Clinical trial NCT00617929: Antithymocyte Globulin, Clofarabine, and Rituximab in Treating Patients After an Unsuccessful Stem Cell Transplant
Official title: Conditioning for Graft Failure After Hematopoietic Stem Cell Transplantation
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Cancer
Keywords: chronic myelogenous leukemia
acute lymphoblastic leukemia
chronic myeloid leukemia
lymphoblastic leukemia
acute myeloid leukemia
chronic eosinophilic leukemia
primary myelofibrosis
chronic myelomonocytic leukemia
chronic neutrophilic leukemia
de novo myelodysplastic syndromes
disseminated neuroblastoma
juvenile myelomonocytic leukemia
Burkitt lymphoma
rhabdomyosarcoma
myelodysplastic syndromes
Hodgkin lymphoma
lymphoblastic lymphoma
breast cancer
follicular lymphoma
mantle cell lymphoma
marginal zone lymphoma
recurrent neuroblastoma
recurrent ovarian epithelial cancer
recurrent ovarian germ cell tumor
recurrent small lymphocytic lymphoma
recurrent malignant testicular germ cell tumor
recurrent Wilms tumor and other childhood kidney tumors
recurrent/refractory childhood Hodgkin lymphoma
refractory hairy cell leukemia
refractory multiple myeloma
relapsing chronic myelogenous leukemia
secondary acute myeloid leukemia
secondary myelodysplastic syndromes
splenic marginal zone lymphoma
stage I multiple myeloma
stage II multiple myeloma
stage III multiple myeloma
stage II ovarian epithelial cancer
stage III adult Burkitt lymphoma
stage III adult diffuse large cell lymphoma
stage III adult diffuse mixed cell lymphoma
stage III adult diffuse small cleaved cell lymphoma
stage III adult Hodgkin lymphoma
stage III adult immunoblastic large cell lymphoma
stage III adult lymphoblastic lymphoma
stage III chronic lymphocytic leukemia
stage III grade 1 follicular lymphoma
stage III grade 2 follicular lymphoma
stage III grade 3 follicular lymphoma
stage III mantle cell lymphoma
stage III marginal zone lymphoma
stage III ovarian epithelial cancer
stage III small lymphocytic lymphoma
stage III malignant testicular germ cell tumor
stage IIIA breast cancer
stage IIIB breast cancer
stage IIIC breast cancer
stage IV adult Burkitt lymphoma
stage IV adult diffuse large cell lymphoma
stage IV adult diffuse mixed cell lymphoma
stage IV adult diffuse small cleaved cell lymphoma
stage IV adult Hodgkin lymphoma
stage IV adult immunoblastic large cell lymphoma
stage IV adult lymphoblastic lymphoma
stage IV breast cancer
stage IV chronic lymphocytic leukemia
stage IV grade 1 follicular lymphoma
stage IV grade 2 follicular lymphoma
stage IV grade 3 follicular lymphoma
stage IV mantle cell lymphoma
stage IV marginal zone lymphoma
stage IV ovarian epithelial cancer
stage IV small lymphocytic lymphoma
refractory chronic lymphocytic leukemia
Lead sponsor: Masonic Cancer Center, University of Minnesota
Sponsor class: OTHER
First posted: 2008-02-18
Enrollment: 12
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

Eligibility criteria: Patient 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

Primary outcomes:
measure: Rate of Sustained Donor Engraftment
timeFrame: Day 42 post transplantation
measure: Survival at 100 Days Post Transplant
timeFrame: Day 100 post transplantation
Secondary outcomes:
measure: Treatment-related Death
timeFrame: Day 100 post transplantation
measure: Time to Primary Neutrophil Engraftment
timeFrame: Day 42 post transplantation
measure: Survival
timeFrame: One year post transplantation
measure: Chimerism
timeFrame: Day 28 post transplantation
measure: Acute Graft-vs-host Disease
timeFrame: Day 30-100
Other outcomes:
Locations:
city: Minneapolis
country: United States
facility: Masonic Cancer Center at University of Minnesota
state: Minnesota
Study officials:
affiliation: Masonic Cancer Center, University of Minnesota
name: Jakub Tolar, MD
role: PRINCIPAL_INVESTIGATOR
References: