Dose EScalation Induction of EvERolimus
- Conditions
- Breast CancerHormone Receptor Positive Tumor
- Interventions
- Drug: 3 weeks Conventional Everolimus DosingDrug: 3 weeks Dose Induction of EverolimusDrug: Open Label Phase with conventional 10mg Everolimus Dosing week 4-24Drug: Standard Care after 24 weeks
- Registration Number
- NCT02387099
- Lead Sponsor
- German Breast Group
- Brief Summary
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.
- Detailed Description
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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- Female
- Target Recruitment
- 156
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Conventional Everolimus dosing according to label 3 weeks Conventional Everolimus Dosing 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 Conventional Everolimus dosing according to label Open Label Phase with conventional 10mg Everolimus Dosing week 4-24 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 Conventional Everolimus dosing according to label Standard Care after 24 weeks 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 3 week Dose Induction of Everolimus 3 weeks Dose Induction of Everolimus 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 3 week Dose Induction of Everolimus Open Label Phase with conventional 10mg Everolimus Dosing week 4-24 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 3 week Dose Induction of Everolimus 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
- Primary Outcome Measures
Name Time Method cumulative rate Mucositis grade 2-4 (WHO's oral toxicity scale (OTS)) week1 to week 12 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
- Secondary Outcome Measures
Name Time Method cumulative rate Mucositis grade 2-4 (WHO's oral toxicity scale (OTS)) week 1 to 24 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.Patients on conventional dose Everolimus 10mg week 12 and week 24 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.
cumulative rate Mucositis any grade (WHO's oral toxicity scale (OTS)) week 1 to 12 and week 1 to 24 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.Clinical Benefit Rate (CBR) week 24 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.
Safety other than Mucositis week 1 to 24 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 to Mucositis grade 2-4 (WHO's oral toxicity scale (OTS)) week 1 to 24 To compare the time to grade ≥2 mucositis/stomatitis
Cumulative Dose week 4 To compare the cumulative dose at 4 weeks
RDI week 1 to 24 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.
QoL FACTB week 4, week 12, End of Therapy Visit (week 25-28) To compare quality of life using the FACT-B questionnaire and the QSDQ
QoL QSDQ daily till week12 To compare quality of life using the FACT-B questionnaire and the QSDQ
Trial Locations
- Locations (3)
University of Erlangen
🇩🇪Erlangen, Germany
Sana Klinikum Offenbach / German Breast Group
🇩🇪Neu Isenburg, Hessen, Germany
TU Dresden
🇩🇪Dresden, Sachsen, Germany