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Phase I/Ib Trial of LSZ102 Single Agent or LSZ102 + LEE011 or LSZ102 + BYL719 in ER+ Breast Cancers

Primary Purpose

Advanced or Metastatic ER+ Breast Cancer

Status
Terminated
Phase
Phase 1
Locations
International
Study Type
Interventional
Intervention
LSZ102
LEE011
BYL719
Sponsored by
Novartis Pharmaceuticals
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Advanced or Metastatic ER+ Breast Cancer focused on measuring LSZ102, LEE011, ribociclib, Kisqali, BYL719, alpelisib, ER+ breast cancer, advanced ER+ breast cancer, metastatic ER+ breast cancer, SERD, SERM, fulvestrant, tamoxifen, aromatase inhibitor, ESR1, mtESR1, wtESR1, estrogen receptor, endocrine therapy

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Written informed consent must be obtained prior to any procedures
  • Histologically and/or cytologically confirmed diagnosis of ER+/HER2- breast cancer
  • Advanced or metastatic breast cancer
  • Must be able to swallow tablets and capsules

Exclusion Criteria:

  • Symptomatic CNS metastases
  • Patients whose laboratory values do not meet protocol criteria
  • Clinically significant cardiac disease
  • Impaired gastrointestinal function (GI) or GI disease that may significantly alter the absorption of oral medications

Other protocol defined inclusion/exclusion criteria may apply.

Sites / Locations

  • Massachusetts General Hospital Massachusetts General Hospital
  • Memorial Sloan Kettering Cancer Center
  • MD Anderson Cancer Center SC - LSZ102X2101
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm 6

Arm 7

Arm Type

Experimental

Experimental

Experimental

Experimental

Experimental

Experimental

Experimental

Arm Label

Arm A

Arm B

Arm C

Arm 1

Arm 2

Arm 3

Arm 4

Arm Description

Patients will get LSZ102 single agent during dose escalation.

Patients will get LSZ102 in combination with LEE011 during dose escalation.

Patients will get LSZ102 in combination with BYL719 during dose escalation.

Patients will get LSZ102 single agent during dose expansion

Patients will get LSZ102 + LEE011 (LEE011 intermittent regimen) during dose expansion

Patients will get LSZ102 + LEE011 (LEE011 continuous regimen) during dose expansion

Patient will get LSZ102 in combination with BYL719 during dose expansion

Outcomes

Primary Outcome Measures

Incidence of dose limiting toxicities (DLTs)
The dose escalation part of the study will be guided by well-established statistical methods/models to estimate the maximum tolerated doses (MTD)and/or recommended doses for expansion (RDE). Safety, pharmacokinetic and pharmacodynamics data will guide dose escalation decisions.
Safety and tolerability of LSZ102, LSZ102 + LEE011 and LSZ102 + BYL719
Incidence and severity of adverse events, serious adverse events, clinical laboratory values, vital signs, ECGs, dose interruptions, dose reductions and dose intensity.

Secondary Outcome Measures

Overall response rate (ORR)
Assessment of preliminary anti-tumor activity of LSZ102, LSZ102 + LEE011 and LSZ102 + BYL719. ORR is defined as the proportion of patients with a best overall response of complete response or partial response.
Duration of Response (DOR)
Assessment of preliminary anti-tumor activity of LSZ102, LSZ102 + LEE011 and LSZ102 + BYL719
Progression Free Survival (PFS)
Assessment of preliminary anti-tumor activity of LSZ102, LSZ102 + LEE011 and LSZ102 + BYL719
Disease control rate (DCR)
Assessment of preliminary anti-tumor activity of LSZ102, LSZ102 + LEE011 and LSZ102 + BYL719
Plasma concentration of study medications
Plasma concentration versus time
Plasma concentration under fasted condition and fed condition
Plasma concentration versus time under fasted and fed conditions
Levels of Pharmacodynamic marker Estrogen receptor (ER)
To assess pharmacodynamics effect
Levels of Pharmacodynamic marker Progesterone receptor (PgR)
To assess the pharmacodynamic effect
Levels of Pharmacodynamic marker pS6
To assess the pharmacodynamic effect
Pharmacokinetics (PK) parameter AUC
AUC = Area under curve
PK parameter Cmax
Cmax = Maximum observed plasma concentration after drug administration
PK parameter Tmax
Tmax = Time to reach Cmax
PK parameter Cmin
Cmin = Minimum observed plasma concentration after drug administration

