|Phase II, Phase I||Biomarker/Laboratory analysis, Treatment||Active||18 to 69||NCI||070195|
07-C-0195, NCI-07-C-0195, NCT00520130
Major problems with stem cell transplantation (SCT) for cancer treatment are a lack of suitable donors for patients without an HLA tissue-matched sibling and graft-versus-host disease (GVHD), a serious side effects of immune-suppressing chemotherapy that is given to bring the cancer under control before SCT. In GVHD, the patient s immune system attacks the transplanted donor cells.
This study will try to improve the results of SCT from unrelated HLA-matched donors using targeted immune-depleting chemotherapy to bring the cancer under control before transplantation and to lower the chance of graft rejection, followed by reduced-intensity transplant chemotherapy to make the procedure less toxic.
To evaluate the safety and effectiveness of targeted immune-depleting chemotherapy followed by reduced-intensity transplant chemotherapy in patients with advanced cancers of the blood and immune system.
To evaluate the safety and effectiveness of two different drug combinations to prevent GVHD. Both regimens have been successful in preventing GVHD, but they work by different mechanisms and affect the rebuilding of the immune system after the transplant.
People 18 to 69 years of age with advanced or high-risk cancers of the blood and immune system who do not have a suitable HLA-matched sibling.
All patients receive chemotherapy before transplant to treat the cancer and suppress immune function.
All patients receive a conditioning regimen of cyclophosphamide for 4 days and fludarabine for 4 days before SCT to prepare for the transplant.
Patients are randomly assigned to one of two combination drug treatments to prevent GHVD as follows:
- Group 1: Tacrolimus starting 3 days before SCT and continuing for 6 months, plus methotrexate on days 1, 3, 6, and 11 post-SCT, plus sirolimus starting 3 days before the SCT and continuing through day 14 following SCT.
- Group 2: Alemtuzumab for 4 days starting 8 days before SCT, plus cyclosporine starting 1 day before SCT and continuing for 6 months.
Patients receive the donor s stem cells and immune cells 2 days after the conditioning regimen.
Patients are followed at the clinic regularly for the first 6 months after SCT, and then less often for at least 5 years. Some visits may include bone marrow aspirates and biopsies, blood draws, and other tests to monitor disease status.
A skin biopsy, oral mucosa biopsy, and saliva collection are done to study chronic GVHD.
Further Study Information
- The major limitations to the broader applicability of allogeneic hematopoietic stem cell transplantation (HSCT) for the treatment of malignancies are lack of suitable donors and therapy-related toxicities which include delayed and incomplete immune reconstitution and graft-versus-host disease (GVHD). Based on the theory that the rapid establishment of donor chimerism was essential for an optimal graft-versus-tumor effect, we have employed a strategy of targeted immunedepleting chemotherapy prior to reduced-intensity allogeneic HSCT. It is our intent to investigate this approach in the setting of HLA-matched unrelated donors in a pilot manner.
- A clearly superior GVHD prophylaxis regimen has not been established in the unrelated donor transplant setting. The best results that have been reported are with the combination of alemtuzumab plus cyclosporine [AC] and the combination of tacrolimus, methotrexate, and sirolimus [TMS]. These two regimens work by mechanisms which are biologically distinct and potentially have markedly different effects upon immune reconstitution that have not been well studied. In addition neither of these regimens has been assessed for their affects on chronic GVHD using the NIH Consensus Conference Criteria. It is our intent to study the effects that these two regimens have on immune reconstitution and chronic GVHD in the setting sequential targeted immune-depleting chemotherapy and reduced-intensity allogeneic HSCT from HLA-matched unrelated donors.
- Primary objectives:
1. to assess the effects of two biologically distinct GVHD prophylaxis regimens, TMS and AC, on immune reconstitution in patients receiving targeted-immune depletion and reduced-intensity allogeneic HSCT from HLA-matched unrelated donors. As part of a comprehensive assessment of immune reconstitution, the primary immunologic endpoint will be the determination of CD4+ T cell receptor V BETA repertoire by CDR3 spectratyping at 3 months post-transplant.
2. to assess overall safety of these two regimens in this setting, as determined by engraftment, acute GVHD, early and late treatment-related mortality, and overall survival.
