Neo-adjuvant chemotherapy combined with Stereotactic Body Radiotherapy to the primary tumour +/- durvalumab (MEDI4736), +/- oleclumab (MEDI9447) in luminal B breast cancer: a phase ll randomised trial

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Institut Jules Bordet

Participant type

Patients

Age range

18-64 years

Gender

Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

17 Oct 2019 → ongoing

Decision date (initial)

2024-10-17

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

AstraZeneca

External identifiers

EU CT number

2024-511849-19-00

EudraCT number

2018-004165-13

ClinicalTrials.gov

NCT03875573

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety

To demonstrate improved tumour response of the primarytumour and nodal metastases in arms 2 or 3 versus arm 1.

Secondary objectives 9

1. At surgery: • To evaluate the complete pathological response rate defined as ypT0/Tis ypN0: absence of residual invasive disease, residual in situ carcinoma is accepted
2. • To evaluate the complete pathological response rate defined as ypT0 ypN0: absence of residual invasive disease and in situ carcinoma.
3. • To evaluate the response to the primary tumour irrespective of the response to the pathological lymph nodes
4. • To evaluate the response to the pathological lymph nodes irrespective of the response to the primary tumour.
5. • To evaluate the feasibility to perform breast-sparing surgery of the arms 2 and 3 versus arm 1.
6. • Demonstrate an increase in TIL levels of the primary breast cancer between baseline and the week 6 biopsy.
7. Follow-up phase: • To evaluate the ability to control invasive disease and survival in arms 2 and 3 versus arm 1 at year 3 and 5 years after surgery.
8. • To evaluate the severity and duration of AEs of the arms 2 and 3 versus arm 1.
9. • To evaluate the cosmetic changes to the breast of the arms 2 and 3 versus arm 1

Conditions and MedDRA coding

Luminal B Breast Cancer

Study design 1 period

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 21

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 (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.
6. Agreement to perform new study related biopsies to provide tissue samples
7. 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)
8. 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.
9. Multifocal, multicentric unilateral or bilateral breast adenocarcinoma tumours are allowed provided that all biopsiable foci are ER+/HER2- according to local testing and all foci are able to receive SBRT treatment within the defined dosimetric constraints. In some cases a separate biopsy of every focus is not mandatory, but only if every of the following conditions are present. • small focal lesion • lesion in close proximity to the main primary cancer from which a biopsy was taken • the investigator and the radiologist consider the lesion to be clearly related to the main primary breast cancer from which a biopsy was taken • the lesion will be removed during the same lumpectomy than the main primary breast cancer 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.
10. Serum pregnancy test (for subjects of childbearing potential) negative within 2 weeks prior to first dose of study administration.
11. 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
12. 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
13. 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
14. Adequate renal function as defined below: • Creatinine ≤ 1.5 x UNL or eGFR≥40ml/min/1.73m2 15. Adequate coagulant function as defined below
15. Adequate coagulant function as defined below: • International Normalized Ratio (INR) ≤ 1.5 x ULN
16. Completion of all necessary screening procedures within 28 days prior to randomisation (except if written differently).
17. Willingness to provide tissue and blood samples for immunomonitoring and translational research activities
18. Left ventricular ejection fraction (LVEF) ≥ 50%. LVEF performed in routine is accepted if done within 6 months prior to beginning of screening
19. Signed Informed Consent form (ICF) obtained prior to any study related procedure.
20. Inclusion criterion for phase II only (all phase II subjects): 20. Tumour sample provided for central PD-L1 IHC assessment (Testing done during screening period).
21. Inclusion criterion applicable to FRANCE only (Safety run-in and Phase II subjects) 21. Affiliated to the French Social Security System (applicable only to subjects treated in France)

Exclusion criteria 25

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). Contra-indication for subjects with known sensitivity to acetaminophen/paracetamol, diphenhydramine or equivalent antihistamine (this is a contra-indication for treatment with oleclumab).
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 breas
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 [antiHBc] 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. 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)
15. Any live (attenuated) vaccine within 30 days of planned start of study therapy
16. Prior systemic immunosuppressive medication (excluding corticosteroids) within 30 days of planned start of study therapy
17. Prior radiation therapy to the ipsilateral breast
18. Prior immunotherapy, including tumour vaccine, cytokine, antiCTLA4, PD-1/PD-L1, including durvalumab, blockade or similar agents
19. Concomitant use of other investigational drugs
20. 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. Subjects 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
21. 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
22. 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
23. Prior organ transplantation
24. Subjects with urinary outflow obstruction
25. Exclusion criterion applicable to FRANCE only (Safety run-in and Phase II subjects). 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

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Residual cancer burden (RCB 0-1 vs. RCB 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. (15).

Secondary endpoints 7

1. At surgery: • Rate of pCR - ypT0/Tis ypN0, defined as the absence of residual invasive cancer at the time of definitive surgery.
2. Rate of pCR - no DCIS (yp DCIS (ypT0 ypN0), defined as the absence of residual invasive and in situ cancer at time of definitive surgery
3. Complete pathologic response rate (pCR) of the primary tumour (ypT0/ Tis), irrespective of the response rate of the resected nodal metastases.
4. Complete pathologic response rate (pCR) of the resected nodal metastases (ypN0), irrespective of the response rate of the primary tumour.
5. % of breast conservation surgery in arms 2 and 3 versus arm 1
6. Change in TIL levels between baseline and the week 6 biopsy.
7. Follow-up Phase: Efficacy endpoints at 3 years and 5 years after surgery will be measured, as defined by the Standardized Definitions for Efficacy End Points in Neoadjuvant Breast Cancer Clinical Trials (NeoSTEEP) (88). The following endpoints will be assessed: event-free survival (EFS), breast cancer event-free survival (BC-EFS), overall survival (OS) and distant recurrence-free survival (DRFS). Furthermore, the occurrence of ipsilateral locoregional recurrence (breast, chestwall or lo

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 5

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Institut Jules Bordet

Sponsor organisation

Institut Jules Bordet

Address

Mijlenmeersstraat 90

City

Anderlecht

Postcode

1070

Country

Belgium

Scientific contact point

Organisation

Institut Jules Bordet

Contact name

CTSU

Public contact point

Organisation

Institut Jules Bordet

Contact name

CTSU

Locations

2 EU/EEA countries · 7 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 22 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

3 submissions — initial application plus substantial / non-substantial modifications