Lenalidomide and Dinutuximab With or Without Isotretinoin in Treating Younger Patients With Refractory or Recurrent Neuroblastoma
|ClinicalTrials.gov Identifier: NCT01711554|
Recruitment Status : Suspended (Scheduled interim monitoring)
First Posted : October 22, 2012
Last Update Posted : March 5, 2018
|Condition or disease||Intervention/treatment||Phase|
|Recurrent Neuroblastoma Refractory Neuroblastoma||Biological: Dinutuximab Drug: Isotretinoin Other: Laboratory Biomarker Analysis Drug: Lenalidomide Other: Pharmacological Study||Phase 1|
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I. To determine the maximum tolerated dose (MTD) and/or recommended phase II dose (RP2D) of lenalidomide in combination with fixed doses of dinutuximab (ch14.18) and isotretinoin given to children with refractory or recurrent neuroblastoma.
II. To define the toxicities of lenalidomide administered in combination with ch14.18 and isotretinoin.
III. To describe the differences in immune function modulation between "low" versus "high" dose lenalidomide given with ch14.18 and isotretinoin.
I. To determine the pharmacokinetics of lenalidomide given in this combination regimen.
II. To determine the steady state pharmacokinetics of isotretinoin (day 28, course one) given in combination with lenalidomide.
III. To measure peak and trough levels of ch14.18 in patients receiving lenalidomide and to compare to historical controls of patients receiving ch14.18 in combination with interleukin 2 (IL-2) and granulocyte-macrophage colony-stimulating factor (GM-CSF).
IV. To describe the immunological effects of lenalidomide (T cells, natural killer [NK] cells, monocytes, cytokines, chemokines) within this three drug regimen.
V. To define the incidence and titers of human anti-chimeric antibody (HACA) on this regimen.
VI. To describe, within the context of a phase I study, the response rate to lenalidomide combined with ch14.18 and isotretinoin in patients with recurrent/refractory neuroblastoma.
VII. To summarize, within the context of a phase I study, the event-free survival of patients with recurrent/refractory neuroblastoma or in complete response (CR) after progressing, and who are treated with lenalidomide combined with ch14.18 and isotretinoin.
VIII. To determine, within the context of a phase I study, if killer-cell immunoglobulin-like receptor (KIR) receptor-ligand mismatch or specific Fc gamma receptor (Fc gamma R) alleles are associated with anti-tumor response.
IX. To quantify neuroblastoma tumor cell "load" using a 5-gene TaqMan Low Density Array (TLDA) assay in peripheral blood at study entry, following, with each disease evaluation and at end of therapy and bone marrow at study entry, with each response evaluation when bone marrow is sampled, and at end of therapy.
X. To compare the toxicities of this regimen with the historical toxicity data from the Children's Oncology Group (COG) ANBL0032 and ANBL0931 studies of ch14.18 with IL-2, GM-CSF and isotretinoin.
XI. To describe the tolerability and ability to give full doses of ch14.18 and lenalidomide over extended periods of time, i.e. in courses 6-12.
OUTLINE: This is a dose-escalation study of lenalidomide.
Patients receive lenalidomide orally (PO) once daily (QD) on days 1-21, dinutuximab intravenously (IV) over 10 hours on days 8-11, and isotretinoin PO twice daily (BID) on days 15-28. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up periodically.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||62 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||A Phase I Study of Lenalidomide and Anti-GD2 Mab Ch14.18 +/- Isotretinoin in Patients With Refractory/Recurrent Neuroblastoma|
|Actual Study Start Date :||February 4, 2013|
|Estimated Primary Completion Date :||December 31, 2018|
U.S. FDA Resources
Experimental: Treatment (lenalidomide, dinutuximab, isotretinoin)
Patients receive lenalidomide PO QD on days 1-21, dinutuximab IV over 10 hours on days 8-11, and isotretinoin PO BID on days 15-28. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.
Other Names:Drug: Isotretinoin
Other Names:Other: Laboratory Biomarker Analysis
Correlative studiesDrug: Lenalidomide
Other Names:Other: Pharmacological Study
- Maximum tolerated dose defined as the highest dose level tested at which 0/6 or 1/6 patients experience dose-limiting toxicity (DLT) graded using National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events (CTCAE) criteria, version 4.0 [ Time Frame: Up to 28 days ]All toxicities observed will be summarized in terms of type (organ affected or laboratory determination), severity (by NCI CTCAE), and attribution. Tables will be created to summarize these toxicities and side effects by dose level and by course as well as with Kaplan-Meier plots (i.e. time to first delay or dose reduction) in order to assess the tolerability of the regime over multiple courses.
