E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Untreated operable small triple negative breast cancer |
|
E.1.1.1 | Medical condition in easily understood language |
Untreated triple negative breast cancer |
|
E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10075566 |
E.1.2 | Term | Triple negative breast cancer |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To determine the effect of 6 weeks of pre-operatory durvalumab in pCR in patients with early small (cT1N0) triple negative breast cancer |
|
E.2.2 | Secondary objectives of the trial |
• To assess if preoperative treatment with durvalumab is associated with decreased tumor size as determined by RECIST 1.1 criteria by breast US • To evaluate the safety of the administration of 6 weeks of durvalumab
|
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Patient should understand, sign, and date the written informed consent form (including the consent to collect tissue, blood and stool samples, as specified by the protocol) prior to any protocol-specific procedures performed. Patient should be able and willing to comply with study visits and procedures as per protocol. 2. Female patients aged 18 years or older 3. Histologically confirmed untreated invasive carcinoma of the breast (ER < 1%, PR < 1%, HER2 negative) as locally determined 4. Candidates for initial breast surgery, cT1 as measured by breast US. Bilateral and multifocal tumors are allowed, assuming tumor evaluations and pre- and post-treatment biopsies are performed in the same target lesion 5. No evidence of metastatic disease or confirmed lymph node involvement 6. Eastern Cooperative Oncology Group (ECOG) performance status 0/1 7. Patients of child-bearing potential are eligible, provided they have a negative serum β-hCG pregnancy test within 2 weeks or urine pregnancy test within 48 hours prior to the first dose of study treatment, and agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods with a failure rate of < 1% per year during the treatment period and for 3 months after the last dose of durvalumab 8. A woman is considered of childbearing potential following menarche and until becoming post-menopausal (≥ 12 months of non-therapy-induced amenorrhea) unless permanently sterile. Permanent sterilization methods include hysterectomy, bilateral oophorectomy and bilateral salpingectomy. 9. Sexually active women of childbearing potential must agree to use a highly effective method of contraception supplemented by a barrier method, or to abstain from sexual activity during the study and for at least 3 months after the last study treatment administration. Female subjects should also refrain from breastfeeding throughout this period. 10. A highly effective birth control method is a one, which can achieve a failure rate of less than 1% per year when used consistently and correctly. Such methods include: combined (estrogen and progestogen containing) hormonal contraception; progestogen-only hormonal contraception associated with inhibition of ovulation; intrauterine device (IUD); intrauterine hormone-releasing system (IUS); bilateral tubal occlusion; vasectomized partner (on the understanding that this is the only one partner during the whole study duration), and sexual abstinence during the entire period of risk associated with study treatment. To prevent the risk of interaction between the study drug and hormonal contraceptives, hormonal contraceptives should be supplemented with a barrier method (preferably male condom). Following methods are considered as unacceptable methods (non-exhaustive list): periodic abstinence (calendar, symptothermal, post-ovulation methods) and withdrawal (coitus interruptus). 11. Blood tests demonstrating: • Creatinine ≤ 1.5 x ULN • Bilirubin ≤ 1.5 x ULN, AST or ALT < 3 x ULN, ALP < 2.5 x ULN (patients with known Gilbert disease who have serum bilirubin level ≤ 3 x the institutional ULN may be enrolled) • For patients not receiving therapeutic anticoagulation: INR or aPTT ≤ 1.5 x ULN. For patients receiving therapeutic anticoagulation: stable anticoagulant regimen • Adequate bone marrow function as shown by: ANC ≥ 1.5 x 109/L, Platelets ≥ 100 x 109/L, Hb > 9 g/dL, Serum albumin > 2.5 g/dL • Fasting Serum amylase ≤ 2 x ULN • Fasting Serum lipase ≤ ULN 12. Patients must be affiliated to a social security system or beneficiary of the same
|
|
E.4 | Principal exclusion criteria |
