| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| BRCA Mutations and Early Stage HER2-Negative Breast Cancer |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10006187 |
| E.1.2 | Term | Breast cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To evaluate the efficacy, measured by pCR rate, of olaparib monotherapy and olaparib plus durvalumab combination therapy, as assessed by central pathology review. |
|
| E.2.2 | Secondary objectives of the trial |
- To evaluate the efficacy, measured by pCR rate, of olaparib monotherapy and olaparib plus durvalumab combination therapy as assessed by local pathology review
- To evaluate the efficacy, measured by RCB, of olaparib monotherapy and olaparib plus durvalumab combination therapy as assessed by central pathology review
- To evaluate the efficacy, measured by RCB, of olaparib monotherapy and olaparib plus durvalumab combination therapy as assessed by local pathology review
- To evaluate the efficacy of olaparib monotherapy and olaparib plus durvalumab combination therapy in terms of change from baseline tumour volume.
- To evaluate the efficacy of olaparib monotherapy and olaparib plus durvalumab combination therapy by assessment of EFS
- To assess the safety and tolerability profile of olaparib monotherapy and olaparib plus durvalumab combination therapy
- To assess the safety and tolerability profile of olaparib monotherapy when given as adjuvant
therapy to participants who achieve pCR |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
- Males or Females ≥18 years
- Minimum body weight of 30 kg
- Capable of giving signed informed consent.
- Male and Female participants of childbearing potential must use effective methods of contraception
- Histologically confirmed, newly diagnosed, primary, operable, non-metastatic invasive breast cancer with the following characteristics:
--ER-negative or ER-low defined as IHC nuclear staining ≤10%
- HER2-negative (not eligible for anti-HER2 therapy) defined as:
-- IHC 0, 1+ without in situ hybridization OR
-- In situ hybridization non-amplified with ratio less than 2.0 OR
-- In situ hybridization average HER2 copy number < 6 signals/cells
- Clinical TNM staging (per AJCC 8th Edition) as follows:
-- T1b (>5 mm but ≤10 mm), N0, no known metastases (M0 or MX); OR
-- T1c (>10 mm but ≤20 mm), N0, no known metastases (M0 or MX); OR
-- T1 (>1 mm but ≤20 mm), N1, no known metastases (M0 or MX); OR
-- T2 (>20 mm but ≤50 mm), N0, no known metastases (M0 or MX).).
- Documented deleterious or suspected deleterious mutation in BRCA1 or BRCA2 from local BRCA testing using either a germline or tumour test.
- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
- Participants must have adequate organ and bone marrow function
- Participant must be willing to undergo a baseline research core needle biopsy prior to start of study
treatment.
- Participant must be willing to have any leftover tumour tissue/FFPE from the diagnostic
biopsy submitted for research purposes, if available.
For a complete overview of the inclusion criteria refer to the protocol. |
|
| E.4 | Principal exclusion criteria |
- Any evidence of other diseases (such as severe or uncontrolled systemic diseases or active, uncontrolled infections, including but not limited to, uncontrolled ventricular arrhythmia, uncontrolled hypertension, recent [within 3 months] myocardial infarction, uncontrolled major seizure disorder, renal transplant, active bleeding diseases, unstable spinal cord compression, superior vena cava syndrome, extensive interstitial bilateral lung disease on High Resolution Computed Tomography scan
- Refractory nausea and vomiting, chronic gastrointestinal disease likely to interfere with absorption of the study medication, inability to swallow the formulated product
- History of another primary malignancy except for malignancy treated with curative intent with no known active disease for ≥5 years before the first dose of study intervention and of low potential risk for recurrence
- Participants with MDS or AML
- For higher risk (Cohort B) participants only: Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [eg, colitis or Crohn’s disease], diverticulitis [with the exception of diverticulosis], systemic lupus erythematosus, sarcoidosis, granulomatosis with polyangiitis, Graves’ disease, rheumatoid arthritis, hypophysitis, uveitis, etc), autoimmune pneumonitis, and autoimmune myocarditis
- Known active hepatitis infection, positive hepatitis C antibody, hepatitis B virus surface antigen or hepatitis B virus core antibody
- Known to have tested positive for human immunodeficiency virus unless currently on effective anti-retroviral therapy with an undetectable viral load within 6 months
- History of arrhythmia (multifocal premature ventricular contractions, bigeminy, trigeminy, ventricular tachycardia), which is symptomatic or requires treatment (Common Terminology Criteria for Adverse Events [CTCAE] Grade 3), symptomatic or uncontrolled atrial fibrillation despite treatment, or asymptomatic sustained ventricular tachycardia
- Participant must not have had any prior treatment for the current breast cancer, including
surgery, chemotherapy, hormonal therapy, radiation, or experimental therapy
- For higher risk (Cohort B) participants only: Prior exposure to anti-PD1, anti-PD-L1, or
anti-CTLA4 agents (ICIs); OR an agent directed to other co-inhibitory or co-stimulatory T-cell receptors
- Any concurrent anticancer treatment
- Major surgical procedure (excluding placement of vascular access, local surgery of isolated lesions, or diagnostic staging) within 2 weeks of the first dose of study intervention
- For higher risk (Cohort B) participants only: Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab.
- Concomitant use of:
-- Known strong cytochrome P450 (CYP3A) inhibitors or moderate CYP3A inhibitors within 2 weeks prior to first dose of study intervention
-- Known strong CYP3A inducers or moderate CYP3A inducers .The required washout period prior to starting study therapy is 5 weeks for enzalutamide or phenobarbital and 3 weeks for other agents
For a complete overview of the exclusion criteria refer to the protocol. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
pCR is defined as ypT0/Tis ypN0 (ie, no invasive residual in breast and the axillary lymph nodes on
evaluation of the complete resected breast specimen and all sampled regional lymph nodes) following completion of neoadjuvant systemic therapy. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Following completion of neoadjuvant systemic therapy (by central pathology review) |
|
| E.5.2 | Secondary end point(s) |
1.) pCR is defined as ypT0/Tis ypN0 (ie, no invasive residual in breast and the axillary lymph nodes on evaluation of the complete resected breast specimen and all sampled regional lymph nodes) following completion of neoadjuvant systemic therapy.
2.) RCB index value using 6 variables to categorize response in 1 of 4 classes: RCB 0 (pCR), I (minimal RCB), II (moderate RCB), and III (extensive RCB).
3.) Percentage change in tumour volume from baseline after 3 and 6 cycles of treatment will be measured using MRI
4.) EFS is defined as time from the first dose of study intervention administration to any of the following events: progression of disease that precludes surgery, local or distant recurrence after surgery, second primary malignancy (breast or other invasive cancers), or death due to any cause.
5.) Safety and tolerability will be evaluated in terms of AEs/SAEs, physical examination, vital signs including blood pressure, pulse, heart rate, body temperature, body weight and height, clinical laboratory assessments including clinical chemistry/haematology parameters, and ECGs. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1.) Following completion of neoadjuvant systemic therapy (by local pathology review)
2.) Following completion of neoadjuvant systemic therapy (by central and local pathology review)
3.) After 3 and 6 cycles of treatment (tumour volume will be assessed by local radiology review)
4.) At the time of the event
5.) At the time of the event |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 39 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Israel |
| United Kingdom |
| United States |
| Austria |
| Belgium |
| Germany |
| Italy |
| Spain |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| Last subject last visit / the last scheduled assessment. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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