Low-Intensity Stem Cell Transplantation With Multiple Lymphocyte Infusions to Treat Advanced Kidney Cancer
Condition: Renal Cell Carcinoma; Graft-Versus-Host Disease; Engraftment Syndrome
MeSH terms: Carcinoma; Carcinoma, Renal Cell; Graft vs Host Disease
Intervention: Pentostatin; Sirolimus; Cyclophosphamide; Allogeneic Hematopoietic Stem Cell Transplant (HSCT); Th2 rapa cells; Donor Lymphocyte Harvest; Induction Therapy; GVHD prophylaxis; Donor Hematopoietic Stem Cell Harvest
Intervention description: Pentostatin: 2- 4mg/m^2(CrCL based dosing) intravenous (IV) on days 1, 8, and 15; Sirolimus: 4 mg by mouth (PO) on days -3 to +7 post-transplant (No Sirolimus administered after day 7 post-stem cell transplant (SCT)); Cyclosporine: 2 mg/kg every 12 hours PO or IV starting on day -4 of hematopoietic stem cell transplant (HSCT); Allogeneic Hematopoietic Stem Cell Transplant; Th2 rapa cell Transplantation; Apheresis; Pentostatin and cyclophosphamide (PC) conditioning regimen.; Short course of sirolimus plus maintenance therapy with sirolimus A.; Following lymphocyte harvest, donors for recipients will undergo stem cell mobilization and harvest.
Intervention MeSH terms: Sirolimus; Cyclophosphamide; Pentostatin
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 25.0
Sex: All
Minimum age: 18 Years
Maximum age: 75 Years
Healthy volunteers: No
Keywords: Metastatic Renal Cell Carcinoma; Allogeneic Hematopoietic Stem Cell Transplant; Th2 Cells; Sirolimus; Pentostatin; Kidney Cancer; Renal Cell Carcinoma; Metastatic Renal Cell Cancer

Summary:

      Background:

      Low-dose chemotherapy is easier for the body to tolerate than typical high-dose chemotherapy
      and involves a shorter period of complete immune suppression.

      Donor immune cells called lymphocytes, or T cells, fight residual tumor cells that might have
      remained in the recipients body after stem cell transplant, in what is called a
      graft-versus-tumor (GVT) effect.

      The immune-suppressing drug sirolimus appears to help prevent graft-versus-host disease
      (GVHD), a side effect of stem cell transplant in which donated T cells sometimes attack
      healthy tissues, damaging organs such as the liver, intestines and skin.

      Th2 cells are cells collected from the transplant donor and grown in a high concentration of
      sirolimus.

      Objectives:

      To determine whether stem cell transplantation using low-dose chemotherapy and
      sirolimus-generated Th2 cells can cause a remission of advanced kidney cancer.

      Eligibility:

      Patients between 18 and 75 years of age who have kidney cancer that has spread beyond the
      kidney and who have a tissue-matched sibling stem cell donor.

      Design:

      Patients undergo stem cell transplantation as follows:

        -  Low-intensity chemotherapy with pentostatin and cyclophosphamide over a 21-day period to
           reduce the level of the immune system to prepare for the transplant. Pentostatin is
           given through a vein (intravenous (IV)) on days 1, 8 and 15; cyclophosphamide tablets
           are taken by mouth for 21 consecutive days.

        -  Sirolimus tablets, taken by mouth, starting 2 days before the transplant and continuing
           until 60 days after the transplant.

        -  IV infusions of stem cells and Th2 cells.

      Following the transplant, patients have the following procedures:

        -  Additional Th2 cell infusions on days 14 and 45 after the transplant.

        -  Follow-up visits at the National Institutes of Health (NIH) Clinical Center twice a week
           for the first 6 months after the transplant and then less frequently for at least 5
           years to evaluate response to treatment and treatment side effects. Evaluations include
           a bone marrow aspirate and biopsy 1 month after transplant and periodic blood tests and
           imaging procedures (e.g., computed tomography (CT) or magnetic resonance imaging (MRI)
           scans).
    

Eligibility criteria:

        -  INCLUSION CRITERIA: Recipient

        Diagnosis of metastatic renal cell carcinoma, either clear cell type or non-clear cell
        type. The diagnosis must be confirmed by the Laboratory of Pathology of National Cancer
        Institute (NCI) or Hackensack (there will be no central pathology review).

        The consent process will include a discussion of the potential role of high-dose
        interleukin-2 (IL-2) therapy prior to protocol enrollment. High-dose IL-2 therapy is not
        widely available, but may be available on an NCI protocol (Dr. Yang) or through Dr. Alter
        for Hackensack patients. IL-2 therapy may also be administered by any other qualified
        physician; the Novartis web-site has a list of such physicians. For subjects who are deemed
        to be eligible for high-dose IL-2 and elect to receive this therapy, such subjects must
        have progressive disease post-IL-2 to enter this study; such subjects must also have
        received and have had progressive disease after therapy with one of the agents listed
        below.

        Subject must have progressive disease after therapy consisting of one of the following Food
        and Drug Administration (FDA)-approved agents: sorafenib, sunitinib, or temsirolimus.

        Patients 18 - 75 years of age. Subjects older than 75 will not be enrolled due to an
        increased rate of transplant-related complications.

        Must have consenting sibling matched at 6/6 human leukocyte antigen (HLA) antigens (A, B,
        DR).

