Antithymocyte Globulin, Clofarabine, and Rituximab in Treating Patients After an Unsuccessful Stem Cell Transplant

Phase 2

Terminated

Conditions: Cancer

Interventions: Biological: anti-thymocyte globulin
Biological: rituximab
Drug: clofarabine
Procedure: stem cell transplantation

Registration Number: NCT00617929

Lead Sponsor: Masonic Cancer Center, University of Minnesota

Brief Summary: RATIONALE: Antithymocyte globulin, clofarabine, and rituximab may stop the patient's immune system from rejecting the donor's stem cells when they do not exactly match the patient's blood. The donated stem cells may replace the patient's immune cells and help destroy any remaining cancer cells (graft-versus-tumor effect). Sometimes the transplanted cells from a donor can also make an immune response against the body's normal cells. Giving antithymocyte globulin before transplant and cyclosporine and mycophenolate mofetil before and after transplant may stop this from happening.

PURPOSE: This phase II trial is studying how well giving antithymocyte globulin together with clofarabine and rituximab works in treating patients after an unsuccessful stem cell transplant.

Detailed Description: OBJECTIVES:

Primary

* To determine the rate of sustained donor engraftment at 42 days and survival at 100 days post transplantation in patients treated with anti-thymocyte globulin, clofarabine, and rituximab.

Secondary

* To determine incidence of treatment-related mortality at day 100 post transplantation.

* To determine incidence of neutrophil recovery by day 42 post transplantation.

* To determine survival at day 100 and 1 year post transplantation.

* To determine the proportion of patients with chimerism at day 28 post transplantation.

* To determine incidence and severity of grades II-IV acute graft-vs-host disease by day 100 post transplantation.

OUTLINE:

* Conditioning regimen: Patients receive rituximab intravenously (IV) on day -7, anti-thymocyte globulin IV over 4-6 hours on days -6 to -4, and clofarabine IV over 1 hour on days -4 to -2.

* Hematopoietic stem cell transplantation (HSCT): Patients undergo HSCT on day 0. Patients may receive umbilical cord blood, peripheral blood stem cells, or bone marrow from unrelated or related donors.

* Graft-vs-host disease (GVHD) prophylaxis: Patients receive oral cyclosporine twice daily or cyclosporine IV every 8 hours beginning on day -3 and continuing for 100 or 180 days post transplantation followed by a taper; mycophenolate mofetil IV every 8 hours beginning on day -3 and continuing for 30 days (or 7 days after engraftment with no evidence of GVHD); and filgrastim (G-CSF) IV once daily beginning on day 1 and continuing until blood counts recover.

After completion of study therapy, patients are followed on days 100, 180, and 360.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 12

Inclusion Criteria

Timing of relevant evaluations: Taking in account the need for rapid intervention, if white blood count is less than 200 on day +20, bone marrow aspirate should be performed on day +21. Unless there is an increase in absolute neutrophil count (ANC) to > 500 in the following 7 days, bone marrow aspirate should be repeated on day +28. If the white blood count is still less than 200 and bone marrow is acellular, bone marrow (BM) or peripheral blood stem cell (PBSC) donor should be reactivated and availability of cord blood (CB) units assessed. If the BM or PBSC donor is not confirmed within 14 days of the request for the donation (typically second donation from the same donor), CB unit should be used instead.

Primary or secondary graft failure after hematopoietic stem cell transplantation defined as a > 50% loss of donor chimerism from previous maximum or less than 25% donor beyond day +42 with pancytopenia and no evidence of relapse. Patients with any diagnosis, type of donor, hematopoietic cell graft or conditioning regimen should be considered for this study.

primary graft failure is defined as:
- ANC < 500
- BM < 10% on two occasions (Day +21 and Day +28)
- Donor chimerism need not to be considered, provided there is no evidence of malignancy
secondary graft failure is defined as < 5% cellularity and ANC < 500 for more than 7 days any time after primary engraftment).
- Women of childbearing potential must agree to use adequate contraception (diaphragm, birth control pills, injections, intrauterine device [IUD], surgical sterilization, subcutaneous implants, or abstinence, etc.) for the duration of treatment.
- Patients or their guardian are able and willing to provide written informed consent.

