A Study of LOXO-783 in Patients With Breast Cancer/Other Solid Tumors

Study Overview
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Brief Summary
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The main purpose of this study is to learn more about the safety, side effects, and effectiveness of LOXO-783. LOXO-783 may be used to treat breast cancer and other solid tumors that have a change in a particular gene (known as the PIK3CA gene). Participation could last up to 36 months (3 years) and possibly longer if the disease does not get worse.

Official Title
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A Study of LOXO-783 Administered as Monotherapy and in Combination With Anticancer Therapies for Patients With Advanced Breast Cancer and Other Solid Tumors With a PIK3CA H1047R Mutation

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: LOXO-783
* Drug: Fulvestrant
* Drug: Imlunestrant
* Drug: Abemaciclib
* Drug: Anastrozole, Exemestane, or Letrozole
* Drug: Paclitaxel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Have advanced breast cancer or another solid tumor with the presence of a phosphatidylinositol 3-kinase catalytic subunit alpha (PIK3CA) H1047R mutation (or other Sponsor and safety review committee (SRC)-approved, activating PIK3CA mutations other than H1047R mutation) Have adequate archival tumor tissue sample available or be approved by the Sponsor for enrollment if no tumor sample is available. Have stopped all cancer treatment and have recovered from the major side effects Have adequate organ function, as measured by blood tests Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) scale Patients must have Measurable disease --- Patients with non-breast tumor types must have at least 1 measurable lesion Non-measurable bone disease (at least 1 bone lesion in breast cancer patients only) For patients with an estrogen receptor (ER)+ breast cancer diagnosis: If female, must be postmenopausal If male, must agree to use hormone suppression Phase 1a: -- Dose escalation and backfill patients: Advanced solid tumor Patients may have had up to 5 prior regimens for advanced disease Phase 1b: Part A: ER+/human epidermal growth factor receptor 2 (HER2)- advanced breast cancer Patients may have had up to 5 prior regimens for advanced disease ---- Prior cyclin dependent kinase (CDK)4/6 inhibitor therapy required Part B: ER+/HER2- advanced breast cancer Patients may have had up to 2 prior regimens for advanced disease. Part C: ER+/HER2- advanced breast cancer Patients may have had up to 5 prior regimens for advanced disease. ---- Prior CDK4/6 inhibitor therapy required. Have a diagnosis of diabetes mellitus Type 2 Part D: Advanced breast cancer Patients may have had up to 5 prior regimens for advanced disease. Part E: Advanced solid tumor Patients may have had up to 3 prior regimens for advanced disease advanced disease Part F: ER+/HER2- advanced breast cancer Patients may have had up to 5 prior regimens for advanced disease Prior cyclin dependent kinase (CDK)4/6 inhibitor therapy required Exclusion Criteria: Medical Conditions Colorectal cancer Endometrial cancers with specific concurrent oncogenic alterations A history of known active or suspected Diabetes mellitus Type 1 or Diabetes mellitus Type 2 requiring antidiabetic medication (Phase 1a and all parts of Phase 1b except Part C). Serious concomitant systemic disorder Known or suspected history of untreated or uncontrolled central nervous system (CNS) involvement. Active uncontrolled systemic bacterial, viral, fungal, or parasitic infection, or other clinically significant active disease process Prior exposure to phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) inhibitor(s), except in certain circumstances

