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
- 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 patient s 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 donor s 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.
- 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.
- Donors: Stem cell donors whose blood matches one of the recipients on six out of six 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.
- 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.
- 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.
- 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.
Biological: NK Cell Infusion
Biological: Stem Cell Infusion
|Study Design:||Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||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 Hematologic Malignancies|
- Feasibility & amp; Toxicity [ Time Frame: 1 Year ] [ Designated as safety issue: Yes ]
- Efficacy [ Time Frame: 1 Year ] [ Designated as safety issue: No ]
- Incidence of cGVHD in allogeneic PBSCT followed by NK-DLI [ Time Frame: 5 years ] [ Designated as safety issue: Yes ]
- Compare disease-free and overall survival [ Time Frame: 5 years ] [ Designated as safety issue: No ]
- Incidence of viral infection and/or reactivation in allogeneic PBSCT followed by NK-DLI [ Time Frame: 5 years ] [ Designated as safety issue: Yes ]
- Correlate post-transplant cell numbers with select immunologic parameters [ Time Frame: 5 years ] [ Designated as safety issue: No ]
- Impact of KIR expression and KIR reactivity on PFS [ Time Frame: 5 years ] [ Designated as safety issue: No ]
|Study Start Date:||January 2011|
|Estimated Study Completion Date:||October 2018|
|Estimated Primary Completion Date:||December 2016 (Final data collection date for primary outcome measure)|
Pre-BMT Prep Regimen with Stem Cell and NK Cell Infusions coupled with Induction therapy
Biological: NK Cell Infusion
Post-transplant Day 21 (plus-minus 3 days): (1 x 105, 1 x 106 or 1 x 107) NK cells/kg by IV infusion. Followed by a second NK cell infusion of the same cell dose, on Day 49 plus-minus 7 days.Biological: Stem Cell Infusion
Transplant Day 0: & gt; 4 x 106/kg CD34+ stem cells by IV infusion Filgrastim, 5 microgram/kg per day SQ from day 0 until ANC & gt; 5000/microliters x2
- 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. NK mediated killing appears to confer improved outcomes after HSCT for patients with AML and 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 APCs and that the post-transplant period may be favorable for expansion and survival of adoptively transferred NK cells.
-Primary objectives are 1) 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 HLA-matched T cell depleted (TCD) PBSCT in patients with metastatic or recurrent pediatric solid tumors and high risk leukemias who
have unrelated donors or related donors; and 2) to determine if patients treated in this manner experience rapid, sustained donor engraftment and acceptable rates of aGVHD (less than 25% incidence of grade III or grade IV).
-Secondary objectives will assess DFS and OS of patients treated on this study, the incidence of cGVHD and viral infection, and evaluate biologic correlates of NK expansion and NK activity.
-Patients 4-35 years with hematologic malignancies (e.g., ALL, AML, CML, HD, NHL), with a 5/6 or 6/6 HLA-matched related or 9/10 or 10/10 HLA matched unrelated donor.
- 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 myeloblative regimen based on current COG standard-of- care preparative regimen will also be included.
- Donors will undergo 1-3 apheresis sessions for filgrastim mobilized 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 105, 1 x 106 and 1 x 107 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.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01287104
|United States, Maryland|
|National Institutes of Health Clinical Center, 9000 Rockville Pike|
|Bethesda, Maryland, United States, 20892|
|Principal Investigator:||Nirali N Shah, M.D.||National Cancer Institute (NCI)|