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
NCT ID: NCT05216432
Last Updated: 2025-09-22
Study Results
The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.
Basic Information
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RECRUITING
PHASE1
930 participants
INTERVENTIONAL
2021-12-08
2027-04-30
Brief Summary
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Detailed Description
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Conditions
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Study Design
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NON_RANDOMIZED
PARALLEL
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- locally 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- locally advanced or metastatic breast cancer with PIK3CA mutation per local assessment
Part 2 (RP2D determined in Part 1) Patients with HR+, HER2-locally advanced or metastatic breast cancer with PIK3CA mutation per local assessment will be enrolled in protocol defined groups
TREATMENT
NONE
Study Groups
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RLY-2608 for patients with unresectable or metastatic solid tumors
Multiple doses of RLY-2608 for oral administration.
RLY-2608
RLY-2608 is a mutant-selective, oral PI3Kα inhibitor.
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.
RLY-2608
RLY-2608 is a mutant-selective, oral PI3Kα 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).
RLY-2608+fulvestrant+palbo125mg for HR+HER2- locally advanced metastatic breast cancer
Oral dose of RLY-2608 in addition to fulvestrant and palbociclib 125mg as determined during Part 1 Dose Escalation.
RLY-2608
RLY-2608 is a mutant-selective, oral PI3Kα 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.
RLY-2608+fulvestrant+ribo400mg for HR+HER2- locally advanced metastatic breast cancer
Oral dose of RLY-2608 in addition to fulvestrant and ribociclib 400mg as determined during Part 1 Dose Escalation.
RLY-2608
RLY-2608 is a mutant-selective, oral PI3Kα 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).
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.
RLY-2608+fulvestrant+ribo600mg for HR+HER2- locally advanced metastatic breast cancer
Oral dose of RLY-2608 in addition to fulvestrant and ribociclib 600mg as determined during Part 1 Dose Escalation.
RLY-2608
RLY-2608 is a mutant-selective, oral PI3Kα 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).
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.
RLY-2608+fulvestrant+PF-07220060 100 mg for HR+ HER2- locally advanced or metastatic breast cancer
Oral dose of RLY-2608 in addition to fulvestrant and PF-07220060 100 mg as determined during Part 1 Dose Escalation
RLY-2608
RLY-2608 is a mutant-selective, oral PI3Kα 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).
PF-07220060 100mg
PF-07220060 100 mg is taken orally twice daily at the same time with RLY-2608 during each 28-day cycle.
RLY-2608+fulvestrant+PF-07220060 300 mg for HR+ HER2- locally advanced or metastatic breast cancer
Oral dose of RLY-2608 in addition to fulvestrant and PF-07220060 300 mg as determined during Part 1 Dose Escalation
RLY-2608
RLY-2608 is a mutant-selective, oral PI3Kα 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).
PF-07220060 300 mg
PF-07220060 300 mg is taken orally twice daily at the same time with RLY-2608 during each 28-day cycle.
Interventions
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RLY-2608
RLY-2608 is a mutant-selective, oral PI3Kα 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.
PF-07220060 100mg
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
PF-07220060 300 mg is taken orally twice daily at the same time with RLY-2608 during each 28-day cycle.
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
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.
Key Inclusion for RLY-2608 Single Agent Arm
* \[For Part 1: Escalation\]: 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.
Key Inclusion for Combination Arms:
* 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).
* Had previous treatment for breast cancer with: \[Does not apply to triplet combination arms, Part 2 Dose Expansion, Group 2\]:
1. ≤1 line of chemotherapy in the metastatic setting
2. ≥1 CDK4/6 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
\[For double combination arm; Part 2 Dose Expansion, Group 2\]: Received prior treatment with a PI3Kα, AKT, or mTOR 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.
\[For triple combination arms; Part 1 dose escalation\]: Participants who had previous treatment for breast cancer with PI3Kα, AKT, mTOR inhibitors and discontiuned due to participant/physician decision, intolerance, or disease progression will be considered.
\[For triple combination arms, Part 2 Dose Expansion, Group 2\]: Participants must be intolerant to or have declined standard therapy for locally advanced or metastatic HR+/HER2- PIK3CA-mutated breast cancer. Prior endocrine therapy and CDK4/6inhibitors are allowed as follows:
1. Participants must have progressed during (neo)adjuvant endocrine therapy or within12 months of completing (neo)adjuvant endocrine therapy with an AI or tamoxifen.
2. If a CDK4/6 inhibitor was included as part of (neo)adjuvant therapy, disease must have recurred/progressed \>12 months after completion of the CDK4/6 inhibitor portion of (neo)adjuvant therapy
Exclusion Criteria
1. 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).
2. Immune checkpoint inhibitors.
3. 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
18 Years
ALL
No
Sponsors
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Relay Therapeutics, Inc.
INDUSTRY
Responsible Party
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Locations
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The University of Arizona Cancer Center
Tucson, Arizona, United States
University of California-San Diego
San Diego, California, United States
HealthONE
Denver, Colorado, United States
Yale University
New Haven, Connecticut, United States
Florida Cancer Specialists
Orlando, Florida, United States
Boca Raton Clinical Research (BRCR) Global
Plantation, Florida, United States
University of Chicago Medical Center
Chicago, Illinois, United States
Community Health Network
Indianapolis, Indiana, United States
Massachusetts General Hospital
Boston, Massachusetts, United States
Dana-Farber Cancer Institute
Boston, Massachusetts, United States
University of Michigan
Ann Arbor, Michigan, United States
Washington University School of Medicine St. Louis
St Louis, Missouri, United States
Renown Regional Medical Center
Reno, Nevada, United States
Rutgers University
New Brunswick, New Jersey, United States
NYU Langone
New York, New York, United States
Columbia University Herbert Irving Comprehensive Cancer Center
New York, New York, United States
Memorial Sloan Kettering
New York, New York, United States
Tennessee Oncology
Nashville, Tennessee, United States
University of Texas Southwestern Medical Center
Dallas, Texas, United States
The University of Texas M.D. Anderson Cancer Center
Houston, Texas, United States
University of Utah- Huntsman Cancer Center
Salt Lake City, Utah, United States
Inova Schar Cancer Center
Fairfax, Virginia, United States
NEXT Virginia
Fairfax, Virginia, United States
UW Carbone Cancer Center
Madison, Wisconsin, United States
St Vincents Hospital
Sydney, New South Wales, Australia
Peter MacCallum Cancer Center
Melbourne, Victoria, Australia
The Alfred Hospital
Melbourne, Victoria, Australia
Centre Léon Bérard
Lyon, Auvergne-Rhône-Alpes, France
Institute Bergonié
Bordeaux, , France
Gustave Roussy
Villejuif, , France
Istituto Europeo di Oncologia IRCCS
Milan, , Italy
Vall d'Hebron Instituto de Oncologia
Barcelona, Barcelona, Spain
START Barcelona
Barcelona, Catalonia, Spain
Instituto Valenciano de Oncologia
Valencia, Valencia, Spain
Institut Catala D'Oncologia - Badalona (ICO Badalona)
Barcelona, , Spain
START Madrid - Hospital Fundacion Jimenez Diaz
Madrid, , Spain
Hospital Universitario 12 de Octubre
Madrid, , Spain
Countries
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Central Contacts
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Other Identifiers
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RLY-2608-101
Identifier Type: -
Identifier Source: org_study_id
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