A Phase Ib Dose Escalation Study of the Combination of LEE011 With Letrozole and Dose Expansion of LEE011 With Hormonal Therapy for the Treatment of Pre-(With Goserelin) and Postmenopausal Women With Hormone Receptor Positive, HER2-negative, Advanced Breast Cancer

The purpose of the Phase Ib is to:

1. determine the recommended dose of LEE011 in combination with a standard dose of letrozole as well as to provide additional safety and anti-tumor activity data in Asian non-Japanese patients
2. determine the recommended dose of LEE011 in combination with a standard dose of letrozole as well as to provide additional safety and activity data in Japanese patients
3. evaluate the safety and anti-tumor activity of LEE011 at the RP2D established in the dose escalation part in combination with a standard dose of letrozole, fulvestrant or tamoxifen plus goserelin in Japanese patients.

Study Overview

• Status: Completed
• Conditions: Hormone Receptor Positive, HER2-negative, Advanced Breast Cancer
• Intervention / Treatment: Drug: goserelin; Drug: Fulvestrant; Drug: LEE011; Drug: Letrozole; Drug: Tamoxifen

• Study Type: Interventional
• Enrollment (Actual): 88
• Phase: Phase 1

Contacts and Locations

Study Locations

• Hong Kong
  • Hong Kong, Hong Kong
    • Novartis Investigative Site
• Japan
  • Aichi
    • Nagoya-city, Aichi, Japan, 467-8602
      • Novartis Investigative Site
  • Hokkaido
    • Sapporo-city, Hokkaido, Japan, 003-0804
      • Novartis Investigative Site
  • Kanagawa
    • Yokohama-city, Kanagawa, Japan, 241-8515
      • Novartis Investigative Site
  • Osaka
    • Osaka-city, Osaka, Japan, 540-0006
      • Novartis Investigative Site
    • Suita, Osaka, Japan, 565 0871
      • Novartis Investigative Site
  • Saitama
    • Hidaka-city, Saitama, Japan, 350-1298
      • Novartis Investigative Site
    • Kitaadachi-gun, Saitama, Japan, 362-0806
      • Novartis Investigative Site
  • Shizuoka
    • Sunto Gun, Shizuoka, Japan, 411 8777
      • Novartis Investigative Site
  • Tokyo
    • Bunkyo ku, Tokyo, Japan, 113-8677
      • Novartis Investigative Site
    • Bunkyo ku, Tokyo, Japan, 113-8431
      • Novartis Investigative Site
    • Koto ku, Tokyo, Japan, 135 8550
      • Novartis Investigative Site
    • Shinagawa-ku, Tokyo, Japan, 142-8666
      • Novartis Investigative Site
    • Shinjuku-ku, Tokyo, Japan, 160-0023
      • Novartis Investigative Site
• Singapore
  • Singapore, Singapore, 168583
    • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Women with advanced (locoregionally recurrent or metastatic) breast cancer not amenable to curative therapy (surgery and/or radiotherapy).
• Patient has a histologically and/or cytologically confirmed diagnosis of estrogen receptor positive and/or progesterone receptor positive breast cancer
• Patient has HER2-negative breast cancer
• Patient has adequate bone marrow and organ function

Exclusion Criteria:

• Patient who received any CDK4/6 inhibitor.
• Patient has a known hypersensitivity to any of the excipients of LEE011 or letrozole
• Patients with inflammatory breast cancer.
• Patient who received any prior systemic anti-cancer therapy (including hormonal therapy and chemotherapy) for advanced breast cancer
• Patient is currently using other anti-cancer therapy
• Patient has had major surgery within 14 days prior to starting study drug or has not recovered from major side effects.
• Patient who has received radiotherapy ≤ 4 weeks
• Patient has a concurrent malignancy or malignancy within 3 years
• Patient has metastases to the central nervous system (CNS).
• Patient has a known history of HIV infection

Other protocol-defined inclusion/exclusion criteria may apply

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: LEE011 +Letrozole; LEE011 - 3 weeks on 1 week off Letrozole 2.5mg - Once daily	Drug: LEE011; LEE011 as 50 mg and 200 mg hard gelatin oral capsules as individual patient supply packaged in bottles. LEE011 will be taken QD - days 1-21 of each 28 days cycle.; Drug: Letrozole; 25mg
Experimental: LEE011 + Tamoxifen; LEE011 - 3 weeks on 1 week off Tamoxifen 20mg - Once daily	Drug: goserelin; Drug: Tamoxifen; 20 mg
Experimental: LEE011 + Fulvestrant; LEE011 - 3 weeks on 1 week off Fulvestrant 500 mg - Dosed every 28 days (Day 1 for each cycle) with 1 additional dose on Day 15 of Cycle 1	Drug: Fulvestrant; 500 mg

