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Breast CancerPhase 2DesireeNCT02387099

Dose EScalation Induction of EvERolimus

A Phase 2 study testing 3 weeks Dose Induction of Everolimus, 3 weeks Conventional Everolimus Dosing and Open Label Phase with conventional 10mg Everolimus Dosing week 4-24 in people with Breast Cancer and Hormone Receptor Positive Tumor, run by GBG Forschungs GmbH at 14 sites in Germany.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial 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… Read more about this study

Who is it for?
Ages 18 years and older, women only
What is being tested?
3 weeks Dose Induction of Everolimus, 3 weeks Conventional Everolimus Dosing and Open Label Phase with conventional 10mg Everolimus Dosing week 4-24
Could I receive a placebo?
No, everyone receives an active treatment
How many people
156 participants
Where
14 sitesGermany
Study dates
May 2015to Jul 2021
Phase
Phase 2
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • Women only
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Locally advanced or metastatic stage of disease not amenable to curative treatment by surgery or radiotherapy alone.
  • No indication for chemotherapy (e.g. symptomatic visceral metastasis) -Histological confirmed hormone receptor-positive (HR+), HER2- negative carcinoma of the breast.
  • Postmenopausal women
  • Disease progression following prior therapy with non steroidal aromatase inhibitors (NSAI), defined as:
  • Recurrence while on, or following completion of an adjuvant treatment with Letrozole or Anastrozole, or
  • Progression while on or following completion of Letrozole or Anastrozole treatment for ABC/MBC. Note: Non-steroidal aromatase inhibitors (i.e. Letrozole or Anastrozole) do not have to be the last treatment prior to enrollment. Other prior anticancer therapy, e.g. Tamoxifen, Fulvestrant, Exemestane, is also allowed. Patients must have recovered to grade 1 or better from any adverse events (except alopecia) related to previous therapy prior to enrollment.
  • 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 progressive disease.

Who cannot join

  • Concurrent immunotherapy or hormonal therapy (contraceptive and/or replacement therapy). Bisphosphonates or denosumab may be continued or started before randomization.
  • Life expectancy of less than 3 months.
  • Parenchymal brain metastases, unless adequately controlled by surgery and/or radiotherapy.
  • 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.
  • 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.
  • Currently active infection.
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  • History of other malignancies within the last 5 years which significantly affect the diagnosis, assessment or prognosis of metastatic breast cancer.
  • Malabsorption syndrome or insufficient gastrointestinal function, preexisting diagnosis of ulcerative colitis.
  • Concurrent treatment with other experimental drugs; participation in another clinical trial with any investigational not marketed drug within 30 days prior to study entry.
  • Insufficiently controlled diabetes, known HIV infection or chronic hepatitis B or C and seriously impaired liver function (Child-Pugh, class A, B or C).

Trial locations and contacts

14 sites in 1 country.

14 sites in 1 country

Germany14 sites

  • Study site

    Bielefeld, 33604

  • Study site

    Cologne, 50931

  • TU Dresden

    Dresden, Saxony, 01307

  • University of Erlangen

    Erlangen, 91054

  • Study site

    Essen, 45136

  • Study site

    Goslar, 38642

  • Study site

    Hanau, 63450

  • Study site

    Karlsruhe, 76135

  • Study site

    Kiel, 24105

  • Study site

    Mainz, 55131

  • Study site

    München, 80638

  • Sana Klinikum Offenbach / German Breast Group

    Neu-Isenburg, Hesse, 63263

  • Study site

    Rotenburg (Wümme), 27356

  • Study site

    Weinheim, 69469

Other trials in Germany

About this study

Official title: A Multicenter, Randomized, Double-blind, Phase II Study to Evaluate the Tolerability of an Induction Dose Escalation of Everolimus in Patients With Metastatic Breast Cancer

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;

Read more

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.

Read the 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.

