Neo-adjuvant Chemotherapy Combined With Stereotactic Body Radiotherapy to the Primary Tumour +/- Durvalumab, +/- Oleclumab in Luminal B Breast Cancer:

NCT03875573 | Active Not Recruiting Phase 2 DMC

• 1 other identifier: IJB-LBC-NEOCHECKRAY-2018
• Study Type: interventional
• Target: 147
• Locations: 2 countries
• Sites: 7

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:

1. 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. 2.arm 1 with the addition of the anti-PD-L1 antibody durvalumab
3. 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.

Conditions

Luminal B

Keywords

Breast Cancer

Outcome Measures

Primary Outcomes (3)

• Safety Run-in: Evaluation of the immune related or radiation therapy related toxicity of special interest

  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

  7 months

• Safety Run-in: Evaluation of the feasibility of the primary surgery

  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.

  7 months

• Phase II: Demonstration of the tumour response in arms 2 or 3 versus arm 1

  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.

  24 months

Secondary Outcomes (9)

• 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

Study Arms (3)

Chemotherapy and radiotherapy

EXPERIMENTAL

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).

Radiation: Stereotactic Body Radiotherapy

Chemotherapy and pre-operative radiotherapy plus durvalumab

EXPERIMENTAL

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.

Drug: Durvalumab; Radiation: Stereotactic Body Radiotherapy

Chemotherapy & pre-op radiotherapy + durvalumab + oleclumab

EXPERIMENTAL

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.

Drug: Durvalumab; Radiation: Stereotactic Body Radiotherapy; Drug: Oleclumab

Interventions

Durvalumab DRUG

an anti PD-L1 intravenous administration at 1500 mg every 4 weeks for 19 weeks.

Also known as: MEDI4736

Chemotherapy & pre-op radiotherapy + durvalumab + oleclumab; Chemotherapy and pre-operative radiotherapy plus durvalumab

Stereotactic Body Radiotherapy RADIATION

Pre-operative radiation therapy (boost dose) 3x8 Gy on the primary tumour at week 5 given in 3 fractions. The 3 fractions will be spread at the minimum over 3 days and at the maximum over 6 days.

Also known as: SBRT

Chemotherapy & pre-op radiotherapy + durvalumab + oleclumab; Chemotherapy and pre-operative radiotherapy plus durvalumab; Chemotherapy and radiotherapy

Oleclumab DRUG

an anti-CD73 intravenous administration at 3000 mg every 2 weeks for the first 4 administrations then every 4 weeks for the last 3 administrations.

Also known as: MEDI9447

Chemotherapy & pre-op radiotherapy + durvalumab + oleclumab

Eligibility Criteria

• Age: 18 Years+
• Gender Eligibility Details: Must be female by biological birth.
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age ≥ 18 years old
• Female
• 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:
• If the MammaPrint result is not known at time of termination of all other screening procedures, the investigator is allowed to randomize the subject and start study treatment without waiting for the result of the MammaPrint in the following situations: (Ki67 \> 20 % or grade III) and Age\<50 years+ cN0 OR Age ≥ 50 years + cN+ • 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.
• The requirement for an MRI is not applicable in the case of medical contraindications to perform MRI (e.g., obesity or claustrophobia). In this situation, tumour evaluations should be performed by ultrasound.

You may not qualify if:

• 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:
• 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.

Sponsors & Collaborators

• Jules Bordet Institute: lead
• Institut Curie: collaborator
• AstraZeneca: collaborator

Study Sites (7)

Institut Jules Bordet

Brussels, 1000, Belgium

Location

Cliniques Universitaires Saint-Luc

Brussels, 1200, Belgium

Location

Universitaire Ziekenhuizen

Leuven, 3000, Belgium

Location

CHU UCL Namur Sainte-Elisabeth

Namur, 5000, Belgium

Location

GZA - Ziekenhuizen (Campus St. Augustinus)

Wilrijk, 2610, Belgium

Location

Centre Georges François Leclerc

Dijon, 21079, France

Location

Institut Curie

Paris, 75248, France

Location

Related Publications (2)

• De Caluwe A, Romano E, Poortmans P, Gombos A, Agostinetto E, Marta GN, Denis Z, Drisis S, Vandekerkhove C, Desmet A, Philippson C, Craciun L, Veys I, Larsimont D, Paesmans M, Van Gestel D, Salgado R, Sotiriou C, Piccart-Gebhart M, Ignatiadis M, Buisseret L. First-in-human study of SBRT and adenosine pathway blockade to potentiate the benefit of immunochemotherapy in early-stage luminal B breast cancer: results of the safety run-in phase of the Neo-CheckRay trial. J Immunother Cancer. 2023 Dec 6;11(12):e007279. doi: 10.1136/jitc-2023-007279.

  PMID: 38056900 DERIVED

• De Caluwe A, Buisseret L, Poortmans P, Van Gestel D, Salgado R, Sotiriou C, Larsimont D, Paesmans M, Craciun L, Stylianos D, Vandekerckhove C, Reyal F, Isabelle V, Eiger D, Piccart M, Romano E, Ignatiadis M. Neo-CheckRay: radiation therapy and adenosine pathway blockade to increase benefit of immuno-chemotherapy in early stage luminal B breast cancer, a randomized phase II trial. BMC Cancer. 2021 Aug 6;21(1):899. doi: 10.1186/s12885-021-08601-1.

  PMID: 34362344 DERIVED

MeSH Terms

Conditions

Breast Neoplasms

Interventions

durvalumab; Radiosurgery

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Radiotherapy; Therapeutics; Stereotaxic Techniques; Neurosurgical Procedures; Surgical Procedures, Operative; Investigative Techniques

Study Officials

• Alex De Caluwe, MD

  Jules Bordet Institute

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: 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.

Study Record Dates

• First Submitted: February 8, 2019
• First Posted: March 14, 2019
• Study Start: November 6, 2019
• Primary Completion: May 30, 2025
• Study Completion (Estimated): September 30, 2029
• Last Updated: December 20, 2024

Record last verified: 2024-03

Locations

BE (5); FR (2)