First-in-Human Study of Mutant-selective PI3Kα Inhibitor, RLY-2608, as a Single Agent in Advanced Solid Tumor Patients and in Combination With Fulvestrant in Patients With Advanced Breast Cancer

Overview

This is an open-label, FIH study designed to evaluate the maximum tolerated dose, recommended Phase 2 dose, safety, tolerability, PK, pharmacodynamics, and preliminary antineoplastic activity of RLY-2608, in advanced solid tumor patients with a Phosphatidylinositol-4,5-bisphosphate-3 kinase, catalytic subunit alpha (PIK3CA) mutation in blood and/or tumor per local assessment. The study will evaluate both RLY-2608 as a single agent for patients with unresectable or metastatic solid tumors and RLY-2608 + fulvestrant combination arm for patients with HR+ HER2- locally advanced or metastatic breast cancer. This study consists of 2 parts, a dose escalation (Part 1) and a dose expansion (Part 2).

Full Title of Study: “A First-in-Human Study of Mutant-selective PI3Kα Inhibitor, RLY-2608, as a Single Agent in Advanced Solid Tumor Patients and in Combination With Fulvestrant in Patients With Advanced Breast Cancer”

Study Type

• Study Type: Interventional
• Study Design
  • Allocation: Non-Randomized
  • Intervention Model: Parallel Assignment
  • Primary Purpose: Treatment
  • Masking: None (Open Label)
• Study Primary Completion Date: January 31, 2025

Interventions

• Drug: RLY-2608
  • RLY-2608 is a mutant-selective, oral PI3Kα inhibitor.
• Drug: Fulvestrant
  • 500 mg fulvestrant is administered intramuscularly on Cycle 1 Day 1, Day 15, and Day 1 of each subsequent cycle (where a cycle is 28 days).

Arms, Groups and Cohorts

• Experimental: RLY-2608 for patients with unresectable or metastatic solid tumors
  • Multiple doses of RLY-2608 for oral administration.
• Experimental: RLY-2608 + fulvestrant combination for HR+ HER2- locally advanced or metastatic breast cancer
  • Oral dose of RLY-2608 in addition to fulvestrant as determined during Part 1 Dose Escalation.

Clinical Trial Outcome Measures

Primary Measures

• Determination of maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) of RLY-2608 as a single agent
  • Time Frame: 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
• Determination of maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) of RLY-2608 in combination with fulvestrant
  • Time Frame: 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 patients with adverse events and serious adverse events of RLY-2608 as a single agent
  • Time Frame: Every cycle (4-week cycles) until study discontinuation, approximately 24 months
• Number of patients with adverse events and serious adverse events of RLY-2608 in combination with fulvestrant
  • Time Frame: Every cycle (4-week cycles) until study discontinuation, approximately 24 months

Secondary Measures

• PIK3CA gene status in plasma circulating tumor deoxyribonucleic acid (ctDNA) and tumor tissue
  • Time Frame: Day 1 of Cycle 1 (each cycle is 28 days)
• Pharmacokinetic parameters including maximum plasma drug concentration (Cmax) of RLY-2608 (and its metabolites, as appropriate) as single agent
  • Time Frame: Approximately every 2 weeks in Cycle 1 (4-week cycle) and every cycle through end of treatment, approximately 24 months
• Pharmacokinetic parameters including area under the plasma concentration versus time curve from time 0 to 24 hours postdose (AUC0-24) of RLY-2608 (and its metabolites, as appropriate) as single agent
  • Time Frame: Approximately every 2 weeks in Cycle 1 (4-week cycle) and every cycle through end of treatment, approximately 24 months
• Pharmacokinetic parameters including terminal elimination half-life (t1/2) of RLY-2608 (and its metabolites, as appropriate) as single agent
  • Time Frame: Approximately every 2 weeks in Cycle 1 (4-week cycle) and every cycle through end of treatment, approximately 24 months
• Pharmacokinetic parameters including maximum plasma drug concentration (Cmax) of RLY-2608 (and its metabolites, as appropriate) when RLY-2608 is administered in combination with fulvestrant
  • Time Frame: Approximately every 2 weeks in Cycle 1 (4-week cycle) and every cycle through end of treatment, approximately 24 months
• Pharmacokinetic parameters including area under the plasma concentration versus time curve from time 0 to 24 hours postdose (AUC0-24) of RLY-2608 (and its metabolites, as appropriate) when RLY-2608 is administered in combination with fulvestrant
  • Time Frame: Approximately every 2 weeks in Cycle 1 (4-week cycle) and every cycle through end of treatment, approximately 24 months
• Pharmacokinetic parameters including terminal elimination half-life (t1/2) of RLY-2608 (and its metabolites, as appropriate) when RLY-2608 is administered in combination with fulvestrant
  • Time Frame: Approximately every 2 weeks in Cycle 1 (4-week cycle) and every cycle through end of treatment, approximately 24 months
• Changes in circulating blood of fasting glucose in RLY-2608 as a single agent
  • Time Frame: Approximately every week in Cycle 1 (4-week cycle), every two weeks in Cycle 2 (4-week cycle), and every cycle starting with Cycle 3 through end of treatment, approx 24 months
• Changes in circulating blood of insulin in RLY-2608 as a single agent
  • Time Frame: Approximately every week in Cycle 1 (4-week cycle), every two weeks in Cycle 2 (4-week cycle), and every cycle starting with Cycle 3 through end of treatment, approx 24 months
• Changes in circulating blood of C-peptide in RLY-2608 as a single agent
  • Time Frame: Approximately every week in Cycle 1 (4-week cycle), every two weeks in Cycle 2 (4-week cycle), and every cycle starting with Cycle 3 through end of treatment, approx 24 months
• Changes in circulating blood of HbA1c in RLY-2608 as a single agent
  • Time Frame: Once in Cycle 2 (4-week cycle) and then once every 3rd cycle beginning with Cycle 5 through end of treatment, approximately 24 months
• Changes in circulating blood of fasting glucose in RLY-2608 in combination with fulvestrant
  • Time Frame: Approximately every week in Cycle 1 (4-week cycle), every two weeks in Cycle 2 (4-week cycle), and every cycle starting with Cycle 3 through end of treatment, approx 24 months
• Changes in circulating blood of insulin in RLY-2608 in combination with fulvestrant
  • Time Frame: Approximately every week in Cycle 1 (4-week cycle), every two weeks in Cycle 2 (4-week cycle), and every cycle starting with Cycle 3 through end of treatment, approx 24 months
• Changes in circulating blood of C-peptide in RLY-2608 in combination with fulvestrant
  • Time Frame: Approximately every week in Cycle 1 (4-week cycle), every two weeks in Cycle 2 (4-week cycle), and every cycle starting with Cycle 3 through end of treatment, approx 24 months
• Changes in circulating blood of HbA1c in RLY-2608 in combination with fulvestrant
  • Time Frame: Once in Cycle 2 (4-week cycle) and then once every 3rd cycle beginning with Cycle 5 through end of treatment, approximately 24 months
• Overall response rate (ORR) as assessed by RECIST v1.1
  • Time Frame: Approximately every 8 weeks during treatment and every 12 weeks after the last dose in the absence of progressive disease, approximately 36 months
• Duration of Response (DOR) as assessed by RECIST v1.1
  • Time Frame: Approximately every 8 weeks during treatment and every 12 weeks after the last dose in the absence of progressive disease, approximately 36 months
• Disease Control Rate (DCR) as assessed by RECIST v1.1
  • Time Frame: Approximately every 8 weeks during treatment and every 12 weeks after the last dose in the absence of progressive disease, approximately 36 months
• Quality of Life as assessed by the European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC QLQ-C30)
  • Time Frame: Once every cycle (4-week cycles) through end of treatment, approximately 24 months

Participating in This Clinical Trial

Key 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

• Other potentially oncogenic PIK3CA mutations may be considered but must be approved by the Sponsor prior to enrollment. Part 1 – Ability to provide archived tumor tissue or be willing to undergo pretreatment tumor biopsy to assess PIK3CA status retrospectively Part 2 – Submit tumor tissue prior to study drug initiation for determination of PIK3CA mutation retrospectively. Key Inclusion for RLY-2608 Single Agent Arm – [For Part 1]: Evaluable disease per RECIST v1.1 – [For Part 2]: Measurable disease per RECIST v1.1 – Disease that is refractory to standard therapy, intolerant to standard therapy, or has declined standard therapy. – Part 1- histologically or cytologically confirmed diagnosis of unresectable or metastatic solid tumor – Part 2 – Unresectable or metastatic solid tumor with PIK3CA mutation(s) and one of the following tumor types: Group 1: clear cell ovarian cancer Group 2: head and neck squamous cell carcinoma Group 3: cervical cancer Group 4: other solid tumors, excluding colorectal, clear cell ovarian, head and neck squamous cell, and cervical cancers Group 5: unresectable or metastatic solid tumors with PIK3CA double mutations Key Inclusion for RLY-2608 + Fulvestrant Arm – [For Part 1 and Part 2]: Evaluable disease per RECIST v1.1 – Male or postmenopausal female with histologically or cytologically confirmed diagnosis of HR+, HER2- unresectable or metastatic breast cancer that is not amenable to curative therapy. Premenopausal or perimenopausal females must have a histologically or cytologically confirmed diagnosis of HR+ HER2- advanced or metastatic breast cancer that is not amenable to curative therapy and must have been previously treated with GnRH agonist at least 4 weeks prior to start of study drug – [For Part 1 and Part 2]: Had previous treatment for advanced or metastatic breast cancer with: 1. ≤1 chemotherapy regimen, 2. ≥1 cyclin-dependent kinases (CDK) 4/6 inhibitor, and 3. ≥1 antiestrogen therapy including, but not limited to, selective estrogen-receptor degraders (eg, fulvestrant), selective estrogen receptor modulators (eg, tamoxifen), and aromatase inhibitors (AI) (letrozole, anastrozole, exemestane), and 4. ≥1 PARP inhibitor if documented germline BRCA1/2 mutation Note: Chemotherapy for local or loco-regional treatment is not included in enumeration or previous treatment [For Part 2, Group 2]: Received prior treatment with a PI3Kα inhibitor and discontinued the inhibitor due to intolerance and not disease progression, where intolerance is defined as treatment discontinuation due to treatment related AE (eg. hyperglycemia, rash, diarrhea, stomatitis) other than severe hypersensitivity reaction and/or life-threatening reactions, such as anaphylaxis and Stevens-Johnson syndrome. Key Exclusion Criteria Prior treatment with PI3Kα inhibitors (except for RLY-2608 + fulvestrant arm, Part 2, Group 2). Type 1 or Type 2 diabetes requiring antihyperglycemic medication, or fasting plasma glucose ≥140 mg/dL and glycosylated hemoglobin (HbA1c) ≥7.0%. History of hypersensitivity to PI3K inhibitors QT interval corrected using Fridericia's formula (QTcF) > 480 msec or history of prolonged QT syndrome, Torsades de pointes or familial history of prolonged QT syndrome Clinically significant, uncontrolled cardiovascular disease CNS metastases or primary CNS tumor that is associated with progressive neurologic symptoms

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: N/A

Are Healthy Volunteers Accepted: No

Investigator Details

• Lead Sponsor
  • Relay Therapeutics, Inc.
• Provider of Information About this Clinical Study
  • Sponsor
• Overall Contact(s)
  • Relay Therapeutics Inc, 617-322-0731, ClinicalTrials@relaytx.com