Neo-adjuvant Chemotherapy Combined With Stereotactic Body Radiotherapy to the Primary Tumour +/- Durvalumab, +/- Oleclumab in Luminal B Breast Cancer: a Phase ll Randomised Trial
Overview
- Phase
- Phase 2
- Intervention
- Stereotactic Body Radiotherapy
- Conditions
- Luminal B
- Sponsor
- Jules Bordet Institute
- Enrollment
- 147
- Locations
- 7
- Primary Endpoint
- Safety Run-in: Evaluation of the immune related or radiation therapy related toxicity of special interest
- Status
- Active, not recruiting
- Last Updated
- last year
Overview
Brief Summary
Neo-CheckRay is a multicenter, open-label phase II study that randomizes luminal B breast cancer subjects candidate for neo-adjuvant chemotherapy in a 1:1:1 ratio in 3 arms:
- the combination of weekly paclitaxel followed by dose-dense doxorubicin-cyclophosphamide (ddAC) and pre-operative radiation therapy (boost dose) on the primary tumour
- arm 1 with the addition of the anti-PD-L1 antibody durvalumab
- arm 2 with the addition of the anti-CD73 antibody oleclumab The primary tumour will be excised 2-6 weeks after completion of ddAC. A safety run-in is planned for the 6 first subjects before starting the randomized phase II trial. Those 6 subjects will receive the treatment given in Arm 3.
Detailed Description
This trial consists of a safety run-in followed by a phase II randomised trial. The goal of the safety run-in is to assess the safety of adding SBRT to the neo-adjuvant systemic treatment. The doses of the IMPs will be identical in the safety run-in and the phase II randomised trial. Individual subject timelines are also identical in the safety run-in and the phase II randomised trial. The safety run-in is done as a precursor to the phase II randomised part of the Neo-CheckRay trial. Six subjects will be included in the safety run-in. These subjects are not part of the phase II total recruitment. Subjects in the safety run-in will receive the following treatments corresponding to arm 3 of the phase II randomised trial. This consists of: * q1w paclitaxel 80 mg/m² IV for 12 administration (12 weeks) followed by q2w dose-dense doxorubicin-cyclophosphamide IV (60 mg/m² and 600 mg/m² respectively) for 4 administrations (8 weeks) * Anti-PD-L1 antibody durvalumab 1500 mg IV q4w for 5 administration (20 weeks) * Anti-CD73 antibody oleclumab 3000 mg IV q2w for 4 administrations (8 weeks), followed by q4w for 3 administrations (12 weeks) * Pre-operative radiation therapy (boost dose) 3x8 Gy on the primary tumour at week 5 If all requirements are meet during the safety run-in, then the phase II part of the study will be opened. The phase II will consist of luminal B breast cancer subjects candidate for neo-adjuvant chemotherapy will be randomised in a 1:1:1 ratio between 3 arms: 1. Arm 1: the combination of weekly paclitaxel 80 mg/m² IV followed by q2w dose- dense doxorubicin-cyclophosphamide (ddAC) (60 mg/m² doxorubicin IV and 600 mg/m² cyclophosphamide IV) and pre-operative radiation therapy on the primary tumour (3x8 Gy). 2. Arm 2: drugs regimen of Arm 1 with the addition of the anti-PD-L1 antibody durvalumab IV 1500 mg q4w. 3. Arm 3: drugs regimen of Arm 2 with the addition of the anti-CD73 antibody oleclumab IV 3000 mg q2w for 4 administrations, followed by q4w for 3 administrations. The primary tumour will be excised 2-6 weeks after completion of ddAC. The study treatments end at surgery. All treatment after surgery, such as post-operative radiotherapy and hormonal therapy, will be performed according to standard of care and local site guidelines. The patient will then be followed for the next 5 years.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Age ≥ 18 years old
- •ECOG performance status ≤ 1
- •Weight ≥ 35 kg
- •Histological diagnosis of invasive breast adenocarcinoma that is estrogen receptor-positive (ER-positive) and HER2- negative, as per the updated American Society of Clinical Oncology (ASCO) - College of American Pathologists (CAP) guidelines and performed according to local testing. In addition, only tumours with Proliferation Index Ki67 ≥ 15% or histology grade III are accepted.
- •Agreement to perform new study related biopsies to provide tissue samples
- •MammaPrint genomic high risk score according to centralised testing, except for specific conditions as mentioned below. Mammaprint will only be tested for luminal B breast tumours with either Proliferation Index Ki67 ≥ 15% or histology grade III tumours. (Testing to be done during screening period).
- •MammaPrint result status at time of termination of all other screening procedures
- •MammaPrint is high risk: subject may be randomized.
- •MammaPrint is low risk: subjet can not be randomized.
- •MammaPrint result is not yet known:
Exclusion Criteria
- •Pregnant and/or lactating women.
- •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.
- •TNM stage cT4 breast cancer including inflammatory breast cancer
- •Presence of any distant metastasis
- •Contra-indication for treatment by paclitaxel, doxorubicin or cyclophosphamide, or known allergy to any tested substances or any excipients (e.g; chemotherapy or immunotherapy formulations). Contra-indication for subjects with known sensitivity to acetaminophen/paracetamol, diphenhydramine or equivalent antihistamine (this is a contra-indication for treatment with oleclumab).
- •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.
- •Active or prior documented autoimmune disease (including inflammatory bowel disease, celiac disease, Wegner'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
- •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
- •Known history of, or any evidence of active, non-infectious pneumonitis.
- •Active infection including:
Arms & Interventions
Chemotherapy and radiotherapy
The combination of weekly paclitaxel 80 mg/m² IV followed by q2w dose-dense doxorubicin-cyclophosphamide (ddAC) (60 mg/m² doxorubicin IV and 600 mg/m² cyclophosphamide IV) and pre-operative radiation therapy on the primary tumour (3x8 Gy).
