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

Official title

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

Overview

Study STX-478-101 (LY4064809) 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, tamoxifen, 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.

Interventions

• Drug STX-478
  STX-478 is a mutant-selective PI3Kα inhibitor
• Drug Fulvestrant
  Fulvestrant
• Drug Ribociclib
  Ribociclib
• Drug Palbociclib
  Palbociclib
• Drug Letrozole
  Letrozole
• Drug Anastrozole
  Anastrozole
• Drug Exemestane
  Exemestane
• Drug Tamoxifen
  Tamoxifen
• Drug Abemaciclib
  Abemaciclib
• Drug Imlunestrant
  Imlunestrant

Primary outcome measures

• Number of participants who experience at least 1 Dose Limiting Toxicity (DLT) [Time frame: First 28 days of treatment]
• Proportion of participants who experience at least 1 DLT during the first 28 days of treatment [Time frame: First 28 days of treatment]
• Objective response rate (ORR) defined as the percentage of participants with partial response or complete response based on RECIST 1.1 [Time frame: 12 months]
• Incidence of TEAEs/SAEs ≥ grade 2 [Time frame: 12 months]
• Frequency of TEAEs according to CTCAE v5.0 criteria [Time frame: 12 months]

Secondary outcome measures (10)

• Cmax of STX-478 [Time frame: 12 months]
• AUC(0-inf) of STX-478 [Time frame: 12 months]
• AUC(0-t) of STX-478 [Time frame: 12 months]
• AUC(0-τ) of STX-478 [Time frame: 12 months]
• Change from baseline in ctDNA levels [Time frame: 12 months]
• Changes in circulating markers of glucose metabolism as assessed by changes in circulating glycosylated hemoglobin (HbA1c) [Time frame: 12 months]
• Changes in circulating markers of glucose metabolism as assessed by circulating fasting plasma glucose [Time frame: 12 months]
• Changes in circulating markers of glucose metabolism as assessed by circulating C-peptide [Time frame: 12 months]
• Change in ECOG performance status [Time frame: 12 months]
• Disease Control Rate (DCR) per RECIST v1.1, measured as percentage of participants with Complete Response [Time frame: 12 months]

Eligibility criteria

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 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

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 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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Sequential

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 28 centers

• Ellison Clinic at Saint John's — Los Angeles
• UCSF Medical Center at Mission Bay — San Francisco
• University of Colorado Cancer Center — Aurora
• Yale-New Haven Hospital — New Haven
• Florida Cancer Specialists ORLANDO/DDU — Lake Mary
• Moffitt Cancer Center — Tampa
• Winship Cancer Institute, Emory University — Atlanta
• University of Iowa — Iowa City
• … and 20 more centers

Spain · 12 centers

• Hospital Quiron Barcelona — Barcelona
• South Texas Accelerated Research Therapeutics (START) Barcelona- HM Nou Delfos — Barcelona
• Instituto Oncologico Dr Rosell (IOR) — Barcelona
• Hospital Universitari Vall d'Hebron — Barcelona
• Hospital San Pedro — Logroño
• MD Anderson Cancer Center — Madrid
• Hospital Clinico San Carlos — Madrid
• Hospital Universitario Fundación Jiménez Díaz — Madrid
• … and 4 more centers

Italy · 9 centers

• Azienda Ospedaliera Nazionale Santi Antonio e Biagio e Cesare Arrigo — Alessandria
• Spedali Civili di Brescia — Brescia
• Istituto Nazionale per lo Studio e la Cura dei Tumori — Milan
• Istituto Europeo di Oncologia — Milan
• Fondazione IRCCS San Gerardo dei Tintori — Monza
• Azienda Ospedaliero Universitaria Pisana - Stabilimento Santa Chiara — Pisa
• Ospedale Santa Maria delle Croci — Ravenna
• Fondazione Policlinico Universitario Agostino Gemelli — Roma
• … and 1 more center

France · 6 centers

• Institut Bergonié - Centre Régional de Lutte Contre Le Cancer de Bordeaux et Sud Ouest — Bordeaux
• Centre Leon Berard — Lyon
• Institut Paoli-Calmettes — Marseille
• Centre Antoine-Lacassagne — Nice
• Institut Claudius Regaud — Toulouse
• Gustave Roussy — Villejuif

Japan · 4 centers

• National Hospital Organization Kyushu Cancer Center — Fukuoka
• Kansai Medical University Hospital — Hirakata
• The Cancer Institute Hospital of JFCR — Kōtō City
• Kyoto University Hospital — Kyoto

Belgium · 2 centers

• Institut Jules Bordet — Anderlecht
• UZ Leuven — Leuven

Netherlands · 2 centers

• Netherlands Cancer Institute — Amsterdam
• Erasmus MC — Rotterdam

Germany · 1 center

• Universitätsklinikum Erlangen — Erlangen

Ireland · 1 center

• Mater Misericordiae Hospital — Dublin

Identifiers

NCT: NCT05768139 · 27691 · 2023-504807-94-00 · 2023-000442-41 · J6M-OX-JSGA · STX-478-101

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