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

Purpose

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).

Conditions

  • PIK3CA Mutation
  • Solid Tumor, Adult
  • HER2-negative Breast Cancer
  • Breast Cancer
  • Metastatic Breast Cancer
  • Advanced Breast Cancer
  • Unresectable Solid Tumor

Eligibility

Eligible Ages
Over 18 Years
Eligible Genders
All
Accepts Healthy Volunteers
No

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 - 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 advanced or metastatic breast cancer with: 1. ≤1 line of chemotherapy, 2. ≥1 cyclin-dependent kinases (CDK) 4/6 inhibitor, and 3. ≥1 antiestrogen therapy 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 is not to be included in enumeration or previous treatment [For RLY-2608 + fulvestrant arm; Part 2, Group 2]: Received prior treatment with a PI3Kα 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.

Exclusion Criteria

Prior treatment with PI3Kα, 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

Study Design

Phase
Phase 1
Study Type
Interventional
Allocation
Non-Randomized
Intervention Model
Parallel Assignment
Intervention Model Description
Single Agent Arm: 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- 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- advanced or metastatic breast cancer with PIK3CA mutation per local assessment Part 2 (RP2D determined in Part 1) Patients with HR+, HER2- advanced or metastatic breast cancer with PIK3CA mutation per local assessment will be enrolled protocol defined groups
Primary Purpose
Treatment
Masking
None (Open Label)

Arm Groups

ArmDescriptionAssigned Intervention
Experimental
RLY-2608 for patients with unresectable or metastatic solid tumors
Multiple doses of RLY-2608 for oral administration.
  • Drug: RLY-2608
    RLY-2608 is a mutant-selective, oral PI3Kα inhibitor.
Experimental
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.
  • Drug: RLY-2608
    RLY-2608 is a mutant-selective, oral PI3Kα inhibitor.
  • Drug: 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).
    Other names:
    • Faslodex
Experimental
RLY-2608+fulvestrant+palbociclib 125 mg for HR+ HER2- locally advanced or metastatic breast cancer
Oral dose of RLY-2608 in addition to fulvestrant and palbociclib 125mg as determined during Part 1 Dose Escalation.
  • Drug: RLY-2608
    RLY-2608 is a mutant-selective, oral PI3Kα inhibitor.
  • Drug: 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).
    Other names:
    • Faslodex
  • Drug: 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.
    Other names:
    • Ibrance
Experimental
RLY-2608+fulvestrant+ribociclib 400 mg for HR+ HER2- locally advanced or metastatic breast cancer
Oral dose of RLY-2608 in addition to fulvestrant and ribociclib 400mg as determined during Part 1 Dose Escalation.
  • Drug: RLY-2608
    RLY-2608 is a mutant-selective, oral PI3Kα inhibitor.
  • Drug: 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).
    Other names:
    • Faslodex
  • Drug: 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.
Experimental
RLY-2608+fulvestrant+ribociclib 600 mg for HR+ HER2- locally advanced or metastatic breast cancer
Oral dose of RLY-2608 in addition to fulvestrant and ribociclib 600mg as determined during Part 1 Dose Escalation.
  • Drug: RLY-2608
    RLY-2608 is a mutant-selective, oral PI3Kα inhibitor.
  • Drug: 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).
    Other names:
    • Faslodex
  • Drug: 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.
    Other names:
    • Kisqali

Recruiting Locations

Massachusetts General Hospital
Boston, Massachusetts 02114

More Details

Status
Recruiting
Sponsor
Relay Therapeutics, Inc.

Study Contact

Relay Therapeutics Inc
617-322-0731
ClinicalTrials@relaytx.com