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
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Study Summary
To evaluate the safety, tolerability, pharmacokinetics (PK), and preliminary antitumor activity of STX-478 in patients with advanced solid tumors with certain mutations like breast cancer, HNSCC, Gynecologic cancers To evaluate STX-478 for the treatment of HR+/HER2- breast cancer and other solid tumors. To evaluate STX-478 as a monotherapy in a variety of solid tumors including breast and gynecological cancers, head and neck squamous cell carcinoma (“HNSCC”) and others, as well as a monotherapy and in combination with approved agents in patients with HR+/HER2- breast cancer. To evaluate the safety and tolerability of STX-478 in multiple ascending doses for patients with locally advanced or metastatic HR+/HER2- breast cancer driven by PI3Kα-mutations. To characterize the safety profile of STX-478 and establish a maximum tolerated dose (“MTD”) or a lower optimal-biologically active dose, if appropriate, as the recommended Phase 2 dose (“RP2D”) as a monotherapy for breast cancer and other solid tumor types, and as a combination agent in PI3Kα-mutant HR+/HER-2- breast cancer. Part 1 will evaluate STX-478 as monotherapy in participants with advanced solid tumors. Part 2 will evaluate STX-478 therapy as combination therapy with fulvestrant in participants with hormone receptor positive (HR+) breast cancer. Part 3 will evaluate STX-478 as combination therapy with fulvestrant and a CDK4/6 Inhibitor (either Ribociclib or Palbociclib) in participants with HR+ breast cancer. Efficacy, safety, pharmacokinetics, pharmacodynamics, patient-reported quality of life, and biomarkers (e.g., glucose metabolism, circulating tumor DNA) will be assessed. Part 2 comprises two subparts (Table 2) to define RP2D and assess the initial efficacy of STX-478 in combination with fulvestrant in patients with HR+/HER2− breast cancer expressing PI3Kα H1047X or other kinase domain mutations. To evaluates the optimal dosing, safety, and preliminary efficacy of STX-478 as monotherapy in patients with locally-advanced or metastatic HR+/HER2− breast cancer or other solid tumor types with PI3Kα H1047X mutations, other kinase domain mutations, or helical domain mutations (Part 1), and STX-478 in combination with fulvestrant in patients with locally-advanced or metastatic HR+/HER2− breast cancer with PI3Kα H1047X or other kinase domain mutations (Part 2) To evaluate the STX-478 alone or in combination in advanced PI3Kαm solid tumor patients. A first-in-human study of STX-478 as monotherapy and in combination with other anti-cancer drugs in patients with advanced solid tumors.
Study objectives: Dose determination; safety and tolerability assessment, PK evaluation, objective response rate and clinical benefit rate assessment per RECIST v1.1.
To investigate LY4064809 alone and in combination with other anticancer therapies in pts with PIK3CAm ABC and other solid tumors.
Study of LY4064809 includes dose escalation of LY4064809 monotherapy followed by dose expansion of LY4064809 in combination with endocrine therapy (ET) ± CDK4/6 inhibitor (CDK4/6i) therapy
Study objectives: Dose determination; safety and tolerability assessment, PK evaluation, objective response rate and clinical benefit rate assessment per RECIST v1.1
- Has an advanced or refractory solid tumor malignancy that is metastatic or locally advanced and unresectable (as specified by Cohort) Has a new or recent tumor biopsy (collected at screening, if feasible) or will provide an adequate tissue sample prior to screening Has a tumor that harbors a documented PI3Kα mutation (cohort specific criterion for cohort-specific mutation types) Is ≥18 years of age at the time of signing the ICF Has an ECOG performance status score of 0 or 1 at screening Has adequate organ function as defined per protocol 1. Patients with metastatic or locally advanced, unresectable, advanced or refractory solid malignant tumors (cancer type specified by cohort) 2. Patients who have undergone a new or recent tumor biopsy (taken at screening if possible) or who can provide sufficient tumor tissue specimens before screening 3. Patients with tumors in which PI3Kα mutations have been detected (meeting the criteria for the specific mutation type described for each cohort) 4. Patients aged 18 years or older at the time of signing the ICF 5. Patients with an ECOG performance status score of 0 or 1 at screening 6. Patients with adequate organ function as defined in the protocol Patients (pts) without (w/o) diabetes (DM) or prediabetes (pDM). Pts with pDM/DM were eligible;
- Eligible pts must have PIK3CAm ABC or other solid tumors with measurable disease or non-measurable bone-only disease (ABC pts only).
- Pts with pre-diabetes/controlled diabetes are allowed
- 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 an established diagnosis of uncontrolled diabetes mellitus (defined as HbA1c ≥8% and/or FBG ≥140 mg/dL [7.7 mmol/L] and/or requiring or required insulin). Has had prior treatment with PI3K/AKT/mTOR inhibitor(s), except in certain circumstances 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. Endocrine therapy does not require a washout period if the patient is enrolling in a cohort with the same combination endocrine therapy. 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. Has had radiotherapy within 14 days before the initiation of study treatment 1. Patients with a history (within 2 years prior to screening) of solid tumors or hematopoietic malignancies histologically different from the cancer being studied. 2. Patients with symptomatic brain or spinal metastases. 3. Patients with a confirmed diagnosis of uncontrolled diabetes (defined as HbA1c ≥ 8% and/or FPG ≥ 140 mg/dL [7.7 mmol/L] and/or insulin requirement). 4. Patients with a history of treatment with a PI3K/AKT/mTOR inhibitor, except in certain circumstances . 5. Patients who have received local or systemic anti-cancer therapy or investigational anti-cancer drugs within 14 days or four half-lives (whichever is longer) prior to starting study drug administration. A washout period of up to 28 days is required. If patients are enrolled in a cohort receiving the same endocrine therapy as before entering the study, no washout period for endocrine therapy is required. 6. Patients whose symptoms have not recovered to baseline levels or CTCAE v5.0 Grade 1 or less, excluding alopecia and peripheral neuropathy. 7. Patients who have received radiation therapy within 14 days prior to the start of administration of the study drug. Patients w/ uncontrolled diabetes (DM) (HbA1c ≥8% / FPG ≥140mg/dL / on insulin) were excluded. Pts with uncontrolled DM (HbA1c ≥8% / FBG ≥140mg/dL) were excluded. Pts with prior PI3K/AKT/mTORi were excluded except for intolerance.
- Pts with uncontrolled diabetes mellitus (HbA1c ≥8% and/or fasting blood glucose ≥140 mg/dL [7.7 mmol/L]) and/or requiring insulin are excluded.
- Pts with prior PI3K/AKT/mTOR inhibitors are excluded except in cases of intolerance
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