Clinical trial NCT05216432: 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
Official title: 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
Conditions: PIK3CA Mutation
Solid Tumor, Adult
HER2-negative Breast Cancer
Breast Cancer
Metastatic Breast Cancer
Advanced Breast Cancer
Unresectable Solid Tumor
Endometrial Cancer
Lead sponsor: Relay Therapeutics, Inc.
Sponsor class: INDUSTRY
First posted: 2022-01-31
Enrollment: 890
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
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, and endometrial cancer 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

Brief summary: 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 or endometrial cancer (palbociclib or ribociclib Part 1). 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: 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 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 in other specified solid tumor types.

Key Inclusion for Combination Arms

* \[For Part 1 and Part 2\]: Evaluable disease per RECIST v1.1
* \[For Part 1 and Part 2\]: 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- 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 breast cancer with:

  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

\[For RLY-2608 + fulvestrant arm; Part 2, Group 2\]: Received prior treatment with a PI3Kα or AKT 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.

\[For triple combination arms; Part 1 only\]: Participants who had previous treatment for breast cancer with PI3Kα or AKT inhibitors will be considered.

\[For triple combination arms with ribociclib or palbociclib; Part 1 only\]: endometrial cancer may be enrolled.

Key Exclusion Criteria

Prior treatment with PI3Kα, AKT, or mTOR inhibitors (except for RLY-2608 + fulvestrant arm, Part 2, Group 2; and triplet combinations, Part 1).

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, 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.

Any of the following cardiac criteria:

* Mean resting corrected QT interval (QTc) \>470 msec. For triple combination arm 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

Primary outcomes:
measure: Determination of maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D) of RLY-2608 as a single agent
timeFrame: 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
measure: Determination of maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D) of RLY-2608 in combination with fulvestrant
timeFrame: 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
measure: 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
timeFrame: 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
measure: Number of patients with adverse events and serious adverse events of RLY-2608 as a single agent
timeFrame: Every cycle (4-week cycles) until study discontinuation, approximately 24 months
measure: Number of patients with adverse events and serious adverse events of RLY-2608 in combination with fulvestrant
timeFrame: Every cycle (4-week cycles) until study discontinuation, approximately 24 months
measure: 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), and in combination with CDK4 inhibitor (PF-07220060) and fulvestrant
timeFrame: Every cycle (4-week cycles) until study discontinuation, approximately 24 months
Secondary outcomes:
measure: PIK3CA gene status in plasma circulating tumor deoxyribonucleic acid (ctDNA) and tumor tissue
timeFrame: Day 1 of Cycle 1 (each cycle is 28 days)
measure: Pharmacokinetic parameters including maximum plasma drug concentration (Cmax) of RLY-2608 (and its metabolites, as appropriate) as single agent
timeFrame: Approximately every 2 weeks in Cycle 1 (4-week cycle) and every cycle through end of treatment, approximately 24 months
measure: 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
timeFrame: Approximately every 2 weeks in Cycle 1 (4-week cycle) and every cycle through end of treatment, approximately 24 months
measure: Pharmacokinetic parameters including half-life (t1/2) of RLY-2608 (and its metabolites, as appropriate) as single agent
timeFrame: Approximately every 2 weeks in Cycle 1 (4-week cycle) and every cycle through end of treatment, approximately 24 months
measure: 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
timeFrame: Approximately every 2 weeks in Cycle 1 (4-week cycle) and every cycle through end of treatment, approximately 24 months
measure: 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
timeFrame: Approximately every 2 weeks in Cycle 1 (4-week cycle) and every cycle through end of treatment, approximately 24 months
measure: Pharmacokinetic parameters including half-life (t1/2) of RLY-2608 (and its metabolites, as appropriate) when RLY-2608 is administered in combination with fulvestrant
timeFrame: Approximately every 2 weeks in Cycle 1 (4-week cycle) and every cycle through end of treatment, approximately 24 months
measure: PK parameters including maximum plasma drug concentration (Cmax) of RLY-2608 (and its metabolites, as appropriate) when RLY-2608 is administered in combination with fulvestrant + palbociclib or ribociclib. And in combination (PF-07220060) +fulvestrant
timeFrame: Approximately every 2 weeks in Cycle 1 (4-week cycle) and every cycle through end of treatment, approximately 24 months
measure: Pharmacokinetic parameters including area under the plasma concentration vs time curve of RLY-2608 (and its metabolites, as appropriate) administered with fulvestrant + palbociclib or ribociclib, and in combination with PF-07220060 +fulvestrant
timeFrame: Approximately every 2 weeks in Cycle 1 (4-week cycle) and every cycle through end of treatment, approximately 24 months
measure: Pharmacokinetic parameters including half-life (t1/2) of RLY-2608 (and its metabolites, as appropriate) when RLY-2608 is administered in combination with fulvestrant + palbociclib or ribociclib, and in combination with PF-07220060 +fulvestrant
timeFrame: Approximately every 2 weeks in Cycle 1 (4-week cycle) and every cycle through end of treatment, approximately 24 months
measure: Changes in circulating blood of fasting glucose in RLY-2608 as a single agent
timeFrame: 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
measure: Changes in circulating blood of insulin in RLY-2608 as a single agent
timeFrame: 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
measure: Changes in circulating blood of C-peptide in RLY-2608 as a single agent
timeFrame: 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
measure: Changes in circulating blood of HbA1c in RLY-2608 as a single agent
timeFrame: Once in Cycle 2 (4-week cycle) and then once every 3rd cycle beginning with Cycle 5 through end of treatment, approximately 24 months
measure: Changes in circulating blood of fasting glucose in RLY-2608 in combination with fulvestrant
timeFrame: 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
measure: Changes in circulating blood of insulin in RLY-2608 in combination with fulvestrant
timeFrame: 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
measure: Changes in circulating blood of C-peptide in RLY-2608 in combination with fulvestrant
timeFrame: 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
measure: Changes in circulating blood of HbA1c in RLY-2608 in combination with fulvestrant
timeFrame: Once in Cycle 2 (4-week cycle) and then once every 3rd cycle beginning with Cycle 5 through end of treatment, approximately 24 months
measure: Changes in circulating blood of fasting glucose in RLY-2608 in combination with fulvestrant and a CDK4/6 inhibitor (palbociclib, ribociclib) and in combination with CDK4 inhibitor (PF-07220060) and fulvestrant
timeFrame: 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
measure: Changes in circulating blood of insulin in RLY-2608 in combination with fulvestrant and a CDK4/6 inhibitor (palbociclib, ribociclib), and in combination with CDK4 inhibitor (PF-07220060) and fulvestrant
timeFrame: 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
measure: Changes in circulating blood of C-peptide in RLY-2608 in combination with fulvestrant and a CDK4/6 inhibitor (palbociclib, ribociclib), and in combination with CDK4 inhibitor (PF-07220060) and fulvestrant
timeFrame: 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
measure: Changes in circulating blood of HbA1c in RLY-2608 in combination with fulvestrant and a CDK4/6 inhibitor (palbociclib, ribociclib), and in combination with CDK4 inhibitor (PF-07220060) and fulvestrant
timeFrame: Once in Cycle 2 (4-week cycle) and then once every 3rd cycle beginning with Cycle 5 through end of treatment, approximately 24 months
measure: Objective response rate (ORR) as assessed by RECIST v1.1
timeFrame: Approximately every 8 weeks during treatment and every 12 weeks after the last dose in the absence of progressive disease, approximately 36 months
measure: Duration of Response (DOR) as assessed by RECIST v1.1
timeFrame: Approximately every 8 weeks during treatment and every 12 weeks after the last dose in the absence of progressive disease, approximately 36 months
measure: Disease Control Rate (DCR) as assessed by RECIST v1.1
timeFrame: Approximately every 8 weeks during treatment and every 12 weeks after the last dose in the absence of progressive disease, approximately 36 months
measure: Quality of Life as assessed by the European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC QLQ-C30)
timeFrame: Once every cycle (4-week cycles) through end of treatment, approximately 24 months
measure: Clinical benefit rate (CBR) as assessed by RECIST v1.1
timeFrame: [Time Frame: Approximately every 8 weeks during treatment and every 12 weeks after the last dose in the absence of progressive disease, approximately 36 months]
Other outcomes:
Locations:
city: Tucson
country: United States
facility: The University of Arizona Cancer Center
state: Arizona
city: San Diego
country: United States
facility: University of California-San Diego
state: California
city: Denver
country: United States
facility: HealthONE
state: Colorado
city: New Haven
country: United States
facility: Yale University
state: Connecticut
city: Orlando
country: United States
facility: Florida Cancer Specialists
state: Florida
city: Plantation
country: United States
facility: Boca Raton Clinical Research (BRCR) Global
state: Florida
city: Chicago
country: United States
facility: University of Chicago Medical Center
state: Illinois
city: Indianapolis
country: United States
facility: Community Health Network
state: Indiana
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Boston
country: United States
facility: Dana-Farber Cancer Institute
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: Saint Louis
country: United States
facility: Washington University School of Medicine St. Louis
state: Missouri
city: Reno
country: United States
facility: Renown Regional Medical Center
state: Nevada
city: New Brunswick
country: United States
facility: Rutgers University
state: New Jersey
city: New York
country: United States
facility: NYU Langone
state: New York
city: New York
country: United States
facility: Columbia University Herbert Irving Comprehensive Cancer Center
state: New York
city: New York
country: United States
facility: Memorial Sloan Kettering
state: New York
city: Nashville
country: United States
facility: Tennessee Oncology
state: Tennessee
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center
state: Texas
city: Houston
country: United States
facility: The University of Texas M.D. Anderson Cancer Center
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah- Huntsman Cancer Center
state: Utah
city: Fairfax
country: United States
facility: Inova Schar Cancer Center
state: Virginia
city: Fairfax
country: United States
facility: NEXT Virginia
state: Virginia
city: Madison
country: United States
facility: UW Carbone Cancer Center
state: Wisconsin
city: Sydney
country: Australia
facility: St Vincents Hospital
state: New South Wales
city: Melbourne
country: Australia
facility: Peter MacCallum Cancer Center
state: Victoria
city: Melbourne
country: Australia
facility: The Alfred Hospital
state: Victoria
city: Bordeaux Cedex
country: France
facility: Institute Bergonié
city: Villejuif
country: France
facility: Gustave Roussy
city: Milano
country: Italy
facility: Istituto Europeo di Oncologia IRCCS
city: Barcelona
country: Spain
facility: START Barcelona
state: Catalonia
city: Barcelona
country: Spain
facility: Vall d'Hebron Instituto de Oncologia
city: Barcelona
country: Spain
facility: Institut Catala D'Oncologia - Badalona (ICO Badalona)
city: Madrid
country: Spain
facility: START Madrid - Hospital Fundacion Jimenez Diaz
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre
city: Valencia
country: Spain
facility: Instituto Valenciano de Oncologia
Study officials:
References: