Phase I-II, FIH, TROP2 ADC, Advanced Unresectable/Metastatic Solid Tumors, Refractory to Standard Therapies (A264)

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

A Phase I-II, First-in-Human Study of SKB264 in Patients With Locally Advanced Unresectable /Metastatic Solid Tumors Who Are Refractory to Available Standard Therapies

A Phase I-II, First-in-Human Study of SKB264 in Patients with Locally Advanced Unresectable/Metastatic Solid Tumors who are refractory to Available Standard Therapies. Patient must have historically documented, incurable, locally advanced or metastatic cancer that are refractory to standard therapies of one of the following types: Triple negative breast cancer Epithelial ovarian cancer Non-small cell lung cancer Gastric adenocarcinoma/Gastroesophageal junction adenocarcinoma Small cell lung cancer HR+/ HER2-breast cancer Head and neck squamous cell carcinoma Endometrial carcinoma Urothelial carcinoma

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).

Epithelial Ovarian Cancer, Gastric Adenocarcinoma, Gastroesophageal Junction Adenocarcinoma, Urothelial Carcinoma, Non-Small Cell Lung Cancer, Small-Cell Lung Cancer, Endometrial Carcinoma, Head and Neck Squamous Cell Carcinoma, Breast Cancer

Five dose levels have been selected for evaluation in the Phase I part of the study: 2, 4, 6, 9, and 12 mg/kg of SKB264

To determine the maximum tolerated dose (MTD) and/or recommended doses for expansion (RDEs). RDEs will not exceed MTD.

To evaluate the objective response rate (ORR) [Complete Response (CR) + Partial Response (PR)] of SKB264 when administered intravenously (IV) as monotherapy at the RDEs to patients with metastatic or locally advanced unresectable tumors.

From date of enrollment until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 12 months

To determine the dose limiting toxicities (DLTs) of SKB264 when administered IV twice (on Days 1 and 15) every 2 weeks in 4 weeks (28 days) cycles as monotherapy to patients with metastatic or locally advanced unresectable tumors.

Percentage of patients with adverse events (AEs), serious adverse events (SAEs), AEs with Grade ≥ 3 per NCI CTCAE v5.0, adverse events of Special Interest (AESI) and AEs related to study drug.

from the date of informed consent until 30 days after last infusion of study drug or begin a new anti cancer therapy, whichever occurs first

ORR (Objective Response Rate) as determined by the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1, which will be complete response (CR) + partial response (PR)

From date of enrollment until the date of first documented progression or date of death from any cause, whichever came first, approximately 12 months

To evaluate preliminary efficacy in patients treated with SKB264 as monotherapy based on DOR(Duration of Response).

From date of enrollment until the date of first documented progression or date of death from any cause, whichever came first, approximately 12 months

To evaluate preliminary efficacy in patients treated with SKB264 as monotherapy based on PFS(Progression-Free Survival).

From date of enrollment until the date of first documented progression or date of death from any cause, whichever came first, approximately 12 months

To evaluate preliminary efficacy in patients treated with SKB264 as monotherapy based on OS(Overall Survival)

From date of enrollment until the date of first documented progression or date of death from any cause, whichever came first, approximately 12 months

Percentage of patients with adverse events (AEs), serious adverse events (SAEs), AEs with Grade ≥ 3 per NCI CTCAE v5.0, adverse events of Special Interest (AESI) and AEs related to study drug.

from the date of informed consent until 30 days after last infusion of study drug or begin a new anti cancer therapy, whichever occurs first

To evaluate efficacy in patients treated with SKB264 as monotherapy based on DOR(Duration of Response)

From date of enrollment until the date of first documented progression or date of death from any cause, whichever came first, approximately 12 months.

To evaluate efficacy in patients treated with SKB264 as monotherapy based on PFS (Progression-Free Survival)

From date of enrollment until the date of first documented progression or date of death from any cause, whichever came first, approximately 12 months.

From date of enrollment until the date of first documented progression or date of death from any cause, whichever came first, approximately 12 months.

To assess levels of TROP2 expression in tumor tissue and correlation of those levels with responses and toxicity.

