Working...
ClinicalTrials.gov
ClinicalTrials.gov Menu

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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT03875573
Recruitment Status : Not yet recruiting
First Posted : March 14, 2019
Last Update Posted : March 14, 2019
Sponsor:
Collaborators:
Institut Curie
AstraZeneca
Information provided by (Responsible Party):
Jules Bordet Institute

Tracking Information
First Submitted Date  ICMJE February 8, 2019
First Posted Date  ICMJE March 14, 2019
Last Update Posted Date March 14, 2019
Estimated Study Start Date  ICMJE June 15, 2019
Estimated Primary Completion Date June 15, 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 12, 2019)
  • Safety Run-in: 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: Primary surgery [ Time Frame: 7 months ]
    Feasibility of performing surgery within 6 weeks after the last neo-adjuvant treatment. This would that there were no significant delays or toxicities that would results in surgery being delayed.
  • Phase II: 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 vs. RCB 1-2-3) at time of surgery.
Original Primary Outcome Measures  ICMJE Same as current
Change History No Changes Posted
Current Secondary Outcome Measures  ICMJE
 (submitted: March 12, 2019)
  • Phase II: response to the primary tumour irrespective of the response to the pathological lymph nodes [ Time Frame: 24 months ]
    Complete pathologic response rate (pCR) of the primary tumour (ypT0), irrespective of the response rate of the resected nodal metastases
  • Phase II: response to the pathological lymph nodes irrespective of the response to the primary tumour [ Time Frame: 24 months ]
    Complete pathological response rate (pCR) of the resected nodal metastases (ypN0), irrespective of the response rate of the primary tumour.
  • Phase II: feasibility to perform breast-sparing surgery of the arms 2 and 3 versus arm 1 [ Time Frame: 24 months ]
    Calculating the percentage of breast conservation surgery in arms 2 and 3 versus arm 1
  • Phase II: the ability to control invasive disease in arms 2 and 3 versus arm 1 [ Time Frame: 24 months ]
    Invasive Disease-Free Survival (iDFS) 3 years after surgery.
  • Phase II: severity and duration of AEs [ Time Frame: 24 months ]
    Evaluate the duration and severity of AEs based on CTCAE 5.0.
  • Phase II: Cosmetic changes to the breast [ Time Frame: 24 months ]
    Changes in breast appearance are defined as:
    • Breast fibrosis
    • Telangiectasia
    • Dyspigmentation of the skin
    • Oedema of the breast/chest
    These will be evaluated according the LENT-SOMA scoring scale . The global cosmetic result after breast conservation will be based on Harris´s 4-point scale
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Neo-adjuvant Chemotherapy Combined With Stereotactic Body Radiotherapy to the Primary Tumour +/- Durvalumab, +/- Oleclumab in Luminal B Breast Cancer:
Official Title  ICMJE Neo-adjuvant Chemotherapy Combined With Stereotactic Body Radiotherapy to the Primary Tumour +/- Durvalumab, +/- Oleclumab in Luminal B Breast Cancer: a Phase ll Randomised Trial
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. 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.
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 followed by q2w dose-dense doxorubicin-cyclophosphamide (60 mg/m² and 600 mg/m² respectively)
  • Anti-PD-L1 antibody durvalumab 1500 mg q4w
  • Anti-CD73 antibody oleclumab 3000 mg q2w for 5 cycles, followed by q4w for 2 cycles
  • 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 or 3x lower dose if recommended after safety run-in).
  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 5 cycles, followed by q4w for 2 cycles.