Patient

Exclusion Criteria

The presence of any of the following excludes a patient from study enrollment:

Uncontrolled active infection defined as more than one week with no response to appropriately chosen antibiotics
Evidence of recurrence of primary malignancy.
Pregnant or lactating. The agents used in this study may be teratogenic to a fetus and there is no information on the excretion of agents into breast milk. All females of childbearing potential must have a blood test or urine study within 2 weeks prior to registration to rule out pregnancy. Women of childbearing age must use appropriate methods as described.
Allergy to rituximab.
Evidence of HIV infection or positive HIV serology.
Autologous recovery defined as defined as greater than 90% recipient PCR product in the competitive VNTR PCR performed on gradually increasing white blood cell count.

Donor Inclusion Criteria:

Related donors must be 2-75 years of age and in good health.
Meets match criteria
Able and willing to undergo cell collection procedures (bone marrow cell collection or leukapheresis)
Not pregnant or lactating.
HIV-1, HIV-2 negative; HTLV-1, HTLV-2 negative, Hepatitis B and C negative.
Patients or their guardian are able and willing to provide informed consent

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Conditioning for Graft Failure	rituximab	Primary or secondary graft failure after hematopoietic stem cell transplantation defined as a \> 50% loss of previously best donor chimerism or less than 25% donor chimerism beyond day +42 with pancytopenia and no evidence of relapse. Patients with any diagnosis, type of donor, hematopoietic cell graft or conditioning regimen should be considered for this study. Patients receive anti-thymocyte globulin, rituximab, and clofarabine.
Conditioning for Graft Failure	stem cell transplantation	Primary or secondary graft failure after hematopoietic stem cell transplantation defined as a \> 50% loss of previously best donor chimerism or less than 25% donor chimerism beyond day +42 with pancytopenia and no evidence of relapse. Patients with any diagnosis, type of donor, hematopoietic cell graft or conditioning regimen should be considered for this study. Patients receive anti-thymocyte globulin, rituximab, and clofarabine.
Conditioning for Graft Failure	anti-thymocyte globulin	Primary or secondary graft failure after hematopoietic stem cell transplantation defined as a \> 50% loss of previously best donor chimerism or less than 25% donor chimerism beyond day +42 with pancytopenia and no evidence of relapse. Patients with any diagnosis, type of donor, hematopoietic cell graft or conditioning regimen should be considered for this study. Patients receive anti-thymocyte globulin, rituximab, and clofarabine.
Conditioning for Graft Failure	clofarabine	Primary or secondary graft failure after hematopoietic stem cell transplantation defined as a \> 50% loss of previously best donor chimerism or less than 25% donor chimerism beyond day +42 with pancytopenia and no evidence of relapse. Patients with any diagnosis, type of donor, hematopoietic cell graft or conditioning regimen should be considered for this study. Patients receive anti-thymocyte globulin, rituximab, and clofarabine.

Primary Outcome Measures

Name	Time	Method
Survival at 100 Days Post Transplant	Day 100 post transplantation	Percent of patients alive from beginning of study to Day 100 post transplantation
Rate of Sustained Donor Engraftment	Day 42 post transplantation	Rate of Sustained Donor Engraftment is defined as the percent of paticipants with an absolute neutrophile count (ANC) of 500 or more without a subsequent graft rejection.

Secondary Outcome Measures

Name	Time	Method
Time to Primary Neutrophil Engraftment	Day 42 post transplantation	Time to primary neutrophil engraftment is defined as the percent of patients with an absolute neutrophil count (ANC) of 500 or more neutrophils in a cubic millimeter of blood.
Survival	One year post transplantation	Percent of patients alive from beginning of study to one year post transplantation
Acute Graft-vs-host Disease	Day 30-100	Percent of patients with Acute Graft-vs-host Disease - a process where T-cells present in the donor's bone marrow at the time of transplant identify the transplant patient as "non-self' and attack the patient's skin, liver, stomach, and/or intestines.
Treatment-related Death	Day 100 post transplantation	Percent of patients who died related to the treatment in this study.
Chimerism	Day 28 post transplantation	Occurrence of genetically distinct cell types in a single organism