| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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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 |
Safety Run-in
· To evaluate safety and toxicity of adding SBRT directed to the primary tumour to the combination durvalumab-oleclumab-paclitaxel.
· To evaluate feasibility of performing surgery (breast conserving surgery or mastectomy) within 6 weeks after the end of neo-adjuvant treatment.
Phase II Primary objective
• To demonstrate improved tumour response of the primary tumour and nodal metastases in arms 2 or 3 versus arm 1.
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| E.2.2 | Secondary objectives of the trial |
Phase II Secondary objectives
· To evaluate the response to the primary tumour irrespective of the response to the pathological lymph nodes.
· To evaluate the response to the pathological lymph nodes irrespective of the response to the primary tumour.
· To evaluate the feasibility to perform breast-sparing surgery of the arms 2 and 3 versus arm 1.
· To evaluate the ability to control invasive disease in arms 2 and 3 versus arm 1 during three years after surgery.
· To evaluate the severity and duration of AEs of the arms 2 and 3 versus arm 1.
· To evaluate the cosmetic changes to the breast of the arms 2 and 3 versus arm 1.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Subjects must meet all of the following criteria in order to be eligible for this study:
1. Age ≥ 18 years old
2. Female
3. ECOG performance status ≤ 1
4. Weight ≥ 35 kg
5. Histological diagnosis of invasive breast adenocarcinoma that is estrogen receptor-positive, and HER2- negative as per the updated American Society of Clinical Oncology (ASCO) - College of American Pathologists (CAP) guidelines according to local testing
• ER-positive is defined as having an immunohistochemistry (IHC) of 1% or more and/or and Allred score of 3 or more
• HER2 negative is defined as having an IHC of 0 or 1+ without ISH OR IHC 2+ and ISH non-amplified with ratio less than 2.0 and if reported, average HER2 copy number < 4 signals/cells OR ISH non-amplified with ratio less than 2.0 and if reported, average HER2 copy number < 4 signals/cells [without IHC]; note: a IHC of 3+ is always considered HER2 positive, independently of the ISH result.
6. Agreement to perform new study related biopsies to provide tissue samples.
7. Confirmed Mammaprint genomic high risk score according to central testing. Mammaprint will only be tested for luminal B breast tumours with either Proliferation Index Ki67 ≥ 15% or histology grade 3 tumours. (Testing to be done during screening period).
8. Tumour size ≥ 1.5 cm, determined by MRI imaging.
9. N0 or N1
10. Multifocal, multicentric unilateral or bilateral breast adenocarcinoma tumours are allowed provided that all foci are ER+/HER2- according to local testing and all foci are able to receive SBRT treatment within the defined dosimetric constraints. For bilateral, multifocal or multicentric disease, the site selected for pre-treatment biopsy should correspond to the site of largest measurable disease meeting eligibility criteria. The location of tumour biopsy site (laterality, quadrant, position from the nipple and type of imaging modality to guide biopsy) should be collected.
11. Serum pregnancy test (for subjects of childbearing potential) negative within 2 weeks prior to first dose of study administration.
12. Women of childbearing potential must agree to use 1 highly effective method of contraception during the screening period, during the course of the study and at least 12 months after the last administration of study treatment. It is strongly recommended for the male partner of a female subject to also use male condom plus spermicide throughout this period.
13. Adequate bone marrow function as defined below:
• Absolute neutrophil count ≥1500/µL, i.e. 1.5x109/L
• Hemoglobin ≥ 9.0 g/dL
• Platelets ≥100000/µL, i.e. 100x109/L
14. Adequate liver function as defined below:
• Serum total bilirubin ≤ 1.5 x ULN. In case of known Gilbert’s syndrome ≤ 3 x UNL is allowed
• AST (SGOT) ≤ 3.0 x ULN
• ALT (SGPT) ≤ 3.0 x ULN
15. Adequate renal function as defined below:
• Creatinine ≤ 1.5 x UNL or eGFR≥40ml/min/1.73m2
16. Adequate coagulant function as defined below:
• International Normalized Ratio (INR) ≤ 1.5 x ULN unless subject is receiving anticoagulant therapy as long as INR and activated partial thromboplastin time (aPTT) is within therapeutic range of intended use of anticoagulants
17. Completion of all necessary screening procedures within 21 days prior to randomisation.
18. Willingness to provide tissue and blood samples for immuno-monitoring and translational research activities
19. Left ventricular ejection fraction (LVEF) ≥ 50%. LVEF performed in routine is accepted if done within 6 months prior to
20. beginning of screening.
21. Signed Informed Consent form (ICF) obtained prior to any study related procedure.
Inclusion criterion for phase II only (all phase II subjects):
22. Confirmed tumour PD-L1 IHC assessment according to central testing for stratification purposes. (Testing done during screening period).
Inclusion criterion applicable to FRANCE only (Safety run-in and Phase II subjects)
23. Affiliated to the French Social Security System (applicable only to subjects treated in France)
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| E.4 | Principal exclusion criteria |
Subjects meeting one of the following criteria are not eligible for this study:
1. Pregnant and/or lactating women.
2. Subject with a significant medical, neuro-psychiatric, substance abuse or surgical condition, currently uncontrolled by treatment, which, in the principal investigator’s opinion, may interfere with completion of the study.
