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

Study Overview
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Brief Summary
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This is an open, multicenter study of stage I/II in Chinese subjects with unresectable locally advanced/metastatic solid tumors. It is divided into dose escalation period and cohort expansion period. A total of 9 dose groups (Q3W on the first day of intravenous administration every three weeks) were designed in the dose escalation period. The initial dose was 1.0mg/kg, Q3W, and the observation period of DLT was 21 days. In the dose expansion phase, 5 cohorts were set up.

Detailed Description
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A total of nine (Q3W, the first day of intravenous administration every three weeks) dose groups were designed in the dose escalation period. The dose groups were 1.0, 2.1, 4.2, 5.3, 6.3, 7.3, 8.4, 9.4 and 10.5 mg/kg, respectively. The BOIN design with accelerated titration was used, and the DLT observation period was 21 days. The specific steps for conducting a clinical trial using the BOIN design are as follows: 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-climbing 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. 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. 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. Once MTDS have been identified and the maximum sample size of 45 patients has not been reached, sponsors may enroll up to 12 additional patients in the selected MTDS to obtain more information on the safety and efficacy of the selected dose. In the additional extension process, the cull boundary in the decision table is used for toxicity monitoring. The Safety Monitoring Committee (SMC) will conduct an ongoing safety assessment during the dose escalation period. The safety data of each dose group should be reviewed and decided by the SMC before starting the administration of the next dose group. If additional safety, efficacy, and PK data are required for a dose group by SMC resolution, subjects will be allowed to continue to be enrolled in this dose group after completing the BOIN dose increment; 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 (i.e. to Phase Ib). 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 the same dose level as MTD or at a lower dose level than MTD; Rdes may also be different for different indications.

Official Title
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Phase I/II Clinical Study Evaluating the Safety, Tolerability, Pharmacokinetics/Pharmacodynamics, and Antitumor Activity of JSKN003 in Chinese Subjects With Advanced Solid Tumors

Conditions
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Advanced Solid Tumor

Intervention / Treatment
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* Drug: JSKN003


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject can understand the informed consent, voluntarily participate in and sign the informed consent; 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; ECOG score 0 or 1, expected survival ≥12 weeks; Subjects with confirmed pathological records of unresectable locally advanced or metastatic solid tumors with HER2 expression (IHC ≥ 1+) or gene mutation (HER2 exon 19 or 20 mutation) who have failed standard therapy, cannot tolerate standard therapy, or lack of effective treatment; For patients enrolled in Phase II cohort1, HER2 IHC can be 0 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. Agrees to provide adequate paraffin sections or fresh tissue specimens of the tumor for testing; Laboratory tests performed within 7 days or echocardiography performed within 28 days prior to initial dosing meet the following criteria: Bone marrow function: Neutrophil absolute count ≥1.5 × 109/L, hemoglobin ≥9.0 g/dL, platelet count ≥100 x 109/L; No blood transfusions or biological response regulators (such as granulocytes, erythrocyte growth factors, etc.) received within 14 days prior to routine blood tests; Kidney function: Serum creatinine ≤1.5 × ULN, or serum creatinine clearance ≥60 mL/min (calculated by Cockcroft-Gault formula); Liver function: Total bilirubin ≤1.5 × ULN; Aminotransferase (ALT/AST) ≤3 × ULN (liver metastasis subjects ≤5 × ULN); Patients with gastrointestinal tumors should have albumin ≥28g/L; Coagulation function: INR or PT≤1.5 × ULN; APTT ≤1.5 × ULN (Subjects receiving anticoagulant therapy should receive a steady dose of anticoagulant); Cardiac function: left ventricular ejection fraction (LVEF) ≥50% was confirmed by echocardiography within 28 days prior to initial administration; Sufficient elution of previous treatment prior to initial administration: Did not receive major surgery within 28 days prior to the administration of this trial (e.g., major abdominal and thoracic surgery; Excluding diagnostic puncture or peripheral vascular access replacement); No radical radiotherapy was received