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

Acute Myeloid Leukemia Clinical Trial

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT02508038
• Other study ID #: UW13090
• Secondary ID: NCI-2015-0116320
• Status: Recruiting
• Phase: Phase 1
• Start date: February 12, 2016
• Est. completion date: December 2025

Study information

• Verified date: November 2023
• Source: University of Wisconsin, Madison
• Contact: Jenny Weiland
• Phone: 608-890-8070
• Email: PedsHemOncResearch[@]g-groups.wisc.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 22
• Est. completion date: December 2025
• Est. primary completion date: December 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 7 Months to 21 Years

Eligibility

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)

• T. 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)

Exclusion Criteria for Donors:

• Lactating females

• Pregnant females

Related Conditions & MeSH terms

• Acute Lymphoblastic Leukemia
• Acute Myeloid Leukemia
• Ewing Sarcoma
• Hematologic Neoplasms
• Hodgkin Lymphoma
• Leukemia
• Lymphoma
• Myelodysplastic Syndrome
• Myelodysplastic Syndromes
• Myeloproliferative Syndrome
• Neuroblastoma
• Neuroectodermal Tumors
• Neuroectodermal Tumors, Primitive
• Non-Hodgkin Lymphoma
• Osteosarcoma
• Precursor Cell Lymphoblastic Leukemia-Lymphoma
• Primitive Neuroectodermal Tumor
• Rhabdomyosarcoma
• Sarcoma, Ewing
• Syndrome

Intervention

Procedure:
• TCRaß+/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.

Locations

Country	Name	City	State
United States	University of Wisconsin Carbone Cancer Center	Madison	Wisconsin

Sponsors (1)

Lead Sponsor	Collaborator
University of Wisconsin, Madison

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Incidence of acute graft versus host disease (GVHD)		Within 100 days post-transplantation
Primary	Incidence of graft failure		At day 28
Secondary	Immune reconstitution	Immune reconstitution outcomes, as determined by immune cell analysis.	Up to 1 year
Secondary	Performance of the CliniMACS Reagent System utilizing the CliniMACS TCRaß-biotin and CliniMACS CD19 reagent to produce a graft with defined cell content.	The performance of the CliniMACS Reagent System will be evaluated by measuring the number of viable stem cells, TCRaß+ cells, TCR?d+ cells, NK cells and B cells in the hematopoietic stem cell graft.	Day 0

External Links

•   University of Wisconsin Carbone Cancer Center