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.
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.
Inclusion Criteria:
1. Willing and able to provide written informed consent prior to study entry
2. Female ≥ 18 years of age
3. Eastern Cooperative Oncology Group (ECOG) Performance Status 0 to 21
4. Histologically confirmed operable primary breast cancer
5. Palpable breast tumour of any size, or tumour with an ultrasound / MRI size of ≥ 1 cm
or mammogram
6. ER+ tumours defined as tumours with ≥1% of tumour cells positive for ER on IHC
staining or an IHC score (Allred) of ≥ 3
7. HER2-negative tumours defined as 0, 1+ or 2+ intensity on IHC and no evidence of
amplification of the HER2 gene on ISH.
8. 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
9. Adequate haematologic and end-organ function within 28 days prior to the first study
treatment
10. 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 .
11. Ability to comply with the protocol
12. Representative formalin-fixed paraffin embedded (FFPE) breast tumour samples with an
associated pathology report that are determined to be available and sufficient for
central testing OR tumour accessible for biopsy.
Exclusion Criteria:
1. Inflammatory breast cancer
2. Concurrent use of HRT (HRT users must stop HRT a minimum of 28 days before the
baseline diagnostic biopsy is taken).
3. 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 1.
4. Previous systemic treatment for other neoplasms within 1 year prior to randomisation..
5. Patients with prior allogeneic stem cell or solid organ transplantation.
6. 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.
7. 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.
8. 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).
9. 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.
10. 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.
11. History 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.
12. History of idiopathic pulmonary fibrosis (including pneumonitis or interstitial lung
disease), drug-induced pneumonitis, organizing pneumonia (i.e., bronchiolitis
obliterans, cryptogenic organizing pneumonia), or evidence of active pneumonitis on
screening chest CT scan (History of radiation pneumonitis in the radiation field
(fibrosis) is permitted).
13. History of HIV infection
14. Known 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.
15. Active tuberculosis
16. History of severe allergic, anaphylactic, or other hypersensitivity reactions to
chimeric or humanized antibodies or fusion proteins
17. Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamster
ovary cells or any component of the atezolizumab formulation.
18. Any 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.
19. Psychological, familial, sociological or geographical conditions that do not permit
compliance with the study protocol.
20. Concurrent treatment with other experimental drugs or participation in another
clinical trial with therapeutic intent within 28 days prior to randomisation.
21. Pregnant and lactating female patients.
22. Major surgical procedure within 4 weeks prior to randomisation or anticipation of need
for a major surgical procedure during the course of the study other than for
diagnosis.
23. Malignancies other than breast cancer within 5 years prior to Cycle 1, Day 1, with the
exception of those with a negligible risk of metastasis or death and treated with
expected curative outcome (such as adequately treated carcinoma in situ of the cervix,
basal or squamous cell skin cancer, or ductal carcinoma in situ treated surgically
with curative intent)
24. Severe infections within 28 days prior to enrolment in the study including but not
limited to hospitalization for complications of infection, bacteraemia, or severe
pneumonia.
25. Significant cardiovascular disease, such as history of symptomatic congestive heart
failure New York Heart Association cardiac disease (Class II or greater with a LVEF
<50% by either ECHO or MUGA), myocardial infarction within 3 months prior to
enrolment, severe cardiac arrhythmia requiring medication or severe conduction
abnormalities, unstable arrhythmias, acute coronary syndromes (including unstable
angina), or history of coronary angioplasty/stenting/bypass grafting within past 6
months.
26. Patients with uncontrolled Type 1 diabetes mellitus. Patients with Type 1 diabetes
controlled on a stable insulin regimen are eligible .
27. Evidence of bleeding diathesis or coagulopathy.
Exclusion criteria for Atezolizumab + Cobimetinib arm
1. Inability to swallow medication or malabsorption condition that would alter the
absorption of orally administered medications.
2. History of or symptoms of neurosensory retinal detachment, central serous
chorioretinopathy, retinal vein occlusion or neovascular macular degeneration.
3. Patients will be excluded from the study if they are currently known to have any of
the following risk factors for ocular toxicity: (a) History of or ongoing serous
retinopathy; (b) History of retinal vein occlusion (RVO)
Exclusion criteria for Atezolizumab + Ipatasertib arm
1. Inability to swallow medication or malabsorption condition that would alter the
absorption of orally administered medications.
2. Clinically significant abnormalities of glucose metabolism
3. History of or active inflammatory bowel disease (e.g., Crohn's disease and ulcerative
colitis) or active bowel inflammation (e.g., diverticulitis).
4. Treatment 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.
Exclusion criteria for Atezolizumab + Cobimetinib + Bevacizumab arm
1. Inability to swallow medication or malabsorption condition that would alter the
absorption of orally administered medications.
2. Known history or symptoms of neurosensory retinal detachment, central serous
chorioretinopathy, retinal vein occlusion or neovascular macular degeneration.
3. Patients will be excluded from the study if they are known to have any of the
following risk factors for ocular toxicity: (a) History of or ongoing serous
retinopathy; (b) History of retinal vein occlusion (RVO)
4. Uncontrolled hypertension defined by systolic pressure > 150 mmHg and/or diastolic
pressure > 110 mmHg, with or without anti-hypertensive medication Patients with
initial blood pressure elevations are eligible if initiation or adjustment of
anti-hypertensive medication lowers blood pressure to meet entry criteria.
5. History of stroke or transient ischemic attack within 6 months prior to randomisation
6. Clinically significant peripheral vascular disease (e.g., aortic aneurysm requiring
surgical repair or recent peripheral arterial thrombosis) within 6 months prior to
randomisation
7. History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess
within 6 months prior to randomisation.
8. History of haemoptysis (≥ 1/2 teaspoon of bright red blood per episode) or other
serious haemorrhage or at risk of bleeding (gastrointestinal history of bleeds,
gastrointestinal ulcers etc.) within 1 month prior to randomisation .
9. Patients who have had major surgery (or where surgical wounds have not healed) within
28 days prior to C1 D1.
