A Phase III Multi-center, Randomized, Open-label Trial to Evaluate Efficacy and Safety of Ribociclib With Endocrine Therapy as an Adjuvant Treatment in Patients With Hormone Receptor-positive, HER2-negative Early Breast Cancer (New Adjuvant TriAl With Ribociclib [LEE011]: NATALEE)

Official Summary

A phase III, multicenter, randomized, open-label trial to evaluate the efficacy and safety of ribociclib with Endocrine Therapy (ET) as an adjuvant treatment in women and men with Hormone Receptor positive (HR+), Human Epidermal Growth Factor Receptor 2 negative (HER2-) Early Breast Cancer (EBC).

Study Design

• Study Type: INTERVENTIONAL
• Allocation: RANDOMIZED
• Model: PARALLEL
• Masking: NONE
• Enrollment: 5,101 participants

Interventions

• DRUG: Ribociclib — Ribociclib orally taken at 400 mg on days 1 to 21 of a 28-day cycle
• OTHER: Endocrine Therapy (ET) — Endocrine Therapy (ET) will be administered according to the local clinical guidelines and current local prescribing information

Primary Outcomes

• Invasive Disease-Free Survival (iDFS) (Up to approximately 139 months)

Secondary Outcomes

• Recurrence-free survival (RFS) (Up to approximately 139 months)
• Distant disease-free survival (DDFS) (Up to approximately 139 months)
• Overall Survival (OS) (Up to approximately 139 months)
• Change from baseline in the global health status Quality of life scale score as assessed by EORTC QLQ-C30 (Up to approximately 139 months)
• Change from baseline in the physical functioning sub-scale score as assessed by EORTC QLQ-C30 (Up to approximately 139 months)

Eligibility Criteria

Inclusion Criteria

1. Signed and dated Patient Informed Consent Form (PICF) obtained prior to any trial-specific screening procedure.
2. Patient is ≥ 18 years-old at the time of PICF signature.
3. Patient is female with known menopausal status at the time of randomization or initiation of adjuvant ET (whichever occurs earlier), or male.

   Postmenopausal status is defined as:
   * Patient underwent bilateral oophorectomy, or
   * Age ≥ 60 years, or
   * Age \< 60 years and amenorrhea for 12 or more months (in the absence of chemotherapy, tamoxifen, toremifene or ovarian suppression) and Follicle-stimulating hormone (FSH) and plasma estradiol are in the postmenopausal ranges per local normal ranges.
   * If taking tamoxifen or toremifene and age \<60 years, then FSH and plasma estradiol level in postmenopausal ranges.

   Notes
   * In women who are premenopausal at the beginning of adjuvant chemotherapy, amenorrhea is not a reliable indicator of menopausal status as ovarian function may still be intact or resume despite anovulation/amenorrhea. For these women with therapy-induced amenorrhea, serial measurements of FSH and/or estradiol per local clinical guidelines are required for determination of postmenopausal status.
   * All women who do not meet the criteria for postmenopausal status are considered premenopausal for the purpose of this trial.
4. Patient with histologically confirmed unilateral primary invasive adenocarcinoma of the breast with a date of initial cytologic or histologic diagnosis (i.e. date of the pathology report that confirmed the BC diagnosis) within 18 months prior to randomization. Patient with a multicentric and/or multifocal tumor is eligible if all histopathologically examined lesions meet the pathologic criteria in inclusion criteria 5 and 6.
5. Patient has breast cancer that is positive for ER and/or PgR according to the local laboratory as determined on the most recently analyzed tissue sample.
6. Patient has HER2-negative breast cancer defined as a negative in situ hybridization test or an immunohistochemistry (IHC) status of 0 or 1+. If IHC is 2+, a negative in situ hybridization (FISH, CISH, or SISH) test is required to confirm the HER2-negative status (based on the most recently analyzed tissue sample tested by a local laboratory).
7. Patient (except those enrolled in China) has available archival tumor tissue from the surgical specimen, for submission to a central laboratory (Note: in patients that underwent neoadjuvant systemic therapy and had a pathologic complete response, archival tumor tissue at the time of the initial diagnosis or before the administration of neoadjuvant therapy is mandatory).
8. Patient, after surgical resection where tumor was removed completely, with the final surgical specimen microscopic margins free from tumor, and belongs to one of the following categories:

   * Anatomic Stage Group III, or
   * Anatomic Stage Group IIB, or
   * Anatomic Stage Group IIA (subset)

   Notes:
   * For patients whose tumors are Anatomic Stage IIA, N0:
   * If Grade is 1 or unknown (Gx), patient is not eligible.
   * If Grade 2, the gene expression test results (by Oncotype DX, Prosigna/PAM50, MammaPrint or EndoPredict EPclin) or Ki67 levels should be used if obtained as per local practice (i.e. are not mandatory for the purpose of the trial). Results must be available at screening.
   * Patients that received neoadjuvant treatment must meet the above criteria (for stage, and if Stage IIA, N0, also for grade and Ki67 or gene expression test) in any presurgical staging/sample and/or in the surgical specimen.
   * Categorization into the AJCC 8th edition Anatomic Stage Groups requires determination of the T, N and M categories. ALND is the preferred method for axillary lymph node staging, however SLN dissection can be used to determine the N category in the following cases:
   * No metastasis in SLN (patient is considered as pN0).
   * Only micrometastasis in SLN (patient is considered as pN1mi).
   * Patients with T1-2 and no clinically-evident nodes prior to surgery, no neoadjuvant chemotherapy, at least one macrometastasis in 1 or 2 SLNs, no matted nodes or gross extranodal disease at the time of SLN dissection (patient is considered as pN1).

   In all other cases, ALND is required to determine the N category.
9. If indicated, patient has completed adjuvant and/or neoadjuvant chemotherapy according to the institutional guidelines, prior to screening.
10. If indicated, patient has completed adjuvant radiotherapy according to the institutional guidelines, prior to screening.
11. Patient has no contraindication for the adjuvant ET in the trial and is planned to be treated with ET for 5 years (since randomization date) or more.
12. Patient may have already received any standard neoadjuvant and/or adjuvant ET at the time of PICF signature, but randomization should occur within 12 months of the initial start date of ET. Ovarian suppression or short term ET for fert

Trial Locations

• University of Alabama at Birmingham-Kirklin Clinic, Birmingham, Alabama, United States
• Cancer Treatment Centers of America, Goodyear, Arizona, United States
• St Bernards Medical Center, Jonesboro, Arkansas, United States
• Comprehensive Blood and Cancer, Bakersfield, California, United States
• UCLA Beverly Hills, Beverly Hills, California, United States
• UCLA Burbank, Burbank, California, United States
• Encino Research Center, Encino, California, United States
• St. Jude Heritage Medical Group, Fullerton, California, United States
• UCLA Hematology Oncology, Laguna Hills, California, United States
• Southern CA Oncology Rsrch Alliance, Los Angeles, California, United States
• ...and 10 more locations

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