The AdAPT Trial; Adenovirus After Allogeneic Pediatric Transplantation

NCT03339401 | Terminated Phase 2 Results DMC FDA Drug

• 1 other identifier: CMX001-999
• Study Type: interventional
• Target: 29
• Locations: 9 countries
• Sites: 36

Brief 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.

Conditions

Adenovirus

Keywords

Adenovirus; Pediatric; Hematopoietic Cell Transplant; Brincidofovir; Standard of care

Outcome Measures

Primary Outcomes (1)

• 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

Study Arms (2)

Brincidofovir

EXPERIMENTAL

Brincidofovir (BCV) for the treatment of adenovirs (AdV) infection in high-risk pediatric allogeneic hematopoietic cell transplant (HCT) recipients. Brincidofovir (BCV) treatment began no later than 100 days post-transplant and was to continue for a maximum of 16 weeks. Brincidofovir (BCV) was discontinued once AdV viremia was confirmed undetectable. Subjects who did NOT receive concurrent cyclosporine on Day 1: * If ≥48kg body weight, one 100mg oral tablet BIW (or 10mL of 10mg/mL oral suspension if unable to take tablets). * If \<48kg body weight, 2mg/kg oral volume of 10mg/mL oral suspension BIW. Subjects who received cyclosporine on Day 1 (or initiated cyclosporine at any time): * 1.4mg/kg (maximum of 70mg) oral volume of 10mg/mL oral suspension BIW. * 2mg/kg (maximum of 100mg) oral volume of 10mg/mL oral suspension BIW if discontinued cyclosporine.

Drug: Brincidofovir

Standard of Care

OTHER

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. Management of these subjects was prescribed by the investigator as being in the best interests of the subject and may have included a "watch-and-wait" approach, with or without decreased immunosuppression (ergo, no treatment), or treatment administration with other available antivirals, most commonly cidofovir intravenously. Decisions regarding SoC, including administration of therapy, dose and regimen of therapy, modification of immunosuppression, and monitoring was the responsibility of the clinical team caring for the subject, according to institutional guidelines, local practices, and applicable guidelines for the management of AdV infection.

Other: Standard of Care

Interventions

Standard of Care OTHER

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.

Also known as: SoC

Standard of Care

Brincidofovir DRUG

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

Also known as: BCV

Brincidofovir

Eligibility Criteria

• Age: 2 Months - 25 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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 α/β 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:
• 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
• 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.

You may not qualify if:

• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• Concurrent HIV, active hepatitis B virus, or hepatitis C virus infection.
• 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.
• Estimated creatinine clearance \<30 mL/min or use of renal replacement therapy within 7 days prior to Day 1.
• Previous receipt of BCV at any time or receipt of CDV (IV or intravesicular) or letermovir within 48 hours prior to Day 1.
• 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.

Sponsors & Collaborators

• Jazz Pharmaceuticals: lead

Study Sites (36)

Children's Hospital of Los Angeles

Los Angeles, California, 90027, United States

Location

University of California San Francisco

San Francisco, California, 94143, United States

Location

University of Chicago

Chicago, Illinois, 60637, United States

Location

Joseph M. Sanzari Childrens Hospital-Regional Cancer Care

Hackensack, New Jersey, 07601, United States

Location

Memorial Sloan Kettering Cancer Center

New York, New York, 10065, United States

Location

Duke University Medical Center

Durham, North Carolina, 27705, United States

Location

Cincinnati Childrens Hospital Medical Center

Cincinnati, Ohio, 45229, United States

Location

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, 19104, United States

Location

St. Jude Children's Research Hospital

Memphis, Tennessee, 38105, United States

Location

University of Washington-Seattle Childrens Hospital

Seattle, Washington, 98105, United States

Location

Medical College of Wisconsin

Milwaukee, Wisconsin, 53226, United States

Location

IHOPe-Institut d'Homatologie et d'Oncologie Pediatrique

Lyon, 69008, France

Location

Hopital Necker-Enfants Malades

Paris, 75015, France

Location

Hopital Universitaire Robert Debre

Paris, 75019, France

Location

Universitatsklinik fur Kinder-und Jugendmedizin

Tübingen, Baden-Wurttemberg, 72076, Germany

Location

Dr. von Haunersches Kinderspital, Abteilung fur Padiatrische

München, Bavaria, 80337, Germany

Location

Charite Universitatsmedizin Berlin, Campus Virchow-Klinikum

Berlin, 13353, Germany

Location

Our Lady's Children Hospital

Dublin, D12 N512, Ireland

Location

Fondazione MBBM-CTMO Pediatrico

Monza, 20900, Italy

Location

Ospedale Pediatrico Bambino Gesu

Roma, 00165, Italy

Location

Leiden University Medical Center (LUMC)

Leiden, 2333, Netherlands

Location

Princess Maxima Center Utrecht

Utrecht, 3584, Netherlands

Location

Uniwerstytecki Azpital Kliniczny we Wroclawiu

Wroclaw, Lower Silesian Voivodeship, 50-556, Poland

Location

Hospital Sant Joan de Deu

Esplugues de Llobregat, Barcelona, 08950, Spain

Location

Hospital Infantil Universitario Nino Jesus

Madrid, 28009, Spain

Location

Royal Marsden Hospital

Sutton, Surrey, SM2 5PT, United Kingdom

Location

Newcastle-upon-Tyne Hospitals-Great Childrens Hospital

Newcastle upon Tyne, Tyneside, NE1 4LP, United Kingdom

Location

Birmingham Childrens Hospital

Birmingham, West Midlands, B4 6NH, United Kingdom

Location

Leeds Children's Hospital

Leeds, West Yorkshire, LS1 3EX, United Kingdom

Location

Bristol Royal Hospital for Children

Bristol, BS2 8BJ, United Kingdom

Location

Royal Hospital for Sick Children

Glasgow, G51 4TF, United Kingdom

Location

University College London Hospital

London, NW1 2BU, United Kingdom

Location

St Marys Hospital

London, W2 1NY, United Kingdom

Location

Great Ormond Street Hospital for Children

London, WCIN 3JH, United Kingdom

Location

Royal Manchester Childrens Hospital

Manchester, M13 9WL, United Kingdom

Location

Sheffield Children's Hospital

Sheffield, S10 2TH, United Kingdom

Location

MeSH Terms

Conditions

Adenoviridae Infections

Interventions

Standard of Care; brincidofovir

Condition Hierarchy (Ancestors)

DNA Virus Infections; Virus Diseases; Infections

Intervention Hierarchy (Ancestors)

Quality Indicators, Health Care; Quality of Health Care; Health Services Administration; Health Care Quality, Access, and Evaluation

Limitations and Caveats

The study was terminated in May 2019 due to poor subject accrual rates. As a result, statistical analyses were not performed. Limited demographic, efficacy, and safety data are provided for the 29 subjects who were enrolled as descriptive summaries.

Results Point of Contact

• Title: Chief Medical Officer
• Organization: Chimerix, Inc.

dmoore@chimerix.com

919-806-1074

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 8, 2017
• First Posted: November 13, 2017
• Study Start: December 22, 2017
• Primary Completion: May 10, 2019
• Study Completion: May 10, 2019
• Last Updated: January 25, 2021
• Results First Posted: January 25, 2021

Record last verified: 2021-01

Data Sharing

• IPD Sharing: Will not share

Locations

US (11); IE (1); PL (1); GB (11); IT (2); DE (3); FR (3); ES (2); NL (2)