Substantially improving the cure rate of high-risk BRCA1-like breast cancer patients with personalized therapy (SUBITO) - an international randomized phase III trial

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Het Nederlands Kanker Instituut-Antoni van Leeuwenhoek Ziekenhuis Stichting

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

1 Jan 2017 → ongoing

Decision date (initial)

2025-01-29

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

KWF Dutch Cancer Society · ZonMw · AstraZeneca/ Daiichi Sankyo

External identifiers

EU CT number

2024-516196-32-00

EudraCT number

2016-002493-13

ClinicalTrials.gov

NCT02810743

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Therapy, Efficacy

To investigate whether neoadjuvant systemic treatment of intensified alkylating chemotherapy with peripheral stem cell rescue (mCTC) (and adjuvant capecitabine for patients without (near) pathologic complete response) compared to AC-CP chemotherapy (and adjuvant capecitabine for patients without (near) pathologic complete response) followed by 1-year olaparib monotherapy substantially improves overall survival (OS) in patients with stage III, HER2-negative, HR impaired or HR deficient breast cancer.

Secondary objectives 8

1. Key secondary objective: To investigate whether neoadjuvant systemic treatment of intensified alkylating chemotherapy with peripheral stem cell rescue (mCTC) (and adjuvant capecitabine for patients without (near) pathologic complete response) compared to AC-CP chemotherapy (and adjuvant capecitabine for patients without (near) pathologic complete response) followed by 1-year olaparib monotherapy substantially improves overall survival (OS) in patients with stage III, HER2-negative, HR-impaired (BRCA1-like and/or BRCA1pm) breast cancer who do not have a known germline BRCA1/2 mutation.
2. To compare the toxicity between (neo)adjuvant systemic treatment of intensified alkylating chemotherapy with peripheral stem cell rescue (mCTC) and optimized, standard dosed AC-CP chemotherapy followed by 1-year olaparib monotherapy
3. To investigate whether neoadjuvant systemic treatment of intensified alkylating chemotherapy with peripheral stem cell rescue (mCTC) compared to the AC-CP regimen substantially improves pathological complete remission (pCR) rate in patients with stage III, HER2-negative, HR impaired or HR deficient breast cancer.
4. To investigate whether neoadjuvant systemic treatment of intensified alkylating chemotherapy with peripheral stem cell rescue (mCTC) compared to the AC-CP-olaparib regimen substantially improves recurrence-free survival (RFS) in i) patients with stage III, HER2-negative, HR impaired or HR deficient breast cancer; ii) patients with stage III, HER2-negative, HR-impaired (BRCA1-like and/or BRCA1pm) breast cancer who do not have a known germline BRCA1/2 mutation.
5. To investigate potential heterogeneity in efficacy (pCR, OS and RFS), safety, quality of life, cost-effectiveness, and neurocognitive functioning regarding mCTC treatment versus the standard-dosed regimen for the following factors: BRCA1 germline mutation present versus absent, BRCA2 germline mutation present versus absent, combined group of BRCA1 or BRCA2 germline mutation present versus absent, stage IIIa/b versus stage IIIc, BRCA1 promoter hypermethylation present versus absent, cT1-2 versus cT3-4, age <45 years versus age ≥45 years, histological grade I+II versus III
6. To investigate cost-effectiveness of mCTC compared to the AC-CP-olaparib regimen in i) patients with stage III, HER2-negative, HR impaired or HR deficient breast cancer; ii) patients with stage III, HER2-negative, HR-impaired (BRCA1-like and/or BRCA1pm) breast cancer who do not have a known germline BRCA1/2 mutation.
7. To investigate patient reported outcomes, including an interview, quality of life and neuro-cognitive functioning of patients treated with mCTC compared to the AC-CP-olaparib regimen in i) patients with stage III, HER2-negative, HR impaired or HR deficient breast cancer; ii) patients with stage III, HER2-negative, HR-impaired (BRCA1-like and/or BRCA1pm) breast cancer who do not have a known germline BRCA1/2 mutation.
8. To investigate the difference in overall survival between patients randomized in the SUBITO trial and usual care patients by expanding the usual care arm with patients who have the same characteristics treated outside of the trial in the Netherlands (using data from the Netherlands Cancer Registry (NCR)).

Conditions and MedDRA coding

breast cancer

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 7

1. Males or females ≥18 and <66 years of age and fit to undergo autologous stem cell transplantation
2. Histologically confirmed adenocarcinoma of the breast
3. The tumor must be: HER2-negative (either score 0 or 1 at immunohistochemistry or negative at in situ hybridization [CISH or FISH] in case of score 2 at immunohistochemistry);AND Hormone receptor negative; or in case of a histological grade III tumor an estrogen receptor of <50% and progesterone receptor of <50% (Unless BRCA1 or BRCA2 germline mutation carrier)
4. Patients treated in the neoadjuvant setting
5. Women and men with stage III adenocarcinoma of the breast (according to AJCC staging manual 7th edition; Stage IIIA: T0-2N2 or T3N1-2; Stage IIIB: T4N0-2; Stage IIIC: any TN3) harboring signs of a breast cancer with features of homologous recombination deficiency (HRD) Based on the results of the preliminary work, the following HRD working definition will be employed: The patient is a known BRCA1 or BRCA2 mutation carrier; and/or the tumor exhibits a BRCA1 promoter hypermethylation, and/or the tumor exhibits a BRCA1-like DNA copy number profile
6. Eastern Cooperative Oncology Group (ECOG) performance status 0-1
7. Provision of informed consent

Exclusion criteria 6

1. Evidence of distant metastases
2. Previous radiation therapy
3. Previous chemotherapy (except for ddAC cycles 1-3 for the current breast cancer, or another third generation chemotherapy cycle 1
4. Any previous treatment with a PARP-inhibitor, including olaparib
5. Pre-existing neuropathy from any cause > Grade 1
6. Pregnant; or breastfeeding and not willing to stop breastfeeding in order to be able to participate in the study

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Overall survival, defined as the time from randomization to death from any cause in all patients.

Secondary endpoints 8

1. Key secondary endpoint: Overall survival, defined as the time from randomization to death from any cause in patients without a germline BRCA1/2 mutation.
2. Recurrence-free interval, defined as time from randomization to invasive ipsilateral breast tumor recurrence, locoregional- or distant recurrence, or death from breast cancer, whichever comes first, in all patients, regardless of germline BRCA1/2 status.
3. Recurrence-free interval defined as time from randomization to invasive ipsilateral breast tumor recurrence, locoregional- or distant recurrence, or death from breast cancer, whichever comes first, in patients with an HR impaired tumor (i.e. harboring a BRCA1-like copy number profile or BRCA1 promotor hypermethylation, in the absence of a known germline BRCA1/2 mutation).
4. (non-)hematological toxicity determined according to CTCAE v4.03.
5. cost-effectiveness measured by costs per quality-adjusted life years (QALYs) and incremental cost-effectiveness ratio (ICER).
6. Patient reported outcomes; including an interview, quality of life (QoL) determined by a comprehensive panel of QoL questionnaires and cognitive function
7. Several potential biomarkers
8. The difference in overall survival between patients treated in the SUBITO trial and patients with the same characteristics treated outside of the trial in the Netherlands (using data from the Netherlands Cancer Registry (NCR)).

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Comparator 6

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Het Nederlands Kanker Instituut-Antoni van Leeuwenhoek Ziekenhuis Stichting

Sponsor organisation

Het Nederlands Kanker Instituut-Antoni van Leeuwenhoek Ziekenhuis Stichting

Address

Plesmanlaan 121

City

Amsterdam

Postcode

1066 CX

Country

Netherlands

Scientific contact point

Organisation

Het Nederlands Kanker Instituut-Antoni van Leeuwenhoek Ziekenhuis Stichting

Contact name

Prof. Dr. S.C. Linn

Public contact point

Organisation

Het Nederlands Kanker Instituut-Antoni van Leeuwenhoek Ziekenhuis Stichting

Contact name

Prof. Dr. S.C. Linn

Locations

2 EU/EEA countries · 10 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 23 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications