Metastatic Breast CancerPhase 2MIRACLENCT02313051
Everolimus trIal for Advanced prememopausaL Breast Cancer Patients
A Phase 2 study testing Everolimus, Goserelin and Letrozole in people with Metastatic Breast Cancer, run by Chinese Academy of Medical Sciences at 1 site in China.
Trial summary
Everolimus has been approved to be effective when used with exemestane after progression on non-steroidal aromatase inhibitors in postmenopausal women based on the BOLERO-2 clinical trial. However, the superiority of addition of everolimus to endocrine therapy hasn't been established in the premenopausal women. Read more about this study
- Who is it for?
- Ages 18 years and older, women only
- Conditions the study is for
- Metastatic Breast Cancer
- What is being tested?
- Everolimus, Goserelin and Letrozole
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 200 participants
- Where
- 1 siteChina
- Study dates
- Dec 2014to Dec 2017
- 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
- Adult women (≥ 18 years of age) with metastatic or locally advanced breast cancer not amenable to curative surgery.
- Histological confirmation of estrogen and/or progesterone-receptor positive (ER+), human epidermal growth factor receptor 2 negative (HER2 -) breast cancer.
- ER/PR positive: nuclear reaction > 1%, HER2 negative: HER2; IHC 0,1+ or FISH/CISH (-) in case of IHC 2+
- Patients who:
- received Tamoxifen for at least 6 months during adjuvant treatment and recurred during or within 24 months after the end of adjuvant treatment completion,
- progressed during tamoxifen treatment for advanced disease.
Show all 21Show fewer
- Pre-menopausal status was defined as either :
- The patient has a history of regular menstrual periods within 12 weeks prior to study enrollment
- The patient has FSH and E2 levels with in pre-menopausal range based on local laboratory assessments measured (i.e, FSH ≤ 40 mIU/mL and E2 ≥10 pg/mL)within 12 weeks prior to study enrollment.
- ECOG performance status of 0,1, or 2
- At least one measurable lesion or mainly lytic bone lesions in the absence of measurable disease(RECIST1.1)
- Adequate bone marrow, hepatic, and renal function
- Adequate bone marrow and coagulation function as shown by:
- Absolute neutrophil count (ANC) ≥ 1.5 109/L;Platelets>100 x109/L;Hemoglobin (Hgb) > 9.0g/dLINR < 2
- Adequate liver function as shown by:
- Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 2.5x ULN (or <5 if hepatic metastases are present)
- Total serum bilirubin < 1.5 x ULN (<3 x ULN for patients known to have Gilberts Syndrome)
- Adequate renal function as shown by:
- Serum creatinine< 1.5 x ULN
- Fasting serum cholesterol <300 mg/dL or 7.75 mmol/L and fasting triglycerides <2.5 x ULN. In case one or both of these thresholds are exceeded, the patient can only be included after initiation of statin therapy and when the above mentioned values have been achieved.
- Written informed consent
Who cannot join
- Patients who have received endocrine treatment other than Tamoxifen for adjuvant or metastatic/locally advanced breast cancer.
- Patients who have received goserelin at adjuvant setting
- Patients who received more than one line of chemotherapy for metastatic or locally advanced breast cancer
- Previous treatment with mTOR inhibitors.
- Another malignancy within 5 years prior to enrollment with the exception of adequately treated in-situ carcinoma of the cervix, uteri, basal or squamous cell carcinoma or non-melanomatous skin cancer.
- Symptomatic brain or other CNS metastases
Show all 10Show fewer
- Patients receiving chronic treatment with immunosuppressive agents.
- Any severe and/or uncontrolled medical conditions, eg. currently active infection
- Pregnant or lactating
- Patients unwilling to or unable to comply with the protocol.
Trial locations and contacts
1 site in 1 country.
China1 site
Cancer Institute and Hospital, Chinese Academy of Medical Sciences
Beijing, 100021
Binghe Xu, MD, Ph.D, +86-10-87788826, xubinghe@medmail.com.cn
Ying Fan, MD, 861087788114, fanyingfy@medmail.com.cn
About this study
Official title: A Multicenter, Randomized Phase ll Study of Letrozole Versus Letrozole Plus Everolimus for Hormone Receptor-PositivePremenopausal Women With Recurrent or Metastatic Breast Cancer on Goserelin Treatment After Progression on Tamoxifen
Everolimus has been approved to be effective when used with exemestane after progression on non-steroidal aromatase inhibitors in postmenopausal women based on the BOLERO-2 clinical trial. However, the superiority of addition of everolimus to endocrine therapy hasn't been established in the premenopausal women. This is a phase 2, multicentre clinical trial to evaluate the role of everolimus in the first-line endocrine treatment of premenopausal MBC patients after progression on tamoxifen.
