Ex-Vivo Expanded and Activated Donor NK Cells and Hu14.18-IL2 in Treating Patients with Relapsed or Refractory Neuroblastoma

Status: Active

Description

This phase I trial studies the side effects of ex-vivo expanded and activated donor NK cells and hu14.18-IL2 in treating patients with neuroblastoma that has come back or does not respond to treatment. Expanded and activated donor NK cells may be able to kill the cancer cells better. Hu14.18-IL2 binds to NK cells and may be able to activate them, improving their ability to stay alive, multiply, and kill cancer cells. Giving ex-vivo expanded and activated donor NK cells and hu14.18-IL2 may work better in treating patients with neuroblastoma.

Eligibility Criteria

Inclusion Criteria

  • The target tumor is limited to neuroblastoma; patients must have had histologic verification of neuroblastoma and/or demonstration of tumor cells in the bone marrow with increased urinary catecholamines at the time of initial diagnosis
  • Patients must have resistant/refractory or recurrent neuroblastoma
  • Tumor imaging and bone marrow evaluation for histologic analysis of marrow tumor cell quantity must be obtained within 4 weeks (28 days) prior to enrollment onto study; patients must have ONE of the following: * Measurable tumor on magnetic resonance imaging (MRI), computed tomography (CT), or x-ray; measurable is defined as minimum of 20 mm in at least one dimension; for patients who are in first response (i.e., those patients with persistent sites of tumor after frontline therapy but who have never relapsed), a biopsy of a lesion or bone marrow must demonstrate viable neuroblastoma cells or patients must have a lesion positive on iobenguane (MIBG) scan or positron emission tomography (PET) scan; if the lesion was irradiated, the MIBG scan, PET scan or biopsy must be done at least 4 weeks after radiation is completed * MIBG or PET scan with positive uptake at minimum of one site; if lesion was radiated, the scan must be done at least 4 weeks after radiation completed * Bone marrow with tumor cells seen on routine morphology of bilateral aspirate and/or biopsy on at least one bone marrow sample
  • Karnofsky > 50 for patients > 16 years of age and Lansky > 50 for patients =< 16 years of age
  • Patients must have a life expectancy of >= 4 months
  • Patients are eligible > 100 days after autologous stem cell infusion following myeloablative therapy; patients receiving an autologous stem cell infusion to support non-myeloablative therapy (including 131iodine [I]-MIBG given as a single agent) are eligible >= 6 weeks following the stem cell infusion provided they meet the hematologic and other organ function criteria for eligibility; patients who have received an allogeneic stem cell transplant are excluded
  • Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study
  • Chemotherapy must not have been received within 2 weeks of entry onto this study
  • Therapy with biologic agents (non-myelosuppressive) must have been completed >= 7 days prior to study entry; for agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur
  • Radiation therapy (XRT) >= 2 weeks for local palliative XRT; >= 6 months must have elapsed after XRT involving > 50% of the craniospinal axis or > 50% of the pelvis
  • Patients are eligible >= 6 weeks after therapeutic 131I-MIBG or stem cell infusion to support 131I-MIBG, whichever is later
  • Patients, who have previously received in vivo anti-GD2 monoclonal antibodies for biologic therapy or for tumor imaging, are eligible unless they have had an anaphylactic reaction attributed to anti-GD2 therapy
  • Patients must not have received growth factor(s) within 1 week of entry onto this study
  • Patients who require or are likely to require corticosteroid or other immunosuppressive drugs for intercurrent disease (any other significant medical problem related to or independent from the neuroblastoma or its treatment) while tentatively scheduled to receive treatment on this study are ineligible; the only exception is for patients known to require 2 mg/kg or less of hydrocortisone (or an equivalent dose of an alternative corticosteroid) as premedication for blood product transfusion in order to avoid allergic transfusion reactions
  • Absolute neutrophil count >= 750/uL
  • Platelet count >= 50,000/uL
  • Hemoglobin >= 8 g/dL
  • Note: transfusions are permitted to meet these platelet and hemoglobin criteria if the reason for the cytopenias are judged to be secondary to marrow involvement with tumor per principal investigator (PI) or PI designee
  • Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 60 ml/min/1.73 m^2, OR
  • Serum creatinine based on age/gender as follows: * Age 6 months to < 1 year: maximum serum creatinine 0.5 mg/dL for male and 0.5 mg/dL for female * Age 1 to < 2 years: maximum serum creatinine 0.6 mg/dL for male and 0.6 mg/dL for female * Age 2 to < 6 years: maximum serum creatinine 0.8 mg/dL for male and 0.8 mg/dL for female * Age 6 to < 10 years: maximum serum creatinine 1 mg/dL for male and 1 mg/dL for female * Age 10 to < 13 years: maximum serum creatinine 1.2 mg/dL for male and 1.2 mg/dL for female * Age 13 to < 16 years: maximum serum creatinine 1.5 mg/dL for male and 1.4 mg/dL for female * Age >= 16 years: maximum serum creatinine 1.7 mg/dL for male and 1.4 mg/dL for female
  • Total bilirubin =< 1.5 x upper limit of normal (ULN) for age, and
  • Serum glutamic pyruvic transaminase (SGPT) (alanine aminotransferase [ALT]) =< 5 x ULN for age
  • Shortening fraction of >= 27% by echocardiogram OR
  • Ejection fraction of >= 55% by gated radionuclide study
  • No evidence of dyspnea at rest, and
  • Pulse oximetry > 94% on room air
  • If pulmonary function tests (PFTs) are performed, the forced expiratory volume 1 (FEV1)/forced vital capacity (FVC) must be greater than 60%
  • Patients with prior history of ventilator support related to lung injury such as pneumonia, hemorrhagic pneumonitis, capillary leakage are excluded
  • Patients with a history of central nervous system disease must have no clinical or radiological evidence of central nervous system (CNS) disease at the time of protocol enrollment and with CNS toxicity =< grade 2; patients with seizure disorders may be enrolled if seizures are well controlled
  • Availability of 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
  • The patient or legal guardian must provide written informed consent
  • DONOR: Haploidentical by human leukocyte agent (HLA)-typing * 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: Donor preference based on KIR/KIR ligand mismatch * In addition to HLA determination, KIR genotyping will be performed on potential donors; when more than one potential donor is available, preference will be given to the donor who demonstrates 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; 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
  • DONOR: Testing for communicable disease will be performed according to the University of Washington (UW) Hematopoietic Stem Cell Transplant Program guidelines set forth in the most current standard operating policies and procedures (UW Foundation for the Accreditation of Cellular Therapy [FACT]-accredited Clinical Hematopoietic Cell Processing Laboratory [CHCPL] standard of procedure [SOP]) for hematopoietic cell donor evaluation and selection
  • DONOR: The potential donor must be in good general health as determined by the evaluating medical provider using the UW Hematopoietic Stem Cell Transplant Program guidelines set forth in the most current standard operating policies and procedures (UW FACT-accredited CHCPL SOP) for hematopoietic cell donor evaluation and selection

