Immunotherapy of Relapsed Refractory Neuroblastoma With Expanded NK Cells
|The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.|
|ClinicalTrials.gov Identifier: NCT02573896|
Recruitment Status : Recruiting
First Posted : October 12, 2015
Last Update Posted : May 23, 2019
|Condition or disease||Intervention/treatment||Phase|
|Neuroblastoma||Drug: Ch14.18 Biological: NK Cells Drug: Lenalidomide||Phase 1|
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 were given these in combination in the NANT 2011-04 study where the safety and immunomodulatory effect were established. The dose level proposed in this study is based off of these data. 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.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||24 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||A Phase I Dose Escalation Study of Autologous Expanded Natural Killer (NK) Cells for Immunotherapy of Relapsed Refractory Neuroblastoma With Dinutuximab +/- Lenalidomide|
|Actual Study Start Date :||November 16, 2018|
|Estimated Primary Completion Date :||January 2021|
|Estimated Study Completion Date :||August 2022|
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.
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 Cells
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.
- Feasibility of expanding NK cells from neuroblastoma patients and cryopreserving, shipping, and infusing multiple doses of NK cells. [ Time Frame: 2.5-3 years ]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 10^7 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 of 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 ]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 ]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 ]Response will be determined by the evaluation of CT/MRI scans and bone marrow biopsy
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02573896
|Contact: Araz Marachelian, MD, MSfirstname.lastname@example.org|
|United States, California|
|Children's Hospital Los Angeles||Recruiting|
|Los Angeles, California, United States, 90027-0700|
|Contact: Araz Marachelian, MD 323-361-5687 email@example.com|
|UCSF Helen Diller Family Comprehensive Cancer Center||Recruiting|
|San Francisco, California, United States, 94115|
|Contact: Kieuhoa Vo, MD|
|United States, Georgia|
|AFLAC Cancer Center and Blood Disorders Service of Children's Healthcare of Atlanta - Egleston Campus||Recruiting|
|Atlanta, Georgia, United States, 30322|
|Contact: Kelly Goldsmith, MD 404-785-0853 firstname.lastname@example.org|
|United States, Illinois|
|University of Chicago Comer Children's Hospital||Recruiting|
|Chicago, Illinois, United States, 60637|
|Contact: Ami Desai, MD 773-843-3943 email@example.com|
|United States, Massachusetts|
|Childrens Hospital Boston, Dana-Farber Cancer Institute.||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||Recruiting|
|Ann Arbor, Michigan, United States, 48109|
|Contact: Rajen Mody, MD email@example.com|
|United States, North Carolina|
|University of North Carolina, Chapel Hill||Recruiting|
|Chapel Hill, North Carolina, United States, 27599|
|Contact: Patrick Thompson, MD firstname.lastname@example.org|
|United States, Ohio|
|Cincinnati Children's Hospital Medical Center||Recruiting|
|Cincinnati, Ohio, United States, 45229-3039|
|Contact: Brian Weiss, MD 513-636-9863 email@example.com|
|Nationwide Children's Hospital||Recruiting|
|Columbus, Ohio, United States, 43205|
|Contact: Keri Streby, MD|
|United States, Pennsylvania|
|Children's Hospital of Philadelphia||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||Recruiting|
|Fort Worth, Texas, United States, 76104|
|Contact: Meaghan Granger, MD 682-885-4007 email@example.com|
|United States, Washington|
|Seattle Children's Hospital||Recruiting|
|Seattle, Washington, United States, 98105|
|Contact: Navin Pinto, MD 206-987-5783|
|Study Chair:||Araz Marachelian, MD, MS||Children's Hospital Los Angeles|