A Multicenter Randomized, Double Blind, Placebo- Controlled, Phase II Study to Compare Endocrine Treatment Alone Versus Endocrine Treatment With Everolimus in Patients With HR+/HER2- Metastatic Breast Cancer and Progression After Previous Treatment With Exemestane and Everolimus
- 1. Written informed consent prior to beginning specific protocol procedures,
including expected cooperation of the patients for the treatment and follow-up, must
be obtained and documented according to the local regulatory requirements.
2. Complete baseline documentation must be submitted via the web-based data
collection system MedCODES® to the GBG Forschungs GmbH.
3. Histological confirmed hormone receptor positive (HR+); HER2-negative carcinoma
of the breast. Every effort should be made to make paraffin embedded tissue or slides
from the original tumor and/or from metastatic tissue available for confirmation of
diagnosis and additional translational research.
4. Postmenopausal women 5. HER2-negative, hormone-receptor-positive, locally advanced
or metastatic stage of disease not amenable to curative treatment by surgery or
6. No indication for chemotherapy 7. Patients must have either measurable or
non-measurable target lesions according to RECIST criteria. Complete staging work-up
within 4 weeks prior to registration including chest and abdominal CT scan or MRI
(exceptionally chest X-ray and abdominal ultrasound), and bone scan. Further tests
have to be performed according to RECIST or as clinically indicated.
8. Disease progression during or after previous exemestane and everolimus treatment
as follows (everolimus has to be given previously for at least 12 weeks,
treatment-free interval of everolimus for a maximum of 6 weeks until randomization)
9. The following previous systemic treatments are eligible:
- Previous participation in other everolimus-containing trials, e.g. the GeparQuinto,
BOLERO, 4EVER study is allowed.
- (Neo)Adjuvant and up to 1 chemotherapy regimen for metastatic breast cancer
- Maximum of two lines as palliative endocrine monotherapy
- Treatment with bisphosphonates and/or denosumab (adjuvant and/or palliative) 10. At
least 4 weeks since radiotherapy, with full recovery. The measurable disease must be
completely outside the radiation field or there must be pathologic proof of newly
11. Age ≥ 18 years 12. ECOG performance status 0-2 13. Laboratory requirements:
- Absolute neutrophil count at least 1500 cells/microliter,
- hemoglobin ≥9.0 g/dL (hemoglobin <9.0 g/dL is acceptable if it is corrected by
growth factor or transfusion)
- platelet count at least 100,000 cells/microliter.
- bilirubin at least 1.5x the upper limit of normal for the institution (ULN);
- elevation of transaminases and alkaline phosphatase <3x ULN or <5x ULN for
patients with liver metastases.
- BUN (blood urea nitrogen) ≤ULN
- Fasting plasma glucose (FPG) ≤160 mg/dL or ≤8.9 mmol/L
- Fasting serum cholesterol ≤ 300mg/dl or 7.75mmol/L (LDL cholesterol <190mg/dl)
and fasting triglyceride ≤2.5xULN (<300mg/dl). In case one or both of these
thresholds are exceeded the patient can only be included after initiation of a
statin therapy and when above mentioned values have been achieved.
INR ≤2.0 Creatinine not more than 2.0 x ULN or creatinine-clearance >40 ml/min (according
Urine dipstick for proteinuria <2+. Patients discovered to have ≥2+ proteinuria on
dipstick urinalysis should undergo a 24 hour urine collection and must demonstrate ≤1 g of
protein in 24 hours 14. Patients must be available and compliant for treatment and
follow-up. Patients registered on this trial must be treated and followed up at the
participating or a cooperating center.
- 1. No documented progression on everolimus plus exemestane 2. Known hypersensitivity
reaction to the compounds or incorporated substances 3. Treatment with
medroxyprogesteronacetate, megestrolacetate, or high-dose estradiol within 12 weeks
of study entry.
4. Concurrent immunotherapy or hormonal therapy (contraceptive and/or replacement
therapy). Bisphosphonates or denosumab may be continued 5. Life expectancy of less
than 3 months. 6. Parenchymal brain metastases, unless adequately controlled by
surgery and/or radiotherapy.
7. Any ongoing toxicity from prior anti-cancer therapy that is grade 3-4 and/or that
is progressing in severity, except alopecia or anemia controlled by growth factors.
8. Any previous adverse event grade 3-4 or serious adverse event during treatment
with exemestane and everolimus which led to treatment discontinuation 9. Known or
suspected congestive heart failure (>NYHA I) and/or coronary heart disease, angina
pectoris requiring anti-anginal medication, previous history of myocardial infarction
≤ 6months, evidence of transmural infarction on ECG, un- or poorly controlled
arterial hypertension (i.e. BP >150/100 mmHg under treatment with two
antihypertensive drugs), rhythm abnormalities requiring permanent treatment,
clinically significant valvular heart disease 10. Currently active infection 11.
History of other malignancies within the last 5 years which significantly affect the
diagnosis, assessment or prognosis of metastatic breast cancer.
12. Malabsorption syndrome or insufficient gastrointestinal function, preexisting
diagnosis of ulcerative colitis 13. Concurrent treatment with other experimental
drugs; participation in another clinical trial with any investigational not marketed
drug within 30 days prior to study entry.
14. Insufficiently controlled diabetes 15. known HIV infection or chronic hepatitis B
or C 16. seriously impaired liver function (Child-Pugh, class C) 17. Any serious
and/or unstable pre-existing medical, psychiatric, or other condition that could
interfere with subject's safety, provision of informed consent, or compliance to
study procedures (including severe pulmonary conditions, AIDS and serious active
infection and diabetes mellitus).
18. Male patients 19. Known HIV infection or chronic or history of hepatitis B or C
20. Seriously impaired liver function (Child-Pugh, class C)