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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

ConditionsPIK3CA MutationSolid Tumor, AdultHER2-negative Breast CancerBreast CancerMetastatic Breast CancerAdvanced Breast CancerUnresectable Solid Tumor
Trial statusRecruiting
Trial phasePhase 1
Trial typeInterventional
Biological sexAll
Age18+
SponsorRelay Therapeutics, Inc.

About this trial

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).

Eligibility criteria

This trial does not accept healthy volunteers

Qualifiers

[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

Disqualifiers

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.

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.

Trial design

Design model

Parallel

Treatments tested in this trial

  • RLY-2608

    Drug

    RLY-2608 is a mutant-selective, oral PI3Kα inhibitor.

  • Fulvestrant

    Drug

    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

    Drug

    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

    Drug

    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

    Drug

    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

    Drug

    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

    Drug

    PF-07220060 300 mg is taken orally twice daily at the same time with RLY-2608 during each 28-day cycle.

Treatment groups

930 Participants
are divided into 7 treatment groups

7

Treatment groups

See each treatment group below.

Group A: RLY-2608 for patients with unresectable or metastatic solid tumorsExperimental treatment 1 intervention
Group B: RLY-2608 + fulvestrant combination for HR+ HER2- locally advanced or metastatic breast cancerExperimental treatment 2 interventions
Group C: RLY-2608+fulvestrant+palbo125mg for HR+HER2- locally advanced metastatic breast cancerExperimental treatment 3 interventions
Group D: RLY-2608+fulvestrant+ribo400mg for HR+HER2- locally advanced metastatic breast cancerExperimental treatment 3 interventions
Group E: RLY-2608+fulvestrant+ribo600mg for HR+HER2- locally advanced metastatic breast cancerExperimental treatment 3 interventions
Group F: RLY-2608+fulvestrant+PF-07220060 100 mg for HR+ HER2- locally advanced or metastatic breast cancerExperimental treatment 3 interventions
Group G: RLY-2608+fulvestrant+PF-07220060 300 mg for HR+ HER2- locally advanced or metastatic breast cancerExperimental treatment 3 interventions

Trial outcomes

Primary outcomes

1

Determination of maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D) of RLY-2608 as a single agent

Time frame
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
2

Determination of maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D) of RLY-2608 in combination with fulvestrant

Time frame
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
3

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

Time frame
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
4

Number of patients with adverse events and serious adverse events of RLY-2608 as a single agent

Time frame
Every cycle (4-week cycles) until study discontinuation, approximately 24 months

Secondary outcomes

1

PIK3CA gene status in plasma circulating tumor deoxyribonucleic acid (ctDNA) and tumor tissue

Time frame
Day 1 of Cycle 1 (each cycle is 28 days)
2

Pharmacokinetic parameters including maximum plasma drug concentration (Cmax) of RLY-2608 (and its metabolites, as appropriate) as single agent

Time frame
Approximately every 2 weeks in Cycle 1 (4-week cycle) and every cycle through end of treatment, approximately 24 months
3

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

Time frame
Approximately every 2 weeks in Cycle 1 (4-week cycle) and every cycle through end of treatment, approximately 24 months
4

Pharmacokinetic parameters including half-life (t1/2) of RLY-2608 (and its metabolites, as appropriate) as single agent

Time frame
Approximately every 2 weeks in Cycle 1 (4-week cycle) and every cycle through end of treatment, approximately 24 months

Other outcomes

Sponsors and contacts

Click on the lead sponsor to view all of their trials.

Relay Therapeutics, Inc.

Lead sponsor

Source ClinicalTrials.gov
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