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 every 3 months for the next 36 months.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:
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.
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Luminal B
Intervention  ICMJE
  • Drug: Durvalumab
    an anti PD-L1 intravenous administration at 1500 mg every 4 weeks for 19 weeks.
    Other Name: MEDI4736
  • Radiation: Stereotactic Body Radiotherapy
    Pre-operative radiation therapy (boost dose) 3x8 Gy on the primary tumour at week 5. Given over 3 days in 3 fractions (1X8 Gy daily)
    Other Name: SBRT
  • Drug: Oleclumab
    an anti-CD73 intravenous administration at 3000 mg every 4 weeks for 19 weeks.
    Other Name: MEDI9447
Study Arms  ICMJE
  • Experimental: Chemotherapy and radiotherapy
    The combination of weekly paclitaxel 80 mg/m² IV followed by every 2 week dose-dense doxorubicin-cyclophosphamide (ddAC) (60 mg/m² doxorubicin IV and 600 mg/m² cyclophosphamide IV) and pre-operative Stereotactic Body Radiotherapy on the primary tumour (3x8 Gy or 3x lower dose if recommended after safety run-in).
    Intervention: Radiation: Stereotactic Body Radiotherapy
  • Experimental: Chemotherapy and pre-operative radiotherapy plus durvalumab
    The combination of weekly paclitaxel 80 mg/m² IV followed by every 2 week 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 or 3x lower dose if recommended after safety run-in) with the addition of the anti-PD-L1 antibody durvalumab IV 1500 mg every 4 weeks.
    Interventions:
    • Drug: Durvalumab
    • Radiation: Stereotactic Body Radiotherapy
  • Experimental: Chemotherapy & pre-op radiotherapy + durvalumab + oleclumab
    The combination of weekly paclitaxel 80 mg/m² IV followed by every 2 week 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 or 3x lower dose if recommended after safety run-in) with the addition of the anti-PD-L1 antibody durvalumab IV 1500 mg every 4 weeks and the addition of the anti-CD73 antibody oleclumab IV 3000 mg every 2 weeks for 5 cycles, followed by every 4 for 2 cycles.
    Interventions:
    • Drug: Durvalumab
    • Radiation: Stereotactic Body Radiotherapy
    • Drug: Oleclumab
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Not yet recruiting
Estimated Enrollment  ICMJE
 (submitted: March 12, 2019)
147
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE June 15, 2025
Estimated Primary Completion Date June 15, 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Age ≥ 18 years old
  • Female
  • ECOG performance status ≤ 1
  • Histological diagnosis of 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
    • 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.
  • Mandatory new biopsy to provide tissue samples
  • 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 ≥ 20% or histology grade 3 tumours. (Testing to be done during screening period).
  • Must have histologically or cytologically confirmed invasive carcinoma of no special type (NST) or invasive lobular carcinoma (ILC)
  • Tumour size ≥ 1.5 cm, determined by MRI imaging.
  • N0 or N1
  • 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.
  • No contraindication for immunotherapy
  • Serum pregnancy test (for subjects of childbearing potential) negative within 72 hours prior to first dose of study administration.
  • 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.
  • 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
  • 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

  • Adequate renal function as defined below:

    • Creatinine ≤ 2.0 x UNL
  • 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
  • Completion of all necessary screening procedures within 14 days +/- 3 days prior to randomisation.
  • Willingness to provide tissue and blood samples for immuno-monitoring and translational research activities
  • Baseline left ventricular ejection fraction (LVEF) ≥ 50%.
  • Signed Informed Consent form (ICF) obtained prior to any study related procedure.

Inclusion criterion for phase II only (all phase II subjects):

• Confirmed tumour PD-L1 IHC assessment according to central testing for stratification purposes. (Testing done during screening period).

Inclusion criterion applicable to FRANCE only

• Affiliated to the French Social Security System (applicable only to subjects treated in France)

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 excipients (e.g; chemotherapy or immunotherapy formulations)
  • 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 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.
  • 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)
  • 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
  • Has received a live (attenuated) vaccine within 30 days of planned start of study therapy
  • Has received prior systemic immunosuppressive medication within 30 days of planned start of study therapy
  • Prior radiation therapy to the ipsilateral breast.
  • Concomitant use of other investigational drugs

Exclusion criterion applicable to FRANCE only

• 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.

Sex/Gender  ICMJE
Sexes Eligible for Study: Female
Gender Based Eligibility: Yes
Gender Eligibility Description: Must be female by biological birth.
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Alex De Caluwe, MD +3225413485 alex.decaluwe@bordet.be
Contact: Christie Freeman ctsu.neocheckray@bordet.be
Listed Location Countries  ICMJE Belgium
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03875573
Other Study ID Numbers  ICMJE IJB-LBC-NEOCHECKRAY-2018
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Jules Bordet Institute
Study Sponsor  ICMJE Jules Bordet Institute
Collaborators  ICMJE
  • Institut Curie
  • AstraZeneca
Investigators  ICMJE
Study Chair: Alex De Caluwe, MD Jules Bordet Institute
PRS Account Jules Bordet Institute
Verification Date January 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP