A Clinical Trial Evaluating SCB-219M in in Chemotherapy-induced Thrombocytopenia (CIT)

Study Overview
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Brief Summary
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A Phase I Clinical Study to Evaluate the Safety, Tolerability, Immunogenicity, Preliminary Efficacy and Pharmacokinetics of SCB-219M in the patients with chemotherapy-induced thrombocytopenia (CIT)

Official Title
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A Phase I Clinical Study to Evaluate the Safety, Tolerability, Immunogenicity, Preliminary Efficacy and Pharmacokinetics of SCB-219M in the Patients With Chemotherapy-induced Thrombocytopenia

Conditions
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Chemotherapy-induced Thrombocytopenia (CIT)

Intervention / Treatment
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* Biological: Recombinant Human Tumor Necrosis Factor Receptor II -Fc-TPO Mimetic Peptide Fusion Protein


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 18   75 years of age (inclusive), willing to participate in this study and sign the informed consent form, and attend the visits throughout the study; Body weight ≥ 45 kg; Dose escalation stage: Histopathologically or cytopathologically confirmed malignant solid tumors; Dose expansion stage: Histopathologically or cytopathologically confirmed malignant solid tumors (including but not limited to ovarian cancer, non-small cell lung cancer, breast cancer, colorectal cancer, and urinary bladder cancer); Dose escalation stage: Patients who are receiving paclitaxel or gemcitabine alone or in combination with platinum (e.g., cisplatin and carboplatin). The chemotherapy regimen may be combined with targeted therapy at the discretion of the investigator; Dose expansion stage: Patients who are receiving chemotherapy for 21 days as a cycle, with the cytotoxic chemotherapy regimen including at least one of the following drugs: antimetabolites, including gemcitabine, etc.; platinum drugs, including carboplatin, nedaplatin, cisplatin, lobaplatin, etc.; anthracyclines, including adriamycin, daunorubicin, epirubicin, etc.; alkylating agents, including cyclophosphamide, ifosfamide, etc.; or other cytotoxic chemotherapy drugs that can cause thrombocytopenia. The chemotherapy regimen may be combined with targeted therapy or immunotherapy at the discretion of the investigator; Dose escalation stage: PLT count within 30 × 109   75 × 109/L (inclusive) in the chemotherapy cycle prior to enrollment; Dose expansion stage: PLT count within 30 × 109   75 × 109/L (inclusive) in the chemotherapy cycle prior to enrollment; there are two PLT counts within the above range, and the time interval between the two PLT counts is at least 24 hours; Ability to receive the same chemotherapy regimen as the previous cycle of chemotherapy (dose delay or dose adjustment of chemotherapy due to PLT decrease is acceptable); Toxicities related to prior anti-tumor treatment have decreased to ≤ Grade 2 (CTCAE version 5.0) before enrollment (except for alopecia barbae, alopecia and subjective description of symptoms); ECOG PS score: 0   2; A life expectancy of at least 3 months, as assessed by the investigator; Hematology, blood chemistry, and coagulation function at enrollment: 75 × 109/L ≤ PLT count ≤ 200 × 109/L; PT/APTT/INR within 80% -120% (inclusive) of the normal range; Absolute neutrophil count ≥ 1.5 × 109/L; Hemoglobin ≥ 90 g/L (no red blood cell transfusion and no use of erythropoiesis-stimulating agents within 14 days); Albumin ≥ 25 g/L; Renal function at screening: serum creatinine ≤ 1.5 × ULN and creatinine clearance > 40 mL/min; Liver function at screening: Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 × ULN (or ≤ 5 × ULN in case of liver metastasis); Total bilirubin ≤ 2 × ULN unless a subject has Gilbert's syndrome or asymptomatic cholelithiasis; Eligible subjects of childbearing potential (male and female) must agree to use a reliable method of contraception during the study and for at least 90 days after the last dose; female subjects of childbearing potential must have a negative blood human chorionic gonadotropin (HCG) test within 28 days prior to enrollment; male subjects are not allowed to donate sperm from the first dose to 90 days after the last dose; Acceptable methods of contraception include: total abstinence; double barrier method (e.g. condom plus diaphragm with spermicide); use of intrauterine devices (IUDs) or hormonal contraceptives (e.g. oral drugs, implants, transdermal patches, hormonal vaginal devices or extended-Release injections), or hysterectomy/bilateral salpingectomy/bilateral tubal ligation in female subjects of childbearing potential or sexual partners of male subjects; and vasectomy or confirmed azoospermia in male subjects or sexual partners of female subjects. Exclusion Criteria: Pregnant or lactating women; Known allergies to protein drugs (e.g., recombinant proteins, and monoclonal antibodies) or excipients of the investigational product; Acute infections not clinically controlled and requiring intravenous antibiotics; Treatment with recombinant human thrombopoietin (rh-TPO) or recombinant human interleukin 11 (rh IL-11) within 10 days before the first dose; or treatment with thrombopoietin receptor agonist (TPO-RA) within 1 month before the first dose; Patients who have received anticoagulant or antiplatelet drugs (such as warfarin, cyclocoumarol, etc., aspirin requiring a washout period for ≥ 7 days) within 5 terminal half-lives before the first dose or need to continue to receive these drugs during the study; Clinically significant thrombocytopenia related to non-tumor chemotherapeutic drugs within 6 months prior to screening as assessed by the investigator, including but not limited to ethylenediaminetetraacetic acid (EDTA) -dependent pseudothrombocytopenia, hypersplenism, infection, bleeding, etc.; clinically significant bleeding events within 2 weeks prior to screening; platelet transfusion within 7 days before the first dose; Hematological diseases, including leukemia, primary immune thrombocytopenia (ITP), essential thrombocytosis, myeloproliferative disorders, multiple myeloma and myelodysplastic syndrome; Known solid tumors with splenic metastasis or bone metastasis with a potential effect on bone marrow hematopoiesis as assessed by the investigator; Splenectomy; Severe cardiovascular disease (or history) as assessed by the investigator at screening: Previous congestive heart failure, and current New York Heart Association (NYHA) functional class III/IV; Diseases associated with increased thrombotic events (e.g., atrial fibrillation, atrial flutter, unstable angina); QTc > 470 ms (or QTc > 480 ms for subjects with bundle branch block); Myocardial infarction in the past 6 months; A subject using a pacemaker or defibrillator can be included in case of normal cardiac function; Known coagulopathy, or arteriovenous thrombotic disease (e.g., stroke, deep vein thrombosis, pulmonary embolism) in the past 6 months, or transient ischemic attack in the past 6 months; Major surgery or radiotherapy within 4 weeks before the first dose, unless radiotherapy-related toxicities have decreased to ≤ Grade 2 (CTCAE version 5.0) (patients with > Grade 2 alopecia barbae, alopecia, or subjective description of symptoms can be included in this study); Patients with active central nervous system or leptomeningeal metastases or who have failed local therapy for these diseases; however, the subjects with asymptomatic brain metastases are allowed to be enrolled. Poorly controlled hypertension at screening as defined by SBP ≥ 160 mmHg and/or DBP ≥ 100 mmHg measured at 2-hour intervals at rest; Subjects with a positive history of human immunodeficiency virus (HIV) antibody or a positive HIV serological test at screening; subjects with active hepatitis B infection, i.e. positive hepatitis B surface antigen (HBsAg) and hepatitis B virus deoxyribonucleic acid (HBV DNA) > lower limit of detection at screening; subjects with seropositive hepatitis C virus (HCV) antibody and HCV-RNA > lower limit of detection; Live vaccines within 4 weeks before the first dose (among SARS-CoV-2 vaccines, subjects having received adenovirus vaccine should be evaluated by the investigator for inclusion, while subjects having received other types of SARS-CoV-2 vaccines are allowed for inclusion); Subjects who have participated in any clinical study of other drugs or devices within 4 weeks before the first dose, or plan to do so during the study; Poor compliance or other factors that are considered unsuitable for the study in the opinion of the investigator.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

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<br>For single dose escalation, the dose level will be 2µg/kg -15 µg/kg. | Biological: Recombinant Human Tumor Necrosis Factor Receptor II -Fc-TPO Mimetic Peptide Fusion Protein<br>* Recombinant Human Tumor Necrosis Factor Receptor II -Fc-TPO Mimetic Peptide Fusion Protein for injection (Strength: 1 mg/ml, 0.5ml/vial)<br>|
| Experimental: Dose Expansion - Group A<br>For dose expansion, the dose level is recommended to be the bioeffective dose obtained from dose escalation and administered once weekly (group A) for a treatment cycle(21 days). | Biological: Recombinant Human Tumor Necrosis Factor Receptor II -Fc-TPO Mimetic Peptide Fusion Protein<br>* Recombinant Human Tumor Necrosis Factor Receptor II -Fc-TPO Mimetic Peptide Fusion Protein for injection (Strength: 1 mg/ml, 0.5ml/vial)<br>|
| Experimental: Dose Expansion - Group B<br>For dose expansion, the dose level is recommended to be the bioeffective dose obtained from dose escalation and administered once weekly ( group B )for a treatment cycle(21 days). | Biological: Recombinant Human Tumor Necrosis Factor Receptor II -Fc-TPO Mimetic Peptide Fusion Protein<br>* Recombinant Human Tumor Necrosis Factor Receptor II -Fc-TPO Mimetic Peptide Fusion Protein for injection (Strength: 1 mg/ml, 0.5ml/vial)<br>|
| Experimental: Dose Expansion - Group C<br>For dose expansion, the dose level is recommended to be the bioeffective dose obtained from dose escalation and administered twice weekly (C group) for a treatment cycle(21 days). | Biological: Recombinant Human Tumor Necrosis Factor Receptor II -Fc-TPO Mimetic Peptide Fusion Protein<br>* Recombinant Human Tumor Necrosis Factor Receptor II -Fc-TPO Mimetic Peptide Fusion Protein for injection (Strength: 1 mg/ml, 0.5ml/vial)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose escalation: Occurrence of DLT. |  | Occurrence of DLT from enrollment to day 21. | 
| Dose escalation: Frequency of DLT. |  | Frequency of DLT from enrollment to day 21. | 
| Dose escalation and Dose expansion: Occurrence of adverse events during treatment |  | AEs will be collected up to day 63. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose escalation: Cmax | Cmax : Maximum serum concentration | up to 21 days after treatment | 
| Dose escalation: Cmax/D | Cmax/D :Dose normalized Cmax | up to 21 days after treatment | 
| Dose escalation: tmax | tmax : Time to Cmax | up to 21 days after treatment | 
| Dose escalation: AUC0-24h | AUC0-24h: Area under the serum concentration-time curve from 0 h to 24 h | up to 21 days after treatment | 
| Dose escalation: AUC0-last | AUC0-last :Area under the serum concentration-time curve from 0 h on Day 1 to the last time point with a quantifiable concentration | up to 21 days after treatment | 
| Dose escalation: AUC0-inf | AUC0-inf : Area under the serum concentration-time curve from 0 h extrapolated to infinity | up to 21 days after treatment | 
| Dose escalation: t1/2 | t1/2 : Apparent half-life | up to 21 days after treatment | 
| Dose escalation: CL/F | CL/F: Systemic clearance | up to 21 days after treatment | 
| Dose escalation: Vz/F | Vz/F: Volume of distribution | up to 21 days after treatment | 
| Dose escalation: λz | λz: Elimination rate constant | up to 21 days after treatment | 
| Dose escalation: Preliminary efficacy assessment.The percentage of subjects requiring platelet infusion and the frequency of infusion during the DLT observation period. |  | up to 28 days after administration | 
| Dose escalation: Preliminary efficacy assessment. Duration of PLT count ≥50×10^9/L and percentage of subjects during the DLT observation period. |  | up to 28 days after administration | 
| Dose escalation: Preliminary efficacy assessment. Duration of PLT count ≥75×10^9/L and percentage of subjects during the DLT observation period. |  | up to 28 days after administration | 
| Dose escalation: Preliminary efficacy assessment. Duration of PLT count ≥100×10^9/L and percentage of subjects during the DLT observation period. |  | up to 28 days after administration | 
| Dose expansion: C0 | C0: The concentration before administration (within 1 hour before administration) | up to 168 hours after the last treatment | 
| Dose expansion: C24 | C24: Concentration at 24 h after administration | up to 168 hours after the last treatment | 
| Dose expansion: Cmax | Cmax : Maximum concentration | up to 168 hours after the last treatment | 
| Dose expansion: Cmax/D | Cmax/D : Dose normalized Cmax | up to 168 hours after the last treatment | 
| Dose expansion: Cmin ss | Cmin ss: Minimum steady state concentration | up to 168 hours after the last treatment | 
| Dose expansion: Cav ss | Cav ss: Average steady state concentration | up to 168 hours after the last treatment | 
| Dose expansion: Rac | Rac: Accumulation ratio | up to 168 hours after the last treatment | 
| Dose expansion: tmax | tmax : Time to Cmax | up to 168 hours after the last treatment | 
| Dose expansion: AUC0-last | AUC0-last :AUC to the last quantifiable concentration | up to 168 hours after the last treatment | 
| Dose expansion: AUC0-inf | AUC0-inf : AUC extrapolated to infinity | up to 168 hours after the last treatment | 
| Dose expansion: t1/2 | t1/2 : Apparent half-life | up to 168 hours after the last treatment | 
| Dose expansion: CL/F | CL/F: Systemic clearance | up to 168 hours after the last treatment | 
| Dose expansion: Vz/F | Vz/F: Volume of distribution | up to 168 hours after the last treatment | 
| Dose expansion: λz | λz: Elimination rate constant | up to 168 hours after the last treatment | 
| Dose expansion: Preliminary efficacy assessment. Incidence of grade 3/4 thrombocytopenia (CTCAE version 5.0). |  | up to 63 days after administration | 
| Dose expansion: Preliminary efficacy assessment. The percentage of subjects requiring platelet infusion and the frequency of infusion in each treatment cycle. |  | up to 63 days after administration | 
| Dose expansion: Preliminary efficacy assessment. Change in platelet nadir from the previous qualifying cycle to the treatment cycle. |  | up to 63 days after administration | 
| Dose expansion: Preliminary efficacy assessment. The percentage of subjects without dose reduction > 20% in the next cycle of chemotherapy due to thrombocytopenia after the first cycle of chemotherapy. |  | up to 63 days after administration | 
| Dose expansion: Preliminary efficacy assessment. The percentage of subjects without dose delay > 4 days in the next cycle of chemotherapy due to thrombocytopenia after the first cycle of chemotherapy. |  | up to 63 days after administration | 
| Dose expansion: Preliminary efficacy assessment. Duration of PLT count ≥50×10^9/L and percentage of subjects after treatment. |  | up to 63 days after administration | 
| Dose expansion: Preliminary efficacy assessment. Duration of PLT count ≥75×10^9/L and percentage of subjects after treatment. |  | up to 63 days after administration | 
| Dose expansion: Preliminary efficacy assessment. Duration of PLT count ≥100×10^9/L and percentage of subjects after treatment. |  | up to 63 days after administration | 
| Dose expansion: Preliminary efficacy assessment. Percentage of subjects not requiring platelet infusion or other platelet-raising agents (rh-TPO or rh IL-11, etc.) at the end of the second treatment cycle. |  | up to 63 days after administration |