Being tested
3 weeks Dose Induction of Everolimus, 3 weeks Conventional Everolimus Dosing, Open Label Phase with conventional 10mg Everolimus Dosing week 4-24, Standard Care after 24 weeks
Keywords
Stage IIIB, Stage IV, Recurrent, Metastatic
Medical subject headings
Breast Neoplasms, Recurrence, Neoplasm Metastasis

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • 3 weeks Dose Induction of EverolimusDrug

    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

  • 3 weeks Conventional Everolimus DosingDrug

    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

  • Open Label Phase with conventional 10mg Everolimus Dosing week 4-24Drug

    All patients will receive open label Everolimus with Exemestane for 21 weeks according to label

  • Standard Care after 24 weeksDrug

    It is up to the discretion of the investigator to continue with Everolimus+Exemestane beyond 24 weeks

Study groups in NCT02387099
Study groupRoleWhat they receive
Conventional Everolimus dosing according to labelActive comparatoreverolimus 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
Receives: Drug: 3 weeks Conventional Everolimus Dosing; Drug: Open Label Phase with conventional 10mg Everolimus Dosing week 4-24; Drug: Standard Care after 24 weeks
3 week Dose Induction of EverolimusExperimentalan 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
Receives: 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

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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

    Measured: week1 to week 12

Secondary outcomes (10)

  1. 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.

    Measured: week 1 to 24

  2. 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.

    Measured: week 1 to 12 and week 1 to 24

  3. 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.

    Measured: week 12 and week 24

  4. 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.

    Measured: week 24

  5. 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.

    Measured: week 1 to 24

  6. Time to Mucositis grade 2-4 (WHO's oral toxicity scale (OTS))

    To compare the time to grade ≥2 mucositis/stomatitis

    Measured: week 1 to 24

  7. Cumulative Dose

    To compare the cumulative dose at 4 weeks

    Measured: week 4

  8. 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.

    Measured: week 1 to 24

  9. QoL FACTB

    To compare quality of life using the FACT-B questionnaire and the QSDQ

    Measured: week 4, week 12, End of Therapy Visit (week 25-28)

  10. QoL QSDQ

    To compare quality of life using the FACT-B questionnaire and the QSDQ

    Measured: daily till week12

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted12 Mar 2015 (estimated)
  2. Study startMay 2015
  3. Primary completionMay 2021
  4. Study completionJul 2021

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
Quadruple blind
Who is masked
Participant, Care provider, Investigator, Outcomes assessor
Enrolment
156 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02387099
Sponsor's protocol ID
GBG 86
Acronym
Desiree
Status last verified
Feb 2022
First submitted
5 Mar 2015
Last updated
23 Feb 2022
Results posted
No
Data monitoring committee
Yes

Publications

  • Schmidt M, Lubbe K, Decker T, Thill M, Bauer L, Muller V, Link T, Furlanetto J, Reinisch M, Mundhenke C, Hoffmann O, Zahn MO, Muller L, Denkert C, van Mackelenbergh M, Fasching PA, Burchardi N, Nekljudova V, Loibl S. A multicentre, randomised, double-blind, phase II study to evaluate the tolerability of an induction dose escalation of everolimus in patients with metastatic breast cancer (DESIREE). ESMO Open. 2022 Dec;7(6):100601. doi: 10.1016/j.esmoop.2022.100601. Epub 2022 Nov 7.

    PubMed 36356410

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing 3 weeks Dose Induction of Everolimus, 3 weeks Conventional Everolimus Dosing and Open Label Phase with conventional 10mg Everolimus Dosing week 4-24 in people with Breast Cancer and Hormone Receptor Positive Tumor, run by GBG Forschungs GmbH at 14 sites in Germany.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 7 inclusion and 10 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 23 Feb 2022. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 14 sites in Germany. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

cumulative rate Mucositis grade 2-4 (WHO's oral toxicity scale (OTS)) (time frame: week1 to week 12). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02387099, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 23 Feb 2022.

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