Exclusion Criteria

  • Female patients who are pregnant or of reproductive potential not willing to use an effective method of birth control during study treatment and for at least 12 months thereafter; serum or urine pregnancy test must be performed within 7 days of enrollment
  • Human immunodeficiency virus (HIV) infection
  • Uncontrolled, serious active infection at screening
  • Symptoms of congestive heart failure or uncontrolled cardiac rhythm disturbance
  • Symptomatic pleural effusions or ascites (requiring constant or intermittent drainage)
  • < 2 weeks since major surgery (i.e., laparotomy or thoracotomy)
  • Prior organ allografts
  • Prior allogeneic bone marrow- or stem cell-transplant
  • History of ventilator support related to lung injury (e.g., pneumonia, hemorrhagic pneumonitis, capillary leakage)
  • Any other ongoing serious medical problem unrelated to cancer or its treatment that is not covered by the detailed exclusion criteria and which is expected to interfere with the anti-tumor effect of infused EA-NK cells or the action of hu14.18-IL2 or to significantly increase the severity of the toxicities experienced from this immunotherapy regimen
  • 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 treatment studies that would interfere with the endpoints of this study from screening up to 28 days after the last immunotherapy (EA-NK cells or last infusion of hu14.18-IL2) in the opinion of the PI or PI designee is not permitted
  • History of anaphylaxis attributed to prior anti-GD2 therapy
  • DONOR: A serum or urine pregnancy test for females of reproductive potential must be conducted within 7 days prior to initiation of apheresis

Locations & Contacts

Wisconsin

Madison
University of Wisconsin Hospital and Clinics
Status: Active
Contact: Kenneth Brian De Santes
Phone: 608-263-8563
Email: kbdesantes@pediatrics.wisc.edu

Trial Objectives and Outline

PRIMARY OBJECTIVES:

I. Evaluation of the safety of activated, expanded, haploidentical natural killer (EA-NK) cells administered to lymphodepleted patients with relapsed or refractory neuroblastoma followed by daily infusions of hu14.18-IL2 for 7 days (24 mg/m^2/course intravenously [IV]).

SECONDARY OBJECTIVES:

I. Determination of the immunocytokine serum levels and immunogenicity of hu14.18-IL2 given as daily infusions for 7 consecutive days.

II. Evaluation of immune reconstitution.

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

IV. Evaluation of the longevity of EA-NK cells.

V. Evaluation of activity and phenotype of NK cells.

OUTLINE:

STAGE I: Patients receive cyclophosphamide IV over 2 hours and mesna IV at hours 0, 4, and 8 on day 1. Patients also receive fludarabine phosphate IV over 30 minutes on days 2, 3, 4, 5, and 6. Patients in cohort A receive EA-NK cells IV on day 8 of all courses and hu14.18-IL2 IV over 4 hours daily on days 9-15 of courses 3 and 4. Patients in cohort B receive EA-NK cells IV on day 8 and hu14.18-IL2 IV over 4 hours daily on days 9-15 of all courses. Treatment repeats every 28 days for up to 4 courses in the absence of disease progression or unacceptable toxicity.

STAGE II: Patients achieving complete response, partial response, or stable disease receive hu14.18-IL2 IV over 4 hours daily on days 1-7. Treatment repeats every 28 days for up to 4 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 3, 6, 12, and 24 months.

Trial Phase & Type

Trial Phase

Phase I

Trial Type

Treatment

Lead Organization

Lead Organization
University of Wisconsin Hospital and Clinics

Principal Investigator
Kenneth Brian De Santes

Trial IDs

Primary ID UW16009
Secondary IDs NCI-2017-01267, 2016-1195
Clinicaltrials.gov ID NCT03209869