Adenovirus Infection
Conditions
Keywords
Allogeneic Hematopoietic Cell Transplant, Adenoviremia, Adenovirus, Stem Cell Transplant, Posoleucel, ALVR105, Bone Marrow Transplant
Brief summary
This study will assess the safety and efficacy of Posoleucel for the treatment of adenovirus (AdV) infection in pediatric and adult allo-HCT recipients receiving standard of care (SoC).
Detailed description
During the period of immune recovery after allogeneic hematopoietic cell transplant (allo-HCT), viral infections and reactivations, including those with AdV, are an important cause of morbidity and mortality. Progression to AdV disease is associated with significant morbidity and mortality rates. This Phase 3, multicenter, randomized, double-blind, placebo-controlled study will assess the safety and efficacy of Posoleucel for the treatment of AdV infection in pediatric and adult allo-HCT recipients receiving SoC.
Interventions
DRUGPosoleucel
Administered as 2-4 milliliter infusion, visually identical to placebo
DRUGPlacebo
Administered as 2-4 milliliter infusion, visually identical to Posoleucel
Sponsors
AlloVir
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention model description
This is a Phase 3, multicenter, randomized, double-blind, placebo-controlled study with option for blinded crossover to assess the safety and efficacy of posoleucel as compared to placebo for the treatment of AdV infection in pediatric and adult recipients of HCT with AdV infections receiving SoC.
Eligibility
Sex/Gender
ALL
Healthy volunteers
No
Inclusion criteria
* Undergone allogeneic cell transplantation ≥21 days prior to dosing * Meet one of the below criteria: 1. AdV viremia DNA ≥10,000 copies/mL, OR 2. AdV viremia DNA results of ≥1,000 copies/mL, AND 1. has absolute lymphocyte count \<180/mm3, OR 2. has received T cell depletion OR 3. had a cord blood transplant.
Exclusion criteria
* Grade 3 or higher acute GVHD * Ongoing therapy with high-dose systemic corticosteroids * Uncontrolled viral (other than AdV), bacterial, or fungal infection(s) * Pregnant or lactating female unwilling to discontinue nursing prior to randomization * History of severe prior reactions to blood product transfusions NOTE: Other protocol-defined inclusion/exclusion criterion may apply.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Undetectable Adenovirus Infection | Day 29 through Day 43 (Day 29 + 14 days; up to 43 days post-first infusion) | Viral load of adenovirus was measured at the central laboratory using quantitative polymerase chain reaction (qPCR) from blood and stool samples at each study visit and on Day 29 from a nasopharyngeal swab. There was a 14-day window for participants who crossed over from posoleucel to placebo; and for participants who crossed over from placebo to posoleucel, the pre-dose cross-over Day 1 viral load was used. Participants missing the primary endpoint but having undetectable viremia before Day 29 and after Day 43 were imputed as successes. Undetectable adenovirus viremia was less than the lower limit of quantification (LLOQ). |
| Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) | Up to 34 weeks | A TEAE was defined as an adverse event (AE) with a start date and time on or after the first dose of study treatment. A serious AE (SAE) was an AE that met at least one of the following serious criteria: fatal, life-threatening, required inpatient hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity; was a congenital anomaly/birth defect; or other important medical event. TEAEs of special interest (AESI) included acute or chronic graft versus host disease, cytokine release syndrome, infusion-related reactions, and graft failure or rejection. Treatment-related refers to the assessment of a relationship between study treatment and the event by the investigator. |
Secondary
| Measure | Time frame |
|---|---|
| Number of Participants Who Achieved Adenovirus Viremia <400 Copies/mL at Day 29 | Day 29 |
| Number of Participants With Overall Disease Progression | From Day 29 up to Week 10 |
| Number of Participants With Adenovirus Disease Recurrence | 34 weeks |
| Time to Undetectable Adenovirus Viremia (Less Than LLOQ) | Pre-dose to 34 weeks |
| Area Under the Curve (AUC) Adenovirus Viral Load | Pre-dose and Day 29 |
Countries
Canada, Italy, Spain, Sweden, United Kingdom, United States
Participant flow
Recruitment details
Participants were enrolled at 47 study centers in the United States, Canada, Italy, Spain, Sweden, and the United Kingdom, and participated from April 2022 to January 2024.
Pre-assignment details
Participants with adenovirus infection receiving standard of care following allogeneic hematopoietic stem cell transplant (allo-HCT) were randomized in a 1:1 ratio to receive either posoleucel or placebo. Randomization was stratified by level of viremia (≥10,000 copies/mL or \<10,000 copies/mL adenovirus DNA) and age (≥12 years or \<12 years).
