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Genetically Modified Donor Stem Cell Transplant Followed by Zoledronic Acid in Treating Younger Patients with Relapsed / Refractory Hematologic Malignancies or High Risk Solid Tumors

Trial Status: Active

This phase I trial studies the side effects of zoledronic acid given after genetically modified donor stem cell transplant in treating younger patients with hematologic malignancies or high risk tumors that have returned after a period of improvement (relapsed) or do not respond to treatment (refractory). Giving chemotherapy before a donor peripheral blood stem cell transplant helps stop the growth of cells in the bone marrow, including normal blood-forming cells (stem cells) and cancer cells. When healthy stem cells from a donor that have been genetically modified are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. Sometimes the transplanted cells from a donor can make an immune response against the body's normal cells (called graft-versus-host disease). Giving mycophenolate mofetil and tacrolimus after the transplant may stop this from happening. Giving zoledronic acid after the transplant may help strengthen the immune system and make the immune cells work better.

Inclusion Criteria

  • Patients with a hematologic malignancy or solid tumor
  • Patients with more than one malignancy (hematologic or solid tumor) are eligible
  • Hematologic Malignancy * No human leukocyte antigen (HLA) identical sibling or suitable unrelated donor, or time needed to find an acceptable unrelated donor match would likely result in disease progression such that the patient may become ineligible for any type of potentially curative transplant * Relapsed or primary therapy-refractory acute myeloid leukemia (AML) with bone marrow blast < 20% * High-risk refractory or relapsed acute lymphoblastic leukemia (ALL) in patients for whom transplantation is deemed indicated (relapse occurring < 30 months from diagnosis, patients relapsing after previous allogeneic transplant, relapse after 2nd remission, primary induction failure or hypodiploidy) * Patients with relapsed Hodgkin lymphoma unable to achieve 2nd remission or very good partial remission (VGPR) and therefore ineligible to receive autologous stem cell transplantation * Patients with Hodgkin lymphoma relapsing after autologous stem cell transplant * Patients with primary refractory or relapsed non-Hodgkin lymphoma (NHL) unable to achieve 2nd remission or very good partial remission (VGPR) and therefore ineligible to receive autologous stem cell transplantation * Patients with NHL relapsing after autologous stem cell transplant * Patients with myelodysplastic syndrome (MDS)/myeloproliferative syndrome (MPS)
  • Solid Tumor * Failed or ineligible to receive autologous transplant or if autologous transplant would not offer > 20% chance of cure * Neuroblastoma ** High risk with relapsed or refractory disease * Soft tissue sarcoma (rhabdomyosarcoma, Ewing sarcoma, primitive neuroectodermal tumor, or other high-risk extracranial solid tumors) ** Relapsed or primary refractory metastatic ** 1st complete remission, but very high-risk features (i.e., < 20% survival with conventional therapy) * Osteosarcoma ** Failure to achieve complete remission (CR) following initial therapy ** Relapsed with pulmonary or bone metastases and did not achieve a CR with surgery and/or chemotherapy
  • Patients must have a performance status of Karnofsky >= 60 for patients > 16 years of age and Lansky >= 60 for patients =< 16 years of age
  • Patients must have a life expectancy of >= 3 months
  • Patient must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study
  • Study enrollment no earlier than 3 months after preceding hematopoietic cell transplantation (HSCT)
  • Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 60 ml/min/1.73m^2
  • Total bilirubin < 3 mg/dL
  • Alanine aminotransferase (ALT) =< 5 x upper limit of normal (ULN) for age
  • Ejection fraction of > 40% by multigated acquisition (MUGA) or echocardiogram
  • No evidence of dyspnea at rest
  • No supplemental oxygen requirement
  • If measured, carbon monoxide diffusion capacity (DLCO) > 50%
  • Patients with a history of central nervous system disease must not have severe peripheral neuropathy, signs of leukencephalopathy, or active central nervous system (CNS) infection; patients with seizure disorders may be enrolled if seizures are well controlled on anticonvulsant therapy
  • Availability of an eligible haploidentical donor
  • Women of childbearing potential must have a negative pregnancy test at study entry; all sexually active patients will be educated regarding the teratogenic potential of the chemotherapy they receive, as well as the infectious risks of intercourse; contraceptive methods will be discussed and sexually active patients must agree to use an effective birth control method for the duration of the study; a medically acceptable method of contraception appropriate to the patient’s underlying disease, risk factors and lifestyle will be offered in consultation with gynecology or adolescent medicine and will commence on study entry; in general, most postmenarchal female patients may qualify to receive depot medroxyprogesterone acetate (DMPA) 150 mg intramuscularly (IM) or 104 mg/0.65 mL for subcutaneous (SC) injection; injection needs to be repeated every 3 months while on study; prior to IM injection, ensure that platelet count is > 30,000 x 10^9/L; patients ineligible or refusing injectable contraceptives will be offered other medically acceptable contraceptives if appropriate, such as oral contraceptives or birth control patch, or barrier methods
  • Patient or legal guardian must provide written informed consent
  • DONOR: Donor eligibility will be determined in compliance with Code of Federal Regulations 21 CFR 1271, subpart C; for a donor to be eligible, the donor must meet donor criteria for human cells, tissues and cellular and tissue-based products; specifically, a donor is eligible under these provisions only if: * Donor screening in accordance with 1271.75 indicates that the donor: ** Is free from risk factors for, and clinical evidence of, infection due to relevant communicable disease agents and diseases; and ** Is free from communicable disease risks associated with xenotransplantation; and * The results of donor testing for relevant communicable disease agents in accordance with 1271.80 and 1271.85 are negative or nonreactive, except as provided in 1271.80 (d) * If a donor does not meet these criteria, he/she is not eligible
  • DONOR: Haploidentical family members, between the ages of 18 and 65 years, identified as an eligible donor by HLA-typing; a biological parent will generally be used as the donor
  • DONOR: In addition to HLA determination, KIR genotyping will be performed on potential donors; preference will be given to donors who demonstrate KIR incompatibility with recipient HLA class I ligands defined as the donor expressing a KIR gene for which the corresponding HLA class I ligand is not expressed by the recipient; KIR genotyping and HLA class I typing will be performed in the University of Wisconsin HLA laboratory; the following KIR genes and corresponding HLA class I ligands will be analyzed: * KIR Gene; HLA Class I Ligand * KIR3DLI; HLA Bw4 * KIR2DL1; HLA C^LYS80 * KIR2DL2/3; HLA C^ASN80 If all potential donors show the same degree of KIR/KIR-ligand mismatch, donors will be preferentially selected based on B haplotype KIR gene content according to the method described by Cooley et al., using the donor KIR B-content group calculator
  • DONOR: Negative testing for relevant communicable diseases * Testing for infectious disease includes: ** Hepatitis B surface antigen (HBsAg) ** Hepatitis B core antibody (Anti-HBc) ** Hepatitis C antibody (Anti-HCV) ** HIV 1 & 2 antibody (Anti-HIV-1, 2 plus O) ** Human T-lymphotropic virus (HTLV) I/II antibody (Anti-HTLV I/II) ** Rapid plasma reagin (RPR) (Syphilis Treponema pallidum [TP]) ** Cytomegalovirus (CMV) (Capture CMV) ** Multiplex (MPX) for: Hepatitis (Hep) B (hepatitis B virus [HBV]-PCR), HepC (hepatitis C virus [HCV]-PCR), HIV (HIV-PCR) ** Nucleic acid testing (NAT) for West Nile Virus (WNV-PCR) ** Trypanosoma cruzi (T. Cruzi) - enzyme immunoassay (EIA) (Chagas) * Laboratory testing for infectious disease will be performed at the time of initial donor assessment and must be performed within 30 days of the HSC collection; if multiple collections of HSC occur from the same donor, the infectious disease testing shall be performed within 30 days prior to each collection
  • DONOR: The potential donor must be in good general health as determined by the evaluating medical provider using the University of Wisconsin (UW) Hematopoietic Stem Cell Transplant Program guidelines set forth in the most current standard operating policies and procedures for hematopoietic donor evaluation and selection
  • DONOR: Written informed consent
  • DONOR: Must be 18 years of age or older

Exclusion Criteria

  • Female patients who are pregnant or breast-feeding or of reproductive potential not willing to use an effective method of birth control during study treatment and for at least 12 months thereafter
  • Human immunodeficiency virus (HIV) infection
  • Symptoms of congestive heart failure as defined by the New York Heart Association (NYHA): Functional Classification class III or IV, or medically uncontrolled cardiac rhythm disturbance
  • Active infection
  • Any other ongoing serious medical problem unrelated to cancer or its treatment) that is not covered by the exclusion criteria and which is expected to significantly increase the risk of transplantation
  • Prior organ allograft
  • Any mental or physical condition, in the opinion of the Principal Investigator (PI) (or PI designee), which could interfere with the ability of the subject (or the only parent or legal guardian available to care for the subject) to understand or adhere to the requirements of the study
  • Enrollment in any other clinical study from screening up to day 100; enrollment in another clinical study not interfering with the endpoints of this study after day 100 according to the judgment of the PI (or PI designee) will be allowed, but will be clearly documented in the case report form (CRF) and in the patient’s medical file
  • DONOR: Lactating females
  • DONOR: Pregnant females * NOTE: a serum or urine pregnancy test for females of reproductive potential must be conducted within 7 days prior to initiation of recipient’s conditioning regimen


University of Wisconsin Hospital and Clinics
Status: ACTIVE
Contact: Mario Otto
Phone: 608-265-9645


I. Evaluation of safety.


I. Evaluation of immune reconstitution.

Ia. Reconstitution of T, B and natural killer (NK) cell subsets as assessed by immune cell phenotyping using flow cytometry.

Ib. Reconstitution of T V-beta repertoire and T V-gamma delta repertoire using spectratyping and T-cell receptor excision circle (TREC) analysis; both methods employing polymerase chain reaction (PCR) methodology.

Ic. Reconstitution of NK cell killer cell immunoglobulin-like receptor (KIR) repertoire by fluorescence activated cell sorting (FACS) analysis.

Id. Donor chimerism using short tandem repeat (STR) analysis or flow cytometry.

II. Additional assessments of safety.

IIa. Incidence and severity of acute infusional toxicity on day of stem cell infusion.

IIb. Serious adverse events throughout the study.

IIc. “Unexpected serious therapy-related toxicity” as adverse events (AE) and “expected serious therapy related toxicity” from Day -12 to Day -1 (during lymphodepletion regimen).

IId. Incidence of treatment related mortality (TRM) at all visits throughout the study.

IIe. Chronic graft-versus-host disease (GVHD) at 1 and 2 years post-transplant.

IIf. Incidence of infections post-transplant: viral infections; bacterial infections; fungal infections.

III. Evaluation of CliniMACS System efficiency.

IIIa. Percentage of viable cluster of differentiation (CD)34+ cells recovered after the T cell receptor (TCR) alpha/beta- and CD19- depletion procedure.

IIIb. Log depletion of CD19+ cells.

IIIc. Log depletion of TCR alpha/beta+ cells.

IIId. Viable CD34+ blood stem cells, CD20+ B cells, CD56+CD16+cells, TCR alpha/beta- and TCR gamma delta cell counts analyzed by flow cytometry after processing prior to transplantation.

IIIe. Number of grafts with >= 4 x 10^6 CD34+ stem cells/kg body weight (BW) of recipient (target).

IIIf. Number of grafts with =< 25 x 10^3 TCR alpha/beta+ cells/kg BW of the recipient (target).

IIIg. Number of grafts with =< 1 x 10^5 CD19+ cells/kg BW of the recipient (target).


I. Evaluation of immune cell function.

Ia. T cell activity measured by analyzing mitogen-induced T cell stimulation and proliferation.

Ib. Gamma delta T cell and NK cell activity measured by evaluation of interferon (IFN) gamma production and CD107a expression.

II. Evaluation of the anti-tumor effect of treatment.

IIa. Overall survival at day 100, 1 year and 2 years post-transplant.

IIb. Disease free survival at day 100, 1 year and 2 years post-transplant.

III. Evaluation of the effect of zoledronate treatment on gamma delta T cells and NK.

IIIa. Engraftment of gamma delta T cells and NK cells.

IIIb. Phenotype of gamma delta T cells and NK cells.

IIIc. Activity of gamma delta T cells and NK cells.

OUTLINE: A conditioning regimen (reduced intensity or myeloablative) prior to Peripheral Blood Stem Cell graft from a haploidentical donor depleted of TCR alpha/beta+ and CD19+ cells using the CliniMACS TCR alpha/beta-biotin and CD19 Systems in conjunction with post-HSCT administration of Zoledronate (Zoledronic acid).

CONDITIONING REGIMENS: Patients with high-risk leukemia receive myeloablative conditioning with anti-thymocyte globulin intravenously (IV) over 4-6 hours on days -12 through -9, Fludarabine IV over 30 minutes on days –8 through -5, Thiotepa IV every 12 hours on day –4 and Total Body Irradiation (TBI) on days -3 through -1. All other patients receive reduced intensity conditioning consisting of anti-thymocyte globulin intravenously (IV) over 4-6 hours on days -12 through -9, fludarabine IV over 30 minutes on days -8 through -5, thiotepa IV every 12 hours on day -4, and melphalan IV on days -3 and -2.

PERIPHERAL BLOOD STEM CELL TRANSPLANTATION: Patients undergo TCR-alpha/beta+ and CD19+ depleted KIR/KIR ligand-mismatched haploidentical donor peripheral blood stem cell transplantation on day 0. If the graft contains less than 4 x 10^6 CD34+ cells/kg, a second HSC graft may be administered.

PROPHYLAXIS FOR GVHD: Patients receiving a graft containing > 25 x 10^3 CD3+ TCR alpha/beta+ cells receive mycophenolate mofetil IV twice daily over 2 hours on days 1 to 30 with a rapid taper. Patients with TCR alpha/beta+ cells exceeding 100,000/kg also receive tacrolimus IV continuously or orally (PO) every 12 hours on days 0-90 with a taper at the discretion of the Principal Investigator.

ZOLEDRONIC ACID ADMINISTRATION: Patients receive five doses of Zoledronate (IV) at 28 day intervals beginning on Day +28 post-HSCT.

After completion of study treatment, patients are followed up at 6, 9, 12, and 24 months.

Trial Phase Phase I

Trial Type Treatment

Lead Organization
University of Wisconsin Hospital and Clinics

Principal Investigator
Mario Otto

  • Primary ID UW13090
  • Secondary IDs NCI-2015-01163, 2015-0290
  • ID NCT02508038