Description:
This is a phase II study randomizing patients with stage I with T1 > 1.5 cm, stage II or III
triple negative breast cancer (TNBC) to preoperative cisplatin versus paclitaxel. The study
is designed to evaluate the ability of the Homologous Recombination Deficiency (HRD) assay to
predict pathologic response to preoperative chemotherapy.
Title
- Brief Title: Cisplatin vs Paclitaxel for Triple Negative Breast Cancer
- Official Title: A Randomized Phase II Study of Preoperative Cisplatin Versus Paclitaxel in Patients With Triple Negative Breast Cancer: Evaluating the Homologous Recombination Deficiency (HRD) Biomarker
Clinical Trial IDs
- ORG STUDY ID:
13-383
- SECONDARY ID:
TBCRC030
- NCT ID:
NCT01982448
Conditions
- Triple Negative Breast Cancer
Interventions
Drug | Synonyms | Arms |
---|
Cisplatin | Platinol ®-AQ | Arm A: Cisplatin |
Paclitaxel | Taxol | Arm B: Paclitaxel |
Purpose
This is a phase II study randomizing patients with stage I with T1 > 1.5 cm, stage II or III
triple negative breast cancer (TNBC) to preoperative cisplatin versus paclitaxel. The study
is designed to evaluate the ability of the Homologous Recombination Deficiency (HRD) assay to
predict pathologic response to preoperative chemotherapy.
Detailed Description
Cisplatin and paclitaxel are active in triple-negative breast cancer (TNBC). Despite
different mechanisms of action, effective predictive biomarkers to preferentially inform drug
selection have not been identified. The homologous recombination deficiency (HRD) assay
(Myriad Genetics, Inc.) detects impaired double-strand DNA break repair and may identify
patients with BRCA1/2-proficient tumors that are sensitive to DNA-targeting therapy. The
primary objective of TBCRC 030 was to detect an association of HRD with pathologic response
(residual cancer burden (RCB)-0/1) to singleagent cisplatin or paclitaxel.
This prospective phase II study enrolled patients with germline BRCA1/2 wild-type/unknown
stage I-III TNBC in a 12-week randomized study of preoperative cisplatin or paclitaxel. The
HRD assay was carried out on baseline tissue; positive HRD was defined as a score >=33.
Crossover to an alternative chemotherapy was offered if there was inadequate response.
Trial Arms
Name | Type | Description | Interventions |
---|
Arm A: Cisplatin | Experimental | Cisplatin given by IV infusion at a dose of 75 mg/m2 every 3 weeks (1 cycle) for 4 cycles as preoperative chemotherapy. Participants with inadequate clinical response after 12 weeks (as judged either clinically or radiologically by a provider) were able to crossover to an alternative provider-selected preoperative chemotherapy regimen. Definitive breast surgery following no later than 42 days after administration of last chemotherapy. | |
Arm B: Paclitaxel | Experimental | Paclitaxel given by IV infusion at a dose of 80 mg/m2 weekly for 12 weeks (4 cycles) as neoadjuvant chemotherapy. Participants with inadequate clinical response after 12 weeks (as judged either clinically or radiologically by a provider) were able to 'crossover' to an alternative provider-selected preoperative chemotherapy regimen. Definitive breast surgery following no later than 42 days after administration of last chemotherapy. | |
Eligibility Criteria
Inclusion Criteria:
1. Participants must meet the following criteria on screening examination to be eligible
to participate in the study
2. Pathologic documentation of invasive breast cancer by biopsy (FNA alone is not
adequate).
3. AJCC clinical stage I with T1 > 1.5 cm, stage II or III invasive breast cancer.
4. Participants with multicentric or bilateral disease are eligible if at least one
lesion meets stage eligibility criteria for the study and no tumor is HER2-positive.
5. Tumors must be HER2 negative defined as HER2 0 or 1+ by immunohistochemistry (IHC)
assays and /or lack of gene amplification by FISH defined as a ratio < 2 on invasive
tumor by local review.
