New treatment for advanced solid tumors with specific mutations

A Multi-Center, Open-Label, Phase I Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Preliminary Anti-tumor Activity of Pan-RAS Inhibitor YL-17231 in Patients With Advanced Solid Tumors Harboring Mutations in KRAS, HRAS, or NRAS

This study is testing a new drug called YL-17231 to see if it is safe and effective for people with advanced solid tumors that have certain mutations.

Quick facts

• Phase: Phase 1
• Study type: Interventional
• Enrollment: 60 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: Shanghai YingLi Pharmaceutical Co. Ltd. (Industry-sponsored)
• Drugs / interventions: chemotherapy, Immunotherapy
• Locations: 3 sites (Cincinnati, Ohio and 2 other locations)
• Trial ID: NCT06096974 on ClinicalTrials.gov

What this trial studies

This Phase 1 clinical trial evaluates the safety and tolerability of YL-17231, a pan-RAS inhibitor, in patients with advanced solid tumors that have mutations in KRAS, HRAS, or NRAS. The study employs a 3 + 3 dose escalation design to determine the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) of the drug. Participants will receive oral doses of YL-17231, starting at 0.25 mg daily, with safety and pharmacodynamic effects monitored throughout the trial. The study aims to gather data on drug levels, side effects, and preliminary anti-tumor activity.

Who should consider this trial

Good fit: Ideal candidates include patients with unresectable or metastatic advanced solid tumors harboring KRAS, HRAS, or NRAS mutations who have not responded to standard therapies.

Not a fit: Patients with solid tumors that do not have mutations in KRAS, HRAS, or NRAS may not benefit from this study.

Why it matters

Potential benefit: If successful, this treatment could provide a new therapeutic option for patients with advanced solid tumors that currently have limited or no effective treatments.

How similar studies have performed: Other studies targeting RAS mutations have shown promise, indicating that this approach may lead to meaningful advancements in treatment.

Eligibility criteria

Inclusion Criteria:

* Unresectable or metastatic advanced solid tumors with no standard therapies, or having progressed on or intolerable to standard therapies.
* Advanced solid tumors harboring mutations in KRAS, HRAS or NRAS as determined by laboratory testing, including local laboratory testing.
* Measurable disease with at least one lesion amenable to response assessment per RECIST 1.1.
* Demonstrate adequate organ function as defined below. All screening laboratories should be performed within 7 days of study treatment initiation.

  1）Absolute neutrophil count (ANC) ≥1.2 × 10\^9/L；2）Platelets ≥100 × 10\^9/L Hemoglobin ≥9 g/dL or ≥5.6 mmol/L；3）Measured or calculated creatinine clearance (CrCl)(Cockcroft-Gault) ≥60 mL/min；4）Total bilirubin ≤1.5 × ULN (patients with Gilbert's syndrome, total bilirubin ≤3.0 × ULN) ；5）Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 × ULN or ≤5 × ULN for patients with liver metastases
* Has an ECOG performance status of 0-1.
* Life expectancy ≥12 weeks at baseline.
* Women of childbearing potential must have negative serum or urine pregnancy test within 72 hours prior to receiving the first study drug administration. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
* For women of childbearing potential, must be willing to use an adequate method of contraception from 30 days prior to the first study drug administration and at least 3 months following last day study drug administration.
* Male patients of childbearing potential must be surgically sterile, or must agree to use adequate method of contraception during the study and at least 3 months following the last day of study drug administration.
* Age ≥18 years at screening.
* Able and willing to provide written informed consent and to follow study instructions.
* Washout from prior anti-tumor therapy:1）Cytotoxic therapies ≥ 3 weeks Mitomycin C or nitrosoureas ≥ 6 weeks；2）Small molecule agents ≥2 weeks or 5x T1/2, whichever is longer；3）Biologic agents (e.g., antibodies) ≥ 4weeks Immunotherapy (e.g., CTLA4, PD-1, PD-L1 inhibitors) ≥ 4 weeks；4）Radiotherapy ≥ 4 weeks；5）Limited field radiotherapy or palliative radiotherapy ≥ 2 weeks ；6）Major surgery, excluding biopsy ≥ 4 weeks (exception: patients may enroll if fully recovered or without intolerable or clinically significant adverse effects, but at least 14 days must have elapsed between major surgery and first study drug administration)；7）Study drug with an investigational product, or non-approved use of a drug or device ≥ 4 weeks (≥2 weeks or 5x T1/2, whichever is longer for small molecule agents

