| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| premenopausal women with hormone receptor positive, HER2-negative, advanced breast cancer |
|
| E.1.1.1 | Medical condition in easily understood language |
| Advanced, Metastatic Breast Cancer |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10072737 |
| E.1.2 | Term | Advanced breast cancer |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To determine whether treatment with tamoxifen/NSAI + goserelin + LEE011 prolongs PFS compared to treatment with tamoxifen/NSAI + goserelin + placebo in premenopausal women with HR+, HER2-negative breast cancer |
|
| E.2.2 | Secondary objectives of the trial |
Key secondary:
To determine whether treatment with tamoxifen/NSAI + goserelin + LEE011 prolongs OS compared to treatment with tamoxifen/NSAI + goserelin + placebo |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Patient is an adult, female ≥ 18 years old and < 60 years old at the
time of informed consent and has signed informed consent before any
trial related activities are conducted and according to local guidelines.
2. Confirmed negative serum pregnancy test (β-hCG) before starting
study treatment or patient has had a hysterectomy.
3. Patient is premenopausal or perimenopausal at the time of study
entry.
4. Patient has advanced (locoregionally recurrent or metastatic) breast
cancer not amenable to curative therapy (e.g. surgery and/or
radiotherapy).
5. Patients who received (neo) adjuvant therapy for breast cancer are
eligible:
• If the patient has never received any prior endocrine therapy OR if ≥
12 months have elapsed since the patient's last dose of adjuvant
therapy, then the patient is eligible to receive tamoxifen + goserelin OR
a NSAI + goserelin for advanced breast cancer based on the
investigator's choice.
• if tamoxifen or fulvestrant was the last prior (neo) adjuvant therapy
and the last dose was given < 12 months prior to randomization, then
the patient is eligible to receive a NSAI (letrozole or anastrazole) +
goserelin for advanced breast cancer.
• If letrozole, anastrozole, or exemestane was the last prior (neo)
adjuvant therapy and the last dose was given < 12 months prior to
randomization, then the patient is eligible to receive tamoxifen +
goserelin for advanced breast cancer.
6. Patients who received ≤ 14 days of tamoxifen or a NSAI (letrozole or
anastrozole) with or without goserelin or goserelin <= 28 days for
advanced breast cancer prior to randomization are eligible. Patients
must continue treatment with the same hormonal agent + goserelin
during the study. No treatment interruption is required for these
patients prior to randomization.
Note: Patients receiving goserelin for reasons other than for advanced
breast cancer treatment are eligible (e.g. endometriosis). Patients who
received <= 28 days goserelin for advanced breast cancer are eligible.
7. Patients who have received up to 1 line of chemotherapy for advanced
breast cancer and have been discontinued 28 days before randomization
are eligible.
Note: if a cytotoxic chemotherapy regimen was discontinued for reasons
other than disease progression and lasted less than 21 d, this regimen
does not count as a prior line of chemotherapy.
8. Patient has a histologically and/or cytologically confirmed diagnosis
of estrogen-receptor positive and/or progesterone receptor positive
breast cancer by local laboratory (based on most recently analyzed
biopsy).
9. Patient has HER2-negative breast cancer (based on most recently
analyzed biopsy) defined as a negative in situ hybridization test or an
IHC status of 0, 1+ or 2+. If IHC is 2+, a negative in situ hybridization
(FISH, CISH, or SISH) test is required by local laboratory testing.
10. Patient must have either:
• Measurable disease, i.e., at least one measurable lesion as per RECIST
1.1 criteria.
OR
• If no measurable disease is present, then at least one predominantly
lytic bone lesion must be present. (Patients with no measurable disease
and only one predominantly lytic bone lesion that has been previously
irradiated are eligible if there is documented evidence of disease
progression of the bone lesion after irradiation).
11. Patient has ECOG PS 0 or 1.
12. Patient has adequate bone marrow and organ function as defined by
the following laboratory values (as assessed by central laboratory).
Other inclusion criteria as per full protocol may apply. |
|
| E.4 | Principal exclusion criteria |
1. Patient who has received a prior CDK4/6 inhibitor.
2. Patient has a known hypersensitivity to any of the excipients of
LEE011 or goserelin or hormonal treatment assigned (tamoxifen, NSAI
(letrozole or anastrozole)).
3. Patient is postmenopausal.
4. Patients who currently have inflammatory breast cancer on screening.
5. Patient who received any prior hormonal anti-cancer therapy for
advanced breast cancer, except for ≤ 14 days of tamoxifen or NSAI or
goserelin >= days for advanced breast cancer prior to randomization.
6. Patient who has not had resolution of all acute toxic effects of prior
anti-cancer therapy to NCI CTCAE version 4.03 Grade ≤1 (except
alopecia or other toxicities not considered a safety risk for the patient at
investigator's discretion).
7. Patient has a concurrent malignancy or malignancy within 3 years of
randomization, with the exception of adequately treated basal cell skin
carcinoma, squamous cell skin carcinoma, non-melanomatous skin
cancer or curatively resected cervical cancer.
8. Patient with CNS metastases.
Note: CNS involvement must be ruled out by assessments if a patient has
any signs or symptoms indicating potential CNS metastases
9. Patient has impairment of gastrointestinal (GI) function or GI disease
that may significantly alter the absorption of the study drugs (e.g.,
ulcerative diseases, uncontrolled nausea, vomiting, diarrhea,
malabsorption syndrome, or small bowel resection)
10. Patient has a known history of HIV infection (testing not mandatory)
11. Patient has any other concurrent severe and/or uncontrolled medical
condition that would, in the investigator's judgment, contraindicate
patient participation in the clinical study (e.g., chronic pancreatitis,
chronic active hepatitis, etc.)
12. Clinically significant, uncontrolled hearth disease and/or
cardiac repolarization abnormality.
13. Patient is currently receiving any of the substances described in the
protocol and cannot be discontinued 7 days prior to the start of the
treatment.
14. Patient has had major surgery within 14 days prior to starting study
drug or has not recovered from major side effects.
15. Patient is currently receiving warfarin or other Coumadin derived
anti-coagulant, for treatment, prophylaxis or otherwise. Therapy with
heparin, low molecular weight heparin (LMWH), or fondaparinux is
allowed.
16. Patient is currently receiving or has received systemic
corticosteroids ≤ 2 weeks prior to starting study drug, or who have not
fully recovered from side effects of such treatment.
17. Patient is concurrently using other antineoplastic agents (except for
patients who are receiving ≤ 14 days of tamoxifen or NSAI or goserelin
<= 28 days for advanced breast cancer prior to randomization).
18. Patient who has received radiotherapy ≤ 4 weeks or limited field
radiation for palliation ≤ 2 weeks prior to randomization, and who has
not recovered to grade 1 or better from related side effects of such
therapy (with the exception of alopecia) and/or if ≥ 25% of the bone
marrow was irradiated.
19. Pregnant or nursing (lactating) women, where pregnancy is defined
as the state of a female after conception and until the termination of
gestation, confirmed by a positive hCG laboratory test.
20. Women of child-bearing potential, defined as all women
physiologically capable of becoming pregnant, unless they are using
highly effective methods of contraception during dosing of study
treatment and for 21 days after stopping study medication. Highly
effective contraception methods include:
a. Total abstinence (when this is in line with the preferred and usual
lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation,
symptothermal, post-ovulation methods) and withdrawal are not
acceptable methods of contraception.
b. Total hysterectomy or tubal ligation at least six weeks before taking study treatment.
c. Male sterilization (at least 6 months prior to screening). For female
subjects on the study, the vasectomized male partner should be the sole
partner for that subject.
• Combination of the following:
a. Placement of an intrauterine device (IUD) or intrauterine system
(IUS)
b. Barrier methods of contraception: Condom or Occlusive cap
(diaphragm or cervical/vault caps) with spermicidal
foam/gel/film/cream/ vaginal suppository
Other exclusion criteria as per full protocol may apply. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| PFS per local assessment and RECIST 1.1 |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| median PFS of 13.4 months |
|
| E.5.2 | Secondary end point(s) |
Key secondary:
Overall Survival (OS) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
- patient reported outcome
- hospital resource utilization |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 119 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Argentina |
| Australia |
| Austria |
| Brazil |
| Bulgaria |
| Canada |
| China |
| Colombia |
| Czech Republic |
| Denmark |
| Finland |
| France |
| Germany |
| Greece |
| Hong Kong |
| Hungary |
| India |
| Israel |
| Italy |
| Japan |
| Korea, Republic of |
| Lebanon |
| Mexico |
| Norway |
| Poland |
| Portugal |
| Russian Federation |
| Saudi Arabia |
| Singapore |
| Slovakia |
| South Africa |
| Spain |
| Sweden |
| Switzerland |
| Taiwan |
| Thailand |
| Turkey |
| United Arab Emirates |
| United Kingdom |
| United States |
| Jordan |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
The end of the treatment (EOT) is defined as when the patient
permanently discontinues all study treatment and all the end of
treatment procedures are completed. The end of study (EOS) for a
given patient is defined a when the patient discontinues from follow-up
assessments as detailed in Table 7-1. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 12 |
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