Read the detailed description
Endocrine therapy is the cornerstone of treatment for patients with hormone receptor (HR)-positive advanced breast cancer. The selection of endocrine agents takes account of the menopausal status, the type of previous adjuvant endocrine treatment, the disease free interval and past medical history.
In premenopausal women with HR-positive advanced breast cancer, ovarian function suppression combined with aromatase inhibitors is a standard first-line choice of hormone treatment, especially patients progressed after tamoxifen. Unfortunately, not all patients have a response to first-line endocrine therapy, and even patients who have a response will eventually become resistant.
An emerging mechanism of endocrine resistance in aberrant signaling through the phosphatidylinositol 3-kinase (PI3K)-Akt-mammalian target of rapamycin (mTOR) signaling pathway7-9. Growing evidence supports a close interaction between the mTOR pathway and ER signaling. Everolimus is a sirolimus derivative that inhibits mTORactivation11. In preclinical models, the use of everolimus in combination with aromatase inhibitors results in synergistic inhibition of the proliferation and induction of apoptosis12. In a randomized, phase 2 study comparing neoadjuvant everolimus plus letrozole with letrozole alone in patients with newly diagnosed ER-positive breast cancer, the response rate for the combination was higher than that for letrozole alone. Recently, the Breast Cancer Trials of Oral Everolimus-2 (BOLERO-2) study showed that the addition of everolimus to exemestane significantly improved progression-free survival, with observed medians of 11 and 4 months, corresponding to a 62% reduction in the hazard ratio14 which is impressive and practice changing.
However, different from western countries, the majority (50-55%) of patients are premenopausal women in Asia including China.The benefit of everolimus plus endocrine therapy in premenopausal women have not yet been well delineated. Although there was a report that efficacy was comparable between premenopausal metastatic breast cancer patients treated with letrozole plus goserelin and postmenopausal patients treated with letrozole alone as first line hormone therapy, it is generally accepted that endocrine treatment outcome in premenopausal women, especially in younger age is known to be poor. So the addition of everolimusin this population would be a potential viable treatment option to overcome resistance to endocrine therapies that needs to be evaluated.
In addition, the feasibility of patients progressed on the endocrine continue to receive the same endocrine agent plus everolimus is unclear. At the same time, the difference between concurrent and sequential medication of endocrine agent and everolimus is not yet addressed.
Based on this rationale, the investigators introduced randomized trial to evaluate the efficacy of addition of everolimus to letrozole with LHRH agonist in premenopausal metastatic breast cancer patients who failed to tamoxifen treatment and also explore the best schedule of endocrine therapy together with everolimus.
- Conditions
- Metastatic Breast Cancer
- Being tested
- Everolimus, Goserelin, Letrozole
- Keywords
- metastatic breast cancer, everolimus
- Medical subject headings
- Breast Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
EverolimusDrug
Also called Certican, Rad001
mTOR inhibitor
GoserelinDrug
Also called Zoladex
LetrozoleDrug
Also called Femara
| Study group | Role | What they receive |
|---|---|---|
| Everolimus arm | Experimental | Everolimus+letrozole Receives: Drug: Everolimus; Drug: Goserelin; Drug: Letrozole |
| Controll arm | Active comparator | letrozole alone, and when progress, followed by everolimus Receives: Drug: Goserelin; Drug: Letrozole |
What is being measured
The primary outcome is the main question the study is designed to answer.
