
| other Total, other adverse events | 85 / 86 |
| serious Total, serious adverse events | 8 / 86 |
Outcome results
Primary
Objective Response Rate
Objective response rate (ORR) (complete response \[CR\]+ partial response \[PR\]) by RECIST (Response Evaluation Criteria In Solid Tumors). Complete Response (CR): Disappearance of all target lesions Partial Response (PR): At least a 30% decrease in the sum of the LD (longest diameter) of target lesions, taking as reference the baseline sum LD Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started Progressive Disease (PD): At least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions
Time frame: 3 years
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cisplatin or Carboplatin | Objective Response Rate | Not Evaluable | 3 Participants |
| Cisplatin or Carboplatin | Objective Response Rate | Complete Response | 3 Participants |
| Cisplatin or Carboplatin | Objective Response Rate | Partial Response | 19 Participants |
| Cisplatin or Carboplatin | Objective Response Rate | Stable Disease > 6 Months | 4 Participants |
| Cisplatin or Carboplatin | Objective Response Rate | Progressive Disease | 57 Participants |
Primary
Response Rate Categorized by p63/p73 Ratio
Response rate categorized by pre-specified ΔNp63/TAp73 expression ratio cutoff in the primary tumors from this patient cohort as a bio-marker to predict response to cisplatin or carboplatin. Response is defined as partial or completed response as determined by RECIST. Expression ratio was measured using quantitative RT-PCR (Reverse transcription polymerase chain reaction).
Time frame: 3 years
Population: Patients from either cohort with a tumor sample available to evaluate for expression ratio.
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| Cisplatin or Carboplatin | Response Rate Categorized by p63/p73 Ratio | p63/p73 > 2 | Response | 9 Participants |
| Cisplatin or Carboplatin | Response Rate Categorized by p63/p73 Ratio | p63/p73 > 2 | No Response | 24 Participants |
| Cisplatin or Carboplatin | Response Rate Categorized by p63/p73 Ratio | p63/p73 < 2 | Response | 5 Participants |
| Cisplatin or Carboplatin | Response Rate Categorized by p63/p73 Ratio | p63/p73 < 2 | No Response | 23 Participants |
Comparison: H0: no association between expression ratio and response rate Ha: Participants with expression ratio greater than 2 would have higher response ratep-value: 0.54t-test, 2 sided
Secondary
Objective Response Rate Categorized by Subgroup
The number of participants achieving an objective response (as determined by RECIST) categorized by treatment cohort and whether the treatment was first or second line treatment. First line treatment means that the drug used was the first drug used for the treatment of the primary cancer. Second line treatment means that a first line treatment failed to produce the desired response, so a new drug was used for treatment.
Time frame: 3 years
Population: Response rate is divide by drug cohort and categorized by first or second-line treatment
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| Cisplatin or Carboplatin | Objective Response Rate Categorized by Subgroup | Cisplatin | First line: Response | 12 Participants |
| Cisplatin or Carboplatin | Objective Response Rate Categorized by Subgroup | Cisplatin | First line: No response | 22 Participants |
| Cisplatin or Carboplatin | Objective Response Rate Categorized by Subgroup | Cisplatin | Second line: Response | 2 Participants |
| Cisplatin or Carboplatin | Objective Response Rate Categorized by Subgroup | Cisplatin | Second line: No response | 7 Participants |
| Cisplatin or Carboplatin | Objective Response Rate Categorized by Subgroup | Carboplatin | First line: Response | 8 Participants |
| Cisplatin or Carboplatin | Objective Response Rate Categorized by Subgroup | Carboplatin | First line: No response | 27 Participants |
| Cisplatin or Carboplatin | Objective Response Rate Categorized by Subgroup | Carboplatin | Second line: Response | 0 Participants |
| Cisplatin or Carboplatin | Objective Response Rate Categorized by Subgroup | Carboplatin | Second line: No response | 8 Participants |
Secondary
Progression Free Survival and Overall Survival
Median progression free survival and overall survival (progression determined using RECIST) during a median follow-up time of 50 months.
Time frame: 5 years
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Cisplatin or Carboplatin | Progression Free Survival and Overall Survival | Median Progression Free Survival | 2.9 Months |
| Cisplatin or Carboplatin | Progression Free Survival and Overall Survival | Median Overall Survival | 11 Months |