MC# 23-06 - First-in-Human Study of STX-478, a Mutant-Selective PI3Kα Inhibitor as Monotherapy and in Combination With Other Antineoplastic Agents in Participants With Advanced Solid Tumor

  • Agent(s): STX-478
  • Disease Type(s): Breast, Cervical, Endometrial, Ovarian, Solid Tumor, Squamous Cell Carcinoma of Head and Neck
  • Phase(s): I, II
  • Drug Classification(s): Small Molecule, Targeted Therapy
  • Molecular Target(s): PI3Kα
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Mechanism of Action

PI3Kα small molecule inhibitor

Purpose

In this study, the sponsor and investigators want to learn:

  • How much of STX-478 can be given with an acceptable level of side effects alone or in combination with fulvestrant 
  • The effects of STX-478 (good and bad) alone or in combination with fulvestrant 
  • How much of STX-478 is absorbed into the blood and how fast it is removed
Inclusion Criteria
  1. Has an advanced or refractory solid tumor malignancy that is metastatic or locally advanced and unresectable
  2. Has a new or recent tumor biopsy (collected at screening, if feasible) or archival tumor specimen within 12 months prior to screening
  3. Has a tumor that harbors a documented PI3Kα mutation (see the cohort-specific criterion for cohort-specific mutation types) obtained either from tumor or plasma samples determined by PCR or NGS-based assay as an FDA-approved test in US, or obtained as part of normal clinical care in a CLIA-certified or similarly certified laboratory
  4. Has at least 1 measurable tumor lesion per RECIST 1.1
  5. Is ≥18 years of age at the time of signing the ICF
  6. Has an ECOG performance status score of 0 or 1 at screening
  7. Cohort-specific:
    • Cohort A0: breast cancer, monotherapy (Parts 1.1 [dose escalation], 1.2-DS [RP2D selection], and 1.3 [RP2D expansion])
      • Histologically- or cytologically-confirmed breast cancer with PI3Kα H1047X mutations or other kinase domain mutations meeting the following criteria:
        • Stage III (locally advanced) disease not amenable to curative therapy or stage IV disease
        • HR+/HER2–
      • Must have received prior therapy for stage III or IV disease, including the following:
        • Must have progressed or is intolerant to at least 1 CDK4/6 inhibitor regimen
        • Must have progressed or is intolerant to at least 1 antiestrogen therapy including, but not limited to, SERDs (eg, fulvestrant), SERMs (eg, tamoxifen), and AIs (eg, letrozole, anastrozole, and exemestane)
        • Can have progressed or is intolerant to no more than 1 prior systemic chemotherapy regimen
        • Can have progressed or is intolerant to an approved HER-2 directed therapy if indicated and available
    • Cohort A1: gynecological cancer, monotherapy (Part 1.2-DE [dose expansion])
      • Histologically- or cytologically-confirmed gynecological cancer with PI3Kα H1047X mutations or other kinase domain mutations, such as one of the following:
        • Endometrial cancer
        • Ovarian cancer
        • Cervical carcinoma
      • Disease not amenable to further therapy with curative intent
      • Participant received standard therapy option(s) or additional standard therapy option(s) were either refused by the participant or are contraindicated, or the participant is deemed by the investigator not to be an appropriate candidate for standard therapy option(s)
    • Cohort A2: HNSCC, monotherapy (Part 1.2-DE [dose expansion])
      • Histologically- or cytologically-confirmed HNSCC with PI3Kα H1047X mutations or other kinase domain mutations
      • Disease not amenable to further therapy with curative intent
      • Participant received standard therapy option(s) or additional standard therapy option(s) were either refused by the participant or are contraindicated, or the participant is deemed by the investigator not to be an appropriate candidate for standard therapy option(s)
    • Cohort A3: other solid tumors, monotherapy (Part 1.2-DE [dose expansion])
      • Histologically or cytologically-confirmed solid tumors with PI3Kα H1047X mutations or other kinase domain mutations other than the tumor types permitted in Cohorts A0, A1, and A2
      • Disease not amenable to further therapy with curative intent
      • Participant received standard therapy option(s) or additional standard therapy option(s) were either refused by the participant or are contraindicated, or the participant is deemed by the investigator not to be an appropriate candidate for standard therapy option(s)
    • Cohort A4: solid tumors, monotherapy (Part 1.2-DE [dose expansion])
      • Solid tumors with PI3Kα helical domain mutations (ie, E542/E545)
      • Disease not amenable to further therapy with curative intent
      • Participant received standard therapy option(s) or additional standard therapy option(s) were either refused by the participant or are contraindicated, or the participant is deemed by the investigator not to be an appropriate candidate for standard therapy option(s)
    • Cohort B: breast cancer, combination therapy with STX-478 and fulvestrant (Part 2.1 [RP2D selection] and Part 2.2 [RP2D expansion])
      • Histologically- or cytologically-confirmed breast cancer with PI3Kα H1047X mutations or other kinase domain mutations meeting the following criteria:
        • Stage III (locally advanced) disease not amenable to curative therapy or stage IV disease
        • HR+/HER2–
      • Systemic treatment for stage III (locally advanced) or stage IV disease with at least 1 but not more than 2 prior lines of therapy, including the following: 
        • Must have progressed on a CDK4/6 inhibitor, or deemed by the investigator intolerant to such therapy
        • Must have progressed on or is intolerant to an antiestrogen therapy including, but not limited to, SERDs, SERMs (eg, tamoxifen), and AI (eg, letrozole, anastrozole, and exemestane)
        • Note: Antiestrogen treatment may have been as monotherapy or combination therapy with other antineoplastic agents
        • Can have progressed or is intolerant to an approved HER-2 directed therapy if indicated and available
Exclusion Criteria
  1. Has history (within ≤2 years before screening) of a solid tumor or hematological malignancy that is histologically distinct from the cancers being studied
  2. Has symptomatic brain or spinal metastases
  3. Has a tumor with mutations/deletions in PTEN and activating mutations in AKT or mTOR confirmed by a CLIA-certified laboratory
  4. Has an established diagnosis of diabetes mellitus type 1 or has uncontrolled diabetes mellitus type 2 (based on FPG and HbA1c thresholds defined in the inclusion criteria) requiring antihyperglycemic medication
  5. Cohorts A0, A1, A2, A3, A4, and B: Has had prior treatment with PI3K/AKT/mTOR inhibitor(s).  Note: Participants in Cohort A0 may have received prior treatment with an approved PI3K-inhibitor. Upon approval by the sponsor, participants in Cohort A0 who have prematurely discontinued treatment with an approved PI3K-inhibitor due to intolerance may be included.
  6. Has had treatment with any local or systemic antineoplastic therapy or investigational anticancer agent within 14 days or 4 half-lives, whichever is longer, prior to the initiation of study treatment up to a maximum washout period of 28 days
  7. Has toxicities from previous anticancer therapies that have not resolved to baseline levels or CTCAE grade ≤1, with the exception of alopecia and peripheral neuropathy 
  8. Has had radiotherapy within 14 days before the initiation of study treatment

Location

  • Dallas, TX - Mary Crowley Cancer Research - Medical City
More Info: https://clinicaltrials.gov/ct2/show/NCT05768139

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Re: MC# 23-06