Back to resultsA Phase 2A Study of ALXN1007 in Participants With Newly Diagnosed Acute Lower Gastrointestinal Graft-Versus-Host Disease (GIGVHD)
Primary Purpose
Acute Graft-Versus-Host Disease, GIGVHD
Status
Terminated
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
ALXN1007 10 mg/kg once weekly
ALXN1007 20 mg/kg once weekly
ALXN1007 20 mg/kg twice weekly
Sponsored by
About this trial
This is an interventional treatment trial for Acute Graft-Versus-Host Disease focused on measuring GIGVHD
Eligibility Criteria
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.
Sites / Locations
- City of Hope
- Emory University Hospital
- Barbara Ann Karmanos Cancer Institute
- University of Minnesota Medicine - Hematology, Oncology and Transplantation Office
- Washington University in St. Louis
- Hackensack University Medical Center
- Roswell Park Cancer Institute
- Abramson Cancer Perelman Center for Advanced Medicine, University of Pennsylvania
- The University of Texas MD Anderson Cancer Center
- CHU de Grenoble - Hôpital Nord
- Groupe Hospitalier Sud - Hôpital Haut-Lévêque - Centre François
- Hôpital Saint-Louis
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm Type
Experimental
Experimental
Experimental
Arm Label
ALXN1007 10 mg/kg once weekly
ALXN1007 20 mg/kg once weekly
ALXN1007 20 mg/kg twice weekly
Arm Description
Cohort 1, the first dosing cohort, received 10 mg/kg ALXN1007 IV once weekly for 8 weeks.
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.
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.
Outcomes
Primary Outcome Measures
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.
Secondary Outcome Measures
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.
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.
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.
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT02245412
Brief Title
A Phase 2A Study of ALXN1007 in Participants With Newly Diagnosed Acute Lower Gastrointestinal Graft-Versus-Host Disease
Acronym
GIGVHD
Official Title
A Phase 2A Study of ALXN1007 in Subjects With Newly Diagnosed Acute Graft-Versus-Host Disease Involving the Lower Gastrointestinal Tract
Study Type
Interventional
2. Study Status
Record Verification Date
December 2018
Overall Recruitment Status
Terminated
Why Stopped
Terminated early at the Sponsor's discretion, not due to safety concerns.
Study Start Date
November 14, 2014 (Actual)
Primary Completion Date
February 27, 2017 (Actual)
Study Completion Date
February 27, 2017 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Alexion
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes
5. Study Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Acute Graft-Versus-Host Disease, GIGVHD
Keywords
GIGVHD
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Sequential Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
25 (Actual)
8. Arms, Groups, and Interventions
Arm Title
ALXN1007 10 mg/kg once weekly
Arm Type
Experimental
Arm Description
Cohort 1, the first dosing cohort, received 10 mg/kg ALXN1007 IV once weekly for 8 weeks.
Arm Title
ALXN1007 20 mg/kg once weekly
Arm Type
Experimental
Arm Description
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.
Arm Title
ALXN1007 20 mg/kg twice weekly
Arm Type
Experimental
Arm Description
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.
Intervention Type
Biological
Intervention Name(s)
ALXN1007 10 mg/kg once weekly
Intervention Description
ALXN1007 is a recombinant humanized monoclonal antibody that binds to complement component C5a and its metabolite C5a desArg.
Intervention Type
Biological
Intervention Name(s)
ALXN1007 20 mg/kg once weekly
Intervention Description
ALXN1007 is a recombinant humanized monoclonal antibody that binds to complement component C5a and its metabolite C5a desArg.
Intervention Type
Biological
Intervention Name(s)
ALXN1007 20 mg/kg twice weekly
Intervention Description
ALXN1007 is a recombinant humanized monoclonal antibody that binds to complement component C5a and its metabolite C5a desArg.
Primary Outcome Measure Information:
Title
Overall Acute Graft-Versus-Host Disease (GVHD) Response Rate At Day 28
Description
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
Secondary Outcome Measure Information:
Title
Pharmacokinetics (PK): Time To Maximum Observed Concentration In Plasma (Tmax) Of IV ALXN1007
Description
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
Title
PK: Maximum Observed Concentration In Plasma (Cmax) Of IV ALXN1007
Description
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
Title
PK: Area Under The Plasma (Or Serum) Concentration Versus Time Curve (AUC) Of IV ALXN1007
Description
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
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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.
Facility Information:
Facility Name
City of Hope
City
Duarte
State/Province
California
ZIP/Postal Code
91010
Country
United States
Facility Name
Emory University Hospital
City
Atlanta
State/Province
Georgia
ZIP/Postal Code
30322
Country
United States
Facility Name
Barbara Ann Karmanos Cancer Institute
City
Detroit
State/Province
Michigan
ZIP/Postal Code
48201
Country
United States
Facility Name
University of Minnesota Medicine - Hematology, Oncology and Transplantation Office
City
Minneapolis
State/Province
Minnesota
ZIP/Postal Code
55455
Country
United States
Facility Name
Washington University in St. Louis
City
Saint Louis
State/Province
Missouri
ZIP/Postal Code
63110
Country
United States
Facility Name
Hackensack University Medical Center
City
Hackensack
State/Province
New Jersey
ZIP/Postal Code
07601
Country
United States
Facility Name
Roswell Park Cancer Institute
City
Buffalo
State/Province
New York
ZIP/Postal Code
14263
Country
United States
Facility Name
Abramson Cancer Perelman Center for Advanced Medicine, University of Pennsylvania
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19104
Country
United States
Facility Name
The University of Texas MD Anderson Cancer Center
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States
Facility Name
CHU de Grenoble - Hôpital Nord
City
Grenoble
State/Province
Isere
ZIP/Postal Code
38043
Country
France
Facility Name
Groupe Hospitalier Sud - Hôpital Haut-Lévêque - Centre François
City
Gironde
ZIP/Postal Code
33604
Country
France
Facility Name
Hôpital Saint-Louis
City
Paris
ZIP/Postal Code
75010
Country
France
12. IPD Sharing Statement
Learn more about this trial
A Phase 2A Study of ALXN1007 in Participants With Newly Diagnosed Acute Lower Gastrointestinal Graft-Versus-Host Disease
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