A Trial to Evaluate Efficacy and Safety of Ribociclib With Endocrine Therapy as Adjuvant Treatment in Patients With HR+/HER2- Early Breast Cancer (NATALEE)

• ClinicalTrials.gov Identifier: NCT03701334
• Recruitment Status: Active, not recruiting
• First Posted: October 10, 2018
• Last Update Posted: October 3, 2023
• Sponsor: Novartis Pharmaceuticals
• Collaborator: Translational Research in Oncology
• Information provided by (Responsible Party): Novartis ( Novartis Pharmaceuticals )

Tracking Information

• First Submitted Date: September 21, 2018
• First Posted Date: October 10, 2018
• Last Update Posted Date: October 3, 2023
• Actual Study Start Date: December 7, 2018
• Estimated Primary Completion Date: May 29, 2026 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: June 20, 2023)

Invasive Disease-Free Survival (iDFS) [ Time Frame: Up to approximately 91 months ]

iDFS using STEEP criteria (Standardized Definitions for Efficacy End Points in Adjuvant Breast Cancer Trials), as assessed by Investigator. iDFS is defined as time from the date of randomization to the date of the first event of local invasive breast recurrence, regional invasive recurrence, distant recurrence, death (any cause), contralateral invasive BC, or second primary non-breast invasive cancer (excluding basal and squamous cell carcinomas of the skin).

Original Primary Outcome Measures (submitted: October 7, 2018)

Invasive Disease-Free Survival [ Time Frame: 3.5 years ]

Invasive Disease-Free Survival for ribociclib + Endocrine Therapy versus Endocrine Therapy in patients with HR-positive, HER2-negative Early Breast Cancer using STEEP criteria (Standardized Definitions for Efficacy End Points in Adjuvant Breast Cancer Trials), as assessed by Investigator

Current Secondary Outcome Measures (submitted: June 20, 2023)

• Recurrence-free survival (RFS) [ Time Frame: Up to approximately 91 months ]
  RFS using STEEP criteria (Standardized Definitions for Efficacy End Points in Adjuvant Breast Cancer Trials). RFS is defined as the time from date of randomization to date of first event of local invasive breast recurrence, regional invasive recurrence, distant recurrence, or death (any cause).
• Distant disease-free survival (DDFS) [ Time Frame: Up to approximately 91 months ]
  DDFS using STEEP criteria. DDFS is defined as the time from date of randomization to date of first event of distant recurrence, death (any cause), or second primary non-breast invasive cancer (excluding basal and squamous cell carcinomas of the skin).
• Overall Survival (OS) [ Time Frame: Up to approximately 91 months ]
  OS is defined as the time from date of randomization to date of death due to any cause.
• Change from baseline in the global health status Quality of life scale score as assessed by EORTC QLQ-C30 [ Time Frame: Up to approximately 91 months ]
  The EORTC QLQ-C30 contains functional scales, symptom scales, single items scale and a global health status/QoL scale. All of the scales and single-item measures range in score from 0 to 100. A high scale score represents a higher response level.
• Change from baseline in the physical functioning sub-scale score as assessed by EORTC QLQ-C30 [ Time Frame: Up to approximately 91 months ]
  The EORTC QLQ-C30 contains functional scales, symptom scales, single items scale and a global health status/QoL scale. All of the scales and single-item measures range in score from 0 to 100. A high scale score represents a higher response level.
• PK parameters: Ctrough and other applicable parameters for ribociclib [ Time Frame: Cycle 1 Day 15 ]
  Pharmacokinetics of ribociclib: Ctrough and other applicable parameters

Original Secondary Outcome Measures (submitted: October 7, 2018)

• Recurrence-free survival [ Time Frame: 3.5 years ]
  using STEEP criteria (Standardized Definitions for Efficacy End Points in Adjuvant Breast Cancer Trials)
• Distant disease-free survival [ Time Frame: 3.5 years ]
  using STEEP criteria (Standardized Definitions for Efficacy End Points in Adjuvant Breast Cancer Trials)
• Overall Survival [ Time Frame: 7.5 years ]
  overall survival
• Change from baseline in the global health status Quality of life scale score as assessed by EORTC QLQ-C30 [ Time Frame: 3.5 years ]
  Patient reported outcomes for health-related quality of life in the two treatment arms
• Change from baseline in the physical functioning sub-scale score as assessed by EORTC QLQ-C30 [ Time Frame: 3.5 years ]
  Patient reported outcomes for health-related quality of life in the two treatment arms
• PK parameter Cmax for ribociclib [ Time Frame: 3.5 years ]
  Pharmacokinetics of ribociclib when given in combination with Non-Steroidal Aromatase Inhibitor (and goserelin if applicable)
• PK parameter Tmax for ribociclib [ Time Frame: 3.5 years ]
  Pharmacokinetics of ribociclib when given in combination with Non-Steroidal Aromatase inhibitor (and goserelin if applicable)
• PK parameter AUC0-24 for ribociclib [ Time Frame: 3.5 years ]
  Pharmacokinetics of ribociclib when given in combination with Non-Steroidal Aromatase inhibitor (and goserelin if applicable)

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Trial to Evaluate Efficacy and Safety of Ribociclib With Endocrine Therapy as Adjuvant Treatment in Patients With HR+/HER2- Early Breast Cancer
• Official Title: 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)
• Brief Summary: A phase III multi-center, randomized, open-label trial to evaluate efficacy and safety of ribociclib with endocrine therapy as adjuvant treatment in patients with HR+/HER2- Early Breast Cancer (EBC)

Detailed Description

The trial will include pre and postmenopausal women and men with HR-positive, HER2-negative EBC, with an Anatomic Stage Group III, IIB or a subset of Stage IIA cases, after adequate surgical resection, radiotherapy (if indicated), adjuvant or neoadjuvant chemotherapy (if indicated), and who are deemed to be eligible for adjuvant ET for at least 60 months of duration.

