A Phase 1, Open-Label, Single Center, Dose Escalation Study of the Safety and Pharmacokinetics of mAb AZD5396 and mAb AZD8076 Delivered as dMAbs in Healthy Adults
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- 入组人数
- 61
- 试验地点
- 1
- 主要终点
- Evaluation of the pain experienced by the participant
研究概览
简要总结
This is a Phase 1, open-label, single center, dose escalation study to evaluate the safety, tolerability and pharmacokinetic profile of mAb AZD5396 and mAb AZD8076 following delivery of optimized dMAb AZD5396 and dMAb AZD8076 with Hylenex® Recombinant, administered by intramuscular injection (IM) followed immediately by electroporation (EP) using the CELLECTRA™ 2000 with Side Port needle device, in a 2-dose regimen (Days 0 and 3) or a 4-dose regimen (Days 0, 3, 28 and 31) in healthy adults.
The hypothesis is that the administration of dMAb AZD5396 and dMAb AZD8076 will be safe and associated with expression of mAb AZD5396 and mAb AZD8076 in serum.
详细描述
The study will apply a single ascending dose (SAD) modified 3+3 design. Participants will be enrolled sequentially beginning with Cohort A1. The first participant in cohort A1 will be dosed on Day 0. If no stopping event (DLT) is observed after 14 days of the initial dose, the remaining two participants in that cohort will be dosed. If there are 0 DLT events after 14 days of the initial dosing of the third subject, enrollment will be completed, and then cohort A2 will open. Same process will be followed for Cohorts B, C and E. Because cohorts D, F & G are a similar or lower dose and the safety profile would have been already established in previous cohorts, the 14-day waiting periods will not apply to Cohorts D, F or G.
If one dose limiting toxicity (DLT) is observed in the first three participants enrolled in any cohort, an ad hoc DSMB will review the event and make a decision if the study should continue. If the DSMB agrees that the study should continue, the remaining participants will be enrolled in the cohort and dosed, but the next cohort will not open until the 28-day period of safety is completed. However, if any additional DLT occurs (i.e., >1 DLT in 6 total participants in a given cohort), then that dose will be deemed not tolerated
The following Investigational product administration- and/or EP-related adverse events are defined as DLTs:
- Grade 3 or greater local injection site erythema, swelling, and/or induration recorded ≥ 1 hour after Investigational product administration
- Pain or tenderness at the injection site that requires overnight hospitalization despite proper use of non-narcotic analgesics.
- Grade 3 or greater systemic symptoms assessed by the Principal Investigator as related to Investigational product administration.
- Grade 3 or greater clinically significant laboratory abnormalities assessed by the Principal Investigator as related to Investigational product administration.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Prevention
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 60 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Age 18-60 years.
- •Able to provide consent to participate and having signed an Informed Consent Form (ICF).
- •Able and willing to comply with all study procedures.
- •Body mass index (BMI) between 20 and 31, inclusive.
- •Screening laboratory must be within normal limits or have only Grade 0-1 findings.
- •Normal screening ECG or screening ECG with no clinically-significant findings.
- •Women of child-bearing potential agree to one of the following:
- •use medically effective contraception (oral contraception, barrier methods, spermicide, etc.)
- •have a partner who is sterile from enrollment to 6 months following the last injection
- •have a partner who is medically unable to induce pregnancy Abstinence is acceptable per Investigator discretion and as long as it is documented that the subject will use medically effective contraception when engaging in sexual activities and notifies the study team.
- •Sexually active men who are considered sexually fertile must agree to one of the following:
- •use a barrier method of contraception during the study and continue its use for at least 6 months following the last injection
- •have a partner who is permanently sterile or is medically unable to become pregnant
- •No history of clinically significant immunosuppressive or autoimmune disease. Individuals with HIV infection who have been virologically suppressed for more than 1 year and with current CD4 cell count entry greater than 500 cells/ul will be allowed into the study.
排除标准
- •Administration of an investigational compound either currently or within 6 months of first dose.
- •Administration of any vaccine within 4 weeks of first dose.
- •Administration of a SARS-CoV-2 vaccine in the last 14 days or plans to have any standard of care vaccines within 14 days form the last administration of study products.
- •Positive SARS-CoV-2 infection at screening visit.
- •Administration of any monoclonal or polyclonal antibody product within 4 weeks of the first dose.
- •Administration of any blood product within 3 months of first dose.
- •Co-morbid conditions including poorly-controlled diabetes (HbA1C > 7), poorly-controlled hypertension (BP > 140/95 repeatedly), asthma, and any cardiovascular disease.
- •Pregnancy or breast feeding or plans to become pregnant during the course of the study.
- •Positive serologic test for hepatitis B surface antigen (HBsAg); or any potentially communicable infectious disease as determined by the Principal Investigator or Medical Director.
- •Positive serologic test for hepatitis C (exception: successful treatment with confirmation of sustained virologic response);
- •Baseline evidence of kidney disease as measured by creatinine greater than 1.5 mg/dL (CKD Stage II or greater);
- •Baseline screening lab with Grade 2 or higher abnormality, except for Grade 2 creatinine.
- •Chronic liver disease or cirrhosis.
- •Immunosuppressive illness including hematologic malignancy, history of solid organ or bone marrow transplantation.
- •Current or anticipated concomitant immunosuppressive therapy (inhaled, topical skin and/or eye drop-containing corticosteroids, low-dose methotrexate, or prednisone at a dose less than 10 mg/day or steroid dose-equivalent are not exclusionary).
- •Current or anticipated treatment with TNF-α inhibitors such as infliximab, adalimumab, etanercept.
- •Prior major surgery or any radiation therapy within 6 months of first dose.
- •Any pre-excitation syndromes, e.g., Wolff-Parkinson-White syndrome.
- •Presence of a cardiac pacemaker or automatic implantable cardioverter defibrillator (AICD)
- •Fewer than two acceptable sites available for IM injection and EP considering the deltoid and anterolateral quadriceps muscles. The following are unacceptable sites:
- •Tattoos, keloids or hypertrophic scars located within 2 cm of intended administration site.
- •Implantable-Cardioverter-defibrillator (ICD) or pacemaker (to prevent a life-threatening arrhythmia) that is located ipsilateral to the deltoid injection site (unless deemed acceptable by a cardiologist).
- •Any metal implants or implantable medical device within the electroporation site.
- •Prisoner or participants who are compulsorily detained (involuntary incarceration) for treatment of either a physical or psychiatric illness.
- •Active drug or alcohol use or dependence that, in the opinion of the investigator, would interfere with adherence to study requirements or assessment of immunologic endpoints.
- •Not willing to allow storage and future use of samples for SARS-CoV-2 virus related research.
- •Any illness or condition that in the opinion of the investigator may affect the safety of the participant or the evaluation of any study endpoint.
- •Participants with known bleeding diatheses or that are using blood thinners for 30 days before study enrollment including warfarin, heparin, Clopidogrel, Apixaban (Eliquis), Dabigatran (Pradaxa), Edoxaban (Savaysa), Rivaroxaban (Xarelto). The use of low dose aspirin (81 mg daily) is acceptable.
- •Participants with concomitant intramuscular medications.
研究组 & 干预措施
Cohort A1 - 1x 0.5 mg
Participants (n=3) will be administered 0.5 mg of dMAb AZD5396 and 0.5 mg of dMAb AZD8076 with Hylenex® delivered intramuscularly using the side port needle followed by electroporation (EP) with OpBlock 0078 parameter on D0, for a total dose of 0.5 mg of each plasmid.
干预措施: dMAb AZD5396 (Combination Product)
Cohort A1 - 1x 0.5 mg
Participants (n=3) will be administered 0.5 mg of dMAb AZD5396 and 0.5 mg of dMAb AZD8076 with Hylenex® delivered intramuscularly using the side port needle followed by electroporation (EP) with OpBlock 0078 parameter on D0, for a total dose of 0.5 mg of each plasmid.
干预措施: dMAb AZD8076 (Combination Product)
Cohort A1 - 1x 0.5 mg
Participants (n=3) will be administered 0.5 mg of dMAb AZD5396 and 0.5 mg of dMAb AZD8076 with Hylenex® delivered intramuscularly using the side port needle followed by electroporation (EP) with OpBlock 0078 parameter on D0, for a total dose of 0.5 mg of each plasmid.
干预措施: CELLECTRA™ 2000 with Side Port needle, OpBlock 0078 Electroporation device (Combination Product)
Cohort A1 - 1x 0.5 mg
Participants (n=3) will be administered 0.5 mg of dMAb AZD5396 and 0.5 mg of dMAb AZD8076 with Hylenex® delivered intramuscularly using the side port needle followed by electroporation (EP) with OpBlock 0078 parameter on D0, for a total dose of 0.5 mg of each plasmid.
干预措施: Hylenex (Drug)
Cohort A2 - 1x 1 mg
Participants (n=3) will be administered 1 mg of dMAb AZD5396 and 1 mg of dMAb AZD8076 with Hylenex® delivered intramuscularly using the side port needle followed by electroporation (EP) with OpBlock 0078 parameter on D0, for a total dose of 1 mg of each plasmid.
干预措施: dMAb AZD5396 (Combination Product)
Cohort A2 - 1x 1 mg
Participants (n=3) will be administered 1 mg of dMAb AZD5396 and 1 mg of dMAb AZD8076 with Hylenex® delivered intramuscularly using the side port needle followed by electroporation (EP) with OpBlock 0078 parameter on D0, for a total dose of 1 mg of each plasmid.
干预措施: dMAb AZD8076 (Combination Product)
Cohort A2 - 1x 1 mg
Participants (n=3) will be administered 1 mg of dMAb AZD5396 and 1 mg of dMAb AZD8076 with Hylenex® delivered intramuscularly using the side port needle followed by electroporation (EP) with OpBlock 0078 parameter on D0, for a total dose of 1 mg of each plasmid.
干预措施: CELLECTRA™ 2000 with Side Port needle, OpBlock 0078 Electroporation device (Combination Product)
Cohort A2 - 1x 1 mg
Participants (n=3) will be administered 1 mg of dMAb AZD5396 and 1 mg of dMAb AZD8076 with Hylenex® delivered intramuscularly using the side port needle followed by electroporation (EP) with OpBlock 0078 parameter on D0, for a total dose of 1 mg of each plasmid.
干预措施: Hylenex (Drug)
Cohort B - 2x 0.5 mg
Participants (n=6) will be administered 0.5 mg of dMAb AZD5396 and 0.5 mg of dMAb AZD8076 with Hylenex® delivered intramuscularly using the side port needle followed by electroporation (EP) with OpBlock 0078 parameter on D0 and D3, for a total dose of 1 mg of each plasmid.
干预措施: dMAb AZD5396 (Combination Product)
Cohort B - 2x 0.5 mg
Participants (n=6) will be administered 0.5 mg of dMAb AZD5396 and 0.5 mg of dMAb AZD8076 with Hylenex® delivered intramuscularly using the side port needle followed by electroporation (EP) with OpBlock 0078 parameter on D0 and D3, for a total dose of 1 mg of each plasmid.
干预措施: dMAb AZD8076 (Combination Product)
Cohort B - 2x 0.5 mg
Participants (n=6) will be administered 0.5 mg of dMAb AZD5396 and 0.5 mg of dMAb AZD8076 with Hylenex® delivered intramuscularly using the side port needle followed by electroporation (EP) with OpBlock 0078 parameter on D0 and D3, for a total dose of 1 mg of each plasmid.
干预措施: CELLECTRA™ 2000 with Side Port needle, OpBlock 0078 Electroporation device (Combination Product)
Cohort B - 2x 0.5 mg
Participants (n=6) will be administered 0.5 mg of dMAb AZD5396 and 0.5 mg of dMAb AZD8076 with Hylenex® delivered intramuscularly using the side port needle followed by electroporation (EP) with OpBlock 0078 parameter on D0 and D3, for a total dose of 1 mg of each plasmid.
干预措施: Hylenex (Drug)
Cohort C - 2x 1 mg
Participants (n=6) will be administered 1mg of dMAb AZD5396 and 1 mg of dMAb AZD8076 with Hylenex® delivered intramuscularly using the side port needle followed by electroporation (EP) with OpBlock 0078 parameter on D0 and D3, for a total dose of 2 mg of each plasmid.
干预措施: dMAb AZD5396 (Combination Product)
Cohort C - 2x 1 mg
Participants (n=6) will be administered 1mg of dMAb AZD5396 and 1 mg of dMAb AZD8076 with Hylenex® delivered intramuscularly using the side port needle followed by electroporation (EP) with OpBlock 0078 parameter on D0 and D3, for a total dose of 2 mg of each plasmid.
干预措施: dMAb AZD8076 (Combination Product)
Cohort C - 2x 1 mg
Participants (n=6) will be administered 1mg of dMAb AZD5396 and 1 mg of dMAb AZD8076 with Hylenex® delivered intramuscularly using the side port needle followed by electroporation (EP) with OpBlock 0078 parameter on D0 and D3, for a total dose of 2 mg of each plasmid.
干预措施: CELLECTRA™ 2000 with Side Port needle, OpBlock 0078 Electroporation device (Combination Product)
Cohort C - 2x 1 mg
Participants (n=6) will be administered 1mg of dMAb AZD5396 and 1 mg of dMAb AZD8076 with Hylenex® delivered intramuscularly using the side port needle followed by electroporation (EP) with OpBlock 0078 parameter on D0 and D3, for a total dose of 2 mg of each plasmid.
干预措施: Hylenex (Drug)
Cohort D - 2x 0.25 mg
Participants (n=6) will be administered 1 mg of dMAb AZD5396 and 1 mg of dMAb AZD8076 with Hylenex® delivered intramuscularly using the side port needle followed by electroporation (EP) with OpBlock 0078 parameter on D0 and D3, for a total dose of 2 mg of each plasmid.
干预措施: dMAb AZD5396 (Combination Product)
Cohort D - 2x 0.25 mg
Participants (n=6) will be administered 1 mg of dMAb AZD5396 and 1 mg of dMAb AZD8076 with Hylenex® delivered intramuscularly using the side port needle followed by electroporation (EP) with OpBlock 0078 parameter on D0 and D3, for a total dose of 2 mg of each plasmid.
干预措施: dMAb AZD8076 (Combination Product)
Cohort D - 2x 0.25 mg
Participants (n=6) will be administered 1 mg of dMAb AZD5396 and 1 mg of dMAb AZD8076 with Hylenex® delivered intramuscularly using the side port needle followed by electroporation (EP) with OpBlock 0078 parameter on D0 and D3, for a total dose of 2 mg of each plasmid.
干预措施: CELLECTRA™ 2000 with Side Port needle, OpBlock 0078 Electroporation device (Combination Product)
Cohort D - 2x 0.25 mg
Participants (n=6) will be administered 1 mg of dMAb AZD5396 and 1 mg of dMAb AZD8076 with Hylenex® delivered intramuscularly using the side port needle followed by electroporation (EP) with OpBlock 0078 parameter on D0 and D3, for a total dose of 2 mg of each plasmid.
干预措施: Hylenex (Drug)
Cohort E - 2x 2 mg
Participants (n=5) will be administered 2 mg of dMAb AZD5396 and 2 mg of dMAb AZD8076 with Hylenex® delivered intramuscularly using the side port needle followed by electroporation (EP) with OpBlock 0078 parameter on D0 and D3, for a total dose of 4 mg of each plasmid.
干预措施: dMAb AZD5396 (Combination Product)
Cohort E - 2x 2 mg
Participants (n=5) will be administered 2 mg of dMAb AZD5396 and 2 mg of dMAb AZD8076 with Hylenex® delivered intramuscularly using the side port needle followed by electroporation (EP) with OpBlock 0078 parameter on D0 and D3, for a total dose of 4 mg of each plasmid.
干预措施: dMAb AZD8076 (Combination Product)
Cohort E - 2x 2 mg
Participants (n=5) will be administered 2 mg of dMAb AZD5396 and 2 mg of dMAb AZD8076 with Hylenex® delivered intramuscularly using the side port needle followed by electroporation (EP) with OpBlock 0078 parameter on D0 and D3, for a total dose of 4 mg of each plasmid.
干预措施: CELLECTRA™ 2000 with Side Port needle, OpBlock 0078 Electroporation device (Combination Product)
Cohort E - 2x 2 mg
Participants (n=5) will be administered 2 mg of dMAb AZD5396 and 2 mg of dMAb AZD8076 with Hylenex® delivered intramuscularly using the side port needle followed by electroporation (EP) with OpBlock 0078 parameter on D0 and D3, for a total dose of 4 mg of each plasmid.
干预措施: Hylenex (Drug)
Cohort F - 2x 0.5 mg
Participants (n=5) will be administered 0.5 mg of dMAb AZD5396 and 0.5 mg of dMAb AZD8076 with Hylenex® delivered intramuscularly using the side port needle followed by electroporation (EP) with OpBlock 0070 parameter on D0 and D3, for a total dose of 1 mg of each plasmid.
干预措施: dMAb AZD5396 (Combination Product)
Cohort F - 2x 0.5 mg
Participants (n=5) will be administered 0.5 mg of dMAb AZD5396 and 0.5 mg of dMAb AZD8076 with Hylenex® delivered intramuscularly using the side port needle followed by electroporation (EP) with OpBlock 0070 parameter on D0 and D3, for a total dose of 1 mg of each plasmid.