1.Patients non-candidate for upfront breast surgery or candidate for neoadjuvant chemotherapy 2.Any systemic therapy (...) or radiotherapy for current breast cancer disease before study entry 3.Known hypersensibility to durvalumab or any of its components 4.Patients with prior allogeneic stem cell or solid organ transplantation 5.Administration of a live, attenuated vaccine within 4 weeks prior to enrolment or anticipation that such a live, attenuated vaccine will be required during the study or within 5 months after the last dose of durvalumab 6.Treatment with systemic immunostimulatory agents (...) within 4 weeks or five half-lives of the drug, whichever is shorter, prior to enrolment 7.Treatment with systemic immunosuppressive medication (...) within 2 weeks prior to initiation of study treatment, or anticipation of need for systemic immunosuppressive medication during study treatment, with the following exceptions: • Patients who received acute, low-dose systemic immunosuppressant medication, or systemic corticosteroids at physiologic doses not to exceed <<10 mg/day>> of prednisone or its equivalent, or a one-time pulse dose of systemic immunosuppressant medication (...) are eligible for the study • Patients who received mineralocorticoids (e.g., fludrocortisone), corticosteroids for COPD or asthma, or low-dose corticosteroids for orthostatic hypotension or adrenal insufficiency are eligible for the study • Patients who received intranasal, inhaled, topical or local steroid injections (e.g., intra articular injection) 8.Active or history of autoimmune disease or immune deficiency, with the exception of history of treated autoimmune-related hypothyroidism and Type 1 diabetes mellitus on insulin regimen 9.History of idiopathic pulmonary fibrosis, organizing pneumonia or interstitial lung disease 10.History of HIV infection 11.Patients with active hepatitis infection (defined as having a positive HBsAg test at screening) or hepatitis C. Patients with past HBV infection or resolved HBV infection (defined as having a negative HBsAg test and a positive to anti-HBc antibody test) are eligible. Patients positive for HCV antibody are eligible only if PCR is negative for HCV RNA 12.Active tuberculosis 13.Current treatment with anti-viral therapy for HBV 14. Participation in another clinical study with an investigational product during the last 28 days and while on study treatment 15.Prior treatment with CD137 agonists or immune checkpoint blockade therapies, including antiCTLA-4, antiPD-1, and antiPD-L1 therapeutic antibodies 16.Psychological, familial, sociological or geographical conditions that do not permit compliance with the study protocol 17.Serious uncontrolled concomitant disease that would put the patient at high risk of treatment-related complications 18.Patient has clinically significant, uncontrolled heart disease and/or recent cardiac events including any of the following: • History of angina pectoris, coronary artery bypass graft (CABG), symptomatic pericarditis, or myocardial infarction within 12 months prior to the start of study treatment • History of documented congestive heart failure (New York Heart Association functional classification III-IV) • Documented cardiomyopathy • Patient has a Left Ventricular Ejection Fraction (LVEF) < 50% as determined by Multiple Gated acquisition (MUGA) scan or echocardiogram (ECHO) • History of any cardiac arrhythmias (e.g., ventricular tachycardia), complete left bundle branch block, high grade AV block (e.g., bifascicular block, Mobitz type II and third degree AV block), supraventricular, nodal arrhythmias, or conduction abnormality in the previous 12 months. • Uncontrolled hypertension defined by a Systolic Blood Pressure (SBP) ≥ 160 mmHg and/or Diastolic Blood Pressure (DBP) ≥ 100 mmHg, with or without antihypertensive medication. Initiation or adjustment of antihypertensive medication(s) is allowed prior to screening. • Long QT syndrome, family history of idiopathic sudden death or congenital long QT syndrome, or any of the following: o Risk factors for Torsades de Pointe (TdP) including uncorrected hypokalemia or hypomagnesemia, history of cardiac failure, or history of clinically significant/symptomatic bradycardia o Concomitant medication(s) with a known risk to prolong the QT interval and/or known to cause Torsades de Pointe that cannot be discontinued or replaced by safe alternative medication o Bradycardia (heart rate < 50 at rest), by ECG or pulse. 19.Female patients who are pregnant or breastfeeding, or adults of reproductive potential who are not using effective birth control methods. If barrier contraceptives are being used, these must be continued throughout the trial by both sexes 20.Patients unwilling to or unable (as assessed by the investigator) to comply with the protocol 21.Patient under guardianship or deprived of her liberty by a judicial or administrative decision or incapable of giving its consent. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint is pCR rate after 6 weeks of durvalumab, defined as the absence of invasive disease in the breast and negative axillary nodes (ypT0/yTis ypN0) |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
E.5.2 | Secondary end point(s) |
• Objective response rate by ultrasound after 6 weeks of durvalumab • Incidence, nature and severity of Adverse Events graded according to NCI-CTCAE v5.0 collected during durvalumab treatment and up to 4 weeks post-surgery
|
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 1 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | |