Anti-Covid-19 Vaccine in Children With Acute Leukemia and Their Siblings

Study Overview
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Brief Summary
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Mortality in case of SARS-CoV-2 infection (Covid-19) during acute leukemia (AL) treatment is around 30%, i.e. more than 10 times the one of general population. Severe forms are reported in children receiving chemotherapy for AL. However, the main risk, largely underestimated, is related to delay in chemotherapy administration in case of infection, leading to an increased risk of relapse. Therefore, it is justified to propose an anti-Covid-19 vaccination to these patients. Vaccination of siblings also seems necessary given the uncertainty regarding vaccine response in children with AL and given that household is the main source of contamination. The messenger ribonucleic acid (mRNA) vaccine COMIRNATY® (BNT162b2) is already approved by health authorities for individuals older than 12. In immunocompromised children with AL, safety and efficacy data are unknown. The benefit/risk balance encourages to use the vaccine without health authority approval in children aged 1 to 15 with AL. Regarding household, parents are vaccinated for several months as standard of care, but vaccination will be proposed to siblings aged 12 to 15 years old in this protocol. The primary objective of this study is to evaluate safety and immunogenicity of COMIRNATY® (BNT162b2) vaccine (two injections 21-28 days apart) in children with acute leukemia (1 to 15 years old) and their siblings (≥12-15 years old). A secondary objective of the study is to compare the quality of humoral and cellular vaccine responses in children with AL and healthy children.

Official Title
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Anti-Covid-19 Vaccine Protection in Immunocompromised Children (1 to 15 Years Old) With Acute Leukemia and Their Siblings (≥12 Years Old). Phase I-II Trial Evaluating Post-vaccine Safety and Humoral and Cellular Immunogenicity.

Conditions
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Acute Leukemia, Acute Lymphoblastic Leukemia, Acute Myeloid Leukemia

Intervention / Treatment
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* Biological: vaccine COMIRNATY® (BNT162b2)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Children aged 1 to 15 years old : With acute lymphoblastic leukemia undergoing chemotherapy (at least 2 weeks from the last injection of PEG-asparaginase) or for whom the last chemotherapy is less than or equal to 12 months With acute myeloid leukemia within 12 months from the end of treatment Healthy siblings aged 12 to 15 years old living in the same household than the child with AL more than 50% of the time Informed consent from parents Patient affiliated to health insurance Exclusion Criteria: Documented SARS-CoV-2 infection ongoing or that occurred less than 3 months ago Known clinical allergy to polyethylene glycol (PEG) Pregnant woman during first pregnancy quarter or lactating woman Platelet <50 Giga(G) G/L or neutrophils <0.5 G/L at time of vaccination Vaccination within 4 weeks from the 1st injection or planning to receive an approved vaccine 4 weeks after the last injection Any hemorrhagic trouble considered as a contraindication to intramuscular injection History of severe adverse event after a vaccine administration including anaphylaxis and associated symptoms such as rash, respiratory issues, angioedema and abdominal pain, or history of allergic reaction that could be exacerbated by a vaccine component Participant vaccinated against tuberculosis within the past year

Ages Eligible for Study
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Minimum Age: 1 Year
Maximum Age: 15 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: Prevention
Intervention Model: Single Group Assignment
Interventional Model Description: Dose finding, stratified on the age group (≥1-<2 years, ≥2-<5 years, ≥5-<12 years)
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Anti Covid with COMIRNATY® (BNT162b2) vaccine<br>Two injections of COMIRNATY® (BNT162b2) vaccine 21-28 days apart | Biological: vaccine COMIRNATY® (BNT162b2)<br>* two injections of COMIRNATY® (BNT162b2) vaccine 21-28 days apart, of either 10, 20, 30 µg of vaccine, depending on the observed responses of previous children<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose limiting toxicity (DLT) | Dose limiting toxicity (DLT) defined by the presence within 7 days following vaccine injection of a grade ≥3 adverse event related to the vaccine. They are derived from CTCAE v5.0 and FDA guide  Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials . Any other unexpected grade 3-4 clinical adverse event according to CTCAE v5.0 related to vaccination. A committee of critical events and DLTs surveillance will validate if declared grade 3-4 serious adverse events are related to vaccine. | within 7 days from first dose | 
| co-primary endpoint: Increase in anti-Spike Immunoglobulin G (IgG) titer AND positive anti-Spike neutralizing test | Increase in anti-Spike IgG will be defined as four times or more increase in anti-Spike IgG titer AND positive neutralizing test (from 1/5 dilution). The patient will be considered as having a  significant seroconversion  to vaccination if these 2 efficacy criteria are present - If these 2 efficacy criteria are present, the patient is considered as having a  significant seroconversion  to vaccination | at 2 months from first dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Anti-Spike IgG levels |  | between 21 and 28 days from first dose | 
| Anti-Spike IgG levels |  | at 6 months from first dose | 
| Anti-Spike IgG levels |  | at 12 months from the 1st dose | 
| Anti-nucleocapsid IgG levels |  | between 21 and 28 days from the first dose | 
| Anti-nucleocapsid IgG levels |  | 6 months from the first dose | 
| Anti-nucleocapsid IgG levels |  | 12 months from the first dose | 
| Neutralization ability of anti-Spike IgG (in case of anti-Spike IgG detection) |  | at 2 months from the first injection | 
| Neutralization ability of anti-Spike IgG (in case of anti-Spike IgG detection) |  | at 6 months from the first injection | 
| Neutralization ability of anti-Spike IgG (in case of anti-Spike IgG detection) |  | at 12 months from the first injection | 
| Anti-SARS-CoV-2 T cell specific response (Elispot) |  | at 2 months after the first injection | 
| Anti-SARS-CoV-2 T cell specific response (Elispot) |  | at 6 months after the first injection | 
| Anti-SARS-CoV-2 T cell specific response (Elispot) |  | at 12 months after the first injection | 
| Positivity of SARS-CoV-2 polymerase chain reaction (PCR) in nasopharynx | Positivity of SARS-CoV-2 PCR in nasopharynx in case of infection | at 8 days | 
| Positivity of SARS-CoV-2 PCR in nasopharynx | Positivity of SARS-CoV-2 PCR in nasopharynx in case of infection | at 15 days | 
| Positivity of SARS-CoV-2 PCR in nasopharynx | Positivity of SARS-CoV-2 PCR in nasopharynx in case of infection | at 28 days from infection | 
| Rate of symptomatic SARS-CoV-2 infections | Symptomatic SARS-CoV-2 infections will be defined by the presence of at least one symptom amongst fever, dyspnea, cough, chest pain, anosmia, ageusia, diarrhea or vomiting, AND a positive SARS-CoV-2 PCR, | within 12 months after vaccination | 
| Genotype of the SARS-CoV-2 variant in case of infection |  | within 12 months after vaccination | 
| Time between chemotherapy planned date and effective date in case of infection |  | within 12 months after vaccination | 
| Covid19 World Health Organization (WHO) progression scale | Covid19 WHO scale in 10 items in case of infection Uninfected; non viral RNA detected: 0 Asymptomatic; viral RNA detected: 1 Symptomatic; Independent: 2 Symptomatic; Assistance needed: 3 Hospitalized; No oxygen therapy: 4 Hospitalized; oxygen by mask or nasal prongs: 5 Hospitalized; oxygen by non-invasive ventilation (NIV) or High flow: 6 Intubation and Mechanical ventilation, pO2/Fraction of inspired oxygen (FIO2)>=150 OR saturation by pulse oximetry (SpO2) SpO2/FIO2>=200: 7 Mechanical ventilation, (pO2/FIO2<150 OR SpO2/FIO2<200) OR vasopressors (norepinephrine >0.3 microg/kg/min): 8 Mechanical ventilation, pO2/FIO2<150 AND vasopressors (norepinephrine >0.3 microg/kg/min), OR Dialysis OR extracorporeal membrane oxygenation (ECMO): 9 Dead: 10 | within 12 months after vaccination | 
| SARS-CoV-2 PCR of the household (contact cases) | In case of infection in a vaccinated child, SARS-CoV-2 PCR of the household (contact cases) from the diagnosis and within 7 days of contact, depending on the contagion (if 1st PCR is negative) | within 12 months after vaccination |