Progression free survival
the time from randomization to the time of disease progression or relapse or death
Measured: 6 months after last patient was evaluated
Secondary outcomes (4)
Overall survival
time from randomization to death
Measured: 1 year after the last patient was followed-up
Number of Participants with Adverse Events as a Measure of Safety and Tolerability
Measured: during screening and treatment, withing 28 days after last medication
Clinical benefit rate
Measured: at the time of tumor assessment of last patient
Duration of clinical benefit
from the date of confirmed response to the confirmed progression
Measured: 6 months after last patient was evaluated
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted9 Dec 2014 (estimated)
- Study startDec 2014
- Primary completionDec 2016 (estimated)
- Study completionDec 2017 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Metastatic Breast CancerStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
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
- None (open label)
- Enrolment
- 200 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Chinese Academy of Medical Sciences
- Sponsor type
- University, hospital or other
- Collaborators
- Novartis Pharmaceuticals
- Responsible party
- Principal investigator, Binghe Xu, Chinese Academy of Medical Sciences
- Investigators
- Bing he Xu, MD, Principal investigator, Cancer Institute and Hospital, Chinese Academy of Medical Sciences
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02313051
- Sponsor's protocol ID
- CBCSG016
- Acronym
- MIRACLE
- Status last verified
- Nov 2014
- First submitted
- 24 Nov 2014
- Last updated
- 9 Dec 2014
- Results posted
- No
- Data monitoring committee
- No
Publications
Fan Y, Sun T, Shao Z, Zhang Q, Ouyang Q, Tong Z, Wang S, Luo Y, Teng Y, Wang X, Wang S, Liu Q, Feng J, Shen K, Song Y, Wang J, Ma F, Li Q, Zhang P, Xu B. Effectiveness of Adding Everolimus to the First-line Treatment of Advanced Breast Cancer in Premenopausal Women Who Experienced Disease Progression While Receiving Selective Estrogen Receptor Modulators: A Phase 2 Randomized Clinical Trial. JAMA Oncol. 2021 Oct 1;7(10):e213428. doi: 10.1001/jamaoncol.2021.3428. Epub 2021 Oct 21.
PubMed 34436536
Study at a glance
From the registry record, last updated by the sponsor on 9 Dec 2014. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Multicenter, Randomized Phase ll Study of Letrozole Versus Letrozole Plus Everolimus for Hormone Receptor-PositivePremenopausal Women With Recurrent or Metastatic Breast Cancer on Goserelin Treatment After Progression on Tamoxifen
- ClinicalTrials.gov ID
- NCT02313051
- Acronym / sponsor ID
- MIRACLE / CBCSG016
- Conditions
- Metastatic Breast Cancer
- Keywords
- metastatic breast cancer, everolimus
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 200 participants (estimated)
- Lead sponsor
- Chinese Academy of Medical SciencesUniversity, hospital or other
- Collaborators
- Novartis Pharmaceuticals
- Study start
- Dec 2014
- Primary completion
- Dec 2016 (estimated)
- Study completion
- Dec 2017 (estimated)
- First posted
- 9 Dec 2014 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Everolimus has been approved to be effective when used with exemestane after progression on non-steroidal aromatase inhibitors in postmenopausal women based on the BOLERO-2 clinical trial. However, the superiority of addition of everolimus to endocrine therapy hasn't been established in the premenopausal women. This is a phase 2, multicentre clinical trial to evaluate the role of everolimus in the first-line endocrine treatment of premenopausal MBC patients after progression on tamoxifen.
Detailed description
Endocrine therapy is the cornerstone of treatment for patients with hormone receptor (HR)-positive advanced breast cancer. The selection of endocrine agents takes account of the menopausal status, the type of previous adjuvant endocrine treatment, the disease free interval and past medical history.
In premenopausal women with HR-positive advanced breast cancer, ovarian function suppression combined with aromatase inhibitors is a standard first-line choice of hormone treatment, especially patients progressed after tamoxifen. Unfortunately, not all patients have a response to first-line endocrine therapy, and even patients who have a response will eventually become resistant.
An emerging mechanism of endocrine resistance in aberrant signaling through the phosphatidylinositol 3-kinase (PI3K)-Akt-mammalian target of rapamycin (mTOR) signaling pathway7-9. Growing evidence supports a close interaction between the mTOR pathway and ER signaling. Everolimus is a sirolimus derivative that inhibits mTORactivation11. In preclinical models, the use of everolimus in combination with aromatase inhibitors results in synergistic inhibition of the proliferation and induction of apoptosis12. In a randomized, phase 2 study comparing neoadjuvant everolimus plus letrozole with letrozole alone in patients with newly diagnosed ER-positive breast cancer, the response rate for the combination was higher than that for letrozole alone. Recently, the Breast Cancer Trials of Oral Everolimus-2 (BOLERO-2) study showed that the addition of everolimus to exemestane significantly improved progression-free survival, with observed medians of 11 and 4 months, corresponding to a 62% reduction in the hazard ratio14 which is impressive and practice changing.
However, different from western countries, the majority (50-55%) of patients are premenopausal women in Asia including China.The benefit of everolimus plus endocrine therapy in premenopausal women have not yet been well delineated. Although there was a report that efficacy was comparable between premenopausal metastatic breast cancer patients treated with letrozole plus goserelin and postmenopausal patients treated with letrozole alone as first line hormone therapy, it is generally accepted that endocrine treatment outcome in premenopausal women, especially in younger age is known to be poor. So the addition of everolimusin this population would be a potential viable treatment option to overcome resistance to endocrine therapies that needs to be evaluated.
In addition, the feasibility of patients progressed on the endocrine continue to receive the same endocrine agent plus everolimus is unclear. At the same time, the difference between concurrent and sequential medication of endocrine agent and everolimus is not yet addressed.
Based on this rationale, the investigators introduced randomized trial to evaluate the efficacy of addition of everolimus to letrozole with LHRH agonist in premenopausal metastatic breast cancer patients who failed to tamoxifen treatment and also explore the best schedule of endocrine therapy together with everolimus.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Everolimus arm | Experimental | Drug: Everolimus, Drug: Goserelin, Drug: LetrozoleEverolimus+letrozole |
| Controll arm | Active comparator | Drug: Goserelin, Drug: Letrozoleletrozole alone, and when progress, followed by everolimus |
Who may qualify
- Ages
- 18 years and older
- Sex
- Female only
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (21 listed)
- Adult women (≥ 18 years of age) with metastatic or locally advanced breast cancer not amenable to curative surgery.
- Histological confirmation of estrogen and/or progesterone-receptor positive (ER+), human epidermal growth factor receptor 2 negative (HER2 -) breast cancer.
- ER/PR positive: nuclear reaction > 1%, HER2 negative: HER2; IHC 0,1+ or FISH/CISH (-) in case of IHC 2+
- Patients who:
- Pre-menopausal status was defined as either :
Key exclusion criteria (10 listed)
- Patients who have received endocrine treatment other than Tamoxifen for adjuvant or metastatic/locally advanced breast cancer.
- Patients who have received goserelin at adjuvant setting
- Patients who received more than one line of chemotherapy for metastatic or locally advanced breast cancer
- Previous treatment with mTOR inhibitors.
- Another malignancy within 5 years prior to enrollment with the exception of adequately treated in-situ carcinoma of the cervix, uteri, basal or squamous cell carcinoma or non-melanomatous skin cancer.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| EverolimusAlso: Certican, Rad001mTOR inhibitor | Drug | Everolimus arm |
| GoserelinAlso: Zoladex | Drug | Controll arm, Everolimus arm |
| LetrozoleAlso: Femara | Drug | Controll arm, Everolimus arm |
Primary outcome
Progression free survival
Time frame: 6 months after last patient was evaluated
the time from randomization to the time of disease progression or relapse or death
4 secondary outcomes
Overall survival
Time frame: 1 year after the last patient was followed-up
Number of Participants with Adverse Events as a Measure of Safety and Tolerability
Time frame: during screening and treatment, withing 28 days after last medication
Clinical benefit rate
Time frame: at the time of tumor assessment of last patient
Duration of clinical benefit
Time frame: 6 months after last patient was evaluated
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 9 Dec 2014.
- Derived from this study: PubMed 34436536Fan Y, Sun T, Shao Z, Zhang Q, Ouyang Q, Tong Z, Wang S, Luo Y, Teng Y, Wang X, Wang S, Liu Q, Feng J, Shen K, Song Y, Wang J, Ma F, Li Q, Zhang P, Xu B. Effectiveness of Adding Everolimus to the First-line Treatment of Advanced Breast Cancer in Premenopausal Women Who Experienced Disease Progression While Receiving Selective Estrogen Receptor Modulators: A Phase 2 Randomized Clinical Trial. JAMA Oncol. 2021 Oct 1;7(10):e213428. doi: 10.1001/jamaoncol.2021.3428. Epub 2021 Oct 21.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Bing he Xu, MD principal investigator
Cancer Institute and Hospital, Chinese Academy of Medical Sciences
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Everolimus, Goserelin and Letrozole in people with Metastatic Breast Cancer, run by Chinese Academy of Medical Sciences at 1 site in China.
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 21 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: status not confirmed, as of the sponsor's last update on 9 Dec 2014. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in China. 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?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Ying Fan, MD (861087788114, fanyingfy@medmail.com.cn), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Progression free survival (time frame: 6 months after last patient was evaluated). 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 NCT02313051, 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 9 Dec 2014.