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A Study to Evaluate the Safety and Tolerability, Pharmacokinetics, Pharmacodynamics and Preliminary Efficacy of TJ011133 as Monotherapy and in Combination With Azacitidine (AZA) in Patients With Acute Myeloid Leukemia (AML) or Myelodysplastic Syndrome (MDS)

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ClinicalTrials.gov Identifier: NCT04202003
Recruitment Status : Recruiting
First Posted : December 17, 2019
Last Update Posted : April 8, 2021
Sponsor:
Information provided by (Responsible Party):
I-Mab Biopharma Co. Ltd.

Brief Summary:
This study is a phase I/II study of TJ011133 as Monotherapy and in Combination with Azacitidine (AZA) in Patients with Acute Myeloid Leukemia (AML) or Myelodysplastic Syndrome (MDS). This study include Phase I and Phase IIa study. Phase I study ClinicalTrials.gov ID is NCT04202003 and this is for phase IIa study. Phase IIa study is designed to preliminarily assess the efficacy and safety of TJ011133 in combination with AZA as first-line treatment in patients with newly diagnosed AML who are intolerant to standard induction chemotherapy or patients with treatment naive, intermediate and high-risk MDS.

Condition or disease Intervention/treatment Phase
Acute Myeloid Leukemia (AML) Myelodysplastic Syndromes(MDS) Drug: TJ011133 Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 80 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Multicenter, Open-label, Phase 1/2a Study to Evaluate the Safety and Tolerability, Pharmacokinetics, Pharmacodynamics and Preliminary Efficacy of TJ011133 as Monotherapy and in Combination With Azacitidine (AZA) in Patients With Acute Myeloid Leukemia (AML) or Myelodysplastic Syndrome (MDS)
Actual Study Start Date : March 25, 2020
Estimated Primary Completion Date : April 2023
Estimated Study Completion Date : August 2023


Arm Intervention/treatment
Experimental: TJ011133
This is an open-label Phase 1/2a clinical study. The study will be conducted in two parts: Part I: Phase 1 dose escalation, TJ011133 is tentatively scheduled to be administered once weekly in 28-day treatment cycles;Part II: Phase 2a study TJ011133 will be administered at a dose of 30 mg/kg once weekly, and AZA will be administered at a dose of 75 mg/m2 by subcutaneous injection for 7 consecutive days from D1 to D7 in 28-day treatment cycles.
Drug: TJ011133
This is an open-label Phase 1/2a clinical study. The study will be conducted in two parts: Part I: Phase 1 dose escalation, TJ011133 is tentatively scheduled to be administered once weekly in 28-day treatment cycles;Part II: Phase 2a study TJ011133 will be administered at a dose of 30 mg/kg once weekly, and AZA will be administered at a dose of 75 mg/m2 by subcutaneous injection for 7 consecutive days from D1 to D7 in 28-day treatment cycles.




Primary Outcome Measures :
  1. Dose Limiting Toxicities(DLT) [ Time Frame: 28days after first dose ]
    To evaluate the safety and tolerance of TJ011133 monotherapy in patients with r/r AML or MDS

  2. Maximum tolerable dose(MTD) [ Time Frame: Through study completion, an average of 1 year ]
    To explore the maximum tolerable dose (MTD) of TJ011133 monotherapy for patients with r/r AML or MDS, the recommended phase II dose (RP2D) and the optimal dosage regimen.

  3. Recommended phase II dose [ Time Frame: Through study completion, an average of 1 year ]
    Recommended phase II dose (RP2D)

  4. Complete response rate (CR rate) only for phase 2a [ Time Frame: Through study completion,an average of 1 year ]
    Preliminary efficacy endpoints (only for Phase 2a): for response assessment in AML/MDS patients, the complete response rate (CR rate) will be evaluated according to the ELN2017/IWG 2006 criteria



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria

Phase 1 single dose escalation:

  • Male or female, aged ≥ 18 and ≤ 70 years at the time of signing informed consent form;
  • For the disease under study, enrollment may be considered if one of the following is satisfied:

    1. Subjects must be with pathologically diagnosed as acute myeloid leukemia (AML) according World Health Organization (WHO) 2016 classification criteria, with the exception of acute promyelocytic leukemia; it is a recurrent or refractory disease without other available appropriate conventional treatments;
    2. Subjects with intermediate- and high-risk relapsed/refractory MDS (IPSS-R score >3.5) who are pathologically confirmed and meeting the diagnostic criteria of World Health Organization (WHO) 2016 or who are unable to tolerate the treatment of demethylation drugs or other drugs (e.g., treatment-emergent Grade 3 or higher drug-related hepatic and/or renal toxicities leading to permanent withdrawal during treatment), and the investigator judges that there is no other appropriate treatment;
  • For patients with MDS, a blast percentage of < 20% is required in bone marrow aspiration smear or bone marrow biopsy pathology at screening;
  • ECOG score 0-2;
  • Subjects have been recovered from the toxicity of previous anti-AML/MDS treatments (according to NCI CTC AE 5.0 ≤ Grade 1, except alopecia) ;
  • Subjects must have adequate liver function, renal function and coagulation function. The laboratory tests within 7 days before the first dose should meet the following requirements:

    1. Liver function:

      • Serum total bilirubin ≤ 1.5 × upper limit of normal (ULN);
      • AST and ALT ≤ 2.5 × ULN.
    2. Renal function:

      -Serum creatinine ≤ 1.5 × ULN or estimated creatinine clearance ≥ 50 mL/min according to the Cockcroft-Gault equation (Appendix 5).

    3. Coagulation function:

      • International normalized ratio (INR) or prothrombin time (PT) ≤ 1.5 × ULN;
      • Activated partial thromboplastin time (aPTT) ≤ 1.5 × ULN.

Subjects for Phase 2a combination therapy:

  • Male or female, aged ≥ 18 years at the time of signing informed consent form;
  • For the disease under study, enrollment may be considered only if the following conditions are met:

Newly diagnosed AML with intolerance to standard induction chemotherapy/intermediate- and high-risk (International Prognostic Scoring System IPSS-R) MDS (only applicable for Phase 2a study); symptomatic treatment such as hydroxycarbamide, erythropoietin, and/or hematopoietic growth factors are allowed within 7 days of the first dose;

  • The subject's ECOG score has to meet the following criteria:

    • Newly diagnosed AML with intolerance to standard induction

      • Newly diagnosed intermediate- and high-risk MDS: ECOG score 0 - 2
  • Subjects must have adequate liver function, renal function and coagulation function. The laboratory tests within 7 days before the first dose should meet the following requirements::

    1. Liver function:

      • Serum total bilirubin ≤ 1.5 × upper limit of normal (ULN); total bilirubin ≤ 3 × ULN is allowed for subjects aged 18 - 74 years (only for newly diagnosed AML subjects who are intolerant to standard induction chemotherapy)
      • AST and ALT ≤ 3 × ULN.
    2. Renal function:

      -Estimated creatinine clearance ≥ 50 mL/min according to the Cockcroft-Gault equation (Appendix 5); creatinine clearance ≥ 30 mL/min is allowed for subjects aged 18 - 74 years (only for newly diagnosed AML subjects who are intolerant to standard induction chemotherapy)

    3. Coagulation function:

      • International normalized ratio (INR) or prothrombin time (PT) ≤ 1.5 × ULN;
      • Activated partial thromboplastin time (aPTT) ≤ 1.5 × ULN.

All subjects:

  • Expected survival ≥ 12 weeks;
  • White blood cell count (WBC) ≤ 25 × 103/μL within 7 days prior to the first dose (hydroxycarbamide or leukapheresis is allowed to meet this criterion);
  • Subjects must be willing to provide available diagnostic evidence or undergo bone marrow aspiration and biopsy before study treatment, and must be willing to undergo bone marrow aspiration and biopsy after receiving study treatment;
  • Subjects must give informed consent before starting the study and sign written consent voluntarily by themselves (or their legal representatives). Subjects or their legal representatives should be able to communicate well with investigators and agree to adhere with the study protocol and complete the study.

Exclusion Criteria

Phase 1 single dose escalation:

  • Previously received treatment with other drug therapies targeting CD47;
  • Previously received CAR-T cell therapy;
  • Previously received treatment with PD1 or PDL1 antibody;
  • Previously received or planned to receive allogeneic stem cell transplantation during the study, or autologous stem cell transplantation within 3 months prior to the first dose of study drug;
  • Subjects have received chemotherapy, immunotherapy, radiotherapy, major surgery within 4 weeks prior to the first dose;
  • Subjects' cardiac function meet any of the following criteria:

