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

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

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).

Study Overview

• Status: Completed
• Conditions: Breast Cancer; Advanced Breast Cancer; Metastatic Breast Cancer; Solid Tumor, Adult; HER2-negative Breast Cancer; Hormone Receptor Positive Tumor; Unresectable Solid Tumor; PIK3CA Mutation
• Intervention / Treatment: Drug: RLY-5836; Drug: Fulvestrant; Drug: Palbociclib; Drug: Ribociclib; Drug: Abemaciclib

• Study Type: Interventional
• Enrollment (Actual): 41
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Florida
    • Orlando, Florida, United States, 32827
      • Sarah Cannon Research Institute at Florida Cancer Specialists
  • Indiana
    • Indianapolis, Indiana, United States, 46250
      • Community Cancer Center North
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
  • New Jersey
    • New Brunswick, New Jersey, United States, 08903
      • Rutgers Cancer Institute of New Jersey
  • New York
    • New York, New York, United States, 10065
      • Memorial Sloan Kettering Cancer Center-Main Campus
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • Tennessee Oncology, PLLC
  • Utah
    • Salt Lake City, Utah, United States, 84112
      • Huntsman Cancer Institute, University of Utah

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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%.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: RLY-5836 Single Agent Arm; RLY-5836 single agent arm for participants with unresectable or metastatic solid tumors	Drug: RLY-5836; RLY-5836 is a mutant-selective, oral PI3Kα inhibitor.
Experimental: RLY-5836 + Fulvestrant Arm; RLY-5836 + fulvestrant combination arm for participants with HR+, HER2- locally advanced or metastatic breast cancer	Drug: RLY-5836; RLY-5836 is a mutant-selective, oral PI3Kα inhibitor.; Drug: Fulvestrant; 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.; Other Names: Faslodex
Experimental: RLY-5836 + Palbociclib + Fulvestrant Arm; RLY-5836 + palbociclib + fulvestrant triple combination arm for participants with HR+, HER2- locally advanced or metastatic breast cancer	Drug: RLY-5836; RLY-5836 is a mutant-selective, oral PI3Kα inhibitor.; Drug: Fulvestrant; 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.; Other Names: Faslodex; Drug: Palbociclib; 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.; Other Names: Ibrance
Experimental: RLY-5836 + Ribociclib + Fulvestrant Arm; RLY-5836 + ribociclib + fulvestrant triple combination arm for participants with HR+, HER2- locally advanced or metastatic breast cancer	Drug: RLY-5836; RLY-5836 is a mutant-selective, oral PI3Kα inhibitor.; Drug: Fulvestrant; 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.; Other Names: Faslodex; Drug: Ribociclib; 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.; Other Names: Kisqali
Experimental: RLY-5836 + Abemaciclib + Fulvestrant Arm; RLY-5836 + abemaciclib + fulvestrant triple combination arm for participants with HR+, HER2- locally advanced or metastatic breast cancer	Drug: RLY-5836; RLY-5836 is a mutant-selective, oral PI3Kα inhibitor.; Drug: Fulvestrant; 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.; Other Names: Faslodex; Drug: Abemaciclib; Abemaciclib 150 mg BID will be taken orally in combination with RLY-5836 and fulvestrant for 28-day cycles.; Other Names: Verzenio

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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	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

Collaborators and Investigators

• Sponsor: Relay Therapeutics, Inc.

Study record dates

Study Major Dates

• Study Start (Actual): March 29, 2023
• Primary Completion (Actual): March 18, 2025
• Study Completion (Actual): April 11, 2025

Study Registration Dates

• First Submitted: January 23, 2023
• First Submitted That Met QC Criteria: March 7, 2023
• First Posted (Actual): March 8, 2023

Study Record Updates

• Last Update Posted (Actual): May 16, 2025
• Last Update Submitted That Met QC Criteria: May 13, 2025
• Last Verified: May 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Site; Skin Diseases; Breast Diseases; Neoplasms; Breast Neoplasms; Antineoplastic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Enzyme Inhibitors; Protein Kinase Inhibitors; Hormone Antagonists; Estrogen Receptor Antagonists; Estrogen Antagonists; Fulvestrant; Palbociclib
• Other Study ID Numbers: RLY-5836-101

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No