A Phase I Study of NK Cell Infusion Following Allogeneic Peripheral Blood Stem Cell Transplantation From Related or Matched Unrelated Donors in Pediatric Patients With Solid Tumors and Leukemias

NCT01287104 | Completed Phase 1 Results DMC FDA Drug

• 2 other identifiers: 11007311-C-0073
• Study Type: interventional
• Target: 34
• Locations: 1 country
• Sites: 1

Brief Summary

Background:

• Bone marrow stem cells, which are found in the bone marrow and blood stream, can be collected and transplanted to treat a variety of types of cancer in a process known as hematopoietic stem cell transplantation (HSCT). When stem cells are taken from one person, most commonly a sibling or a family member, and then given to another person, this is referred to as allogeneic HSCT. Allogeneic HSCT has proven to be an especially effective treatment for patients with some types of cancers of the blood (leukemia) and certain solid tumors. The transplanted stem cells travel to the patient's bone marrow and begin producing normal blood cells, and also attack patients cancer cells.
• Because allogenic HSCT does not always prevent the cancer from returning, researchers are interested in determining whether another type of immune cell taken from the stem cell donors white blood cells, called a "natural killer" (NK) cell, can be given in addition to the HSCT to help fight the tumor. In the laboratory, NK cells have been shown to kill tumor cells, but it is not yet know if this will occur when given to patients after HSCT. Objectives:
• To determine the safety, effectiveness, and immune system response of giving NK white blood cells to individuals who have received allogeneic HSCT.
• To identify possible side effects from the treatment. Eligibility:
• Donors: Stem cell donors whose blood matches one of the recipients on six out of six human leukocyte antigen (HLA) (blood immune marker) types. The donor may not be the identical twin of a recipient.
• Recipients: Individuals between 4 and 35 years of age who have been diagnosed with pediatric solid tumors that have not responded to standard treatment, or individuals between 4 and 18 years of age who have been diagnosed with leukemia that has not responded to standard treatment.
• Other eligibility requirements which include a physical exam and blood laboratory evaluation are included to make sure it is safe for both the donor to donate and the recipient to undergo the transplant procedure. Design:
• Donors and recipients will be screened with a full medical history and physical examination, and will provide blood and urine samples; recipients will have tumor imaging studies and other tests as required by the researchers.
• Donors:
• Participants will receive filgrastim injections (to stimulate the bone marrow) for 1 week to make stem cells travel from bone marrow to blood.
• Participants will provide stem cells and NK cells through apheresis.
• Recipients:
• Participants will have three cycles of chemotherapy to treat the underlying cancer and weaken the immune system so that it will accept the donor cells.
• Participants will then receive preparative chemotherapy for the transplant and two days after the last dose of chemotherapy, participants will have allogenic HSCT using the donated stem cells.
• Participants will receive an infusion of NK cells on days 7 and 35 after the HSCT. - Participants will remain in the hospital for monitoring after the HSCT and NK cell treatments, and will be followed closely as outpatients for the first 6 months after the transplant and then less frequently for at least 5 years.

Conditions

Leukemia; Lymphoma

Keywords

Leukemia/Lymphoma; Hematologic Malignancies; Leukemia; Lymphoma; Ewing Sarcoma; Rhabdomyosarcoma; Neuroblastoma; Healthy Donor

Outcome Measures

Primary Outcomes (2)

• Number of Patients Who Received 2 Doses of Natural Killer (NK) Cell Infusions

  Participants received 2 doses of natural killer infusions within 56 days of hematopoietic stem cell transplant (HSCT).

  within 56 days of hematopoietic stem cell transplant (HSCT)

• Number of Patients Who Received the Highest Dose Level of NK Cells (1x10^6 NK Cells/kg for Patients With Related Donors and 1 x10^5 NK Cells/kg for Patients With Unrelated Donors) With Sustained Donor Lymphoid Engraftment

  Donor engraftment is defined as \>95% donor lymphoid chimerism (cluster of differentiation 3+T-cells on peripheral blood).