    • Subjects have any kind of clinically significant rhythm abnormalities or conduction abnormalities that require clinical intervention;
    • Subjects have congenital QT prolongation syndrome or QTc > 450 msec in men, QTc > 470 msec in women (QTc calculated using Fridericia's correction formula [Appendix 6]), or on medications that may cause QT prolongation or torsades de pointes;
    • Subjects have any kind of clinically significant cardiovascular diseases, including acute myocardial infarction, unstable angina, coronary artery bypass surgery or peripheral artery bypass surgery, cerebrovascular events (thromboembolic or hemorrhagic cerebrovascular events, excluding transient ischemic attack), New York Heart Association (NYHA) (Appendix 7) ≥ Grade 3 congestive cardiac failure, or left ventricular ejection fraction (LVEF) < 40% within 3 months prior to enrollment; Phase 2a combination therapy
  • Previously received treatment with demethylated drugs or cytotoxic drugs in patients with MDS;
  • Previously received any anti-tumor therapy for AML;
  • AML with a good prognosis, including cytogenetic alterations, such as t (8;21), inv (16) or t (16;16) or t (15;17);
  • Subjects are known to have allergy to AZA or mannitol;
  • Subjects' cardiac function meet any of the following criteria:

    • Subjects have any kind of clinically significant rhythm abnormalities or conduction abnormalities that require clinical intervention;
    • Subjects have congenital QT prolongation syndrome or taking drugs that may cause QT prolongation or torsades de pointes;
    • Subjects have any kind of clinically significant cardiovascular diseases, including acute myocardial infarction, unstable angina, coronary artery bypass surgery or peripheral artery bypass surgery, cerebrovascular events (thromboembolic or hemorrhagic cerebrovascular events, excluding transient ischemic attack), New York Heart Association (NYHA) (Appendix 7) ≥ Grade 3 congestive cardiac failure within 3 months prior to enrollment;
  • Subjects have undergone major surgery within 4 weeks prior to the first dose;

All subjects:

  • Subjects have received vaccination within 4 weeks prior to the first dose and/or planned vaccination after participating in the study;
  • Subjects have received clinical trial drug treatment within 4 weeks prior to the first dose or currently participating in other interventional clinical trials;
  • Subjects are known to have hereditary or acquired hemorrhagic disorders;
  • Subjects have hypertension uncontrollable with drug therapy (systolic blood pressure ≥ 140 mmHg, or diastolic blood pressure ≥ 90 mmHg at rest);
  • Subjects suffer from disease that requires long-term use of systemic steroid therapy or other immunosuppressive therapy. However, subjects who use physiologic replacement doses of hydrocortisone or drugs of equivalent doses (Appendix 8), i.e., up to 20 mg of hydrocortisone (or 5 mg of prednisone) in the morning and up to 10 mg of hydrocortisone (or 2.5 mg of prednisone) at night, may be considered for enrollment;
  • Subjects are known to have central nervous system (CNS) involvement;
  • Subjects are known to have HIV infection (anti-HIV positive), active hepatitis B (HBsAg positive, or HBcAb positive and HBV-DNA PCR positive), or active hepatitis C (anti-HCV antibody positive and HCV-RNA PCR positive), or syphilis infection (anti-TP test positive);
  • Subjects have a history of solid organ transplantation;
  • Subjects plan to receive other anti-tumor therapies, including but not limited to chemotherapy, biotherapy, immunotherapy, hormone therapy and traditional Chinese medicine, while participating in the study;
  • Subjects have a history of autoimmune disease or active autoimmune disease;
  • Subjects have uncontrolled active infection;
  • Subjects have severe electrolyte disturbances that cannot be corrected;
  • Subjects have a history of other malignancies, except for clinically cured malignancies (no relapse for at least 5 years), cured carcinoma in situ, and skin cancer other than malignant melanoma;
  • Subjects have a history of psychotropic drug abuse and are unable to quit or have mental disorders, or have concomitant diseases that seriously endanger patients' safety or hinder the study completion at the discretion of investigators;
  • Subjects are women during pregnancy or lactation, or women and men with fertility planning;
  • The investigators consider that patients have other factors that may affect the results of the study and interfere with their full participation in the study, including previous or existing health conditions or medical or laboratory abnormalities, or put them at high risk.
  • Subjects with MDS who meet any of the following must also be excluded:
  • Subjects have uncorrected serum folic acid deficiency or vitamin B12 deficiency;
  • MDS transformed from previously existing myeloproliferative tumors (MPN) or MDS/MPN types conforming to WHO 2016 classification standard include chronic myelomonocytic leukemia (CMML), atypical chronic myeloid leukemia (aCML), juvenile myelomonocytic leukemia (JMML), etc..

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04202003


Contacts
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Contact: Jianxiang Wang, Doctor 022-23909278 wangjx@ihcams.ac.cn
Contact: Wei Huang, Master 021-60575756 wei.huang@i-mabbiopharma.com

Locations
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China, Beijing
Peking Union Medical College Hospital Recruiting
Beijing, Beijing, China, 100032
Contact: Jian Li, doctor       lijian@pumch.cn   
Peking University International Hospital Recruiting
Beijing, Beijing, China, 102206
Contact: Bin Jiang, doctor       jiangbin1442@126.com   
Principal Investigator: Bin Jiang         
Principal Investigator: Meixiang zhang         
China, Chongqing
The First Affiliated Hospital of Chongqing Medical University Not yet recruiting
Chongqing, Chongqing, China, 400016
Contact: Li Wang, Doctor         
Principal Investigator: Li Wang, Doctor         
China, Fujian
The First Affiliated Hospital of Xiamen University Not yet recruiting
Xiamen, Fujian, China, 361003
Contact: Bing Xu, Doctor       xubingzhangjian@126.com   
Principal Investigator: Bing Xu, Doctor         
China, Guangdong
Zhujiang Hospital Of Southern Medical University Not yet recruiting
Guangzhou, Guangdong, China, 510280
Contact: Yanjie He, Doctor         
Principal Investigator: Yanjie He, Doctor         
Sun Yat-sen University Cancer Center Not yet recruiting
Guangzhou, Guangdong, China
Contact: Yang Liang, Doctor         
Principal Investigator: Yang Liang, Doctor         
Shenzhen Second People's Hospital Not yet recruiting
Shenzhen, Guangdong, China, 518020
Contact: Xin Du         
Principal Investigator: Xin Du         
China, Guizhou
The Affiliated Hospital of Guizhou Medical University Not yet recruiting
Guiyang, Guizhou, China, 550004
Contact: Jishi Wang, Doctor         
Principal Investigator: Jishi Wang, Doctor         
China, Hebei
The Second Hospital of HeBei Medical University Not yet recruiting
Shijiazhuang, Hebei, China, 050000
Contact: Jinhai Ren, Doctor       jinhai1966@sina.cn   
Principal Investigator: Jinhai Ren, Doctor         
China, Jiangsu
Jiangsu Province Hospital Not yet recruiting
Suzhou, Jiangsu, China, 221006
Contact: Sixuan Qian, Doctor         
Principal Investigator: Sixuan Qian, Doctor         
China, Shandong
Qilu Hospital of Shandong University Not yet recruiting
Jinan, Shandong, China, 266000
Contact: Chunyan Ji, Doctor       18661807392@163.com   
Principal Investigator: Chunyan Ji, Doctor         
China, Shanxi
The Second Affiliated Hospital of Xi'an Jiaotong University(Xibei Hospital) Not yet recruiting
Xi'an, Shanxi, China, 710004
Contact: Aili He, Doctor         
Principal Investigator: Aili He, Doctor         
China, Tianjin
Institute of Hematology and Blood Disease Hospital, Chinese Academy of Medical Recruiting
Tianjin, Tianjin, China, 300020
Contact: Jianxiang Wang, Doctor       wangjx@ihcams.ac.cn   
Contact: Doctor         
Principal Investigator: Jianxiang Wang, Doctor         
Principal Investigator: Zhijian Xiao, Doctor         
Principal Investigator: Junyuan Qi, Doctor         
Tianjin Medical University General Hospital Not yet recruiting
Tianjin, Tianjin, China, 300052
Contact: Rong Fu, Doctor       florai@sina.com   
Principal Investigator: Rong Fu, Doctor         
China, Zhejiang
The First Affiliated Hospital, Zhejiang University School of Medicine Not yet recruiting
Hangzhou, Zhejiang, China, 310003
Contact: Hongyan Tong, Doctor       hongyantong@aliyun.com   
Principal Investigator: Hongyan Tong, Doctor         
Sponsors and Collaborators
I-Mab Biopharma Co. Ltd.
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Responsible Party: I-Mab Biopharma Co. Ltd.
ClinicalTrials.gov Identifier: NCT04202003    
Other Study ID Numbers: TJ011133AML102
First Posted: December 17, 2019    Key Record Dates
Last Update Posted: April 8, 2021
Last Verified: April 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Additional relevant MeSH terms:
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Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Preleukemia
Myelodysplastic Syndromes
Syndrome
Disease
Pathologic Processes
Neoplasms by Histologic Type
Neoplasms
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions