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

• Status: Not yet recruiting
• Trial end date: 2025-12-31
• Target enrollment: 0
• Participant gender: All

Summary

This is an open, multicenter study of stage Ia/Ib 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.

• Phase: Phase 1
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Jiangsu Alphamab Biopharmaceuticals Co., Ltd

Criteria

Inclusion Criteria:

1. Subject can understand the informed consent, voluntarily participate in and sign the informed consent;

2. 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;

3. ECOG score 0 or 1, no deterioration within 2 weeks prior to administration, expected survival ≥12 weeks;

4. 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;

5. 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.

6. Agrees to provide adequate paraffin sections or fresh tissue specimens of the tumor for testing;

7. 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);

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;

8. 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 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);

9. 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: Locally advanced or metastatic breast cancer confirmed histologically and/or cytologically, who has received first-line standard treatment for locally advanced or metastatic breast cancer and whose disease progresses during or after treatment, and who has been treated with at least first-line chemotherapy regimens, Previous pathological records confirm+B72ed low HER2 expression (defined as IHC 1+ or IHC 2+ with FISH -);

• Cohort 2: Unresectable locally advanced/metastatic breast cancer confirmed histologically and/or cytologically, who has received first-line standard treatment for locally advanced or metastatic breast cancer and developed disease progression during or after treatment, who has been treated with trastuzumab (or biological analogues) and taxoids, Previous pathological records confirmed HER2 positive (defined as IHC 3+ or FISH +);

• Cohort 3: Patients with locally advanced or metastatic gastric cancer who have been histologically and/or cytologically confirmed, who have received first-line standard therapy for locally advanced or metastatic gastric cancer and developed disease progression during or after treatment, who have received trastuzumab (or biological analogues), Previous pathological records confirmed HER2 positive (defined as IHC 3+ or IHC 2+ and FISH +);

• Cohort 4: Patients with histologically and/or cytologically confirmed locally advanced or metastatic colorectal cancer who have received at least two systematic treatment regimens for locally advanced or metastatic colorectal cancer and developed disease progression during or after treatment, who have received bevacizumab or cetuximab, Previous pathologic records confirmed HER2 positive (defined as IHC 3+ or IHC 2+ and FISH +) and written tumor genetic tests confirmed RAS/BRAF wild type.

• Cohort 5: Locally advanced or metastatic solid tumors confirmed histologically and/or cytologically with HER2 expression (IHC 1+ or above) or genetic mutation (HER2 exon 19 or 20 mutation) after failure of standard treatment, inability to tolerate standard treatment, or lack of effective treatment.

Exclusion Criteria:

1. 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;

2. 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;

3. Previously received topoisomerase I inhibitor antibody conjugate drug;

4. 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;

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. There were no suspected or confirmed cases of severe novel coronavirus (SARS-COV-2) infection in the 4 weeks prior to the knowledge. For patients with prior (suspected) infection with the novel coronavirus, the investigator should confirm that the patient has no acute symptoms and no sequelae of the novel coronavirus infection;

7. 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.;

8. 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);

9. 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); 10. A history of life-threatening allergic reactions or a known allergy to any component or excipient of JSKN003 pharmaceutical preparation; 11. History of trastuzumab induced allergic reactions (≥ grade 3), angioedema, or severe hypotension; 12. Other conditions, including but not limited to psychiatric disorders, alcoholism, or drug abuse, that the investigator considers unsuitable for participation in the clinical trial.