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Phase II Trial of Natalizumab + Prednisone for Initial Therapy of Acute GI GVHD

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ClinicalTrials.gov Identifier: NCT02176031
Recruitment Status : Completed
First Posted : June 26, 2014
Results First Posted : April 17, 2020
Last Update Posted : April 17, 2020
Sponsor:
Collaborator:
Biogen
Information provided by (Responsible Party):
Corey S. Cutler, MD, MPH, Dana-Farber Cancer Institute

Study Type Interventional
Study Design Allocation: N/A;   Intervention Model: Single Group Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Graft Versus Host Disease
Interventions Drug: Natalizumab
Drug: Methylprednisolone
Enrollment 21
Recruitment Details This study enrolled subjects with newly diagnosed acute gastrointestinal (GI) graft-versus-host-disease (GVHD) from 2 academic medical centers in the United States. The last patient completed the study in February 2019.
Pre-assignment Details  
Arm/Group Title Natalizumab
Hide Arm/Group Description

Natalizumab-

  • (Day 0 and 28) Fixed dose Intravenous infusion over one hour. 2 hours observation completion of the infusion
  • At 4 weeks, if there has been less than a complete response participants can be treated with a second dose of natalizumab.
  • If participants have no response after one dose, they will be not be given a second dose.
  • Participants who receive a second dose of natalizumab will be evaluated for response at day 56 after first treatment dose administered.
  • Participants will be assessed for response to therapy with natalizumab at day +28, day +56, day +100, day + 180, and day +365.
  • Commercial supplies of Methylprednisolone (or equivalent steroid) will be utilized. The formulation, preparation and route of administration will be as per package insert
Period Title: Overall Study
Started 21
Completed 9
Not Completed 12
Arm/Group Title Natalizumab
Hide Arm/Group Description

Natalizumab-

  • (Day 0 and 28) Fixed dose Intravenous infusion over one hour. 2 hours observation completion of the infusion
  • At 4 weeks, if there has been less than a complete response participants can be treated with a second dose of natalizumab.
  • If participants have no response after one dose, they will be not be given a second dose.
  • Participants who receive a second dose of natalizumab will be evaluated for response at day 56 after first treatment dose administered.
  • Participants will be assessed for response to therapy with natalizumab at day +28, day +56, day +100, day + 180, and day +365.
  • Commercial supplies of Methylprednisolone (or equivalent steroid) will be utilized. The formulation, preparation and route of administration will be as per package insert
Overall Number of Baseline Participants 21
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Median (Full Range)
Unit of measure:  Years
Number Analyzed 21 participants
63
(38 to 74)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 21 participants
Female
6
  28.6%
Male
15
  71.4%
Race and Ethnicity Not Collected   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 0 participants
[1]
Measure Analysis Population Description: Race and Ethnicity were not collected from any participant.
Region of Enrollment  
Measure Type: Count of Participants
Unit of measure:  Participants
United States Number Analyzed 21 participants
21
 100.0%
Acute GVHD Staging (Adapted from Glucksberg, H. et al. Transplantation 1974; 18:295)   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Gastrointestinal Stage 1 Number Analyzed 21 participants
4
  19.0%
Gastrointestinal Stage 2 Number Analyzed 21 participants
5
  23.8%
Gastrointestinal Stage 3 Number Analyzed 21 participants
4
  19.0%
Gastrointestinal Stage 4 Number Analyzed 21 participants
8
  38.1%
No liver involvement Number Analyzed 21 participants
20
  95.2%
Liver Stage 2 Number Analyzed 21 participants
1
   4.8%
No skin involvement Number Analyzed 21 participants
17
  81.0%
Skin Stage 2 Number Analyzed 21 participants
4
  19.0%
[1]
Measure Description:

Skin Stage:

  • 1: Maculopapular rash <25% of body area
  • 2: Maculopapular rash 25-50% of body area
  • 3: Generalized erythroderma
  • 4: Generalized erythroderma with bullous formation and often with desquamation

Liver Stage:

  • 1: Bilirubin 2.0-3.0 mg/dL
  • 2: Bilirubin 3.1-6.0 mg/dL
  • 3: Bilirubin 6.1-15.0 mg/dL
  • 4: Bilirubin >15.0 mg/dL

GI Stage:

  • 1: Diarrhea >30 mL/kg or 500 mL/day
  • 2: Diarrhea >60 mL/kg or 1000 mL/day
  • 3: Diarrhea >90 mL/kg or 1500 mL/day
  • 4: Diarrhea >90 mL/kg or 2000 mL/day; or severe abdominal pain with or without ileus
Disease Status of Underlying Malignancy at time of Hematopoietic Stem Cell Transplantation (HSCT)  
Measure Type: Count of Participants
Unit of measure:  Participants
First Complete Remission Number Analyzed 21 participants
9
  42.9%
Second Complete Remission Number Analyzed 21 participants
5
  23.8%
Relapsed Disease Number Analyzed 21 participants
2
   9.5%
Progressive Disease Number Analyzed 21 participants
2
   9.5%
Treatment Failure Number Analyzed 21 participants
3
  14.3%
Eastern Cooperative Oncology Group (ECOG) Performance Status at HSCT  
Measure Type: Count of Participants
Unit of measure:  Participants
00 - Fully Active Number Analyzed 21 participants
2
   9.5%
01 - Restricted Number Analyzed 21 participants
9
  42.9%
02 - Self Care Number Analyzed 21 participants
7
  33.3%
03 - Capable of Limited Self Care Number Analyzed 21 participants
3
  14.3%
Conditioning Regimen  
Measure Type: Count of Participants
Unit of measure:  Participants
Myeloablative Number Analyzed 21 participants
3
  14.3%
Non-myeloablative Number Analyzed 21 participants
18
  85.7%
Donor type  
Measure Type: Count of Participants
Unit of measure:  Participants
Matched Unrelated Number Analyzed 21 participants
15
  71.4%
Matched Related Number Analyzed 21 participants
5
  23.8%
Mismatch Unrelated Number Analyzed 21 participants
1
   4.8%
Donor source  
Measure Type: Count of Participants
Unit of measure:  Participants
Bone marrow and Peripheral Blood Stem Cells Number Analyzed 21 participants
1
   4.8%
Peripheral Blood Stem Cells Number Analyzed 21 participants
20
  95.2%
Acute GVHD Grading (Adapted from Glucksberg, H. et al. Transplantation 1974; 18:295)   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Overall Grade II Number Analyzed 21 participants
9
  42.9%
Overall Grade III Number Analyzed 21 participants
12
  57.1%
[1]
Measure Description:
  • Overall Grade I: Stage 1-2 skin involvement; no liver or GI involvement; ECOG Performance Score 0
  • Overall Grade II: Stage 1-3 skin involvement; Stage 0 liver or GI involvement, ECOG Performance Score 1
  • Overall Grade III: Stage 2-3 skin, liver, or GI involvement; ECOG Performance Score 2
  • Overall Grade IV: Stage 1-4 skin involvement, Stage 2-4 liver or GI involvement, ECOG Performance Score 3
1.Primary Outcome
Title GVHD-free Survival Rate
Hide Description Graft-versus-host disease (GVHD) free survival is defined as achieving complete response without death or relapse or requiring secondary immunosuppressive therapy . Proportions are reported descriptively. GVHD-free survival was assessed using the Kaplan-Meier method.
Time Frame Day 56
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Natalizumab
Hide Arm/Group Description:

Natalizumab-

  • (Day 0 and 28) Fixed dose Intravenous infusion over one hour. 2 hours observation completion of the infusion
  • At 4 weeks, if there has been less than a complete response participants can be treated with a second dose of natalizumab.
  • If participants have no response after one dose, they will be not be given a second dose.
  • Participants who receive a second dose of natalizumab will be evaluated for response at day 56 after first treatment dose administered.
  • Participants will be assessed for response to therapy with natalizumab at day +28, day +56, day +100, day + 180, and day +365.
  • Commercial supplies of Methylprednisolone (or equivalent steroid) will be utilized. The formulation, preparation and route of administration will be as per package insert.
Overall Number of Participants Analyzed 21
Measure Type: Number
Unit of Measure: percentage of patients
33.3
2.Secondary Outcome
Title Graft-verus-host Disease (GVHD) Response Rate
Hide Description
  • Complete Response (CR) is defined as resolution of all signs and symptoms of acute GVHD.
  • Very Good Partial Response (VGPR) is defined by no rash or residual erythematous rash involving less than 25% of the body surface, and total serum bilirubin concentration less than 2 mg/dL or less than 25% of baseline at enrollment and tolerating food or enteral feeding, predominantly formed stools, no overt gastrointestinal bleeding or abdominal cramping, and no more than occasional nausea and vomiting.
  • Partial Response (PR) is defined as an improvement of one stage in one or more organs without progression in any other organ.
  • Non-response (NR) is defined as no reduction in any GVHD organ staging.
  • Progression is defined as either new organ involvement on day +8 or thereafter, or increased organ specific symptoms sufficient to increase the organ stage by one or more or the initiation of an additional GVHD agent.
  • Overall Response Rate (ORR) is the sum of CR, VGPR, and PR.
Time Frame 28 Days, 56 Days
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Natalizumab
Hide Arm/Group Description:

Natalizumab-

  • (Day 0 and 28) Fixed dose Intravenous infusion over one hour. 2 hours observation completion of the infusion
  • At 4 weeks, if there has been less than a complete response participants can be treated with a second dose of natalizumab.
  • If participants have no response after one dose, they will be not be given a second dose.
  • Participants who receive a second dose of natalizumab will be evaluated for response at day 56 after first treatment dose administered.
  • Participants will be assessed for response to therapy with natalizumab at day +28, day +56, day +100, day + 180, and day +365.
  • Commercial supplies of Methylprednisolone (or equivalent steroid) will be utilized. The formulation, preparation and route of administration will be as per package insert.
Overall Number of Participants Analyzed 21
Measure Type: Count of Participants
Unit of Measure: Participants
Overall Response at Day 28
12
  57.1%
Complete Response at Day 28
7
  33.3%
Very Good Partial Response at Day 28
2
   9.5%
Partial Response at Day 28
3
  14.3%
Non-response/Progression of GVHD at Day 28
7
  33.3%
Overall Response at Day 56
11
  52.4%
Complete Response at Day 56
7
  33.3%
Very Good Partial Response at Day 56
2
   9.5%
Partial Response at Day 56
2
   9.5%
Non-response/Progression of GVHD at Day 56
6
  28.6%
3.Secondary Outcome
Title GI aGVHD Response Rate
Hide Description Gastrointestinal (GI) acute graft-versus-host disease (GVHD) Response is defined by complete response, very good partial response, or partial response in signs and symptoms of GI aGVHD.
Time Frame Day 28, Day 56
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Natalizumab
Hide Arm/Group Description:

Natalizumab-

  • (Day 0 and 28) Fixed dose Intravenous infusion over one hour. 2 hours observation completion of the infusion
  • At 4 weeks, if there has been less than a complete response participants can be treated with a second dose of natalizumab.
  • If participants have no response after one dose, they will be not be given a second dose.
  • Participants who receive a second dose of natalizumab will be evaluated for response at day 56 after first treatment dose administered.
  • Participants will be assessed for response to therapy with natalizumab at day +28, day +56, day +100, day + 180, and day +365.
  • Commercial supplies of Methylprednisolone (or equivalent steroid) will be utilized. The formulation, preparation and route of administration will be as per package insert.
Overall Number of Participants Analyzed 21
Measure Type: Number
Unit of Measure: percentage of patients
Overall response rate for GI GVHD at Day 28 57
Overall response rate for GI GVHD at Day 56 52
4.Secondary Outcome
Title Overall Survival (OS) Rate
Hide Description Overall survival (OS) is defined from the date of natalizumab infusion to death or censored at last clinical evaluation. OS was estimated using the Kaplan-Meier method.
Time Frame 2 years
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Natalizumab
Hide Arm/Group Description:

Natalizumab-

  • (Day 0 and 28) Fixed dose Intravenous infusion over one hour. 2 hours observation completion of the infusion
  • At 4 weeks, if there has been less than a complete response participants can be treated with a second dose of natalizumab.
  • If participants have no response after one dose, they will be not be given a second dose.
  • Participants who receive a second dose of natalizumab will be evaluated for response at day 56 after first treatment dose administered.
  • Participants will be assessed for response to therapy with natalizumab at day +28, day +56, day +100, day + 180, and day +365.
  • Commercial supplies of Methylprednisolone (or equivalent steroid) will be utilized. The formulation, preparation and route of administration will be as per package insert.
Overall Number of Participants Analyzed 21
Measure Type: Number
Unit of Measure: percentage of patients
43
5.Secondary Outcome
Title Rate of GVHD Flares
Hide Description Number of subjects who experienced graft-versus-host disease (GVHD) flares requiring therapy after initial complete response (CR) or partial response (PR) by day 28 after the first dose of Natalizumab.
Time Frame by Day 28
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Natalizumab
Hide Arm/Group Description:

Natalizumab-

  • (Day 0 and 28) Fixed dose Intravenous infusion over one hour. 2 hours observation completion of the infusion
  • At 4 weeks, if there has been less than a complete response participants can be treated with a second dose of natalizumab.
  • If participants have no response after one dose, they will be not be given a second dose.
  • Participants who receive a second dose of natalizumab will be evaluated for response at day 56 after first treatment dose administered.
  • Participants will be assessed for response to therapy with natalizumab at day +28, day +56, day +100, day + 180, and day +365.
  • Commercial supplies of Methylprednisolone (or equivalent steroid) will be utilized. The formulation, preparation and route of administration will be as per package insert

Natalizumab

Methylprednisolone

Overall Number of Participants Analyzed 21
Measure Type: Count of Participants
Unit of Measure: Participants
0
   0.0%
6.Secondary Outcome
Title Percentage Steroid Dose Was Reduced at Day 28, 56, and 100 in Comparison to Steroid Dose at First Administration of Natalizumab.
Hide Description Median percentage steroid dose was reduced at Day 28, Day 56, and Day 100 in comparison to steroid dose at first administration of Natalizumab.
Time Frame Day 28, 56, and 100
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Natalizumab
Hide Arm/Group Description:

Natalizumab-

  • (Day 0 and 28) Fixed dose Intravenous infusion over one hour. 2 hours observation completion of the infusion
  • At 4 weeks, if there has been less than a complete response participants can be treated with a second dose of natalizumab.
  • If participants have no response after one dose, they will be not be given a second dose.
  • Participants who receive a second dose of natalizumab will be evaluated for response at day 56 after first treatment dose administered.
  • Participants will be assessed for response to therapy with natalizumab at day +28, day +56, day +100, day + 180, and day +365.
  • Commercial supplies of Methylprednisolone (or equivalent steroid) will be utilized. The formulation, preparation and route of administration will be as per package insert.
Overall Number of Participants Analyzed 21
Median (Inter-Quartile Range)
Unit of Measure: percentage of steroid dose
Median reduction in steroid dose at day 28
42
(20 to 50)
Median reduction in steroid dose at day 56
71
(60 to 81)
Median reduction in steroid dose at day 100
85
(63 to 93)
Time Frame 1 year
Adverse Event Reporting Description All grade 2 related and unexpected and all grade 3 and higher adverse events experienced by participants were collected from the time of the first dose of study treatment, through the study and until the final study visit. Grade 4 skin rash, diarrhea and increased bilirubin were expected adverse events as a result of acute graft-versus-host disease (aGVHD) and did not require reporting. All positive John Cunningham (JC) viral loads required reporting regardless of grade.
 
Arm/Group Title Natalizumab
Hide Arm/Group Description

Natalizumab-

  • (Day 0 and 28) Fixed dose Intravenous infusion over one hour. 2 hours observation completion of the infusion
  • At 4 weeks, if there has been less than a complete response participants can be treated with a second dose of natalizumab.
  • If participants have no response after one dose, they will be not be given a second dose.
  • Participants who receive a second dose of natalizumab will be evaluated for response at day 56 after first treatment dose administered.
  • Participants will be assessed for response to therapy with natalizumab at day +28, day +56, day +100, day + 180, and day +365.
  • Commercial supplies of Methylprednisolone (or equivalent steroid) will be utilized. The formulation, preparation and route of administration will be as per package insert.
All-Cause Mortality
Natalizumab
Affected / at Risk (%)
Total   12/21 (57.14%)    
Hide Serious Adverse Events
Natalizumab
Affected / at Risk (%) # Events
Total   8/21 (38.10%)    
Blood and lymphatic system disorders   
Thrombocytopenia  1  1/21 (4.76%)  1
Thrombotic microangiopathy  1  1/21 (4.76%)  1
Cardiac disorders   
Hypotension  1  1/21 (4.76%)  1
Paroxysmal atrial tachycardia  1  1/21 (4.76%)  1
Hepatobiliary disorders   
Hepatic failure  1  1/21 (4.76%)  1
Infections and infestations   
Stenotrophomonas bacteremia  1  1/21 (4.76%)  1
Klebsiella infection  1  1/21 (4.76%)  1
Sepsis  1  2/21 (9.52%)  2
CMV viremia  1  1/21 (4.76%)  1
C. diff colitis  1  1/21 (4.76%)  1
Nervous system disorders   
Subarachnoid hemorrhage  1  1/21 (4.76%)  1
Intraparenchymal hemorrhage  1  1/21 (4.76%)  1
Renal and urinary disorders   
Acute kidney injury  1  2/21 (9.52%)  2
Respiratory, thoracic and mediastinal disorders   
Hypoxia  1  1/21 (4.76%)  1
Adult respiratory distress syndrome  1  2/21 (9.52%)  2
Bronchopneumonia  1  1/21 (4.76%)  1
Diffuse alveolar hemorrhage  1  1/21 (4.76%)  1
1
Term from vocabulary, CTCAE (4.0)
Indicates events were collected by systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
Natalizumab
Affected / at Risk (%) # Events
Total   19/21 (90.48%)    
Blood and lymphatic system disorders   
Anemia  1  2/21 (9.52%)  2
Blood and lymphatic system disorders - other  1  4/21 (19.05%)  4
Thrombotic thrombocytopenic purpura  1  1/21 (4.76%)  1
Eye disorders   
Blurred vision  1  1/21 (4.76%)  1
Gastrointestinal disorders   
Abdominal pain  1  3/21 (14.29%)  3
Cecal infection  1  1/21 (4.76%)  1
Colitis  1  1/21 (4.76%)  1
Diarrhea  1  6/21 (28.57%)  6
Duodenal ulcer  1  1/21 (4.76%)  1
Dyspepsia  1  1/21 (4.76%)  1
Gastrointestinal disorders - other  1  4/21 (19.05%)  4
Gastroparesis  1  1/21 (4.76%)  1
Nausea  1  1/21 (4.76%)  1
General disorders   
Edema limbs  1  2/21 (9.52%)  2
Localized edema  1  1/21 (4.76%)  1
Multi-organ failure  1  2/21 (9.52%)  2
Hepatobiliary disorders   
Hepatobiliary disorders - other  1  1/21 (4.76%)  1
Portal hypertension  1  1/21 (4.76%)  1
Infections and infestations   
Enterocolitis infectious  1  3/21 (14.29%)  3
Infections and infestations - other  1  2/21 (9.52%)  2
Small intestine infection  1  2/21 (9.52%)  2
Urinary tract infection  1  1/21 (4.76%)  1
Investigations   
Weight loss  1  2/21 (9.52%)  2
Alanine aminotransferase increased  1  1/21 (4.76%)  1
Aspartate aminotransferase increased  1  1/21 (4.76%)  1
Blood bilirubin increased  1  2/21 (9.52%)  2
Investigations - other  1  1/21 (4.76%)  1
Platelet count decreased  1  3/21 (14.29%)  3
Metabolism and nutrition disorders   
Hyperglycemia  1  6/21 (28.57%)  6
Hypertriglyceridemia  1  1/21 (4.76%)  1
Hypokalemia  1  1/21 (4.76%)  1
Musculoskeletal and connective tissue disorders   
Arthralgia  1  1/21 (4.76%)  1
Musculoskeletal and connective tissue disorder - other  1  1/21 (4.76%)  1
Myositis  1  1/21 (4.76%)  1
Pain in extremity  1  1/21 (4.76%)  1
Trismus  1  1/21 (4.76%)  1
Nervous system disorders   
Encephalopathy  1  1/21 (4.76%)  1
Headache  1  1/21 (4.76%)  1
Nervous system disorders - other  1  1/21 (4.76%)  1
Renal and urinary disorders   
Acute kidney injury  1  2/21 (9.52%)  2
Hoarseness  1  1/21 (4.76%)  1
Reproductive system and breast disorders   
Genital edema  1  1/21 (4.76%)  1
Respiratory, thoracic and mediastinal disorders   
Respiratory failure  1  1/21 (4.76%)  1
Skin and subcutaneous tissue disorders   
Dry skin  1  1/21 (4.76%)  1
Vascular disorders   
Hypertension  1  2/21 (9.52%)  2
1
Term from vocabulary, CTCAE (4.0)
Indicates events were collected by systematic assessment
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Dr. Corey Cutler
Organization: Dana-Farber Cancer Institute
Phone: 617-632-3470
EMail: CSCUTLER@PARTNERS.ORG
Layout table for additonal information
Responsible Party: Corey S. Cutler, MD, MPH, Dana-Farber Cancer Institute
ClinicalTrials.gov Identifier: NCT02176031    
Other Study ID Numbers: 14-140
First Submitted: June 25, 2014
First Posted: June 26, 2014
Results First Submitted: March 2, 2020
Results First Posted: April 17, 2020
Last Update Posted: April 17, 2020