Substantially Improving the Cure Rate of High-risk BRCA1-like Breast Cancer

Study Overview
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Brief Summary
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Investigator-initiated, international, multicentre, randomized, open-label, (neo)adjuvant phase III study in target population (stage III, HER2-negative, BRCA1-like breast cancer patients) comparing optimized standard-dose chemotherapy with intensified, alkylating chemotherapy with stem cell rescue.

Official Title
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Substantially Improving the Cure Rate of High-risk BRCA1-like Breast Cancer Patients With Personalized Therapy (SUBITO) - an International Randomized Phase III Trial

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: ddAC-CP-Olaparib
* Drug: ddAC-mini CTC


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Women and men with stage III adenocarcinoma of the breast harboring signs of a breast cancer with features of homologous recombination deficiency (HRD) Age of 18-65 years The tumor must be HER2-negative Treatment must start within 8 weeks after the last surgical resection Eastern Cooperative Oncology Group (ECOG) performance status 0-1 Exclusion Criteria: Previous radiation therapy Previous chemotherapy Any previous treatment with a PARP-inhibitor, including olaparib Pre-existing neuropathy from any cause in excess of Grade 1 Chronic concomitant use of known strong or moderate CYP3A inducers

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: ddAC-CP-Olaparib<br>ddAC; doxorubicin 60 mg/m² as an i.v. bolus and cyclophosphamide 600 mg/m² as an i.v. bolus on day 1 every 2 weeks ddAC must be supported with prophylactic pegfilgrastim 6 mg s.c. given 24-48 hours after completion of administration of EVERY chemotherapy cycle CP; carboplatin/paclitaxel (CP) consisting of carboplatin (AUC 6) on day 1 and paclitaxel (80 mg/m2) on day 1,8 and 15 of a 21 days cycle. In total 4 courses of CP will be administered. Olaparib will be administered in Dutch centers only, as monotherapy for one year at a dose of 300 mg BID, starting 3 weeks after adjuvant radiotherapy, or, if radiotherapy is not indicated, 3-5 weeks after the last CP cycle. Patients without a (near) pCR will receive adjuvant capecitabine at a starting dose of 1000-1250 mg/m2, twice a day, on days 1-14 every 3 weeks for eight cycles. | Drug: ddAC-CP-Olaparib<br>* ddAC-CP-Olaparib<br>|
| Active Comparator: ddAC-mini CTC<br>ddAC; doxorubicin 60 mg/m² as an i.v. bolus and cyclophosphamide 600 mg/m² as an i.v. bolus on day 1 every 2 weeks ddAC must be supported with prophylactic pegfilgrastim 6 mg s.c. given 24-48 hours after completion of administration of EVERY chemotherapy cycle intensified alkylating 'mini' CTC (2x) cyclophosphamide 3000 mg/m2 day 1 mesna 500 mg (push) + 2000 mg in 24 hours day 1 carboplatin (400 mg/m2; (or AUC=5 in patients with a calculated creatinine-clearance of <100 ml/min)) days 1,2 thiotepa 250 mg/m2 day 2 Patients without a (near) pCR will receive adjuvant capecitabine at a starting dose of 1000-1250 mg/m2, twice a day, on days 1-14 every 3 weeks for eight cycles. | Drug: ddAC-mini CTC<br>* ddAC - mini CTC<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival | time from randomization to death from any cause. | assessed up to 120 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Recurrence free interval | time from randomization to local recurrence, second primary, distant recurrence or death, whichever comes first | assessed up to 120 months | 
| Incidence of toxicity, graded according to National Cancer Institute Common Toxicity Criteria (NCI-CTC) version 4.03 | Incidence of toxicity, graded according to National Cancer Institute Common Toxicity Criteria (NCI-CTC) version 4.03 | up to 30 days after end of treatment | 
| cost-effectiveness measured by costs per quality-adjusted life years (QALYs) | cost-effectiveness measured by costs per quality-adjusted life years (QALYs) | assessed up to 120 months | 
| Patient reported outcomes | Patient reported outcomes; including quality of life (QoL) determined by a comprehensive panel of QoL questionnaires | assessed up to 24 months | 
| cost-effectiveness measured by incremental cost-effectiveness ratio (ICER) | cost-effectiveness measured by incremental cost-effectiveness ratio (ICER) | assessed up to 120 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Stage III, HER2 negative, homologous recombination deficiency (HRD)