Immunotherapy of Relapsed Refractory Neuroblastoma With Expanded NK Cells
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|ClinicalTrials.gov Identifier: NCT02573896|
Recruitment Status : Active, not recruiting
First Posted : October 12, 2015
Last Update Posted : July 29, 2022
|Condition or disease||Intervention/treatment||Phase|
|Neuroblastoma||Drug: Dinutuximab 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 dinutuximab and will assess the feasibility of adding lenalidomide at the recommended Phase II dose of the expanded NK cells with dinutuximab, for treatment of children with refractory or recurrent neuroblastoma.
Dinutuximab 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 dinutuximab. 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. Dinutuximab 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 dinutuximab 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 dinutuximab; 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)|
|Actual Enrollment :||13 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 :||January 14, 2019|
|Estimated Primary Completion Date :||September 2022|
|Estimated Study Completion Date :||August 2023|
Experimental: NK cells with Dinutuximab & Lenalidomide
Patients in this arm will receive a designated dose of NK cells on Day 5 and 17.5 mg/m2/dose of dinutuximab 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 dinutuximab 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.
- NK cell production feasibility (lowest dose level) [ Time Frame: After cell expansion, day 4 of protocol therapy ]Proportion of patients whose NK cell product is at least 80% of 10^7 NK cells per kg (sufficient cells to give at least 1 dose at the lowest dose level).
- NK cell production feasibility [ Time Frame: After cell expansion, day 4 of protocol therapy ]Proportion of patients whose NK cell product is at least 80% of the planned dose for one dose
- MTD/RP2D determination [ Time Frame: all toxicities from enrollment through 30 days following end of protocol therapy ]Proportion of patients with any Grade 3 or greater non-hematological toxicities on any course
- Describe Non-Hematological Toxicities [ Time Frame: all toxicities from enrollment through 30 days following end of protocol therapy ]Proportion of patients with any Grade 3 or greater non-hematological toxicities on any course
- Describe Hematological Toxicities [ Time Frame: all toxicities from enrollment through 30 days following end of protocol therapy ]Proportion of patients with any Grade 3 or greater hematological toxicities on any course
- Overall Response [ Time Frame: From Day 1 of protocol therapy through 30 days following end of protocol therapy ]Proportion of patients evaluable for response with a best overall response of CR/CR-MD/PR
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
|United States, California|
|Children's Hospital Los Angeles|
|Los Angeles, California, United States, 90027-0700|
|UCSF Helen Diller Family Comprehensive Cancer Center|
|San Francisco, California, United States, 94115|
|United States, Georgia|
|AFLAC Cancer Center and Blood Disorders Service of Children's Healthcare of Atlanta - Egleston Campus|
|Atlanta, Georgia, United States, 30322|
|United States, Illinois|
|University of Chicago Comer Children's Hospital|
|Chicago, Illinois, United States, 60637|
|United States, Massachusetts|
|Childrens Hospital Boston, Dana-Farber Cancer Institute.|
|Boston, Massachusetts, United States, 02115|
|United States, Michigan|
|C.S Mott Children's Hospital|
|Ann Arbor, Michigan, United States, 48109|
|United States, Ohio|
|Cincinnati Children's Hospital Medical Center|
|Cincinnati, Ohio, United States, 45229-3039|
|Nationwide Children's Hospital|
|Columbus, Ohio, United States, 43205|
|United States, Pennsylvania|
|Children's Hospital of Philadelphia|
|Philadelphia, Pennsylvania, United States, 19104-4318|
|United States, Texas|
|Cook Children's Healthcare System|
|Fort Worth, Texas, United States, 76104|
|United States, Washington|
|Seattle Children's Hospital|
|Seattle, Washington, United States, 98105|
|Study Chair:||Araz Marachelian, MD, MS||Children's Hospital Los Angeles|