A Phase 2 interventional study of 3 weeks Dose Induction of Everolimus and 3 weeks Conventional Everolimus Dosing in Breast Cancer and Hormone Receptor Positive Tumor, sponsored by German Breast Group. Completed at 14 sites in Germany. Open to female participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2022-02-23.
Sponsored by German Breast Group · Phase 2, Interventional, and Treatment
The BOLERO-2 study demonstrated a benefit for patients who received everolimus in addition to exemestane in patients who progressed during/after a non-steroidal aromatase inhibitor;
Routine use of everolimus shows an high rate of intolerability due to mucositis/stomatitis especially during the first 12 weeks of treatment leading cause for treatment discontinuation not related to tumor progression;
GeparQuinto study (setting III: non-responders): everolimus was given as salvage treatment in combination with paclitaxel for patients without response to 4 cycles epirubicin/cyclophosphamide with/without bevacizumab.
A dose-escalation schema was successfully used to improve tolerability of everolimus together with the cytotoxic Agent.
Everolimus plus exemestane has improved the prognosis of metastatic breast cancer significantly. Desiree-study aims to improve the tolerability, which is necessary in order to achieve an adequate dose intensity for the patients in Routine care.
The BOLERO-2 study demonstrated an enormous benefit for patients who received everolimus in addition to exemestane in patients who progressed during/after a non steroidal (NSAI), which led to approval of everolimus in this indication. However, experience from routine use report a high rate of intolerability of this innovative treatment approach especially during the first 12 weeks of treatment. Most common side effect is mucositis/Mucositis which is considered the leading cause for treatment discontinuation not related to tumor progression.
This outside clinical trial experience is contrary to findings from BOLERO-2, where the number of patients still taking full-dose (10mg) of everolimus at 4, 8, and 12 weeks is 77.8%, 75.6%, and 75.6%, respectively. These findings are in concordance with non-interventional studies. However, findings might be biased by positive pre-selection.
In the non-responder part (setting III) of the neoadjuvant GeparQuinto study, everolimus was given as salvage treatment in combination with paclitaxel for patients without response to 4 cycles epirubicin/cyclophosphamide +/- bevacizumab. A dose-escalation schema was successfully used to improve tolerability of everolimus together with the cytotoxic agent. In fact the addition of everolimus to paclitaxel led only to increases of grades 1-4 leukopenia, grades 1-2 thrombocytopenia, leukopenia, skin changes and hyperlipidemia. Grades 3-4 hematological and nonhematological toxic effects were infrequent with no differences between treatment arms.
Moreover, Ravaud et al performed a metaanalysis of clinical trials in order to evaluate the potential relationship between everolimus exposure, safety and efficacy. Previous studies have shown that maximum everolimus concentrations are reached 1-2 hours after administering 5-70 mg oral doses, maximum everolimus concentrations increase in a dose-proportional manner between 5 mg and 10 mg and that continuous 5-10 mg once-daily dosing enables steady state to be achieved within 1 week.
The metaanalysis shows that a two-fold increase in the minimum concentration of everolimus increased the probability of tumor size reduction (odds ratio 1.4), which was associated with a trend for reduced risk of PFS events (risk ratio [RR] 0.9), but with an increased risk of grade 3 pulmonary toxicity (RR1.93), Mucositis (RR 1.49), and metabolic toxicity (RR 1.3).
Taking together these results suggest a dose-dependent antitumor effect of everolimus that have to be balanced against the correlated increased toxicities. For this reason the optimal dose and schedule need to be explored within randomized prospective clinical trial, in order to increase compliance and tolerability, maximizing efficacy.
12,544 studies on the registry are indexed under Breast Neoplasms; 2,892 are open to participants now.
This study's enrollment of 156 is above the median of 72 across 9,303 interventional studies indexed under Breast Neoplasms.
Browse Breast Neoplasms studies →German Breast Group is the lead sponsor of 33 studies on the registry; none are open to participants now.
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Eligibiltiy according to Everolimus label (ie. postmenopausal women)
Inclusion Criteria (most important)
Disease progression following prior therapy with non steroidal aromatase inhibitors (NSAI), defined as:
Exclusion Criteria (most important):
everolimus 10 mg/day, week 1-3: 4x2.5 mg/day (blinded); week 4-24: 10mg/day (open according to label) + further treatment according to standard of care
Drug: 3 weeks Conventional Everolimus Dosing · Drug: Open Label Phase with conventional 10mg Everolimus Dosing week 4-24 · Drug: Standard Care after 24 weeks
an escalating dose of everolimus as follows: week 1: 1x2.5 mg verum + 3x placebo/day; week 2: 2x2.5 mg verum + 2x placebo/day; week 3: 3x2,5 mg verum + 1x placebo/day; week 4-24: 10 mg/day (open according to label) + further treatment according to standard of care
Drug: 3 weeks Dose Induction of Everolimus · Drug: Open Label Phase with conventional 10mg Everolimus Dosing week 4-24 · Drug: Standard Care after 24 weeks
Comparing a conventional dosing approach starting with 10 mg at first dose versus a dose-escalating schema over 21 days in patients receiving everolimus in combination with exemestane for treatment of metastatic breast cancer. All patients will be treated within the approved indication of everolimus in combination with exemestane. Patients will be randomized in a 1:1 ratio
Comparing a conventional dosing approach starting with 10 mg at first dose versus a dose-escalating schema over 21 days in patients receiving everolimus in combination with exemestane for treatment of metastatic breast cancer. All patients will be treated within the approved indication of everolimus in combination with exemestane. Patients will be randomized in a 1:1 ratio
All patients will receive open label Everolimus with Exemestane for 21 weeks according to label
It is up to the discretion of the investigator to continue with Everolimus+Exemestane beyond 24 weeks
cumulative rate Mucositis grade 2-4 (WHO's oral toxicity scale (OTS))
To compare the cumulative rate of mucositis/stomatitis grade 2-4 (WHO's oral toxicity scale (OTS)) at 12 weeks after start of treatment using a conventional and a dose-escalating schema of everolimus in combination with exemestane in patients with metastatic breast cancer and progression or relapse after non-steroidal aromatase-inhibitor treatment. Endpoint measurement: First episode of mucositis WHO's OTS 2-4 any time during a 12 week period after start of everolimus
Time frame: week1 to week 12
cumulative rate Mucositis grade 2-4 (WHO's oral toxicity scale (OTS))
To compare the cumulative rate of mucositis/stomatitis grade 2-4 (WHO's oral toxicity scale (OTS)) at 24 weeks after start of treatment. Incidence of first episodes of mucositis/stomatitis WHO's OTS grade 2-4 any time during a 24 week period.
Time frame: week 1 to 24
cumulative rate Mucositis any grade (WHO's oral toxicity scale (OTS))
To compare the cumulative rate of mucositis/stomatitis grade 1 and any grade (WHO's oral toxicity scale (OTS)) at 12 and 24 weeks after start of treatment. Incidence of first episodes of mucositis/stomatitis WHO's OTS grade 1 and any grade any time during a 12 and 24 week period.
Time frame: week 1 to 12 and week 1 to 24
Patients on conventional dose Everolimus 10mg
To compare the rate of patients on 10mg daily at 12 weeks and 24 weeks after start of everolimus treatment. Average dose of treatment during week 12 and during week 24.
Time frame: week 12 and week 24
Clinical Benefit Rate (CBR)
To compare the clinical benefit rate (CR, PR und SD \>=16 Weeks) at 24 weeks after start of everolimus treatment. Clinical benefit rate (CBR) is defined as all patients with no evidence for tumor progression at 24 weeks after start of everolimus treatment.
Time frame: week 24
Safety other than Mucositis
To compare the safety with regard to other organ signs and symptoms.Safety by toxicity grades in general is defined by the NCI-CTCAE version 4.03.
Time frame: week 1 to 24
Time to Mucositis grade 2-4 (WHO's oral toxicity scale (OTS))
To compare the time to grade ≥2 mucositis/stomatitis
Time frame: week 1 to 24
Cumulative Dose
To compare the cumulative dose at 4 weeks
Time frame: week 4
RDI
To compare the relative dose intensity for everolimus. Relative dose intensity for everolimus is the ratio of Actual Total Dose Intensity (ATDI) and Planned Total Dose Intensity (PTDI), expressed as a percentage.
Time frame: week 1 to 24
QoL FACTB
To compare quality of life using the FACT-B questionnaire and the QSDQ
Time frame: week 4, week 12, End of Therapy Visit (week 25-28)
QoL QSDQ
To compare quality of life using the FACT-B questionnaire and the QSDQ
Time frame: daily till week12
Biomarker for Breast Cancer
Other objectives: Potential biomarkers predicting safety and compliance will be determined after completion of study treatment
Time frame: Baseline and End of Therapy Visit (week 25-28)
This study is completed, as verified in Feb 2022. You cannot join it, but the record below documents what was studied.
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German Breast Group