Phase 2 Trial of Prophylactic Rituximab Therapy for Prevention of CGVHD
Study Details
Study Description
Brief Summary
To determine if rituximab administered after allogeneic transplantation decreases the incidence of chronic graft-vs-host disease (cGvHD)
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 2 |
Detailed Description
To test if prophylactic anti-B-cell therapy (weekly rituximab) given within 60 to 90 days after allogeneic transplantation will decrease allogeneic donor B-cell immunity and possibly the incidence of chronic graft-vs-host disease (cGvHD).
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Prophylactic Rituximab Rituximab will be infused after a non-myeloablative transplantation regimen of total lymphoid irradiation (TLI) + anti-thymoglobulin (ATG), with the intention of reducing chronic graft-vs-host disease (cGvHD) |
Procedure: Total lymphoid irradiation
Total lymphoid irradiation (TLI) administered at 80cGy for 10 days
Other Names:
Drug: Rituximab
Rituximab 375 mg/m2 administered as an intravenous (IV) infusion once weekly for 4 doses.
Other Names:
Drug: Anti-thymoglobulin, rabbit (ATG, rabbit ATG)
Rabbit anti-thymoglobulin (ATG) administered from Day -11 through Day -7 (5 doses) at 1.5 mg/kg/day, for a total dose of 7.5 mg/kg.
Drug: Cyclosporine
Cyclosporine (CSP) administered orally at 6.25 mg/kg twice-a-day (BID) from Day -3 until through Day +56 post-peripheral blood progenitor cell (PBPC) infusion. Dose may be adjusted to maintain a therapeutic level of cyclosporine, or in response to renal insufficiency. If at Day +56, chimerism assessment demonstrates > 40% donor cells in the CD3+ lineage, and the patient is without evidence of GvHD, then cyclosporine taper will begin (6% reduction per week).
Other Names:
Drug: Mycophenylate mofetil
Mycophenylate mofetil (MMF) will be administered at 15 mg/kg po Day 0, at 5 to 10 hours after mobilized PBPC infusion is complete
Other Names:
Drug: Filgrastim
Filgrastim provided as needed for neutrophil support
Other Names:
Drug: Granisetron
Granisetron administered as an anti-nausea agent (anti-emetic) at 1 mg orally 30 to 60 minutes before TLI
Other Names:
Drug: Solumedrol
Solumedrol, an anti-inflammatory glucocorticoid containing methylprednisolone sodium succinate, administered at 1 mg/kg as a premedication for anti-thymoglobulin (ATG)
Other Names:
Drug: Acetaminophen
Acetaminophen administered orally at 650 mg 1 hour prior to infusion of PBPC
Other Names:
Drug: Diphenhydramine
Diphenhydramine administered by intravenous infusion at 50 mg 1 hour prior to infusion of PBPC
Other Names:
Drug: Hydrocortisone
Hydrocortisone administered by intravenous infusion at 100 mg 1 hour prior to infusion of PBPC
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Chronic Graft-vs-Host Disease (cGvHD) [4 years]
The cumulative percentage of participants who develop chronic graft-vs-host disease (cGvHD). Chronic cGvHD was defined as at least one instance of a clinically-accepted marker for cGvHD (see Filipovich, et al. Biology of Blood and Marrow Transplantation. 2005;11:945-955)
Secondary Outcome Measures
- Incidence of Relapse [4 years]
Subjects who Relapsed following after Allogeneic HSCT
- Mortality [Day 100 and 1 year]
Number of participants who died within 100 days and within 1 year, non-relapse and associated with relapse.
- Overall Survival [4 years]
Eligibility Criteria
Criteria
Recipient Inclusion Criteria:
-
Between 18 and 76 years of age
-
Chronic lymphocytic leukemia (CLL):
-
Unmutated IgG VH gene status
-
Mutated IgG VH genes (> 2% nucleotide change compared to somatic sequence)
-
Complete remission benefit most from allogeneic hematopoietic stem cell transplant (HSCT).
(Physicians will be encouraged to provide aggressive chemotherapy prior to nonmyeloablative transplantation.)
-
Mantle cell lymphoma (MCL): Transplant physicians believe subject would benefit from allogeneic HSCT.
-
Adequate renal (Cr < 2.4 mg/dL) and hepatic (Bilirubin < 3.0 mg/dL, Aspartate aminotransferase (AST) < 100 IU) function.
-
Men and women of reproductive potential must agree to use an acceptable method of birth control during treatment and for six months after completion of treatment.
-
All subjects must provide written informed consent
Donor Inclusion Criteria:
-
Genotypically or phenotypically human leukocyte antigen (HLA)-identical.
