Clinical trial NCT00361413: Alefacept for Prevention of Graft Versus Host Disease (GVHD)
Official title: An Investigator Initiated Double Blind Randomized Study of Alefacept Treatment Prevention of Graft Versus Host Disease in Myeloablative Stem Cell Transplantation
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Graft Versus Host Disease
Keywords: Stem cell transplantation
GVHD
Graft Versus Host Disease
Lead sponsor: Hadassah Medical Organization
Sponsor class: OTHER
First posted: 2006-08-08
Enrollment: 26
Sex: ALL
Minimum age (years): 14
Maximum age (years): 75
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: Alefacept (AMEVIVE®) is an immunosuppressive dimeric fusion protein. It was shown to interfere with lymphocyte activation by specifically binding to the lymphocyte antigen, CD2, and inhibiting LFA-3/CD2 interaction. Alefacept was evaluated in two randomized, double-blind, placebo-controlled studies in adults with chronic (\>1 year) plaque psoriasis and a minimum body surface area involvement of 10% who were candidates for or had previously received systemic therapy or phototherapy. The response to alefacept was significantly better in both studies. In both studies, onset of response to alefacept treatment (defined as at least 50% reduction of baseline Psoriasis Area and Severity Index (PASI)) began 60 days after the start of therapy.

Graft versus host disease (GVHD) is the most ominous side effect of allogeneic stem cell transplantation (SCT). It causes severe inflammatory process, which is usually located to the skin, gut and liver. Treatment of GVHD consists of various immuno-suppressive and immuno-modulating drugs, including steroids, cyclosporine, tacrolimus, methotrexate etc. These drugs unfortunately can also cause severe immunologic failure that makes the patient prone to infection and malignancy, and other medication-specific side effects. In spite of this effect on the immune system, not all of the patients achieve control of GVHD, which usually rapidly leads to death. Despite the use of innovative immunosuppressive modalities, the prognosis of steroid resistant GVHD is usually poor.

It was shown that CD2 depletion of allografts could prevent GVHD. Alefacept was never systemically tried in GVHD but A phase II study of BTI-322, a rat monoclonal IgG2b directed against the CD2 antigen in steroid-refractory acute GVHD showed a total response rate of 55%. We showed that alefacept might have a beneficial effect in controlling steroid resistant aGVHD and chronic GVHD. It was also shown to dramatically change the nature of transfusion associated GVHD.


Eligibility criteria: Inclusion Criteria:

1. Patient age 14-75 years old with a disease necessitating allogeneic SCT.
2. In order to increase security, only full matched donors will be allowed and must be willing and capable of donating peripheral blood stem cells preferably, or bone marrow progenitor cells using conventional techniques, and lymphocytes if indicated.
3. Patients must sign written informed consents.
4. Patients must have an ECOG PS ≤ 2; creatinine \< 2.0 mg/dl; ejection fraction \> 40%; DLCO \> 50% of predicted; serum bilirubin \< 3 gm/dl; elevated GPT or GOT \> 3 x normal values.

Exclusion Criteria:

1. Not fulfilling any of the inclusion criteria.
2. Active life-threatening infection.
3. Overt untreated infection.
4. Hypersensitivity to alefacept.
5. HIV seropositivity, Hepatitis B or C antigen positivity with active hepatitis.
6. Pregnant or lactating women.
7. Donor contraindication (HIV seropositive confirmed by western blot).
8. Hepatitis B antigenemia.
9. Evidence of bone marrow disease.
10. Unable to donate bone marrow or peripheral blood due to concurrent medical condition.
11. Inability to comply with study requirements.

Primary outcomes:
measure: Acute GVHD occurrence.
timeFrame: 100d
measure: Acute GVHD grading.
timeFrame: 100d
Secondary outcomes:
measure: Time to acute GVHD.
timeFrame: 100d
measure: Chronic GVHD occurrence.
timeFrame: 180d
measure: Chronic GVHD grading.
timeFrame: 180d
measure: Engraftment/graft rejection.
timeFrame: 21d
measure: Overall survival.
timeFrame: 180d
measure: Disease free survival.
timeFrame: 180d
measure: Infections.
timeFrame: 180d
measure: Transplant-related mortality (TRM).
timeFrame: 180d
measure: Immune reconstitution
timeFrame: 180d
measure: Toxicity assessment according to the Common Terminology Criteria for Adverse Events (CTCAE)
timeFrame: 180d
Other outcomes:
Locations:
city: Jerusalem
country: Israel
facility: Department of Stem Cell Transplantation & Cancer Immunotherapy
Study officials:
affiliation: Hadassah Medical Organization
name: Michael Y Shapira, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Shapira MY, Resnick IB, Bitan M, Ackerstein A, Tsirigotis P, Gesundheit B, Zilberman I, Miron S, Leubovic A, Slavin S, Or R. Rapid response to alefacept given to patients with steroid resistant or steroid dependent acute graft-versus-host disease: a preliminary report. Bone Marrow Transplant. 2005 Dec;36(12):1097-101. doi: 10.1038/sj.bmt.1705185.