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

Breast Cancer Clinical Trial

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05216432
• Other study ID #: RLY-2608-101
• Status: Recruiting
• Phase: Phase 1
• Start date: December 8, 2021
• Est. completion date: August 31, 2026

Study information

• Verified date: May 2024
• Source: Relay Therapeutics, Inc.
• Contact: Relay Therapeutics Inc
• Phone: 617-322-0731
• Email: ClinicalTrials[@]relaytx.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 400
• Est. completion date: August 31, 2026
• Est. primary completion date: December 31, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

• [For Part 1 and Part 2]: 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 breast cancer with:

1. =1 line of chemotherapy in the metastatic setting

2. =1 cyclin-dependent kinases (CDK) 4/6 inhibitor, in either the adjuvant and/or metastatic setting

3. =1 antiestrogen therapy in either adjuvant and/or metastatic setting, 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 with chemotherapy and PARP inhibitors is not to be included in enumeration or previous treatment

[For RLY-2608 + fulvestrant arm; Part 2, Group 2]: Received prior treatment with a PI3Ka 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 PI3Ka, 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

Related Conditions & MeSH terms

• Advanced Breast Cancer
• Breast Cancer
• Breast Neoplasms
• HER2-negative Breast Cancer
• Metastatic Breast Cancer
• Neoplasms
• Solid Tumor, Adult

Intervention

Drug:
• RLY-2608
RLY-2608 is a mutant-selective, oral PI3Ka inhibitor.
• 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).
• 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.
• 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.
• 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.

Locations

Country	Name	City	State
France	Institute Bergonié	Bordeaux Cedex
France	Gustave Roussy	Villejuif
Italy	Istituto Europeo di Oncologia IRCCS	Milano
Spain	Institut Catala D'Oncologia - Badalona (ICO Badalona)	Barcelona
Spain	Vall d'Hebron Instituto de Oncologia	Barcelona
Spain	Hospital Universitario 12 de Octubre	Madrid
Spain	START Madrid - Hospital Fundacion Jimenez Diaz	Madrid
Spain	Instituto Valenciano de Oncologia	Valencia
United States	University of Michigan	Ann Arbor	Michigan
United States	Dana-Farber Cancer Institute	Boston	Massachusetts
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	University of Chicago Medical Center	Chicago	Illinois
United States	University of Texas Southwestern Medical Center	Dallas	Texas
United States	HealthONE	Denver	Colorado
United States	NEXT Virginia	Fairfax	Virginia
United States	The University of Texas M.D. Anderson Cancer Center	Houston	Texas
United States	Community Health Network	Indianapolis	Indiana
United States	UW Carbone Cancer Center	Madison	Wisconsin
United States	Tennessee Oncology	Nashville	Tennessee
United States	Columbia University Herbert Irving Comprehensive Cancer Center	New York	New York
United States	Memorial Sloan Kettering	New York	New York
United States	Florida Cancer Specialists	Orlando	Florida
United States	Boca Raton Clinical Research (BRCR) Global	Plantation	Florida
United States	The University of Arizona Cancer Center	Tucson	Arizona

Sponsors (1)

Lead Sponsor	Collaborator
Relay Therapeutics, Inc.

