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Testing a new drug for advanced solid tumors and breast cancer with specific mutations

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

Phase 1 Interventional Relay Therapeutics, Inc. · NCT05216432

This study is testing a new drug called RLY-2608 to see if it can help people with advanced solid tumors and breast cancer that have specific mutations.

Quick facts

PhasePhase 1
Study typeInterventional
Enrollment930 (estimated)
Ages18 Years and up
SexAll
SponsorRelay Therapeutics, Inc. Industry-sponsored
Drugs / interventionschemotherapy
Locations37 sites (Tucson, Arizona and 36 other locations)
Trial IDNCT05216432 on ClinicalTrials.gov

What this trial studies

This open-label, first-in-human study evaluates the safety, tolerability, and preliminary effectiveness of RLY-2608, a mutant-selective PI3Kα inhibitor, in patients with advanced solid tumors harboring PIK3CA mutations. The study consists of two parts: a dose escalation phase and a dose expansion phase, assessing RLY-2608 as a single agent and in combination with fulvestrant and CDK4/6 inhibitors for patients with advanced breast cancer. Participants will undergo assessments to determine the maximum tolerated dose and pharmacokinetics of the drug.

Who should consider this trial

Good fit: Ideal candidates include adults with unresectable or metastatic solid tumors and documented PIK3CA mutations.

Not a fit: Patients without PIK3CA mutations or those with tumors that are not advanced or metastatic may not benefit from this study.

Why it matters

Potential benefit: If successful, this study could provide a targeted treatment option for patients with specific mutations in advanced solid tumors and breast cancer.

How similar studies have performed: Other studies targeting PIK3CA mutations have shown promise, indicating potential for success with this approach.

Eligibility criteria

Show full inclusion / exclusion 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 \[Escalation\] - 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

Key Exclusion Criteria

Prior treatment with:

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

Where this trial is running

Tucson, Arizona and 36 other locations

Study contacts

How to participate

  1. Review the eligibility criteria above with your treating physician.
  2. Visit the official trial page on ClinicalTrials.gov for the most current contact information and recruitment status.
  3. Contact the listed study coordinator or principal investigator to request pre-screening. Pre-screening is free and never obligates you to enroll.
View on ClinicalTrials.gov → Find more trials like this →
Conditions PIK3CA MutationSolid Tumor, AdultHER2-negative Breast CancerBreast CancerMetastatic Breast CancerAdvanced Breast CancerUnresectable Solid Tumor
Last reviewed 2026-06-13 by the Find a Trial editorial team. Information on this page is for educational purposes and is not medical advice. Always consult qualified healthcare professionals about clinical trial participation.