Exclusion Criteria:

* Known symptomatic brain metastases requiring dexamethasone ≥4mg (or equivalent) or requiring steroid dose increase within 14 days prior to the first dose of YL-17231.
* Any concurrent chemotherapy, immunotherapy, or biologic or hormonal therapy for cancer treatment.
* Unresolved toxicities from prior therapy, defined as having not resolved to NCI CTCAE v.5.0 Grade ≤1 1 or baseline, with exception of endocrinopathies from prior therapy and successfully treated (such as hypothyroidism), alopecia, vitiligo, and ≤ grade 2 peripheral neuropathy.
* Human immunodeficiency virus (HIV) infection with a current or a known history of AIDS-defining illness or HIV infection with a CD4+ T cell count \<350 cells/µL and an HIV viral load more than 400 copies/µL.
* Patients with active viral (any etiology) hepatitis are excluded. However, patients with serologic evidence of chronic hepatitis B virus (HBV) infection (defined by a positive hepatitis B surface antigen test and a positive anti-hepatitis core antigen antibody test) who have a viral load below the limit quantification (HBV DNA titer \<1000 cps/mL or 200 IU/mL), and are not currently on viral suppressive therapy may be eligible and should be discussed with the Medical Monitor. Patients with a history of hepatitis C virus (HCV) infection who have completed curative antiviral treatment and have a viral load below the limit of quantitation may be eligible and should be discussed with the Medical Monitor.
* Any of the following cardiac criteria experienced currently or within the last 6 months:

  1. Congestive heart failure (New York Heart Association ≥ Class 2).
  2. Any clinically significant abnormalities (as assessed by the Investigator) in rhythm, conduction, or morphology of resting electrocardiograms (ECGs), e.g., complete left bundle branch block or third-degree heart block.
  3. Acute coronary syndrome within 6 months.
  4. Clinically significant cardiac arrhythmia.
* Mean QTC interval corrected (Frederica) for heart rate \>450 ms.
* Left ventricular ejection fraction (LVEF) \<50% or the lower limit of normal (per institutional standard).
* Evidence of severe or uncontrolled systemic diseases, including uncontrolled hypertension, uncontrolled diabetes mellitus, active bleeding diatheses, or active infection, as determined by the investigator.
* Any condition that impairs a patient's ability to swallow whole pills. Presence of an active gastrointestinal disease or other condition that will interfere significantly with the absorption, distribution, metabolism, or excretion of YL-17231, as determined by the investigator.
* History noninfectious pneumonitis required steroids treatment or concurrent pneumonitis or interstitial lung diseases.
* An active additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer.
* Known allergy to any component of YL-17231.
* Patient has known psychiatric, substance abuse or other disorders that would interfere with cooperation with the requirements of the trial, in the opinion of the investigator.
* Patients who are pregnant or breastfeeding or expecting to conceive within the projected duration of the trial, starting with the screening visit through 3 months after the last dose of trial treatment.

Where this trial is running

Cincinnati, Ohio and 2 other locations

• The Lindner Center for Research & Education at The Christ Hospital — Cincinnati, Ohio, United States (Recruiting)
• MD Anderson Cancer Center — Houston, Texas, United States (Recruiting)
• Huntsman Cancer Institute and Hospital, University of Utah — Salt Lake City, Utah, United States (Recruiting)

Study contacts

• Study coordinator: David S. Hong, MD

Conditions Advanced Solid Tumors; KRAS, HRAS, or NRAS Mutations