A Phase II Study Investigating Preoperative Combination Strategies for Immunotherapy in Patients With Untreated, Operable ER+, HER2-negative Primary Breast Cancer
Overview
- Phase
- Phase 2
- Intervention
- Atezolizumab
- Conditions
- Breast Cancer
- Sponsor
- Queen Mary University of London
- Enrollment
- 71
- Locations
- 1
- Primary Endpoint
- 2-fold Increase in GzmB+ CD8+ T cell levels
- Status
- Completed
- Last Updated
- last year
Overview
Brief Summary
International, open label, window of opportunity phase II trial that aims to evaluate the effects of immunotherapy based treatment combinations in women with untreated, histologically confirmed, operable, ER+, HER2-negative breast cancer.
Detailed Description
ECLIPSE is an international, open label, window of opportunity phase II trial that aims to evaluate the effects of immunotherapy based treatment combinations in women with untreated, histologically confirmed, operable, ER+, HER2-negative breast cancer. The study is designed with the flexibility to open new treatment arms as new treatments become available, or modify the patient population e.g. with regards to biomarker status. Only combinations with adequate safety data will be tested. The trial will include Luminal B and non-Luminal B patients irrespective of PD-L1 status, but the number of patients with non-Luminal B tumours will be capped at 50% of the total study population. Luminal B tumours will be defined as high Ki67 (≥20%) and/or histological grade 3 or alternatively defined via PAM50 assay. All other types will be defined as non-Luminal B. Eligible patients will be randomised with an approximately equal ratio (1:1:1:1) to one of four treatment arms (three experimental arms: (1) Atezolizumab + Cobimetinib, (2) Atezolizumab + Ipatasertib, (3) Atezolizumab + Cobimetinib + Bevacizumab and a control arm: Atezolizumab alone. Additional patients may be enrolled to ensure balance among treatment arms with respect to demographic and baseline characteristics, including potential predictive biomarkers, to enable further subgroup analysis. Thereafter, the randomisation ratio will depend on the number of experimental arms that are open for enrolment (e.g. if an arm is added or enrolment in an arm is suspended pending analysis of results. Randomisation will take into account arm-specific exclusion criteria and patients will be ineligible for a specific arm if they meet any of the exclusion criteria outlined for that arm. Patients will receive treatment for 3 weeks prior to surgery or neoadjuvant therapy. Thereafter, patients will either be considered for definitive surgery or primary medical treatment (e.g. neoadjuvant chemotherapy) at the discretion of the treating physician. Surgery or neoadjuvant chemotherapy should be started within 3 weeks (±3 days) from the start of the study treatment. Patients will not be allowed to receive endocrine therapy prior to surgery.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Willing and able to provide written informed consent prior to study entry
- •Female ≥ 18 years of age
- •Eastern Cooperative Oncology Group (ECOG) Performance Status 0 to 21
- •Histologically confirmed operable primary breast cancer
- •Palpable breast tumour of any size, or tumour with an ultrasound / MRI size of ≥ 1 cm or mammogram
- •ER+ tumours defined as tumours with ≥1% of tumour cells positive for ER on IHC staining or an IHC score (Allred) of ≥ 3
- •HER2-negative tumours defined as 0, 1+ or 2+ intensity on IHC and no evidence of amplification of the HER2 gene on ISH.
- •Patients with either: (a) Luminal B breast cancer defined as: high Ki67 defined as ≥20% and /or histological grade 3 and / or Luminal B according to PAM50 assay or (b) Non-Luminal B breast cancer
- •Adequate haematologic and end-organ function within 28 days prior to the first study treatment
- •Patients 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, (IUD, oral contraceptive, sub dermal implant and double barrier (condom with a contraceptive sponge or contraceptive pessary) beginning 14 days before the first dose of study drug and for 5 months after the last dose of investigational product .
