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
Study Identifier:
RLY-2608-101
CT.gov Identifier:
EudraCT Identifier:
EU Trial (CTIS) Number:
Study Contact Information:
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Study Summary
To evaluate RLY-2608 for the treatment of PI3Ka mutant cancer.
To evaluate the maximum tolerated 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.
To evaluate both RLY-2608 as a single agent for patients with unresectable or metastatic solid tumors and RLY-2608 + fulvestrant combination arm for patients with HR+ HER2- locally advanced or metastatic breast cancer
To evaluate the clinical activity of RLY-2608 as a single agent in advanced solid tumor patients (pts) with PI3KCA mutations and in combination with fulvestrant in pts with PIK3CAmutant, HR+, HER2- metastatic breast cancer (MBC).
Adverse events (AEs) per CTCAE v5, PK, biomarkers (mutant ctDNAs and insulin pathway markers) and anti-tumor activity are assessed serially. Dose escalation employs a Bayesian Optimal Interval design to identify MTD and RP2D.
Following dose escalation, expansion cohorts will enroll patients with select PIK3CA-mutated solid tumors for treatment with RLY-2608 monotherapy and patients with HR+/HER2– MBC for treatment with RLY-2608 and fulvestrant.
To define the MTD, safety, pharmacokinetics (PK), and anti-tumor activity of RLY-2608 in PIK3CA-mutant solid tumor patients (pts) and of RLY-2608 plus fulvestrant (combo) in pts with PIK3CA-mutant, HR+HER2-BC, who had received prior CDK4/6 inhibitor and endocrine therapy.
To investigate the maximum tolerated dose (MTD), recommended phase 2 doses (RP2Ds), safety, pharmacokinetics (PK), pharmacodynamics (PD) and anti-tumor activity of RLY-2608 monotherapy in pts with PIK3CA-mutant advanced solid tumors; and of RLY-2608 plus fulvestrant with or without ribociclib in pts with PIK3CA-mutant, HR+, HER2– BC.
To report efficacy and safety of RLY-2608 + standard-dose fulvestrant (F) in pts with PIK3CA-mutant, HR+HER2- BC.
Key objectives were investigator-assessed efficacy per RECIST 1.1 and adverse events (AEs) per CTCAE v5.0. Safety was assessed in all pts, and efficacy in pts without detectable PTEN/AKT co-alterations treated at the RP2D.
Key endpoints included determination of MTD and RP2D, safety and tolerability, PK/PD, and preliminary efficacy per RECIST 1.1
Medical Condition
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Phase
The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
I
Sex
Female & Male
Age
18+ years
Study Drug
Study Status
Indicates the current recruitment status or the expanded access status
Recruiting
Requirements information
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 [Escalation] - Ability to provide archived tumor tissue or be willing to undergo pretreatment tumor biopsy to assess PIK3CA status retrospectively Part 2 [Expansion] - 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: 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
- 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 with other specified solid tumor types.
- Key Inclusion for Combination Arms:
- Doublet combination arms [Part 1 and Part 2]: Evaluable disease per RECIST v1.1
- Triplet combination arms:
- [Part 1 and Part 2 Dose Expansion, Group 1]: Evaluable disease per RECIST.
- [Part 2 Dose Expansion, Group 2]: Measurable disease per RECIST. Bone-only lytic or lytic/blastic disease with at least 1 measurable soft-tissue component per RECIST may be eligible.
- [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- locally advanced or metastatic breast cancer that is not amenable to curative therapy and must have initiated treatment with a gonadotropin-releasing hormone (GnRH) agonist at least 4 weeks prior to start of study drug with continuation of GnRH agonist for the duration of study treatment (GnRH agonist recommended for males).
- Had previous treatment for breast cancer with: [Does not apply to triplet combination arms, Part 2 Dose Expansion, Group 2]:
- ≤1 line of chemotherapy in the metastatic setting
- ≥1 CDK4/6 inhibitor in either the adjuvant and/or metastatic setting
- ≥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
- ≥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 double combination arm; Part 2 Dose Expansion, Group 2]: Received prior treatment with a PI3Kα, AKT, or mTOR 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 dose escalation]: Participants who had previous treatment for breast cancer with PI3Kα, AKT, mTOR inhibitors and discontiuned due to participant/physician decision, intolerance, or disease progression will be considered.
- [For triple combination arms, Part 2 Dose Expansion, Group 2]: Participants must be intolerant to or have declined standard therapy for locally advanced or metastatic HR+/HER2- PIK3CA-mutated breast cancer. Prior endocrine therapy and CDK4/6inhibitors are allowed as follows:
- Participants must have progressed during (neo)adjuvant endocrine therapy or within12 months of completing (neo)adjuvant endocrine therapy with an AI or tamoxifen.
- If a CDK4/6 inhibitor was included as part of (neo)adjuvant therapy, disease must have recurred/progressed >12 months after completion of the CDK4/6 inhibitor portion of (neo)adjuvant therapy
Exclusion criteria
- Prior treatment with:
- PI3K, 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.
- Triplet combinations RLY-2608 + CDK4 or CDK4/6 inhibitor + fulvestrant, Part 2 expansion, Group 2 only:
- i. Prior systemic chemotherapy or antibody drug conjugate for locally advanced or metastatic disease. ii. Prior CDK2, CDK4, or CDK4/6 inhibitor as treatment for locally advanced or metastatic disease.
- iii. 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.
- Type 1 or Type 2 diabetes requiring antihyperglycemic medication, or fasting plasma glucose ≥140 mg/dL and glycosylated hemoglobin (HbA1c) ≥7.0%.
- History of allergy or hypersensitivity to any components or excipients of PI3K inhibitors. For combination arms only: allergy or hypersensitivity to any components or excipients of 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.
- The following cardiac criteria:
- 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.
- CNS metastases or primary CNS tumor that is associated with progressive neurologic symptoms
Clinical Study Information for Healthcare Providers
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Study Locations
Location
Investigator
Status
Condition(s) Treated at Site
Location
START Barcelona
Barcelona, Spain, 08023
Investigator
Tatiana Hernandez Guerrero
Status
Recruiting
Condition(s) Treated at Site
Gene Mutations
Solid Tumor
Breast Cancers
Location
START Madrid, Spain (FJD)
Madrid, Spain, 28040
Investigator
Victor Moreno Garcia
Status
Recruiting
Condition(s) Treated at Site
Gene Mutations
Solid Tumor
Breast Cancers