Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12623000657628
Ethics application status
Approved
Date submitted
2/06/2023
Date registered
19/06/2023
Date last updated
15/04/2024
Date data sharing statement initially provided
19/06/2023
Type of registration
Prospectively registered

Titles & IDs
Public title
Investigating the impact of adding olaparib, or olaparib and durvalumab together, to standard chemotherapy before surgery in young, pre-menopausal women with HER2-negative breast cancer.
Scientific title
BCT 2301 (OLIO): A phase II, randomised, non-comparative two-arm trial of neoadjuvant chemotherapy plus either olaparib or olaparib + durvalumab in young, pre-menopausal women with HRD-enriched, HR-positive, HER2-negative early breast cancer
Secondary ID [1] 308124 0
BCT 2301
Universal Trial Number (UTN)
Trial acronym
OLIO
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Breast Cancer 327836 0
Condition category
Condition code
Cancer 324912 324912 0 0
Breast

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Study treatment is for 12 weeks.

Arm A:
Olaparib: 100 mg tablet taken twice daily for weeks 1-12 with weekly paclitaxel intravenously (IV) 80 mg/m^2 for 12 weeks
Arm B:
Olaparib: 100 mg tablet taken twice daily for weeks 1-12; and
Durvalumab: 1500 mg intravenously (IV) every 4 weeks for 12 weeks (i.e. 3 treatments)
with weekly paclitaxel intravenously (IV) 80 mg/m^2 for 12 weeks.

Olaparib tablets can be taken by participants at home. Olaparib should be taken twice daily, at approximately the same times each day (approximately 12 hours apart), with one glass of water. Olaparib tablets should be swallowed whole and not chewed, crushed, dissolved or divided. Participants will be provided with a diary to record when they take olaparib tablets and the diary will be checked at each clinic visit.

Durvalumab and paclitaxel will be administered at study/clinic visits by hospital/clinic staff as according to institution guidelines.

Durvalumab is administered before administration of paclitaxel. On days on which all three drugs are given, olaparib is taken first followed by durvalumab, followed by paclitaxel. Durvalumab may be administered any time after taking olaparib. Paclitaxel can be delivered after durvalumab if no infusion related symptoms are observed during the durvalumab infusion. Infusions of durvalumab and paclitaxel are administered by clinic/hospital staff according to institutional guidelines.
Intervention code [1] 324581 0
Treatment: Drugs
Comparator / control treatment
This is a non-comparative randomised clinical trial evaluating the pCR rate of olaparib + paclitaxel, with or without durvalumab, in HRD-positive breast cancer patients. The primary focus is to assess whether any of the two treatment arms have an acceptable pCR rate. All comparisons between the arms are purely exploratory to inform the design of a subsequent trial.
Control group
Active

Outcomes
Primary outcome [1] 332725 0
The pathologic complete response (pCR) rate in each arm. pCR is defined as ypT0/is ypN0 assessed by examination of tissue (breast and nodes) removed at surgery.
Timepoint [1] 332725 0
At the time of definitive surgery
Secondary outcome [1] 414511 0
The Residual Cancer Burden (RCB) rate (class 0 or 1) in Treatment Arm A and Treatment Arm B.
Timepoint [1] 414511 0
At the time of definitive surgery.
Secondary outcome [2] 414512 0
Event free survival (EFS) in Treatment Arm A and Treatment Arm B.
Timepoint [2] 414512 0
The length of time from randomisation until the first evidence of disease progression (loco-regional or distant) or date of death due to any cause, assessed for up to 5 years post-surgery.
Secondary outcome [3] 414513 0
Overall survival (OS) in Treatment Arm A and Treatment Arm B.
Timepoint [3] 414513 0
The length of time from randomisation until the date of death from any cause, assessed for up to 5 years post-surgery.
Secondary outcome [4] 414514 0
Safety in Treatment Arm A and Treatment Arm B assessed as laboratory abnormalities, worst grade of adverse events (AEs) and serious adverse events (SAEs) documented using NCI CTCAE v5.0.