Participants by arm
| Arm | Count |
|---|---|
| Posoleucel, Then Placebo Participants were randomized to receive 2 sequential infusions of posoleucel, separated by 14 ± 3 days. The Primary Study Period included a 4-week efficacy evaluation followed by a 20-week safety follow-up.
Eligible participants who experienced progression to active target organ disease or progression of existing target organ disease could cross-over to placebo treatment between Day 29 and Week 10. In the Cross-Over Period, participants received 2 sequential infusions of placebo, separated by 14 ± 3 days. The Cross-over Period included a 4-week efficacy evaluation followed by a 20-week safety follow-up. | 30 |
| Placebo, Then Posoleucel Participants were randomized to receive 2 sequential infusions of placebo, separated by 14 ± 3 days. The Primary Study Period included a 4-week efficacy evaluation followed by a 20-week safety follow-up.
Eligible participants who experienced progression to active target organ disease or progression of existing target organ disease could cross-over to posoleucel treatment between Day 29 and Week 10. In the Cross-Over Period, participants received 2 sequential infusions of placebo, separated by 14 ± 3 days. The Cross-over Period included a 4-week efficacy evaluation followed by a 20-week safety follow-up. | 27 |
| Total | 57 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 3 | 2 |
| Overall Study | Discontinuation or withdrawal by participants/parent/legal guardian | 2 | 2 |
| Overall Study | Never received primary or cross-over study treatment | 1 | 3 |
| Overall Study | Non-compliance with protocol requirements or study-related procedures | 1 | 0 |
| Overall Study | Study terminated | 13 | 7 |
Baseline characteristics
| Characteristic | Posoleucel, Then Placebo | Placebo, Then Posoleucel | Total |
|---|---|---|---|
| Age, Continuous | 16.2 years STANDARD_DEVIATION 17.1 | 14.9 years STANDARD_DEVIATION 15.8 | 15.6 years STANDARD_DEVIATION 16.36 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 5 Participants | 2 Participants | 7 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 22 Participants | 23 Participants | 45 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 3 Participants | 2 Participants | 5 Participants |
| Race/Ethnicity, Customized Asian | 3 Participants | 2 Participants | 5 Participants |
| Race/Ethnicity, Customized Black or African American | 3 Participants | 1 Participants | 4 Participants |
| Race/Ethnicity, Customized Not Reported | 3 Participants | 1 Participants | 4 Participants |
| Race/Ethnicity, Customized Other | 2 Participants | 3 Participants | 5 Participants |
| Race/Ethnicity, Customized White | 19 Participants | 20 Participants | 39 Participants |
| Sex: Female, Male Female | 9 Participants | 11 Participants | 20 Participants |
| Sex: Female, Male Male | 21 Participants | 16 Participants | 37 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 2 / 28 | 1 / 23 | 0 / 5 | 1 / 4 |
| other Total, other adverse events | 27 / 28 | 23 / 23 | 5 / 5 | 3 / 4 |
| serious Total, serious adverse events | 16 / 28 | 16 / 23 | 3 / 5 | 1 / 4 |
Outcome results
Primary
Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs)
A TEAE was defined as an adverse event (AE) with a start date and time on or after the first dose of study treatment. A serious AE (SAE) was an AE that met at least one of the following serious criteria: fatal, life-threatening, required inpatient hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity; was a congenital anomaly/birth defect; or other important medical event. TEAEs of special interest (AESI) included acute or chronic graft versus host disease, cytokine release syndrome, infusion-related reactions, and graft failure or rejection. Treatment-related refers to the assessment of a relationship between study treatment and the event by the investigator.
Time frame: Up to 34 weeks
Population: The safety population included all participants who received any amount of posoleucel or placebo and had at least one post-treatment safety assessment.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Posoleucel, Then Placebo | Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) | Any TEAE | 27 Participants |
| Posoleucel, Then Placebo | Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) | Any TEAE related to study treatment | 7 Participants |
| Posoleucel, Then Placebo | Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) | Any AESI | 6 Participants |
| Posoleucel, Then Placebo | Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) | Any SAE | 16 Participants |
| Posoleucel, Then Placebo | Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) | Any SAE related to study treatment | 1 Participants |
| Posoleucel, Then Placebo | Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) | Any TEAE leading to study treatment discontinuation | 2 Participants |
| Posoleucel, Then Placebo | Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) | Any TEAE leading to study discontinuation | 1 Participants |
| Posoleucel, Then Placebo | Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) | Any TEAE leading to death | 2 Participants |
| Placebo, Then Posoleucel | Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) | Any TEAE leading to study treatment discontinuation | 1 Participants |
| Placebo, Then Posoleucel | Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) | Any SAE related to study treatment | 1 Participants |
| Placebo, Then Posoleucel | Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) | Any TEAE related to study treatment | 9 Participants |
| Placebo, Then Posoleucel | Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) | Any TEAE leading to death | 1 Participants |
| Placebo, Then Posoleucel | Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) | Any TEAE leading to study discontinuation | 2 Participants |
| Placebo, Then Posoleucel | Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) | Any SAE | 16 Participants |
| Placebo, Then Posoleucel | Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) | Any AESI | 9 Participants |
| Placebo, Then Posoleucel | Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) | Any TEAE | 23 Participants |
| Posoleucel (Cross-over Period) | Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) | Any TEAE leading to study discontinuation | 0 Participants |
| Posoleucel (Cross-over Period) | Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) | Any AESI | 1 Participants |
| Posoleucel (Cross-over Period) | Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) | Any SAE | 3 Participants |
| Posoleucel (Cross-over Period) | Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) | Any SAE related to study treatment | 1 Participants |
| Posoleucel (Cross-over Period) | Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) | Any TEAE leading to study treatment discontinuation | 0 Participants |
| Posoleucel (Cross-over Period) | Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) | Any TEAE leading to death | 0 Participants |
| Posoleucel (Cross-over Period) | Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) | Any TEAE | 5 Participants |
| Posoleucel (Cross-over Period) | Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) | Any TEAE related to study treatment | 1 Participants |
| Placebo (Cross-over Period) | Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) | Any AESI | 2 Participants |
| Placebo (Cross-over Period) | Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) | Any SAE | 1 Participants |
| Placebo (Cross-over Period) | Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) | Any TEAE related to study treatment | 1 Participants |
| Placebo (Cross-over Period) | Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) | Any TEAE | 3 Participants |
| Placebo (Cross-over Period) | Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) | Any SAE related to study treatment | 1 Participants |
| Placebo (Cross-over Period) | Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) | Any TEAE leading to death | 1 Participants |
| Placebo (Cross-over Period) | Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) | Any TEAE leading to study discontinuation | 1 Participants |
| Placebo (Cross-over Period) | Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) | Any TEAE leading to study treatment discontinuation | 2 Participants |
Primary
Number of Participants With Undetectable Adenovirus Infection
Viral load of adenovirus was measured at the central laboratory using quantitative polymerase chain reaction (qPCR) from blood and stool samples at each study visit and on Day 29 from a nasopharyngeal swab. There was a 14-day window for participants who crossed over from posoleucel to placebo; and for participants who crossed over from placebo to posoleucel, the pre-dose cross-over Day 1 viral load was used. Participants missing the primary endpoint but having undetectable viremia before Day 29 and after Day 43 were imputed as successes. Undetectable adenovirus viremia was less than the lower limit of quantification (LLOQ).
Time frame: Day 29 through Day 43 (Day 29 + 14 days; up to 43 days post-first infusion)
Population: The modified intent-to-treat (mITT) population included all randomized participants who received at least one dose of posoleucel or placebo. Only participants in the mITT population who completed through Day 29 or discontinued early were included.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Posoleucel, Then Placebo | Number of Participants With Undetectable Adenovirus Infection | 11 Participants |
| Placebo, Then Posoleucel | Number of Participants With Undetectable Adenovirus Infection | 9 Participants |
95% CI: [0.26, 3.69]
Secondary
Area Under the Curve (AUC) Adenovirus Viral Load
Time frame: Pre-dose and Day 29
Population: Data not collected due to early termination after DSMB futility analysis concluded the study was unlikely to meet its primary endpoint.
Secondary
Number of Participants Who Achieved Adenovirus Viremia <400 Copies/mL at Day 29
Time frame: Day 29
Population: Data not collected due to early termination after DSMB futility analysis concluded the study was unlikely to meet its primary endpoint.
Secondary
Number of Participants With Adenovirus Disease Recurrence
Time frame: 34 weeks
Population: Data not collected due to early termination after DSMB futility analysis concluded the study was unlikely to meet its primary endpoint.
Secondary
Number of Participants With Overall Disease Progression
Time frame: From Day 29 up to Week 10
Population: Data not collected due to early termination after Data and Safety Monitoring Board (DSMB) futility analysis concluded the study was unlikely to meet its primary endpoint.
Secondary
Time to Undetectable Adenovirus Viremia (Less Than LLOQ)
Time frame: Pre-dose to 34 weeks
Population: Data not collected due to early termination after DSMB futility analysis concluded the study was unlikely to meet its primary endpoint.