Exclusion Criteria
- •Inflammatory breast cancer
- •Concurrent use of HRT (HRT users must stop HRT a minimum of 28 days before the baseline diagnostic biopsy is taken).
- •Previous systemic or local treatment for the new primary breast cancer currently under investigation (including surgery, radiotherapy, cytotoxic and endocrine treatments); prior treatment for previous breast cancer or other neoplasms is allowed as long as it was completed ≥1 year prior to Day 1 Cycle
- •Previous systemic treatment for other neoplasms within 1 year prior to randomisation..
- •Patients with prior allogeneic stem cell or solid organ transplantation.
- •Prior treatment with CD137 agonists, AKT inhibitors, anti-CTLA-4, anti-programmed death-1 (PD-1), or anti-PD-L1 therapeutic antibody or pathway-targeting agents.
- •Patients must not have had oral or IV steroids for 14 days prior to study entry; the use of inhaled corticosteroids, physiologic replacement doses of glucocorticoids (i.e. for adrenal insufficiency) and mineralocorticoids (e.g. fludrocortisone) is allowed.
- •Received therapeutic oral or intravenous antibiotics within 14 days prior to randomisation (Patients receiving prophylactic antibiotics (e.g., for prevention of a urinary tract infection or chronic obstructive pulmonary disease) are eligible).
- •Administration of a live, attenuated vaccine (e.g., FluMist®) within 28 days prior to randomisation, treatment, or within 5 months following the last dose of atezolizumab.
- •Treatment with systemic immunostimulatory agents (including but not limited to interferons or interleukin \[IL\] -2) within 28days or five half-lives of the drug, whichever is shorter, prior to enrolment.
Arms & Interventions
Atezolizumab alone
1200mg of Atezolizumab D1 C1
Intervention: Atezolizumab
Atezolizumab + Cobimetinib
Atezolizumab (1200mg IV D1 C1) + Cobimetinib (60mg PO D1 - 21 of C1)
Intervention: Atezolizumab
Atezolizumab + Cobimetinib
Atezolizumab (1200mg IV D1 C1) + Cobimetinib (60mg PO D1 - 21 of C1)
Intervention: Cobimetinib
Atezolizumab + Ipatasertib
Atezolizumab (1200mg IV D1 C1)+ Ipatasertib (400mg OD D1 - 21 of C1)
Intervention: Atezolizumab
Atezolizumab + Ipatasertib
Atezolizumab (1200mg IV D1 C1)+ Ipatasertib (400mg OD D1 - 21 of C1)
Intervention: Ipatasertib
Atezolizumab + Ipatasertib + Bevacizumab
Atezolizumab (1200mg IV D1 C1)+ Cobimetinib (60mg PO D1 - 21 of C1) + Bevacizumab (10mg/kg IV D1 C1)
Intervention: Atezolizumab
Atezolizumab + Ipatasertib + Bevacizumab
Atezolizumab (1200mg IV D1 C1)+ Cobimetinib (60mg PO D1 - 21 of C1) + Bevacizumab (10mg/kg IV D1 C1)
Intervention: Ipatasertib
Atezolizumab + Ipatasertib + Bevacizumab
Atezolizumab (1200mg IV D1 C1)+ Cobimetinib (60mg PO D1 - 21 of C1) + Bevacizumab (10mg/kg IV D1 C1)
Intervention: Bevacizumab
Outcomes
Primary Outcomes
2-fold Increase in GzmB+ CD8+ T cell levels
Time Frame: Baseline and at 3weeks
Secondary Outcomes
- Status and changes of CD8 in pre- and end-of treatment tumour and/or blood samples(Baseline and at 3weeks)
- Status and changes of PD-L1 in pre- and end-of treatment tumour and/or blood samples(Baseline and at 3weeks)
- Percentage change in Ki67 expression between pre- and end of study-treatment tumour biopsies(Baseline and at 3weeks)
- Percentage change in caspase3 expression(Baseline and at 3weeks)