6. ER and PgR status by IHC must be known. Tumor must be ER and PR negative (≤5%
staining) by local review.
7. Known BRCA1/2 (BReast CAncer) status is not required for study entry. However patients
known to have a germline deleterious BRCA1/2 mutation should be encouraged to consider
a preoperative trial specifically designed for BRCA1/2 carriers, if available.
8. Breast imaging should include imaging of the ipsilateral axilla. For subjects with a
clinically positive axilla, a needle aspiration, core biopsy or SLN procedure will be
performed to confirm the presence of metastatic disease in the lymph nodes.
For patients with a clinically negative axilla, baseline assessment of the axilla will be
performed at the discretion of the treating investigator.
For patients with pathologically positive axillary lymph nodes prior to preoperative
therapy, a level I and II lymph node dissection at the time of definitive surgery is
recommended.
9. Patients with a prior history of contra-lateral breast cancer are eligible if they have
no evidence of recurrence of their initial primary breast cancer within the last 5 years.
10. Women ≥ 18 years of age. 11. ECOG performance status ≤1 (see Appendix A). 12.
Laboratory Evaluation
1. Absolute neutrophil count (ANC) ≥ 1,500 / mm3
2. Platelet count ≥ 100,000/ mm3
3. Bilirubin ≤ 1.5x upper limit of normal (ULN), for patients with Gilbert syndrome,
direct bilirubin will be measured instead of total bilirubin
4. ALT, AST ≤3.0 x ULN ALK Phos <2.5 x ULN
5. Creatinine ≤ 1.5 mg/dl or creatinine clearance ≥ 60 cc/min
6. Hemoglobin ≥ 9 mg/dl
7. Use of an effective means of contraception is required in subjects of childbearing
potential since study agents are known to be teratogenic. Should a woman become
pregnant or suspect she is pregnant while participating in this study, she should
inform her treating physician immediately. Women of child-bearing potential and men
must agree to use adequate contraception (barrier method of birth control; abstinence)
prior to study entry and for the duration of study participation.
8. Ability to understand and the willingness to sign a written informed consent document
9. Individuals with a history of other malignancies are eligible if they have been
disease-free for at least 5 years and are deemed by the investigator to be at low risk
for recurrence of that malignancy and did not receive prior chemotherapy. Individuals
with the following cancers are eligible if diagnosed and treated within the past 5
years: cervical cancer in situ, and basal cell or squamous cell carcinoma of the skin.
10. Patient must be willing to undergo mandatory research biopsy and blood draw. Prior to
biopsy procedures patients must be able to be off medications that could increase the
risk of bleeding
Exclusion Criteria:
1. Participants with axillary adenopathy only are not eligible for this study.
2. Prior chemotherapy: Prior non-taxane or platinum containing chemotherapy will be
allowed if the prior exposure was at least 5 years ago and the exposure is thought not
to potentially interact with the primary outcome of the trial or put the patient at
undue risk, and should be reviewed with study PI on a case by case basis.
3. Any prior treatment for the current breast cancer, including chemotherapy, hormonal
therapy, radiation or experimental therapy.
4. Ipsilateral breast recurrence, unless prior treatment consisted of excision alone for
DCIS or breast conserving treatment and hormonal therapy for DCIS or invasive breast
cancer.
5. Ongoing use of any other investigational or study agents.
6. Peripheral neuropathy of any etiology > grade 1 (NCI CTCAE Version 4.0- Appendix B)
7. Significant hearing loss that would prevent cisplatin administration.
8. Renal dysfunction for which exposure to cisplatin would be unsafe or require cisplatin
dose modification (i.e., Cre > 1.5 mg/dl or GFR < 60 cc/min).
Maximum Eligible Age: | N/A |
Minimum Eligible Age: | 18 Years |
Eligible Gender: | Female |
Healthy Volunteers: | No |
Primary Outcome Measures
Measure: | Number of Participants With Pathologic Response by HR-deficiency (HRD) Status |
Time Frame: | Evaluated after definitive breast surgery, up to 4-5 months from enrollment. |
Safety Issue: | |
Description: | Pathologic response was assessed using the MD Anderson residual cancer burden (RCB) method (Symmans et al. JCO 2007). Responders are defined as RCB 0/1 and non-responders as RCB 2/3. Participants who crossed over due inadequate clinical response after 12 weeks were counted as non-responders. HRD status was determined with baseline diagnostic tissue using the HRD assay (Myriad Genetics, Inc.; required minimum 100 mm2 of tumor tissue) which detects impaired double-strand DNA break repair. The positive threshold for HRD was a score >/= 33. |
Secondary Outcome Measures
Measure: | Number With Pathologic Complete Response (pCR) by HR-deficiency (HRD) Status |
Time Frame: | Evaluated after definitive breast surgery, up to 4-5 months from enrollment. |
Safety Issue: | |
Description: | Pathologic response was assessed using the MD Anderson residual cancer burden (RCB) method (Symmans et al. JCO 2007). pCR is defined as RCB-0. HRD status was determined with baseline diagnostic tissue using the HRD assay (Myriad Genetics, Inc.; required minimum 100 mm2 of tumor tissue) which detects impaired double-strand DNA break repair. The positive threshold for HRD was a score >/= 33. |
Measure: | Number of Pathologic Response |
Time Frame: | Evaluated after definitive breast surgery, up to 4-5 months from enrollment. |
Safety Issue: | |
Description: | Pathologic response was assessed using the MD Anderson residual cancer burden (RCB) method (Symmans et al. JCO 2007). Responders are defined as RCB 0/1 and non-responders as RCB 2/3. Participants who crossed over due inadequate clinical response after 12 weeks were counted as non-responders. HRD status was determined with baseline diagnostic tissue using the HRD assay (Myriad Genetics, Inc.; required minimum 100 mm2 of tumor tissue) which detects impaired double-strand DNA break repair. The positive threshold for HRD was a score >/= 33. |
Measure: | Number With Pathologic Response |
Time Frame: | Evaluated after definitive breast surgery, up to 4-5 months from enrollment. |
Safety Issue: | |
Description: | Pathologic response was assessed using the MD Anderson residual cancer burden (RCB) method (Symmans et al. JCO 2007). Responders are defined as RCB 0/1 and non-responders as RCB 2/3. Participants who crossed over due inadequate clinical response after 12 weeks were counted as non-responders. HRD status was determined with baseline diagnostic tissue using the HRD assay (Myriad Genetics, Inc.; required minimum 100 mm2 of tumor tissue) which detects impaired double-strand DNA break repair. The positive threshold for HRD was a score >/= 33. |
Measure: | Positive Predictive Value (PPV) of HRD Score |
Time Frame: | Evaluated after definitive breast surgery, up to 4-5 months from enrollment. |
Safety Issue: | |
Description: | Pathologic response was assessed using the MD Anderson residual cancer burden (RCB) method (Symmans et al. JCO 2007). Responders are defined as RCB 0/1 and non-responders as RCB 2/3. Participants who crossed over due inadequate clinical response after 12 weeks were counted as non-responders. HRD status was determined with baseline diagnostic tissue using the HRD assay (Myriad Genetics, Inc.; required minimum 100 mm2 of tumor tissue) which detects impaired double-strand DNA break repair. The positive threshold for HRD was a score >/= 33.
PPV was calculated as the probability of pathological response among the HRD positive group. |
Details
Phase: | Phase 2 |
Primary Purpose: | Interventional |
Overall Status: | Active, not recruiting |
Lead Sponsor: | Dana-Farber Cancer Institute |
Trial Keywords
- TRIPLE NEGATIVE BREAST CANCER
- CISPLATIN
- PACLITAXEL
Last Updated
June 18, 2021