Low-Dose Total-Body Irradiation and Fludarabine Phosphate Followed By Donor Peripheral Blood Stem Cell Transplant in Treating Patients With Stage IV Kidney Cancer

Study Overview
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Brief Summary
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The reason for doing this study is to see if cancer will respond to immune therapy after transplantation of blood stem cells (from the bone marrow) using a new kind of treatment regimen that is less toxic than that previously used for blood stem cell transplants. This type of transplant uses much less chemotherapy and radiation than standard bone marrow transplants. The treatment consists of medications that weaken the immune system so it doesn't reject the donor's marrow cells. Researchers hope that the immune cells from the donor will attack the tumor. This is called a graft versus tumor effect and has been seen in other types of cancer. In addition, 65 days or more after the transplant the patient may be eligible for an immune treatment that uses additional immune cells from the donor to increase the effect of the stem cells against the cancer.

Detailed Description
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PRIMARY OBJECTIVES: I. To determine whether mixed or full donor hematopoietic chimerism can be safely established using a non-myeloablative conditioning regimen. II. To determine whether mixed chimerism can be safely converted to full donor hematopoietic chimerism by infusions of donor lymphocytes (DLI). III. To evaluate potential efficacy of this approach as a treatment for metastatic renal cancer. OUTLINE: CONDITIONING REGIMEN: Patients receive fludarabine phosphate intravenously (IV) on days -4 to -2 and undergo low-dose total-body irradiation (TBI) on day 0. TRANSPLANTATION: Patients undergo allogeneic peripheral blood stem cell transplant on day 0. IMMUNOSUPRESSION: Patients receive cyclosporine orally (PO) twice daily (BID) or IV once daily (QD) or BID on days -3 to 35 with taper to day 56, and mycophenolate mofetil PO or IV over 2 hours thrice daily (TID) on days 0-40. DLI: Patients with stable mixed chimerism on day 56 with no evidence of graft-vs-host disease (GVHD) may receive escalating doses of non-mobilized DLI over 30 minutes. Patients may receive up to 4 DLIs at escalating doses if there is disease progression with no evidence of GVHD. After completion of study treatment, patients are followed up periodically for 5 years.

Official Title
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Phase I/II Study of HLA-Matched Non-Myeloablative Peripheral Blood Mobilized Hematopoietic Progenitor Cell Transplantation as Treatment for Patients With Metastatic Renal Cell Carcinoma. A Multi-Center Trial.

Conditions
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Recurrent Renal Cell Cancer, Stage IV Renal Cell Cancer

Intervention / Treatment
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* Drug: fludarabine phosphate
* Radiation: total-body irradiation
* Procedure: nonmyeloablative allogeneic hematopoietic stem cell transplantation
* Drug: cyclosporine
* Drug: mycophenolate mofetil
* Procedure: peripheral blood stem cell transplantation
* Biological: therapeutic allogeneic lymphocytes
* Other: laboratory biomarker analysis


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with histologically confirmed stage IV renal cancer who have stable (including those rendered to be in remission) or progressive disease Human lymphocyte antigen (HLA) genotypically identical related donor willing to undergo leukapheresis initially for collection of peripheral blood stem cells (PBSC) and subsequently for collection of peripheral blood mononuclear cells (PBMC) Ionized calcium level within normal limits DONOR: HLA genotypically identical family member (excluding identical twins) DONOR: Donor must consent to filgrastim (G-CSF) administration and leukapheresis DONOR: Donor must have adequate veins for leukapheresis or agree to placement of central venous catheter (femoral, subclavian) DONOR: Age < 75 years Exclusion Criteria: Patients who have positive serologies for human immunodeficiency virus (HIV)1 and 2, human T-lymphotropic virus (HTLV)-1 Patients unwilling to use contraceptive techniques during and for 12 months following treatment Serum creatinine > 2.0; the Fred Hutchinson Cancer Research Center (FHCRC) Patient Care Conference (PCC) may approve patients with elevated serum creatinine following presentation and approval; centers outside the FHCRC that have a PCC or equivalent should obtain their institutional approval; if there is not a comparable group at the institution, please contact the FHCRC Principal Investigator for FHCRC approval through PCC Cardiac ejection fraction < 50%; ejection fraction is required if the patient has a history of anthracyclines or history of cardiac disease Diffusion capacity of carbon monoxide (DLCO) < 50% of predicted, total lung capacity (TLC) < 50%, forced expiratory volume in one second (FEV1) < 50% Liver function tests including total bilirubin, serum glutamate pyruvate transaminase (SGPT) and serum glutamic oxaloacetic transaminase (SGOT) > 2 x the upper limit of normal unless due to the malignancy Karnofsky score < 80 Brain metastasis Ongoing active bacterial, viral or fungal infection Pregnancy or breastfeeding Patients with other active non-hematologic malignancies (except non-melanoma skin cancers) Patients with a history of other non-hematologic malignancies (except non-melanoma skin cancers) currently in a complete remission, who are less than 5 years from the time of complete remission, and have a > 20% risk of disease recurrence The addition of cytotoxic agents for cytoreduction with the exception of Gleevec (imatinib mesylate), cytokine therapy, hydroxyurea, low dose cytarabine, chlorambucil, or rituxan will not be allowed within three weeks of the initiation of conditioning DONOR: Age less than 12 years DONOR: Pregnancy DONOR: Infection with HIV DONOR: Inability to achieve adequate venous access DONOR: Known allergy to G-CSF DONOR: Current serious systemic illness DONOR: Failure to meet criteria for donation as described in the Standard Practice Guidelines of the institution

