Graft vs Host DiseasePhase 2Rituximab GVHDNCT00578591
Rituximab for GVHD
A Phase 2 study testing Rituximab in people with Graft vs Host Disease and Alogenic Hematopoietic Transplant, run by Baylor College of Medicine at 2 sites in United States.
Trial summary
This is a prospective, open-label pilot study in which 4 doses of Rituximab are administered to patients who have developed SR-aGVHD following allogeneic hematopoietic transplant (AHT). Read more about this study
- Who is it for?
- Ages Up to 70 years
- Conditions the study is for
- Graft vs Host Disease, Alogenic Hematopoietic Transplant
- What is being tested?
- Rituximab
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 0 participants
- Where
- 2 sitesUnited States
- Study dates
- Jun 2007to not given
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages Up to 70 years
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Who may be able to join
- Diagnosis of acute graft-versus-host disease (aGVHD)
- Steroid-refractory aGVHD with any of the following: a) No change in the stage of skin aGVHD after 1 week of 2 mg/kg per day or more methylprednisolone. b) Progression of acute GVHD (ie, increase in disease stage by at least 1) of skin GVHD or lack of response of visceral (liver, GI) aGVHD despite treatment with 2 mg/kg per day or more methylprednisolone for at least 72 hours. c) Progression of visceral aGVHD despite treatment with 2 mg/kg per day or more methylprednisolone for at least 48 hours d) Visceral aGVHD progressing to stage 4 after 24 hours of 2 mg/kg per day or more methylprednisolone.
- Grade II-IV aGVHD requiring systemic therapy within 24-48 hours of diagnosis. Biopsy confirmation of aGVHD is strongly recommended but not required; enrollment should not be delayed awaiting biopsy or pathology results.
- Patients must have received corticosteroids at greater than or equal to 2 mg/kg/day for a minimum of 72 hours prior to study entry (first-line aGVHD treatment).
- ANC greater than 500/uL x 3 days (must have evidence of engraftment).
- Patient is <100 days posttransplant
Show all 10Show fewer
- Any age, sex, ethnicity.
- Karnofsky score/Lansky score of greater than 20
- Men and women of child-bearing potential must use adequate birth control measures (e.g., abstinence, oral contraceptives, intrauterine device, barrier method with spermicide, or surgical sterilization) for the duration of the study and should continue such precautions for 6 months after receiving the study drug infusion.
- Parent(s)/legal guardian must give informed consent.
Who cannot join
- Chronic GVHD (defined as GVHD occurring beyond 100 days of the hematopoietic transplant).
- Isolated upper gastrointestinal GVHD as sole manifestation of acute GVHD.
- Isolated grade I or II skin GVHD as sole manifestation of aGVHD.
- GVHD following donor lymphocyte infusion (DLI).
- Other investigational agents for the treatment or prophylaxis of GVHD within the past 2 weeks. An investigational drug is defined as one that is being given on study, requiring informed consent.
- Use of rituximab in the conditioning regimen for hematopoietic transplant.
Show all 17Show fewer
- Prophylactic immunosuppression tapered or stopped for treatment of leukemia relapse or minimal residual disease.
- Patients with uncontrolled infection(s) i.e. documented bacterial, viral or fungal infection within 72 hours prior to study entry. Neither continuation of antibiotics for a controlled infection nor prophylactic/empiric antibiotics warrant exclusion. Patients with a C. difficile infection will not be excluded.
- Patients with any one of the following opportunistic infections documented within 8 weeks prior to study entry are excluded: pneumocystis carinii, aspergillosis, histoplasmosis, atypical mycobacterium infection or other pathogenic molds/fungi.
- Patients with hypotension believed to be secondary to sepsis syndrome or heart failure requiring > 1 inotropic agent, or dopamine >5mcg/kg/minute for blood pressure support.
- Mechanical ventilatory support.
- Relapsed, refractory, or second malignancies at the time of study entry.
- Previous grade IV severe adverse reaction to rituximab.
- Any allergy to murine products.
- Documented HIV or HBV infection.
- Patients with grade IV renal, hepatic, pulmonary, or neurologic toxicity by National Cancer Institute (NCI) Common Toxicity Criteria (CTC). 17. Patients with history of congestive heart failure, defined as cardiac dysfunction requiring inotropic support other than dopamine at <= 5mcg/kg/minute.
- 18. Autologous or syngeneic transplants.
Trial locations and contacts
2 sites in 1 country.
United States2 sites
Methodist Hospital
Houston, Texas, 77030
Texas Children's Hospital
Houston, Texas, 77030
About this study
Official title: CHIMERIC MONOCLONAL CD-20 ANTIBODY (RITUXIMAB) FOR STEROID REFRACTORY ACUTE GRAFT VERSUS HOST DISEASE (SR-AGVHD): A PILOT STUDY
This is a prospective, open-label pilot study in which 4 doses of Rituximab are administered to patients who have developed SR-aGVHD following allogeneic hematopoietic transplant (AHT). The study is designed to determine the overall survival at 180 days after treatment with rituximab, and evaluates the safety and clinical response to rituximab in this study population. Study entry: Patients must enter study on or before day +100 posttransplant.
Read the detailed description
Acute graft-versus-host disease (aGVHD), one of the most important complications of allogeneic hematopoietic stem cell transplantation (HSCT) is associated with significant morbidity and mortality. Grades II to IV aGVHD occur in 30% to 50% of matched related donor recipients and 50% to 70% of unrelated donor recipients. Standard first-line treatment consists of methylprednisolone at a dose of 2 mg/kg/d or equivalent that produces response rates of 63% to 95% for grade II, 17% to 39% for grade III, and 0% to 6% for grade IV aGVHD. In aggregate, approximately 40% to 50% of patients with acute GVHD experience a complete or partial response with primary therapy, whereas 20% to 60% require salvage treatments. The 1994 consensus conference on acute GVHD grading reported 100-day survival rates of 78% to 90% with grade I, 66% to 92% with grade II, 29% to 62% for grade III, and 23% to 25% for grade IV. The higher mortality rates were directly attributable to acute GVHD or to the subsequent immunosuppression from high-dose corticosteroids and other medications required for treatment of GVHD.
Despite several studies seeking to improve first-line therapy for acute GVHD, standard care remains moderate-dose corticosteroids. Higher initial doses of corticosteroids, a more prolonged steroid tapering course, and addition of murine or equine anti-T-cell antibodies to standard GVHD therapy all failed to improve response rates. Acute GVHD therefore remains an unfavorable complication of transplantation that is difficult to manage. Various immunosuppressants including, Anti-thimocyte globulin (ATG), Denileukin Diftitox, Mycophenolate mofetil, Pentostatin, Infliximab, Rapamycin, Inolimomab and Daclizumab have been tried with variable success (table-1 in full protocol); there remains no consensus on the second-line treatment of aGVHD.
Acute graft-versus-host-disease (aGVHD) is mediated by donor T-cells. The preventative and therapeutic strategies described above have therefore focused on quantitative reduction in T cells or reduction of their function through immune-modulation. The role of B-lymphocytes in the pathogenesis of GHVD is unclear. Recent reports of successful use of rituximab in cGVHD support the hypothesis that a coordinated B and T cell response is instrumental in cGVHD. The significance of B-cells in pathogenesis of aGVHD is unknown.
Steroid Refractory Acute Graft-Versus-Host-Disease (SR-aGVHD) Initial treatment for aGVHD routinely consists of intensifying the dose of corticosteroids. This condition is called steroid-resistant (SR) aGVHD and requires secondary intervention.
Rituximab is a human/murine chimeric monoclonal anti CD-20 antibody that is extensively used in patients with B-cell non-Hodgkin's lymphoma, or with autoimmune disease. The incidental observation of improvement in aGVHD following rituximab infusion for transplant-associated thrombotic thrombocytopenic purpura (TA-TTP) and subsequent complete resolution of multi-agent refractory aGVHD in two patients forms the basis of this proposed pilot study. Table-2 (in full protocol) describes the patients and their responses to rituximab at our own institution.
- Being tested
- Rituximab
- Keywords
- Graft Versus Host Disease, GVHD, allogeneic hematopoietic transplant, AHT, posttransplant, Rituximab
- Medical subject headings
- Graft vs Host Disease
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
RituximabDrug
Rituximab 375 mg/m^2 is given weekly X 4. For patients with a partial response, an additional 4 doses will be permitted as needed (after 4 weeks from the last dose).
Diagnosis of grade II to IV aGVHD will be confirmed, whenever possible, by a biopsy taken from at least one of the following three sites: skin, gut, or liver.
| Study group | Role | What they receive |
|---|---|---|
| Patient | Experimental | Four Rituximab doses administered to patients who have developed SR-aGVHD following allogeneic hematopoietic transplant (AHT) Receives: Drug: Rituximab |
What is being measured
The primary outcome is the main question the study is designed to answer.
Complete response rate at 4 and 8 weeks in patients with SR-GVHD treated with Rituximab.
Measured: 2 months
Secondary outcomes (13)
Survival at day 180 after txt with rituximab.
Measured: 6 months
Partial response rates at 4 weeks and 8 weeks, mixed response rate, and disease progression in patients treated with these regimens.
Measured: 2 months
Treatment failure rate at 2 weeks (no response, progression, or mortality).
Measured: 2 weeks
Safety of rituximab in SR-GVHD
Measured: 2 years
Time to aGVHD improvement.
Measured: 2 years
Incidence of GVHD flares requiring further therapeutic intervention within 90 days of therapy.
Measured: 3 months
Incidence of discontinuation of immune suppression without flare by days 90, 180, and 270 post therapy.
Measured: 9 months
Incidence of chronic GVHD by 9 months (Day 270)
Measured: 9 months
Measurement of total dose of steroids.
Measured: 1 year
Overall survival at 6, 9 and 12-month post initiation of therapy.
Measured: 1 year
Incidence of systemic infections within 3 months of initiation of therapy.
Measured: 3 months
Relapse of primary disease.
Measured: 2 years
- Changes in the Karnofsky/Lansky performance status. - Incidence of Epstein-Barr virus-associated lymphoma - Recovery of T-and B-cells.
Measured: 1 year
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted21 Dec 2007 (estimated)
- Study startJun 2007
Why it stopped: No eligible patients were identified so the study was terminated.
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Graft vs Host DiseaseStudies of the same condition, open and under way.
- More trials run by Baylor College of MedicineThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 0 participants (actual)
Sponsor and investigators
- Lead sponsor
- Baylor College of Medicine
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Rammurti Kamble, Baylor College of Medicine
- Investigators
- Rammurti Kamble, MD, Principal investigator, Baylor College of Medicine/TCH/Methodist
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00578591
- Sponsor's protocol ID
- 19734
- Other IDs
- RITUXIMAB GVHD
- Acronym
- Rituximab GVHD
- Status last verified
- Jul 2012
- First submitted
- 19 Dec 2007
- Last updated
- 9 Jul 2012
- Results posted
- No
- Data monitoring committee
- Yes
Study at a glance
From the registry record, last updated by the sponsor on 9 Jul 2012. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- CHIMERIC MONOCLONAL CD-20 ANTIBODY (RITUXIMAB) FOR STEROID REFRACTORY ACUTE GRAFT VERSUS HOST DISEASE (SR-AGVHD): A PILOT STUDY
- ClinicalTrials.gov ID
- NCT00578591
- Acronym / sponsor ID
- Rituximab GVHD / 19734
- Keywords
- Graft Versus Host Disease, GVHD, allogeneic hematopoietic transplant, AHT, posttransplant, Rituximab
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- WithdrawnReason stopped: No eligible patients were identified so the study was terminated.
- Enrolment
- 0 participants (actual)
- Lead sponsor
- Baylor College of MedicineUniversity, hospital or other
- Study start
- Jun 2007
- First posted
- 21 Dec 2007 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
This is a prospective, open-label pilot study in which 4 doses of Rituximab are administered to patients who have developed SR-aGVHD following allogeneic hematopoietic transplant (AHT). The study is designed to determine the overall survival at 180 days after treatment with rituximab, and evaluates the safety and clinical response to rituximab in this study population. Study entry: Patients must enter study on or before day +100 posttransplant.
Detailed description
Acute graft-versus-host disease (aGVHD), one of the most important complications of allogeneic hematopoietic stem cell transplantation (HSCT) is associated with significant morbidity and mortality. Grades II to IV aGVHD occur in 30% to 50% of matched related donor recipients and 50% to 70% of unrelated donor recipients. Standard first-line treatment consists of methylprednisolone at a dose of 2 mg/kg/d or equivalent that produces response rates of 63% to 95% for grade II, 17% to 39% for grade III, and 0% to 6% for grade IV aGVHD. In aggregate, approximately 40% to 50% of patients with acute GVHD experience a complete or partial response with primary therapy, whereas 20% to 60% require salvage treatments. The 1994 consensus conference on acute GVHD grading reported 100-day survival rates of 78% to 90% with grade I, 66% to 92% with grade II, 29% to 62% for grade III, and 23% to 25% for grade IV. The higher mortality rates were directly attributable to acute GVHD or to the subsequent immunosuppression from high-dose corticosteroids and other medications required for treatment of GVHD.
Despite several studies seeking to improve first-line therapy for acute GVHD, standard care remains moderate-dose corticosteroids. Higher initial doses of corticosteroids, a more prolonged steroid tapering course, and addition of murine or equine anti-T-cell antibodies to standard GVHD therapy all failed to improve response rates. Acute GVHD therefore remains an unfavorable complication of transplantation that is difficult to manage. Various immunosuppressants including, Anti-thimocyte globulin (ATG), Denileukin Diftitox, Mycophenolate mofetil, Pentostatin, Infliximab, Rapamycin, Inolimomab and Daclizumab have been tried with variable success (table-1 in full protocol); there remains no consensus on the second-line treatment of aGVHD.
Acute graft-versus-host-disease (aGVHD) is mediated by donor T-cells. The preventative and therapeutic strategies described above have therefore focused on quantitative reduction in T cells or reduction of their function through immune-modulation. The role of B-lymphocytes in the pathogenesis of GHVD is unclear. Recent reports of successful use of rituximab in cGVHD support the hypothesis that a coordinated B and T cell response is instrumental in cGVHD. The significance of B-cells in pathogenesis of aGVHD is unknown.
Steroid Refractory Acute Graft-Versus-Host-Disease (SR-aGVHD) Initial treatment for aGVHD routinely consists of intensifying the dose of corticosteroids. This condition is called steroid-resistant (SR) aGVHD and requires secondary intervention.
Rituximab is a human/murine chimeric monoclonal anti CD-20 antibody that is extensively used in patients with B-cell non-Hodgkin's lymphoma, or with autoimmune disease. The incidental observation of improvement in aGVHD following rituximab infusion for transplant-associated thrombotic thrombocytopenic purpura (TA-TTP) and subsequent complete resolution of multi-agent refractory aGVHD in two patients forms the basis of this proposed pilot study. Table-2 (in full protocol) describes the patients and their responses to rituximab at our own institution.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Patient | Experimental | Drug: RituximabFour Rituximab doses administered to patients who have developed SR-aGVHD following allogeneic hematopoietic transplant (AHT) |
Who may qualify
- Ages
- Up to 70 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
Key inclusion criteria (10 listed)
- Diagnosis of acute graft-versus-host disease (aGVHD)
- Steroid-refractory aGVHD with any of the following: a) No change in the stage of skin aGVHD after 1 week of 2 mg/kg per day or more methylprednisolone. b) Progression of acute GVHD (ie, increase in disease stage by at least 1) of skin GVHD or lack of response of visceral (liver, GI) aGVHD despite treatment with 2 mg/kg per day or more methylprednisolone for at least 72 hours. c) Progression of visceral aGVHD despite treatment with 2 mg/kg per day or more methylprednisolone for at least 48 hours d) Visceral aGVHD progressing to stage 4 after 24 hours of 2 mg/kg per day or more methylprednisolone.
- Grade II-IV aGVHD requiring systemic therapy within 24-48 hours of diagnosis. Biopsy confirmation of aGVHD is strongly recommended but not required; enrollment should not be delayed awaiting biopsy or pathology results.
- Patients must have received corticosteroids at greater than or equal to 2 mg/kg/day for a minimum of 72 hours prior to study entry (first-line aGVHD treatment).
- ANC greater than 500/uL x 3 days (must have evidence of engraftment).
Key exclusion criteria (17 listed)
- Chronic GVHD (defined as GVHD occurring beyond 100 days of the hematopoietic transplant).
- Isolated upper gastrointestinal GVHD as sole manifestation of acute GVHD.
- Isolated grade I or II skin GVHD as sole manifestation of aGVHD.
- GVHD following donor lymphocyte infusion (DLI).
- Other investigational agents for the treatment or prophylaxis of GVHD within the past 2 weeks. An investigational drug is defined as one that is being given on study, requiring informed consent.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| RituximabRituximab 375 mg/m^2 is given weekly X 4. For patients with a partial response, an additional 4 doses will be permitted as needed (after 4 weeks from the last dose). Diagnosis of grade II to IV aGVHD will be confirmed, whenever possible, by a biopsy taken from at least one of the following three sites: skin, gut, or liver. | Drug | Patient |
Primary outcome
Complete response rate at 4 and 8 weeks in patients with SR-GVHD treated with Rituximab.
Time frame: 2 months
13 secondary outcomes
Survival at day 180 after txt with rituximab.
Time frame: 6 months
Partial response rates at 4 weeks and 8 weeks, mixed response rate, and disease progression in patients treated with these regimens.
Time frame: 2 months
Treatment failure rate at 2 weeks (no response, progression, or mortality).
Time frame: 2 weeks
Safety of rituximab in SR-GVHD
Time frame: 2 years
Time to aGVHD improvement.
Time frame: 2 years
Incidence of GVHD flares requiring further therapeutic intervention within 90 days of therapy.
Time frame: 3 months
Incidence of discontinuation of immune suppression without flare by days 90, 180, and 270 post therapy.
Time frame: 9 months
Incidence of chronic GVHD by 9 months (Day 270)
Time frame: 9 months
Measurement of total dose of steroids.
Time frame: 1 year
Overall survival at 6, 9 and 12-month post initiation of therapy.
Time frame: 1 year
Incidence of systemic infections within 3 months of initiation of therapy.
Time frame: 3 months
Relapse of primary disease.
Time frame: 2 years
- Changes in the Karnofsky/Lansky performance status. - Incidence of Epstein-Barr virus-associated lymphoma - Recovery of T-and B-cells.
Time frame: 1 year
Results and safety
The study was withdrawn before enrolling participants, so there are no results.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 9 Jul 2012.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Rammurti Kamble, MD principal investigator
Baylor College of Medicine/TCH/Methodist
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Rituximab in people with Graft vs Host Disease and Alogenic Hematopoietic Transplant, run by Baylor College of Medicine at 2 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 10 inclusion and 17 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: withdrawn, as of the sponsor's last update on 9 Jul 2012. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study was withdrawn before enrolling participants, so there are no results.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Complete response rate at 4 and 8 weeks in patients with SR-GVHD treated with Rituximab. (time frame: 2 months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 9 Jul 2012.