A Study of LY3484356 in Participants With Advanced or Metastatic Breast Cancer or Endometrial Cancer

Study Overview
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Brief Summary
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The reason for this study is to see if the study drug LY3484356 alone or in combination with other anticancer therapies is safe and effective in participants with advanced or metastatic breast cancer or endometrial cancer.

Official Title
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EMBER: A Phase 1a/1b Study of LY3484356 Administered as Monotherapy and in Combination With Anticancer Therapies for Patients With ER+ Locally Advanced or Metastatic Breast Cancer and Other Select Non-Breast Cancers

Conditions
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Breast Cancer, Advanced Breast Cancer, Metastatic Breast Cancer, Endometrial Cancer

Intervention / Treatment
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* Drug: LY3484356
* Drug: Abemaciclib
* Drug: Everolimus
* Drug: Alpelisib
* Drug: Trastuzumab
* Drug: Aromatase Inhibitor (AI)
* Drug: Pertuzumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: All study parts: Participants must be willing to provide adequate archival tissue sample Participants must be willing to use highly effective birth control Participants must have adequate organ function Participants must be able to swallow capsules Dose escalation- Participants must have one of the following: Parts A and B: ER+ HER2- breast cancer with evidence of locally advanced unresectable or metastatic disease who have had the following: Part A: may have had up to 1 prior regimen of any kind for in the advanced/metastatic setting and no prior cyclin-dependent kinase 4/6 (CDK4/6) inhibitor therapy. Part B: may have had up to 2 prior regimens, no more than 1 of which may be endocrine therapy in the advanced/metastatic setting, and must have received a prior CDK4/6 inhibitor Cohort E4: No prior everolimus. Cohort E5: No prior alpelisib and must have a phosphatidylinositol 3-kinase catalytic α (PIK3Cα) mutation as determined by local testing. Part C: ER+, human epidermal growth factor receptor 2 positive (HER2+) breast cancer with evidence of locally advanced unresectable or metastatic disease who have had at least 2 HER2-directed therapies in any setting. Part D: ER+, EEC that has progressed after platinum containing chemotherapy and no prior fulvestrant or aromatase inhibitor therapy. Part E: ER+ and HER2+ breast cancer with evidence of locally advanced, unresectable, or metastatic disease. Part E: Participants must have received induction taxane chemotherapy combined with trastuzumab + pertuzumab as first-line treatment for advanced/metastatic disease and must not have progressed on this regimen. Part E: Participants must not have received more than 1 HER2-directed regimen or any endocrine therapy for advanced disease or any prior CDK4/6 inhibitor therapy. Participants with ER+/HER2- breast cancer enrolled in this study must have had evidence of clinical benefit while on endocrine therapy for at least 24 months in the adjuvant setting or at least 6 months in the advanced/metastatic setting or have untreated de novo metastatic breast cancer Exclusion Criteria: Participants must not have certain infections such as hepatitis or tuberculosis or HIV that are not well controlled Participants must not have another serious medical condition Participants must not have cancer of the central nervous system that is unstable Participants must not be pregnant or breastfeeding

