A Phase 2A Study of ALXN1007 in Participants With Newly Diagnosed Acute Lower Gastrointestinal Graft-Versus-Host Disease

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Phase 2A Study of ALXN1007 in Subjects With Newly Diagnosed Acute Graft-Versus-Host Disease Involving the Lower Gastrointestinal Tract

Conditions
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GIGVHD, Acute Graft-Versus-Host Disease

Intervention / Treatment
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* Biological: ALXN1007 10 mg/kg once weekly
* Biological: ALXN1007 20 mg/kg once weekly
* Biological: ALXN1007 20 mg/kg twice weekly


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ALXN1007 10 mg/kg once weekly<br>Cohort 1, the first dosing cohort, received 10 mg/kg ALXN1007 IV once weekly for 8 weeks. | Biological: ALXN1007 10 mg/kg once weekly<br>* ALXN1007 is a recombinant humanized monoclonal antibody that binds to complement component C5a and its metabolite C5a desArg.<br>|
| Experimental: ALXN1007 20 mg/kg once weekly<br>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. | Biological: ALXN1007 20 mg/kg once weekly<br>* ALXN1007 is a recombinant humanized monoclonal antibody that binds to complement component C5a and its metabolite C5a desArg.<br>|
| Experimental: ALXN1007 20 mg/kg twice weekly<br>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. | Biological: ALXN1007 20 mg/kg twice weekly<br>* ALXN1007 is a recombinant humanized monoclonal antibody that binds to complement component C5a and its metabolite C5a desArg.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Day 28 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Predose up to 72 hours postdose | 
| 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. | Predose up to 72 hours postdose | 
| 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. | Predose up to 72 hours postdose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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GIGVHD