The AdAPT Trial; Adenovirus After Allogeneic Pediatric Transplantation

Adenovirus Clinical Trial

— AdAPT  

Official title:

Study to Assess the Safety, Overall Tolerability, and Antiviral Activity of Brincidofovir Versus Standard of Care for Treatment of Adenovirus in High-risk Pediatric Allogeneic Hematopoietic Transplant Recipients

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT03339401
• Other study ID #: CMX001-999
• Status: Terminated
• Phase: Phase 2
• Start date: December 22, 2017
• Est. completion date: May 10, 2019

Study information

• Verified date: January 2021
• Source: Chimerix
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This study was designed to assess the safety, overall tolerability, and antiviral activity of "short course" brincidofovir (BCV) therapy, as compared with current standard of care (SoC), for the treatment of adenovirus (AdV) infections in high-risk (i.e., T cell depleted) pediatric allogeneic hematopoietic cell transplant (HCT) recipients. A virologic response-driven approach to the duration of treatment was to be evaluated, in which subjects randomized to BCV therapy were to be treated until AdV viremia was confirmed as undetectable or until a maximum of 16 weeks of therapy, whichever occurred first. The formulation of BCV used in this study was oral tablet/suspension.

Description:

This was a randomized, open-label, multi-center study of the safety, overall tolerability, and antiviral activity of BCV, as compared with SoC, in pediatric (and young adults in the United States) recipients of high-risk (i.e., T cell-depleted and/or unrelated cord blood graft, or a T cell-replete graft from ahaploidentical donor with post-transplant cyclophosphamide administration) allogeneic HCT. Subjects with AdV detected in plasma after their qualifying transplant could be screened for participation in the study. Subjects who met all applicable entry criteria were randomized in a 2:1 ratio to receive either BCV or SoC (i.e., investigator-assigned therapy). The formulation of BCV used in this study was oral tablet/suspension. Subjects were randomized within 100 days post-transplant; for study purposes, the day of randomization was defined as Day 1. During randomization, subjects were stratified based on the following variables: last AdV viremia (≥10,000 copies/mL versus <10,000 copies/mL) measurement available from the designated central virology laboratory prior to randomization, time from transplant to randomization (≥28 days versus <28 days), and T cell-depletion methodology (receipt of alemtuzumab or ex vivo depletion versus receipt of anti-thymocyte globulin [ATG] or no T cell depletion).

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 29
• Est. completion date: May 10, 2019
• Est. primary completion date: May 10, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 2 Months to 25 Years

Eligibility

Inclusion Criteria:

Subjects were high-risk allogeneic hematopoietic cell transplant (HCT) recipients aged 2 months to <18 years (<26 years in the United States) who met adenovirus (AdV) viremia criteria within 7 days of randomization (Day 1), and all other eligibility criteria. High-risk was defined as having received 1 of the following:

• A T cell-depleted graft:

• Ex vivo T cell depletion via positive selective (e.g., CD34+ cell) or negative selection (e.g., T cell receptor a/ß or CD3+ cell removal by column filtration); or

• Serotherapy with ATG (cumulative dose of =3 mg/kg rabbit-derived ATG or =30 mg/kg of equine-derived ATG) administered within 10 days prior to transplant or at any time post-transplant and prior to Day 1; or

• Serotherapy with alemtuzumab administered within 30 days prior to transplant or at any time post-transplant and prior to Day 1; or

• A cord blood graft from an unrelated donor with or without T cell depletion, or

• A T cell-replete graft from a haploidentical donor with high-dose cyclophosphamide (e.g., cumulative dose of =100 mg/kg) administered at any time post-transplant and prior to Day 1.

Subjects must have had qualifying AdV viremia within 100 days of transplant, which was defined as having either:

1. Confirmed AdV viremia of =1000 copies/mL on 2 consecutive AdV DNA polymerase chain reaction (PCR) test results drawn =48 hours apart from the designated central virology laboratory, with the second result being greater than the first; or

2. A single AdV viremia result of =10,000 copies/mL from the designated central virology laboratory Subjects who were previously treated with intravenous (IV) cidofovir (CDV) could have a cumulative exposure to IV CDV of no more than 10 mg/kg within 21 days prior to Day 1.

Written informed consent (and assent, where applicable) to participate in the study was obtained from each subject and his/her legal guardian(s) in accordance with national or local law and institutional practice.

Exclusion Criteria:

1. Any United States National Institutes of Health (NIH)/National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Grade 4 diarrhea (i.e., life-threatening consequences with urgent intervention indicated) within 7 days prior to Day 1.

2. Any CTCAE Grade 2 or 3 diarrhea (i.e., increase of =4 stools/day over baseline [pre-transplant] diarrheal output), unless attributed to AdV, within 7 days prior to Day 1.

3. NIH Stage 4 acute graft versus host disease (GVHD) of the skin (i.e., generalized erythroderma with bullous formation) within 7 days prior to Day 1.

4. NIH Stage =2 acute GVHD of the liver (i.e., bilirubin >3 mg/dL [SI: >51 µmol/L]) within 7 days prior to Day 1.

5. NIH Stage =2 acute GVHD of the gut (i.e., diarrhea >556 mL/m2/day for pediatric patients [or >1000 mL/day for young adults at centers in the United States only], or severe abdominal pain with or without ileus) within 7 days prior to Day 1.

6. Poor clinical prognosis (including active malignancy or use of vasopressors other than low dose (e.g., =5 µg/kg/min) dopamine for renal perfusion within 7 days prior to Day 1.

7. Requirement for mechanical ventilation within 7 days prior to Day 1 or requirement for sustained oxygen delivery for >24 hours within 7 days prior to Day 1.

8. Concurrent HIV, active hepatitis B virus, or hepatitis C virus infection.

9. Specified out of range laboratory results (including alanine aminotransferase >5x the upper limit of normal [ULN], aspartate aminotransferase >5x ULN, total bilirubin >3 mg/dL [SI: >51 µmol/L], or prothrombin time-international normalized ratio >2x ULN) within 7 days prior to Day 1.

10. Estimated creatinine clearance <30 mL/min or use of renal replacement therapy within 7 days prior to Day 1.

11. Previous receipt of BCV at any time or receipt of CDV (IV or intravesicular) or letermovir within 48 hours prior to Day 1.

12. Received any anti-AdV-specific cell-based therapy within 6 weeks prior to Day 1 or previously received an anti-AdV vaccine at any time.

When applicable, female subjects of childbearing potential (i.e., not pre-menarche) were not pregnant or breastfeeding, and if sexually active, agreed to use 2 acceptable forms of contraception, 1 of which must have been a barrier method and the other a highly-effective method of contraception. Male subjects, if sexually active and capable of fathering a child, agreed to use a barrier method of contraception while enrolled in the study and for at least 90 days after the last dose of BCV.

Related Conditions & MeSH terms

• Adenoviridae Infections
• Adenovirus

Intervention

Other:
• Standard of Care
Local institutional standard of care (SoC) (i.e., investigator-assigned therapy) for the treatment of adenovirus infection in high-risk pediatric allogeneic hematopoietic cell transplant (HCT) recipients.

Drug:
• Brincidofovir
Brincidofovir (BCV) for the treatment of adenovirus infection in high-risk pediatric allogeneic hematopoietic cell transplant (HCT) recipients.

Locations

Country	Name	City	State
France	IHOPe-Institut d'Homatologie et d'Oncologie Pediatrique	Lyon
France	Hopital Necker-Enfants Malades	Paris
France	Hopital Universitaire Robert Debre	Paris
Germany	Charite Universitatsmedizin Berlin, Campus Virchow-Klinikum	Berlin
Germany	Dr. von Haunersches Kinderspital, Abteilung fur Padiatrische	München	Bavaria
Germany	Universitatsklinik fur Kinder-und Jugendmedizin	Tübingen	Baden-Wurttemberg
Ireland	Our Lady's Children Hospital	Dublin
Italy	Fondazione MBBM-CTMO Pediatrico	Monza
Italy	Ospedale Pediatrico Bambino Gesu	Roma
Netherlands	Leiden University Medical Center (LUMC)	Leiden
Netherlands	Princess Maxima Center Utrecht	Utrecht
Poland	Uniwerstytecki Azpital Kliniczny we Wroclawiu	Wroclaw	Dolnoslaskie
Spain	Hospital Sant Joan de Deu	Esplugues De Llobregat	Barcelona
Spain	Hospital Infantil Universitario Nino Jesus	Madrid
United Kingdom	Birmingham Childrens Hospital	Birmingham	West Midlands
United Kingdom	Bristol Royal Hospital for Children	Bristol
United Kingdom	Royal Hospital for Sick Children	Glasgow
United Kingdom	Leeds Children's Hospital	Leeds	West Yorkshire
United Kingdom	Great Ormond Street Hospital for Children	London
United Kingdom	St Marys Hospital	London
United Kingdom	University College London Hospital	London
United Kingdom	Royal Manchester Childrens Hospital	Manchester
United Kingdom	Newcastle-upon-Tyne Hospitals-Great Childrens Hospital	Newcastle Upon Tyne	Tyneside
United Kingdom	Sheffield Children's Hospital	Sheffield
United Kingdom	Royal Marsden Hospital	Sutton	Surrey
United States	University of Chicago	Chicago	Illinois
United States	Cincinnati Childrens Hospital Medical Center	Cincinnati	Ohio
United States	Duke University Medical Center	Durham	North Carolina
United States	Joseph M. Sanzari Childrens Hospital-Regional Cancer Care	Hackensack	New Jersey
United States	Children's Hospital of Los Angeles	Los Angeles	California
United States	St. Jude Children's Research Hospital	Memphis	Tennessee
United States	Medical College of Wisconsin	Milwaukee	Wisconsin
United States	Memorial Sloan Kettering Cancer Center	New York	New York
United States	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania
United States	University of California San Francisco	San Francisco	California
United States	University of Washington-Seattle Childrens Hospital	Seattle	Washington

Sponsors (1)

Lead Sponsor	Collaborator
Chimerix

Countries where clinical trial is conducted

United States,  France,  Germany,  Ireland,  Italy,  Netherlands,  Poland,  Spain,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Time-averaged Area Under the Concentration-time Curve for Plasma Adenovirus Viremia (Log10 Copies/mL).	The primary efficacy endpoint for this study was the time-averaged area under the concentration-time curve for plasma adenovirus (AdV) viremia (log10 copies/mL) from randomization through Week 16 post-randomization. Due to the small number of subjects enrolled in the study, formal efficacy analyses were not performed. Individual subject AdV viremia profiles show the differential anti-adenoviral effect of brincidofovir (BCV) in comparison to standard of care (SoC) therapy.	From randomization to 16 weeks post-randomization