Clinical trial NCT01982448: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Triple Negative Breast Cancer
Keywords: TRIPLE NEGATIVE BREAST CANCER
CISPLATIN
PACLITAXEL
Lead sponsor: Dana-Farber Cancer Institute
Sponsor class: OTHER
Collaborators: name: Myriad Genetics, Inc.
name: Translational Breast Cancer Research Consortium
First posted: 2013-11-13
Enrollment: 147
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

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).

Primary outcomes:
measure: Number of Participants With Pathologic Response by HR-deficiency (HRD) Status
timeFrame: Evaluated after definitive breast surgery, up to 4-5 months from enrollment.
Secondary outcomes:
measure: Number With Pathologic Complete Response (pCR) by HR-deficiency (HRD) Status
timeFrame: Evaluated after definitive breast surgery, up to 4-5 months from enrollment.
measure: Number of Pathologic Response
timeFrame: Evaluated after definitive breast surgery, up to 4-5 months from enrollment.
measure: Number With Pathologic Response
timeFrame: Evaluated after definitive breast surgery, up to 4-5 months from enrollment.
measure: Positive Predictive Value (PPV) of HRD Score
timeFrame: Evaluated after definitive breast surgery, up to 4-5 months from enrollment.
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama
state: Alabama
city: Indianapolis
country: United States
facility: Indiana University- Simon Cancer Center
state: Indiana
city: Baltimore
country: United States
facility: Johns Hopkins University
state: Maryland
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center
state: Massachusetts
city: Boston
country: United States
facility: Dana-Farber Cancer Institute
state: Massachusetts
city: Weymouth
country: United States
facility: South Shore Hospital
state: Massachusetts
city: Basking Ridge
country: United States
facility: Memorial Sloan Kettering Cancer Center-Basking Ridge
state: New Jersey
city: Middletown
country: United States
facility: Memorial Sloan Kettering Cancer Center-Monmouth
state: New Jersey
city: Commack
country: United States
facility: Memorial Sloan Kettering Cancer Center-Commack
state: New York
city: Harrison
country: United States
facility: Memorial Sloan Kettering Cancer Center-West Harrison
state: New York
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: Rockville Centre
country: United States
facility: Memorial Sloan Kettering Cancer Center-Rockville Centre
state: New York
city: Sleepy Hollow
country: United States
facility: Memorial Sloan Kettering Cancer Center-Sleepy Hollow
state: New York
city: Chapel Hill
country: United States
facility: University of North Carolina- Lineberger Cancer Center
state: North Carolina
city: Durham
country: United States
facility: Duke University
state: North Carolina
city: Pittsburgh
country: United States
facility: Universtiy of Pittsburgh- Magee-Womens Hospital
state: Pennsylvania
city: Nashville
country: United States
facility: Vanderbilt-Ingram Cancer Center
state: Tennessee
city: Houston
country: United States
facility: Baylor College of Medicine
state: Texas
city: Kirkland
country: United States
facility: Seattle Cancer Alliance at EvergreenHealth
state: Washington
city: Seattle
country: United States
facility: University of Washignton
state: Washington
Study officials:
affiliation: Dana-Farber Cancer Institute
name: Erica Mayer, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Mayer EL, Abramson V, Jankowitz R, Falkson C, Marcom PK, Traina T, Carey L, Rimawi M, Specht J, Miller K, Stearns V, Tung N, Perou C, Richardson AL, Componeschi K, Trippa L, Tan-Wasielewski Z, Timms K, Krop I, Wolff AC, Winer EP. TBCRC 030: a phase II study of preoperative cisplatin versus paclitaxel in triple-negative breast cancer: evaluating the homologous recombination deficiency (HRD) biomarker. Ann Oncol. 2020 Nov;31(11):1518-1525. doi: 10.1016/j.annonc.2020.08.2064. Epub 2020 Aug 13.