Malignant neoplasm of breast
Conditions
Interventions
This study will enroll approximately 1155 patients (approximately 525 patients in Cohort 1 and approximately 630 patients in Cohort 2) with advanced TNBC across up to 350 sites globally. The study wi
Drug
Biological/vaccine
Sponsors
Hospital Perola Byington
Hospital Perola Byington
Eligibility
Age
18 Years to 65 Years
Inclusion criteria
Inclusion criteria: Women or men with 18 to 65 years with locally advanced unresectable or metastatic triple-negative adenocarcinoma of the breast who have not received prior systemic chemotherapy in this setting may be eligible for this study. In patients with BRCA-associated tumors, platinum chemotherapy as potentially the preferred treatment option should be taken into consideration when determining whether this study may be appropriate for these patients. Patients may have received prior chemotherapy in the neoadjuvant or adjuvant setting if treatment was completed at least 12 months prior to randomization. Locally advanced unresectable disease must not be amenable to resection with curative intent. Patients must have sufficient tumor tissue and comply with all eligibility criteria to be enrolled. Signature (s) of Free and Informed Consent (s) signed; Women or men, aged 18 or over at the moment of signing the Informed Consent Term; Provision and ability to conduct all assessments related to the study, including PRO assessments, in the investigator's judgment; Measurable disease according to RECIST (Pre-irradiated lesions may be considered as measurable disease only if the progressive disease has been unequivocally documented at that location since the radiation.); Functional Capacity of 0 or 1 according to the Collaboration Group in East-American Oncology; Adequate hematological and organ function within 14 days before the first treatment of the study on Day 1 of Cycle 1; Life expectancy of at least 6 months; For women of childbearing potential: agree to remain abstinent or use contraception and agree to refrain from donating eggs; For men agree to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods and agree to refrain from donating sperm, a histologically documented triple-negative breast adenocarcinoma that is locally advanced or metastatic and is not amenable to resection with curative intent; Dispatch of a formalin-fixed and paraffin-embedded tumor tissue block (FFPE) or at least 15 freshly cut serial tumor blades not stained from the most recently collected tumor tissue (for PD-L1 status and other secondary and exploratory assessments required by the Protocol). Cytology or FNA samples will not be acceptable. Tumor tissue of bone metastases that is submitted to decalcification will not be acceptable; If a more recent sample is insufficient or unavailable, a patient may still be eligible if the patient can provide a block of tissue (preferred) or at least 15 unblotted serial slides of an older tumor archived tissue or is willing to consent and undergo an extra thick or excisional needle biopsy of the non-target lesion on pre-treatment (if it is accessible and the biopsy can be safely obtained). In general, at least three biopsies per thick needle will be required;
Exclusion criteria
Exclusion criteria: Inability to adhere to study and follow-up procedures; History of malabsorption syndrome or other condition that would interfere with enteral absorption or result in inability or unwillingness to swallow pills; Active infection requiring systemic antimicrobial treatment (including antibiotics, antifungal agents and antiviral agents); Known HIV infection (there should be a negative HIV test at screening); A clinically significant history of liver disease consistent with Child-Pugh B or C Class including active viral hepatitis or other hepatitis, current drug / drug or alcohol or cirrhosis abuse; Current treatment with antiviral therapy for HBV; Large surgical procedure, open biopsy or significant traumatic injury within 28 days prior to Cycle 1 Day 1 or anticipated need for a large surgical procedure during the study; Placement of a vascular access device will not be considered a major surgery; Pregnancy or lactation or intention to become pregnant during the study or within 28 days after the final dose of ipatasertibe / placebo, 5 months after the final dose of atezolizumab / placebo and 6 months after the final dose of paclitaxel, whichever occurs later; Class II, III or IV heart failure according to the New York Heart Association, ejection fraction left ventricle less than 50% or active ventricular arrhythmia requiring medication; Unstable angina present or history of myocardial infarction within 6 months before Day 1 of Cycle 1; Congenital long QT syndrome or QT interval corrected by the Fridericia formula (QTcF) at screening more than 480 ms; History or presence of an abnormal ECG that is clinically significant in the investigator's opinion (including complete left bundle branch block, second or third degree heart block or evidence of prior myocardial infarction); Need for chronic corticosteroid therapy more than 10 mg prednisone