3. to determine and monitor incidence, organ severity and overall severity of chronic GVHD prospectively using the newly developed NIH Consensus Conference diagnosis and staging criteria and preliminarily validate those tools for use in clinical practice and trials (Pavletic, Imanguli, and Cowen).
- Secondary objectives include further assessment of immune reconstitution, study of engraftment kinetics, and assessment of those patients who receive higher doses of anthracyclines for long and short term toxicities
- Adults (18 74 years) with advanced or high risk hematologic malignancies including AML, ALL, MDS, CLL, NHL, HL,CML, multiple myeloma, and MPD who lack a suitable HLA matched sibling.
- An unrelated donor matched at a minimum of 7 of 8 alleles (HLA-A,-B,-C, and DRB1) by high resolution typing, identified through the National Marrow Donor Program.
- Life expectancy of at least 3 months, ECOG less than or equal to 2 and relatively normal major organ functions.
- Patients will receive disease-specific induction chemotherapy (EPOCH-F/R or FLAG) prior to transplant for disease control and immune depletion. If disease is controlled (greater than PR) and immune depletion objectives have been met, patients may forgo induction chemotherapy and move forward to the transplant conditioning regimen.
- All patients will receive an identical conditioning regimen consisting of cyclophosphamide 1200 mg/m(2)/day IV for 4 days and fludarabine 30 mg/m(2)/day for 4 days.
- Patients will be stratified according to degree of HLA-match and randomized at the time of enrollment to one of two GHVD prophylaxis regimens:
- Arm A (TMS): Tacrolimus, starting day -3 before transplant, given initially at 0.02 mg/kg/day CIV and then an equivalent oral dose for six months, methotrexate 5 mg/m(2) IV on days +1, +3, +6, and +11 post-transplant, and sirolimus given as an initial loading dose of 12 mg p.o. on day -3 pre-transplant and subsequently 4 mg daily through day +63 post transplant.
- Arm B (AC): Alemtuzumab at 20 mg/day IV over 8 h on days -8 to -4 pre-transplant and cyclosporine, starting day -1 before transplant, given initially at 2mg/kg IV every 12 hours and then an equivalent oral dose for six months and.
- A maximum of 105 patients will be enrolled and randomly assigned to the two arms in order to yield 44 patients per arm (88 total patients) who are able to be evaluated for development of severe chronic GVHD. This represents an increase of 20 patients over the number permitted prior to this amendment: 25 patients (50 total) randomly assigned to each arm within the 8/8 match group and 13/arm (26 total) within the 7/8 match group (maximum study enrollment = 76 transplanted patients from among up to 85 patients registered).
- ELIGIBILITY CRITERIA RECIPIENT ON STANDARD CARE THERAPY:
- The patient is 18 74 years of age.
- The patient has a potentially suitable 8/8 donor if they are between the ages of 69-74 years of age or a potentially suitable 8/8 or 7/8 unrelated donor(s) in the National Marrow Registry or Other Available Registry if they are between the ages of 18-74.
- The patient currently does not meet the protocol s eligibility/enrollment criteria for any reason.
- There is a high likelihood that the patient, in the opinion of the PI or LAI, will meet the protocol s eligibility/enrollment criteria to proceed to transplant after standard therapy is completed.
- The patient or legal guardian is able to give informed consent.
EXCLUSION CRITERIA RECIPIENT ON STANDARD CARE THERAPY:
- HIV infection. There is theoretical concern that the degree of immune suppression associated with the treatment may result in progression of HIV infection.
- Pregnant or lactating. Patients of childbearing potential must use an effective method of contraception. The effects of the chemotherapy, the subsequent transplant and the medications used after the transplant are highly likely to be harmful to a fetus. The effects upon breast milk are also unknown and may be harmful to the infant.
Trial Lead Organizations/Sponsors
National Cancer Institute
|Steven Zivko Pavletic||Principal Investigator|
|Ashley E Carpenter||Ph: (301) 594-5525|
|NIH - Warren Grant Magnuson Clinical Center|
|For more information at the NIH Clinical Center contact National Cancer Institute Referral Office||Ph: (888) NCI-1937|
Link to the current ClinicalTrials.gov record.
NLM Identifer NCT00520130
ClinicalTrials.gov processed this data on April 07, 2014
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