干预措施: dMAb AZD8076 (Combination Product)
Cohort F - 2x 0.5 mg
Participants (n=5) will be administered 0.5 mg of dMAb AZD5396 and 0.5 mg of dMAb AZD8076 with Hylenex® delivered intramuscularly using the side port needle followed by electroporation (EP) with OpBlock 0070 parameter on D0 and D3, for a total dose of 1 mg of each plasmid.
干预措施: Hylenex (Drug)
Cohort F - 2x 0.5 mg
Participants (n=5) will be administered 0.5 mg of dMAb AZD5396 and 0.5 mg of dMAb AZD8076 with Hylenex® delivered intramuscularly using the side port needle followed by electroporation (EP) with OpBlock 0070 parameter on D0 and D3, for a total dose of 1 mg of each plasmid.
干预措施: CELLECTRA™ 2000 with Side Port needle, OpBlock 0070 Electroporation device (Combination Product)
Cohort G - 4x 0.5 mg
Participants (n=5) will be administered 0.5 mg of dMAb AZD5396 and 0.5 mg of dMAb AZD8076 with Hylenex® delivered intramuscularly using the side port needle followed by electroporation (EP) with OpBlock 0078 parameter on D0, D3, D28 and D31, for a total dose of 2 mg of each plasmid.
干预措施: dMAb AZD5396 (Combination Product)
Cohort G - 4x 0.5 mg
Participants (n=5) will be administered 0.5 mg of dMAb AZD5396 and 0.5 mg of dMAb AZD8076 with Hylenex® delivered intramuscularly using the side port needle followed by electroporation (EP) with OpBlock 0078 parameter on D0, D3, D28 and D31, for a total dose of 2 mg of each plasmid.
干预措施: dMAb AZD8076 (Combination Product)
Cohort G - 4x 0.5 mg
Participants (n=5) will be administered 0.5 mg of dMAb AZD5396 and 0.5 mg of dMAb AZD8076 with Hylenex® delivered intramuscularly using the side port needle followed by electroporation (EP) with OpBlock 0078 parameter on D0, D3, D28 and D31, for a total dose of 2 mg of each plasmid.
干预措施: CELLECTRA™ 2000 with Side Port needle, OpBlock 0078 Electroporation device (Combination Product)
Cohort G - 4x 0.5 mg
Participants (n=5) will be administered 0.5 mg of dMAb AZD5396 and 0.5 mg of dMAb AZD8076 with Hylenex® delivered intramuscularly using the side port needle followed by electroporation (EP) with OpBlock 0078 parameter on D0, D3, D28 and D31, for a total dose of 2 mg of each plasmid.
干预措施: Hylenex (Drug)
结局指标
主要结局
Evaluation of the pain experienced by the participant
时间窗: Immediately after EP, 5 minutes after EP and 10 minutes after EP
Visual analogue scale (VAS). A VAS consists of a horizontal line, 10 cm in length, anchored by word descriptors at each end (no pain = 0 cm; worst pain = 10 cm). The VAS score is determined by measuring in centimeters from the left hand end of the line to the point that the patient marks. Absolute initial value and change over time will be described.
Serum concentration of dMAb AZD5396 nm/mL.
时间窗: Up to 72 Weeks after administration of the investigational products
The number and percentage of participants in which detection of monoclonal antibody dMAb AZD5396 in serum is achieved will be summarized with a point estimate and corresponding exact 90% Clopper- Pearson confidence interval. These will be summarized per time point within each cohort. We will also estimate the time to 50% decline from peak concentration.
Frequency and nature of injection site reaction
时间窗: 7 days after administration of the investigational products
Injection site reactions occurring up to 7 days after administration of the investigational product
Serum concentration of dMAb AZD8076 nm/mL.
时间窗: Up to 72 Weeks after administration of the investigational products
The number and percentage of participants in which detection of monoclonal antibody dMAb AZD8076 in serum is achieved will be summarized with a point estimate and corresponding exact 90% Clopper- Pearson confidence interval. These will be summarized per time point within each cohort. We will also estimate the time to 50% decline from peak concentration.
Frequency and nature of Serious Adverse Events
时间窗: 72 Weeks after administration of the investigational products
SAE will be classified using the CTCAE v5 throughout the study
Evaluation of laboratory related adverse events
时间窗: Up to 7 days after administration of the investigational product
Laboratory AEs will be assessed and graded in accordance with the "Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials", issued in September 2007.
Frequency and nature of systemic reactions
时间窗: 7 days after administration of the investigational products
Systemic reactions occurring up to 7 days after administration of the investigational product.
次要结局
未报告次要终点
研究者
Pablo Tebas
Professor of Medicine. University of Pennsylvania
University of Pennsylvania