BK Virus Infection, Hemorrhagic Cystitis
Conditions
Keywords
Allogeneic Hematopoietic Cell Transplant, ALVR105, Posoleucel
Brief summary
Study to Evaluate Viralym-M (ALVR105) for the Treatment of Virus-Associated Hemorrhagic Cystitis (HC).
Detailed description
The study hypothesis is that the administration of posoleucel (ALVR105) to patients with virus-associated HC will demonstrate superiority for the time to resolution of HC (as measured by resolution of macroscopic hematuria) compared to patients treated with placebo. The primary hypothesis will be tested in patients with BK virus (BKV) viruria to demonstrate superiority over placebo in this population (BK Intent-to-Treat \[ITT\] Population). A supplementary analysis will be conducted in all patients with any virus-associated HC (cytomegalovirus \[CMV\], human herpesvirus 6 \[HHV-6\], Epstein-Barr virus \[EBV\], JC virus \[JCV\], and/or adenovirus \[AdV\]) in order to evaluate efficacy in this broader population (ITT Population).
Interventions
BIOLOGICALPosoleucel (ALVR105)
Administered as 2-4 milliliter infusion, visually identical to placebo
BIOLOGICALPlacebo
Administered as 2-4 milliliter infusion, visually identical to Posoleucel (ALVR105)
Sponsors
AlloVir
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
1 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria Participants must meet all of the following criteria in order to be eligible to participate in the study: * Male or female ≥1 year of age. * Had an allogeneic hematopoietic cell transplant (HCT) performed ≥21 days and ≤1 year prior to randomization. * Myeloid engraftment confirmed, defined as an absolute neutrophil count ≥500/mm³ for 3 consecutive laboratory values obtained on different days, and platelet count \>10,000/mm³ at the time of randomization. * Diagnosed with HC based on the following criteria (all 3 criteria must be met): 1. Clinical signs and/or symptoms of cystitis. 2. Grade ≥3 hematuria, defined as macroscopic hematuria with visible clots. 3. Viruria with ≥1 target virus (ie, BKV, JCV, AdV, CMV, EBV, and/or HHV-6). * At least 1 identified, suitably matched posoleucel (ALVR105) cell line for infusion is available. Key
Exclusion criteria
Participants who meet any of the following criteria will be excluded from participation in the study: * Ongoing therapy with high-dose systemic corticosteroids (ie, prednisone dose \>0.5 mg/kg/day or equivalent). * Therapy with antithymocyte globulin, alemtuzumab (Campath-1H), or other immunosuppressive T cell-targeted monoclonal antibodies ≤28 days before randomization. * Evidence of active Grade \>2 acute graft versus host disease (GVHD). * Uncontrolled or progressive bacterial or fungal infections. * Uncontrolled or progressive viral infections not targeted by posoleucel (ALVR105). * Uncontrolled or progressive EBV-associated post-transplant lymphoproliferative disorder. * Known or presumed pneumonia secondary to any organism that is not considered to be well-controlled by antimicrobial therapy. * Pregnant or lactating or planning to become pregnant. Note: Other protocol defined Inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to Resolution of Macroscopic Hematuria | Up to 24 weeks | Time to macroscopic hematuria resolution is calculated from time of randomization to the first date of observed macroscopic hematuria resolution. Kaplan-Meier estimates reported as median number of days to resolution. Participants were censored at the last follow-up time of any participant in the ITT population if they took definitive therapies to stop bladder bleeding or received treatment for hemorrhagic cystitis with non-PSL VSTs before achieving resolution or deceased. Participants were also censored at last follow up if they failed to achieve resolution by end of study. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Days in the Hospital for Any Reason | Until event occurrence through Week 24 | — |
| Number of Participants With Treatment Emergent Acute Graft Versus Host Disease (GVHD) | Up to 24 weeks | Grading of acute GVHD is reported according to CTCAE version 5.0 which ranges from Grade 0 (best/no disease) to Grade IV (worst). Participants with Grade I-IV are included. |
| Time Until Bladder Pain is Resolved | Until event occurrence through Week 24 | — |
| Time to Resolution for All Target Viruses | Until event occurrence through Week 24 | — |
| Average Daily Bladder Pain | Until event occurrence through Week 6 | — |
| Number of Participants With Treatment Emergent Cytokine Release Syndrome (CRS) | Up to 24 weeks | CRS is defined as a supraphysiologic response following any immune therapy that results in the activation or engagement of endogenous or infused T cells and/or other immune effector cells. Symptoms can be progressive, must include fever at the onset, and may include hypotension, capillary leak (hypoxia), and end organ dysfunction. |
Countries
France, Italy, South Korea, Spain, Sweden, United Kingdom, United States
Participant flow
Recruitment details
Participants were enrolled from March 2021 to Jan 2024 across 57 study centers in the United States, Canada, France, Italy, Spain, Sweden, the United Kingdom and South Korea.
Pre-assignment details
Overall 144 participants were screened and a total of 97 participants were randomized in the study.
Participants by arm
| Arm | Count |
|---|---|
| Posoleucel (ALVR105) All participants received 2 infusions of either PSL or placebo separated by 14 (±3) days. Administering the second infusion as early as 11 days after the first infusion was encouraged if feasible. Participants who weighed \<40 kg at the time of screening received 2×10\^7 PSL cells (or placebo), while those who weighed ≥40 kg at the time of screening received 4×10\^7 PSL cells (or placebo). All infusions were administered (IV) (via peripheral or central line) over approximately 5 minutes as a slow push. | 57 |
| Placebo All participants received 2 infusions of either PSL or placebo separated by 14 (±3) days. Administering the second infusion as early as 11 days after the first infusion was encouraged if feasible. Participants who weighed \<40 kg at the time of screening received 2×10\^7 PSL cells (or placebo), while those who weighed ≥40 kg at the time of screening received 4×10\^7 PSL cells (or placebo). All infusions were administered (IV) (via peripheral or central line) over approximately 5 minutes as a slow push. | 40 |
| Total | 97 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 |
| Overall Study | Death | 2 | 1 |
| Overall Study | Missing | 0 | 1 |
| Overall Study | Not Treated | 0 | 1 |
| Overall Study | Other | 1 | 0 |
| Overall Study | Physician Decision | 1 | 3 |
| Overall Study | Study Terminated by Sponsor | 5 | 3 |
| Overall Study | Withdrawal by Subject | 10 | 5 |
Baseline characteristics
| Characteristic | Placebo | Total | Posoleucel (ALVR105) |
|---|---|---|---|
| Age, Continuous | 47.0 years STANDARD_DEVIATION 16.6 | 45.8 years STANDARD_DEVIATION 16.54 | 44.9 years STANDARD_DEVIATION 16.59 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 7 Participants | 20 Participants | 13 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 30 Participants | 68 Participants | 38 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 3 Participants | 9 Participants | 6 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 3 Participants | 10 Participants | 7 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 11 Participants | 9 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 5 Participants | 10 Participants | 5 Participants |
| Race (NIH/OMB) White | 30 Participants | 63 Participants | 33 Participants |
| Sex: Female, Male Female | 16 Participants | 35 Participants | 19 Participants |
| Sex: Female, Male Male | 24 Participants | 62 Participants | 38 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 2 / 57 | 1 / 40 |
| other Total, other adverse events | 54 / 57 | 36 / 39 |
| serious Total, serious adverse events | 28 / 57 | 19 / 39 |
Outcome results
Primary
Time to Resolution of Macroscopic Hematuria
Time to macroscopic hematuria resolution is calculated from time of randomization to the first date of observed macroscopic hematuria resolution. Kaplan-Meier estimates reported as median number of days to resolution. Participants were censored at the last follow-up time of any participant in the ITT population if they took definitive therapies to stop bladder bleeding or received treatment for hemorrhagic cystitis with non-PSL VSTs before achieving resolution or deceased. Participants were also censored at last follow up if they failed to achieve resolution by end of study.
Time frame: Up to 24 weeks
Population: BK Intent-to-Treat \[ITT\] Population: All patients randomized who had BKV in their urine at baseline.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Posoleucel (ALVR105) | Time to Resolution of Macroscopic Hematuria | 36 Days |
| Placebo | Time to Resolution of Macroscopic Hematuria | 31 Days |
p-value: 0.625395% CI: [0.55, 1.55]Log Rank
Secondary
Average Daily Bladder Pain
Time frame: Until event occurrence through Week 6
Population: Data not collected due to early termination after DSMB futility analysis concluded the study was unlikely to meet its primary endpoint.
Secondary
Days in the Hospital for Any Reason
Time frame: Until event occurrence through Week 24
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 Treatment Emergent Acute Graft Versus Host Disease (GVHD)
Grading of acute GVHD is reported according to CTCAE version 5.0 which ranges from Grade 0 (best/no disease) to Grade IV (worst). Participants with Grade I-IV are included.
Time frame: Up to 24 weeks
Population: Modified ITT Population (mITT): All randomized participants who receive any dose of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Posoleucel (ALVR105) | Number of Participants With Treatment Emergent Acute Graft Versus Host Disease (GVHD) | 11 Participants |
| Placebo | Number of Participants With Treatment Emergent Acute Graft Versus Host Disease (GVHD) | 9 Participants |
Secondary
Number of Participants With Treatment Emergent Cytokine Release Syndrome (CRS)
CRS is defined as a supraphysiologic response following any immune therapy that results in the activation or engagement of endogenous or infused T cells and/or other immune effector cells. Symptoms can be progressive, must include fever at the onset, and may include hypotension, capillary leak (hypoxia), and end organ dysfunction.
Time frame: Up to 24 weeks
Population: mITT: All randomized participants who receive any dose of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Posoleucel (ALVR105) | Number of Participants With Treatment Emergent Cytokine Release Syndrome (CRS) | 1 Participants |
| Placebo | Number of Participants With Treatment Emergent Cytokine Release Syndrome (CRS) | 0 Participants |
Secondary
Time to Resolution for All Target Viruses
Time frame: Until event occurrence through Week 24
Population: Data not collected due to early termination after DSMB futility analysis concluded the study was unlikely to meet its primary endpoint.
Secondary
Time Until Bladder Pain is Resolved
Time frame: Until event occurrence through Week 24
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.