Trial Title:
Pan-RAS Inhibitor YL-17231 in Patients With Advanced Solid Tumors Harboring Mutations in KRAS, HRAS, or NRAS
NCT ID:
NCT06096974
Condition:
Advanced Solid Tumors
Conditions: Official terms:
Neoplasms
Conditions: Keywords:
KRAS, HRAS, or NRAS Mutations
Study type:
Interventional
Study phase:
Phase 1
Overall status:
Not yet recruiting
Study design:
Allocation:
N/A
Intervention model:
Sequential Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
YL-17231
Description:
YL-17231 will be administered orally once daily in a continuous regimen
Arm group label:
Dose Escalation and Expansion
Summary:
This study will evaluate the safety, tolerability, drug levels, pharmacodynamic effects,
and clinical activity of YL 17231 in patients with advanced solid tumors harboring
mutations in KRAS, HRAS, or NRAS.
Detailed description:
The study is a Phase 1, multi-center, open label study in 2 parts.
Part 1 (Phase Ia):
This is a 3 + 3 design dose escalation study, to evaluate the safety and tolerability,
and to determine the MTD and/or RP2D of YL-17231 treatment when administered orally QD in
patients with advanced solid tumors harboring mutations in KRAS, HRAS or NRAS. Up to 9
doses cohorts are planned for the dose escalation part of the study, with the starting
dose of 0.25mg QD. The actual number of dose cohorts to be explored in this study will be
determined by the non-tolerable dose based on dose limiting toxicities (DLTs) in
conjunction with the PK and preliminary efficacy signal data. If suggested by safety and
PK findings from planned dose treatment cohorts, additional dose levels may be evaluated
and dosing interval may be modified under the Safety Monitoring Committee (SMC) guidance.
In Part 1, the 3+3 trial design for the dose escalation will be used and a total of 9
dose levels starting dose of 0.25 mg OD is planned.
One cycle is 21 days. DLT observation period is one cycle. The maximum tolerated dose
(MTD) is the highest dose at which ≤1 of 6 patients experiences a DLT during the DLT
observation period. The study will identify a maximum tolerated dose (MTD) if possible,
with safety and tolerability data. All available data, including safety, tolerability,
PK, PD and preliminary anti-tumor activity from each cohort will be reviewed by the SMC
to determine the RP2D.
Patients may be permitted an intra-patient dose-escalation of YL-17231 to a higher dose
level that has been cleared and deemed safe by the SMC if they have completed Cycle 2 at
their initial enrolled dose level and continued on-study with no treatment related ≥
Grade 2 AEs. The Investigator must consult with the Medical Monitor to confirm if the
patient is permitted be dose-escalated to a dose-level already cleared by the SMC.
Backfilling Additional patients (up to total of 12) may be enrolled in the dose levels
which have been cleared and deemed safe by SMC to further evaluate the safety,
tolerability and PK. This is referred to as backfilling.
Part 2 (Phase Ib):
This is a dose expansion phase to further evaluate the safety, tolerability and
preliminary anti-tumor activity of YL 17231 at the RP2D selected by SMC.
The number of patients to be enrolled for the expansion cohorts, the RP2D and the desired
patient population will be determined by the emerging data from part 1 of the study,
including safety, tolerability, PK, PD and preliminary anti-tumor efficacy, as well as
any other relevant evolving clinical data, and will be clarified through a protocol
amendment.
Criteria for 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.
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
The Lindner Center for Research & Education at The Christ Hospital
Address:
City:
Cincinnati
Zip:
45219
Country:
United States
Contact:
Last name:
Alexander Starodub
Phone:
513-321-4333
Facility:
Name:
MD Anderson Cancer Center
Address:
City:
Houston
Zip:
77030
Country:
United States
Contact:
Last name:
David Hong, PhD
Phone:
713-563-1930
Facility:
Name:
Huntsman Cancer Institute and Hospital, University of Utah
Address:
City:
Salt Lake City
Zip:
84112
Country:
United States
Contact:
Last name:
Ignacio Garrido-Laguna
Phone:
801-585-0255
Start date:
October 2023
Completion date:
April 2026
Lead sponsor:
Agency:
Shanghai YingLi Pharmaceutical Co. Ltd.
Agency class:
Industry
Source:
Shanghai YingLi Pharmaceutical Co. Ltd.
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT06096974
