First-in-Human Study of Mutant-selective PI3Kα Inhibitor, RLY-2608, as a Single Agent in Patients With Advanced Solid Tumors and in Combination With Endocrine Therapy +/- a CDK4/6 or CDK4 Inhibitor in Patients With Advanced Solid Tumors or Advanced Breast Cancer
1 other identifier
interventional
930
5 countries
37
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. It will also evaluate RLY-2608 in combination RLY-2608 + fulvestrant and in triple combination RLY-2608 + fulvestrant + CDK4/6 inhibitor (palbociclib or ribociclib) or CDK4 inhibitor (PF-07220060) 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).
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at P75+ for phase_1
Started Dec 2021
Longer than P75 for phase_1
37 active sites
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
Click on a node to explore related trials.
Study Timeline
Key milestones and dates
Study Start
First participant enrolled
December 8, 2021
CompletedFirst Submitted
Initial submission to the registry
December 20, 2021
CompletedFirst Posted
Study publicly available on registry
January 31, 2022
CompletedPrimary Completion
Last participant's last visit for primary outcome
April 30, 2027
ExpectedStudy Completion
Last participant's last visit for all outcomes
April 30, 2027
September 22, 2025
September 1, 2025
5.4 years
December 20, 2021
September 17, 2025
Conditions
Outcome Measures
Primary Outcomes (6)
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
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
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), and in combination with CDK4 inhibitor (PF-07220060) and 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
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
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
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), and in combination with CDK4 inhibitor (PF-07220060) and fulvestrant
Every cycle (4-week cycles) until study discontinuation, approximately 24 months
Secondary Outcomes (26)
PIK3CA gene status in plasma circulating tumor deoxyribonucleic acid (ctDNA) and tumor tissue
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
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
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
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
Approximately every 2 weeks in Cycle 1 (4-week cycle) and every cycle through end of treatment, approximately 24 months
- +21 more secondary outcomes
Study Arms (7)
RLY-2608 for patients with unresectable or metastatic solid tumors
EXPERIMENTALMultiple doses of RLY-2608 for oral administration.
RLY-2608 + fulvestrant combination for HR+ HER2- locally advanced or metastatic breast cancer
EXPERIMENTALOral dose of RLY-2608 in addition to fulvestrant as determined during Part 1 Dose Escalation.
RLY-2608+fulvestrant+palbo125mg for HR+HER2- locally advanced metastatic breast cancer
EXPERIMENTALOral dose of RLY-2608 in addition to fulvestrant and palbociclib 125mg as determined during Part 1 Dose Escalation.
RLY-2608+fulvestrant+ribo400mg for HR+HER2- locally advanced metastatic breast cancer
EXPERIMENTALOral dose of RLY-2608 in addition to fulvestrant and ribociclib 400mg as determined during Part 1 Dose Escalation.
RLY-2608+fulvestrant+ribo600mg for HR+HER2- locally advanced metastatic breast cancer
EXPERIMENTALOral dose of RLY-2608 in addition to fulvestrant and ribociclib 600mg as determined during Part 1 Dose Escalation.
RLY-2608+fulvestrant+PF-07220060 100 mg for HR+ HER2- locally advanced or metastatic breast cancer
EXPERIMENTALOral dose of RLY-2608 in addition to fulvestrant and PF-07220060 100 mg as determined during Part 1 Dose Escalation
RLY-2608+fulvestrant+PF-07220060 300 mg for HR+ HER2- locally advanced or metastatic breast cancer
EXPERIMENTALOral dose of RLY-2608 in addition to fulvestrant and PF-07220060 300 mg as determined during Part 1 Dose Escalation
Interventions
RLY-2608 is a mutant-selective, oral PI3Kα inhibitor.
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).
125mg palbociclib is taken orally once daily for 28-day cycles that include 21 days of treatment followed by 7 days off treatment.
400mg ribociclib is taken orally once daily for 28-day cycles that include 21 days of treatment followed by 7 days off treatment.
600mg ribociclib is taken orally once daily for 28-day cycles that include 21 days of treatment followed by 7 days off treatment.
PF-07220060 100 mg is taken orally twice daily at the same time with RLY-2608 during each 28-day cycle.
PF-07220060 300 mg is taken orally twice daily at the same time with RLY-2608 during each 28-day cycle.
Eligibility Criteria
You may qualify if:
- 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 \[Escalation\] - Ability to provide archived tumor tissue or be willing to undergo pretreatment tumor biopsy to assess PIK3CA status retrospectively Part 2 \[Expansion\] - Submit tumor tissue prior to study drug initiation for determination of PIK3CA mutation retrospectively.
- \[For Part 1: Escalation\]: Evaluable disease per RECIST v1.1
- \[For Part 2: Expansion\]: 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 In addition, the SRC (with Sponsor approval) may choose to open additional group(s) of 20 participants to study the clinical activity, safety, and PK/PD with other specified solid tumor types.
- Doublet combination arms \[Part 1 and Part 2\]: Evaluable disease per RECIST v1.1
- Triplet combination arms:
- \[Part 1 and Part 2 Dose Expansion, Group 1\]: Evaluable disease per RECIST.
- \[Part 2 Dose Expansion, Group 2\]: Measurable disease per RECIST. Bone-only lytic or lytic/blastic disease with at least 1 measurable soft-tissue component per RECIST may be eligible.
- \[For Part 1 and Part 2\]: 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- locally advanced or metastatic breast cancer that is not amenable to curative therapy and must have initiated treatment with a gonadotropin-releasing hormone (GnRH) agonist at least 4 weeks prior to start of study drug with continuation of GnRH agonist for the duration of study treatment (GnRH agonist recommended for males).