Full Information

First Posted
March 23, 2016
Last Updated
July 28, 2022
Sponsor
Novartis Pharmaceuticals
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1. Study Identification

Unique Protocol Identification Number
NCT02734615
Brief Title
Phase I/Ib Trial of LSZ102 Single Agent or LSZ102 + LEE011 or LSZ102 + BYL719 in ER+ Breast Cancers
Official Title
A Phase I/Ib, Open Label Study of LSZ102 Single Agent and LSZ102 in Combination With Either LEE011 (LSZ102 + LEE011) or BYL719 (LSZ102 + BYL719) in Patients With Advanced or Metastatic ER+ Breast Cancer Who Have Progressed After Endocrine Therapy
Study Type
Interventional

2. Study Status

Record Verification Date
July 2022
Overall Recruitment Status
Terminated
Why Stopped
Sponsor's decision
Study Start Date
June 14, 2016 (Actual)
Primary Completion Date
September 13, 2021 (Actual)
Study Completion Date
September 13, 2021 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Novartis Pharmaceuticals

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
To characterize the safety and tolerability, identify recommended doses and regimens for future studies, pharmacokinetics (PK), pharmacodynamics (PD) and anti-tumor activity of LSZ102 as a single agent and in combination with either LEE011 or BYL719 in adult patients with locally advanced or metastatic ER+ breast cancer who have progressed after endocrine therapy.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Advanced or Metastatic ER+ Breast Cancer
Keywords
LSZ102, LEE011, ribociclib, Kisqali, BYL719, alpelisib, ER+ breast cancer, advanced ER+ breast cancer, metastatic ER+ breast cancer, SERD, SERM, fulvestrant, tamoxifen, aromatase inhibitor, ESR1, mtESR1, wtESR1, estrogen receptor, endocrine therapy

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
199 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Arm A
Arm Type
Experimental
Arm Description
Patients will get LSZ102 single agent during dose escalation.
Arm Title
Arm B
Arm Type
Experimental
Arm Description
Patients will get LSZ102 in combination with LEE011 during dose escalation.
Arm Title
Arm C
Arm Type
Experimental
Arm Description
Patients will get LSZ102 in combination with BYL719 during dose escalation.
Arm Title
Arm 1
Arm Type
Experimental
Arm Description
Patients will get LSZ102 single agent during dose expansion
Arm Title
Arm 2
Arm Type
Experimental
Arm Description
Patients will get LSZ102 + LEE011 (LEE011 intermittent regimen) during dose expansion
Arm Title
Arm 3
Arm Type
Experimental
Arm Description
Patients will get LSZ102 + LEE011 (LEE011 continuous regimen) during dose expansion
Arm Title
Arm 4
Arm Type
Experimental
Arm Description
Patient will get LSZ102 in combination with BYL719 during dose expansion
Intervention Type
Drug
Intervention Name(s)
LSZ102
Intervention Description
LSZ102
Intervention Type
Drug
Intervention Name(s)
LEE011
Other Intervention Name(s)
ribociclib, Kisqali
Intervention Description
LEE011
Intervention Type
Drug
Intervention Name(s)
BYL719
Other Intervention Name(s)
alpelisib
Intervention Description
BYL719
Primary Outcome Measure Information:
Title
Incidence of dose limiting toxicities (DLTs)
Description
The dose escalation part of the study will be guided by well-established statistical methods/models to estimate the maximum tolerated doses (MTD)and/or recommended doses for expansion (RDE). Safety, pharmacokinetic and pharmacodynamics data will guide dose escalation decisions.
Time Frame
Day 1 - Day 28 of Cycle 1 (28 day cycle)
Title
Safety and tolerability of LSZ102, LSZ102 + LEE011 and LSZ102 + BYL719
Description
Incidence and severity of adverse events, serious adverse events, clinical laboratory values, vital signs, ECGs, dose interruptions, dose reductions and dose intensity.
Time Frame
Approximately 3 years
Secondary Outcome Measure Information:
Title
Overall response rate (ORR)
Description
Assessment of preliminary anti-tumor activity of LSZ102, LSZ102 + LEE011 and LSZ102 + BYL719. ORR is defined as the proportion of patients with a best overall response of complete response or partial response.
Time Frame
Approximately 3 years
Title
Duration of Response (DOR)
Description
Assessment of preliminary anti-tumor activity of LSZ102, LSZ102 + LEE011 and LSZ102 + BYL719
Time Frame
3 years
Title
Progression Free Survival (PFS)
Description
Assessment of preliminary anti-tumor activity of LSZ102, LSZ102 + LEE011 and LSZ102 + BYL719
Time Frame
3 years
Title
Disease control rate (DCR)
Description
Assessment of preliminary anti-tumor activity of LSZ102, LSZ102 + LEE011 and LSZ102 + BYL719
Time Frame
3 years
Title
Plasma concentration of study medications
Description
Plasma concentration versus time
Time Frame
1 cycle (28 day cycle)
Title
Plasma concentration under fasted condition and fed condition
Description
Plasma concentration versus time under fasted and fed conditions
Time Frame
Up to 2 cycles (28 day cycle)
Title
Levels of Pharmacodynamic marker Estrogen receptor (ER)
Description
To assess pharmacodynamics effect
Time Frame
3 years
Title
Levels of Pharmacodynamic marker Progesterone receptor (PgR)
Description
To assess the pharmacodynamic effect
Time Frame
3 years
Title
Levels of Pharmacodynamic marker pS6
Description
To assess the pharmacodynamic effect
Time Frame
3 years
Title
Pharmacokinetics (PK) parameter AUC
Description
AUC = Area under curve
Time Frame
6 cycles (28 day cycle)
Title
PK parameter Cmax
Description
Cmax = Maximum observed plasma concentration after drug administration
Time Frame
6 cycles (28 day cycle)
Title
PK parameter Tmax
Description
Tmax = Time to reach Cmax
Time Frame
6 cycles (28 day cycle)
Title
PK parameter Cmin
Description
Cmin = Minimum observed plasma concentration after drug administration
Time Frame
6 cycles (28 day cycle)

