ATEZOLIZUMAB for Triple-negative breast cancer

Inclusion criteria

• {"criterion_text":"-1.\tWilling and able to provide written informed consent prior to study entry\n-2.\tFemale ≥ 18 years of age\n-3.\tEastern Cooperative Oncology Group (ECOG) Performance Status 0 to 1\n-4.\tHistologically confirmed TNBC defined as: •\tER negative with <1% of tumour cells positive on IHC or an IHC score (Allred) of ≤2 •\tPR unknown or negative with <1% of tumour cells positive on IHC or Allred score of ≤2 •\tHER2 negative with 0, 1+ or 2+ intensity on IHC and no evidence of amplification of the HER2 gene on ISH\n-5.\tNode-positive (cT1-4 cN1-2 M0) and/or tumour size ≥2 cm (cT2-T4 cN0-2 M0) with no prior treatment; participants entering the trial after undergoing a SLN biopsy will be eligible if they meet other entry criteria\n-6.\tAdequate haematologic and end-organ function within 28 days prior to the first study treatment defined by the following: a.\tANC ≥ 1500 cells/μL (1.5 x 109/L) (without granulocyte colony-stimulating factor support within 2 weeks prior to Cycle 1, Day 1) b.\tPlatelet count ≥ 100,000/μL (100 x 109/L) (without transfusion within 2 weeks prior to Cycle 1, Day 1) c.\tHaemoglobin ≥ 9.0 g/dL (90g/L) (patients may be transfused or receive erythropoietic treatment to meet this criterion) d.\tINR or aPTT  1.5  ULN (for patients not receiving therapeutic anticoagulation. Patients receiving therapeutic anticoagulation must be on a stable anticoagulant regimen e.\tSerum creatinine ≤ 1.5 x ULN or calculated creatinine clearance  50 ml/min f.\tAST or ALT and ALP < 2.5 times the institutional upper limit of normal (ULN), bilirubin ≤ 1.5 x ULN (patients with known Gilbert disease who have serum bilirubin level ≤ 3 × the institutional ULN may be enrolled)\n-7.\tPatients of childbearing potential are eligible provided they have a negative serum or urine pregnancy test within 14 days of Day 1 Cycle 1 of study treatment, preferably as close to the first dose as possible. Patients must agree to use adequate contraception, defined as those methods with a failure rate of < 1 % per year, (see section 6.14) beginning 14 days before the first dose of study drug and for 12 months after the last dose of cyclophosphamide (or 5 months after the last dose of atezolizumab, whichever is longer)\n-8.\tAbility to comply with the protocol\n-9.\tRepresentative formalin-fixed paraffin embedded (FFPE) breast tumour samples (at least 2 core needle biopsies) with an associated pathology report, determined to be available and sufficient for central testing OR tumour accessible for biopsy"}

Exclusion criteria

• {"criterion_text":"-1.\tEvidence of metastatic breast cancer\n-10.\tHistory of autoimmune disease including but not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener’s granulomatosis, Sjögren’s syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis. Patients with autoimmune-related hypothyroidism on a stable dose of thyroid replacement therapy may be eligible for the study following discussion with the medical monitor (See Appendix 1 for complete list)\n-11.\tHistory of Type I or Type II diabetes mellitus requiring insulin. Patients who are on a stable dose of oral diabetes medication ≥ 2 weeks prior to initiation of study treatment are eligible for enrolment\n-12.\tHistory of idiopathic pulmonary fibrosis or organizing pneumonia\n-13.\tHistory of HIV infection\n-14.\tKnown active hepatitis infection (defined as having a positive hepatitis B surface antigen [HBsAg] test at screening) or hepatitis C. Patients with past hepatitis B virus (HBV) infection or resolved HBV infection (defined as having a negative HBsAg test and a positive antibody to hepatitis B core antigen [anti-HBc] antibody test) are eligible. Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV RNA\n-15.\tActive tuberculosis\n-16.\tSevere infection within 4 weeks prior to initiation of study treatment, including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia\n-17.\tTreatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation of study treatment. Patients receiving prophylactic antibiotics (e.g., to prevent a urinary tract infection or chronic obstructive pulmonary disease exacerbation) are eligible for the study\n-18.\tTreatment with a live, attenuated vaccine within 4 weeks prior to initiation of study treatment, or anticipation of need for such a vaccine during atezolizumab treatment or within 5 months after the final dose of atezolizumab\n-19.\tCurrent treatment with anti-viral therapy for HBV\n-2.\tReceived any systemic therapy (e.g. chemotherapy, targeted therapy, immune-therapy) or radiotherapy for current breast cancer disease before study entry\n-20.\tTreatment with systemic immunostimulatory agents (including, but not limited to, interferon and interleukin 2 [IL-2]) within 4 weeks or 5 half-lives of the drug (whichever is longer) prior to initiation of study treatment\n-21.\tPatients receiving concomitant immunosuppressive agents or chronic systemic corticosteroids (≥10 mg prednisolone or an equivalent dose of other anti-inflammatory corticosteroids) use for ≥28 days at the time of study entry except in cases outlined below: Topical applications (e.g. rash), inhaled sprays (e.g. obstructive airways diseases), eye drops or local injections (e.g. intra-articular) are allowed. Patients on stable low dose of corticosteroids for at least two weeks before randomisation are allowed\n-22.\tSignificant cardiovascular disease, such as: •\tHistory of myocardial infarction, acute coronary syndromes or coronary angioplasty/stenting/bypass grafting within the past 6 months •\tCongestive heart failure (CHF) New York Heart Association (NYHA) Class III or IV or history of CHF NYHA class III or IV, unless an echocardiogram or multigated acquisition scan performed within 3 months before day 1 reveals a left ventricular ejection fraction ≥ 50%;\n-23.\tAny other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that, in the investigator’s opinion, gives reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug, may affect the interpretation of the results, render the patient at high risk from treatment complications or interferes with obtaining informed consent\n-24.\tPsychological, familial, sociological or geographical conditions that do not permit compliance with the study protocol\n-25.\tConcurrent treatment with other experimental drugs. Participation in another clinical trial with any investigational drug within 30 days prior to study entry\n-26.\tTreatment with strong CYP3A inhibitors or strong CYP3A inducers within 2 weeks or 5 drug-elimination half-lives, whichever is longer, prior to initiation of study drug\n-27.\tPersistent toxicities (≥CTCAE grade 2) caused by previous cancer therapy, excluding alopecia and peripheral neuropathy\n-28.\tPregnant or nursing women\n-29.\tInability to swallow medication or malabsorption condition that would alter the absorption of orally administered medications\n-3.\tPrior exposure to any CD137 agonists or immune checkpoint blockade therapies, including antiCTLA-4, anti-PD-1 or anti-PD-L1 antibody\n-30.\tClinically significant abnormalities of glucose metabolism as defined by any of the following: a.\tGlycosylated haemoglobin (HbA1C) ≥7.5% at screening (64 mmol/mol) (conversion equation for HbA1C [IFCC-HbA1C (mmol/mol) = [DCCT-HbA1C (%) – 2.15] x 10.929) b.\tFasting Plasma Glucose ≥ 7.0mmol/L (126 mg/dL) at screening. Fasting is defined as no caloric intake for at least 8 hours c.\tHistory of Type I or Type II diabetes mellitus requiring insulin. Patients who are on a stable dose of oral diabetes medication ≥ 2 weeks prior to initiation of study treatment are eligible for enrolment\n-31.\tHistory of or active inflammatory bowel disease (e.g., Crohn's disease and ulcerative colitis) or active bowel inflammation (e.g., diverticulitis)\n-32.\tTreatment with strong CYP3A inhibitors or strong CYP3A inducers within 2 weeks or 5 drug-elimination half-lives, whichever is longer, prior to initiation of study drug\n-4.\tConcurrent bilateral invasive breast cancer\n-5.\tInflammatory breast cancer\n-6.\tActive malignancy (except for non-melanoma skin cancer, or histologically confirmed complete excision of carcinoma in-situ) within the past 36 months prior to study entry\n-7.\tMajor surgery within the last 28 days or anticipation of the need for major surgery during study treatment; minor surgeries including insertion of an indwelling catheter, core needle biopsy, or sentinel lymph node biopsy is allowed\n-8.\tKnown intolerance to any of the study drugs (ie, paclitaxel, doxorubicin, epirubicin, cyclophosphamide) or any of their excipients\n-9.\tPre-existing peripheral neuropathy grade ≥ 2"}

Primary endpoints

• {"endpoint_text":"-Clinical: •\tpCR is defined as no microscopic evidence of residual invasive tumour in all resected specimens of the breast and axilla (ypT0/is ypN0) in all patients. •\tpCR is defined as no microscopic evidence of residual invasive tumour in all resected specimens of the breast and axilla (ypT0/is ypN0) in patients with or without PIK3CA/AKT1/PTEN genetic alterations.","definition_or_measurement_approach":"pCR defined as no microscopic evidence of residual invasive tumour in all resected specimens of the breast and axilla (ypT0/is ypN0); applied to all patients and to patients stratified by PIK3CA/AKT1/PTEN genetic alteration status."}
• {"endpoint_text":"-Biological: 2-fold increase in GzmB+ CD8+ T cell levels from baseline to the end of each treatment phase.","definition_or_measurement_approach":"Measured change in GzmB+ CD8+ T cell levels from baseline to end of each treatment phase; endpoint defined as a 2-fold increase."}

Secondary endpoints

• {"endpoint_text":"-•\tObjective response rate (ORR) as assessed by RECIST 1.1 principles, defined as percentage of subjects with best overall response of complete response (CR) or partial response (PR) in the relevant analysis population.","definition_or_measurement_approach":"Assessed by RECIST 1.1; ORR = proportion with CR or PR."}
• {"endpoint_text":"-•\tORR.","definition_or_measurement_approach":"Objective response rate (method not further specified here; likely RECIST 1.1 as above)."}
• {"endpoint_text":"-•\tStatus and changes of the biomarkers listed below in pre- and end-of treatment tumour and/or blood samples: immune phenotyping, CD8, PD-L1 & MHC-I, immune infiltrates (IFN gene signature expression).","definition_or_measurement_approach":"Biomarker assessment in pre- and end-of-treatment tumour and/or blood samples including immune phenotyping, CD8, PD-L1, MHC-I, immune infiltrates and IFN-γ gene signature."}
• {"endpoint_text":"-•\tIEFS, defined as the time from randomisation to date of first treatment failure that is invasive loco‐regional or distant recurrence or new invasive cancer or death from any cause. IEFS is further detailed according to the standardized STEEP system definition","definition_or_measurement_approach":"Time-to-event measured from randomisation to first invasive loco-regional or distant recurrence, new invasive cancer, or death; per STEEP definitions."}
• {"endpoint_text":"-•\tDEFS, defined as the time from randomisation to the date of first distant recurrence or death attributable to any cause, including breast cancer, non‐breast cancer, or unknown cause. Distant recurrence is defined as metastatic disease‐breast cancer that has either been biopsy confirmed or clinically diagnosed as recurrent invasive breast cancer.","definition_or_measurement_approach":"Time from randomisation to first distant recurrence or death; distant recurrence defined as biopsy-confirmed or clinically diagnosed metastatic breast cancer."}
• {"endpoint_text":"-•\tOS, defined as time from randomisation to death of any cause.","definition_or_measurement_approach":"Overall survival measured from randomisation to death from any cause."}
• {"endpoint_text":"-•\tAssessment of mean changes in function and disease/treatment-related symptoms in all scales of the EORTC QLQ-C30 by treatment arm.","definition_or_measurement_approach":"Mean changes in EORTC QLQ-C30 scales by treatment arm."}
• {"endpoint_text":"-•\tHealth utility assessment as measured by the EQ-5D during the study for health economic evaluations.","definition_or_measurement_approach":"EQ-5D health utility measurement during study."}
• {"endpoint_text":"-•\tIncidence, nature and severity of adverse events with severity determined according to CTCAE v4.03.","definition_or_measurement_approach":"Safety assessed by incidence, nature and severity of AEs graded per CTCAE v4.03."}

Germany

Earliest CTIS Part Ii Submission Date

03-10-2024

Latest Decision Or Authorization Date

14-10-2024

Processing Time Days

11

Number Of Sites

3

Number Of Participants

14

Spain

Earliest CTIS Part Ii Submission Date

03-10-2024

Latest Decision Or Authorization Date

08-10-2024

Processing Time Days

5

Number Of Sites

15

Number Of Participants

95

Primary sponsor

Full Name

Queen Mary University Of London

Organisation Type

Educational Institution

Country Of Registered Address

United Kingdom