Advanced Malignant Solid Tumors
Conditions
Brief summary
A Phase I Study of HEC-921 Injection as Monotherapy and in Combination with Other AntineoplasticTherapy in Patients with Advanced Malignant Solid Tumors
Detailed description
This is a Phase I open-label, multicenter study to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamic (PD) characteristics, immunogenicity and antitumor activity of HEC-921 injection as monotherapy and in combination with other antineoplastic therapies in patients with advanced malignant tumors. The recommended Phase II dose (RP2D) will be determined based on safety, tolerability, and pharmacokinetics.
Interventions
DRUGHEC-921
Patients will receive specific dose of HEC-921 via intravenous infusion.
DRUGOxaliplatin
130 mg/m², administered via intravenous infusion on Day 1
DRUGCapecitabine
1000 mg/m² per dose, orally twice daily on Days 1-14
DRUGBevacizumab
7.5 mg/kg, administered via intravenous infusion on Day 1
Sponsors
Sunshine Lake Pharma Co., Ltd.
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
This study adopts a sequential group design. The monotherapy dose escalation and expansion cohorts will be conducted first, followed by the combination therapy dose escalation and expansion cohorts.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Trial participants aged ≥18 years at the time of signing the informed consent form, either male or female; * Patients with advanced malignant solid tumors confirmed by histology or cytology, who can provide archived or recently collected tumor tissue sections (recently collected samples are preferred), and meet the following requirements: 1. Monotherapy dose escalation and dose expansion phases: Patients with advanced malignant solid tumors who have failed or are intolerant to standard therapy, or for whom no standard therapy exists, and whose tumor tissue is LY6G6D+. During the monotherapy dose escalation phase in the low-dose cohorts , there is no restriction on LY6G6D expression in participants' tumor tissue. 2. Combination Therapy Phase: Histologically confirmed unresectable advanced colon adenocarcinoma or rectal adenocarcinoma, with no prior systemic therapy, deemed by the investigator suitable for receiving CAPOX combined with bevacizumab as first-line treatment for advanced disease; tumor tissue LY6G6D+ . * Eastern Cooperative Oncology Group (ECOG) performance status: 0-1; * Expected survival time ≥12 weeks; * At least one measurable lesion according to Response Evaluation Criteria in Solid Tumors (Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1); * Adequate organ function: * Female or male trial participants of childbearing potential must agree to have no plans for reproduction and to voluntarily use highly effective contraceptive measures with their partner during the study and for 6 months after the last dose; female trial participants of childbearing potential must have a negative serum pregnancy test within 7 days prior to the first dose and must not be breastfeeding; * The patient voluntarily participates, provides fully informed consent, signs the written informed consent form, and demonstrates good compliance.
Exclusion criteria
* Receipt of the following medications or treatments prior to the first dose: 1. Received anti-tumor therapies such as chemotherapy or immunotherapy, or other investigational drugs within 3 weeks prior to the first dose; or received oral fluoropyrimidines, small-molecule targeted drugs, or traditional Chinese medicine with anti-tumor indications within 2 weeks prior to the first dose; 2. Received radiotherapy (palliative radiotherapy for local bone/brain lesions is permitted if completed within 2 weeks prior to the first dose), major surgical procedures (not fully recovered from surgery or injury), or any live or attenuated live vaccines within 4 weeks prior to the first dose; or planned to receive live vaccines after enrollment; 3. Patients who received systemic treatment with corticosteroids (prednisone \>10 mg/day or equivalent) for more than 1 week or other immunosuppressants within 2 weeks prior to the first dose. Inhaled or topical corticosteroids, or systemic prednisone ≤10 mg/day or equivalent doses of similar drugs, are permitted; * Presence of active central nervous system metastases. Screening is permitted if the patient previously received radiotherapy or surgery, imaging within 4 weeks prior to the first dose indicates stable brain metastases without progression or new neurological symptoms, and corticosteroid therapy was discontinued at least 2 weeks prior to the first dose. Patients with leptomeningeal metastases or brainstem metastases are excluded regardless of treatment status; * Occurrence of immune-related adverse events leading to permanent discontinuation during prior treatment with immune checkpoint inhibitors (e.g., anti-PD-(L)1, CTLA-4, LAG-3 inhibitors, etc.); * Prior receipt of LY6G6D-targeted therapy or 4-1BB (CD137)-related therapy (including CAR-T, monoclonal antibodies, bispecific antibodies, etc.); * Presence of symptomatic pleural effusion, ascites, or pericardial effusion requiring repeated interventions (e.g., puncture or drainage); * History of interstitial lung disease or prior non-infectious pneumonia treated with corticosteroids, or evidence of active pneumonia on imaging during the screening period; * Toxicity from prior anti-tumor therapy has not recovered to ≤ Grade 1 as defined by the Common Terminology Criteria for Adverse Events (CTCAE v6.0) or to the level specified in the inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Dose-Limiting Toxicity (DLT) | The DLT observation period is 21 days after the first administration of HEC-921 | Proportion of participants with dose limiting toxicities during DLT observation window, to identify monotherapy and combination derive maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D). |