        Patient or legal guardian must be able to give informed consent.

        All previous therapy must be completed at least 2 weeks prior to study entry. Any grade 3
        or 4 non-hematologic toxicity of any previous therapy must have resolved to grade 2 or
        less.

        Karnofsky performance status greater than or equal to 80%.

        Life expectancy of at least 3 months.

        Left ventricular ejection fraction greater than 40% (multi-gated acquisition scan (MUGA) or
        echo) within 28 days of enrollment.

        Carbon monoxide diffusing capacity (DLCO) greater than 50% of expected value (hemoglobin
        (Hb) corrected), obtained within 28 days of enrollment.

        Creatinine clearance greater than or equal to 40 ml/min. Creatinine clearance will be
        determined by testing of a 24 hour urine collection and simultaneous serum creatinine
        value. In previous studies, the creatine clearance of patients with metastatic renal cell
        cancer who underwent nephrectomy was 53 plus or minus 19.

        Serum total bilirubin less than 2.5 mg/dl, and serum alanine aminotransferase (ALT) and
        aspartate aminotransferase (AST) values less than or equal to 2.5 times the upper limit of
        normal. ALT and AST values above these levels may be accepted (up to a maximum of 5 times
        the upper limit of normal), at the discretion of the principal investigator (PI) or study
        chairperson, if such elevations are thought to be due to liver involvement by malignancy.

        INCLUSION CRITERIA : Donor

        Sibling who is 6/6 HLA-matched with recipient.

        Ability to give informed consent.

        Age 18 years to 80 years. Donors older than 80 will not be eligible due to potentially
        increased complications from the donation procedure.

        Adequate venous access for peripheral apheresis, or consent to use a temporary central
        venous catheter for apheresis.

        Donors must be human immunodeficiency virus (HIV) negative, hepatitis B surface antigen
        negative, and hepatitis C antibody negative. This is to prevent the possible transmission
        of these infections to the recipient. Donors with a history of hepatitis B or hepatitis C
        infections may be eligible. However, eligibility determination of such patients will
        require a hepatology consultation. The risk/benefit of the transplant and the possibility
        of transmitting hepatitis will be discussed with the patient and eligibility will then be
        determined by the principal investigator.

        A donor who is lactating must substitute formula feeding for her infant during the period
        of cytokine administration. Filgrastim may be secreted in human milk, although its
        bioavailability from this source is not known. Limited clinical data suggest that
        administration of filgrastim or to neonates is not associated with adverse outcomes.

        EXCLUSION CRITERIA: Recipient

        Active infection that is not responding to antimicrobial therapy.

        Active central nervous system (CNS) involvement by malignancy.

        HIV infection. There is theoretical concern that the degree of immune suppression
        associated with the treatment may result in progression of HIV infection.

        Chronic active hepatitis B. Patient may be hepatitis B core antibody positive. For patients
        with concomitant positive hepatitis B surface antigen, patient will require a hepatology
        consultation. The risk/benefit profile of transplant and hepatitis B will be discussed with
        the patient and eligibility determined by the principal investigator and protocol
        chairperson.

        Hepatitis C infection. Patient may have hepatitis C infection. However, each patient will
        require a hepatology consultation. The risk/benefit profile of transplant and hepatitis C
        will be discussed with the patient and eligibility determined by the principal investigator
        and protocol chairperson.

        Pregnant or lactating. Patients of childbearing potential must use an effective method of
        contraception from the time of study entry to at least one year post-transplant; effective
        methods include intrauterine device (IUD), hormonal (birth control pills, injections, or
        implants), tubal ligation/hysterectomy, partner s vasectomy, or barrier methods (condom,
        diaphragm, or cervical cap). Males on the protocol, and their partners of child-bearing
        potential, must also use an effective form of contraception at study entry and for one year
        post-transplant. 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; therefore,
        women should not breastfeed during the interval from study entry to one year
        post-transplant.

        History of psychiatric disorder which may compromise compliance with transplant protocol,
        or which does not allow for appropriate informed consent (as determined by principal
        investigator or study chairman).

        EXCLUSION CRITERIA: Donor

        History of psychiatric disorder which may compromise compliance with transplant protocol,
        or which does not allow for appropriate informed consent.

        History of hypertension that is not controlled by medication, stroke, or severe heart
        disease. Individuals with symptomatic angina will be considered to have severe heart
        disease and will not be eligible to be a donor.

        No other medical contraindications to stem cell donation (i.e. severe atherosclerosis,
        autoimmune disease, iritis or episcleritis, deep venous thrombosis, cerebrovascular
        accident). Patients with a history of coronary artery bypass grafting or angioplasty will
        receive a cardiology evaluation and be considered on a case-by-case basis.

        History of prior malignancy. However, cancer survivors who have undergone potentially
        curative therapy may be considered for stem cell donation on a case-by-case basis. The
        risk/benefit of the transplant and the possibility of transmitting viable tumor cells at
        the time of transplantation will be discussed with the patient.

        Donors must not be pregnant. The effects of cytokine therapy on a fetus are unknown. Donors
        of childbearing potential must use an effective method of contraception from the time of
        study entry until at least one year post-transplant.

        Anemia (Hb less than 11 gm/dl) or thrombocytopenia (platelets less than 100,000 per
        microliter).