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

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

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Breast Cancer
• Intervention / Treatment: Drug: ddAC-CP-Olaparib; Drug: ddAC-mini CTC

• Study Type: Interventional
• Enrollment (Estimated): 174
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Sabine Linn, Prof. MD; Phone Number: 9111 +3120512; Email: s.linn@nki.nl
• Study Contact Backup: Name: Vincent de Jong, MD; Phone Number: 9111 +3120512; Email: subito@nki.nl

Study Locations

• France
  • Marseille, France, 13009
    • Institut Paoli Calmettes
  • Paris, France
    • Hopital Tenon, University Marie-Curie
• Netherlands
  • Amsterdam, Netherlands, 1066 CX
    • Antoni van Leeuwenhoek
  • Amsterdam, Netherlands, 1081 HV
    • AZVU
  • Groningen, Netherlands
    • University Medical Center Groningen
  • Leiden, Netherlands, 2333 ZA
    • LUMC
  • Maastricht, Netherlands
    • Maastricht University Medical Center
  • NIjmegen, Netherlands, 6225GA
    • Radboud UMC
  • Rotterdam, Netherlands, 3015CE
    • Erasmus Medical Center Cancer Institute
  • Utrecht, Netherlands, 3584CX
    • University Medical Center Utrecht
  • Overijssel
    • Enschede, Overijssel, Netherlands, 7500 KA
      • Medical spectrum Twente

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: ddAC-CP-Olaparib; 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; ddAC-CP-Olaparib
Active Comparator: ddAC-mini CTC; 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; ddAC - mini CTC

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: The Netherlands Cancer Institute
• Investigators: Principal Investigator: Sabine Linn, Prof. MD, NKI-AVL

Study record dates

Study Major Dates

• Study Start (Actual): January 25, 2017
• Primary Completion (Estimated): October 1, 2024
• Study Completion (Estimated): December 1, 2033

Study Registration Dates

• First Submitted: June 16, 2016
• First Submitted That Met QC Criteria: June 20, 2016
• First Posted (Estimated): June 23, 2016

Study Record Updates

• Last Update Posted (Actual): March 29, 2024
• Last Update Submitted That Met QC Criteria: March 28, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: HER2 negative; Stage III; homologous recombination deficiency (HRD)
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Poly(ADP-ribose) Polymerase Inhibitors; Olaparib
• Other Study ID Numbers: M16BRC

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No