first-in-human study of stx-478 as monotherapy and in combination with other antineoplastic agents in participants with advanced solid tumors

Conditions: Breast Cancer; Solid Tumors, Adult

Summary: study stx-478-101 is a multipart, open-label, phase 1/2 study evaluating the safety, tolerability, pharmacokinetics (pk), and preliminary antitumor activity of stx-478 (ly4064809) in participants with advanced solid tumors with p13ka mutations. 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 endocrine therapy (aromatase inhibitors, fulvestrant or imlunestrant) and a cdk4/6 inhibitor (either ribociclib, palbociclib or abemaciclib) in participants with hr+ breast cancer. each study part will include a 28-day screening period, followed by treatment with stx-478 monotherapy or combination therapy.


Eligibility criteria:
key inclusion criteria: 1. has an advanced or refractory solid tumor malignancy that is metastatic or locally advanced and unresectable (as specified by cohort) 2. has a new or recent tumor biopsy (collected at screening, if feasible) or will provide an adequate tissue sample prior to screening 3. has a tumor that harbors a documented pi3kα mutation (cohort specific criterion for cohort-specific mutation types) 4. is ≥18 years of age at the time of signing the icf 5. has an ecog performance status score of 0 or 1 at screening 6. has adequate organ function as defined per protocol key 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 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). 4. has had prior treatment with pi3k/akt/mtor inhibitor(s), except in certain circumstances 5. 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. 6. 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. 7. has had radiotherapy within 14 days before the initiation of study treatment

Keywords: breast neoplasms neoplasms by site neoplasms breast diseases her2-negative breast cancer hr-positive breast cancer gynecologic cancer endometrial cancer ovarian cancer cervical cancer head and neck cancer head and neck squamous cell carcinoma fulvestrant antineoplastic agents pi3kα pi3k alpha pi3kα mutation alpelisib stx-478 pi3kα inhibitor estrogen receptor antagonists estrogen antagonists hormone receptor antagonists hormone antagonists hormones, hormone substitutes, and hormone antagonists physiological effects of drugs palbociclib ribociclib pik3ca pik3ca mutation aromatase inhibitor letrozole anastrozole exemestane imlunestrant inavolisib capivasertib