Immunotherapy of Relapsed Refractory Neuroblastoma With Expanded NK Cells
Biological: NK Cells
|Study Design:||Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||Immunotherapy of Relapsed Refractory Neuroblastoma With Expanded NK Cells, ch14.18 and Lenalidomide|
- Feasibility of expanding NK cells from neuroblastoma patients and cryopreserving, shipping, and infusing multiple doses of NK cells. [ Time Frame: 2.5-3 years ] [ Designated as safety issue: Yes ]The number of viable NK cells finally available for infusion back into the patient: After NK expansion and verification that the resulting NK cells meet purity, gram stain, and endotoxin release criteria, NK cells will be divided into aliquots, each with sufficient cells for one infusion at the dose level the patient was assigned. So the primary measured endpoint is the number of viable NK cells. The derived endpoints, based on the number of viable NK cells in the final product are: (1) whether there are sufficient cells to give at least 1 dose at the lowest dose level (at least 80% of 107 NK cells per kg), (2) whether there are sufficient cells to give at least one dose at the assigned dose level (at least 80% of the planned dose for one dose), (3) the number of doses possible at the assigned dose level, and (4) the number of doses possible at the RP2D, as well as (5) the number aliquots (treatments) available for each patient at the assigned dose.
- Determination of the Maximum tolerated dose (MTD) and recommended Phase II dose (RP2D) of autologous expanded NK cells [ Time Frame: 2.5-3 years ] [ Designated as safety issue: Yes ]The toxicities and adverse events experienced during and following treatment on this protocol: These will be graded and classified according to the CTCAE v4.03.. The derived endpoints are (1) whether or not the patient experienced DLT, and (2) whether or not the patient discontinued treatment for reasons of toxicity or lack of tolerability. The criteria for whether or not a patient experiences a DLT are based on the toxicities and adverse events that occur during the 1st course.
- Toxicity (Per Patient) [ Time Frame: average 3 months ] [ Designated as safety issue: Yes ]Toxicity will be graded using the CTCAE criteria, version 4. The CTCAE provides descriptive terminology and a grading scale for each adverse event listed. A copy of the CTCAE can be downloaded from the CTEP home page (http://ctep.cancer.gov).
- Evaluation of Clinical Response (Per Patient) [ Time Frame: average 120 days ] [ Designated as safety issue: No ]Response will be determined by the evaluation of CT/MRI scans and bone marrow biopsy
|Study Start Date:||March 2016|
|Estimated Study Completion Date:||June 2019|
|Estimated Primary Completion Date:||December 2018 (Final data collection date for primary outcome measure)|
Experimental: NK cells with Ch14.18 & Lenalidomide
Patients in this arm will receive a designated dose of NK cells on Day 5 and 17.5 mg/m2/dose of Ch14.18 on Day 1-4. Patients on Dose Level 4 will also receive 25mg/m2/dose of Lenalidomide during Day -6 through 14 of treatment.
17.5 mg/m2/day of Ch.14.18 will be given for 4 consecutive days (days 1-4 of each course) via intravenous infusion over ten hours.
Other Names:Biological: NK Cells
The designated dose of NK Cells will be infused on Day 5 by IV drip using a Y infusion set with a filter-less chamber. Cells should not be delivered at a rate faster than 10 ml/kg/hr (as determined by drip rate or syringe push rate), and should not take longer than one hour for total infusion time if possible.
Other Name: Natural Killer CellsDrug: Lenalidomide
25 mg/m2/day of Lenalidomide will be given at Dose Level 4, once daily with or without food by mouth on days -6 through +14.
This NANT trial will determine the maximum tolerated dose (MTD) of autologous expanded natural killer (NK) cells when combined with standard dosing of ch14.18 and will assess the feasibility of adding lenalidomide at the recommended Phase II dose of the expanded NK cells with ch14.18, for treatment of children with refractory or recurrent neuroblastoma.
Ch14.18 is a chimeric antibody against GD2, which is expressed on a majority of neuroblastoma cells. It has been shown to increase EFS and OS in patients with high-risk neuroblastoma when given after autologous stem cell transplant in combination with subcutaneous GM-CSF and intravenous IL-2, followed by isotretinoin. Lenalidomide has been studied in children with solid tumors and can safely be given to patients based on 2 prior trials in children. It was also shown to have immunomodulatory effects and is synergistic with ch14.18. Lenalidomide is also an oral agent that can be given in the outpatient setting. Natural killer cells are lymphocytes of the innate immune system that have the ability to recognize and kill malignant cells, including neuroblastoma. Ch14.18 and lenalidomide both exert part of their anti-cancer effect through the activation of natural killer cells. Patients are being given in combination in NANT 2011-04 where the safety and immunomodulatory effect has been established in that study at the dose level proposed in this study. Natural killer cells are dysfunctional and low in number in many cancer patients, and number and function are further suppressed by chemotherapy and radiation. Investigators hypothesize that autologous NK cells can be expanded and activated ex vivo and readministered to restore number and function, and in combination with lenalidomide and ch14.18 will provide an anti-tumor effect in patients with relapsed or refractory neuroblastoma.
Investigators will determine the feasibility of centralized expansion, cryopreservation, and distribution of autologous NK cells. Investigators will then determine the maximum tolerated dose by assessing the toxicities of autologous expanded NK cells given with ch14.18; by assessing the toxicities, cytokinetics and immunomodulatory effects, Investigators will select the recommended Phase II dose of the two-agent combination after dose escalation of the NK cells and then adding lenalidomide to the combination to establish the three-agent combination.
Cytokinetics (persistence of infused NK cells) and immune function studies will be required for all patients entered on this study. In addition to routine assessment of response, quantification of rare tumor cell detection in blood and bone marrow using TLDA will also provide another measure of possible anti-tumor efficacy to support the rationale for the final schedule chosen.
Please refer to this study by its ClinicalTrials.gov identifier: NCT02573896
|Contact: Araz Marachelian, MD, MSemail@example.com|
|United States, California|
|Children's Hospital Los Angeles||Not yet recruiting|
|Los Angeles, California, United States, 90027-0700|
|Contact: Araz Marachelian, MD 323-361-5687 firstname.lastname@example.org|
|Lucille Salter Packer Children's Hospital, Stanford University||Not yet recruiting|
|Palo Alto, California, United States, 94305|
|Contact: Claire - Twist, MD 650-723-5535 email@example.com|
|UCSF Helen Diller Family Comprehensive Cancer Center||Not yet recruiting|
|San Francisco, California, United States, 94115|
|Contact: Katherine Matthay, MD 415-476-3831 matthayK@peds.ucsf.edu|
|United States, Georgia|
|AFLAC Cancer Center and Blood Disorders Service of Children's Healthcare of Atlanta - Egleston Campus||Not yet recruiting|
|Atlanta, Georgia, United States, 30322|
|Contact: Kelly Goldsmith, MD 404-785-0853 firstname.lastname@example.org|
|United States, Illinois|
|Children's Memorial Hospital - Chicago|
|Chicago, Illinois, United States, 60614|
|University of Chicago Comer Children's Hospital||Not yet recruiting|
|Chicago, Illinois, United States, 60637|
|Contact: Susan L. Cohn, MD 773-702-2571 email@example.com|
|United States, Massachusetts|
|Childrens Hospital Boston, Dana-Farber Cancer Institute.||Not yet recruiting|
|Boston, Massachusetts, United States, 02115|
|Contact: Suzanne - Shusterman, MD 617-632-3725 firstname.lastname@example.org|
|United States, Michigan|
|C.S Mott Children's Hospital||Not yet recruiting|
|Ann Arbor, Michigan, United States, 48109|
|Contact: Gregory Yanik, MD 734-936-8785 email@example.com|
|United States, New York|
|Memorial Sloan-Kettering Cancer Center||Not yet recruiting|
|New York, New York, United States, 10065|
|Contact: Stephen Roberts, MD 212-639-4034 firstname.lastname@example.org|
|United States, Ohio|
|Cincinnati Children's Hospital Medical Center||Not yet recruiting|
|Cincinnati, Ohio, United States, 45229-3039|
|Contact: Brian Weiss, MD 513-636-9863 email@example.com|
|United States, Pennsylvania|
|Children's Hospital of Philadelphia||Not yet recruiting|
|Philadelphia, Pennsylvania, United States, 19104-4318|
|Contact: Yael Mosse, MD 215-590-0965 firstname.lastname@example.org|
|United States, Texas|
|Cook Children's Healthcare System||Not yet recruiting|
|Fort Worth, Texas, United States, 76104|
|Contact: Meaghan Granger, MD 682-885-4007 email@example.com|
|MD Anderson Cancer Center||Not yet recruiting|
|Houston, Texas, United States, 77030|
|Contact: Douglas J Harrison, MD 713-563-0893 DJHarrison@mdanderson.org|
|United States, Washington|
|Seattle Children's Hospital||Not yet recruiting|
|Seattle, Washington, United States, 98105|
|Contact: Julie Park, MD 206-987-1987|
|Study Director:||Araz Marachelian, MD, MS||Children's Hospital Los Angeles|
|Study Chair:||Dean Lee, MD, PhD||M.D. Anderson Cancer Center|