  100 days

Secondary Outcomes (7)

• Number of Participants With Mild, Moderate and/or Severe Chronic Graft Versus Host Disease (cGVHD)

  up to 3 years post-transplant

• Disease-free Survival

  12 months post-transplant

• Overall Survival Since Date of Transplant

  Up to 36 months post-transplant

• Number of Occurrences of Viral Infection and/or Reactivation in Allogeneic Peripheral Blood Stem Cell Transplant (PBSCT) Followed by Natural Killer-donor Lymphocyte Infusion (NK-DLI)

  Within 1-year post-transplant

• Number of Participants With a Decline in Interleukin 7 (IL-7) and Interleukin 15 (IL-15) Cell Numbers Post-Transplant

  3 years

Study Arms (1)

Pre-Bone Marrow Transplant (BMT) Prep Regimen

EXPERIMENTAL

Pre-bone marrow transplant (BMT) Prep Regimen with Stem Cell and natural killer (NK) Cell Infusions coupled with Induction therapy

Biological: Natural Killer (NK) Cell Infusion; Biological: Stem Cell Infusion

Interventions

Natural Killer (NK) Cell Infusion BIOLOGICAL

Post-transplant Day 21 (plus-minus 3 days): (1 x 10(5), 1 x 10(6) or 1 x 10(7) natural killer (NK) cells/kg by intravenous (IV) infusion. Followed by a second NK cell infusion of the same cell dose, on Day 49 plus-minus 7 days.

Pre-Bone Marrow Transplant (BMT) Prep Regimen

Stem Cell Infusion BIOLOGICAL

Transplant Day 0: \>4 x 10(6)/kg cluster of differentiation 34 (CD34)+ stem cells by IV infusion Filgrastim, 5 microgram/kg per day subcutaneous (SQ) from day 0 until absolute neutrophil count (ANC) \>5000/microliters x2

Pre-Bone Marrow Transplant (BMT) Prep Regimen

Eligibility Criteria

• Age: 4 Years - 35 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Hematologic Malignancies Diagnoses:
• Acute lymphoblastic leukemia (ALL) with a history of bone marrow relapse in clinical remission (CR) #2 or greater, or in CR#1 if prior induction failure; or with an M1 marrow if unable to achieve CR.
• Philadelphia chromosome positive ALL patients who;
• Have progressed through or relapsed following tyrosine kinase inhibitor (TKI) therapy or conventional myeloablative therapy
• Are ineligible to receive tyrosine kinase inhibitor (TKI) therapy AND myeloablative hematopoietic stem cell transplant (HSCT)
• Acute Myelogenous Leukemia (AML) with a history of bone marrow relapse in remission CR #2 or greater; or with an M1 marrow if unable to achieve CR; or in CR#1 if prior induction failure; or any of the following High-Risk categories:
• Fms-related tyrosine kinase 3 (FLT3)/internal tandem duplication (ITD)+ with high allelic ratio \> 0.4 (high allelic ration (HR) FLT3/ITD+) regardless of low risk features.
• Presence of monosomy 7, monosomy 5, or del5q, without inv(16)/t(16;16) or t(8;21) cytogenetics or NPM or CEBP(alpha) mutations.
• Acute myelogenous leukemia (AML) without inv(16)/t(16;16), t(8;21), nucleophosmin (NPM), CCAAT/enhancer binding protein (CEPB)(alpha) mutations, monosomy 7, monosomy 5, del5q, or HR FLT3/ITD+, but with evidence of residual AML (greater than or equal to 0.1%) at end of Induction I.
• Hodgkin's and Non-Hodgkin's Lymphoma with refractory disease or relapse after at least one salvage regimen, or after autologous stem cell transplant
• Juvenile Myelocytic Leukemia (JMML) with less than 10% blasts in marrow and blood, who are not eligible for effective standard therapies.
• Age: 4 to less than or equal to 35 years old at the time of enrollment for solid tumor patients and 4 to less than or equal to 35 years old for hematologic malignancies.
• EXCEPTIONS:
• There is no time restriction in regard to prior intrathecal chemotherapy provided there is complete recovery from any acute toxic effects; or
• Subjects receiving standard acute lymphoblastic leukemia (ALL) maintenance chemotherapy will not require washout.