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Written informed consent must be obtained prior to any procedures Histologically and/or cytologically confirmed diagnosis of ER+/HER2- breast cancer Advanced or metastatic breast cancer Must be able to swallow tablets and capsules Exclusion Criteria: Symptomatic CNS metastases Patients whose laboratory values do not meet protocol criteria Clinically significant cardiac disease Impaired gastrointestinal function (GI) or GI disease that may significantly alter the absorption of oral medications Other protocol defined inclusion/exclusion criteria may apply.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Novartis Pharmaceuticals
Organizational Affiliation
Novartis Pharmaceuticals
Official's Role
Study Director
Facility Information:
Facility Name
Massachusetts General Hospital Massachusetts General Hospital
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02114
Country
United States
Facility Name
Memorial Sloan Kettering Cancer Center
City
New York
State/Province
New York
ZIP/Postal Code
10065
Country
United States
Facility Name
MD Anderson Cancer Center SC - LSZ102X2101
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States
Facility Name
Novartis Investigative Site
City
Bruxelles
ZIP/Postal Code
1200
Country
Belgium
Facility Name
Novartis Investigative Site
City
Lyon Cedex
ZIP/Postal Code
69373
Country
France
Facility Name
Novartis Investigative Site
City
Ulm
ZIP/Postal Code
89081
Country
Germany
Facility Name
Novartis Investigative Site
City
Milano
State/Province
MI
ZIP/Postal Code
20133
Country
Italy
Facility Name
Novartis Investigative Site
City
Milano
State/Province
MI
ZIP/Postal Code
20141
Country
Italy
Facility Name
Novartis Investigative Site
City
Koto ku
State/Province
Tokyo
ZIP/Postal Code
135 8550
Country
Japan
Facility Name
Novartis Investigative Site
City
Singapore
ZIP/Postal Code
169610
Country
Singapore

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
34433648
Citation
Jhaveri K, Juric D, Yap YS, Cresta S, Layman RM, Duhoux FP, Terret C, Takahashi S, Huober J, Kundamal N, Sheng Q, Balbin A, Ji Y, He W, Crystal A, De Vita S, Curigliano G. A Phase I Study of LSZ102, an Oral Selective Estrogen Receptor Degrader, with or without Ribociclib or Alpelisib, in Patients with Estrogen Receptor-Positive Breast Cancer. Clin Cancer Res. 2021 Nov 1;27(21):5760-5770. doi: 10.1158/1078-0432.CCR-21-1095. Epub 2021 Aug 25.
Results Reference
result
Links:
URL
https://www.novctrd.com/ctrdweb/trialresult/trialresults/pdf?trialResultId=17965
Description
Study Results

Learn more about this trial

Phase I/Ib Trial of LSZ102 Single Agent or LSZ102 + LEE011 or LSZ102 + BYL719 in ER+ Breast Cancers

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