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

Study Overview
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Brief Summary
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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).

Official Title
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A 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

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

Intervention / Treatment
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* Drug: RLY-2608
* Drug: Fulvestrant
* Drug: Palbociclib 125mg
* Drug: Ribociclib 400mg
* Drug: Ribociclib 600mg


Participation Criteria
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Eligibility Criteria
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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 - 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 line of chemotherapy, ≥1 cyclin-dependent kinases (CDK) 4/6 inhibitor, and ≥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 ≥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. Key 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Interventional 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
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: RLY-2608 for patients with unresectable or metastatic solid tumors<br>Multiple doses of RLY-2608 for oral administration. | Drug: RLY-2608<br>* RLY-2608 is a mutant-selective, oral PI3Kα inhibitor.<br>|
| Experimental: RLY-2608 + fulvestrant combination for HR+ HER2- locally advanced or metastatic breast cancer<br>Oral dose of RLY-2608 in addition to fulvestrant as determined during Part 1 Dose Escalation. | Drug: RLY-2608<br>* RLY-2608 is a mutant-selective, oral PI3Kα inhibitor.<br>Drug: Fulvestrant<br>* 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).<br>* Other names: Faslodex;|
| Experimental: RLY-2608+fulvestrant+palbociclib 125 mg for HR+ HER2- locally advanced or metastatic breast cancer<br>Oral dose of RLY-2608 in addition to fulvestrant and palbociclib 125mg as determined during Part 1 Dose Escalation. | Drug: RLY-2608<br>* RLY-2608 is a mutant-selective, oral PI3Kα inhibitor.<br>Drug: Fulvestrant<br>* 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).<br>* Other names: Faslodex;Drug: Palbociclib 125mg<br>* 125mg palbociclib is taken orally once daily for 28-day cycles that include 21 days of treatment followed by 7 days off treatment.<br>* Other names: Ibrance;|
| Experimental: RLY-2608+fulvestrant+ribociclib 400 mg for HR+ HER2- locally advanced or metastatic breast cancer<br>Oral dose of RLY-2608 in addition to fulvestrant and ribociclib 400mg as determined during Part 1 Dose Escalation. | Drug: RLY-2608<br>* RLY-2608 is a mutant-selective, oral PI3Kα inhibitor.<br>Drug: Fulvestrant<br>* 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).<br>* Other names: Faslodex;Drug: Ribociclib 400mg<br>* 400mg ribociclib is taken orally once daily for 28-day cycles that include 21 days of treatment followed by 7 days off treatment.<br>|
| Experimental: RLY-2608+fulvestrant+ribociclib 600 mg for HR+ HER2- locally advanced or metastatic breast cancer<br>Oral dose of RLY-2608 in addition to fulvestrant and ribociclib 600mg as determined during Part 1 Dose Escalation. | Drug: RLY-2608<br>* RLY-2608 is a mutant-selective, oral PI3Kα inhibitor.<br>Drug: Fulvestrant<br>* 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).<br>* Other names: Faslodex;Drug: Ribociclib 600mg<br>* 600mg ribociclib is taken orally once daily for 28-day cycles that include 21 days of treatment followed by 7 days off treatment.<br>* Other names: Kisqali;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determination of maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) of RLY-2608 as a single agent |  | 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 | 
| Determination of maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) of RLY-2608 in combination with fulvestrant |  | 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 | 
| Determination of maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) of RLY-2608 in combination with fulvestrant and a CDK 4/6 inhibitor (palbociclib, ribociclib) |  | 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 | 
| Number of patients with adverse events and serious adverse events of RLY-2608 as a single agent |  | Every cycle (4-week cycles) until study discontinuation, approximately 24 months | 
| Number of patients with adverse events and serious adverse events of RLY-2608 in combination with fulvestrant |  | Every cycle (4-week cycles) until study discontinuation, approximately 24 months | 
| Number of patients with adverse events and serious adverse events of RLY-2608 in combination with fulvestrant and a CDK 4/6 inhibitor (palbociclib, ribociclib) |  | Every cycle (4-week cycles) until study discontinuation, approximately 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in circulating blood of C-peptide in RLY-2608 as a single agent |  | Approximately every week in Cycle 1 (4-week cycle), every two weeks in Cycle 2 (4-week cycle), and every cycle starting with Cycle 3 through end of treatment, approx 24 months | 
| Changes in circulating blood of HbA1c in RLY-2608 as a single agent |  | Once in Cycle 2 (4-week cycle) and then once every 3rd cycle beginning with Cycle 5 through end of treatment, approximately 24 months | 
| Changes in circulating blood of fasting glucose in RLY-2608 in combination with fulvestrant |  | Approximately every week in Cycle 1 (4-week cycle), every two weeks in Cycle 2 (4-week cycle), and every cycle starting with Cycle 3 through end of treatment, approx 24 months | 
| Changes in circulating blood of insulin in RLY-2608 in combination with fulvestrant |  | Approximately every week in Cycle 1 (4-week cycle), every two weeks in Cycle 2 (4-week cycle), and every cycle starting with Cycle 3 through end of treatment, approx 24 months | 