- Recommended phase II dose [ Time Frame: Up to 28 days ]Determination of the recommended phase II dose of lenalidomide will include consideration of obtaining median peak plasma lenalidomide levels of 5-10 uM (based on laboratory modeling of this regimen in neuroblastoma), acceptable clinical toxicity, and laboratory evidence of an augmentation in immune function.
- Overall survival [ Time Frame: From start of lenalidomide until death for any reason or date that patient was last known to be alive if the patient is still alive, assessed up to 3 years ]Will be summarized with Kaplan-Meier plots.
- Event-free survival [ Time Frame: From the start of treatment with lenalidomide until progression, clinical deterioration mandating that the patient terminate treatment or death due to any cause, whichever occurs first, assessed up to 3 years ]Will be summarized with Kaplan-Meier plots.
- Changes in the levels of T cells, natural killer (NK) cells, monocytes, cytokines, and chemokines [ Time Frame: Baseline to up to 28 days ]These levels and the changes relative to baseline will be summarized by dose level by simple summary statistics: means (possibly after transformation) or medians, ranges, and standard deviations (if numbers and distribution permit). Scatterplots will be used to explore possible associations between the dose and day and toxicity experienced (as reflected in the maximum grade of toxicity experienced, infections or platelet recovery).
- Changes in levels of HACA (or other genotype) and tumor response [ Time Frame: Baseline to up to 3 years ]These levels and the changes relative to baseline will be summarized by dose level by simple summary statistics: means (possibly after transformation) or medians, ranges, and standard deviations (if numbers and distribution permit). Scatterplots will be used to explore possible associations between the dose and day and toxicity experienced (as reflected in the maximum grade of toxicity experienced, infections or platelet recovery).
- Pharmacokinetic determinations of lenalidomide [ Time Frame: Baseline, at 60 and 90 minutes, at 2, 6, 24 hours and days 7 and 22 after last dose of lenalidomide in course 1 ]These will be summarized by dose level with simple summary statistics: means (possibly after transformation) or medians, ranges, and standard deviations (if numbers and distribution permit). Scatterplots will be used to explore possible associations between the dose and estimates of the pharmacokinetic parameters, and between the pharmacokinetic determinations and toxicity experienced (as reflected in the maximum grade of toxicity experienced or in clinical measurements).
- Changes in TaqMan low density array (TLDA) scores [ Time Frame: Baseline to up to 3 years ]Standard descriptive summaries as well as scatterplots will be used. The association between the changes in TLDA scores and overall tumor response will also be summarized graphically and quantitatively. Changes (from baseline) in the TLDA scores over the course of treatment will be plotted and summarized by dose level and course.
- Overall response [ Time Frame: Up to 3 years ]The association between the changes in TLDA scores and overall tumor response will be summarized graphically and quantitatively.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01711554
|United States, California|
|Children's Hospital Los Angeles|
|Los Angeles, California, United States, 90027|
|Lucile Packard Children's Hospital Stanford University|
|Palo Alto, California, United States, 94304|
|UCSF Medical Center-Parnassus|
|San Francisco, California, United States, 94143|
|United States, Colorado|
|Children's Hospital Colorado|
|Aurora, Colorado, United States, 80045|
|United States, Georgia|
|Children's Healthcare of Atlanta - Egleston|
|Atlanta, Georgia, United States, 30322|
|United States, Illinois|
|University of Chicago Comer Children's Hospital|
|Chicago, Illinois, United States, 60637|
|United States, Massachusetts|
|Boston Children's Hospital|
|Boston, Massachusetts, United States, 02115|
|United States, Michigan|
|C S Mott Children's Hospital|
|Ann Arbor, Michigan, United States, 48109|
|United States, North Carolina|
|UNC Lineberger Comprehensive Cancer Center|
|Chapel Hill, North Carolina, United States, 27599|
|United States, Ohio|
|Cincinnati Children's Hospital Medical Center|
|Cincinnati, Ohio, United States, 45229|
|United States, Pennsylvania|
|Children's Hospital of Philadelphia|
|Philadelphia, Pennsylvania, United States, 19104|
|United States, Texas|
|Cook Children's Medical Center|
|Fort Worth, Texas, United States, 76104|
|United States, Washington|
|Seattle Children's Hospital|
|Seattle, Washington, United States, 98105|
|Hospital for Sick Children|
|Toronto, Ontario, Canada, M5G 1X8|
|Principal Investigator:||Araz Marachelian||New Approaches to Neuroblastoma Treatment (NANT)|