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A Study of SI-B003, a PD-1/CTLA-4 Bispecific Antibody, in Patients With Advanced Solid Tumors

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04606472
Recruitment Status : Recruiting
First Posted : October 28, 2020
Last Update Posted : October 28, 2020
Sponsor:
Collaborator:
SystImmune Inc.
Information provided by (Responsible Party):
Sichuan Baili Pharmaceutical Co., Ltd.

Brief Summary:

In phase Ia study, the safety and tolerability of SI-B003 in patients with recurrent or metastatic solid tumors will be investigated to determine the dose-limiting toxicity (DLT), maximum tolerated dose (MTD) or maximum administered dose (MAD) for MTD is not reached of SI-B003.

In the phase Ib study, the safety and tolerability of SI-B003 in specific tumors will be further investigated by selecting multiple doses based on the results of phase Ia study or/and the fixed-dose administration method with the closest exposure level, and recommended phase II dose (RP2D) for phase II clinical studies will be determined.


Condition or disease Intervention/treatment Phase
Solid Tumor Drug: SI-B003 Phase 1

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 159 participants
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase I Clinical Study to Evaluate the Safety, Tolerability, Pharmacokinetic Characteristics and Preliminary Efficacy of SI-B003, a PD-1/CTLA-4 Bispecific Antibody, in Patients With Advanced Solid Tumors
Estimated Study Start Date : October 2020
Estimated Primary Completion Date : September 2022
Estimated Study Completion Date : September 2022


Arm Intervention/treatment
Experimental: Study treatment
Participants receive SI-B003 as intravenous infusion for the first cycle (4 weeks). Participants with clinical benefit could receive additional treatment for more cycles. The administration will be terminated because of disease progression or intolerable toxicity occurring or other reasons.
Drug: SI-B003
Administration by intravenous infusion.




Primary Outcome Measures :
  1. Phase Ia: Dose limiting toxicity (DLT) [ Time Frame: Up to 28 days after the first dose of SI-B003 ]
    DLTs is assessed according to NCI-CTCAE v5.0 during the first cycle (28 days) and were defined as occurrence of any of the following toxicities if judged by the investigator to be possibly, probably or definitely related to study drug administration.

  2. Phase Ia: Maximum tolerated dose (MTD) [ Time Frame: Up to 28 days after the first dose of SI-B003 ]

    MTD is defined as the dose with the estimated DLT rate closest to the target DLT rate (33%) is selected as the MTD.

    If there are two or more estimated values close to the target DLT rate and the same, when the estimated value is lower than the target DLT rate, choose the higher dose, and when the estimated value is greater than or equal to the target toxicity rate, choose a lower dose.


  3. Phase Ia: Maximum administered dose (MAD) [ Time Frame: Up to 28 days after the first dose of SI-B003 ]
    MAD is defined as the maximum administered dose, when MTD is not reached.

  4. Phase Ia: Treatment-Emergent Adverse Event (TEAE) [ Time Frame: Up to approximately 24 months ]
    TEAE is defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally emerging, or any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a pre-existing condition during the treatment of SI-B003. The type, frequency and severity of TEAE will be evaluated during the treatment of SI-B003.

  5. Phase Ib: Recommended Phase II Dose (RP2D) [ Time Frame: Up to 28 days after the first dose of SI-B003 ]
    The RP2D is defined as the dose level chosen by the sponsor (in consultation with the investigators) for the dose expansion arms, based on safety, tolerability, efficacy, PK, and PD data collected during the dose escalation study of SI-B003.


Secondary Outcome Measures :
  1. Cmax [ Time Frame: Up to 28 days after the first dose of SI-B003 ]
    Maximum serum concentration (Cmax) of SI-B003 will be investigated.

  2. Tmax [ Time Frame: Up to 28 days after the first dose of SI-B003 ]
    Time to maximum serum concentration (Tmax) of SI-B003 will be investigated.

  3. T1/2 [ Time Frame: Up to 28 days after the first dose of SI-B003 ]
    Half-life (T1/2) of SI-B003 will be investigated.

  4. AUC0-t [ Time Frame: Up to 28 days after the first dose of SI-B003 ]
    AUC0-t is defined as area under the serum concentration-time curve from time 0 to the time of the last measurable concentration.

  5. CL [ Time Frame: Up to 28 days after the first dose of SI-B003 ]
    Clearance (CL) in the serum of SI-B003 per unit of time will be investigated.

  6. Ctrough [ Time Frame: Up to 28 days after the first dose of SI-B003 ]
    Ctrough is defined as the lowest serum concentration of SI-B003 prior to the next dose will be administered.

  7. Adverse Events of special interest (AESI) [ Time Frame: Up to approximately 24 months ]
    AESI is defined as AE that may not be serious but have special meaning or importance for SI-B003.

  8. ADA (Anti-drug antibody) [ Time Frame: Up to approximately 24 months ]
    Incidence and titer of ADA of SI-B003 will be evaluated.

  9. NAb (Neutralizing antibody ) [ Time Frame: Up to approximately 24 months ]
    Incidence and titer of NAb of SI-B003 will be evaluated.

  10. Objective Response Rate (ORR) [ Time Frame: Up to approximately 24 months ]
    ORR was defined as the percentage of participants, who had a CR or PR. The percentage of participants who experienced a confirmed CR or PR is evaluated by investigator and third-party independent medical imaging agency according to RECIST 1.1.

  11. Duration of Response (DOR) [ Time Frame: Up to approximately 24 months ]
    The DOR for a responder is defined as the time from the participant's initial objective response to the first date of either disease progression or death, whichever occurs first. The DOR is evaluated by investigator and third-party independent medical imaging agency according to RECIST 1.1.

  12. Clinical benefit rate (CBR) [ Time Frame: Up to approximately 24 months ]
    CBR was defined as the percentage of participants, who had a CR, PR or SD. The percentage of participants who experienced a confirmed CR, PR or SD is evaluated by investigator and third-party independent medical imaging agency according to RECIST 1.1.

  13. Progression-free survival rate (PFS) [ Time Frame: Up to approximately 12 months ]
    The PFS is defined as the time from the participant's first dose of SI-B003 to the first date of either disease progression or death, whichever occurs first. 6 and 12 months PFS will be evaluated by investigator and third-party independent medical imaging agency according to RECIST 1.1.

  14. Overall survival rate (OS) [ Time Frame: Up to approximately 12 months after first dose administration ]
    12 months OS will be evaluated by investigator and third-party independent medical imaging agency according to RECIST 1.1.

  15. The correlation of PK and clinical efficacy indexes [ Time Frame: Up to approximately 24 months ]
    The correlation of PK parameters (Cmax, AUC0-t, Ctrough, etc.) and clinical efficacy indexes (ORR, CBR, PFS, etc.) will be evaluated.

  16. Evaluation of iORR [ Time Frame: Up to approximately 24 months ]
    iORR will be evaluated by investigator and third-party independent medical imaging agency according to iRECIST 1.1.

  17. Evaluation of iCR [ Time Frame: Up to approximately 24 months ]
    iCR will be evaluated by investigator and third-party independent medical imaging agency according to iRECIST 1.1.

  18. Evaluation of iPR [ Time Frame: Up to approximately 24 months ]
    iPR will be evaluated by investigator and third-party independent medical imaging agency according to iRECIST 1.1.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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

Inclusion Criteria:

  1. The participants could understand and sign the informed consent form, and must participate voluntarily.
  2. No gender limit.
  3. Age: ≥18 years old and ≤75 years old (phase Ia); ≥18 years old (phase Ib).
  4. Expected survival time ≥ 3 months.
  5. It is confirmed by histology or cytology as recurring or metastatic solid tumor, and there is disease progression confirmed by imaging or other objective evidence after receiving standard treatment; or the participant is a patient with a refractory solid tumor, or is intolerant to standard treatment or there are contraindications to standard treatment.
  6. Agree to provide tumor tissue samples or fresh tissue samples from the primary tumor or metastasis within 6 months (only for stage Ib). If the patient is unable to provide tumor tissue samples, the research center needs to apply to the sponsor.
  7. At least one measurable lesion that meets the definition of RECIST v1.1 at baseline (only for stage Ib).
  8. Physical fitness score ECOG 0 or 1 point.
  9. No serious cardiac dysfunction, left ventricular ejection fraction (LVEF) ≥50%, (hypersensitivity) troponin T<ULN.
  10. The organ function within 7 days prior to the first administration meets the following requirements: a) Bone marrow: absolute neutrophil count (ANC) ≥1.5×109/L, hemoglobin ≥90 g/L, platelet count ≥100×109/L (participants with liver cancer ANC ≥75×109/L); b) Liver: total bilirubin (TBIL) ≤1.5 ULN (TBIL ≤3 ULN in participants with Gilbert's syndrome, liver cancer or liver metastasis), transaminase (AST/ALT) ≤ 3 ULN (for participants with liver cancer or liver metastasis ≤ 5.0 ULN); for participants with liver cancer or liver metastasis, transaminase ≥ 3 ULN and TBIL ≥ 1.5 ULN must be excluded; c) Kidney: Creatinine (Cr) ≤1.5 ULN and creatinine clearance rate (Ccr) ≥ 50mL/min (according to Cockcroft-Gault formula).
  11. Female participants with fertility or male participants whose partners are fertile must take effective contraceptive measures from 7 days prior to the first administration to 24 weeks after the administration. Female participants with fertility must have a negative serum/urine pregnancy test in 7 days prior to the first dose.
  12. The participants are capable and willing to comply with the visits, treatment plans, laboratory examinations and other study-related procedures stipulated in the study protocol.

Exclusion Criteria:

  1. Symptoms of active central nervous system metastasis. However, participants with stable brain metastasis or stable epidural spinal cord compression history can be included. Stable is defined as: a. With or without antiepileptic drugs, the seizure-free state lasts for more than 12 weeks; b. There is no need to use glucocorticoids; c. Continuous multiple MRI (scanning interval at least 8 weeks) showed a stable state in imaging.
  2. Those who have participated in any other clinical trials within 28 days prior to the administration of this trial, except for the clinical trials of listed drugs;
  3. Chemotherapy, biological therapy, immunotherapy, radical radiotherapy, major surgery, targeted therapy (including small molecule inhibitor of tyrosine kinase), and other anti-tumor therapy within 4 weeks or 5 half-lives (whichever is shorter) prior to the first administration; mitomycin and nitrosoureas treatment within 6 weeks prior to the first administration; oral fluorouracil-like drugs such as S-1, capecitabine, or palliative radiotherapy within 2weeks prior to the first administration.
  4. In 14 days prior to administration of this study, those who have received systemic corticosteroids (>10mg/day prednisone, or equivalent other corticosteroids) or immunosuppressive therapy should be excluded except for those who have received inhaled or topical corticosteroids, or hormone therapy of physiological replacement dose due to adrenal insufficiency.
  5. Those who have received live virus vaccines (including live attenuated vaccines) within 28 days prior to the administration of this study.
  6. Participants have grade 3 lung disease defined according to NCI-CTCAE v5.0, including participants with resting dyspnea, or requiring continuous oxygen therapy, or a history of interstitial lung disease (ILD).
  7. Severe systemic infections occurred within 4 weeks prior to screening, including but not limited to severe pneumonia, bacteremia, or severe infection complications caused by fungi, bacteria, and viruses.
  8. Participants at risk of active autoimmune diseases, or with a history of autoimmune diseases, including but not limited to Crohn's disease, ulcerative colitis, systemic lupus erythematosus, sarcoidosis, Wegener syndrome (polyangiitis granuloma Disease, Graves' disease, rheumatoid arthritis, pituitary inflammation, uveitis), autoimmune hepatitis, systemic sclerosis, Hashimoto's thyroiditis, autoimmune vasculitis, autoimmune neuropathy (Guillain-Barré syndrome), etc. Except for the following conditions: Type I diabetes, hormone replacement therapy for stable hypothyroidism (including hypothyroidism caused by autoimmune thyroid disease), psoriasis or vitiligo that does not require systemic treatment.
  9. Complicated with other malignant tumors within 2 years prior to the first administration, except for cured skin squamous cell carcinoma, basal cell carcinoma, superficial bladder cancer, prostate/cervix/breast carcinoma in situ (only phase Ib).
  10. Participants with human immunodeficiency virus antibody (HIVAb) positive, active tuberculosis, active hepatitis B virus infection (HBV-DNA copy number> 104) or hepatitis C virus (HCV) infection.
  11. Participants with poorly controlled hypertension by two kinds of antihypertensive drugs (systolic blood pressure>150 mmHg or diastolic blood pressure>100 mmHg).
  12. Participants with history of severe heart disease, such as: symptomatic congestive heart failure (CHF) ≥ grade 2 (CTCAE 5.0), New York Heart Association (NYHA) ≥ grade 2 heart failure, history of transmural myocardial infarction, unstable angina pectoris etc.
  13. Participants with prolonged QT interval (male QTc> 450 msec or female QTc> 470 msec), complete left bundle branch block, III grade atrioventricular block.
  14. The toxicity of the previous anti-tumor therapy has not recovered to ≤1 (NCI-CTCAE v5.0) or the baseline level, except for peripheral neuropathy (need to be restored to ≤2) and hair loss.
  15. Participants with allogeneic bone marrow or organ transplantation history.
  16. Participants who have a history of allergies to recombinant humanized antibodies or human-mouse chimeric antibodies or any of the components of SI-B003.
  17. In the adjuvant (or neoadjuvant) treatment of anthracyclines, the cumulative dose of anthracyclines is> 360 mg/m2.
  18. Pregnant or breastfeeding women.
  19. Other conditions that the investigator believes that it is not suitable for participating in this clinical trial.

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): NCT04606472


Contacts
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Contact: Chongtian Guo +86-18601668634 guochongtian@baili-pharm.com
Contact: Sa Xiao +86-15013238943 xiaosa@baili-pharm.com

Locations
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China, Beijing
Peking University Cancer Hospital Recruiting
Beijing, Beijing, China, 100142
Contact: Lin Shen    +86-010-53806898    doctorshenlin@sina.cn   
Contact: Jifang Gong    +86-13683208528    goodjf@163.com   
Principal Investigator: Lin Shen         
Sub-Investigator: Jifang Gong         
China, Chongqing
Chongqing Cancer Hospital Not yet recruiting
Chongqing, Chongqing, China, 400030
Contact: Weiqi Nian    +86-13883652913      
Contact: Long Tang    +86-15123223207      
Principal Investigator: Weiqi Nian         
Sub-Investigator: Long Tang         
China, Henan
Henan Cancer Hospital Recruiting
Zhengzhou, Henan, China, 450008
Contact: Suxia Luo       luosxrm@163.com   
Contact: Shan An    +86-13613865536    watermelonas@163.com   
Principal Investigator: Suxia Luo         
Sub-Investigator: Shan An         
China, Shanghai
Shanghai First People's Hospital Not yet recruiting
Shanghai, Shanghai, China, 200080
Contact: Qi Li    +86-13818207333    leeqi2001@hotmail.com   
Contact: Haiyan Zhang    +86-13611956117    13611956117@163.com   
Principal Investigator: Qi Li         
Sub-Investigator: Haiyan Zhang         
Sponsors and Collaborators
Sichuan Baili Pharmaceutical Co., Ltd.
SystImmune Inc.
Investigators
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Principal Investigator: Lin Shen Beijing Cancer Hospital
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Responsible Party: Sichuan Baili Pharmaceutical Co., Ltd.
ClinicalTrials.gov Identifier: NCT04606472    
Other Study ID Numbers: SI-B003-101
First Posted: October 28, 2020    Key Record Dates
Last Update Posted: October 28, 2020
Last Verified: October 2020

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Sichuan Baili Pharmaceutical Co., Ltd.:
Non-small cell lung cancer (NSCLC)
Renal cell carcinoma (RCC)
Urothelial Cancer (UC)
Metastatic colorectal cancer (mCRC)
Triple negative breast cancer (TNBC)
Melanoma
Additional relevant MeSH terms:
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Neoplasms