Countries where clinical trial is conducted

United States,  France,  Italy,  Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Determination of maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D) of RLY-2608 as a single agent		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
Primary	Determination of maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D) of RLY-2608 in combination with fulvestrant		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
Primary	Determination of maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D) of RLY-2608 in combination with fulvestrant and a CDK 4/6 inhibitor (palbociclib, ribociclib)		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
Primary	Number of patients with adverse events and serious adverse events of RLY-2608 as a single agent		Every cycle (4-week cycles) until study discontinuation, approximately 24 months
Primary	Number of patients with adverse events and serious adverse events of RLY-2608 in combination with fulvestrant		Every cycle (4-week cycles) until study discontinuation, approximately 24 months
Primary	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)		Every cycle (4-week cycles) until study discontinuation, approximately 24 months
Secondary	PIK3CA gene status in plasma circulating tumor deoxyribonucleic acid (ctDNA) and tumor tissue		Day 1 of Cycle 1 (each cycle is 28 days)
Secondary	Pharmacokinetic parameters including maximum plasma drug concentration (Cmax) of RLY-2608 (and its metabolites, as appropriate) as single agent		Approximately every 2 weeks in Cycle 1 (4-week cycle) and every cycle through end of treatment, approximately 24 months
Secondary	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		Approximately every 2 weeks in Cycle 1 (4-week cycle) and every cycle through end of treatment, approximately 24 months
Secondary	Pharmacokinetic parameters including half-life (t1/2) of RLY-2608 (and its metabolites, as appropriate) as single agent		Approximately every 2 weeks in Cycle 1 (4-week cycle) and every cycle through end of treatment, approximately 24 months
Secondary	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		Approximately every 2 weeks in Cycle 1 (4-week cycle) and every cycle through end of treatment, approximately 24 months
Secondary	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		Approximately every 2 weeks in Cycle 1 (4-week cycle) and every cycle through end of treatment, approximately 24 months
Secondary	Pharmacokinetic parameters including half-life (t1/2) of RLY-2608 (and its metabolites, as appropriate) when RLY-2608 is administered in combination with fulvestrant		Approximately every 2 weeks in Cycle 1 (4-week cycle) and every cycle through end of treatment, approximately 24 months
Secondary	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)		Approximately every 2 weeks in Cycle 1 (4-week cycle) and every cycle through end of treatment, approximately 24 months
Secondary	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 (palbociclib, ribociclib)		Approximately every 2 weeks in Cycle 1 (4-week cycle) and every cycle through end of treatment, approximately 24 months
Secondary	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)		Approximately every 2 weeks in Cycle 1 (4-week cycle) and every cycle through end of treatment, approximately 24 months
Secondary	Changes in circulating blood of fasting glucose in RLY-2608 as a single agent		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
Secondary	Changes in circulating blood of insulin in RLY-2608 as a single agent		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
Secondary	Changes in circulating blood of C-peptide in RLY-2608 as a single agent		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
Secondary	Changes in circulating blood of HbA1c in RLY-2608 as a single agent		Once in Cycle 2 (4-week cycle) and then once every 3rd cycle beginning with Cycle 5 through end of treatment, approximately 24 months
Secondary	Changes in circulating blood of fasting glucose in RLY-2608 in combination with fulvestrant		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
Secondary	Changes in circulating blood of insulin in RLY-2608 in combination with fulvestrant		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
Secondary	Changes in circulating blood of C-peptide in RLY-2608 in combination with fulvestrant		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
Secondary	Changes in circulating blood of HbA1c in RLY-2608 in combination with fulvestrant		Once in Cycle 2 (4-week cycle) and then once every 3rd cycle beginning with Cycle 5 through end of treatment, approximately 24 months
Secondary	Changes in circulating blood of fasting glucose in RLY-2608 in combination with fulvestrant and a CDK4/6 inhibitor (palbociclib, ribociclib)		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
Secondary	Changes in circulating blood of insulin in RLY-2608 in combination with fulvestrant and a CDK4/6 inhibitor (palbociclib, ribociclib)		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
Secondary	Changes in circulating blood of C-peptide in RLY-2608 in combination with fulvestrant and a CDK4/6 inhibitor (palbociclib, ribociclib)		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
Secondary	Changes in circulating blood of HbA1c in RLY-2608 in combination with fulvestrant and a CDK4/6 inhibitor (palbociclib, ribociclib)		Once in Cycle 2 (4-week cycle) and then once every 3rd cycle beginning with Cycle 5 through end of treatment, approximately 24 months
Secondary	Objective response rate (ORR) as assessed by RECIST v1.1		Approximately every 8 weeks during treatment and every 12 weeks after the last dose in the absence of progressive disease, approximately 36 months
Secondary	Duration of Response (DOR) as assessed by RECIST v1.1		Approximately every 8 weeks during treatment and every 12 weeks after the last dose in the absence of progressive disease, approximately 36 months
Secondary	Disease Control Rate (DCR) as assessed by RECIST v1.1		Approximately every 8 weeks during treatment and every 12 weeks after the last dose in the absence of progressive disease, approximately 36 months
Secondary	Quality of Life as assessed by the European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC QLQ-C30)		Once every cycle (4-week cycles) through end of treatment, approximately 24 months
Secondary	Clinical benefit rate (CBR) 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]