Phase I-II, FIH, TROP2 ADC, Advanced Unresectable/Metastatic Solid Tumors, Refractory to Standard Therapies (KL264-01)

This is an open label, Phase I-II, first in human (FIH) study for SKB264 as monotherapy in patients who have locally advanced unresectable or metastatic solid tumor that is refractory to all standard therapies. TROP2 (trophoblast antigen 2) assessments will not be performed prior to enrollment but it will be assessed retrospectively. Confirmation of TROP2 (trophoblast antigen 2) expression by immunohistology or other means is not required, but the Sponsor will request fresh tumor biopsy or tissue specimens from archived materials for determination of TROP2 (trophoblast antigen 2) expression retrospectively. The patient must be, in the judgment of the investigator, an appropriate candidate for experimental therapy whose tumor is refractory to standard therapies. Patients will receive study drug as a single IV infusion at the prescribed dose level at each administration. Cycles will continue until disease progression or unacceptable toxicity. The study is divided into 2 parts (Phase I and Phase II).

Diagnosis and Main Criteria for Inclusion:

Inclusion criteria

Patients must meet the following criteria for inclusion into the study:

Phase I:

• Patients must be able to provide documented voluntary informed consent.
• Male or female patient aged 18-75 years.
• Histologically documented, incurable, locally advanced or metastatic epithelial origin malignant cancer, priority to include but not limited to the following tumor types:

Breast cancer Ovarian epithelial cancer Non-small cell lung cancer Gastric adenocarcinoma Small cell lung cancer Urothelial carcinoma Note: Confirmation of TROP2 expression by immunohistology or other means is not required, but the Sponsor will request tissue specimens from fresh or archived materials for determination of TROP2 expression.

• Measurable disease by CT/MRI during dose escalation.
• Patients should have an unresectable locally advanced or metastatic solid tumor that is refractory to standard therapies, or have no standard therapies, or standard treatment is not applicable at this stage.
• Granulocyte count ≥ 1.5×109/L, platelet count ≥ 100×109/L, and hemoglobin ≥ 9 g/dL.
• International normalized ratio (INR) and activated partial thromboplastin time (aPTT) ≤ 1.5×ULN.
• Serum bilirubin ≤ 1.5 mg/dL (Patients with known Gilbert disease who have serum bilirubin level ≤ 3 ×ULN may be enrolled)., aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase ≤ 2.5 × upper limit of normal (ULN), with the exception of patients with hepatic metastases (ALT and AST ≤ 5 × ULN) and patients with hepatic and/or bone metastases (alkaline phosphatase ≤ 5 × ULN).
• Creatinine clearance ≥ 50 mL/min calculated by Cockcroft-Gault, Chronic Kidney Disease Epidemiology Collaboration, or Modification of Diet in Renal Disease formulas. Note that 24 hour urine collection is not required but is allowed.
• Eastern Cooperative Oncology Group (ECOG) Performance Status 0 or 1.
• For female patients of childbearing potential and male patients with partners of childbearing potential, agreement (by patient and/or partner) to use a highly effective form(s) of contraception during study treatment. Female and male patient treated with SKB264 should continue contraception use for 7 months after the last dose. Such methods include combined (estrogen and progestogen containing) hormonal contraception, progestogen-only hormonal contraception associated with inhibition of ovulation together with another additional barrier method always containing a spermicide, intrauterine device (IUD), intrauterine hormone-releasing system (IUS), bilateral tubal occlusion or vasectomized partner (on the understanding that this is the only one partner during the whole study duration), and sexual abstinence.

• Oral contraception should always be combined with an additional contraceptive method because of a potential interaction with the study drug. The same rules are valid for male patients involved in this clinical trial if they have a partner of childbirth potential. Male patients must always use a condom.
• Women are excluded from birth control if they had had tubal ligation or a hysterectomy.
• Patients must have recovered (i.e., improvement to Grade 1 or better) from all acute toxicities from previous therapy, excluding alopecia and vitiligo.
• Expected survival ≥ 3 months.

Phase II:

• Patients must be able to provide documented voluntary informed consent.
• Male or female patient aged ≥ 18 years.
• Histologically or cytologically documented, incurable, locally advanced, recurrent or metastatic cancer, including the following tumor types:

• Cohort 1: triple negative breast cancer (< 1% expression for estrogen receptor [ER] and progesterone receptor [PR] and HER2 negative)
• Cohort 2: ovarian cancer, fallopian tube cancer, or primary peritoneal cancer
• Cohort 3: non-small cell lung cancer
• Cohort 4: gastric adenocarcinoma or gastroesophageal junction adenocarcinoma (HER2 negative)
• Cohort 6: HR+/ HER2- breast cancer (≥1% expression for ER and/or PR and HER2 negative)
• Cohort 7: Head and neck squamous cell carcinoma (including primary tumor location of oropharynx, oral cavity, hypopharynx, or larynx. Other primary tumor sites of HNSCC are not eligible)
• Cohort 8: Endometrial carcinoma (including carcinosarcoma, but excluding sarcoma and neuroendocrine endometrial carcinoma)
• Cohort 9: Urothelial carcinoma (including urothelial carcinoma of the renal pelvis, ureter, bladder, or urethra, patients with mixed histology are eligible provided urothelial component > 50% and plasmacytoid component<10%, patients whose tumors contain any neuroendocrine component are not eligible)
• Cohort 10: Cervical cancer (including squamous cell carcinoma, adenosquamous carcinoma, or adenocarcinoma of the cervix) Note: Evaluation of TROP-2 expression is required.
• Measurable disease by CT/MRI.
• Patients should have an unresectable locally advanced or metastatic solid tumor that is refractory to standard therapies.
• Neutrophil count ≥ 1.5×109/L, platelet count ≥ 100×109/L, and hemoglobin ≥ 9 g/dL.
• International normalized ratio (INR) and activated partial thromboplastin time (aPTT) ≤ 1.5×ULN.
• Serum bilirubin ≤ 1.5 ×ULN (Patients with known Gilbert disease who have serum bilirubin level ≤ 3 ×ULN may be enrolled), aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase ≤ 2.5 × upper limit of normal (ULN), with the exception of patients with hepatic metastases (ALT and AST ≤ 5 × ULN) and patients with hepatic and/or bone metastases (alkaline phosphatase ≤ 5 × ULN).
• Creatinine clearance ≥ 30 mL/min calculated by Cockcroft-Gault, Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI), or Modification of Diet in Renal Disease (MDRD) formulas. Note that 24 hour urine collection is not required but is allowed.
• ECOG Performance Status 0 or 1.
• For female patients of childbearing potential and male patients with partners of childbearing potential, agreement (by patient and/or partner) to use a highly effective form(s) of contraception during study treatment. Female and male patient treated with SKB264 should continue contraception use for 6 months after the last dose. Such methods include combined (estrogen and progestogen containing) hormonal contraception, progestogen-only hormonal contraception associated with inhibition of ovulation together with another additional barrier method always containing a spermicide, intrauterine device (IUD), intrauterine hormone-releasing system (IUS), bilateral tubal occlusion or vasectomized partner (on the understanding that this is the only one partner during the whole study duration), and sexual abstinence.

• Oral contraception should always be combined with an additional contraceptive method because of a potential interaction with the study drug. The same rules are valid for male patients involved in this clinical trial if they have a partner of childbirth potential. Male patients must always use a condom.
• Women are excluded from birth control if they had had tubal ligation or a hysterectomy.
• Patients must have recovered (i.e., improvement to Grade 1 or better) from all acute toxicities from previous therapy, excluding alopecia and vitiligo. Note: Subjects with endocrine AE of any grade are permitted to enroll if they are stably maintained on appropriate replacement therapy and are asymptomatic.
• Expected survival ≥ 3 months.

Exclusion criteria

Patients that meet the following criteria will be excluded from entry into the study:

Phase I:

• Severe or uncontrolled cardiac disease requiring treatment, congestive heart failure (New York Heart Association) III or IV, unstable angina pectoris even if medically controlled, history of myocardial infarction during the last 6 months, serious arrhythmias requiring medication (with exception of atrial fibrillation or paroxysmal supraventricular tachycardia).
• Symptomatic brain metastases or any radiation or surgery for brain metastases within 1 months of first infusion of study drug.
• Subjects with second primary cancers (except for cured in situ non-melanoma skin cancer and in situ cervical cancer with no relapse in the last 3 years).
• Require supplemental oxygen for daily activities.
• Documented Grade ≥ 2 peripheral neuropathy.
• History of documented severe dry eye syndrome, severe Meibomian gland disease and/or blepharitis, corneal disease that prevents/delays corneal healing, macular degeneration.
• Subjects previously treated with TROP 2 targeted therapies.
• Any standard cancer therapy (e.g. chemotherapy, hormonal therapy, radiotherapy, immunotherapy, biologic therapy treatment, or therapy with traditional Chinese medicines approved for anti-tumor treatment, etc.) within 4 weeks or five half-lives, whichever is shorter, of first infusion of study drug.
• Any experimental therapy within 4 weeks or five half-lives, whichever is shorter, of first infusion of study drug.
• Any major surgical procedure within 4 weeks of first infusion of study drug.
• Diagnosed active liver disease, including viral or other hepatitis, current or history of alcoholism, or cirrhosis.
• Have known prior positive test results or medical history for human immunodeficiency virus.
• Uncontrolled hypertension (systolic blood pressure ≥ 160 mmHg and/or diastolic blood pressure ≥ 100 mmHg) or diabetes (HbA1c ≥ 9.0%).
• Subjects who require use of strong inhibitors or inducers of CYP3A4 at least 14 days prior to and throughout Study. Use of strong inhibitors or inducers of CYP3A4 is not allowed in this study. List of representative examples of strong inhibitors or inducers of CYP3A4 is provided in Appendix III.
• Pregnancy or lactation.
• Left ventricular ejection fraction < 45% determined by echocardiogram or multiple gated acquisition scan.
• Resting QTc > 480 msec at baseline.
• Ascites requiring paracentesis ≥1 per week.
• Symptomatic pleural effusion (< 90% oxygen saturation).
• Subjects with non-infectious interstitial lung diseases (ILD) or medical history of pneumonia requiring steroid treatments; severe pulmonary dysfunction caused by lung diseases.
• New diagnosed thromboembolic events that requires therapeutic intervention over the last 6 months (patients with stable control of lower limb deep venous thrombosis are allowed).
• The investigator considers other situations that patients are not appropriate to participate in this trial.

Phase II:

• Any patient who was treated in the Phase I part of this study.
• Severe or uncontrolled cardiac disease requiring treatment, congestive heart failure (New York Heart Association) III or IV, unstable angina pectoris even if medically controlled, history of myocardial infarction during the last 6 months, serious arrhythmias requiring medication (with exception of atrial fibrillation or paroxysmal supraventricular tachycardia).
• Subjects with known meningeal metastases, brainstem metastases, spinal cord metastases and/or compression, or other active CNS metastases.
• Patients with active second primary cancers (except for cured in situ non-melanoma skin cancer and in situ cervical cancer with no relapse in the last 3 years, or other malignant cancers that have been cured and no evidence of recurrence).
• Require supplemental oxygen for daily activities.
• Documented Grade ≥ 2 peripheral neuropathy.
• History of documented severe dry eye syndrome, severe Meibomian gland disease and/or blepharitis, corneal disease that prevents/delays corneal healing, macular degeneration.
• Patients previously treated with TROP 2 targeted therapies at any time for early stage or metastatic disease.
• Any standard cancer therapy (e.g. chemotherapy, hormonal therapy, radiotherapy, immunotherapy, biologic therapy treatment, or therapy with traditional Chinese medicines approved for anti-tumor treatment, etc.) within 4 weeks or 5 half-lives, whichever is shorter, of first infusion of study drug.
• Any experimental therapy within 4 weeks or 5 half-lives, whichever is shorter, of first infusion of study drug.
• Any major surgical procedure within 4 weeks of first infusion of study drug.
• Diagnosed active liver disease, including viral or other hepatitis, current or history of alcoholism, or cirrhosis.
• Have known prior positive test results or medical history for human immunodeficiency virus.
• Uncontrolled hypertension (systolic blood pressure ≥ 160 mmHg and/or diastolic blood pressure ≥ 100 mmHg) or diabetes (HbA1c ≥ 9.0%).
• Subjects who require use of strong inhibitors or inducers of CYP3A4 at least 14 days prior to and throughout Study. Use of strong inhibitors or inducers of CYP3A4 is not allowed in this Study. List of representative examples of strong inhibitors or inducers of CYP3A4 is provided in Appendix III.
• Pregnancy or lactation.
• Left ventricular ejection fraction < 45% determined by echocardiogram or multiple gated acquisition scan.
• Resting QTcF > 480 msec at baseline.
• Ascites requiring paracentesis >1 per week.
• Symptomatic pleural effusion (< 90% oxygen saturation).
• History of interstitial lung diseases (ILD) or non-infectious pneumonitis requiring steroid treatments; severe pulmonary dysfunction caused by lung diseases.
• New diagnosed thromboembolic events that requires therapeutic intervention over the last 6 months (patients with stable control of lower limb deep venous thrombosis are allowed).
• Known allergic to any components of SKB264, including excipients (including polysorbate-20); or history of severe hypersensitivity to another biologic therapy.
• The investigator considers other situations that patients are not appropriate to participate in this trial.