A Phase I, Multi-center, Open-label, Dose Escalation, First-In-Human Study to Assess the Safety, Tolerability and Pharmacokinetics of JSKN003 in Subjects With Advanced or Metastatic Solid Malignant Tumors
Overview
- Phase
- Phase 1
- Intervention
- JSKN003
- Conditions
- Advanced Solid Tumors
- Sponsor
- Alphamab (Australia) Co Pty Ltd.
- Enrollment
- 62
- Locations
- 1
- Primary Endpoint
- MTD
- Status
- Completed
- Last Updated
- 8 months ago
Overview
Brief Summary
This study is an open-label, multicenter, first-in-human, Phase I, dose escalation study to evaluate the safety, tolerability, PK, and preliminary anti-tumor activity of JSKN003 in subjects with advanced inoperable or metastatic solid malignant tumors that are expected to be HER2 expression.
Detailed Description
The dose escalation study will utilize single patient accelerated dose titration for the first two dose levels, 1.0 and 2.1 mg/kg, followed by dose cohorts 4.2, 5.2, 6.3, 7.3, and 8.4 mg/kg which will all be enrolled and monitored using the Bayesian optimal interval design, aimed at determining the MTD, RDE/RP2D of JSKN003. The dose-escalation of 9.4 mg/kg and 10.5 mg/kg should be determined per discussion between Safety Monitoring Committee and sponsor if deemed necessary, the SMC had the right of deciding to dose-escalate at other dose levels . Moreover, the SMC is also responsible for deciding the MTD and the recommended dose level for dose-expansion study. Enrolled patients will be sequentially assigned to the planned dose levels as required by the protocol and treated with JSKN003 IV Q3W to observe the occurrence of treatment related AEs and dose limiting toxicities. The DLT observation period is 21 days from administration of the first dose of JSKN003. The study will use a modified ADT design and BOIN design for dosing cohort management to determine the MTD and RDE/RP2D. The starting dose of JSKN003 is 1.0 mg/kg, followed by 2.1, 4.2, 5.3, 6.3, 7.3, 8.4, 9.4 and 10.5 mg/kg. The investigational product will be administered on Day 1 every 3 weeks via intravenous infusion, and the first cycle of JSKN003 treatment is for DLT evaluation.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Be willing and able to provide signed informed consent form (ICF) for the trial.
- •Male or female, 18 years of age or older; willing and able to comply with study requirements.
- •Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1 with no deterioration within 2 weeks of scheduled study treatment, and life expectancy ≥ 12 weeks.
- •Must have a pathologically documented advanced/unresectable or metastatic solid malignant tumor with HER-2 expression (IHC ≥ 1+) that is refractory to or intolerable with standard treatment, or for which no standard treatment is available.
- •Baseline measurable disease according to RECIST 1.
- •Target lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions.
- •Adequate organ function assessed within 7 days prior to first trial treatment \[had not received blood transfusion, erythropoietin (EPO), granulocyte colony stimulating factor (G-CSF) or other relevant medical support within 14 days before the administration of the investigational product\].
- •Have adequate treatment washout period before first trial treatment.
- •Have LVEF ≥ 50% by either echo cardiography (ECHO) or multiple-gated acquisition (MUGA) within 28 days prior to first trial treatment.
- •Female or male subjects of childbearing potential should be willing to use a highly effective method of contraception (with a failure rate of less than 1.0% per year) from first study treatment to 180 days after completion of the trial treatment. Female of childbearing potential should have a negative pregnancy test within 7 days prior to first trial treatment (childbearing potential is defined as premenopausal females without documented tubal ligation or hysterectomy, or postmenopausal females within 1 year).
Exclusion Criteria
- •Clinically active central nervous system (CNS) metastases, defined as untreated and symptomatic, with following exceptions:
- •Clinically stable through MRI/CT scans (at least 2 consecutive scans within prior 6 months including 1 scan within 28 days prior to screening) and no progressive or uncontrolled neurologic symptoms or signs (e.g., seizures, headaches, central nausea/emesis, progressive neurologic deficits, papilledema) for at least 4 weeks prior to the first treatment.
- •Any untreated asymptomatic brain metastases not requiring immediate local or systemic therapy (e.g., mannitol or corticosteroids).
- •Leptomeningeal metastasis is excluded from the study entry.
- •Concurrent malignancy within 5 years prior to entry other than adequately treated cervical carcinoma-in-situ, localized squamous cell cancer of the skin, basal cell carcinoma, prostate cancer, thyroid cancer not requiring treatment, ductal carcinoma in situ of the breast, or \<T1 urothelial carcinoma.
- •Prior treatment with an antibody-drug conjugate (ADC) which consists of a topoisomerase I inhibitor derivative.
- •History of uncontrolled intercurrent illness including but not limited to:
- •Active HBV or HCV infection. If HBsAg and HCV antibody positive, HBV DNA and HCV RNA assay should be performed. Subjects are eligible if HBV DNA ≤ 500 UI/ml (or 2000 copies/ml) or HCV RNA negative.
- •Known HIV infection or known history of acquired immune deficiency syndrome (AIDS);
- •Active tuberculosis infection.
Arms & Interventions
Dose escalation
It's a dose escalation to identify the Maximum Tolerated dose (MTD) , recommended dose for expansion (RDE) or recommended Phase II dose (RP2D) of JSKN003, guided by the modified ADT design and BOIN design.
Intervention: JSKN003
Outcomes
Primary Outcomes
MTD
Time Frame: Postdose of last participant up to 1 year
Maximum tolerated dose
DLTs
Time Frame: Baseline up to 21 days after the first dose
Dose Limiting Toxicities
Adverse Events
Time Frame: Baseline up to 30 days after the last dose of study drug, up to 1 year
Incidence and severity of treatment-emergent adverse events (TEAEs), treatment-related adverse events (TRAEs), serious adverse events (SAEs)
Preliminary RDE/RP2D
Time Frame: Postdose of last participant up to 1 year
recommended dose for expansion / recommended phase 2 dose
Secondary Outcomes
- ORR(Postdose of last participant up to 1 year)
- TTR(Postdose of last participant up to 1 year)
- Anti-JSKN003 antibody(Post last dose up to Day 90)
- Terminal Elimination Half-life (t1/2)(Post last dose up to Day 90)
- Cmax of JSKN003(Post last dose up to Day 90)
- Tmax of JSKN003(Post last dose up to Day 90)
- AUC of JSKN003(Post last dose up to Day 90)
- DoR(Postdose of last participant up to 1 year)
- PFS(Postdose of last participant up to 1 year)