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

Required: PIK3CA primary oncogenic mutation

One or more documented primary oncogenic PIK3CA mutation(s) in blood and/or tumor per local assessment

Allowed: PIK3CA potentially oncogenic mutation (Sponsor approval required)

Other potentially oncogenic PIK3CA mutations may be considered but must be approved by the Sponsor prior to enrollment.

Must have received: CDK4/6 inhibitor — adjuvant and/or metastatic

≥1 CDK4/6 inhibitor in either the adjuvant and/or metastatic setting

Must have received: antiestrogen therapy (selective estrogen-receptor degraders, selective estrogen receptor modulators, aromatase inhibitors, letrozole, anastrozole, exemestane, tamoxifen, fulvestrant) — adjuvant and/or metastatic

≥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)

Must have received: PARP inhibitor — adjuvant and/or metastatic

≥1 PARP inhibitor, if appropriate, if documented germline BRCA1/2 mutation

Cannot have received: PI3K inhibitor

Exception: Allowed for doublet RLY-2608 + fulvestrant arm, Part 2, Group 2; and triplet combinations, Part 1 dose escalation

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).

Cannot have received: AKT inhibitor

Exception: Allowed for doublet RLY-2608 + fulvestrant arm, Part 2, Group 2; and triplet combinations, Part 1 dose escalation

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).

Cannot have received: mTOR inhibitor

Exception: Allowed for doublet RLY-2608 + fulvestrant arm, Part 2, Group 2; and triplet combinations, Part 1 dose escalation

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).

Cannot have received: immune checkpoint inhibitor

Prior treatment with: Immune checkpoint inhibitors.

Cannot have received: systemic chemotherapy

Exception: Triplet combinations RLY-2608 + CDK4 or CDK4/6 inhibitor + fulvestrant, Part 2 expansion, Group 2 only

Prior systemic chemotherapy or antibody drug conjugate for locally advanced or metastatic disease.

Cannot have received: antibody-drug conjugate

Exception: Triplet combinations RLY-2608 + CDK4 or CDK4/6 inhibitor + fulvestrant, Part 2 expansion, Group 2 only

Prior systemic chemotherapy or antibody drug conjugate for locally advanced or metastatic disease.

Cannot have received: CDK2 inhibitor

Exception: Triplet combinations RLY-2608 + CDK4 or CDK4/6 inhibitor + fulvestrant, Part 2 expansion, Group 2 only

Prior CDK2, CDK4, or CDK4/6 inhibitor as treatment for locally advanced or metastatic disease.

Cannot have received: CDK4 inhibitor

Exception: Triplet combinations RLY-2608 + CDK4 or CDK4/6 inhibitor + fulvestrant, Part 2 expansion, Group 2 only

Prior CDK2, CDK4, or CDK4/6 inhibitor as treatment for locally advanced or metastatic disease.

Cannot have received: CDK4/6 inhibitor

Exception: Triplet combinations RLY-2608 + CDK4 or CDK4/6 inhibitor + fulvestrant, Part 2 expansion, Group 2 only

Prior CDK2, CDK4, or CDK4/6 inhibitor as treatment for locally advanced or metastatic disease.

Cannot have received: selective estrogen receptor degrader (fulvestrant)

Exception: Exception: patients who have received fulvestrant or any selective ER degrader as part of neoadjuvant therapy only and with treatment duration ≤6 months.

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.