Alpha/Beta CD19+ Depleted Haploidentical Transplantation + Zometa for Pediatric Hematologic Malignancies and Solid Tumors

Sponsor

University of Wisconsin, Madison (Other)

Overall Status

Recruiting

CT.gov ID

NCT02508038

Collaborator

(none)

Enrollment

Location

Arm

116.6

Anticipated Duration (Months)

0.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This phase I trial studies the safety of transplantation with a haploidentical donor peripheral blood stem cell graft depleted of TCRαβ+ cells and CD19+ cells in conjunction with the immunomodulating drug, Zoledronate, given in the post-transplant period to treat pediatric patients with relapsed or refractory hematologic malignancies or high risk solid tumors.

Condition or Disease	Intervention/Treatment	Phase
Acute Myeloid Leukemia Acute Lymphoblastic Leukemia Hodgkin Lymphoma Non-Hodgkin Lymphoma Myelodysplastic Syndrome Myeloproliferative Syndrome Rhabdomyosarcoma Ewing Sarcoma Primitive Neuroectodermal Tumor Osteosarcoma Neuroblastoma	Procedure: TCRαβ+/CD19+ depleted Haploidentical HSCT Drug: Zoledronate	Phase 1

Detailed Description

CONDITIONING REGIMENS: Patients with high-risk leukemia will 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 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 over 4 hours 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.

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

Follow-up assessments will occur after transplantation.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

22 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

TCR-αβ+ and CD19+ Depleted KIR/KIR Ligand-mismatched Haploidentical Hematopoietic Stem Cell Transplant and Zoledronate for Pediatric Relapsed/Refractory Hematologic Malignancies and High Risk Solid Tumors

Actual Study Start Date :

Feb 12, 2016

Anticipated Primary Completion Date :

May 1, 2023

Anticipated Study Completion Date :

Nov 1, 2025

Arms and Interventions

Arm	Intervention/Treatment
Experimental: TCRαβ+/CD19+ depleted Haploidentical HSCT+ Zoledronate Patients with high-risk leukemia (who are at least one year of age and who have not received TBI as conditioning for a previous HSCT) will receive myeloablative conditioning with ATG, Fludarabine, Thiotepa, and TBI. All other subjects will undergo a reduced-intensity conditioning regimen consisting of ATG, Fludarabine, Thiotepa, and Melphalan prior to transplant with a KIR/KIR ligand mismatched haploidentical donor peripheral blood stem cell graft depleted of TCR-αβ+ and CD19+ cells. Patients will receive 5 doses of zoledronate (at 28 day intervals) starting 28 days after stem cell transplant.	Procedure: TCRαβ+/CD19+ depleted Haploidentical HSCT Patients with high-risk leukemia will receive myeloablative conditioning. All other patients will undergo a reduced-intensity conditioning with ATG, Fludarabine, Thiotepa and Melphalan followed by transplant with a KIR/KIR (Killer cell immunoglobulin-like recetptor) ligand mismatched haploidentical donor peripheral blood stem cell graft depleted of TCRab+ cells and CD19+ cells using the CliniMACS System. Drug: Zoledronate Given IV. Patients will receive five doses of Zoledronate (each 1.25 mg/m2 at a 28 day interval) following transplant. Other Names: Zoledronic Acid Zometa

Arm

Intervention/Treatment

Experimental: TCRαβ+/CD19+ depleted Haploidentical HSCT+ Zoledronate

Patients with high-risk leukemia (who are at least one year of age and who have not received TBI as conditioning for a previous HSCT) will receive myeloablative conditioning with ATG, Fludarabine, Thiotepa, and TBI. All other subjects will undergo a reduced-intensity conditioning regimen consisting of ATG, Fludarabine, Thiotepa, and Melphalan prior to transplant with a KIR/KIR ligand mismatched haploidentical donor peripheral blood stem cell graft depleted of TCR-αβ+ and CD19+ cells. Patients will receive 5 doses of zoledronate (at 28 day intervals) starting 28 days after stem cell transplant.

Procedure: TCRαβ+/CD19+ depleted Haploidentical HSCT

Patients with high-risk leukemia will receive myeloablative conditioning. All other patients will undergo a reduced-intensity conditioning with ATG, Fludarabine, Thiotepa and Melphalan followed by transplant with a KIR/KIR (Killer cell immunoglobulin-like recetptor) ligand mismatched haploidentical donor peripheral blood stem cell graft depleted of TCRab+ cells and CD19+ cells using the CliniMACS System.

Drug: Zoledronate

Given IV. Patients will receive five doses of Zoledronate (each 1.25 mg/m2 at a 28 day interval) following transplant.

Other Names:

Zoledronic Acid

Zometa

Outcome Measures

Primary Outcome Measures

Incidence of acute graft versus host disease (GVHD) [Within 100 days post-transplantation]
Incidence of graft failure [At day 28]

Secondary Outcome Measures

Immune reconstitution [Up to 1 year]
Immune reconstitution outcomes, as determined by immune cell analysis.
Performance of the CliniMACS Reagent System utilizing the CliniMACS TCRαβ-biotin and CliniMACS CD19 reagent to produce a graft with defined cell content. [Day 0]
The performance of the CliniMACS Reagent System will be evaluated by measuring the number of viable stem cells, TCRαβ+ cells, TCRγδ+ cells, NK cells and B cells in the hematopoietic stem cell graft.

Eligibility Criteria

Criteria

Ages Eligible for Study:

7 Months to 21 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Availability of an eligible haploidentical donor
Hematologic malignancy or solid tumor
Patients with more than one malignancy (hematologic or solid tumor) are eligible
Patients with hematologic malignancy must have no 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 AML with bone marrow blast < 20%
High-risk refractory or relapsed 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)
Relapsed Hodgkin lymphoma unable to achieve 2nd remission or Very Good Partial Response (VGPR) and therefore ineligible to receive autologous hematopoietic stem cell transplant (auto-HSCT)
Hodgkin lymphoma relapsing after auto-HSCT
Primary refractory or relapsed non-Hodgkin lymphoma unable to achieve 2nd remission or VGPR and therefore ineligible to receive auto-HSCT
Non-Hodgkin lymphoma relapsing after auto-HSCT
Myelodysplastic Syndrome/Myeloproliferative Syndrome

Solid Tumor

Patients with solid tumor must have failed or have been ineligible to receive auto-HSCT or if auto-HSCT would not offer > 20% chance of cure
Neuroblastoma
high risk with relapsed or refractory disease
Soft tissue sarcomas (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 Response (CR) following initial therapy
Relapsed with pulmonary or bone metastases and did not achieve a CR with surgery and/or chemotherapy
Karnofsky (patients > 16 years) or Lansky (patients 16 years or older) performance score of ≥ 60
Life expectancy of ≥ 3 months
Patient must have fully recovered from acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study
Study enrollment no earlier than 3 months after preceding HSCT
Glomerular Filtration Rate (GFR) ≥ 60 ml/min/1.73m2
Total bilirubin < 3 mg/dL
ALT (alanine aminotransferase, SCPT) ≤ 5 x Upper LImit of Normal (ULN) for age
Ejection fraction of > 40% by Multigated Acquisition Scan (MUGA) or echocardiogram
No evidence of dyspnea at rest
No supplemental oxygen requirement
If measured, carbon monoxide diffusion capacity (DLCO) >50%
No severe peripheral neuropathy, signs of leukoencephalopathy or active Central Nervous System (CNS) infection
Patients with seizure disorders may be enrolled if seizures are well controlled on anticonvulsant therapy
If of reproductive potential, negative pregnancy test and willing to use effective birth control method
Informed consent from patient or legal guardian (if patient is minor)

Inclusion Criteria for Donors:

Donor must be 18 years of age minimum, 65 years of age maximum
Donor must be in good general health as determined by evaluating medical provider
Must meet donor criteria for human cells, tissues, and cellular and tissue-based products per Code of Federal Regulations 21 CFR 1271, subpart C. Specifically:
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)(1).
Haploidentical by HLA-typing
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.
Negative testing for relevant communicable diseases:
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)
HTLV I/II antibody (Anti-HTLV I/II)
RPR (Syphilis TP)
CMV (Capture CMV)
MPX for: HepB (HBV-PCR), HepC (HCV-PCR), HIV (HIV-PCR)
NAT for West Nile Virus (WNV-PCR)
1. Cruzi - EIA (Chagas)

Exclusion Criteria:

Pregnant or breast-feeding
HIV infection
Heart failure or uncontrolled cardiac rhythm disturbance
Uncontrolled, Serious Active Infection
Prior organ allograft
Significant serious intercurrent illness unrelated to cancer or its treatment not covered by other exclusion criteria expected to significantly increase the risk of HSCT
Any mental or physical condition, in the opinion of the 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 (unless PI judges such enrollment would not interfere with endpoints of this study)