3. TNM stage cT4 breast cancer including inflammatory breast cancer
4. Presence of any distant metastasis
5. Contra-indication for treatment by paclitaxel, doxorubicin or cyclophosphamide, or known allergy to any tested substance or excipients (e.g; chemotherapy or immunotherapy formulations)
6. Previously known contra-indication for treatment by radiation therapy such as rare genetic disorders associated with DNA repair disorders such as ataxia-telangiectasia (A-T), Nijmegen Breakage Syndrome (NBS) and Fanconi anemia.
7. Active or prior documented autoimmune disease (including inflammatory bowel disease, celiac disease, Wegener’s granulomatosis) within the past 3 years. NOTE: Subjects with childhood atopy or asthma, vitiligo, alopecia, Grave’s disease, Hashimoto’s thyroiditis, or psoriasis not requiring systemic treatment (within the past 2 years) are not excluded
8. Prior malignancy active within the previous 5 years, except for localised cancers that are considered to have been cured and in the opinion of the investigator present a low risk for recurrence. Examples include basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the cervix or breast
9. Known history of, or any evidence of active, non-infectious pneumonitis.
10. Active infection including:
• Tuberculosis (TB) (clinical evaluation that includes clinical history, physical examination and radiographic findings, and TB testing in line with local practice)
• Hepatitis B (known positive HBV surface antigen (HBsAg) result). Subjects with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible.
• Hepatitis C. Subjects positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA.
11. Significant cardiovascular disease, such as New York Heart Association cardiac disease (Class II or greater), myocardial infarction transient ischemic attack, or stroke within the previous 3 months, unstable arrhythmias, and/or unstable angina
12. Medical condition requiring current systemic anticoagulation, or a history of congenital hypercoagulable condition. Subjects taking aspirin at doses < 325 mg per day are eligible provided that prothrombin time is within the institutional range of normal. Use of local anticoagulation for port maintenance is permitted.
13. Subjects with history of venous thrombosis in the past 12 months prior to the scheduled first dose of study treatment (oleclumab)
14.
15. Diabetes mellitus Type 1 or poorly controlled Type 2 diabetes mellitus defined as a screening hemoglobin A1C ≥ 8 % or a fasting plasma glucose ≥ 160 mg/dL (or 8.8 mmol/L)
16. Any live (attenuated) vaccine within 30 days of planned start of study therapy
17. Prior systemic immunosuppressive medication (excluding corticosteroids) within 30 days of planned start of study therapy
18. Prior radiation therapy to the ipsilateral breast.
19. Prior immunotherapy, including tumour vaccine, cytokine, anti-CTLA4, PD-1/PD-L1, including durvalumab, blockade or similar agents
20. Concomitant use of other investigational drugs
21. 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. Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis after consultation with the Study Physician. Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with durvalumab or oleclumab may be included only after consultation with the Study Physician.
22. Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronic gastrointestinal conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs or compromise the ability of the patient to give written informed consent.
23. History or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject’s participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Safety run-in endpoints
• Occurrence of immune related or radiation therapy related toxicity of special interest
• Feasibility of delivering a sufficient dose of paclitaxel and ddAC
• Feasibility of performing surgery within a specified timeframe after the last neo-adjuvant treatment
Phase II Primary endpoint
· Residual cancer burden (RCB 0 vs. RCB 1-2-3) at time of surgery. RCB 0 is defined as pathological complete response (pCR) and RCB 1 is defined as minimal residual disease. RCB is calculated as a continuous index combining pathologic measurements of the primary tumour (size and cellularity) and nodal metastases (number and size) as defined by Symmans et al.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
Phase II Secondary endpoints
· Complete pathologic response rate (pCR) of the primary tumour (ypT0), irrespective of the response rate of the resected nodal metastases.
· Complete pathologic response rate (pCR) of the resected nodal metastases (ypN0), irrespective of the response rate of the primary tumour.
· % of breast conservation surgery in arms 2 and 3 versus arm 1
· Invasive Disease-Free Survival (iDFS) 3 years after surgery. iDFS will be measured using regular follow-up investigations: lab work, clinical examination and annual breast ultrasound and mammography. Radiologic imaging will not be routinely performed, unless directed by abnormal blood results or clinical examination.
· Duration and severity of AEs based on CTCAE 5.0.
· Changes in breast appearance: breast fibrosis, telangiectasia, dyspigmentation of the skin, and oedema of the breast/chest . The global cosmetic result after breast conservation will be based on Harris´s 4-point scale . This endpoint will be measured every 6 months starting from surgery during a total time period of 3 years.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | No |
| 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 | No |
| 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 | 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 | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| safety run-in: to check the safety of ARM 3 then randomized, open-label phase II |
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| 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 | 3 |
| 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 | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 6 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| 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
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· After last follow up visit of the last subject
· The trial is mature for the analysis of the endpoints as defined in the protocol, if the trial reaches its endpoints
· The database has been fully cleaned and frozen for all analyses
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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 | 5 |
| E.8.9.1 | In the Member State concerned months | 7 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 6 |
| E.8.9.2 | In all countries concerned by the trial months | 8 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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