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: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose Escalation LY3484356<br>LY3484356 given orally. | Drug: LY3484356<br>* Administered orally<br>* Other names: Imlunestrant;|
| Experimental: Part A: Dose Expansion: LY3484356 + Abemaciclib +/- AI<br>LY3484356 and abemaciclib given orally in combination with or without Aromatase Inhibitor (AI) of physician's choice (Anastrozole, Exemestane, or Letrozole) administered orally. | Drug: LY3484356<br>* Administered orally<br>* Other names: Imlunestrant;Drug: Abemaciclib<br>* Administered orally<br>* Other names: LY2835219;Drug: Aromatase Inhibitor (AI)<br>* Anastrozole or Exemestane or Letrozole administered orally (physician choice)<br>|
| Experimental: Part B: Dose Expansion: Cohort E3: LY3484356<br>LY3484356 given orally. | Drug: LY3484356<br>* Administered orally<br>* Other names: Imlunestrant;|
| Experimental: Part B: Dose Expansion: Cohort E4: LY3484356 + Everolimus<br>LY3484356 and everolimus given orally. | Drug: LY3484356<br>* Administered orally<br>* Other names: Imlunestrant;Drug: Everolimus<br>* Administered orally<br>|
| Experimental: Part B: Dose Expansion: Cohort E5: LY3484356 + Alpelisib<br>LY3484356 and alpelisib given orally. | Drug: LY3484356<br>* Administered orally<br>* Other names: Imlunestrant;Drug: Alpelisib<br>* Administered orally<br>|
| Experimental: Part C:Dose Expansion: LY3484356 + Trastuzumab +/- Abemaciclib<br>LY3484356 administered orally in combination with trastuzumab intravenously with or without Abemaciclib. | Drug: LY3484356<br>* Administered orally<br>* Other names: Imlunestrant;Drug: Abemaciclib<br>* Administered orally<br>* Other names: LY2835219;Drug: Trastuzumab<br>* Administered intravenously<br>|
| Experimental: Part D: Dose Expansion: LY3484356 +/- Abemaciclib<br>LY3484356 and Abemaciclib given orally with trastuzumab administered intravenously. | Drug: LY3484356<br>* Administered orally<br>* Other names: Imlunestrant;Drug: Abemaciclib<br>* Administered orally<br>* Other names: LY2835219;|
| Experimental: Part E: Dose Expansion: LY3484356 + Trastuzumab + Pertuzumab<br>LY3484356 administered orally in combination with trastuzumab and pertuzumab administered intravenously. | Drug: LY3484356<br>* Administered orally<br>* Other names: Imlunestrant;Drug: Trastuzumab<br>* Administered intravenously<br>Drug: Pertuzumab<br>* Administered intravenously<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants with Dose Limiting Toxicities (DLTs) and DLT-Equivalent Toxicities | Number of Participants with DLTs and DLT-Equivalent Toxicities | Baseline through Cycle 1 (21/28 Day Cycle) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics (PK): Area Under the Concentration Time Curve (AUC) of LY3484356 | PK: AUC of LY3484356 | Predose Cycle 1 Day 1 through Predose Cycle 2 Day 1 (21/28 Day Cycles) | 
| PK: Maximum Concentration (Cmax) of LY3484356 | PK: Cmax of LY3484356 | Predose Cycle 1 Day 1 through Predose Cycle 2 Day 1 (21/28 Day Cycles) | 
| PK: AUC of LY3484356 in Combination with Other Anticancer Therapies | PK: AUC of LY3484356 in Combination with Other Anticancer Therapies | Predose Cycle 1 Day 1 through Predose Cycle 2 Day 1 (21/28 Day Cycles) | 
| PK: Cmax of LY3484356 in Combination with Other Anticancer Therapies | PK: Cmax of LY3484356 in Combination with Other Anticancer Therapies | Predose Cycle 1 Day 1 through Predose Cycle 2 Day 1 (21/28 Day Cycles) | 
| Overall Response Rate (ORR): Percentage of Participants with Confirmed Complete Response (CR) or Partial Response (PR) as per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 | ORR: Percentage of Participants with Confirmed CR or PR as per RECIST v1.1 | Baseline through Disease Progression or Death (Estimated up to 28 Months) | 
| Duration of Response (DoR): Time From the Date of First Evidence of CR, PR (per RESIST v1.1) to the Date of Objective Progression or Death Due to Any Cause, Whichever is Earlier | DoR: Time From the Date of First Evidence of CR, PR (per RESIST v1.1) to the Date of Objective Progression or Death Due to Any Cause, Whichever is Earlier | Date of CR or PR to Date of Objective Disease Progression or Death Due to Any Cause (Estimated up to 28 Months) | 
| Disease Control Rate (DCR): Percentage of Participants with a Best Overall Response (BOR) of CR, PR, and Stable Disease (SD) as per RECIST v1.1 | DCR: Percentage of Participants with a BOR of CR, PR, and SD as per RECIST v1.1 | Baseline through Measured Progressive Disease (Estimated up to 28 Months) | 
| Clinical Benefit Rate (CBR): Percentage of Participants with a BOR of CR or PR, or SD lasting ≥24 weeks as per RECIST v1.1 | CBR: Percentage of Participants with a BOR of CR or PR, or SD lasting ≥24 weeks as per RECIST v1.1 | Baseline through Measured Progressive Disease (Estimated up to 28 Months) | 
| Progression Free Survival (PFS): Time From Baseline to the Date of Objective Progression or Death Due to Any Cause, Whichever is Earlier | PFS: Time From Baseline to the Date of Objective Progression or Death Due to Any Cause, Whichever is Earlier | Baseline to Objective Progression or Death Due to Any Cause (Estimated up to 28 Months) |