Solid Tumors Clinical Trial
Official title:
Phase IA Study of the Safety, Tolerability, Pharmacokinetics and Efficacy of Recombinant Humanized Anti-PD-1 Monoclonal Antibody (JS001) in Patients With Advanced Solid Tumors
The purpose of this study is to evaluate the safety, tolerance and Dose-Limiting Toxicity (DLT) of Recombinant humanized anti-PD-1 monoclonal antibody (JS001) in patients with advanced solid tumors.
OVERVIEW
This is a Phase 1, open-label, dose-escalation study of JS-001, a humanized monoclonal IgG4
antibody targeting the Programmed Death -1 (PD-1). It is estimated that 12-24 subjects with
advanced or recurrent solid tumors or will be enrolled in the study.
A 3+3 design will be utilized for this Phase 1 study. Four dose levels are planned and
include: 0.3, 1, 3, 10 mg/kg/dose. Each of the 4 dose levels will use 2 dose schedules:
single dose, repeated doses every 2 weeks. Subjects will be assigned to a dose schedule in
the order of study entry.
The study will be the traditional 3 + 3 design with 3 or 6 subjects treated at this dose
level and at all subsequent dose levels depending upon the incidence of DLTs. If no DLTs
occur in a cohort of 3 subjects, a new cohort of 3 subjects will be treated at the next
higher dose level. If 1 of 3 subjects in a cohort experiences a DLT, that cohort will be
expanded to 6 subjects. If only 1 of the 6 subjects has a DLT, then the next cohort of 3
subjects will be treated at the next higher dose level. If 2 or more DLTs occur within a
cohort, then that dose level will be above the MTD (the highest dose where no more than 1 of
6 subjects has experienced a DLT), and the previous lower (tolerated) dose level will be
considered the MTD.
A DLT is defined as a Grade 3 drug-related adverse event occurring within the first cycle (28
days) of dosing (excluding tumor flare defined as local pain, irritation, or rash localized
at sites of known or suspected tumor or a transient Grade 3 infusion adverse event) using
National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE)
version 4.0 in a single dose cohort.
Tumor response will be evaluated using immune-related response criteria (irRC), WHO criteria
, Response Evaluation Criteria in Solid Tumors (RECIST), immune-related RECIST, and
International Workshop to Standardize Response Criteria for non-Hodgkin's Lymphomas (for
lymphomas only).
In the absence of confirmed disease progression and intolerable toxicities, subjects in the
single dose cohorts and multiple dose cohorts will be allowed to continue JS-001
administration with the consent of the subject.
DOSAGE AND ADMINISTRATION
JS-001 will be administered as a 60-minute i.v. infusion. Cohorts will include escalating
dose levels of 0.3, 1, 3, 10mg/kg/dose.
SAFETY EVALUATIONS
Assessment of safety will be determined by vital sign measurements, clinical laboratory
tests, Eastern Cooperative Oncology Group (ECOG) performance status evaluations, diagnostic
imaging, physical examinations, electrocardiograms, and the incidence and severity of adverse
events.
Safety will also include evaluations of immune safety and immunogenicity. Particular
attention will be given to adverse events that may follow enhanced T-cell activation such as
dermatitis and colitis, uveitis, or other immune-related adverse events (irAEs).
An irAE is a clinically significant adverse event of any organ that is associated with drug
exposure, of unknown etiology, and is consistent with an immune-mediated mechanism.
EFFICACY EVALUATIONS
The primary efficacy endpoint is the best response rate (RR). Duration of response,
progression-free survival, time to progression, and overall survival will also be analyzed.
PHARMACOKINETIC EVALUATIONS
Pharmacokinetic parameters include AUC, Cmax, tmax, and t½, etc. STATISTICAL METHODS The
sample size for this study is not determined from power analysis. It is based on the 3+3
design for dose escalation and safety evaluation requirements.
Descriptive statistics will include: mean, standard deviation, median, and minimum and
maximum values for continuous variables; frequencies and percentages for categorical
variables.
The efficacy parameters will be summarized using descriptive statistics. All safety and
pharmacokinetic parameters will be summarized using descriptive statistics.
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