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

• ClinicalTrials.gov Identifier: NCT05216432
• Recruitment Status: Recruiting
• First Posted: January 31, 2022
• Last Update Posted: November 9, 2023
• Sponsor: Relay Therapeutics, Inc.
• Information provided by (Responsible Party): Relay Therapeutics, Inc.

Tracking Information

• First Submitted Date: December 20, 2021
• First Posted Date: January 31, 2022
• Last Update Posted Date: November 9, 2023
• Actual Study Start Date: December 8, 2021
• Estimated Primary Completion Date: January 31, 2025 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: November 7, 2023)

• 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 ]
• Determination of maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) of RLY-2608 in combination with fulvestrant and a CDK 4/6 inhibitor (palbociclib, ribociclib) [ 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 ]
• Number of patients with adverse events and serious adverse events of RLY-2608 in combination with fulvestrant and a CDK 4/6 inhibitor (palbociclib, ribociclib) [ Time Frame: Every cycle (4-week cycles) until study discontinuation, approximately 24 months ]

Original Primary Outcome Measures (submitted: January 18, 2022)

• 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 as a single agent
• 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 ]
  Determination of maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) of RLY-2608 in combination with fulvestrant
• 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 as a single agent
• 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 ]
  Number of patients with adverse events and serious adverse events of RLY-2608 in combination with fulvestrant

Current Secondary Outcome Measures (submitted: November 7, 2023)

• 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 during a dose interval (AUC0-tau) 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 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 during a dose interval (AUC0-tau) 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 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 ]
• 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 and a CDK4/6 inhibitor (palbociclib, ribociclib) [ 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 vs time curve of RLY-2608 (and its metabolites, as appropriate) administered with fulvestrant and CDK4/6 inhibitor (palbocicclib, ribociclib) [ 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 half-life (t1/2) of RLY-2608 (and its metabolites, as appropriate) when RLY-2608 is administered in combination with fulvestrant and a CDK4/6 inhibitor (palbociclib, ribociclib) [ 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 ]
• Changes in circulating blood of fasting glucose in RLY-2608 in combination with fulvestrant and a CDK4/6 inhibitor (palbociclib, ribociclib) [ 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 and a CDK4/6 inhibitor (palbociclib, ribociclib) [ 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 and a CDK4/6 inhibitor (palbociclib, ribociclib) [ 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 and a CDK4/6 inhibitor (palbociclib, ribociclib) [ 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 ]
• Objective 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 ]

Original Secondary Outcome Measures (submitted: January 18, 2022)

• PIK3CA gene status in plasma circulating tumor deoxyribonucleic acid (ctDNA) and tumor tissue [ Time Frame: Every cycle (4-week cycles) through Cycle 3 and every other cycle thereafter until study discontinuation, approximately 24 months ]
  PIK3CA gene status in plasma circulating tumor deoxyribonucleic acid (ctDNA) and tumor tissue
• 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 though Cycle 4 (4-week cycles) ]
  Pharmacokinetic parameters including maximum plasma drug concentration (Cmax) of RLY-2608 (and its metabolites, as appropriate) as single agent
• 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 though Cycle 4 (4-week cycles) ]
  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
• 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 though Cycle 4 (4-week cycles) ]
  Pharmacokinetic parameters including terminal elimination half-life (t1/2) of RLY-2608 (and its metabolites, as appropriate) as single agent
• 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 though Cycle 4 (4-week cycles) ]
  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
• 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 though Cycle 4 (4-week cycles) ]
  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
• 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 though Cycle 4 (4-week cycles) ]
  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
• Changes in circulating blood of fasting glucose in RLY-2608 as a single agent [ Time Frame: Approximately every 2 weeks in Cycle 1 (4-week cycle) and every other cycle (4-week cycles) from Cycle 3, approximately 24 months ]
  Changes in circulating blood of fasting glucose in RLY-2608 as a single agent
• Changes in circulating blood of insulin in RLY-2608 as a single agent [ Time Frame: Approximately every 2 weeks in Cycle 1 (4-week cycle) and every other cycle (4-week cycles) from Cycle 3, approximately 24 months ]
  Changes in circulating blood of insulin in RLY-2608 as a single agent
• Changes in circulating blood of C-peptide in RLY-2608 as a single agent [ Time Frame: Approximately every 2 weeks in Cycle 1 (4-week cycle) and every other cycle (4-week cycles) from Cycle 3, approximately 24 months ]
  Changes in circulating blood of C-peptide in RLY-2608 as a single agent
• Changes in circulating blood of fasting glucose in RLY-2608 in combination with fulvestrant [ Time Frame: Approximately every 2 weeks in Cycle 1 (4-week cycle) and every other cycle (4-week cycles) from Cycle 3, approximately 24 months ]
  Changes in circulating blood of fasting glucose in RLY-2608 in combination with fulvestrant
• Changes in circulating blood of insulin in RLY-2608 in combination with fulvestrant [ Time Frame: Approximately every 2 weeks in Cycle 1 (4-week cycle) and every other cycle (4-week cycles) from Cycle 3, approximately 24 months ]
  Changes in circulating blood of insulin in RLY-2608 in combination with fulvestrant
• Changes in circulating blood of C-peptide in RLY-2608 in combination with fulvestrant [ Time Frame: Approximately every 2 weeks in Cycle 1 (4-week cycle) and every other cycle (4-week cycles) from Cycle 3, approximately 24 months ]
  Changes in circulating blood of C-peptide in RLY-2608 in combination with fulvestrant
• Pharmacodynamic parameters including changes in PI3Kα signaling [ Time Frame: Approximately every 2 weeks in Cycle 1 (4-week cycle) and every other cycle (4-week cycles) from Cycle 3, approximately 24 months ]
  Pharmacodynamic parameters including changes in PI3Kα signaling
• 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 ]
  Overall response rate (ORR) as assessed by RECIST v1.1
• 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 ]
  Duration of Response (DOR) as assessed by RECIST v1.1
• 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 ]
  Disease Control Rate (DCR) as assessed by RECIST v1.1

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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
• Official Title: 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
• Brief Summary: 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 RLY-2608 as a single agent for patients with unresectable or metastatic solid tumors, RLY-2608 + fulvestrant and RLY-2608 + fulvestrant + CDK4/6 inhibitor (palbociclib or ribociclib) combination arms for patients with HR+ HER2- locally advanced or metastatic breast cancer. The RLY-2608 single agent arm, RLY-2608 + fulvestrant combination arm, and triple combination arms will have 2 parts: a dose escalation (Part 1) and a dose expansion (Part 2).
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 1

Study Design

Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

Single Agent Arm:

Part 1(multiple ascending doses, QD or BID):unresectable or metastatic solid tumors with PIK3CA mutation per local assessment; Part 2 (RP2D determined in Part 1) Patients with unresectable or metastatic solid tumors with ≥1 PIK3CA mutation per local assessment will be enrolled protocol defined groups

Double Combination Arm Part 1(multiple ascending doses, QD or BID): HR+, HER2- advanced or metastatic breast cancer with PIK3CA mutation per local assessment Part 2 (RP2D determined in Part 1) Group 1: patients who have not received prior PI3Kα inhibitor Group 2: patients who are intolerant to PI3Kα inhibitor

Triple Combination Arms Part 1(multiple ascending doses, QD or BID): HR+, HER2- advanced or metastatic breast cancer with PIK3CA mutation per local assessment Part 2 (RP2D determined in Part 1) Patients with HR+, HER2- advanced or metastatic breast cancer with PIK3CA mutation per local assessment will be enrolled protocol defined groups

Masking: None (Open Label)
Primary Purpose: Treatment

Condition

• PIK3CA Mutation
• Solid Tumor, Adult
• HER2-negative Breast Cancer
• Breast Cancer
• Metastatic Breast Cancer
• Advanced Breast Cancer
• Unresectable Solid Tumor

Intervention

• 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).
  Other Name: Faslodex
• Drug: Palbociclib 125mg
  125mg palbociclib is taken orally once daily for 28-day cycles that include 21 days of treatment followed by 7 days off treatment.
  Other Name: Ibrance
• Drug: Ribociclib 400mg
  400mg ribociclib is taken orally once daily for 28-day cycles that include 21 days of treatment followed by 7 days off treatment.
• Drug: Ribociclib 600mg
  600mg ribociclib is taken orally once daily for 28-day cycles that include 21 days of treatment followed by 7 days off treatment.
  Other Name: Kisqali

Study Arms

• Experimental: RLY-2608 for patients with unresectable or metastatic solid tumors
  Multiple doses of RLY-2608 for oral administration.
  Intervention: Drug: RLY-2608
• 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.
  Interventions:

  • Drug: RLY-2608
  • Drug: Fulvestrant
• Experimental: RLY-2608+fulvestrant+palbociclib 125 mg for HR+ HER2- locally advanced or metastatic breast cancer
  Oral dose of RLY-2608 in addition to fulvestrant and palbociclib 125mg as determined during Part 1 Dose Escalation.
  Interventions:

  • Drug: RLY-2608
  • Drug: Fulvestrant
  • Drug: Palbociclib 125mg
• Experimental: RLY-2608+fulvestrant+ribociclib 400 mg for HR+ HER2- locally advanced or metastatic breast cancer
  Oral dose of RLY-2608 in addition to fulvestrant and ribociclib 400mg as determined during Part 1 Dose Escalation.
  Interventions:

  • Drug: RLY-2608
  • Drug: Fulvestrant
  • Drug: Ribociclib 400mg
• Experimental: RLY-2608+fulvestrant+ribociclib 600 mg for HR+ HER2- locally advanced or metastatic breast cancer
  Oral dose of RLY-2608 in addition to fulvestrant and ribociclib 600mg as determined during Part 1 Dose Escalation.
  Interventions:

  • Drug: RLY-2608
  • Drug: Fulvestrant
  • Drug: Ribociclib 600mg

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: November 7, 2023): 400
• Original Estimated Enrollment (submitted: January 18, 2022): 190
• Estimated Study Completion Date: August 31, 2025
• Estimated Primary Completion Date: January 31, 2025 (Final data collection date for primary outcome measure)

Eligibility Criteria

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 Combination Arms

• [For Part 1 and Part 2]: Evaluable disease per RECIST v1.1
• Male or female with histologically or cytologically confirmed diagnosis of HR+, HER2- unresectable or metastatic breast cancer that is not amenable to curative therapy. Females may be postmenopausal, premenopausal, or perimenopausal. 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 line of chemotherapy,
  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 appropriate, if documented germline BRCA1/2 mutation Note: Systemic local, loco-regional, or adjuvant treatment is not to be included in enumeration or previous treatment

[For RLY-2608 + fulvestrant arm; 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, AKT, or mTOR 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. For combination arms only: hypersensitivity to fulvestrant, palbociclib, and/or ribociclib, as appropriate for the combination.

For triple combination arms only: history of pneumonitis or interstitial lung disease.

For the single agent and combination arms other than with ribociclib: mean QT interval corrected using Fridericia's formula (QTcF) >480 msec. For the combination arms with ribociclib: mean QTcF ≥450 msec.

Patient has a history of prolonged QT syndrome or torsades de pointes. Patient has a familial history of prolonged QT syndrome.

Clinically significant, uncontrolled cardiovascular disease CNS metastases or primary CNS tumor that is associated with progressive neurologic symptoms

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Relay Therapeutics Inc; 617-322-0731; ClinicalTrials@relaytx.com

• Listed Location Countries: France, Italy, Spain, United States

Administrative Information

• NCT Number: NCT05216432
• Other Study ID Numbers: RLY-2608-101
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Relay Therapeutics, Inc.
• Original Responsible Party: Same as current
• Current Study Sponsor: Relay Therapeutics, Inc.
• Original Study Sponsor: Same as current
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: Relay Therapeutics, Inc.
• Verification Date: November 2023