Addition of Etanercept and Extracorporeal Photopheresis (ECP) to Standard Graft-Versus-Host Disease (GVHD) Prophylaxis in Stem Cell Transplant
Study Details
Study Description
Brief Summary
This research study investigates the benefits and possible risks of adding both etanercept (Enbrel) and ECP (extracorporeal photopheresis) to the conventional preventative (or prophylactic) treatments for graft-versus-host disease (GVHD). GVHD is a common, serious, and too often fatal, complication after matched unrelated donor stem cell transplantation, regardless of the pre-transplant conditioning regimen used (full or reduced intensity).
Reduced intensity transplants which employ lower doses of chemotherapy during the conditioning phase of the transplant, are less toxic than full intensity transplants. Reduced intensity transplants may extend the unrelated donor transplant option to older patients or to patients with existing medical conditions or illness, where a full intensity transplant is not possible. To be successful, reduced intensity transplants need to offset any lower effectiveness in killing cancer cells during the conditioning phase, with the establishment of a donor cell, graft-versus-leukemia effect (GVL). The GVL effect and GVHD are associated with each other and therefore, the goal of GVHD prophylaxis for this study is not so much to prevent all GVHD, but rather to prevent serious and fatal acute GVHD.
Most GVHD-related deaths are either the direct consequence of severe GVHD or from infections associated with intense immunosuppression, a consequence of the standard treatments for acute GVHD, which almost always include high-dose steroids. A more effective prophylaxis therapy that allows for the GVL effect to develop, while limiting the exposure to high-dose steroids may reduce transplant mortality and morbidity. We also will study how key chemical and cellular factors relate to clinical outcome.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 2 |
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Etanercept and ECP Etanercept and ECP (Extracorporeal Photopheresis) in addition to standard GVHD prevention: Etanercept will be given twice weekly by subcutaneous injection starting on the day of HSCT (Hematopoietic stem cell transplantation) conditioning until 8 weeks post transplant. ECP treatments will begin at once weekly starting at 4 weeks post transplant and continue at less frequent intervals until 6 months post transplant. GVHD prophylaxis will consist of a standard two drug regimen: mycophenolate for 4 weeks and tacrolimus (titrated to a therapeutic level) for 8 weeks, then weaned over 4 months with discontinuation by 6 months post-transplant. |
Procedure: stem cell transplant
reduced intensity, matched unrelated donor stem cell transplant
Drug: tacrolimus (standard GVHD prophylaxis)
Tacrolimus(or cyclosporine when necessary)
Tacrolimus will begin on day -3, IV or oral.
Target trough level for tacrolimus is 8-12 ng/ml.
In the absence of GVHD, tacrolimus tapering will begin on day +56 post transplant
Drug: mycophenolate (standard GVHD prophylaxis)
Mycophenolate will begin on day 0 at 10 mg/kg/dose (up to 1 gram per dose) every 8 hours orally or intravenously and will continue until day 28.
Drug: etanercept
Etanercept will be given at a dose 0.4 mg/kg (actual weight) up to a maximum dose of 25 mg, subcutaneously, twice weekly from day 0 to day 56 (16 doses)
Other Names:
Drug: methoxsalen
Methoxsalen (UVADEX) treatments by Extracorporeal photopheresis (ECP) will be started day +28 post transplant and given weekly.
On day +70 post transplant ECP frequency will be given every other week.
On day +100 post transplant ECP will be given monthly until day +180 and stopped.
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Percentage of Patients Alive at 6 Months [6 months]
Overall survival at 6 months
- Percentage of Patients Who Experienced Relapse by 6 Months [6 months]
Relapse rate at 6 months. Relapse is defined as recurrence of disease.
Secondary Outcome Measures
- The Percentage of Patients That Experienced Graft Versus Host Disease [6 Months]
Incidence of acute GVHD grades 2-4 and chronic GVHD in this study population
- Measured Level of Circulating Plasma Markers After Transplant [100 days]
- Regulatory T Cell Numbers Post-transplant [180 days]
Eligibility Criteria
Criteria
Inclusion Criteria:
-
Candidate for unrelated donor (allogeneic) HSCT for hematologic conditions, either malignant or non-malignant.
-
Donor can be unrelated marrow, blood or cord blood.
-
Any disease for which unrelated donor transplant is appropriate is eligible except:
-
Progressive or poorly controlled malignancies for which the likelihood of durable disease control [i.e., patients expected to have at least 6 months PFS from date of transplant] is <25%.
-
This determination of likelihood of durable disease control must take into account the patient's disease status and consideration of the agents and doses used in the reduced intensity conditioning regimen.
-
The determination of adequate disease control will be certified by the PI or designee on the eligibility checklist.
-
Patients may be consented to this trial based on disease control at the time of consent, but later removed from the trial prior to initiation of transplant conditioning regimen if disease status confirmation between consenting and transplant changes. In the event this occurs these patients will be replaced.
-
Must be receiving a recognized reduced intensity transplant as determined by the University of Michigan Blood and Marrow Transplantation Program.
-
Patients age 50 or older are eligible based on age.
-
Patients may be <50 years old if they are eligible for a reduced intensity conditioning regimen based on disease type (eg, indolent lymphoma) or if comorbidities preclude a full-intensity transplant.
-
Patients must have adequate venous access by either peripheral vein or central line so that ECP can be performed.
-
Patients must be expected to tolerate the fluid shifts associated with ECP. The primary reason for expected intolerance of ECP is small size (ie, <30kg weight), but other factors may also be considered in this determination.
Exclusion Criteria:
-
Not a candidate for a reduced intensity transplant conditioning regimen (based on the current U-M BMT program clinical guidelines).
-
Patient has a suitable related donor available for transplant.
-
Karnofsky or Lansky performance status of < 50% at the time of admission for HSCT
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Patients with evidence of HIV infection or other opportunistic infection including but not limited to Tuberculosis and Histoplasmosis.
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Patients with active bacterial, fungal or viral infection not responding to treatment.
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Any medical or psychological conditions that would keep the patient from complying with the protocol and/or would markedly increase the morbidity and mortality from the procedure.
-
Pregnancy.
-
T-cell depleted allograft
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | University of Michigan Cancer Center | Ann Arbor | Michigan | United States | 48109 |
Sponsors and Collaborators
- University of Michigan Rogel Cancer Center
- Mallinckrodt
- Amgen
Investigators
- Principal Investigator: Gregory Yanik, MD, University of Michigan Rogel Cancer Center
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- umcc 2008.003
Study Results
Participant Flow
| Recruitment Details | |
|---|---|
| Pre-assignment Detail |
| Arm/Group Title | Etanercept and ECP |
|---|---|
| Arm/Group Description | Etanercept and ECP (Extracorporeal Photopheresis) in addition to standard GVHD prevention: Etanercept will be given twice weekly by subcutaneous injection starting on the day of HSCT conditioning until 8 weeks post transplant. ECP treatments will begin at once weekly starting at 4 weeks post transplant and continue at less frequent intervals until 6 months post transplant. GVHD prophylaxis will consist of a standard two drug regimen: mycophenolate for 4 weeks and tacrolimus (titrated to a therapeutic level) for 8 weeks, then weaned over 4 months with discontinuation by 6 months post-transplant. |
| Period Title: Overall Study | |
| STARTED | 48 |
| COMPLETED | 48 |
| NOT COMPLETED | 0 |
Baseline Characteristics
| Arm/Group Title | Etanercept and ECP |
|---|---|
| Arm/Group Description | Etanercept and ECP (Extracorporeal Photopheresis) in addition to standard GVHD prevention: Etanercept will be given twice weekly by subcutaneous injection starting on the day of HSCT conditioning until 8 weeks post transplant. ECP treatments will begin at once weekly starting at 4 weeks post transplant and continue at less frequent intervals until 6 months post transplant. GVHD prophylaxis will consist of a standard two drug regimen: mycophenolate for 4 weeks and tacrolimus (titrated to a therapeutic level) for 8 weeks, then weaned over 4 months with discontinuation by 6 months post-transplant. |
| Overall Participants | 48 |
| Age (years) [Median (Full Range) ] | |
| Median (Full Range) [years] |
60
|
| Sex: Female, Male (Count of Participants) | |
| Female |
22
45.8%
|
| Male |
26
54.2%
|
Outcome Measures
| Title | Percentage of Patients Alive at 6 Months |
|---|---|
| Description | Overall survival at 6 months |
| Time Frame | 6 months |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Etanercept and ECP |
|---|---|
| Arm/Group Description | Etanercept and ECP (Extracorporeal Photopheresis) in addition to standard GVHD prevention: Etanercept will be given twice weekly by subcutaneous injection starting on the day of HSCT conditioning until 8 weeks post transplant. ECP treatments will begin at once weekly starting at 4 weeks post transplant and continue at less frequent intervals until 6 months post transplant. GVHD prophylaxis will consist of a standard two drug regimen: mycophenolate for 4 weeks and tacrolimus (titrated to a therapeutic level) for 8 weeks, then weaned over 4 months with discontinuation by 6 months post-transplant. |
| Measure Participants | 48 |
| Number (95% Confidence Interval) [percentage of patients] |
83
|
| Title | Percentage of Patients Who Experienced Relapse by 6 Months |
|---|---|
| Description | Relapse rate at 6 months. Relapse is defined as recurrence of disease. |
| Time Frame | 6 months |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Etanercept and ECP |
|---|---|
| Arm/Group Description | Etanercept and ECP (Extracorporeal Photopheresis) in addition to standard GVHD prevention: Etanercept will be given twice weekly by subcutaneous injection starting on the day of HSCT conditioning until 8 weeks post transplant. ECP treatments will begin at once weekly starting at 4 weeks post transplant and continue at less frequent intervals until 6 months post transplant. GVHD prophylaxis will consist of a standard two drug regimen: mycophenolate for 4 weeks and tacrolimus (titrated to a therapeutic level) for 8 weeks, then weaned over 4 months with discontinuation by 6 months post-transplant. |
| Measure Participants | 48 |
| Number (95% Confidence Interval) [Percentage of patients] |
8
|
| Title | The Percentage of Patients That Experienced Graft Versus Host Disease |
|---|---|
| Description | Incidence of acute GVHD grades 2-4 and chronic GVHD in this study population |
| Time Frame | 6 Months |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Etanercept and ECP |
|---|---|
| Arm/Group Description | Etanercept and ECP (Extracorporeal Photopheresis) in addition to standard GVHD prevention: Etanercept will be given twice weekly by subcutaneous injection starting on the day of HSCT conditioning until 8 weeks post transplant. ECP treatments will begin at once weekly starting at 4 weeks post transplant and continue at less frequent intervals until 6 months post transplant. GVHD prophylaxis will consist of a standard two drug regimen: mycophenolate for 4 weeks and tacrolimus (titrated to a therapeutic level) for 8 weeks, then weaned over 4 months with discontinuation by 6 months post-transplant. |
| Measure Participants | 48 |
| Number (95% Confidence Interval) [percentage of patients] |
46
|
| Title | Measured Level of Circulating Plasma Markers After Transplant |
|---|---|
| Description | |
| Time Frame | 100 days |
Outcome Measure Data
| Analysis Population Description |
|---|
| Plasma markers were not analyzed. |
| Arm/Group Title | Etanercept and ECP |
|---|---|
| Arm/Group Description | Etanercept and ECP (Extracorporeal Photopheresis) in addition to standard GVHD prevention: Etanercept will be given twice weekly by subcutaneous injection starting on the day of HSCT conditioning until 8 weeks post transplant. ECP treatments will begin at once weekly starting at 4 weeks post transplant and continue at less frequent intervals until 6 months post transplant. GVHD prophylaxis will consist of a standard two drug regimen: mycophenolate for 4 weeks and tacrolimus (titrated to a therapeutic level) for 8 weeks, then weaned over 4 months with discontinuation by 6 months post-transplant. |
| Measure Participants | 0 |
| Title | Regulatory T Cell Numbers Post-transplant |
|---|---|
| Description | |
| Time Frame | 180 days |
Outcome Measure Data
| Analysis Population Description |
|---|
| T cell numbers were not analyzed |
| Arm/Group Title | Etanercept and ECP |
|---|---|
| Arm/Group Description | Etanercept and ECP (Extracorporeal Photopheresis) in addition to standard GVHD prevention: Etanercept will be given twice weekly by subcutaneous injection starting on the day of HSCT conditioning until 8 weeks post transplant. ECP treatments will begin at once weekly starting at 4 weeks post transplant and continue at less frequent intervals until 6 months post transplant. GVHD prophylaxis will consist of a standard two drug regimen: mycophenolate for 4 weeks and tacrolimus (titrated to a therapeutic level) for 8 weeks, then weaned over 4 months with discontinuation by 6 months post-transplant. |
| Measure Participants | 0 |
Adverse Events
| Time Frame | ||
|---|---|---|
| Adverse Event Reporting Description | ||
| Arm/Group Title | Etanercept and ECP | |
| Arm/Group Description | Etanercept and ECP (Extracorporeal Photopheresis) in addition to standard GVHD prevention: Etanercept will be given twice weekly by subcutaneous injection starting on the day of HSCT conditioning until 8 weeks post transplant. ECP treatments will begin at once weekly starting at 4 weeks post transplant and continue at less frequent intervals until 6 months post transplant. GVHD prophylaxis will consist of a standard two drug regimen: mycophenolate for 4 weeks and tacrolimus (titrated to a therapeutic level) for 8 weeks, then weaned over 4 months with discontinuation by 6 months post-transplant. | |
All Cause Mortality |
||
| Etanercept and ECP | ||
| Affected / at Risk (%) | # Events | |
| Total | / (NaN) | |
Serious Adverse Events |
