Safety and Tolerability of JSKN003 in Chinese Subjects With Advanced Solid Tumors

This is an open, multicenter study of phase I/II in Chinese subjects with unresectable locally advanced/metastatic solid tumors. It is divided into the dose escalation period and the cohort expansion period. A total of 8 dose groups (Q3W on the first day of intravenous administration) were designed in the dose escalation period. The initial dose was 1.0mg/kg administered Q3W, with a DLT observation period of 21 days. In the dose expansion phase, 7 cohorts were established.

A total of eight dose groups (Q3W, intravenous administration on the first day of each cycle) were designed in the dose escalation period. The dose groups were 1.0, 2.1, 4.2, 5.2, 6.3, 7.3, 8.4 and 10.5 mg/kg. The BOIN design, incorporating accelerated titration, was used, and the DLT observation period was set at 21 days.

The specific steps for implementing the BOIN design in the clinical trial are as follows:

1. Perform the accelerated titration as follows: Assign the first patient to dose level 1. If this patient does not develop dose-limiting toxicity (DLT), the second patient will be treated at the next higher dose level. Treat one patient at a time and continue the dose-escalation process until the first DLT is observed, or a second grade 2 toxicity occurs, or the highest dose is reached. Two more patients were then treated on the current dose. After that, follow steps 2 and 3 and take the number of cases in each group as 3 to treat the follow-up patients.
2. Assign the dose to the next group of subjects according to the dose rise and fall rule shown in the Bayesian Optimal interval (BOIN) decision table.
3. Repeat Step 2 until the set maximum sample size of 45 or the number of evaluable subjects treated at the current dose reaches 12 and the current decision is to maintain the current dose according to the rise and fall rule of the dose rise and fall decision table.

After the dose escalation period was completed, order preserving regression was used to determine MTD. This calculation can be achieved by "Select MTD" in BOIN online software (Zhou et al., 2020). Specifically, the dose whose toxicity rate is closest to the target toxicity rate estimated by isotropic regression is identified as the MTD. During the dose escalation period, the sponsor may, with the approval of the SMC, expand in the appropriate dose group based on the safety, efficacy and external data obtained during the dose escalation period, as long as the number of patients in the extended dose group is consistent with the total sample size during the dose expansion period. Safety monitoring can still be conducted based on the exclusion boundary in the decision table during dose expansion. The patient data of the extended dose group were not involved in the up-down dose decision and the isotonic regression calculation during the dose escalation period.

The Safety Monitoring Committee (SMC) will perform ongoing safety assessment during the dose escalation period. The safety data of each dose group should be reviewed and approved by the SMC before initiating the administration of the next dose group. If additional safety, efficacy, and PK data are required for a dose group by SMC resolution, subjects may continue enrollment in this dose group after completing the BOIN dose eescalation; If the SMC has decided that a dose group can proceed to the cohort extension phase, it is permitted to proceed directly to the cohort extension phase in that dose group. The composition and responsibilities of the SMC will be further detailed in the SMC Constitution.

The recommended dose for cohort expansion (RDE) will be determined by the SMC based on safety/tolerability, PK data, and preliminary antitumor activity, as well as other available data. RDE can be at or below the MTD; RDE may also vary for different indications.

The SMC and sponsor will evaluate the validity of the maximum tolerated dose (MTD) determined by the BOIN design based on data from clinical studies of dose escalation and dose extension, and determine whether it is necessary to explore the higher dose group of 12.6 mg/kg.

Eligibility Criteria:
Inclusion Criteria:

1. Subject is at least 18 years old, male or female, and willing to follow the study procedure on the date of signing the informed consent;
2. ECOG score 0 or 1, expected survival ≥12 weeks;
3. Unresectable locally advanced or metastatic solid tumors with pathologic documented confirmation.
4. Measurable lesions at baseline according to RECIST 1.1 criteria; If the subject has only one measurable lesion at baseline, the lesion area must not have received prior radiotherapy or there is evidence of significant progression after the end of radiotherapy.
5. Agrees to provide adequate paraffin sections or fresh tissue specimens of the tumor for testing;
6. Laboratory tests within 7 days or cardiac ultrasound within 28 days prior to the first dose meet the protocol criteria.
7. Adequate washout from prior therapy prior to the first dose.
8. A fertile female subject or a fertile male subject with fertile partner agrees to use highly effective contraception (annual failure rate less than 1%) from the time of initial dosing to 180 days after the end of dosing. Pregnancy test results must be negative for fertile female subjects within 7 days prior to initial administration (fertile women are defined as premenopausal women with no recorded tubal ligation or hysterectomy, or women who have been menopausal for less than 1 year);

Exclusion Criteria:

1. Subjects with untreated active brain metastases or meningeal metastases;
2. History of other primary malignant tumors;
3. Previously received topoisomerase I inhibitor antibody conjugate drug;
4. Has uncontrolled comorbidities as specified by the protocol；
5. Past or current history of interstitial pneumonia/lung disease requiring systemic hormonal therapy, or suspected interstitial pneumonia/lung disease that cannot be ruled out by imaging during screening;
6. Subjects with uncontrolled large serous cavity effusion or moderate to large serous cavity effusion requiring repeated drainage (recurrent within 2 weeks after intervention) such as pleural effusion, pericardial effusion, ascites, etc.;
7. Toxicity from previous antitumor therapy has not resolved to Grade 1 or lower as defined by NCI-CTCAE v5.0.
8. Systemic corticosteroids (≥10 mg/ day of prednisone, or equivalent of other corticosteroids) or immunosuppressant therapy were required within 14 days prior to initial administration in this study;
9. Has a history of life-threatening anaphylaxis or known hypersensitivity to any component or excipient in the JSKN003 drug formulation.
10. History of trastuzumab-induced anaphylaxis (Grade ≥3), angioedema, or severe hypotension.
11. Subjects with gastrointestinal tumors who are known to have lost 10% or more of their body weight within three months prior to signing the informed consent form.
12. Other conditions that the investigator considers unsuitable to participate in this clinical trial, including but not limited to psychiatric disorders, alcoholism or drug abuse.