Intervention: Stereotactic Body Radiotherapy
Chemotherapy and pre-operative radiotherapy plus durvalumab
The combination of weekly paclitaxel 80 mg/m² IV followed by q2w dose-dense doxorubicin-cyclophosphamide (ddAC) (60 mg/m² doxorubicin IV and 600 mg/m² cyclophosphamide IV) and pre-operative radiation therapy on the primary tumour (3x8 Gy) with the addition of the anti-PD-L1 antibody durvalumab IV 1500 mg q4w.
Intervention: Durvalumab
Chemotherapy and pre-operative radiotherapy plus durvalumab
The combination of weekly paclitaxel 80 mg/m² IV followed by q2w dose-dense doxorubicin-cyclophosphamide (ddAC) (60 mg/m² doxorubicin IV and 600 mg/m² cyclophosphamide IV) and pre-operative radiation therapy on the primary tumour (3x8 Gy) with the addition of the anti-PD-L1 antibody durvalumab IV 1500 mg q4w.
Intervention: Stereotactic Body Radiotherapy
Chemotherapy & pre-op radiotherapy + durvalumab + oleclumab
The combination of weekly paclitaxel 80 mg/m² IV followed by q2w dose-dense doxorubicin-cyclophosphamide (ddAC) (60 mg/m² doxorubicin IV and 600 mg/m² cyclophosphamide IV) and pre-operative radiation therapy on the primary tumour (3x8 Gy) with the addition of the anti-PD-L1 antibody durvalumab IV 1500 mg q4w and the addition of the anti-CD73 antibody oleclumab IV 3000 mg q2w for 4 administrations, followed by q4w for 3 administrations.
Intervention: Durvalumab
Chemotherapy & pre-op radiotherapy + durvalumab + oleclumab
The combination of weekly paclitaxel 80 mg/m² IV followed by q2w dose-dense doxorubicin-cyclophosphamide (ddAC) (60 mg/m² doxorubicin IV and 600 mg/m² cyclophosphamide IV) and pre-operative radiation therapy on the primary tumour (3x8 Gy) with the addition of the anti-PD-L1 antibody durvalumab IV 1500 mg q4w and the addition of the anti-CD73 antibody oleclumab IV 3000 mg q2w for 4 administrations, followed by q4w for 3 administrations.
Intervention: Stereotactic Body Radiotherapy
Chemotherapy & pre-op radiotherapy + durvalumab + oleclumab
The combination of weekly paclitaxel 80 mg/m² IV followed by q2w dose-dense doxorubicin-cyclophosphamide (ddAC) (60 mg/m² doxorubicin IV and 600 mg/m² cyclophosphamide IV) and pre-operative radiation therapy on the primary tumour (3x8 Gy) with the addition of the anti-PD-L1 antibody durvalumab IV 1500 mg q4w and the addition of the anti-CD73 antibody oleclumab IV 3000 mg q2w for 4 administrations, followed by q4w for 3 administrations.
Intervention: Oleclumab
Outcomes
Primary Outcomes
Safety Run-in: Evaluation of the immune related or radiation therapy related toxicity of special interest
Time Frame: 7 months
Immune related or radiation therapy related toxicity of special interest are identifitied as: * Any Grade 4 immune-related AE * Any ≥ Grade 3 colitis * Any ≥ Grade 3 renal failure/nephritis * Any ≥ Grade 3 non-infectious pneumonitis irrespective of duration * Any Grade 3 immune-related AE, excluding colitis, renal failure/nephritis and pneumonitis, that does not downgrade to ≤ Grade 2 within 3 days after onset of the event despite maximal medical supportive care including systemic corticosteroids or does not downgrade to ≤ Grade 1 or baseline within 14 days * Liver transaminase elevation ≥ 5 ULN or total bilirubin \> 3 × ULN will be considered a DLT regardless of duration or reversibility * Any increase in AST or ALT \> 3 × ULN and concurrent increase in total bilirubin \> 2 × ULN
Safety Run-in: Evaluation of the feasibility of the primary surgery
Time Frame: 7 months
Feasibility of performing surgery within 6 weeks after the last neo-adjuvant treatment. This would indicate that there were no significant delays or toxicities that would results in surgery being delayed.
Phase II: Demonstration of the tumour response in arms 2 or 3 versus arm 1
Time Frame: 24 months
To demonstrate improved tumour response of the primary tumour and nodal metastases in arms 2 or 3 versus arm 1 using residual cancer burden (RCB 0-1 vs. RCB 2-3) at time of surgery.
Secondary Outcomes
- Phase II: Evaluation of the severity and duration of AEs of the arms 2 and 3 versus arm 1(5 years)
- Phase II: Evaluation of the rthe complete pathological response rate defined as ypT0/Tis ypN0(24 months)
- Phase II: Evaluation of the complete pathological response rate defined as ypT0 ypN0(24 months)
- Phase II: Evaluation of the response to the primary tumour irrespective of the response to the pathological lymph nodes(24 months)
- Phase II: Evaluation of the response to the pathological lymph nodes irrespective of the response to the primary tumour(24 months)
- Phase II: Evaluation of the the feasibility to perform breast-sparing surgery of the arms 2 and 3 versus arm 1(24 months)
- Phase II: Demonstration of the an increase in TIL levels of the primary breast cancer between baseline and the week 6 biopsy(24 months)
- Phase II: Evaluation of the ability to control invasive disease and survival in arms 2 and 3 versus arm 1 at year 3 and 5 years after surgery(5 years)
- Phase II: Evaluation of the the cosmetic changes to the breast of the arms 2 and 3 versus arm 1(5 years)