within 28 days prior to administration (for palliative radiotherapy, the washout period should be ≥14 days, and the radiotherapy dose should meet local standards for palliative care); No chemotherapy was received within 28 days before administration (the elution period of oral fluorouracil drugs, folic acid drugs and one-week paclitaxel intensive chemotherapy was ≥14 days, and the elution period of nitrosourea and mitomycin was ≥42 days); Did not receive antitumor immunotherapy within 28 days prior to administration; Did not receive endocrine therapy or anti-tumor Chinese patent drugs within 14 days before administration; Did not receive any other interventional clinical trial therapy or other antitumor therapy within 28 days prior to administration of this trial or within 5 half-lives (whichever is shorter, but at least 2 weeks); A fertile female subject or a fertile male subject with a+B72 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); 10. Subjects participating in the cohort expansion period (Ib) stud+B72y will also be required to meet the following conditions based on cohort assignment: Cohort 1: Histologically and/or cytologically confirmed locally advanced or metastatic breast cancer, who has received first-line standard therapy for locally advanced or metastatic breast cancer and has developed disease progression during or after treatment, who has received at least first-line chemotherapy regimen, and whose previous pathological record confirms that HER2 is not highly expressed (defined as HER2 IHC 2+ and FISH negative), Or IHC 0, IHC 1+); Cohort 2: Histologically and/or cytologically confirmed unresectable locally advanced/metastatic breast cancer, who has received first-line standard treatment for locally advanced or metastatic breast cancer and has developed disease progression during or after treatment, who has been treated with trastuzumab (or bioanalogues) and violanoids, Previous pathological records confirmed HER2 positive (defined as HER2 IHC 3+ or FISH +); Cohort 3: Histologically and/or cytologically confirmed locally advanced or metastatic non-small cell lung cancer who has received first-line standard therapy for locally advanced or metastatic non-small cell lung cancer and has developed disease progression during or after treatment with a confirmed HER2 mutation (defined as a HER2 exon 19 or 20 mutation) on previous pathologic records; Cohort 4: Histologically and/or cytologically confirmed locally advanced or metastatic non-small cell lung cancer who has received first-line standard therapy for locally advanced or metastatic non-small cell lung cancer and who has developed disease progression during or after treatment and whose previous pathological record confirms HER2 amplification (defined as FISH+). Cohort 5: Histologically and/or cytologically confirmed locally advanced inoperable/metastatic gastric/gastroesophageal junction adenocarcinoma with low HER2 expression (HER2 IHC 2+ and FISH negative, or IHC 1+) with at least previous first-line standard therapy. Cohort 6: Histologically and/or cytologically confirmed locally advanced inoperable/metastatic HER2-medium high expression solid tumors that have failed systemic treatment, lack effective treatment options, and have no more than 3 previous lines of treatment. High expression in HER2 is defined as HER2 IHC 2+ or 3+. Exclusion Criteria: Untreated subjects with active brain metastases; • Subjects with perimeningeal metastases were admitted if their brain metastases had been treated and were stable (brain imaging at least 4 weeks prior to initial administration showed stable lesions with no new neurological symptoms and no need for immediate local or systemic treatment) or if there was no evidence of new or enlargement of the original brain metastases; Subjects with asymptomatic BMS who do not require immediate local or systemic therapy (such as mannitol or corticosteroids) are admitted; Previous history of other primary malignant tumors; Except basal cell carcinoma of the skin, superficial bladder carcinoma, squamous cell carcinoma of the skin, papillary carcinoma of the thyroid, or cervical carcinoma in situ; Or patients who have received radical therapy and have not relapsed within 5 years of treatment can participate in this trial; Previously received topoisomerase I inhibitor antibody conjugate drug; Have uncontrolled comorbidities, including but not limited to: Subjects with active HBV or HCV infection who are HBsAg positive and/or HCV antibody positive during screening should be tested for HBV DNA and/or HCV RNA. Subjects with HBV DNA≤500 IU/mL (or ≤2000 copies/mL) and/or HCV RNA negative were eligible for inclusion. HBsAg positive subjects must monitor HBV DNA during treatment; Known history of HIV infection or AIDS; Active tuberculosis; Active infection or systematic use of anti-infective drugs for more than 1 week within 28 days prior to administration in this study; Uncontrolled hypertension (resting blood pressure ≥150/95 mmHg) in patients with known hypertension who need to maintain a steady dose of antihypertensive medication for 7 days prior to initial dosing; Cardiovascular diseases of clinical significance: Included risk of cerebrovascular accident, symptomatic cardiac dysfunction (NYHA II-IV) within 6 months, unstable angina or myocardial infarction within 6 months, or prolonged QTc or arrhythmia (baseline QTc > 470 msec for women, Male QTc > 450 msec, hypokalemia, long QT syndrome, resting heart rate > 100 bpm atrial fibrillation or severe valvular disease); Severe unhealed wounds, sores or fractures; 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; 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, bad fluid, etc.; Toxicity of previous antitumor therapy did not return to class 1 as defined by NCI-CTCAE v5.0 (except for alopecia or grade 2 hypothyroidism stabilized by hormone replacement therapy); 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; Allow subjects to inhale or apply hormones topically, or to receive physiological replacement doses of hormone therapy (< 10 mg/ day prednisone, or equivalent of other corticosteroids) for adrenal insufficiency; Allow short-term (< 7 days) corticosteroids for the prevention of (e.g., contrast media allergy) or the treatment of non-autoimmune conditions (e.g., delayed hypersensitivity caused by exposure to allergens); 9. A history of life-threatening allergic reactions or a known allergy to any component or excipient of JSKN003 pharmaceutical preparation; 10. History of trastuzumab induced allergic reactions (≥ grade 3), angioedema, or severe hypotension; 11. Other conditions, including but not limited to psychiatric disorders, alcoholism, or drug abuse, that the investigator considers unsuitable for participation in the clinical trial.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose escalation and expansion period<br>in dose escalation and expansion period，total 9 dose groups were designed. Subjects will be give dose 1.0, 2.1, 4.2, 5.3, 6.3, 7.3, 8.4, 9.4 and 10.5 mg/kg Q3W based on DLT results. | Drug: JSKN003<br>* JSKN003 should be given on the first day of administration every 3 weeks by intravenous drip. Before administration, JSKN003 should be redissolved with sterilized water for injection, and then diluted with 0.9% sodium chloride solution to a concentration of 0.5 5.0mg/ml. It is recommended that subjects' weight be measured on the day of each administration or one day before administration to calculate the dosage of JSKN003.<br>|
| Experimental: cohort 1 in phase II<br>Histologically and/or cytologically confirmed patients with unresectable locally advanced/metastatic breast cancer with low HER2 expression (IHC 1+ or IHC 2+ and FISH - or IHC 0) with an estimated sample size of about 30-50. | Drug: JSKN003<br>* JSKN003 should be given on the first day of administration every 3 weeks by intravenous drip. Before administration, JSKN003 should be redissolved with sterilized water for injection, and then diluted with 0.9% sodium chloride solution to a concentration of 0.5 5.0mg/ml. It is recommended that subjects' weight be measured on the day of each administration or one day before administration to calculate the dosage of JSKN003.<br>|
| Experimental: cohort 2 in phase II<br>Histologically and/or cytologically confirmed HER2 positive (IHC 3+ or FISH +) non-operable locally advanced/metastatic breast cancer with an expected sample size of about 30. | Drug: JSKN003<br>* JSKN003 should be given on the first day of administration every 3 weeks by intravenous drip. Before administration, JSKN003 should be redissolved with sterilized water for injection, and then diluted with 0.9% sodium chloride solution to a concentration of 0.5 5.0mg/ml. It is recommended that subjects' weight be measured on the day of each administration or one day before administration to calculate the dosage of JSKN003.<br>|
| Experimental: cohort 3 in phase II<br>Histologically and/or cytologically confirmed HER2 mutation patients (HER2 exon 19 or 20 mutation) with locally advanced inoperable/metastatic non-small cell lung cancer, with an estimated sample size of about 34 patients. | Drug: JSKN003<br>* JSKN003 should be given on the first day of administration every 3 weeks by intravenous drip. Before administration, JSKN003 should be redissolved with sterilized water for injection, and then diluted with 0.9% sodium chloride solution to a concentration of 0.5 5.0mg/ml. It is recommended that subjects' weight be measured on the day of each administration or one day before administration to calculate the dosage of JSKN003.<br>|
