Neo-adjuvant Chemotherapy Combined With Stereotactic Body Radiotherapy to the Primary Tumour +/- Durvalumab, +/- Oleclumab in Luminal B Breast Cancer: a Phase ll Randomised Trial (Neo-CheckRay)

  • STATUS
    Recruiting
  • End date
    Jan 15, 2026
  • participants needed
    147
  • sponsor
    Jules Bordet Institute
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Updated on 21 October 2022
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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:

  1. the combination of weekly paclitaxel followed by dose-dense doxorubicin-cyclophosphamide (ddAC) and pre-operative radiation therapy (boost dose) on the primary tumour
  2. arm 1 with the addition of the anti-PD-L1 antibody durvalumab
  3. 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.

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 36 months (every 3 months during the first 24 months and every 6 months during the last 12 months).

Details
Condition Luminal B
Treatment durvalumab, Stereotactic body radiotherapy, oleclumab
Clinical Study IdentifierNCT03875573
SponsorJules Bordet Institute
Last Modified on21 October 2022

Eligibility

 Yes No Not Sure

Inclusion Criteria

Age ≥ 18 years old
Female
ECOG performance status ≤ 1
Weight ≥ 35 kg
Histological diagnosis of invasive breast adenocarcinoma that is estrogen receptorpositive, 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
Agreement to perform new study related biopsies to provide tissue samples
Confirmed Mammaprint genomic high risk score according to centralised 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).In case the MammaPrint test returns an unevaluable result or is technically impossible, the sponsor should be contacted as soon as possible to discuss the inclusion of the concerned patient. Under some specific medical conditions and breast cancer disease characteristics, the medical team of the sponsor can accept that the site continues the screening process of the patient. There will be maximum 5% of nonevaluable Mammaprint results among enrolled patients
Tumour size
If subject is cN0: tumour size ≥ 2 cm, as determined by MRI imaging
If subject is cN1, cN2 or cN3: tumour size ≥ 1.5 cm, as determined by MRI imaging
Multifocal, multicentric unilateral or bilateral breast adenocarcinoma tumours are
Serum pregnancy test (for subjects of childbearing potential) negative within 2 weeks prior to first dose of study administration
allowed provided that all foci are ER+/HER2- according to local testing and
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
all foci are able to receive SBRT treatment within the defined dosimetric
Adequate bone marrow function as defined below
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
Adequate liver function as defined below
modality to guide biopsy) should be collected
Adequate renal function as defined below
Absolute neutrophil count ≥1500/µL, i.e. 1.5x10^9/L
Hemoglobin ≥ 9.0 g/dL
Adequate coagulant function as defined below
Platelets ≥100000/µL, i.e. 100x10^9/L
Serum total bilirubin ≤ 1.5 x ULN. In case of known Gilbert's syndrome ≤ 3 x UNL is allowed
Willingness to provide tissue and blood samples for immuno-monitoring and translational research activities
AST (SGOT) ≤ 3.0 x ULN
ALT (SGPT) ≤ 3.0 x ULN
Signed Informed Consent form (ICF) obtained prior to any study related procedure
Inclusion criterion for phase II only (all phase II subjects)
Creatinine ≤ 1.5 x UNL or eGFR ≥ 40ml/min/1.73m²
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
Completion of all necessary screening procedures within 21 days prior to
randomisation
Left ventricular ejection fraction (LVEF) ≥ 50%. LVEF performed in routine is accepted if done within 6 months prior to beginning of screening
• Tumour sample provided for central PD-L1 IHC assessment. (Testing done during screening
period)
Inclusion criterion applicable to FRANCE only (all safety run-in and phase II subject)
• Affiliated to the French Social Security System (applicable only to subjects treated in
France)

Exclusion Criteria

Pregnant and/or lactating women
TNM stage cT4 breast cancer including inflammatory breast cancer
Presence of any distant metastasis
Known history of, or any evidence of active, non-infectious pneumonitis
Subject with a significant medical, neuro-psychiatric, substance abuse or surgical
Active infection including
condition, currently uncontrolled by treatment, which, in the principal investigator's
opinion, may interfere with completion of the study
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
Any live (attenuated) vaccine within 30 days of planned start of study therapy
contra-indication for treatment with oleclumab)
Previously known contra-indication for treatment by radiation therapy such as rare
Prior radiation therapy to the ipsilateral breast
genetic disorders associated with DNA repair disorders such as ataxia-telangiectasia
(A-T), Nijmegen Breakage Syndrome (NBS) and Fanconi anemia
Concomitant use of other investigational drugs
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)
Prior organ transplantation
are not excluded
Subjects with urinary outflow obstruction
Prior malignancy active within the previous 5 years, except for localised cancers that
Exclusion criterion applicable to FRANCE only
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
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
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
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
Subjects with history of venous thrombosis in the past 12 months prior to the
scheduled first dose of study treatment (oleclumab)
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)
Prior systemic immunosuppressive medication (excluding corticosteroids) within 30 days
of planned start of study therapy
Prior immunotherapy, including tumour vaccine, cytokine, anti-CTLA4, PD-1/PD-L1
including durvalumab, blockage or similar agents
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. Subjets with Grade ≥2 neuropathy will be evaluated on a case-by-case basis
after consultation with the Study Physician. Subjects 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
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 subject to give written
informed consent
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
• Vulnerable persons according to the article L.1121-6 of the CSP, adults who are the
subject of a measure of legal protection or unable to express their consent according to
article L.1121-8 of the CSP
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