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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Advanced or Metastatic ER+ Breast Cancer

Intervention / Treatment
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* Drug: LSZ102
* Drug: LEE011
* Drug: BYL719


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A<br>Patients will get LSZ102 single agent during dose escalation. | Drug: LSZ102<br>* LSZ102<br>|
| Experimental: Arm B<br>Patients will get LSZ102 in combination with LEE011 during dose escalation. | Drug: LSZ102<br>* LSZ102<br>Drug: LEE011<br>* LEE011<br>* Other names: ribociclib, Kisqali;|
| Experimental: Arm C<br>Patients will get LSZ102 in combination with BYL719 during dose escalation. | Drug: LSZ102<br>* LSZ102<br>Drug: BYL719<br>* BYL719<br>* Other names: alpelisib;|
| Experimental: Arm 1<br>Patients will get LSZ102 single agent during dose expansion | Drug: LSZ102<br>* LSZ102<br>|
| Experimental: Arm 2<br>Patients will get LSZ102 + LEE011 (LEE011 intermittent regimen) during dose expansion | Drug: LSZ102<br>* LSZ102<br>Drug: LEE011<br>* LEE011<br>* Other names: ribociclib, Kisqali;|
| Experimental: Arm 3<br>Patients will get LSZ102 + LEE011 (LEE011 continuous regimen) during dose expansion | Drug: LSZ102<br>* LSZ102<br>Drug: LEE011<br>* LEE011<br>* Other names: ribociclib, Kisqali;|
| Experimental: Arm 4<br>Patient will get LSZ102 in combination with BYL719 during dose expansion | Drug: LSZ102<br>* LSZ102<br>Drug: BYL719<br>* BYL719<br>* Other names: alpelisib;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Day 1 - Day 28 of Cycle 1 (28 day cycle) | 
| 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. | Approximately 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Approximately 3 years | 
| Duration of Response (DOR) | Assessment of preliminary anti-tumor activity of LSZ102, LSZ102 + LEE011 and LSZ102 + BYL719 | 3 years | 
| Progression Free Survival (PFS) | Assessment of preliminary anti-tumor activity of LSZ102, LSZ102 + LEE011 and LSZ102 + BYL719 | 3 years | 
| Disease control rate (DCR) | Assessment of preliminary anti-tumor activity of LSZ102, LSZ102 + LEE011 and LSZ102 + BYL719 | 3 years | 
| Plasma concentration of study medications | Plasma concentration versus time | 1 cycle (28 day cycle) | 
| Plasma concentration under fasted condition and fed condition | Plasma concentration versus time under fasted and fed conditions | Up to 2 cycles (28 day cycle) | 
| Levels of Pharmacodynamic marker Estrogen receptor (ER) | To assess pharmacodynamics effect | 3 years | 
| Levels of Pharmacodynamic marker Progesterone receptor (PgR) | To assess the pharmacodynamic effect | 3 years | 
| Levels of Pharmacodynamic marker pS6 | To assess the pharmacodynamic effect | 3 years | 
| Pharmacokinetics (PK) parameter AUC | AUC = Area under curve | 6 cycles (28 day cycle) | 
| PK parameter Cmax | Cmax = Maximum observed plasma concentration after drug administration | 6 cycles (28 day cycle) | 
| PK parameter Tmax | Tmax = Time to reach Cmax | 6 cycles (28 day cycle) | 
| PK parameter Cmin | Cmin = Minimum observed plasma concentration after drug administration | 6 cycles (28 day cycle) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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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