ABCSG 45: A clinical trial that examines whether the treatment with the medication olaparib in combination with the chemotherapy carboplatin is more effective than treatment with a standard chemotherapy (anthracycline/taxane-based) against a specific type of breast cancer (triple-negative) with a biologic characteristic (homologous recombination deficiency)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Verein Zur Praevention Und Therapie Boesartiger Erkrankungen Austrian Breast And Colorectal Cancer Study Group

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

17 Jun 2019 → 5 Sep 2025

Decision date (initial)

2024-04-26

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

AstraZeneca Österreich GmbH

External identifiers

EU CT number

2024-512821-10-00

EudraCT number

2016-004384-39

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Efficacy, Others, Pharmacogenomic, Safety, Dose response

To compare the efficacy of 6 cycles of pre-operative carboplatin/olaparib with 6 cycles of pre-operative taxane/anthracycline-based chemotherapy (TAC) in tumors exhibiting positive homologous recombination deficiency (HRD) status when measured by centrally assessed RCB at the time of surgery.

Secondary objectives 2

1. To compare the efficacy of 6 cycles of pre-operative carboplatin/olaparib with 6 cycles of pre-operative taxane/anthracycline-based chemotherapy (TAC) in tumors exhibiting positive HRD status when measured by pCR at the time of surgery.
2. To compare patient-reported quality of life (QoL) and sexual health (SH) in patients treated with pre-operative carboplatin/olaparib vs. patients treated with pre-operative TAC overall and by subgroups defined by menopausal status (only women) or age at randomization at multiple pre-specified time points.

Conditions and MedDRA coding

Early invasive triple negative breast cancer with positive HRD status (acc. to Myriad mychoice© test)

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 21

1. Main study: 1. Signed informed consent prior to any study specific assessments and procedures
2. Main study: 10. Negative pregnancy test (serum or urine) max. 28 days prior to randomization for women with childbearing potential: • Pregnancy testing does not need to be pursued in patients who are judged as postmenopausal before randomization, as determined by local practice, or who have undergone bilateral oophorectomy, total hysterectomy, or bilateral tubal ligation
3. Main study: 11. Women of childbearing potential and male patients randomized into treatment Arm A or B must use adequate contraception for the duration of protocol treatment and for 6 months after the last dose of (N)IMP for women and 3 months for male patients. Adequate contraception is defined as one highly effective form (i.e. total abstinence, (fe)male sterilization) OR two effective forms (e.g. non-hormonal intrauterine device (IUD) and condom/occlusive cap with spermicidal foam/gel/film/cream/suppository)
4. Main study: 12. Patient is willing and able to comply with the protocol for the duration of the study, incl. undergoing treatment, scheduled visits and examinations
5. Main study: 2. Patients must be ≥ 18 years of age
6. Main study: 3. Pre-menopausal (incl. peri-menopausal) and postmenopausal women and men with core-biopsied, early primary triple-negative (acc. to local standards) invasive breast cancer
7. Main study: 4. Positive HRD status (centrally assessed) in core-biopsy sample of the breast
8. Main study: 5. Absence of distant metastasis (M0) as assessed acc. to institutional standards within 90 days prior to randomization
9. Main study: 6. Unilateral early invasive TNBC patients.
10. Main study: 7. Willingness to undergo adequate lymph node procedures (e.g., sentinel/ axillary lymph node dissection) acc. to institutional standards
11. Main study: 8. Patients must have normal organ and bone marrow function measured within 28 days prior to randomization as defined below: • Haemoglobin (Hb) ≥10.0 g/dL • Absolute neutrophil count (ANC) ≥1.5 x 109/L • Absence of known Myelodysplastic Syndrome (MDS)/ Acute Myeloid Leukaemia (AML) and no features suggestive of MDS/ AML on *peripheral blood smear (*For patients randomized according to protocol version 2.0, peripheral blood smear only has to be performed if haematology assessment during screening shows abnormalities that require further clarification) • White blood cell (WBC) count ≥ 3.0 x 109/L • Platelet count ≥100 x 109/L • Total bilirubin ≤1.5 x institutional upper limit of normal (ULN) • AST (SGOT)/ ALT (SGPT) ≤2.5 x institutional ULN • Serum creatinine ≤1.5 x institutional ULN or creatinine clearance using the Cockcroft-Gault equation ≥51 mL/min
12. Main study: 9. ECOG performance status 0-1
13. Substudy: 1. Signed informed consent prior to any substudy specific assessments and procedures. Consent to substudy is optional.
14. Substudy: 2. Completed at least 4 cycles neoadjuvant chemotherapy with TAC or neoadjuvant olaparib and carboplatin in the course of the ABCSG 45 main study.
15. Substudy: 3. Completed locoregional therapy (i.e. adequate breast and axilla surgery with or without adjuvant radiotherapy). Patients must have recovered from any effects of any major surgery.
16. Substudy: 4. Treatment with adjuvant olaparib starts ideally within 8 weeks after last treatment (surgery, or radiotherapy, whichever is last), but in no case longer than 12 weeks.
17. Substudy: 5. Negative pregnancy test (serum or urine) max. 28 days prior to treatment start for women with childbearing potential
18. Substudy: 6. Women of childbearing potential and male patients must use adequate contraception for the duration of protocol treatment and for 6 months after the last dose of olaparib for women and 3 months after the last dose of olaparib for men. Adequate contraception is defined as one highly effective form (i.e. total abstinence, (fe)male sterilization) OR two effective forms (e.g. non-hormonal intrauterine device (IUD) and condom/occlusive cap with spermicidal foam/gel/film/cream/suppository).
19. Substudy: 7. Patient is willing and able to comply with the protocol for the duration of the substudy, including undergoing treatment, scheduled visits and examinations.
20. Substudy: 8. Patients must have adequate organ and bone marrow function measured within 28 days prior to treatment start with no blood transfusions (packed red blood cells and/or platelet transfusions) in the past 28 days prior to testing for organ and bone marrow function
21. Substudy: 9. ECOG performance status 0-1

Exclusion criteria 28

1. Main study: 1. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca/ABCSG staff and/or staff at the study site)
2. Main study: 10. Resting ECG with QTc >470 msec and/ or family history of long QT syndrome • However, ECG measurement can be repeated within 24 hours and patient is ineligible if none of these repeated measurements demonstrate QTc ≤470 msec
3. Main study: 11. Echocardiography (ECHO) and/or multigated acquisition (MUGA) scan with <50% Left Ventricular Ejection Fraction (LVEF)
4. Main study: 12. Whole blood transfusions within 120 days prior to randomization
5. Main study: 13. Major surgery within 14 days prior to randomization and/or patients with insufficient recovery from any major surgery per physician's assessment at the time of randomization
6. Main study: 14. Any medical condition rendering the patient unfit for pre-operative chemotherapy with TAC or carboplatin/olaparib
7. Main study: 15. Patients unable to swallow orally administered medication and patients with gastrointestinal disorders likely to interfere with absorption of the (N)IMP
8. Main study: 16. Pregnant or breast feeding women
9. Main study: 17. Immunocompromised patients, e.g., patients who are known to be serologically positive for human immunodeficiency virus (HIV) or patients who are receiving antiretroviral therapy
10. Main study: 18. Patients with known active hepatic disease (i.e. Hepatitis B or C)
11. Main study: 19. Patients with a known hypersensitivity to olaparib, platins, taxanes, anthracyclines, or cyclophosphamide
12. Main study: 2. Previous randomization in the present study
13. Main study: 20. Patients with uncontrolled seizures
14. Main study: 21. Previous allogeneic bone marrow transplant
15. Main study: 22. Known ≥ grade 2 peripheral neuropathy
16. Main study: 3. Participation in another clinical study with an investigational product during the last 6 months (i.e. 183 days) prior to randomization
17. Main study: 4. Any previous treatment with a PARP inhibitor, including olaparib
18. Main study: 5. Prior ipsilateral invasive breast cancer and/or ipsilateral Ductal Carcinoma in Situ (DCIS) and/or prior chemotherapy for any breast cancer • Patients with contralateral invasive breast cancer and/or contralateral DCIS diagnosed ≥5 years prior to randomization if curatively treated without chemotherapy are eligible
19. Main study: 6. Bilateral invasive breast cancer
20. Main study: 7. Patients with second primary malignancy are ineligible except for the following: • Adequately treated non-metastatic, non-melanoma skin cancer, curatively treated in-situ cancer of the cervix, stage 1 grade 1 endometrial carcinoma or • Other curatively treated malignancies diagnosed ≥5 years prior to randomization with no evidence of disease for at least 5 years
21. Main study: 8. Other severe acute and/or chronic medical and/or psychiatric condition and/or laboratory abnormality that would impart, in the judgment of the Investigator, risk associated with study participation or (N)IMP administration, or which, in the judgment of the Investigator, would make the patient inappropriate for participation in this study
22. Main study: 9. Concomitant use of known strong or moderate Cytochrome P450 3A4 (CYP3A4) inducers. For further details refer to Appendix B
23. Substudy: 1. Exposure to olaparib within 30 days prior to treatment start.
24. Substudy: 2. Known sensitivity or intolerance to olaparib
25. Substudy: 3. Adjuvant radiotherapy within 2 weeks prior to treatment start
26. Substudy: 4. Patients receiving or scheduled to receive adjuvant chemotherapy (e.g. capecitabine).
27. Substudy: 5. Concomitant use of known strong or moderate Cytochrome P450 3A4 (CYP3A4) inhibitors and inducers.
28. Substudy: 6. Persistent toxicities (≥ CTCAE grade 2) caused by previous cancer therapy, excluding alopecia and CTCAE grade 2 peripheral neuropathy.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Main study: Histo-pathological response to pre-operative carboplatin/olaparib compared with pre-operative TAC-based chemotherapy when measured by centrally assessed RCB (RCB-0/I versus RCB-II/III).
2. Substudy: Incidence, nature and severity of adverse events (AEs) graded according to NCI CTCAE, most current version.

Secondary endpoints 2

1. Main study: Occurrence of pCR at the time of surgery.
2. Main study: Quality of Life and sexual health scores and changes from baseline as measured using EORTC QLQ-C30, EORTC QLQ-BR45 and EORTC SHQ-C22.

Investigational products

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

Test 2

Comparator 5

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Verein Zur Praevention Und Therapie Boesartiger Erkrankungen Austrian Breast And Colorectal Cancer Study Group

Sponsor organisation

Verein Zur Praevention Und Therapie Boesartiger Erkrankungen Austrian Breast And Colorectal Cancer Study Group

Address

Nussdorfer Platz 8/8/12

City

Vienna

Postcode

1190

Country

Austria

Scientific contact point

Organisation

Verein Zur Praevention Und Therapie Boesartiger Erkrankungen Austrian Breast And Colorectal Cancer Study Group

Contact name

Trial Office

Public contact point

Organisation

Verein Zur Praevention Und Therapie Boesartiger Erkrankungen Austrian Breast And Colorectal Cancer Study Group

Contact name

Trial Office

Third parties 5

Locations

1 EU/EEA country · 5 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 18 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