First-in-Human Study of RLY-5836 in Advanced Breast Cancer and Other Solid Tumors

Study Overview
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Brief Summary
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This is a Phase 1, first-in-human, open-label study designed to evaluate the maximum tolerated dose (MTD), recommended phase 2 dose (RP2D), safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary anti-tumor activity of RLY-5836 in advanced solid tumors in participants harboring a PIK3CA mutation in blood and/or tumor per local assessment. The study consists of 2 parts, a dose escalation (Part 1) and a dose expansion (Part 2).

Official Title
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A First-in-Human Study of PI3Kα Inhibitor, RLY-5836, in Combination With Targeted and Endocrine Therapies in Participants With Advanced Breast Cancer and as a Single Agent in Advanced Solid Tumors

Conditions
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Unresectable Solid Tumor, PIK3CA Mutation, Solid Tumor, Adult, HER2-negative Breast Cancer, Breast Cancer, Metastatic Breast Cancer, Advanced Breast Cancer, Hormone Receptor Positive Tumor

Intervention / Treatment
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* Drug: RLY-5836
* Drug: Fulvestrant
* Drug: Palbociclib
* Drug: Ribociclib
* Drug: Abemaciclib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient has ECOG performance status of 0-1 One or more documented primary oncogenic PIK3CA mutation(s) in blood and/or tumor per local assessment RLY-5836 single agent arm key inclusion criteria Disease that is refractory to standard therapy, intolerant to standard therapy, or participant has declined standard therapy. A histologically or cytologically confirmed diagnosis of unresectable or metastatic solid tumor Combination arms key inclusion criteria Males, postmenopausal females, or pre-/perimenopausal females previously treated with gonadotropin-releasing GnRH agonist at least 4 weeks prior to start of study drug with histologically or cytologically confirmed diagnosis of HR+, HER2- unresectable or metastatic breast cancer that is not amenable to curative therapy. Had previous treatment for advanced or metastatic breast cancer with antiestrogen therapy including, but not limited to, selective estrogen receptor degraders (e.g., fulvestrant), selective estrogen receptor modulators (e.g., tamoxifen), and aromatase inhibitors (AI) (letrozole, anastrozole, exemestane) Part 1: Prior PI3Kα inhibitor treatment is allowed if taken for < 14 days and not discontinued due to disease progression, hypersensitivity, or ≥ Grade 3 TEAEs. Exclusion Criteria: Part 2: Prior treatment with PI3Kα inhibitors. Type 1 or Type 2 diabetes requiring antihyperglycemic medication, or fasting plasma glucose ≥140 mg/dL and glycosylated hemoglobin (HbA1c) ≥7.0%.

