First-in-Human Study of STX-478 as Monotherapy and in Combination With Other Antineoplastic Agents in Participants With Advanced Solid Tumors

Study Overview
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Brief Summary
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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 in participants with advanced solid tumors with certain mutations. Part 1 will evaluate STX-478 as monotherapy in participants with advanced solid tumors and breast cancer; Part 2 will evaluate STX-478 therapy as combination therapy with fulvestrant in participants with breast cancer. Each study part will include a 28-day screening period, followed by treatment with STX-478 monotherapy or combination therapy.

Official Title
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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 Tumors

Conditions
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Breast Cancer, Gynecologic Cancer, HNSCC, Solid Tumors, Adult

Intervention / Treatment
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* Drug: STX-478
* Drug: Fulvestrant


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: 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 archival tumor specimen within 10 years prior to screening Has a tumor that harbors a documented PI3Kα mutation (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, CE marked in EU, or obtained as part of normal clinical care in a CLIA certified or similarly certified laboratory. Is ≥18 years of age at the time of signing the ICF Has an ECOG performance status score of 0 or 1 at screening Key Exclusion Criteria: 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 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 Cohorts A0, A1, A2, A3, A4, A5 and B: 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 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1.1: Dose Escalation (Advanced Solid Tumors and Breast)<br>Cohort A0: Advanced Solid tumors expressing PI3Kα mutations. Cohort A1: HR+/HER2- breast cancer expressing PI3Kα H1047X mutations or other kinase domain mutations. | Drug: STX-478<br>* STX-478 is a second generation, mutant-selective, oral PI3Kα small molecule allosteric inhibitor.<br>|
| Experimental: Part 1.2-DE: Dose expansion at MTD<br>Cohort A2: Gynecologic cancers Cohort A3: HNSCC Cohort A4: Other solid tumors not included in Cohorts A0, A1, or A2 Mutations for Cohorts A2, A3, and A4: PI3Kα H1047X mutations or other kinase domain mutations Cohort A5: Solid tumors expressing PI3Kα helical domain mutations (E542/E545) | Drug: STX-478<br>* STX-478 is a second generation, mutant-selective, oral PI3Kα small molecule allosteric inhibitor.<br>|
| Experimental: Part 1.2-DS: RP2D Selection (Breast)<br>Recommended Phase 2 dose (RP2D) Cohort A1: HR+/HER2- breast cancer expressing PI3Kα H1047X mutations or other kinase domain mutations. | Drug: STX-478<br>* STX-478 is a second generation, mutant-selective, oral PI3Kα small molecule allosteric inhibitor.<br>|
| Experimental: Part 1.3: RP2D Expansion (Breast)<br>Cohort A1: HR+/HER2- breast cancer expressing PI3Kα H1047X mutations or other kinase domain mutations. | Drug: STX-478<br>* STX-478 is a second generation, mutant-selective, oral PI3Kα small molecule allosteric inhibitor.<br>|
| Experimental: Part 2.1: RP2D Selection<br>Cohort B: HR+/HER2- breast cancer expressing PI3Kα H1047X mutations or other kinase domain mutations. | Drug: STX-478<br>* STX-478 is a second generation, mutant-selective, oral PI3Kα small molecule allosteric inhibitor.<br>Drug: Fulvestrant<br>* Fulvestrant will be administered according to local labeling.<br>* Other names: Faslodex;|
| Experimental: Part 2.2: RP2D Expansion<br>Cohort B: HR+/HER2- breast cancer expressing PI3Kα H1047X mutations or other kinase domain mutations. | Drug: STX-478<br>* STX-478 is a second generation, mutant-selective, oral PI3Kα small molecule allosteric inhibitor.<br>Drug: Fulvestrant<br>* Fulvestrant will be administered according to local labeling.<br>* Other names: Faslodex;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1.1 (Dose Escalation): Number of participants who experience at least 1 Dose Limiting Toxicity (DLT) |  | First 28 days of treatment | 
| Part 1.1 (Dose Escalation): Proportion of participants who experience at least 1 DLT during the first 28 days of treatment. |  | First 28 days of treatment | 
| Part 1.1 (Dose Escalation): Cmax of STX-478 |  | 12 months | 
| Part 1.1 (Dose Escalation): AUC(0-inf) of STX-478 |  | 12 months | 
| Part 1.1 (Dose Escalation): AUC(0-t) of STX-478 |  | 12 months | 
| Part 1.1 (Dose Escalation): AUC(0-τ) of STX-478 |  | 12 months | 
| Part 1.1 (Dose Escalation): Change from baseline in ctDNA levels. |  | 12 months | 
| Part 1.1 (Dose Escalation): Changes in circulating markers of glucose metabolism as assessed by changes in circulating glycosylated hemoglobin [HbA1c] |  | 12 months | 
| Part 1.1 (Dose Escalation): Changes in circulating markers of glucose metabolism as assessed by circulating fasting plasma glucose. |  | 12 months | 
| Part 1.1 (Dose Escalation): Changes in circulating markers of glucose metabolism as assessed by circulating C-peptide. |  | 12 months | 
| Part 1.1 (Dose Escalation): Objective response rate (ORR). |  | 12 months | 
| Part 1.1 (Dose Escalation): Incidence of TEAEs/SAEs ≥ grade 2. |  | 12 months | 
| Part 1.1 (Dose Escalation): Frequency of TEAEs according to CTCAE v5.0 criteria. |  | 12 months | 
| RP2D Selection (Parts 1.2-DS and 2.1): Cmax of STX-478 |  | 12 months | 
| RP2D Selection (Parts 1.2-DS and 2.1): AUC(0-inf) of STX-478 |  | 12 months | 
| RP2D Selection (Parts 1.2-DS and 2.1): AUC(0-t) of STX-478 |  | 12 months | 
| RP2D Selection (Parts 1.2-DS and 2.1): AUC(0-τ) of STX-478 |  | 12 months | 
| RP2D Selection (Parts 1.2-DS and 2.1): Change from baseline in ctDNA levels. |  | 12 months | 
| RP2D Selection (Parts 1.2-DS and 2.1): Changes in circulating markers of glucose metabolism as assessed by changes in circulating glycosylated hemoglobin [HbA1c] |  | 12 months | 
| RP2D Selection (Parts 1.2-DS and 2.1): Changes in circulating markers of glucose metabolism as assessed by circulating fasting plasma glucose. |  | 12 months | 
| RP2D Selection (Parts 1.2-DS and 2.1): Changes in circulating markers of glucose metabolism as assessed by circulating C-peptide |  | 12 months | 
| Parts 1.2-DS and 2.1 (RP2D Selection): ORR |  | 12 months | 
| Parts 1.2-DS and 2.1 (RP2D Selection): Frequency counts and percentages of AEs based on MedDRA and CTCAE v5.0 |  | 12 months | 
| Parts 1.2-DS and 2.1 (RP2D Selection): Proportion of participants with DLTs. |  | 12 months | 
| Parts 1.2-DS and 2.1 (RP2D Selection): Change in ECOG performance status. |  | 12 months | 
| Parts 1.2-DE, 1.3, and 2.2 (Dose Expansion): ORR defined as the percentage of participants with partial response or complete response based on RECIST 1.1. |  | 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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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