Adverse events will be assessed by clinical examination and participant self-report and described by:
1) NCI-CTCAE V5.0 terms – Common Terminology Criteria for Adverse Events;
2) Duration (start and end dates);
3) Severity Grade;
4) Relationship to study treatment (suspected/not suspected);
5) Action taken with regard to study treatment (e.g. omitted, discontinued);
6) Whether the event was reported as a Serious Adverse Event (SAE).

For potential Adverse Events for OLIO, please see list of side effects (Cancer Fields).
Timepoint [4] 414514 0
Frequency of adverse events assessed throughout the study up to 90 days after the last dose of study treatment.

Eligibility
Key inclusion criteria
PRE-SCREENING:
For inclusion in pre-screening for the study, participants must fulfil all the following criteria:
1. Has provided written, informed consent to participate in pre-screening for the study.
2. Female aged >= 18 to <= 44 years at the time of breast cancer diagnosis.
3. Premenopausal as defined as the presence of at least one ovary at the time of diagnosis of breast cancer.
4. Histologically confirmed ER-positive and HER2-negative early breast cancer by local assessment:
a) ER-positive is defined as >= 1% of tumour nuclei positive for ER via IHC analysis [CAP Guidelines 2020]
b) HER2-negative is defined as a negative ISH test or an IHC status of 0, 1+ or 2+. If IHC is 2+, a negative ISH result is also required [CAP Guidelines 2018]
c) PR may be positive or negative.
5. High disease burden defined as either:
a) cT1c-T2, cN1-cN3
OR
b) cT3-T4a-c, cN0-cN3.
Note: multicentric tumours are allowed with at least 1 tumour >= 10 mm at diagnosis. Tumour in each quadrant needs to be confirmed to be hormone receptor-positive and HER2-negative breast cancer as per Pre-screening Eligibility Criteria 4.
Note: Inflammatory breast cancer is allowed
6. High risk as defined by either:
a) Age < 35 years at diagnosis OR
b) Age 35 – 44 years at diagnosis and grade 3 tumour by local pathologist assessment OR
c) Age 35-44 years at diagnosis and tumour Ki67 >= 20% by local pathologist assessment .
7. Planned to complete or has completed a maximum of 1 cycle of neoadjuvant treatment that starts with 4 cycles of standard anthracycline-based chemotherapy.
8. Two FFPE tumour blocks comprising the largest available tumour tissue (area and cellularity) from a new biopsy or previously taken biopsy will be used for assessment of homologous recombination deficiency (HRD) status, as well as for correlative research. If deemed inadequate for the SOPHiA DDM (TM) assay by the test laboratory, other archival blocks can be assessed provided they were obtained within 12 months of pre-screening consent.

RANDOMISATION
In addition to the above listed pre-screening inclusion criteria, participants must fulfil all of the following criteria before randomisation:
1. Has provided written, informed consent to participate in the study.
2. Confirmed HRD-positive status evaluated by SOPHiA DDM(TM) HRD NGS assay.
Note: HRD-positive status is defined as having a Genomic Instability Index (GII) of > 0 and/or identification of a predicted loss of function germline or tumour mutation in one of the following homologous recombination repair genes (BRCA1, BRCA2, PALB2, RAD51C, RAD51D) as determined by the SOPHiA DDM(TM) HRD NGS assay.
3. Has completed at least 3 cycles of anthracycline-based neoadjuvant chemotherapy.
4. Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
5. Body weight >30 kg.
6. Adequate organ function within 28 days before the start of study treatment, as defined by:
a) Haemogoblin >= 10 g/dL
Note: Prior red blood cell transfusion is permitted but must not occur within 28 days before randomisation.
b) Platelets >= 100 x 10^9/L
Note: Prior platelet transfusion is permitted for treatment of chemotherapy-related thrombocytopaenia
c) Absolute neutrophil count >= 1.5 x 10^9/L
d) Creatinine <= 1.5 x ULN or serum creatinine clearance >= 50 mL/min by the Cockcroft-Gault formula or by 24-hour urine collection for determination of creatinine clearance:
e) Total bilirubin <= 1.5x ULN (Total bilirubin must be < 4 x ULN for patients with Gilbert’s Syndrome)
f) AST and ALT <= 2.5x ULN
g) International normalised ration (INR)/ Prothrombin time (PT) <= 1.5 ULN unless participant is receiving anticoagulant therapy. The participant is eligible as long as the INR, PT or activated partial thromboplastin time (aPTT) is within therapeutic range of intended use of anticoagulants.
7. Negative urine or serum pregnancy test within 28 days of the first dose of study treatment and confirmed before Day 1 (-5 days) of study treatment for Women of Childbearing Potential (WOCBP).
8. WOCBP must agree to use a highly effective method of contraception from the signing of informed consent until 9 months after the last dose of study treatment. WOCBP are defined as a premenopausal woman who has NOT had either documented hysterectomy, documented bilateral salpingectomy.
9. Participants with irreversible toxicity not reasonably expected to be exacerbated by treatment with durvalumab may be included only after consultation with BCT and the Study Chair.
Minimum age
18 Years
Maximum age
44 Years
Sex
Females
Can healthy volunteers participate?
No
Key exclusion criteria
PRE-SCREENING
Any one of the following at pre-screening is regarded as a criterion for exclusion from the study:
1. Bilateral invasive breast cancer.
2. Metastatic (Stage IV) breast cancer.
3. Has ER-negative, PR-positive breast cancer.
4. Post-menopausal, defined as no menses for 12 months without an alternative medical cause. An FSH level in the postmenopausal range may be used to confirm a postmenopausal state in women not using hormonal contraception or HRT.
5. Inflammatory breast cancer.