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: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1A: LOXO-783 Monotherapy Dose Escalation<br>LOXO-783 administered orally | Drug: LOXO-783<br>* Oral<br>* Other names: LY3849524;|
| Experimental: Phase 1B: Part A<br>LOXO-783 administered orally in combination with fulvestrant intramuscularly, imlunestrant orally, or an aromatase inhibitor orally | Drug: LOXO-783<br>* Oral<br>* Other names: LY3849524;Drug: Fulvestrant<br>* Intramuscular<br>Drug: Imlunestrant<br>* Oral<br>* Other names: LY3484356;Drug: Anastrozole, Exemestane, or Letrozole<br>* Oral<br>|
| Experimental: Phase 1B: Part B<br>LOXO-783 orally in combination with abemaciclib and either physician's choice aromatase inhibitor orally, fulvestrant intramuscularly, or imlunestrant orally | Drug: LOXO-783<br>* Oral<br>* Other names: LY3849524;Drug: Fulvestrant<br>* Intramuscular<br>Drug: Imlunestrant<br>* Oral<br>* Other names: LY3484356;Drug: Abemaciclib<br>* Oral<br>* Other names: LY2835219;Drug: Anastrozole, Exemestane, or Letrozole<br>* Oral<br>|
| Experimental: Phase 1B: Part C<br>LOXO-783 orally in combination with fulvestrant intramuscularly | Drug: LOXO-783<br>* Oral<br>* Other names: LY3849524;Drug: Fulvestrant<br>* Intramuscular<br>|
| Experimental: Phase 1B: Part D<br>LOXO-783 orally in combination with paclitaxel intravenously | Drug: LOXO-783<br>* Oral<br>* Other names: LY3849524;Drug: Paclitaxel<br>* Intravenous<br>|
| Experimental: Phase 1B: Part E<br>LOXO-783 orally | Drug: LOXO-783<br>* Oral<br>* Other names: LY3849524;|
| Experimental: Phase 1B: Part F<br>Multiple randomized dose levels of LOXO-783 orally with fulvestrant intramuscularly | Drug: LOXO-783<br>* Oral<br>* Other names: LY3849524;Drug: Fulvestrant<br>* Intramuscular<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1 a: To determine the maximum tolerated dose/recommended phase 2 dose (MTD/RP2D) of LOXO-783: Number of patients with dose-limiting toxicities (DLTs) | Number of patients with DLTs | During the first 28-day cycle of LOXO-783 treatment | 
| Phase 1 a: To determine the MTD/RP2D of LOXO-783: Number of patients with DLT-equivalent toxicities | Number of patients with DLT-equivalent toxicities | During the first 28-day cycle of LOXO-783 treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To assess the pharmacokinetics (PK) of LOXO-783: Area under the concentration versus time curve (AUC) | PK of LOXO-783: AUC | Up to 2 months | 
| To assess the PK of LOXO-783: Maximum drug concentration (Cmax) | PK of LOXO-783: Cmax | Up to 2 months | 
| To evaluate the preliminary antitumor activity of LOXO-783: Overall response rate (ORR) | ORR per investigator assessed Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST 1.1) | Up to approximately 36 months or 3 years | 
| To evaluate the preliminary antitumor activity of LOXO-783: Best overall response (BOR) | BOR per investigator assessed RECIST 1.1 | Up to approximately 36 months or 3 years | 
| To evaluate the preliminary antitumor activity of LOXO-783: Duration of response (DOR) | DOR per investigator assessed RECIST 1.1 | Up to approximately 36 months or 3 years | 
| To evaluate the preliminary antitumor activity of LOXO-783: Disease control rate (DCR) | DCR per investigator assessed RECIST 1.1 | Up to approximately 36 months or 3 years | 
| To evaluate the preliminary antitumor activity of LOXO-783: Clinical benefit rate (CBR) | CBR per investigator assessed RECIST 1.1 | Up to approximately 36 months or 3 years | 
| To evaluate the preliminary antitumor activity of LOXO-783: Time to response (TTR) | TTR per investigator assessed RECIST 1.1 | Up to approximately 36 months or 3 years | 
| To evaluate the preliminary antitumor activity of LOXO-783: Progression free survival (PFS) | PFS per investigator assessed RECIST 1.1 | Up to approximately 36 months or 3 years | 
| To evaluate the preliminary antitumor activity of LOXO-783: Overall survival (OS) | OS per investigator assessed RECIST 1.1 | Up to approximately 36 months or 3 years |