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: RLY-5836 Single Agent Arm<br>RLY-5836 single agent arm for participants with unresectable or metastatic solid tumors | Drug: RLY-5836<br>* RLY-5836 is a mutant-selective, oral PI3Kα inhibitor.<br>|
| Experimental: RLY-5836 + Fulvestrant Arm<br>RLY-5836 + fulvestrant combination arm for participants with HR+, HER2- locally advanced or metastatic breast cancer | Drug: RLY-5836<br>* RLY-5836 is a mutant-selective, oral PI3Kα inhibitor.<br>Drug: Fulvestrant<br>* Fulvestrant (500 mg) is administered IM into the buttocks (gluteal area) slowly (1 to 2 minutes per injection) as 2×5 mL injections, 1 in each buttock, on Cycle 1 Day 1, Cycle 1 Day 15, and Day 1 of each subsequent cycle.<br>* Other names: Faslodex;|
| Experimental: RLY-5836 + Palbociclib + Fulvestrant Arm<br>RLY-5836 + palbociclib + fulvestrant triple combination arm for participants with HR+, HER2- locally advanced or metastatic breast cancer | Drug: RLY-5836<br>* RLY-5836 is a mutant-selective, oral PI3Kα inhibitor.<br>Drug: Fulvestrant<br>* Fulvestrant (500 mg) is administered IM into the buttocks (gluteal area) slowly (1 to 2 minutes per injection) as 2×5 mL injections, 1 in each buttock, on Cycle 1 Day 1, Cycle 1 Day 15, and Day 1 of each subsequent cycle.<br>* Other names: Faslodex;Drug: Palbociclib<br>* Palbociclib 125 mg once daily is taken orally in combination with RLY-5836 and fulvestrant for 28-day cycles that include 21 days of treatment followed by 7 days off treatment.<br>* Other names: Ibrance;|
| Experimental: RLY-5836 + Ribociclib + Fulvestrant Arm<br>RLY-5836 + ribociclib + fulvestrant triple combination arm for participants with HR+, HER2- locally advanced or metastatic breast cancer | Drug: RLY-5836<br>* RLY-5836 is a mutant-selective, oral PI3Kα inhibitor.<br>Drug: Fulvestrant<br>* Fulvestrant (500 mg) is administered IM into the buttocks (gluteal area) slowly (1 to 2 minutes per injection) as 2×5 mL injections, 1 in each buttock, on Cycle 1 Day 1, Cycle 1 Day 15, and Day 1 of each subsequent cycle.<br>* Other names: Faslodex;Drug: Ribociclib<br>* Ribociclib 600 mg once daily is taken orally in combination with RLY-5836 and fulvestrant for 28-day cycles that include 21 days of treatment followed by 7 days off treatment.<br>* Other names: Kisqali;|
| Experimental: RLY-5836 + Abemaciclib + Fulvestrant Arm<br>RLY-5836 + abemaciclib + fulvestrant triple combination arm for participants with HR+, HER2- locally advanced or metastatic breast cancer | Drug: RLY-5836<br>* RLY-5836 is a mutant-selective, oral PI3Kα inhibitor.<br>Drug: Fulvestrant<br>* Fulvestrant (500 mg) is administered IM into the buttocks (gluteal area) slowly (1 to 2 minutes per injection) as 2×5 mL injections, 1 in each buttock, on Cycle 1 Day 1, Cycle 1 Day 15, and Day 1 of each subsequent cycle.<br>* Other names: Faslodex;Drug: Abemaciclib<br>* Abemaciclib 150 mg BID will be taken orally in combination with RLY-5836 and fulvestrant for 28-day cycles.<br>* Other names: Verzenio;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D) of RLY-5836 |  | Cycle 1 (4-week cycle) of treatment for MTD and at the end of every cycle (4-week cycles) for RP2D until study discontinuation, approximately 24 months | 
| Number of participants with any dose-limiting toxicity (DLT) |  | Cycle 1, up to 28 days. | 
| Number of participants with adverse events (AEs) |  | Every cycle (4-week cycles) until study discontinuation, approximately 24 months | 
| Number of participants with serious adverse events (SAEs) |  | Every cycle (4-week cycles) until study discontinuation, approximately 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PIK3CA genotype in blood and tumor tissue by next generation nucleic acid sequencing |  | Every cycle (4-week cycles) through Cycle 3 and every other cycle thereafter until study discontinuation, approximately 24 months | 
| PK of RLY-5836: area under the concentration-time curve (AUC) |  | Approximately every 2 weeks in Cycle 1 (4-week cycle) and every cycle through end of treatment (4-week cycles), approximately 24 months | 
| PK of RLY-5836: maximum plasma concentration (Cmax) |  | Approximately every 2 weeks in Cycle 1 (4-week cycle) and every cycle through end of treatment (4-week cycles), approximately 24 months | 
| PK of RLY-5836: time to maximum concentration (tmax) |  | Approximately every 2 weeks in Cycle 1 (4-week cycle) and every cycle through end of treatment (4-week cycles), approximately 24 months | 
| PK of RLY-5836: half-life (t½) |  | Approximately every 2 weeks in Cycle 1 (4-week cycle) and every cycle through end of treatment (4-week cycles), approximately 24 months | 
| PK of RLY-5836: clearance following oral dose (CL/F) |  | Approximately every 2 weeks in Cycle 1 (4-week cycle) and every cycle through end of treatment (4-week cycles), approximately 24 months | 
| Changes in circulating markers of glucose metabolism: changes in circulating glucose |  | Approximately every week in Cycle 1 (4-week cycle), every 2 weeks in Cycle 2 (4-week cycle), and every cycle through end of treatment (4-week cycles), approximately 24 months | 
| Changes in circulating markers of glucose metabolism: changes in circulating insulin |  | Approximately every week in Cycle 1 (4-week cycle), every 2 weeks in Cycle 2 (4-week cycle), and every cycle through end of treatment (4-week cycles), approximately 24 months | 
| Changes in circulating markers of glucose metabolism: changes in circulating C-peptide |  | Approximately every week in Cycle 1 (4-week cycle), every 2 weeks in Cycle 2 (4-week cycle), and every cycle through end of treatment (4-week cycles), approximately 24 months | 
| Changes in circulating markers of glucose metabolism: changes in circulating glycosylated hemoglobin [HbA1c] |  | Approximately every week in Cycle 1 (4-week cycle), every 2 weeks in Cycle 2 (4-week cycle), and every cycle through end of treatment (4-week cycles), approximately 24 months | 
| Preliminary antitumor activity of RLY-5836: duration of response (DOR) per Response Evaluation Criteria in Solid Tumors (RECIST Version 1.1) |  | Approximately every 8 weeks until progressive disease, approximately 36 months | 
| Preliminary antitumor activity of RLY-5836: disease control rate (DCR) per Response Evaluation Criteria in Solid Tumors (RECIST Version 1.1) |  | Approximately every 8 weeks until progressive disease, approximately 36 months | 
| Preliminary antitumor activity of RLY-5836: objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST Version 1.1) |  | Approximately every 8 weeks until progressive disease, approximately 36 months |