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phase Ib Dose escalation - Frequency of dose limiting toxicities (DLTs)	DLTs at each dose level associated with administration of LEE011 and letrozole	first cycle (28 days)
Phase Ib Dose Expansion: Number of participants with adverse events (AEs)	This will be defined by changes in hematology and chemistry values, vital signs and ECGs, frequency and duration of AEs, lab abnormalities and other safety parameters. For LEE011 and letrozole or tamoxifen or fulvestrant	18 months
Phase Ib Dose Expansion: Number of participants with serious adverse events (SAEs)	This will be defined by changes in hematology and chemistry values, vital signs and ECGs, frequency and duration of SAEs, lab abnormalities and other safety parameters. For LEE011 and letrozole or tamoxifen or fulvestrant	18 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of participants with adverse events (AEs) - Phase Ib dose escalation	This will be defined by changes in hematology and chemistry values, vital signs and ECGs, frequency and duration of AEs, lab abnormalities and other safety parameters. For LEE011 and letrozole or tamoxifen or fulvestrant	18 months
Number of participants with serious adverse events (SAEs) - Phase Ib dose escalation	This will be defined by changes in hematology and chemistry values, vital signs and ECGs, frequency and duration of SAEs, lab abnormalities and other safety parameters. For LEE011 and letrozole or tamoxifen or fulvestrant	18 months
Overall Response Rate (ORR) - Phase Ib dose expansion	Anti-tumor activity for LEE011 and letrozole or tamoxifen or fulvestrant	18 months
Clinical Benefit Rate (CBR) - Phase Ib dose expansion	Anti-tumor activity for LEE011 and letrozole or tamoxifen or fulvestrant	18 months
Composite Plasma pharmacokinetics (PK) parameters of LEE011 (and relevant metabolites) and letrozole - Phase Ib	As assessed by PK parameters such as Cmax, Tmax, AUC0-24hours, accumulation ratio and Ctrough for LEE011 (and relevant metabolites) and letrozole, tamoxifen and fulvestrant	C1D1, C1D2, C1D8, C1D15, C1D21, C1D22, C2D15, C3D15
Progression Free Survival (PFS) as per RECIST v1.1- phase Ib dose expansion	Anti-tumor activity for LEE011 and letrozole or tamoxifen or fulvestrant	18 months
Overall Survival (OS) - Phase Ib dose expansion	Anti-tumor activity for LEE011 and letrozole or tamoxifen or fulvestrant	18 months
Disease Control Rate (DCR) - Phase Ib dose expansion	Anti-tumor activity for LEE011 and letrozole or tamoxifen or fulvestrant	18 months
Duration of Response (DOR) - Phase Ib dose expansion	Anti-tumor activity for LEE011 and letrozole or tamoxifen or fulvestrant	18 months

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals
• Investigators: Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Publications and helpful links

General Publications

• Yap YS, Chiu J, Ito Y, Ishikawa T, Aruga T, Kim SJ, Toyama T, Saeki T, Saito M, Gounaris I, Su F, Ji Y, Han Y, Gazdoiu M, Masuda N. Ribociclib, a CDK 4/6 inhibitor, plus endocrine therapy in Asian women with advanced breast cancer. Cancer Sci. 2020 Sep;111(9):3313-3326. doi: 10.1111/cas.14554. Epub 2020 Jul 28.

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start (Actual): February 4, 2015
• Primary Completion (Actual): September 29, 2022
• Study Completion (Actual): September 29, 2022

Study Registration Dates

• First Submitted: January 5, 2015
• First Submitted That Met QC Criteria: January 6, 2015
• First Posted (Estimated): January 7, 2015

Study Record Updates

• Last Update Posted (Actual): June 8, 2023
• Last Update Submitted That Met QC Criteria: June 6, 2023
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Keywords: Tamoxifen; Hormone receptor positive; Fulvestrant; Letrozole; HER2-negative; Advanced breast cancer; LEE011,; Postmenopausal Asian women; Pre and Postmenopausal Japanese women
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Hormone Antagonists; Bone Density Conservation Agents; Aromatase Inhibitors; Steroid Synthesis Inhibitors; Estrogen Antagonists; Estrogen Receptor Antagonists; Selective Estrogen Receptor Modulators; Estrogen Receptor Modulators; Letrozole; Fulvestrant; Goserelin; Tamoxifen
• Other Study ID Numbers: CLEE011A2115C

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No