Approximately 5,000 patients will be randomized (using an Interactive Response Technology system [IRT]) into two treatment arms in a 1:1 ratio.

The trial will include screening, treatment, and follow up phases.

• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Early Breast Cancer

Intervention

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

Study Arms

• Experimental: Ribociclib + Endocrine Therapy
  Participants will receive ribociclib 400 mg once daily on days 1-21 of a 28-day cycle and endocrine therapy once daily continuously
  Interventions:

  • Drug: Ribociclib
  • Other: Endocrine Therapy
• Active Comparator: Endocrine Therapy
  Participants will receive endocrine therapy only once daily continuously
  Intervention: Other: Endocrine Therapy

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: February 17, 2022): 5101
• Original Estimated Enrollment (submitted: October 7, 2018): 4000
• Estimated Study Completion Date: May 29, 2026
• Estimated Primary Completion Date: May 29, 2026 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Patient is ≥ 18 years-old at the time of PICF signature
• Patient is female with known menopausal status at the time of randomization or initiation of adjuvant ET (whichever occurs earlier), or male.
• Patient with histologically confirmed unilateral primary invasive adenocarcinoma of the breast with a date of initial cytologic or histologic diagnosis within 18 months prior to randomization.
• Patient has breast cancer that is positive for ER and/or PgR
• Patient has HER2-negative breast cancer
• Patient has available archival tumor tissue from the surgical specimen
• 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 II or III
• If indicated, patient has completed adjuvant and/or neoadjuvant chemotherapy according to the institutional guidelines
• If indicated, patient has completed adjuvant radiotherapy according to the institutional guidelines
• Patient has an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.
• Patient has no contraindication for the adjuvant ET in the trial and is planned to be treated with ET for 5 years

Exclusion Criteria:

• Patient has received any CDK4/6 inhibitor
• Patient has received prior treatment with tamoxifen, raloxifene or AIs for reduction in risk ("chemoprevention") of breast cancer and/or treatment for osteoporosis within the last 2 years prior to randomization. Patient is concurrently using hormone replacement therapy.
• Patient has received prior treatment with anthracyclines at cumulative doses of 450 mg/m² or more for doxorubicin, or 900 mg/m² or more for epirubicin.
• Patient with a known hypersensitivity to any of the excipients of ribociclib and/or ET
• Patient with distant metastases of breast cancer beyond regional lymph nodes (stage IV according to AJCC 8th edition) and/or evidence of recurrence after curative surgery.
• Patient is concurrently using other anti-neoplastic therapy with the exception of adjuvant ET
• Patient has had major surgery, chemotherapy or radiotherapy within 14 days prior to randomization
• Patient has not recovered from clinical and laboratory acute toxicities related to prior anti-cancer therapies
• Patient has a concurrent invasive malignancy or a prior invasive malignancy whose treatment was completed within 2 years before randomization
• Patient has known HIV infection, Hepatitis B or C infection
• Clinically significant, uncontrolled heart disease and/or cardiac repolarization abnormality
• Patient is currently receiving any of the following substances within 7 days before randomization - Concomitant medications, herbal supplements, and/or fruits that are known as strong inhibitors or inducers of CYP3A4/5 or Medications that have a narrow therapeutic window and are predominantly metabolized through CYP3A4/5
• is currently receiving or has received systemic corticosteroids ≤ 2 weeks prior to starting trial treatment
• Patient has impairment of GI function or GI disease that may significantly alter the absorption of the oral trial treatments
• Patient has any other concurrent severe and/or uncontrolled medical condition that would, in the Investigator's judgment, cause unacceptable safety risks, contraindicate patient participation in the clinical trial or compromise compliance with the protocol
• Participation in other studies involving investigational drug(s) within 30 days prior to randomization or within 5 half-lives of the investigational drug(s) (whichever is longer), or participation in any other type of medical research judged not to be scientifically or medically compatible with this trial.
• Pregnant or breast-feeding (lactating) women or women who plan to become pregnant or breast-feed during the trial

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Argentina, Australia, Austria, Belgium, Brazil, Canada, China, France, Germany, Hungary, Ireland, Italy, Korea, Republic of, Poland, Romania, Russian Federation, Spain, Taiwan, United Kingdom, United States

Administrative Information

• NCT Number: NCT03701334
• Other Study ID Numbers: CLEE011O12301C; 2018-002998-21 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes

Plan Description

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

• Current Responsible Party: Novartis ( Novartis Pharmaceuticals )
• Original Responsible Party: Same as current
• Current Study Sponsor: Novartis Pharmaceuticals
• Original Study Sponsor: Same as current
• Collaborators: Translational Research in Oncology

Investigators

• Study Director: Novartis Pharmaceuticals; Novartis Pharmaceuticals

• PRS Account: Novartis
• Verification Date: October 2023