Ages Eligible for Study
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Maximum Age: 74 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (nonmyeloablative donor PBSC transplantation)<br>CONDITIONING REGIMEN: Patients receive fludarabine phosphate IV on days -4 to -2 and undergo low-dose TBI on day 0. TRANSPLANTATION: Patients undergo allogeneic peripheral blood stem cell transplant on day 0. IMMUNOSUPRESSION: Patients receive cyclosporine PO BID or IV QD or BID on days -3 to 35 with taper to day 56, and mycophenolate mofetil PO or IV over 2 hours TID on days 0-40. DLI: Patients with stable mixed chimerism on day 56 with no evidence of GVHD may receive escalating doses of non-mobilized DLI over 30 minutes. Patients may receive up to 4 DLIs at escalating doses if there is disease progression with no evidence of GVHD. | Drug: fludarabine phosphate<br>* Given IV<br>* Other names: Fludara;Radiation: total-body irradiation<br>* Undergo TBI<br>* Other names: TBI;Procedure: nonmyeloablative allogeneic hematopoietic stem cell transplantation<br>* Undergo nonmyeloablative allogeneic PBSC transplantation<br>Drug: cyclosporine<br>* Given PO or IV<br>* Other names: Sandimmune;Drug: mycophenolate mofetil<br>* Given PO or IV<br>* Other names: MMF;Procedure: peripheral blood stem cell transplantation<br>* Undergo nonmyeloablative allogeneic PBSC transplantation<br>* Other names: transplantation, peripheral blood stem cell;Biological: therapeutic allogeneic lymphocytes<br>* Undergo DLI<br>* Other names: ALLOLYMPH;Other: laboratory biomarker analysis<br>* Correlative studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| True response rate (complete response [CR] or partial response [PR]) greater than the 15% achievable with standard therapy | If 6 or more out of 25 patients achieve a CR or PR, then there is at least 80% confidence that the true response rate exceeds 15% and that this approach is potentially efficacious. | Up to 5 years | 
| Transplant-related mortality | Defined as death before day 200 not related to progression of disease. | Within 200 days of transplant | 
| Rate of grade IV acute GVHD |  | Up to 90 days after last T-cell infusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Survival | Will be examined separately and reported in a descriptive manner and confidence intervals will be presented. | Up to 5 years | 
| Incidence of relapse | Will be examined separately and reported in a descriptive manner and confidence intervals will be presented. | Up to 5 years | 
| Incidence of myelosuppression after initial PBSC infusion | Defined as absolute neutrophil count < 500 for > 2 days, platelets < 20,000 for > 2 days. Will be examined separately and reported in a descriptive manner and confidence intervals will be presented. | Up to 2 months post-transplant | 
| Incidence of aplasia after DLI | Will be examined separately and reported in a descriptive manner and confidence intervals will be presented. | Until 2 months post-transplant | 
| Incidence of grades 2-4 acute GVHD after DLI | Will be examined separately and reported in a descriptive manner and confidence intervals will be presented. | Up to 90 days after last T-cell infusion | 
| Incidence of grades chronic extensive GVHD after DLI | Will be examined separately and reported in a descriptive manner and confidence intervals will be presented for all estimates. | Up to 90 days after last T-cell infusion |