- +10 more criteria
You may not qualify if:
- Prior treatment with:
- PI3Kα, AKT, or mTOR inhibitors (all arms except for doublet RLY-2608 + fulvestrant arm, Part 2, Group 2; and triplet combinations, Part 1 dose escalation).
- Immune checkpoint inhibitors.
- Triplet combinations RLY-2608 + CDK4 or CDK4/6 inhibitor + fulvestrant, Part 2 expansion, Group 2 only:
- i. Prior systemic chemotherapy or antibody drug conjugate for locally advanced or metastatic disease. ii. Prior CDK2, CDK4, or CDK4/6 inhibitor as treatment for locally advanced or metastatic disease.
- iii. Prior treatment with fulvestrant or any selective ER degrader, with the exception of patients who have received fulvestrant or any selective ER degrader as part of neoadjuvant therapy only and with treatment duration ≤6 months.
- Type 1 or Type 2 diabetes requiring antihyperglycemic medication, or fasting plasma glucose ≥140 mg/dL and glycosylated hemoglobin (HbA1c) ≥7.0%.
- History of allergy or hypersensitivity to any components or excipients of PI3K inhibitors. For combination arms only: allergy or hypersensitivity to any components or excipients of fulvestrant, palbociclib, ribociclib, and/or PF-07220060 as appropriate for the combination.
- Past medical history of or ongoing ILD, or pneumonitis requiring intervention. Participants with past history of resolved Grade 1 pneumonitis may be considered, except in triple combination arms.
- The following cardiac criteria:
- Mean resting corrected QT interval (QTc) \>460 msec
- For triple combination arm with ribociclib: Mean QTcF ≥450 msec (this is what we confirmed is shown in the redacted version of the protocol.
- CNS metastases or primary CNS tumor that is associated with progressive neurologic symptoms
Contact the study team to confirm eligibility.
Sponsors & Collaborators
Study Sites (37)
The University of Arizona Cancer Center
Tucson, Arizona, 85724, United States
University of California-San Diego
San Diego, California, 90293, United States
HealthONE
Denver, Colorado, 80218, United States
Yale University
New Haven, Connecticut, 06510, United States
Florida Cancer Specialists
Orlando, Florida, 32827, United States
Boca Raton Clinical Research (BRCR) Global
Plantation, Florida, 33322, United States
University of Chicago Medical Center
Chicago, Illinois, 60637, United States
Community Health Network
Indianapolis, Indiana, 46250, United States
Massachusetts General Hospital
Boston, Massachusetts, 02114, United States
Dana-Farber Cancer Institute
Boston, Massachusetts, 02215, United States
University of Michigan
Ann Arbor, Michigan, 48109, United States
Washington University School of Medicine St. Louis
St Louis, Missouri, 63110, United States
Renown Regional Medical Center
Reno, Nevada, 89502, United States
Rutgers University
New Brunswick, New Jersey, 08901, United States
NYU Langone
New York, New York, 10016, United States
Columbia University Herbert Irving Comprehensive Cancer Center
New York, New York, 10032, United States
Memorial Sloan Kettering
New York, New York, 10065, United States
Tennessee Oncology
Nashville, Tennessee, 37203, United States
University of Texas Southwestern Medical Center
Dallas, Texas, 75235, United States
The University of Texas M.D. Anderson Cancer Center
Houston, Texas, 77030, United States
University of Utah- Huntsman Cancer Center
Salt Lake City, Utah, 84112, United States
Inova Schar Cancer Center
Fairfax, Virginia, 22031, United States
NEXT Virginia
Fairfax, Virginia, 22301, United States
UW Carbone Cancer Center
Madison, Wisconsin, 53792, United States
St Vincents Hospital
Sydney, New South Wales, 2019, Australia
Peter MacCallum Cancer Center
Melbourne, Victoria, 3000, Australia
The Alfred Hospital
Melbourne, Victoria, 3004, Australia
Centre Léon Bérard
Lyon, Auvergne-Rhône-Alpes, 69008, France
Institute Bergonié
Bordeaux, 33076, France
Gustave Roussy
Villejuif, 94805, France
Istituto Europeo di Oncologia IRCCS
Milan, 20141, Italy
Vall d'Hebron Instituto de Oncologia
Barcelona, Barcelona, 08035, Spain
START Barcelona
Barcelona, Catalonia, 08023, Spain
Instituto Valenciano de Oncologia
Valencia, Valencia, 46009, Spain
Institut Catala D'Oncologia - Badalona (ICO Badalona)
Barcelona, 08916, Spain
START Madrid - Hospital Fundacion Jimenez Diaz
Madrid, 28040, Spain
Hospital Universitario 12 de Octubre
Madrid, 28041, Spain
MeSH Terms
Conditions
Interventions
Condition Hierarchy (Ancestors)
Intervention Hierarchy (Ancestors)
Central Study Contacts
Study Design
- Study Type
- interventional
- Phase
- phase 1
- Allocation
- NON RANDOMIZED
- Masking
- NONE
- Purpose
- TREATMENT
- Intervention Model
- PARALLEL
- Sponsor Type
- INDUSTRY
- Responsible Party
- SPONSOR
Study Record Dates
First Submitted
December 20, 2021
First Posted
January 31, 2022
Study Start
December 8, 2021
Primary Completion (Estimated)
April 30, 2027
Study Completion (Estimated)
April 30, 2027
Last Updated
September 22, 2025
Record last verified: 2025-09
Data Sharing
- IPD Sharing
- Will not share