Clinical Trial 22305

• Overview

  Study Title:

  First-in-Human Study of STX-478, a Mutant-Selective PI3Ka Inhibitor as Monotherapy and in Combination with Other Antineoplastic Agents in Participants With Advanced Solid Tumors

  Objective:

  Primary: To determine the OBD and MTD of STX-478 administered as monotherapy in participants with solid tumors expressing PI3Ka mutations. Secondary: 1. To characterize the overall safety and tolerability of STX-478 administered as monotherapy in participants with solid tumors expressing PI3Ka mutations. 2. To evaluate the effect of STX-478 administered as monotherapy on the glucose metabolism of participants with solid tumors expressing PI3Ka mutations.

• Treatments

  Therapies:

  Antineoplastic Agent; CDK4/6 Inhibitor; Hormonal Therapy; Therapy (NOS)

  Medications:

  772256 (Palbociclib); Abemaciclib (); Anastrozole (); Arimadex (Anastrozole); Aromasin (Exemestane); Exemestane (); Faslodex (fulvestrant); Femara (Letrozole); Imlunestrant (); LEE011 (Ribociclib); LY2835219 (Abemaciclib); Letrozole (); Metformin (); Palbociclib (); Ribociclib (); STX478-101 (); Tamoxifen (); fulvestrant ()

• Inclusion Criteria

  Key Inclusion Criteria:
  • Has an advanced or refractory solid tumor malignancy that is metastatic or locally advanced and unresectable
  • Has a new or recent tumor biopsy (collected at screening, if feasible) or archival tumor specimen within 10 years prior to screening
  • Has a tumor that harbors a documented PI3Kalpha; mutation meeting the following criteria: o Mutation is based on results obtained either from tumor or plasma samples o Mutation is determined by PCR or next-generation sequencing (NGS)-based assay as a US FDA approved test in US, CE marked in EU, or obtained as part of normal clinical care in a Clinical Laboratory Improvement Amendments (CLIA) or similarly-certified laboratory o Mutation meets specific criteria for mutation types outlined for individual cohorts o Presence of genetic alterations concurrent with PI3Kalpha; mutation do not impact the activation of the PI3Kalpha;/AKT/mTOR-signal transduction pathway as confirmed by an independent expert.
  • For cohorts where exclusion of concurrent mutations (e.g., inactivating mutations or deletions in PTEN , activating mutations in AKT1 or ERBB2 for monotherapy cohorts) is required, results of these co-mutations must be available at the time of eligibility assessment. Is ≥18 years of age at the time of signing the ICF.
  • Is at least 18 years of age at the time of signing the informed consent form (ICF)
  • Has ECOG performance status score of 0 or 1 at screening
  • Is capable of understanding the written ICF, provides signed and witnessed written informed consent, and agrees to comply with the protocol requirements
  • Before study entry, a female participant must meet one of the following: o Be of nonchildbearing potential, defined as one of the following: Postmenopausal: A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. A high FSH level (>35 mIU/mL) in the postmenopausal range may be used to confirm a postmenopausal state in females not using hormonal contraception or hormonal replacement therapy. However, in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient..Permanently sterile: Permanent sterilization methods include hysterectomy, bilateral salpingectomy, bilateral tubal occlusion/ligation procedures, and bilateral oophorectomy. o Be a FCBP (ie, any female participant who does not meet the nonchildbearing criteria above) and: Using a highly effective method of contraception (failure rate > If a female, participant must agree to not donate eggs (ova or oocytes) for the purpose of assisted reproduction during the study and for a period of 1 month after the last dose of STX-478 , 2 months after the last dose of tamoxifen, and at least 2 years after the last dose of fulvestrant when in fulvestrant-containing combination therapies (or as per guidance specified in the respective package insert or approved product labeling for other therapies). FCBP must have a negative serum pregnancy test (β-human chorionic gonadotropin) documented within 14 days prior to initiation of treatment and a negative urine pregnancy test obtained on first day of study treatment if the serum pregnancy test was obtained more than 7 days prior to first day of study treatment.
  • If a FCBP, must have a negative, highly sensitive serum (Beta-human chorionic gonadotropin) pregnancy test at screening and a negative urine pregnancy test prior to the first dose of study treatment
  • If a female participant, must agree not to breastfeed from screening, throughout the study period, and for 1 month after final administration of study treatment
  • Other criteria apply.

• Exclusion Criteria

  Key Exclusion Criteria:
  • Is unable to swallow tablets or has malabsorption syndrome, disease significantly affecting gastrointestinal function, resection of the stomach or small bowel, symptomatic inflammatory bowel disease or ulcerative colitis, or partial or complete bowel obstruction
  • Has history (within 2 years before screening) of a solid tumor or hematological malignancy that is histologically distinct from the cancers being studied
  • Has symptomatic brain or spinal metastases
  • Has a tumor with known mutations/deletions in PTEN and activating mutations in AKT (E17K) confirmed by a CLIA-certified or similarly certified laboratory. Note: Participants whose tumor is known to contain other PI3Kα pathway mutations (e.g., AKT, PTEN) may be excluded from study participation following an independent expert review.
  • Has a history of or suspected allergy to STX-478, other study treatments, or their excipients. Metformin DDI cohort (Cohort A8, Cohort B2, and Cohort F) only: Has a known allergy, intolerance or hypersensitivity to any components of metformin IR that would pose an unacceptable risk to the participant.
  • Has an established diagnosis of uncontrolled diabetes mellitus (defined as HbA1c ≥8% and/or FPG >/= ;140 mg/dL [7.7 mmol/L] and/or requiring or required insulin). Metformin DDI cohort (Cohort A8, Cohort B2, and Cohort F) only: Has HbA1c ≥6.5% or FPG ≥126 mg/dL [7.0 mmol/L] at screening or requiring metformin for glucose management within 2 weeks prior to first study drug administration.
  • Has any condition requiring systemic corticosteroids (daily prednisone equivalent doses
  • 10 mg/day) or other immunosuppressive therapy within 2 weeks prior to the start of study treatment
  • Has untreated HIV infection
  • Has active hepatitis B (HBV) or HCV. (some exceptions exist)
  • Has uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrythmia, or psychiatric illness/social situation that would limit compliance with study requirements Note: Participants with a history of myocardial infarction, unstable angina, or acute coronary syndrome within the 6 months prior to enrollment are excluded.
  • Cohorts A0, A1, A2, A3, A4, A5 and B: Has had prior treatment with PI3K/AKT/mTOR inhibitor(s) Note: Upon approval by the sponsor, participants who have prematurely discontinued treatment with a PI3K-, AKT- and/or mTOR-inhibitor due to intolerance may be included on a case-by-case basis.
  • 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
  • Has toxicities from previous anticancer therapies that have not resolved to baseline levels or CTCAE grade 0-1, with the exception of alopecia and peripheral neuropathy
  • Has had radiotherapy within 14 days before the initiation of study treatment
  • Has had major surgery (eg, requiring general anesthesia) within the 3 weeks before screening, will not have fully recovered from prior surgery, or has surgery planned during the time in which the participant is expected to participate in the study
  • Other exclusions apply

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