Primary: 1/ To evaluate the safety and tolerability of ribociclib with letrozole in men and postmenopausal women with HR+, HER2- aBC who received no prior hormonal therapy for advanced disease.Secondary: To assess the clinical efficacy of ribociclib…
ID
Source
Brief title
Condition
- Breast neoplasms malignant and unspecified (incl nipple)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Adverse events.
Secondary outcome
Imaging parameters, FACT-B.
Background summary
Approximately 75% of breast cancer express estrogen receptor and/or
progesterone receptor (HR+) and are dependent of estrogen for growth. Studies
of ER+ breast cancer cell lines indicate that estrogens and anti-estrogens act
in early to mid-G1 phase, via cyclin D1 expression. G1/S transition is under
the control of CDKs, particularly CDK4, CDK6 and CDK2. CDK4 and CDK6 are
activated by binding to D-type cyclins and act early in G1 phase.
The interplay between the ER pathway and the cell cycle control machinery -
particularly the control of G1-S transition mediated by cyclin d and CDK 4/5 -
provides a strong rational for the combined use of interventions designed to
control both nodes as a way to stop the HR+ breast cancer proliferation. This
mechanistic approach is corroborated by preclinical evidence of synergistic
activity of CDK inhibitors and hormonal agents against HR+ breast cancer in
cell lines and animal models and also clinical superiority with the combination
(CDKi + hormonal agents) vs. endocrine therapy alone in recent phase II/III
trials (PALOMA -1/2/3 with palbociclib; MONALEESA-2 with ribociclib).
Ribociclib (LEE011) is an oral selective inhibitor of CDK 4/6 which has
demonstrated activity in HR+ BC cell lines in combination with multiple
hormonal partners, as well as in clinical studies. While studies in combination
with fulvestrant (MONALEESA-3) and NSAI/tamoxifen in pre-menopausal patients
(MONALEESA-7) are ongoing, the phase III trial MONALEESA-2 (ribociclib +
letrozole vs. letrozole) was recently declared as a positive study by IDMC
assessment. These results reinforce the activity of this combination for the
treatment of HR+ advanced breast cancer.
The purpose of this study is to further evaluate the overall safety and
tolerability and clinical efficacy of ribociclib in combination with letrozole
in a broader group of patients with HR+, HER2- aBC who have not received prior
hormonal treatment for the advanced disease.
Study objective
Primary:
1/ To evaluate the safety and tolerability of ribociclib with letrozole in men
and postmenopausal women with HR+, HER2- aBC who received no prior hormonal
therapy for advanced disease.
Secondary:
To assess the clinical efficacy of ribociclib + letrozole measured by
Time-to-Progression (TTP), overall response rate (ORR) and clinical benefit
rate (CBR).
To assess treatment impact on patient reported outcome measured by variations
of Functional Assessment of Cancer Therapy - Breast (FACT-B) questionnaire
scores.
Study design
Open-label, multicenter, phase IIIb study.
Treatment cycles of 4 weeks.
All patients will be treated with ribociclib 600 mg o.d. during the first 3
weeks of each cycle and 2.5 mg letrozole o.d. continuously.
If patient is male or pre / peri postmenopausal woman, goserelin or leuprolide
is given on day 1 of the cycle.
Treatment period until disease progression or unacceptable side effects or
until 24 months after the inclusion of the last patient, whichever event occurs
first.
Approx. 3000 patients.
Intervention
Treatment with ribociclib and letrozole (and goserelin or leuprolide for men
and pre / peri postmenopausal women).
Study burden and risks
Risk: Adverse effects of the combination of ribociclib and letrozole.
Burden: Cycles of 4 weeks. Cycle 1-2: 2 visits, cycle 3 onwards 1 visit per
cycle. Screening visit and 2 end of trial visits (<7 and 30 after
discontinuation of study treatment). Duration of visits generally 2-3 hours.
Physical examination: Once per cycle up to cycle 13, thereafter every 2nd cycle
up to cycle 12 and therafter every 3rd cycle till cycle 36.
Blood tests (15 ml/occasion): Up to cycle 7, thereafter only if needed.
ECG: Once during cycle 1-2, thereafter only if needed.
CT-/MRI-scan: Preferably every 2nd cycle.
FACT-B questionnaire: N/A for The Netherlands.
Raapopseweg 1
Arnhem 6824 DP
NL
Raapopseweg 1
Arnhem 6824 DP
NL
Listed location countries
Age
Inclusion criteria
• Patient is an adult, male or female >= 18 years old at the time of informed
consent.
• Advanced (locoregionally recurrent or metastatic) breast cancer not amenable
to curative
therapy.
• In the case of women, both pre/perimenopausal and postmenopausal patients are
allowed. See protocol page 51 for more details.
• Patient has a histologically and/or cytologically confirmed diagnosis of
estrogen-receptor positive and/or progesterone receptor positive and
HER2-negative breast cancer. See protocol page 51 for more details.
• Patients has an ECOG performance status of <=2.
• Patient has adequate bone marrow and organ function. See protocol page 40 for
more details.
• Patient must have a screening ECG with QTcF interval < 450 msec and resting
heart rate >= 50 bpm.
Exclusion criteria
• Patient who received any CDK4/6 inhibitor.
• Patient has a known hypersensitivity to any of the excipients of the study
medication.
• Patient who received any prior systemic hormonal therapy for advanced breast
cancer; no more than one prior regimen of chemotherapy for the treatment of
metastatic disease. See protocol page 52 for details.
• Patient is concurrently using any other anti-cancer therapy.
• Central nervous system metastases. See protocol page 53 for exceptions.
• Known history of HIV.
• Clinically significant, uncontrolled heart diseases, including long QT
syndrome or family history of idiopathic sudden death or congenital long QT
syndrome. See protocol page 53 for details.
• Concommitant treatment with medications mentioned in items 13-14 on page
53/54 (CYP3A4/5 inducers/inhibitors, corticosteroids).
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2016-003467-19-NL |
| ClinicalTrials.gov | NCT02941926 |
| CCMO | NL59317.068.16 |