None listed
Conditions
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 breast cancer before surgery will do a better job of controlling the cancer. BCT is trialing a remote telehealth pre-screening process for the OLIO trial to broaden clinical trials access to regional and remote patients and improve clinical trial recruitment. Please visit https://www.breastcancertrials.org.au/research/remote-telehealth-pre-screening-process/ for further information. Who is it for? You may be eligible for this study if you are a pre-menopausal woman between 18 and 45 years of age, and have been diagnosed with HR-positive, HER2-negative early breast cancer. Trial Details. Participants 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.
Interventions
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 s
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.
Sponsors
Breast Cancer Trials
Study design
Allocation
Randomised controlled trial
Intervention model
Parallel
Primary purpose
Treatment
Masking
Open (masking not used)
Eligibility
Sex/Gender
All
Age
18 Years to 44 Years
Healthy volunteers
No
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 or 10 slides 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.
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. 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: HIV testing is not 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: Testing for hepatitis B or hepatitis C is not 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.
Outcome results
None listed