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, priority to include but not limited to the following tumor types (the sponsor will add or remove indications based on real-time study results): Triple negative breast cancer Epithelial ovarian cancer Non-small cell lung cancer (For Cohort 3B, only EGFR wild-type NSCLC will be enrolled) Gastric adenocarcinoma or gastroesophageal junction adenocarcinoma (gastroesophageal junction adenocarcinoma is defined as tumor with center located within 5cm below/above the anatomical esophagogastric junction per Siewert classification system) Small cell lung cancer HR+/ HER2- breast cancer Head and neck squamous cell carcinoma (including primary tumor location of oropharynx, oral cavity, hypopharynx, or larynx. Other primary tumor sites of HNSCC, including nasopharynx (any histology) or unknown primary tumor are not eligible) Endometrial carcinoma (including carcinosarcoma, but except sarcoma and neuroendocrine endometrial carcinoma) 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% (Pathology will be locally assessed), patients whose tumors contain any neuroendocrine component are not eligible) 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 Trop-2 expression. Measurable disease by CT/MRI. For Cohort 1, 2, 3A, 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. For other cohorts, prior lines of therapy as below: Cohort 3B: EGFR wild-type NSCLC: Patients have received platinum-containing chemotherapy in combination with anti-PD-1/L1 monoclonal antibodies as the only prior line of therapy; Prior neoadjuvant and/or adjuvant system therapy/ radical chemoradiotherapy would be counted as a line of therapy if the patient progressed to unresectable locally advanced, recurrent or metastatic disease during or within 6 months of completing neoadjuvant or adjuvant therapy. Cohort 4: GC or GEJC: Patients who have been treated with only one prior therapy of chemotherapy and anti-PD-1/L1 monoclonal antibodies therapy and progressed during or after treatment. Prior neoadjuvant and/or adjuvant system therapy would be counted as a line of therapy if the patient progressed to unresectable locally advanced, recurrent or metastatic disease during or within 6 months of completing neoadjuvant or adjuvant therapy. Cohort 5: Second-line ES-SCLC: Patients who must have progressed on or after treatment with an anti-PD-1/L1 monoclonal antibodies administrated as part of first-line platinum-based systemic therapy for ES-SCLC. Previously treated limited stage SCLC will not be eligible. Cohort 6: HR+/ HER2-BC : Patients who have received previously at least two and no more than four lines of chemotherapy for unresectable locally advanced or metastatic disease with at least one taxane-containing in any setting. Prior neoadjuvant and/or adjuvant chemotherapy would be counted as a line of therapy if the patients progressed to unresectable locally advanced, recurrent or metastatic disease during or within 12 months of completing neoadjuvant or adjuvant therapy. Patients should also have previously presented a progression on anticancer hormonal therapy with a CDK 4/6 inhibitor and/ or a relapse during or after adjuvant endocrine therapy combined with an approved CDK4/6 inhibitor in this setting. Note: 1) Patients with HR+/HER2-BC and visceral crisis will be excluded. 2) For patients who have known BRCA mutation and HR+/HER2-BC, prior PARP inhibitor is required before enrolled in this study (where available and not medically contraindicated). 3) For patients with unknown BRCA status, prior PARP inhibitor is not required. 4) Patients who previously received therapy with an anti- HER2 ADC (T-Dxd) for HER2 low expressing tumors are eligible and this therapy will count as one chemotherapy line for unresectable locally advanced or metastatic disease. Cohort 7: HNSCC: Patients who have been previously treated with therapy of anti-PD-1/L1 monoclonal antibodies (either as a single-agent or in combination with platinum-based chemotherapy) as first-line treatment in recurrent/metastatic (R/M) setting and progressed during or after treatment. Prior definitive/multimodal therapy for locally advanced (LA) HNSCC that included anti-PD-1/PD-L1 monoclonal antibodies and platinum therapy would be counted as a line of therapy if the patient progressed during or within 6 months of completing definitive therapy. Cohort 8: Endometrial cancer: Patients who have previously failed with first-line platinum-based chemotherapy; patients with microsatellite stability/non-mismatch repair deficiency (MSS/pMMR) endometrial carcinoma must have received prior platinum-based therapy and progressed during or after treatment. Patients with known high microsatellite instability/mismatch repair deficiency (MSI-H/dMMR) endometrial carcinoma must have received prior platinum-based therapy and anti-PD-1/L1 monoclonal antibodies therapy and progressed during or after treatment. Prior neoadjuvant/adjuvant chemotherapy would be counted as a line of therapy if the patient progressed to unresectable locally advanced, recurrent or metastatic disease during or within 12 months of completing neoadjuvant or adjuvant therapy. Note: 1) If anti-PD-1/L1 monoclonal antibodies therapy is not approved for second-line treatment for MSI-H/dMMR endometrial cancer patients in certain regions, prior treatment with anti-PD-1/L1 monoclonal antibodies is not required. 2) If MMR/MSI status is unknown, patients who have been only treated with platinum based therapy is acceptable. Cohort 9: UC: Patients who have failed with prior first-line platinum-based therapy and received prior anti-PD-1/L1 monoclonal antibodies therapy and progressed during or after the latest treatment. Prior neoadjuvant/adjuvant system therapy would be counted as a line of therapy if the patient progressed to unresectable locally advanced, recurrent or metastatic disease during or within 12 months after completing neoadjuvant or adjuvant therapy. 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 (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). Symptomatic brain metastases or any radiation or surgery for brain metastases within 1 months of first infusion of study drug. 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 or topoisomerase I-containing antibody drug conjugates 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). The investigator considers other situations that patients are not appropriate to participate in this trial.