Metastatic Breast Cancer
Conditions
Brief summary
Open label multicentric phase II randomized trial, using high throughput genome analysis as a therapeutic decision tool, which aims at comparing a targeted treatment administered according to the identified molecular anomalies of the tumor with maintenance chemotherapy (targeted substudy 1) as well as immunotherapy with maintenance chemotherapy in patients without actionable genomic alterations or non eligible to substudy 1 (immune substudy 2).
Detailed description
Screening phase: New frozen biopsy or an archived frozen sample or ctDNA sample will be sent to the genomic platforms for DNA extraction and genomic analysis (DNA microarrays and Next generation sequencing). Patients can be considered as pre-eligible for the targeted substudy 1 randomisation phase when both following mandatory conditions have been met: stable or responding disease has been observed (investigator judgment) after 6 to 8 cycles of chemotherapy (or at least after 4 cycles of chemotherapy if stopped for toxicity) and targetable alteration has been identified by the Molecular Tumor Board (MTB). If not eligible for the substudy 1 randomisation phase, patients can be considered as pre-eligible for the immune substudy 2 randomization phase when both following mandatory conditions are met: stable or responding disease (investigator judgment) is observed after 6 to 8 cycles of chemotherapy (or at least after 4 cycles if treatment was stopped due to toxicity) AND not eligible to randomization in the substudy 1 (because patient had no targetable alteration identified by the Molecular Tumor Board, or failed to have a genomic profile for the tumor \[low tumor cells percentage, technical issue during genomic analysis, etc.\], or a non inclusion criteria that precluded entry into the substudy 1) Randomization phase: The mandatory post-chemotherapy wash-out period, of 28 days for 21 or 28 day-cycle chemotherapies or of 15 days for weekly (except monoclonal antibodies) or daily chemotherapies,will provide time to achieve all the required tests and examinations. The randomization program will allocate the following treatments with a 2:1 ratio in favor of Arm A of the considered substudy: Substudy 1 : targeted therapies versus standard maintenance chemotherapy * Arm A1 / targeted arm: targeted maintenance from a list of 8 targeted drugs guided by the genomic analysis, or * Arm B1 / chemotherapy arm : maintenance chemotherapy (or no antineoplastic treatment in case of toxicity at the time of randomization) Substudy 2 : immunotherapy versus standard maintenance chemotherapy * Arm A2 / immunotherapy maintenance arm: MEDI4736 or * Arm B2 / chemotherapy arm: chemotherapy continued as a maintenance chemotherapy (or no antineoplastic treatment in case of toxicity)
Interventions
DRUGAZD2014
Target: m-TOR
DRUGAZD4547
Target: EGFR
DRUGAZD5363
Target: AKT
DRUGAZD8931
Target: HER2, EGFR
DRUGSelumetinib
Target: MEK
DRUGVandetanib
Target: VEGF, EGFR
DRUGBicalutamide
target: Androgen receptor
DRUGOlaparib
Target: PARP
DRUGAnthracyclines
DNA intercalation
DRUGTaxanes
Target: mitotic tubulin and microtubules
DRUGcyclophosphamide
Alkylating agents
DRUGDNA intercalators
DNA intercalators
DRUGMethotrexate
DNA intercalators
DRUGvinca alkaloids
Target: mitotic tubulin and microtubules
DRUGPlatinum based chemotherapies
Platinum based chemotherapies
DRUGBevacizumab
Target: VEGF
DRUGMitomycin C
Alkylating agents
DRUGEribulin
Microtubule modulator
DRUGMEDI4736
Target: PD-L1
Sponsors
Fondation ARC
AstraZeneca
UNICANCER
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Screening phase: Inclusion Criteria: * Women (or men) with histologically proven breast cancer * Metastatic relapse or progression or stage IV at diagnosis * No Her2 over-expression * Patients with metastases that can be biopsied, except bone metastases * Patients who are eligible for a first or a second line of chemotherapy in metastatic setting (left to the discretion of investigators), or who are currently treated with a first or second line of chemotherapy with a maximum of 2 cycles at the time of biopsy. Screening of patients currently treated with a second line chemotherapy should have a stable disease * For patients with ER+ disease, relapse or progression occurred during endocrine therapy, whatever the line, or less than 12 months after the end of endocrine therapy in adjuvant context * Age ≥18 years * WHO Performance Status 0/1 * Presence of measurable target lesion according to RECIST criteria v1.1
Exclusion criteria
* Spinal cord compression and/or symptomatic or progressive brain metastases * Bone metastases when this is the only site of biopsiable disease * Patients with all target lesions in a previously irradiated region, except if clear progression has been observed prior to study in at least one of them * Patient who received more than 2 lines of chemotherapy at the time of the biopsy * Tumor progression observed with the current line of treatment when under 2nd line * Patients who already had a genomic profile (both CGH and NGS analysis) in which no SAFIR02 targetable alterations have been identified * Abnormal coagulation contraindicating biopsy * Inability to swallow * Major problem with intestinal absorption Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG Any factors increasing the risk of QTc prolongation or arrhythmic events Experience of any of the following in the preceding 12 months: coronary artery bypass graft, angioplasty, vascular stent, myocardial infarction, past or current uncontrolled angina pectoris, congestive heart failure NYHA Grade ≥2, torsades de pointes, current uncontrolled hypertension, cardiomyopathy Past medical history of interstitial lung disease, drug-induced interstitial disease, radiation pneumonitis which requires steroid treatment or any evidence of clinically interstitial lung disease Previous or current malignancies of other histologies within the last 5 years, Evidence of severe or uncontrolled systemic disease (active bleeding diatheses, or active Hepatitis B, C and HIV) * diagnosis of acne rosacea, severe psoriasis and severe atopic eczema * Prior exposure to anthracyclines or mitoxantrone with cumulative exposure in excess of 360 mg/m² for doxorubicin, 720 mg/m² for epirubicin, or 72 mg/m² for mitoxantrone * Previous treatment with the same agent or in the same class as one of those used in the SAFIR02 trial (patients who received this previous targeted agent without the target prescreening are eligible but may not be eligible for randomisation in substudy 1 if the treatment allocated by the MTB is in the same class) History of retinal degenerative disease, eye injury or corneal surgery in the previous 3 months, past history of central serous retinopathy or retinal vein occlusion, intraocular pressure \>21 mmHg, or uncontrolled glaucoma. * History of hemorrhagic or thrombotic stroke, TIA or other CNS bleeds * Renal disease including glomerulonephritis, nephritic syndrome, Fanconi syndrome, renal tubular acidosis * Patients using drugs that are known potent inhibitors or potent inducers or substrates of cytochrome P450 Randomized phase: Substudy 1: Inclusion Criteria: * Patients who received 6 to 8 cycles of chemotherapy, or having received at least 4 cycles of chemotherapy definitively stopped for toxicity reasons, and who are presenting a SD or PR at randomization * presenting at least one genomic alteration from the predefined list * Age ≥25 years for patients planned to receive AZD4547 * 28-day wash-out period from chemo prior to randomization and grade ≤1 residual toxicities
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free survival in the targeted drug arm compared to standard maintenance therapy arm | from randomization to disease progression or death from any cause, whichever comes first, up to 16 months (estimated treatment duration average: 4 months) | To evaluate whether treatment with targeted agents guided by high throughput molecular analysis (CGH array, next generation sequencing) improves progression-free survival as compared to standard maintenance therapy in patients with metastatic Breast Cancer |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| overall response rates and changes in tumor size in each substudy | tumor response is assessed every 21 days from treatment initiation until first progression or death from any cause, whichever comes first, up to 16 months (estimated treatment duration average: 4 months) | tumor response is defined as a complete or partial response, upon RECIST v1.1 criteria |
| progression-free survival in patients treated with anti-PDL1 antibody (MEDI4736) compared to standard maintenance therapy arm | from randomization to disease progression or death from any cause, whichever comes first, up to 16 months (estimated treatment duration average: 4 months) | To evaluate whether treatment with MEDI4736 improves progression-free survival as compared to standard maintenance therapy in patients with metastatic Breast Cancer |
| overall survival in each substudy | from randomization to death (any cause), up to 16 months | To evaluate whether treatment with targeted agents guided by high throughput molecular analysis (CGH array, next generation sequencing) or MEDI4736 improves overall survival as compared to standard maintenance therapy in patients with metastatic Breast Cancer |
| efficacy (response rate, change in tumor size, progression-free survival, overall survival) and safety of each individual targeted agent (substudy 1) | tumor response is assessed every 21 days from treatment initiation until first progression or death from any cause, whichever comes first, up to 16 months (estimated treatment duration average: 4 months) | tumor response is defined as a complete or partial response, upon RECIST v1.1 criteria |
| correlate molecular characteristics in patients with the efficacy endpoints (response rate, progression-free and overall survival) in each substudy | from randomization or treatment initiation to disease progression or death from any cause, whichever comes first, up to 16 months (estimated treatment duration average: 4 months) | tumor response is defined as a complete or partial response, upon RECIST v1.1 criteria |
| evaluate safety, in each substudy | toxicities will be assessed during the whole treatment period (4 months expected in average) followed by a 1-year post-treatment follow-up period, and reported during the visits scheduled by the study flow chart | Toxicities are graded according to the CTCAE V4 |
Countries
France
Outcome results
None listed