| Changes in circulating blood of C-peptide in RLY-2608 in combination with fulvestrant |  | Approximately every week in Cycle 1 (4-week cycle), every two weeks in Cycle 2 (4-week cycle), and every cycle starting with Cycle 3 through end of treatment, approx 24 months | 
| Changes in circulating blood of HbA1c in RLY-2608 in combination with fulvestrant |  | Once in Cycle 2 (4-week cycle) and then once every 3rd cycle beginning with Cycle 5 through end of treatment, approximately 24 months | 
| Changes in circulating blood of fasting glucose in RLY-2608 in combination with fulvestrant and a CDK4/6 inhibitor (palbociclib, ribociclib) |  | Approximately every week in Cycle 1 (4-week cycle), every two weeks in Cycle 2 (4-week cycle), and every cycle starting with Cycle 3 through end of treatment, approx 24 months | 
| Changes in circulating blood of insulin in RLY-2608 in combination with fulvestrant and a CDK4/6 inhibitor (palbociclib, ribociclib) |  | Approximately every week in Cycle 1 (4-week cycle), every two weeks in Cycle 2 (4-week cycle), and every cycle starting with Cycle 3 through end of treatment, approx 24 months | 
| Changes in circulating blood of C-peptide in RLY-2608 in combination with fulvestrant and a CDK4/6 inhibitor (palbociclib, ribociclib) |  | Approximately every week in Cycle 1 (4-week cycle), every two weeks in Cycle 2 (4-week cycle), and every cycle starting with Cycle 3 through end of treatment, approx 24 months | 
| Changes in circulating blood of HbA1c in RLY-2608 in combination with fulvestrant and a CDK4/6 inhibitor (palbociclib, ribociclib) |  | Once in Cycle 2 (4-week cycle) and then once every 3rd cycle beginning with Cycle 5 through end of treatment, approximately 24 months | 
| Objective response rate (ORR) as assessed by RECIST v1.1 |  | Approximately every 8 weeks during treatment and every 12 weeks after the last dose in the absence of progressive disease, approximately 36 months | 
| Duration of Response (DOR) as assessed by RECIST v1.1 |  | Approximately every 8 weeks during treatment and every 12 weeks after the last dose in the absence of progressive disease, approximately 36 months | 
| Disease Control Rate (DCR) as assessed by RECIST v1.1 |  | Approximately every 8 weeks during treatment and every 12 weeks after the last dose in the absence of progressive disease, approximately 36 months | 
| Quality of Life as assessed by the European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC QLQ-C30) |  | Once every cycle (4-week cycles) through end of treatment, approximately 24 months | 
| Changes in circulating blood of insulin in RLY-2608 as a single agent |  | Approximately every week in Cycle 1 (4-week cycle), every two weeks in Cycle 2 (4-week cycle), and every cycle starting with Cycle 3 through end of treatment, approx 24 months | 
| PIK3CA gene status in plasma circulating tumor deoxyribonucleic acid (ctDNA) and tumor tissue |  | Day 1 of Cycle 1 (each cycle is 28 days) | 
| Pharmacokinetic parameters including maximum plasma drug concentration (Cmax) of RLY-2608 (and its metabolites, as appropriate) as single agent |  | Approximately every 2 weeks in Cycle 1 (4-week cycle) and every cycle through end of treatment, approximately 24 months | 
| 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 |  | Approximately every 2 weeks in Cycle 1 (4-week cycle) and every cycle through end of treatment, approximately 24 months | 
| Pharmacokinetic parameters including half-life (t1/2) of RLY-2608 (and its metabolites, as appropriate) as single agent |  | Approximately every 2 weeks in Cycle 1 (4-week cycle) and every cycle through end of treatment, approximately 24 months | 
| Pharmacokinetic parameters including maximum plasma drug concentration (Cmax) of RLY-2608 (and its metabolites, as appropriate) when RLY-2608 is administered in combination with fulvestrant |  | Approximately every 2 weeks in Cycle 1 (4-week cycle) and every cycle through end of treatment, approximately 24 months | 
| 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) when RLY-2608 is administered in combination with fulvestrant |  | Approximately every 2 weeks in Cycle 1 (4-week cycle) and every cycle through end of treatment, approximately 24 months | 
| Pharmacokinetic parameters including half-life (t1/2) of RLY-2608 (and its metabolites, as appropriate) when RLY-2608 is administered in combination with fulvestrant |  | Approximately every 2 weeks in Cycle 1 (4-week cycle) and every cycle through end of treatment, approximately 24 months | 
| Pharmacokinetic parameters including maximum plasma drug concentration (Cmax) of RLY-2608 (and its metabolites, as appropriate) when RLY-2608 is administered in combination with fulvestrant and a CDK4/6 inhibitor (palbociclib, ribociclib) |  | Approximately every 2 weeks in Cycle 1 (4-week cycle) and every cycle through end of treatment, approximately 24 months | 
| Pharmacokinetic parameters including area under the plasma concentration vs time curve of RLY-2608 (and its metabolites, as appropriate) administered with fulvestrant and CDK4/6 inhibitor (palbocicclib, ribociclib) |  | Approximately every 2 weeks in Cycle 1 (4-week cycle) and every cycle through end of treatment, approximately 24 months | 
| Pharmacokinetic parameters including half-life (t1/2) of RLY-2608 (and its metabolites, as appropriate) when RLY-2608 is administered in combination with fulvestrant and a CDK4/6 inhibitor (palbociclib, ribociclib) |  | Approximately every 2 weeks in Cycle 1 (4-week cycle) and every cycle through end of treatment, approximately 24 months | 
| Changes in circulating blood of fasting glucose in RLY-2608 as a single agent |  | Approximately every week in Cycle 1 (4-week cycle), every two weeks in Cycle 2 (4-week cycle), and every cycle starting with Cycle 3 through end of treatment, approx 24 months |