| Incidence and severity of adverse events (AEs) and serious adverse events (SAEs) | From first dose of study drug up to 1-year follow-up | The severity of adverse events (AEs) will be assessed according to the Common Terminology Criteria for Adverse Events (CTCAE) Version 6.0. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) | From first dose of study drug up to 1-year follow-up | The proportion of trial participants achieving complete response (CR) and partial response (PR) by the investigator based on RECIST 1.1 criteria. |
| Disease Control Rate (DCR) | From first dose of study drug up to 1-year follow-up | The proportion of trial participants achieving CR, PR, or stable disease (SD) (≥6 weeks) by the investigator based on RECIST 1.1 criteria. |
| Duration of Response | From first dose of study drug up to 1-year follow-up | Time from the first occurrence of CR or PR to the first occurrence of progressive disease (PD) or death (whichever occurs first). DoR applies only to trial participants achieving CR or PR by the investigator based on RECIST 1.1 criteria. |
| Progression-Free Survival ( PFS) | from the first dose administration to the first documented PD or death from any cause (whichever occurs first) , up to 1-year follow-up | The time from the first dose administration to the first documented PD according to RECIST v1.1 criteria or death from any cause (whichever occurs first) by the investigator based on RECIST 1.1 criteria. |
| Overall Survival ( OS) | Time from the first dose administration to death from any cause,up to 1-year follow-up | Time from the first dose administration to death from any cause by the investigator based on RECIST 1.1 criteria. |
| Maximum observed plasma concentration (Cmax) | From the first dose of the study drug to week 18 | to assess the pharmacokinetic profile |
| Area under the plasma concentration-time curve from time zero to last quantifiable concentration (AUClast) | From the first dose of the study drug to week 18 | to assess the pharmacokinetic profile |
| Positive rate of anti-drug antibodies (ADA) | From the first dose of the study drug to week 18 | The positive rate of anti-drug antibodies (ADA) against HEC-921 injection will be assessed in evaluable participants |
| Area under the plasma concentration-time curve extrapolated to infinity (AUCinf) | From the first dose of the study drug to week 18 | to assess the pharmacokinetic profile |
| Time to maximum observed plasma concentration (Tmax) | From the first dose of the study drug to week 18 | to assess the pharmacokinetic profile |
| Terminal elimination half-life (t1/2) | From the first dose of the study drug to week 18 | to assess the pharmacokinetic profile |
| Mean residence time (MRT) | From the first dose of the study drug to week 18 | to assess the pharmacokinetic profile |
| Clearance (CL) | From the first dose of the study drug to week 18 | to assess the pharmacokinetic profile |
| Apparent volume of distribution at steady state (Vss) | From the first dose of the study drug to week 18 | to assess the pharmacokinetic profile |
| AUC extrapolation ratio (AUC%Extrap) | From the first dose of the study drug to week 18 | to assess the pharmacokinetic profile |
| Maximum steady-state plasma concentration (Cmax,ss) | From the first dose of the study drug to week 18 | to assess the pharmacokinetic profile |
| Minimum steady-state plasma concentration (Cmin,ss) | From the first dose of the study drug to week 18 | to assess the pharmacokinetic profile |
| Average steady-state plasma concentration (Cav,ss) | From the first dose of the study drug to week 18 | to assess the pharmacokinetic profile |
| Area under the plasma concentration-time curve over one dosing interval at steady state (AUCtau) | From the first dose of the study drug to week 18 | to assess the pharmacokinetic profile |
| Steady-state clearance (CLss) | From the first dose of the study drug to week 18 | to assess the pharmacokinetic profile |
| Accumulation index (R) | From the first dose of the study drug to week 18 | to assess the pharmacokinetic profile |
| Degree of fluctuation (DF) | From the first dose of the study drug to week 18 | to assess the pharmacokinetic profile |
| Titer of anti-drug antibodies (ADA) | From the first dose of the study drug to week 18 | Titer of anti-drug antibodies (ADA) against HEC-921 injection will be assessed in evaluable participants. |
| Detection rate of neutralizing antibodies (NAb) in ADA-positive samples | From the first dose of the study drug to week 18 | Neutralizing antibodies (NAb) will be tested in ADA-positive samples collected, if needed. |
Countries
China
Contacts
CONTACTLiu Tianshu, MD
PRINCIPAL_INVESTIGATORLiu Tianshu, MD
Shanghai Zhongshan Hospital
Outcome results
None listed