| Experimental: cohort 4 in phase II<br>Histologically and/or cytologically confirmed HER2 amplification (FISH +) patients with locally advanced/metastatic non-small cell lung , the expected sample size is approximately 34. | Drug: JSKN003<br>* JSKN003 should be given on the first day of administration every 3 weeks by intravenous drip. Before administration, JSKN003 should be redissolved with sterilized water for injection, and then diluted with 0.9% sodium chloride solution to a concentration of 0.5 5.0mg/ml. It is recommended that subjects' weight be measured on the day of each administration or one day before administration to calculate the dosage of JSKN003.<br>|
| Experimental: cohort 5 in phase II<br>Histologically and/or cytologically confirmed HER2 moderately and lowly in expression (HER2 IHC 2+ and FISH-，or IHC 1+) patients with locally advanced inoperable/metastatic gastric cancer or gastroesophageal borderline cancer, with an estimated sample size of about 34 patients. | Drug: JSKN003<br>* JSKN003 should be given on the first day of administration every 3 weeks by intravenous drip. Before administration, JSKN003 should be redissolved with sterilized water for injection, and then diluted with 0.9% sodium chloride solution to a concentration of 0.5 5.0mg/ml. It is recommended that subjects' weight be measured on the day of each administration or one day before administration to calculate the dosage of JSKN003.<br>|
| Experimental: cohort 6 in phase II<br>Histologically and/or cytologically confirmed HER2 moderately and highly in expression patients with solid tumors ( Excepted breast cancer, gastric/gastroesophageal junction cancer, and non-small cell lung cancer). Failured with systematic treatment , lack of effective treatment means, and the number of previous treatment lines does not exceed 3 lines, with an estimated sample size of about 34 patients. | Drug: JSKN003<br>* JSKN003 should be given on the first day of administration every 3 weeks by intravenous drip. Before administration, JSKN003 should be redissolved with sterilized water for injection, and then diluted with 0.9% sodium chloride solution to a concentration of 0.5 5.0mg/ml. It is recommended that subjects' weight be measured on the day of each administration or one day before administration to calculate the dosage of JSKN003.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| DLT (dose escalation period) | Incidence of dose-limiting toxicity (DLT) in dose esclation period | Up to 12 months | 
| Maximum Tolerated Dose (MTD) | MTD (Maximum tolerated Dose) is the dose for which the isotonic estimate of the toxicity rate is closest to the target toxicity rate based on the BOIN Design | Up to 12 months | 
| Percentage of Participants Experiencing Any Treatment Emergent Adverse Events and Serious Treatment Emergent Adverse Events | TEAE and SAE were gradede by CTCAE 5.0 | Throughout the duration of the study, about 2 year | 
| Objective Response Rate (ORR) | Objective response rate (ORR) was defined as the proportion of participants who achieve either complete response [CR] or partial response [PR] per Response Evaluation Criteria in Solid Tumors (RECIST v1.1） | Throughout the duration of the study, about 2 year | 
| Duration Of Response (DOR) | Defined as the time from the first evaluation of objective response to the first evaluation of PD or death from any cause prior to PD | Throughout the duration of the study, about 2 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical benefit rates (CBR) | Clinical benefit rate (CR+PR+[stable disease (SD) ≥ 6 months]) is defined as those participants with best response as CR or PR or else SD with a duration of at least 6 months. SD for 6 months duration was defined as the time from the first dose to the first documentation of PD or to the last adequate response assessment prior to data cut-off date, whichever is earlier. | Throughout the duration of the study, about 2 year | 
| Progression Free Survival (PFS) | PFS is defined as the duration from the start of treatment to the onset of tumor progression or death of any cause | Throughout the duration of the study, about 2 year | 
| Cmax of JSKN003 | Maximum (Peak) Observed blood Concentration (Cmax) of JSKN003 Following First Dose | Throughout the duration of the study, about 2 year | 
| Tmax of JSKN003 | Time of Maximum blood Concentration (Tmax) of JSKN003 Following First Dose | Throughout the duration of the study, about 2 year | 
| AUC of JSKN003 | The blood PK parameters of JSKN003 and its analytes for area under the concentration-versus-time curve from time 0 to the last quantifiable concentration as calculated by the linear-up log-down trapezoidal method (AUClast) and AUC from time 0 to infinity (AUCinf) elimination rate constant associated with the terminal phase were estimated using standard non-compartmental methods. | Throughout the duration of the study, about 2 year | 
| Terminal Elimination Half-life (t1/2) | The blood PK parameters of Terminal elimination half-life for JSKN003 | Throughout the duration of the study, about 2 year | 
| Anti-JSKN003 antibody | Status (positive or negative) and serum titers of anti-JSKN003 antibody | Throughout the duration of the study, about 2 year |