Overview

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).

Eligibility

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
          -  [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 cyclin-dependent kinases (CDK) 4/6 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
        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