| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
ER negative and HER2 negative Early Breast Cancer
or BRCA 1 or 2 germline mutated Early Breast Cancer
|
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| E.1.1.1 | Medical condition in easily understood language |
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| 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) |
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| 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 |
The main objective of the PARTNER trial is to establish if the addition of Olaparib to neoadjuvant platinum-based chemotherapy for Triple negative breast cancer (TNBC) and/or germline mutated BRCA1/2 positive (gBRCA) breast cancer is safe and improves response to treatment as defined by pathological Complete Response (pCR) at surgery.
The main objective of the PARTNERING pathway is to establish if the addition of further new agents:
- Olaparib an PARP (Polyadenosine 5’diphosphoribose polymerisation) inhibitor,
- AZD6738 an ATR (Ataxia telangiectasia mutated and rad3-related) inhibitor and
- Durvalumab an PDL-1 (Programmed death-ligand 1) inhibitor
improves response to treatment in those patients who have not achieved it after initial PARTNER trial therapy. |
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| E.2.2 | Secondary objectives of the trial |
The secondary research questions/objectives for the PARTNER trial are:
Does the addition of olaparib:
- Improve clinical outcomes (relapse free survival, overall survival ...)
- Change the frequency/severity of toxicities experienced
- Adversely affect Quality of life.
Can we identify or validate pharmacogenetic and pharmacogenomic markers that can be correlated with outcomes (pCR and RFS) in patients randomised to receive olaparib with chemotherapy compared with those who receive just chemotherapy.
Can we identify of markers for olaparib and chemotherapy response / resistance which are correlated with outcome.
The secondary research questions for the PARTNERING pathway are:
- Can the tumour content be correlated with the response to treatment.
- Can the response to treatment be correlated with previous Olaparib treatment within the PARTNER trial.
- Can the response to treatment be correlated with BRCA status.
|
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
There are 4 sub-studies:
- PARTNER – Sequential Blood samples (optional:
Patient Information Sheet 2, v3.0, 19 September 2018
- PARTNER – Fresh tissue (optional):
Patient Information Sheet 3, v4.0, 19 September 2018
- PARTNER - Microbiome (optional):
Patient Information Sheet 4, v1.0, 19 September 2018
- PARTNERING pathway - Additional treatment pathway for patients with remaining tumour after PARTNER therapy (optional):
PARTNERING, Patient Information Sheet for pre-screening, v1.0, 19 September 2018
PARTNERING, Patient Information Sheet, v1.0, 19 September 2018 |
|
| E.3 | Principal inclusion criteria |
For the PARTNER trial:
• Written informed consent
• Aged between 16 and 70
• Histologically confirmed invasive breast cancer
• Clinical stage T1-4 N0-2 (tumour or metastatic node diameter > 10mm)
• Confirmed ER-negative and HER2-negative
or
• Germline BRCA mutation positive, irrespective of hormone status but HER2 negative.
• Performance Status 0-1
For the PARTNERING pathway:
• Previous inclusion and treatment within PARTNER trial
• Written informed consent (PARTNERING consent)
• Performance Status 0-1 at registration into PARTNERING
• Availability of an end of chemotherapy biopsy after cycle 6 and prior cycle 7 of PARTNER treatment
• Histologically confirmed residual invasive breast cancer at biopsy performed after Cycle 6 of PARTNER therapy
• Availability of TILs assessment in baseline biopsy prior Cycle 1 AND post Cycle 6 of PARTNER therapy is required
• Body weight >30kg
• Adequate bone marrow, hepatic, and renal function
|
|
| E.4 | Principal exclusion criteria |
For the PARTNER trial:
• T0 tumour in absence of axillary node > 10mm
• TNBC with a non-basal phenotype and over-expressing Androgen Receptor
• Not suitable for neoadjuvant chemotherapy
• Distant metastases apparent prior to randomisation
• Prior history of invasive breast cancer within the last 5 years
• Previous PARP inhibitor use or any previous chemotherapy or targeted agent
• Any previous chemotherapy or agent used for the treatment of cancer within the last 5 years
For the PARTNERING pathway:
• Rapidly progressive disease during PARTNER neoadjuvant treatment
• Tumour cellularity less than 10% in biopsy performed after Cycle 6 of PARTNER therapy.
• Not suitable for treatment with new agents
• Persistent AEs from prior anti-cancer therapy ≥Grade 3
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
For the PARTNER trial:
Stage 1: Primary outcome measure – safety of the addition of olaparib to three weekly carboplatin / weekly paclitaxel chemotherapy.
Stage 2: Primary outcome measure – pCR in each of the two research arms. At the end of stage 2, one of the research treatment will be dropped based on whether one arm is: i) more effective; ii) completed by more patients i.e. is tolerated better; iii) more convenient for patients and staff.
Stage 3: Primary outcome measure - pCR at surgery after neoadjuvant treatment.
pCR rates after neoadjuvant chemotherapy +/- olaparib, defined as no residual invasive carcinoma within the breast (Ductal Carcinoma in situ permitted) AND no evidence of metastatic disease within the lymph nodes.
For the optional PARTNERING pathway:
Primary outcome measure – RCB-0 and RCB-I (Residual Cancer Burden class 0 and I) rate at surgery after the administration of 2 cycles of a combination of new agents.
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|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
For the PARTNER trial:
The timepoint is surgery.
pCR will be assessed by central review (2 readers) of the surgery pathology reports.
For the PARTNERING pathway:
The timepoint is surgery.
|
|
| E.5.2 | Secondary end point(s) |
For the PARTNER trial:
• pCR and Residual Burden Disease at surgery assessed by central pathology review of the diagnosis and surgery slides.
• Relapse Free Survival (RFS), calculated from date of randomisation to date of the first relapse or date of death from all causes, whichever occurs first.
• Breast cancer specific survival (BCSS), calculated from date of randomisation to date of death from breast cancer.
• Distant disease-free survival, calculated from date of randomisation to date of the first distant disease relapse or date of death from all causes, whichever occurs first.
• Local recurrence-free survival, calculated from date of randomisation to date of the first local-recurrence or date of death from all causes, whichever occurs first.
• Overall survival (OS), calculated from date of randomisation to date of death from all causes.
• Time to second cancer (TTSC), calculated from the date of randomisation to the date of diagnosis of second cancer.
• pCR in breast alone.
• Residual Cancer Burden (RCB) I-III will be assessed by central pathology review.
• Rate of breast conservation.
• Radiological response after 4th and final cycles.
• Treatment related toxicities.
• Quality of life (sub-study, separate consent).
No additional secondary end points for the PARTNERING pathway. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Survival endpoints will be measured from the date of randomisation and will be reported for all deaths due to all causes. |
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| 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 | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| 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) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 5 |
| 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 | 50 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 8 |
| 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 |
| Netherlands |
| New Zealand |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| 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
|
For regulatory purposes the end of the intervention period of the trial will be 30 days after the last patient completes surgery.
The non-interventional observation period of the trial will continue for at least 10 years following the completion of surgery of the last patient to have surgery (per the follow-up protocol mentioned above).
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 14 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | 3 |
| E.8.9.2 | In all countries concerned by the trial years | 14 |
| E.8.9.2 | In all countries concerned by the trial months | 5 |
| E.8.9.2 | In all countries concerned by the trial days | 3 |
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