-
Age < 76 unless cleared by institutional PI
-
Capable of giving written, informed consent.
-
Must consent to peripheral blood stem cell (PBSC) mobilization with G-CSF and apheresis
Recipient Exclusion Criteria:
-
Recipient has a 9 of 10 or 10 of 10 HLA identical donor (high resolution molecular genotyping at HLA A, B, C and DrB1, and DQ)
-
Pregnancy
-
Lactating
-
Serious uncontrolled infection
-
HIV seropositivity
-
Hepatitis B or C seropositivity
-
Cardiac function: ejection fraction < 40% or uncontrolled cardiac failure
-
Pulmonary: Diffusing capacity - carbon monoxide (DLCO) < 50% predicted
-
Liver function abnormalities: elevation of bilirubin to ≥ 3 mg/dL and/or AST > 100
-
Renal: creatinine > 2.4
-
Karnofsky performance score ≤ 60%
-
Patients with poorly controlled hypertension (systolic blood pressure > 150 or diastolic blood pressure > 90 repeatedly).
-
Known life-threatening hypersensitivity to rituximab or other anti-B cell antibodies.
-
Inability to comply with the allogeneic transplant treatment.
-
Uncontrolled central nervous system (CNS) involvement with disease
Donor Exclusion Criteria:
-
Identical twin to subject
-
Contra-indication to subcutaneous G-CSF at a dose of 16 mg/kg/d for 5 consecutive days
-
Serious medical or psychological illness
-
Prior malignancy within the preceding five years, with the exception of non-melanoma skin cancers.
-
HIV seropositivity
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Stanford University School of Medicine | Stanford | California | United States | 94305 |
Sponsors and Collaborators
- Stanford University
- The Leukemia and Lymphoma Society
- National Cancer Institute (NCI)
Investigators
- Principal Investigator: David Miklos, Stanford University
Study Documents (Full-Text)
None provided.More Information
Publications
- IRB-02372
- 96160
- BMT172
- SPO
- P01CA049605
- NCT00234013
Study Results
Participant Flow
| Recruitment Details | |
|---|---|
| Pre-assignment Detail |
| Arm/Group Title | Prophylactic Rituximab |
|---|---|
| Arm/Group Description | Participants to receive total lymphoid irradiation + anti-thymoglobulin (TLI + ATG) then nonmyeloablative allogeneic stem cell transplantation, with prophylactic rituximab |
| Period Title: Overall Study | |
| STARTED | 36 |
| COMPLETED | 33 |
| NOT COMPLETED | 3 |
Baseline Characteristics
| Arm/Group Title | Prophylactic Rituximab |
|---|---|
| Arm/Group Description | Participants to receive total lymphoid irradiation + anti-thymoglobulin (TLI + ATG) then nonmyeloablative allogeneic stem cell transplantation, with prophylactic rituximab |
| Overall Participants | 36 |
| Age (years) [Mean (Full Range) ] | |
| Mean (Full Range) [years] |
57
|
| Sex: Female, Male (Count of Participants) | |
| Female |
13
36.1%
|
| Male |
23
63.9%
|
| Ethnicity (NIH/OMB) (Count of Participants) | |
| Hispanic or Latino |
2
5.6%
|
| Not Hispanic or Latino |
33
91.7%
|
| Unknown or Not Reported |
1
2.8%
|
| Race (NIH/OMB) (Count of Participants) | |
| American Indian or Alaska Native |
0
0%
|
| Asian |
0
0%
|
| Native Hawaiian or Other Pacific Islander |
0
0%
|
| Black or African American |
1
2.8%
|
| White |
32
88.9%
|
| More than one race |
0
0%
|
| Unknown or Not Reported |
3
8.3%
|
| Patient Disease characteristics (participants) [Number] | |
| CLL- Chronic Lymphocytic Leukemia |
22
61.1%
|
| MCL- Mantle Cell lymphoma |
13
36.1%
|
| unknown or Not Reported |
1
2.8%
|
Outcome Measures
| Title | Chronic Graft-vs-Host Disease (cGvHD) |
|---|---|
| Description | The cumulative percentage of participants who develop chronic graft-vs-host disease (cGvHD). Chronic cGvHD was defined as at least one instance of a clinically-accepted marker for cGvHD (see Filipovich, et al. Biology of Blood and Marrow Transplantation. 2005;11:945-955) |
| Time Frame | 4 years |
Outcome Measure Data
| Analysis Population Description |
|---|
| 35 total participants were analyzed. No data is available for the withdrawn participant. |
| Arm/Group Title | Prophylactic Rituximab |
|---|---|
| Arm/Group Description | Participants to receive total lymphoid irradiation + anti-thymoglobulin (TLI + ATG) then nonmyeloablative allogeneic stem cell transplantation, with prophylactic rituximab |
| Measure Participants | 35 |
| Number (95% Confidence Interval) [percentage of participants] |
20
55.6%
|
| Title | Incidence of Relapse |
|---|---|
| Description | Subjects who Relapsed following after Allogeneic HSCT |
| Time Frame | 4 years |
Outcome Measure Data
| Analysis Population Description |
|---|
| 35 total participants were analyzed. No data is available for the withdrawn participant. |
| Arm/Group Title | Prophylactic Rituximab |
|---|---|
| Arm/Group Description | Participants to receive total lymphoid irradiation + anti-thymoglobulin (TLI + ATG) then nonmyeloablative allogeneic stem cell transplantation, with prophylactic rituximab |
| Measure Participants | 35 |
| Count of Participants [Participants] |
18
50%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Prophylactic Rituximab |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | .07 |
| Comments | ||
| Method | Log Rank | |
| Comments | ||
| Title | Mortality |
|---|---|
| Description | Number of participants who died within 100 days and within 1 year, non-relapse and associated with relapse. |
| Time Frame | Day 100 and 1 year |
Outcome Measure Data
| Analysis Population Description |
|---|
| 35 total participants were analyzed. No data is available for the withdrawn participant. |
| Arm/Group Title | Prophylactic Rituximab |
|---|---|
| Arm/Group Description | Participants to receive total lymphoid irradiation + anti-thymoglobulin (TLI + ATG) then nonmyeloablative allogeneic stem cell transplantation, with prophylactic rituximab |
| Measure Participants | 35 |
| Mortality within 100 days, all causes |
0
0%
|
| Nonrelapse mortality within 1 year |
1
2.8%
|
| Relapse + mortality within 1 year |
2
5.6%
|
| Title | Overall Survival |
|---|---|
| Description | |
| Time Frame | 4 years |
Outcome Measure Data
| Analysis Population Description |
|---|
| 35 total participants were analyzed. No data is available for the withdrawn participant. |
| Arm/Group Title | Prophylactic Rituximab (CLL Patients) | Prophylactic Rituximab (MCL Patients) |
|---|---|---|
| Arm/Group Description | CLL participants to receive total lymphoid irradiation + anti-thymoglobulin (TLI + ATG) then nonmyeloablative allogeneic stem cell transplantation, with prophylactic rituximab | MCL participants to receive total lymphoid irradiation + anti-thymoglobulin (TLI + ATG) then nonmyeloablative allogeneic stem cell transplantation, with prophylactic rituximab |
| Measure Participants | 22 | 13 |
| Number (95% Confidence Interval) [Percentage of participants by disease] |
73
202.8%
|
69
NaN
|
Adverse Events
| Time Frame | 90 days | |
|---|---|---|
| Adverse Event Reporting Description | ||
| Arm/Group Title | Prophylactic Rituximab | |
| Arm/Group Description | Participants to receive total lymphoid irradiation + anti-thymoglobulin (TLI + ATG) then nonmyeloablative allogeneic stem cell transplantation, with prophylactic rituximab | |
All Cause Mortality |
||
| Prophylactic Rituximab | ||
| Affected / at Risk (%) | # Events | |
| Total | / (NaN) | |
Serious Adverse Events |
||
| Prophylactic Rituximab | ||
| Affected / at Risk (%) | # Events | |
| Total | 4/35 (11.4%) | |
| Blood and lymphatic system disorders | ||
| Neutrophils/granulocytes | 1/35 (2.9%) | 1 |
| Graft vs Host Disease | 1/35 (2.9%) | 1 |
| Gastrointestinal disorders | ||
| Acute Graft vs Host Disease | 1/35 (2.9%) | 1 |
| General disorders | ||
| Flu-like symptom - Headache | 1/35 (2.9%) | 1 |
Other (Not Including Serious) Adverse Events |
||
| Prophylactic Rituximab | ||
| Affected / at Risk (%) | # Events | |
| Total | 4/35 (11.4%) | |
| General disorders | ||
| Flu-like symptoms | 4/35 (11.4%) | 4 |
Limitations/Caveats
More Information
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
| Name/Title | David Miklos, MD, PhD; Associate Professor of Medicine (Blood and Marrow Transplantation) |
|---|---|
| Organization | Stanford University Medical Center |
| Phone | 650-725-4626 |
| dmiklos@stanford.edu |
- IRB-02372
- 96160
- BMT172
- SPO
- P01CA049605
- NCT00234013