You may not qualify if:

• Uncontrolled infection.
• Active central nervous system (CNS) malignancy as defined by:
• Solid Tumors: History of untreated CNS tumor involvement. Extradural masses which have not invaded the brain parenchyma or parameningeal tumors without evidence for leptomeningeal spread will not render the patient ineligible. Patients with previous CNS tumor involvement are eligible IF the CNS tumor(s) has been treated and has been stable or resolving for at least 6 months; and if the patient does not currently require steroids.
• Lymphoma: tumor mass on computed tomography (CT) scan or leptomeningeal disease
• Leukemia: CNS 2 or CNS 3 classification.
• Lactating or pregnant females (due to risk to fetus or newborn).
• Human immunodeficiency virus (HIV) positive (due to unacceptable risk associated with severe immune suppression).
• Hepatitis B surface antigen (HBsAg) positive or hepatitis C antibody positive with elevated liver transaminases. All patients with chronic active hepatitis (including those on treatment) are ineligible.
• Patients who require systemic corticosteroid or other immunosuppressive therapy. Immunosuppressive therapy must be stopped at least 28 days prior to protocol cycle 1, day 1 (C1D1). Topical agents and/or inhaled corticosteroids are permitted.
• High risk of inability to comply with transplant protocol, or inability to give appropriate informed consent in the estimation of the principal investigator (PI), social work, psychiatry, or the stem cell transplant team.
• Fanconi Anemia
• Clinically significant systemic illness (e.g. serious active infections or significant cardiac, pulmonary, hepatic or other organ dysfunction), that in the judgment of the PI would likely compromise the patients ability to tolerate protocol therapy or significantly increase the risk of complications.
• Weight greater than or equal to 15 kilograms and for unrelated donors, greater than or equal to 18 years.
• HLA-matched related or unrelated allogeneic donors. Genotypically identical twins may serve as stem cell donors. Related donors must be 5 or 6/6 antigen matched. Unrelated donors must be 8/8 allele matched.
• For donors less than 18 years of age, he/she must be the oldest suitable donor, their legal guardian must give informed consent, the donor must give verbal assent, and he/she must be cleared by social work and a mental health specialist to participate.

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (1)

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

Related Publications (1)

• Shah NN, Baird K, Delbrook CP, Fleisher TA, Kohler ME, Rampertaap S, Lemberg K, Hurley CK, Kleiner DE, Merchant MS, Pittaluga S, Sabatino M, Stroncek DF, Wayne AS, Zhang H, Fry TJ, Mackall CL. Acute GVHD in patients receiving IL-15/4-1BBL activated NK cells following T-cell-depleted stem cell transplantation. Blood. 2015 Jan 29;125(5):784-92. doi: 10.1182/blood-2014-07-592881. Epub 2014 Dec 1.

  PMID: 25452614 RESULT

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Leukemia; Lymphoma; Hematologic Neoplasms; Sarcoma, Ewing; Rhabdomyosarcoma; Neuroblastoma

Condition Hierarchy (Ancestors)

Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Neoplasms by Site; Osteosarcoma; Neoplasms, Bone Tissue; Neoplasms, Connective Tissue; Neoplasms, Connective and Soft Tissue; Sarcoma; Myosarcoma; Neoplasms, Muscle Tissue; Neuroectodermal Tumors, Primitive, Peripheral; Neuroectodermal Tumors, Primitive; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue

Results Point of Contact

• Title: Dr. Nirali N. Shah
• Organization: National Cancer Institute

shahnn@nih.gov

301-451-0390

Study Officials

• Nirali N Shah, M.D.

  National Cancer Institute (NCI)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: NIH
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: January 29, 2011
• First Posted: February 1, 2011
• Study Start: January 29, 2011
• Primary Completion: June 28, 2018
• Study Completion: June 28, 2018
• Last Updated: August 22, 2019
• Results First Posted: August 22, 2019

Record last verified: 2019-08

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)