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

Phase 1

Completed

Conditions: Lymphoma
Leukemia

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

Registration Number: NCT01287104

Lead Sponsor: National Cancer Institute (NCI)

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.

Detailed Description: Background

* Despite progress in pediatric oncology, some patient subsets with hematologic malignancies and pediatric solid tumors continue to experience extremely poor overall survival. Allogeneic Hematopoietic Stem Cell Transplant (HSCT) is effective in some high-risk hematologic malignancies.

* Allogeneic HSCT can be performed safely in these patient populations, but disease recurrence is common and new approaches to enhance the antitumor effect of this therapy are needed. Natural killer (NK) mediated killing appears to confer improved outcomes after HSCT for patients with acute myelogenous leukemia (AML) and acute lymphoblastic leukemia (ALL), and NK cell infusions have induced complete remissions in patients with AML.

* Preclinical data demonstrates that activated NK cells readily kill pediatric solid tumors and leukemias, that large numbers of activated NK cells can be generated ex vivo using artificial antigen-presenting cells (APCs) and that the post-transplant period may be favorable for expansion and survival of adoptively transferred NK cells.

Objectives

* To assess the feasibility and toxicity of infusing escalating doses of donor-derived activated NK cell donor lymphocyte infusions (NK-DLI) on Days 7 plus or minus 2 days and 49 plus or minus 7 days following human leukocyte antigen (HLA)-matched T cell depleted (TCD) peripheral blood stem cell transplant (PBSCT) in patients with metastatic or recurrent pediatric solid tumors and high risk leukemias who have unrelated donors or related donors;

* To determine if patients treated in this manner experience rapid, sustained donor engraftment and acceptable rates of acute graft versus host disease (aGVHD) (less than 25% incidence of grade III or grade IV).

Eligibility

-Patients 4-35 years with hematologic malignancies (e.g., ALL, AML, Chronic Myelogenous Leukemia (CML), Hodgkins Lymphoma (HD), Non-Hodgkins Lymphoma (NHL), with a 5/6 or 6/6 HLA-matched related or 9/10 or 10/10 HLA matched unrelated donor.

Design

* Pre-transplant disease specific immune depleting chemotherapy and the preparative regimen will be the same as that used previously on 02-C-0259 and 01-C-0125, for those patients undergoing reduced intensity transplant.

* For patients with ALL or AML, a myeloablative regimen based on current Children's Oncology Group (COG) standard-of- care preparative regimen will also be included.

* Donors will undergo 1-3 apheresis sessions for filgrastim mobilized peripheral blood stem cells (PBSC). This product will be T cell and NK cell depleted prior to cryopreservation. NK cells selected from the product will be used for ex vivo activation and expansion using KT64.4-BBL artificial antigen presenting cells.

* A phase 1 cell dose escalation of donor derived NK-DLI will be performed using 3 dose levels (1 x 10(5), 1 x 10(6) and 1 x 10(7) NK cells/kg) infused on days 21 more or less 3 post-PBSCT and a second infusion on day 49 more or less 7 post-PBSCT.

* Three patients will be enrolled at each dose level, with the cohort expanded to 6 if dose-limiting toxicity occurs. An expanded group of 12 patients will be treated at the highest dose level tolerated.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 34

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Pre-Bone Marrow Transplant (BMT) Prep Regimen	Stem Cell Infusion	Pre-bone marrow transplant (BMT) Prep Regimen with Stem Cell and natural killer (NK) Cell Infusions coupled with Induction therapy
Pre-Bone Marrow Transplant (BMT) Prep Regimen	Natural Killer (NK) Cell Infusion	Pre-bone marrow transplant (BMT) Prep Regimen with Stem Cell and natural killer (NK) Cell Infusions coupled with Induction therapy

Primary Outcome Measures

Name	Time	Method
Number of Patients Who Received 2 Doses of Natural Killer (NK) Cell Infusions	within 56 days of hematopoietic stem cell transplant (HSCT)	Participants received 2 doses of natural killer infusions 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	100 days	Donor engraftment is defined as \>95% donor lymphoid chimerism (cluster of differentiation 3+T-cells on peripheral blood).

Secondary Outcome Measures

Name	Time	Method
Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0)	Date treatment consent signed to date off study, approximately 65 months and 2 days.	Here is the count of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned
Number of Participants With Mild, Moderate and/or Severe Chronic Graft Versus Host Disease (cGVHD)	up to 3 years post-transplant	Chronic graft versus host disease was assessed by the National Institutes of Health Consensus Criteria. Severity is rated mild moderate or severe on a scale of 0 (no symptoms) -3 (severe symptoms) . Mild is signs and symptoms that do not interfere substantially with function and do not progress once appropriately treated with local therapy. Moderate is signs and symptoms interfere somewhat with function despite appropriate therapy. Severe is signs and symptoms limit function substantially despite appropriate therapy. Low grade is best outcome and high grade is worse outcome.
Disease-free Survival	12 months post-transplant	Disease free survival is defined as the time interval from start of treatment to documented evidence of disease progression. Progression was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Progressive disease is at least a 20% increase in the sum of the longest diameter of all target lesions.
Overall Survival Since Date of Transplant	Up to 36 months post-transplant	Overall survival is defined as the time from date of transplant until date of death or date last known alive.
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	One or more occurrences of a new infection, reactivation or both (e.g. cytomegalovirus + flu, for example). Viral infections increase a patient's risk for a worse outcome and viral reactivation is a marker for T-cell immune dysregulation (i.e., inflammation).
Number of Participants With a Decline in Interleukin 7 (IL-7) and Interleukin 15 (IL-15) Cell Numbers Post-Transplant	3 years	Cytokine levels are checked in a multiplex format according to manufacturer's instructions (Meso Scale Discovery, Gaithersburg, Maryland, United States of America (USA).
Number of Participants With Presence of Killer-cell Immunoglobulin-like Receptors (KIR) Gene Mismatch	Prior to stem cell transplant (Day 0)	Blood samples and/or buccal swabs were obtained and the presence of Killer-cell immunoglobulin-like receptors (KIR) genes was determined by locus specific polymerase chain reaction (PCR) amplification followed by gel electrophoresis. KIR receptors were examined for a mismatch in the human leukocyte antigen (HLA) ligand. A mismatch in the HLA ligand can signal increased anti-tumor activity, enhanced engraftment, and/or less infectious complications for patients.