Acute Graft-Versus-Host Disease, GIGVHD
Conditions
Keywords
GIGVHD
Brief summary
The objectives of this trial were to evaluate the safety, tolerability, pharmacokinetics/pharmacodynamics (PK/PD) and efficacy of intravenous (IV) ALXN1007 in participants with acute graft-versus-host disease (GVHD) of the lower gastrointestinal (GI) tract.
Detailed description
This was a Phase 2A open-label, non-randomized study to evaluate the safety, tolerability, PK/PD, and efficacy of ALXN1007 (a C5a inhibitor) in up to 36 participants with newly diagnosed acute GVHD of the lower GI tract. All participants meeting the inclusion and exclusion criteria for the study were to receive ALXN1007 over an 8 week treatment period. Participants in Cohort 1, the first dosing cohort, were to receive 10 milligrams/kilogram (mg/kg) ALXN1007 administered IV once weekly for 8 weeks. Participants in Cohort 2 were to receive 20 mg/kg ALXN1007 IV once weekly for 8 weeks. Participants in Cohort 3 were to receive 20 mg/kg ALXN1007 IV twice weekly for 8 weeks. All doses of ALXN1007 were to be administered as a continuous IV infusion.
Interventions
BIOLOGICALALXN1007 10 mg/kg once weekly
ALXN1007 is a recombinant humanized monoclonal antibody that binds to complement component C5a and its metabolite C5a desArg.
BIOLOGICALALXN1007 20 mg/kg once weekly
ALXN1007 is a recombinant humanized monoclonal antibody that binds to complement component C5a and its metabolite C5a desArg.
BIOLOGICALALXN1007 20 mg/kg twice weekly
ALXN1007 is a recombinant humanized monoclonal antibody that binds to complement component C5a and its metabolite C5a desArg.
Sponsors
Alexion Pharmaceuticals, Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Participants must be males or females age 18 years or older. * Participants with Stage 1 to 4 (per the Modified Keystone Grading Schema) acute GVHD of the lower GI tract, without signs of chronic GVHD, at the time of diagnosis, which developed in the first 180 days following allogeneic hematopoietic cell transplantation (HCT) using bone marrow, peripheral blood, or cord blood; or after preplanned donor lymphocyte infusion. * Participants are willing to undergo or must have had an endoscopy of the upper and/or lower GI tract and biopsy to confirm GI GVHD. * Participants must be receiving systemic corticosteroids. * Participants with an absolute neutrophil count (ANC) \>500/microliter (μL) at Screening. * Participants and spouse/partner who are of childbearing potential must be using high effective contraception consisting of 2 forms of birth control (at least 1 of which much be barrier method) starting at Screening and continuing through the entire study (for at least 3 months after the last dose of ALXN1007 if study treatment is stopped early or participant withdraws consent). * Male participants must not donate sperm during the Screening and Treatment periods, and for at least 3 months after the last dose of ALXN1007. * Stage of acute GVHD of the lower GI tract will be determined using the Modified Keystone Grading Schema.
Exclusion criteria
* Participants with a body weight \> 140 kg (for Cohorts dosing 20 mg/kg of ALXN1007 and higher only). * Participants with signs and symptoms of chronic GVHD. * Participants with an active uncontrolled infection. * Participants who test positive for Clostridium difficile (C. difficile) at Screening. * Participants with relapsed/persistent malignancy requiring rapid immune suppression withdrawal. * Participants who received an unplanned (not part of the original transplant therapy plan) donor lymphocyte infusion. * Participants who received previous systemic treatment for acute GVHD, except for a maximum of 3 days (72 hours) of 2 mg/kg corticosteroid therapy. * Participants with unresolved veno-occlusive disease of the liver. * Participants with creatinine clearance \<40 milliliters (mL)/minute at Screening, as calculated by the Cockcroft-Gault formula. * Participants known to be infected with human immunodeficiency virus (HIV), hepatitis B, or hepatitis C. * Participants known to have an uncontrolled thyroid disorder. * Participants who are pregnant, breast feeding, or sexually active and unwilling to use effective birth control for the duration of the study. * Participants who participated in any other investigational drug trial or had exposure to any other investigational agent, device, or procedure \<4 weeks prior to Screening and throughout the entire trial, with the exception of investigational drugs administered prophylactically for cytomegalovirus (CMV) post allogeneic HCT.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Acute Graft-Versus-Host Disease (GVHD) Response Rate At Day 28 | Day 28 | The number of participants with overall acute GVHD response was determined at Day 28. Acute Overall GVHD is defined as improvement from diagnosis in any organ by at least 1 stage, without progression in any other organ, and with no additional therapy being administered. Acute GVHD staging included skin, liver, and GI assessments, which were to be performed using the Modified Keystone Grading Schema. Deaths were considered nonresponders; otherwise last postbaseline values were carried forward for imputation of missing responses. Modified Keystone Grading Schema: Skin - Stages 0 = No Rash, 1 = Rash \<25% body surface area (BSA), 2 = 25% to 50% BSA, 3 = \>50% BSA, 4 = bullae, desquamation; Lower GI Tract (stool volume over 24 hours) - Stages 0 = \<500 mL, 1 = 500 to 1000 mL, 2 = 1001 to 1500 mL, 3 = \>1500 mL, 4 = severe abdominal pain +/- ileus, frank blood, or melena; Liver (bilirubin levels) - Stages 0 = ≤2 mg/dL, 1 = 2.1 to 3 mg/dL, 2 = 3.1 to 6 mg/dL, 3 = 6.1 to 15 mg/dL, 4 = \>15 mg/dL. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Pharmacokinetics (PK): Time To Maximum Observed Concentration In Plasma (Tmax) Of IV ALXN1007 | Predose up to 72 hours postdose | The Tmax of ALXN1007 was measured on Treatment Days 1, 28, and 49, from blood samples collected at time points relative to the dosing of ALXN1007. PK assessments were to have been measured from Baseline, Treatment Days 7, 14, 21, 28, 35, 42, 49, 56, and Follow-up Days 86, 180, and Early Termination (ET). Due to the early termination of the study and the clinical development of the ALXN1007 program, a number of PK analyses were not completed. PK data for the 20 mg/kg ALXN1007 once weekly dosing group and the 20 mg/kg ALXN1007 twice weekly dosing group are not available. |
| PK: Maximum Observed Concentration In Plasma (Cmax) Of IV ALXN1007 | Predose up to 72 hours postdose | The Cmax of ALXN1007 was measured on Treatment Days 1, 28, and 49, from blood samples collected at time points relative to the dosing of ALXN1007. PK assessments were to have been measured from Baseline, Treatment Days 7, 14, 21, 28, 35, 42, 49, 56, and Follow-up Days 86, 180, and Early Termination (ET). Due to the early termination of the study and the clinical development of the ALXN1007 program, a number of PK analyses were not completed. PK data for the 20 mg/kg ALXN1007 once weekly dosing group and the 20 mg/kg ALXN1007 twice weekly dosing group are not available. |
| PK: Area Under The Plasma (Or Serum) Concentration Versus Time Curve (AUC) Of IV ALXN1007 | Predose up to 72 hours postdose | The AUC of ALXN1007 was measured on Treatment Days 1, 28, and 49, from blood samples collected at time points relative to the dosing of ALXN1007. PK assessments were to have been measured from Baseline, Treatment Days 7, 14, 21, 28, 35, 42, 49, 56, and Follow-up Days 86, 180, and Early Termination (ET). Due to the early termination of the study and the clinical development of the ALXN1007 program, a number of PK analyses were not completed. PK data for the 20 mg/kg ALXN1007 once weekly dosing group and the 20 mg/kg ALXN1007 twice weekly dosing group are not available. |
Countries
France, United States
Participant flow
Recruitment details
This study enrolled participants with newly diagnosed acute graft-versus-host disease (GVHD) of the lower gastrointestinal (GI) tract.
Participants by arm
| Arm | Count |
|---|---|
| ALXN1007 10 mg/kg Once Weekly Cohort 1, the first dosing cohort, received 10 mg/kg ALXN1007 IV once weekly for 8 weeks. | 17 |
| ALXN1007 20 mg/kg Once Weekly Cohort 2 received 20 mg/kg ALXN1007 IV once weekly for 8 weeks. For the first 2 participants enrolled, the first ALXN1007 dose was not to be administered on the same day and a safety and tolerability review was to take place after the second (and prior to the third) ALXN1007 dose for each participant. If the ALXN1007 dose was determined to be sufficiently tolerated by the participant, dosing was to continue for that participant. For any other participants enrolled in the dosing cohort, participants were not to proceed to the third ALXN1007 dose prior to the completion of the safety and tolerability review (of the first 2 doses) for the first 2 participants. | 6 |
| ALXN1007 20 mg/kg Twice Weekly Cohort 3 received 20 mg/kg ALXN1007 IV twice weekly for 8 weeks. For the first 2 participants enrolled, the first ALXN1007 dose was not to be administered on the same day and a safety and tolerability review was to take place after the second (and prior to the third) ALXN1007 dose for each participant. If the ALXN1007 dose was determined to be sufficiently tolerated by the participant, dosing was to continue for that participant. For any other participants enrolled in the dosing cohort, participants were not to proceed to the third ALXN1007 dose prior to the completion of the safety and tolerability review (of the first 2 doses) for the first 2 participants. | 2 |
| Total | 25 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Follow-Up Period | Death | 4 | 2 | 1 |
| Follow-Up Period | Other - Terminated by Sponsor | 0 | 0 | 1 |
| Follow-Up Period | Physician Decision | 1 | 0 | 0 |
| Treatment Period | Biopsy did not confirm GI GVHD | 1 | 0 | 0 |
| Treatment Period | Death | 1 | 1 | 0 |
| Treatment Period | Physician Decision | 1 | 1 | 0 |
| Treatment Period | Withdrawal by Subject | 2 | 1 | 0 |
Baseline characteristics
| Characteristic | ALXN1007 10 mg/kg Once Weekly | Total | ALXN1007 20 mg/kg Twice Weekly | ALXN1007 20 mg/kg Once Weekly |
|---|---|---|---|---|
| Acute GVHD Staging Liver Staging Score 0 | 17 Participants | 25 Participants | 2 Participants | 6 Participants |
| Acute GVHD Staging Liver Staging Score 1 | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Acute GVHD Staging Liver Staging Score 2 | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Acute GVHD Staging Liver Staging Score 3 | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Acute GVHD Staging Liver Staging Score 4 | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Acute GVHD Staging Lower GI Tract Staging Score 0 | 7 Participants | 7 Participants | 0 Participants | 0 Participants |
| Acute GVHD Staging Lower GI Tract Staging Score 1 | 4 Participants | 6 Participants | 1 Participants | 1 Participants |
| Acute GVHD Staging Lower GI Tract Staging Score 2 | 1 Participants | 4 Participants | 0 Participants | 3 Participants |
| Acute GVHD Staging Lower GI Tract Staging Score 3 | 5 Participants | 7 Participants | 1 Participants | 1 Participants |
| Acute GVHD Staging Lower GI Tract Staging Score 4 | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Acute GVHD Staging Skin Staging Score 0 | 14 Participants | 21 Participants | 1 Participants | 6 Participants |
| Acute GVHD Staging Skin Staging Score 1 | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Acute GVHD Staging Skin Staging Score 2 | 3 Participants | 4 Participants | 1 Participants | 0 Participants |
| Acute GVHD Staging Skin Staging Score 3 | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Acute GVHD Staging Skin Staging Score 4 | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Continuous | 54.6 years STANDARD_DEVIATION 14.27 | 54.2 years STANDARD_DEVIATION 14.32 | 70.5 years STANDARD_DEVIATION 2.12 | 47.7 years STANDARD_DEVIATION 13.14 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 3 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 14 Participants | 21 Participants | 2 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 2 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 16 Participants | 21 Participants | 2 Participants | 3 Participants |
| Region of Enrollment France | 1 participants | 1 participants | 0 participants | 0 participants |
| Region of Enrollment United States | 16 participants | 24 participants | 2 participants | 6 participants |
| Sex: Female, Male Female | 8 Participants | 11 Participants | 1 Participants | 2 Participants |
| Sex: Female, Male Male | 9 Participants | 14 Participants | 1 Participants | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 6 / 17 | 3 / 6 | 1 / 2 |
| other Total, other adverse events | 17 / 17 | 6 / 6 | 2 / 2 |
| serious Total, serious adverse events | 13 / 17 | 4 / 6 | 2 / 2 |
Outcome results
Primary
Overall Acute Graft-Versus-Host Disease (GVHD) Response Rate At Day 28
The number of participants with overall acute GVHD response was determined at Day 28. Acute Overall GVHD is defined as improvement from diagnosis in any organ by at least 1 stage, without progression in any other organ, and with no additional therapy being administered. Acute GVHD staging included skin, liver, and GI assessments, which were to be performed using the Modified Keystone Grading Schema. Deaths were considered nonresponders; otherwise last postbaseline values were carried forward for imputation of missing responses. Modified Keystone Grading Schema: Skin - Stages 0 = No Rash, 1 = Rash \<25% body surface area (BSA), 2 = 25% to 50% BSA, 3 = \>50% BSA, 4 = bullae, desquamation; Lower GI Tract (stool volume over 24 hours) - Stages 0 = \<500 mL, 1 = 500 to 1000 mL, 2 = 1001 to 1500 mL, 3 = \>1500 mL, 4 = severe abdominal pain +/- ileus, frank blood, or melena; Liver (bilirubin levels) - Stages 0 = ≤2 mg/dL, 1 = 2.1 to 3 mg/dL, 2 = 3.1 to 6 mg/dL, 3 = 6.1 to 15 mg/dL, 4 = \>15 mg/dL.
Time frame: Day 28
Population: Participants in the mFAS Population - In the 10 mg/kg ALXN1007 once weekly dose group, 1 participant was prematurely discontinued after receiving a single dose due to lack of confirmed GI GVHD.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| ALXN1007 10 mg/kg Once Weekly | Overall Acute Graft-Versus-Host Disease (GVHD) Response Rate At Day 28 | 10 Participants |
| ALXN1007 20 mg/kg Once Weekly | Overall Acute Graft-Versus-Host Disease (GVHD) Response Rate At Day 28 | 3 Participants |
| ALXN1007 20 mg/kg Twice Weekly | Overall Acute Graft-Versus-Host Disease (GVHD) Response Rate At Day 28 | 1 Participants |
Secondary
Pharmacokinetics (PK): Time To Maximum Observed Concentration In Plasma (Tmax) Of IV ALXN1007
The Tmax of ALXN1007 was measured on Treatment Days 1, 28, and 49, from blood samples collected at time points relative to the dosing of ALXN1007. PK assessments were to have been measured from Baseline, Treatment Days 7, 14, 21, 28, 35, 42, 49, 56, and Follow-up Days 86, 180, and Early Termination (ET). Due to the early termination of the study and the clinical development of the ALXN1007 program, a number of PK analyses were not completed. PK data for the 20 mg/kg ALXN1007 once weekly dosing group and the 20 mg/kg ALXN1007 twice weekly dosing group are not available.
Time frame: Predose up to 72 hours postdose
Population: PK population: All participants in the 10 mg/kg ALXN1007 once weekly dose group who received at least 1 dose of ALXN1007 and who had evaluable PK and pharmacodynamic (PD) data.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| ALXN1007 10 mg/kg Once Weekly | Pharmacokinetics (PK): Time To Maximum Observed Concentration In Plasma (Tmax) Of IV ALXN1007 | Tmax Day 1 | 1.033 hours |
| ALXN1007 10 mg/kg Once Weekly | Pharmacokinetics (PK): Time To Maximum Observed Concentration In Plasma (Tmax) Of IV ALXN1007 | Tmax Day 28 | 1.03 hours |
| ALXN1007 10 mg/kg Once Weekly | Pharmacokinetics (PK): Time To Maximum Observed Concentration In Plasma (Tmax) Of IV ALXN1007 | Tmax Day 49 | 1.25 hours |
Secondary
PK: Area Under The Plasma (Or Serum) Concentration Versus Time Curve (AUC) Of IV ALXN1007
The AUC of ALXN1007 was measured on Treatment Days 1, 28, and 49, from blood samples collected at time points relative to the dosing of ALXN1007. PK assessments were to have been measured from Baseline, Treatment Days 7, 14, 21, 28, 35, 42, 49, 56, and Follow-up Days 86, 180, and Early Termination (ET). Due to the early termination of the study and the clinical development of the ALXN1007 program, a number of PK analyses were not completed. PK data for the 20 mg/kg ALXN1007 once weekly dosing group and the 20 mg/kg ALXN1007 twice weekly dosing group are not available.
Time frame: Predose up to 72 hours postdose
Population: PK population: All participants in the 10 mg/kg ALXN1007 once weekly dose group who received at least 1 dose of ALXN1007 and who had evaluable PK and PD data.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| ALXN1007 10 mg/kg Once Weekly | PK: Area Under The Plasma (Or Serum) Concentration Versus Time Curve (AUC) Of IV ALXN1007 | AUC Day 28 | 34957 h*ug/mL |
| ALXN1007 10 mg/kg Once Weekly | PK: Area Under The Plasma (Or Serum) Concentration Versus Time Curve (AUC) Of IV ALXN1007 | AUC Day 1 | 13079 h*ug/mL |
| ALXN1007 10 mg/kg Once Weekly | PK: Area Under The Plasma (Or Serum) Concentration Versus Time Curve (AUC) Of IV ALXN1007 | AUC Day 49 | 41919 h*ug/mL |
Secondary
PK: Maximum Observed Concentration In Plasma (Cmax) Of IV ALXN1007
The Cmax of ALXN1007 was measured on Treatment Days 1, 28, and 49, from blood samples collected at time points relative to the dosing of ALXN1007. PK assessments were to have been measured from Baseline, Treatment Days 7, 14, 21, 28, 35, 42, 49, 56, and Follow-up Days 86, 180, and Early Termination (ET). Due to the early termination of the study and the clinical development of the ALXN1007 program, a number of PK analyses were not completed. PK data for the 20 mg/kg ALXN1007 once weekly dosing group and the 20 mg/kg ALXN1007 twice weekly dosing group are not available.
Time frame: Predose up to 72 hours postdose
Population: PK population: All participants in the 10 mg/kg ALXN1007 once weekly dose group who received at least 1 dose of ALXN1007 and who had evaluable PK and PD data.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| ALXN1007 10 mg/kg Once Weekly | PK: Maximum Observed Concentration In Plasma (Cmax) Of IV ALXN1007 | Cmax Day 1 | 270 ug/mL |
| ALXN1007 10 mg/kg Once Weekly | PK: Maximum Observed Concentration In Plasma (Cmax) Of IV ALXN1007 | Cmax Day 28 | 383 ug/mL |
| ALXN1007 10 mg/kg Once Weekly | PK: Maximum Observed Concentration In Plasma (Cmax) Of IV ALXN1007 | Cmax Day 49 | 421 ug/mL |