per day or equivalent dose of other anti-inflammatory corticosteroids or immunosuppressive agents for a chronic disease; Any other disease, metabolic dysfunction, physical examination findings, or clinical laboratory findings that in the investigator's opinion lead to reasonable suspicion of a disease or condition that contravenes the use of a investigational drug or that may affect the interpretation of the results or puts the patient at high risk for treatment complications; History of or known presence of brain or spinal metastases as determined by computed tomography (CT) or magnetic resonance imaging (MRI) evaluation during screening or previous radiographic evaluations; Any previous systemic therapy for locally advanced or metastatic triple inoperable breast adenocarcinoma; Patients who have received palliative radiotherapy for peripheral sites;Pleural effusion, pericardial effusion or uncontrolled ascites; Known hypersensitivity or contraindication to any component of the study treatments, including the excipient of paclitaxel, macrogolglycerol ricinoleate; Peripheral neuropathy Grade greater than or equal to 2; History of Type I or Type II diabetes mellitus requiring insulin; History of or autoimmune disease or active immunodeficiency including, but not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener's granulomatosis, Sjögren's syndrome, Guillain- Barré or multiple sclerosis
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| The co-primary efficacy endpoints are investigator-assessed PFS and OS. Investigator-assessed PFS, defined as the time from randomization to the first occurrence of disease progression, as determined locally by the investigator using RECIST v1.1 (see Appendix 5) or death from any cause, whichever occurs first. Data for patients without the occurrence of disease progression or death as of the clinical data cutoff date will be censored at the time of the last tumor assessment (or at the time of randomization plus 1 day if no tumor assessment was performed after the baseline visit) OS is defined as the time from randomization to death from any cause. Data for patients who have not died as of the clinical data cutoff date will be censored at the last date they are known to be alive. Data for patients who do not have postbaseline information will be censored at the randomization plus 1 day. Both PFS and OS will be compared between treatment arms using the stratified log-rank test. The hazard ratio will be estimated using a stratified Cox proportional hazards model The 95% CI for the hazard ratio will be provided. The stratification factors to be used will be the same as the randomization stratification factors. Results from an unstratified analysis will also be provided. For each treatment arm, Kaplan-Meier methodology will be used to estimate the median PFS and OS, and the Brookmeyer-Crowley method will be used to construct the 95% CI for the median PFS and OS (Brookmeyer and Crowley 1982). Kaplan-Meier curves will be produced as well. | — |
Secondary
| Measure | Time frame |
|---|---|
| An objective response is defined as response (CR or PR) on two consecutive occasions greater than or equal to 4 weeks apart, as determined by the investigator using RECIST v1.1. Patients not meeting these criteria, including patients without any postbaseline tumor assessment, will be considered non-responders. ORR is defined as the proportion of patients who had an objective response. The analysis population for ORR will be all randomized patients with measurable disease at baseline. An estimate of ORR and its 95% CI will be calculated using the Clopper-Pearson method for each treatment arm. ORR will be compared between treatment arms using the stratified Cochran-Mantel-Haenszel test. The stratification factors to be used will be the same as those used for the analysis of the primary endpoint. The difference in ORR between treatment arms will be calculated, and its 95% CI will be calculated using the normal approximation to the binomial distribution. DOR will be assessed in patients who had an objective response as determined by the investigator using RECIST v1.1. DOR is defined as the time from the first occurrence of a documented objective response (CR or PR, whichever status is recorded first) to the first occurrence of progressive disease, as determined by the investigator according to RECIST v1.1, or death, whichever occurs first. Patients who have not progressed and who have not died at the time of analysis will be censored at the time of last tumor assessment date. The Kaplan-Meier approach will be used to estimate the median DOR and the corresponding 95% CIs. Analysis of DOR will include only patients with objective responses. Because of the non-randomized nature of this analysis population, the analysis of DOR will be considered descriptive. | — |
Countries
Andorra, Austria, Belgium, Brazil, Canada, France, Germany, Hungary, Italy, Japan, Mexico, Peru, Spain, Ukraine, United Kingdom, United States
Contacts
Public ContactCamila Araújo
Produtos Roche Químicos e Farmacêuticos S.A
Outcome results
None listed