RANDOMISATION
Any one of the following is regarded as a criterion for exclusion from the study:
1. Participation in another clinical study with an investigational product during the last 4 weeks.
2. Concurrent enrolment in another clinical study, unless:
• It is an observational (non- interventional) clinical study; OR
• It is during the follow-up period of an interventional study; OR
• It is a study with a non-drug intervention that in the opinion of the investigator will not interfere with the endpoints of this clinical trial.
3. Unable to commence study treatment between 2 weeks to 8 weeks following the last dose of anthracycline-based chemotherapy.
4. Any previous treatment with PARP inhibitor, including olaparib or immune-mediated therapy including anti-CTLA-4 (including tremelimumab), anti PD 1, anti-PD-L1 (including durvalumab), anti-PD-L2 antibodies, or therapeutic anticancer vaccines.
5. Participants receiving any systemic chemotherapy (other than standard anthracycline-based neoadjuvant chemotherapy) or radiotherapy within 3 weeks before starting study treatment.
6. Participants who have undergone excisional biopsy of the primary tumour and/or axillary lymph nodes or have undergone sentinel lymph node biopsy before study treatment.
7. Any unresolved toxicity NCI CTCAE Grade >= 2 from previous anticancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria.
8. Peripheral neuropathy > grade 1 by CTCAE v5.0.
9. Has an impaired ability to take oral medications (e.g. medical history of malabsorption or other chronic gastrointestinal disease, or other condition that may harm compliance and/or absorption of the study treatment).
10. Has a known additional, invasive malignancy that is progressing or required active treatment within the last 5 years.
Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, breast ductal carcinoma in situ, curatively treated cervical carcinoma in situ, melanoma in situ, or Stage 1, grade 1 endometrial carcinoma are not excluded.
11. History of allogenic organ transplantation, including bone marrow transplant or double umbilical cord blood transplantation (dUCBT).
12. Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [e.g. colitis or Crohn's disease], diverticulitis [with the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc]). The following are exceptions to this criterion:
a) Participants with vitiligo or alopecia
b) Participants with hypothyroidism (e.g. following Hashimoto syndrome) stable on hormone replacement
c) Any chronic skin condition that does not require systemic therapy
d) Participants without active disease in the last 5 years may be included but only after consultation with BCT and the Study Chair
e) Participants with celiac disease controlled by diet alone.
13. Mean QT interval corrected for heart rate using Fridericia's formula (QTcF) >= 470 ms calculated from 3 ECGs (within 15 minutes at 5 minutes apart).
14. Resting ECG indicating uncontrolled, potentially reversible cardiac conditions, as judged by the investigator (e.g. unstable ischemia, uncontrolled symptomatic arrhythmia, congestive heart failure, QTcF prolongation > 500 ms, electrolyte disturbances, etc.), or participants with congenital long QT syndrome.
15. Has other significant cardiac disease, including:
a) History of myocardial infarction, acute coronary syndrome, or coronary angioplasty/stenting/bypass within the last 6 months
b) Congestive heart failure New York Heart Association (NYHA) class II-IV or history of congestive heart failure NYHA class III or IV.
16. Participants with myelodysplastic syndrome/acute myeloid leukaemia or with features suggestive of MDS/AML.
17. History of active primary immunodeficiency.
18. Current or prior use of immunosuppressive medication within 14 days before the first dose of study treatment. The following are exceptions to this criterion:
a) Intranasal, inhaled, topical steroids, or local steroid injections (e.g. intra-articular injection)
b) Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent
c) Steroids as premedication for hypersensitivity reactions (e.g. CT scan premedication)
d) Standard use of steroids as supportive medications before and after chemotherapy administration.
19. Has a known history of human immunodeficiency virus (HIV) infection.
Note: No HIV testing is required in screening unless clinically indicated.
20. Has a known history of hepatitis B (defined as hepatitis B surface antigen reactive) or known active hepatitis C virus (defined as HCV RNA detected) infection.
Note: No testing for hepatitis B or hepatitis C is required in screening. Hepatitis B or hepatitis C testing should be performed as per standard institutional practice.
21. Concomitant use of known strong CYP3A inhibitors (e.g. itraconazole, telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) or moderate CYP3A inhibitors (e.g. ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil). The required washout period before starting study treatment is 14 days.
22. Concomitant use of known strong (e.g. phenobarbital, enzalutamide, phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John’s Wort) or moderate CYP3A inducers (e.g. bosentan, efavirenz, modafinil). The required washout period before starting study treatment is 5 weeks for enzalutamide or phenobarbital and 3 weeks for other agents.
23. Major surgery within 14 days of starting study treatment and participants must have recovered from any effects of any major surgery.
24. Has a known allergy or hypersensitivity to any of the components or excipients used in the study treatments.
25. Is pregnant, breastfeeding, or expecting to conceive children within the projected duration of the study, starting with the pre-screening visit through to 6 months after the last dose of study treatment.
26. Receipt of live attenuated vaccine within 30 days before the first dose of study treatment. Note: Participants, if enrolled, should not receive live vaccine whilst receiving study treatment and up to 30 days after the last dose of study treatment.
Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed, however intranasal influenza vaccines (e.g. FluMist®) are live attenuated vaccines and are not allowed.
27. Participants considered a poor medical risk due to a serious, uncontrolled medical disorder, non-malignant systemic disease or active, uncontrolled infection. Examples include, but are not limited to, uncontrolled ventricular arrhythmia, recent (within 3 months) myocardial infarction, uncontrolled major seizure disorder, unstable spinal cord compression, superior vena cava syndrome, extensive interstitial bilateral lung disease on High Resolution Computed Tomography (HRCT) scan or any psychiatric disorder that prohibits obtaining informed consent.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Non-comparative. The primary focus of OLIO is to assess whether any of the two treatment arms have an acceptable pCR rate.
Phase
Phase 2
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
31/05/2024
Actual
Date of last participant enrolment
Anticipated
31/05/2027
Actual
Date of last data collection
Anticipated
31/07/2032
Actual
Sample size
Target
56
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD,WA,VIC

Funding & Sponsors
Funding source category [1] 312380 0
Government body
Name [1] 312380 0
National Health and Medical Research Council - MRFF RCRDUN
Country [1] 312380 0
Australia
Primary sponsor type
Other Collaborative groups
Name
Breast Cancer Trials
Address
PO Box 283
The Junction NSW 2291
Country
Australia
Secondary sponsor category [1] 313949 0
None
Name [1] 313949 0
Address [1] 313949 0
Country [1] 313949 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 311738 0
Peter MacCallum Cancer Centre HREC
Ethics committee address [1] 311738 0
Ethics Coordinator
Ethics Committee Secretariat
Peter MacCallum Cancer Centre
Locked Bag 1, A/Beckett Street
Victoria 8006
Ethics committee country [1] 311738 0
Australia
Date submitted for ethics approval [1] 311738 0
04/12/2023
Approval date [1] 311738 0
26/02/2024
Ethics approval number [1] 311738 0
HREC/102919/PMCC Peter Mac No. 23/247

Summary
Brief summary
This study aims to find out if adding the medications olaparib, or olaparib + durvalumab together, to standard chemotherapy given to premenopausal women with HR-positive, HER2-negative, HRD-positive breast cancer before surgery will do a better job of controlling the cancer.

Who is it for?
You may be eligible for this study if you are a pre-menopausal woman between 18 and 44 years of age, have been diagnosed with HR-positive, HER2-negative early breast cancer, and a sample of the tumour is shown to be HRD-positive.

Trial Details.
Researchers will test the cancer to find out if it is HRD-positive. Being HRD-positive could make the tumour more sensitive to the treatments in the main OLIO study. Only about 20% of cancers are expected to be HRD-positive.

Whilst the sample is tested, participants will have standard treatment (4 cycles of anthracycline-based chemotherapy).

Participants with HRD-positive tumours will be randomised 1:1 to receive:
Arm A: An olaparib tablet twice per day with water for 12 weeks, plus have an infusion of paclitaxel into a vein once per week.

Arm B: An olaparib tablet twice per day with water for 12 weeks, plus have an infusion of durvalumab into a vein once every 4 weeks for 3 infusions (Week 1, Week 5 and Week 9), plus have an infusion of paclitaxel into a vein once per week.

Participants will have surgery within 6 weeks after their last dose of study treatment.

The following biological samples will be collected:
* Tumour sample at surgery, if any tumour remains
* Blood samples before starting study treatment and just after surgery.

All participants will be regularly monitored throughout treatment to evaluate their health. There will be end of treatment visits 30 days & 90 days after the last dose of study treatment. Follow-up visits will occur every 6 months after surgery for years 1-3 years post-surgery (6 visits), then every 12 months for years 4-5 (2 visits). Further treatment will be at the discretion of the participant and their treating clinician.

It is hoped this research will provide new treatment options for young women with HR-positive, HER2-negative breast cancer, particularly among those selected for a high HRD score.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 122194 0
Dr Stephen Luen
Address 122194 0
Peter MacCallum Cancer Centre
305 Grattan Street
Melbourne VIC 3000
Country 122194 0
Australia
Phone 122194 0
+61 2 4925 5235
Fax 122194 0
Email 122194 0
corinna.beckmore@bctrials.org.au
Contact person for public queries
Name 122195 0
Ms Corinna Beckmore
Address 122195 0
Breast Cancer Trials
PO Box 283
The Junction NSW 2291
Country 122195 0
Australia
Phone 122195 0
+61 2 4925 5235
Fax 122195 0
Email 122195 0
corinna.beckmore@bctrials.org.au
Contact person for scientific queries
Name 122196 0
Dr Stephen Luen
Address 122196 0
Peter MacCallum Cancer Centre
305 Grattan Street
Melbourne VIC 3000
Country 122196 0
Australia
Phone 122196 0
+61 2 4925 5235
Fax 122196 0
Email 122196 0
corinna.beckmore@bctrials.org.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
All anonymised Individual Patient Data (IPD) collected during the trial.
When will data be available (start and end dates)?
Data will be made available for request after publication of the main/final study results; no end date.
Available to whom?
Researchers who submit a research proposal and BCT Data Request Application, which is assessed by BCT to have appropriate scientific value. Refer to the BCT Data Sharing Guidelines
Available for what types of analyses?
To achieve the aims in the approved proposal.
How or where can data be obtained?
Subject to approval by Breast Cancer Trials concept@bctrials.org.au (refer to BCT Data Sharing Guidelines).


What supporting documents are/will be available?




Results publications and other study-related documents

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