||
| Etanercept and ECP | ||
| Affected / at Risk (%) | # Events | |
| Total | 19/48 (39.6%) | |
| Blood and lymphatic system disorders | ||
| Blood Bone Marrow - Other | 3/48 (6.3%) | 3 |
| Cardiac disorders | ||
| Cardiac ischemia/infarction | 2/48 (4.2%) | 2 |
| Pain - Cardiac | 1/48 (2.1%) | 1 |
| Gastrointestinal disorders | ||
| Diarrhea | 1/48 (2.1%) | 1 |
| Gastrointestinal - Other | 1/48 (2.1%) | 1 |
| Ileus, GI Obstruction | 1/48 (2.1%) | 1 |
| Vomiting | 1/48 (2.1%) | 1 |
| Infections and infestations | ||
| Lung Infection | 1/48 (2.1%) | 1 |
| Stomach Infection | 1/48 (2.1%) | 1 |
| Nervous system disorders | ||
| Confusion | 1/48 (2.1%) | 1 |
| Agitation | 1/48 (2.1%) | 1 |
| Depression | 1/48 (2.1%) | 1 |
| Syncope (fainting) | 1/48 (2.1%) | 1 |
| Pain - Head | 1/48 (2.1%) | 1 |
| Respiratory, thoracic and mediastinal disorders | ||
| Dyspnea (shortness of breath) | 1/48 (2.1%) | 1 |
| Hypoxia | 1/48 (2.1%) | 1 |
| Vascular disorders | ||
| Hemorrhage, CNS | 1/48 (2.1%) | 1 |
| Hemorrhage, GI | 1/48 (2.1%) | 1 |
| Thrombosis/embolism (vascular access-related) | 1/48 (2.1%) | 1 |
| Thrombosis/thrombus/embolism | 1/48 (2.1%) | 1 |
Other (Not Including Serious) Adverse Events |
||
| Etanercept and ECP | ||
| Affected / at Risk (%) | # Events | |
| Total | 47/48 (97.9%) | |
| Blood and lymphatic system disorders | ||
| Blood Bone Marrow - Other | 5/48 (10.4%) | 5 |
| Cardiac disorders | ||
| Atrial Fibrillation | 4/48 (8.3%) | 4 |
| Cardiac ischemia/infarction | 4/48 (8.3%) | 4 |
| Hypertension | 4/48 (8.3%) | 5 |
| Gastrointestinal disorders | ||
| Ascites (non-malignant) | 3/48 (6.3%) | 4 |
| Diarrhea | 12/48 (25%) | 13 |
| Mucositis/stomatitis (clinical exam) | 5/48 (10.4%) | 5 |
| Nausea | 11/48 (22.9%) | 11 |
| Vomiting | 4/48 (8.3%) | 6 |
| Pain-Abdomen | 4/48 (8.3%) | 5 |
| Infections and infestations | ||
| Febrile neutropenia | 13/48 (27.1%) | 13 |
| Blood Infection with Grade 3/4 ANC | 9/48 (18.8%) | 10 |
| Lung Infection | 5/48 (10.4%) | 6 |
| Urinary Tract Infection | 3/48 (6.3%) | 3 |
| Blood Infection with Normal ANC | 8/48 (16.7%) | 8 |
| Catheter-related Infection | 4/48 (8.3%) | 5 |
| Metabolism and nutrition disorders | ||
| ALT, SGPT (serum glutamic pyruvic transaminase) | 5/48 (10.4%) | 5 |
| Albumin, serum-low (hypoalbuminemia) | 3/48 (6.3%) | 4 |
| Bilirubin (hyperbilirubinemia) | 6/48 (12.5%) | 6 |
| Calcium, serum-low (hypocalcemia) | 5/48 (10.4%) | 6 |
| Glucose, serum-high (hyperglycemia) | 17/48 (35.4%) | 35 |
| Phosphate, serum-low (hypophosphatemia) | 11/48 (22.9%) | 18 |
| Potassium, serum-high (hyperkalemia) | 3/48 (6.3%) | 4 |
| Sodium, serum-low (hyponatremia) | 9/48 (18.8%) | 11 |
| Musculoskeletal and connective tissue disorders | ||
| Muscle weakness, generalized | 3/48 (6.3%) | 3 |
| Pain-Back | 5/48 (10.4%) | 5 |
| Nervous system disorders | ||
| Ataxia (incoordination) | 6/48 (12.5%) | 11 |
| Confusion | 5/48 (10.4%) | 5 |
| Dizziness | 3/48 (6.3%) | 3 |
| Anxiety | 3/48 (6.3%) | 3 |
| Somnolence/depressed level of consciousness | 5/48 (10.4%) | 6 |
| Pain-Head | 3/48 (6.3%) | 4 |
| Respiratory, thoracic and mediastinal disorders | ||
| Dyspnea (shortness of breath) | 6/48 (12.5%) | 8 |
| Hypoxia | 10/48 (20.8%) | 14 |
| Vascular disorders | ||
| PTT (Partial Thromboplastin Time) | 4/48 (8.3%) | 6 |
| Thrombosis/thrombus/embolism | 3/48 (6.3%) | 3 |
Limitations/Caveats
More Information
Certain Agreements
All Principal Investigators ARE 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 | Dr. Gregory Yanik |
|---|---|
| Organization | University of Michigan Comprehensive Cancer Center |
| Phone | 734-764-3243 |
| jelevine@umich.edu |
- umcc 2008.003