Lenalidomide and Monoclonal Antibody With or Without Isotretinoin in Treating Younger Patients With Refractory or Recurrent Neuroblastoma
This phase I trial studies the side effects and best dose of lenalidomide when given together with monoclonal antibody with or without isotretinoin in treating younger patients with refractory or recurrent neuroblastoma. Drugs used in chemotherapy, such as lenalidomide and isotretinoin, work in different wants to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as monoclonal antibody Ch14.18, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Giving more than one drug (combination chemotherapy) together with monoclonal antibody therapy may kill more tumor cells
Localized Unresectable Neuroblastoma
Stage 4S Neuroblastoma
Biological: monoclonal antibody Ch14.18
Other: pharmacological study
Other: laboratory biomarker analysis
|Study Design:||Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||A Phase I Study of Lenalidomide and Anti-GD2 Mab Ch14.18 +/- Isotretinoin in Patients With Refractory/Recurrent Neuroblastoma.|
- MTD defined as the highest dose level tested at which 0/6 or 1/6 patients experience dose-limiting toxicity (DLT) graded using the National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events (CTCAE) criteria, version 4.0 [ Time Frame: 28 days ] [ Designated as safety issue: Yes ]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 theses toxicities and side effects by dose level and by course.
- Recommended phase II dose [ Time Frame: 28 days ] [ Designated as safety issue: No ]
- 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 ] [ Designated as safety issue: No ]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, assessed up to 3 years ] [ Designated as safety issue: No ]Will be summarized with Kaplan-Meier plots.
- Changes in the levels of T cells, NK cells, monocytes, cytokines, and chemokines [ Time Frame: Baseline and up to 28 days ] [ Designated as safety issue: No ]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). Scatter plots 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 and up to 3 years ] [ Designated as safety issue: No ]
- Pharmacokinetic determinations of lenalidomide [ Time Frame: Up to end of therapy ] [ Designated as safety issue: No ]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 TLDA scores [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]Standard descriptive summaries as well as scatterplots will be used.
- Overall response [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]
|Study Start Date:||February 2013|
|Estimated Primary Completion Date:||July 2015 (Final data collection date for primary outcome measure)|
Experimental: Treatment (lenalidomide, monoclonal antibody, isotretinoin)
Patients receive lenalidomide PO QD on days 1-21, monoclonal antibody Ch14.18 IV over 10 hours on days 8-11, and isotretinoin PO BID on days 15-28 of dose levels 2-5. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.
Other Names:Biological: monoclonal antibody Ch14.18
Other Names:Drug: isotretinoin
Other Names:Other: pharmacological study
Other Name: pharmacological studiesOther: laboratory biomarker analysis
I. To determine the maximum tolerated dose (MTD) and/or recommended phase II dose (RP2D) of lenalidomide in combination with fixed doses of ch14.18 (monoclonal antibody Ch14.18) given intravenously (IV) for four days (days 8-11) and isotretinoin given twice each day orally for 14 days (days 15-28) and repeated every 28 days 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 sargramostim (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 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.
IX. 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.
OUTLINE: This is a dose-escalation study of lenalidomide.
Patients receive lenalidomide orally (PO) once daily (QD) on days 1-21, monoclonal antibody Ch14.18 IV over 10 hours on days 8-11, and isotretinoin PO twice daily (BID) on days 15-28 of dose levels 2-5. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up periodically.
|United States, California|
|Children's Hospital Los Angeles||Recruiting|
|Los Angeles, California, United States, 90027|
|Contact: Araz Marachelian 323-361-8573 firstname.lastname@example.org|
|Principal Investigator: Araz Marachelian|
|Lucile Packard Children's Hospital Stanford University||Recruiting|
|Palo Alto, California, United States, 94304|
|Contact: Clare J. Twist 650-723-5535 email@example.com|
|Principal Investigator: Clare J. Twist|
|University of California San Francisco Medical Center-Parnassus||Recruiting|
|San Francisco, California, United States, 94143|
|Contact: Katherine K. Matthay 415-476-0603 firstname.lastname@example.org|
|Principal Investigator: Katherine K. Matthay|
|United States, Georgia|
|Children's Healthcare of Atlanta - Egleston||Recruiting|
|Atlanta, Georgia, United States, 30322|
|Contact: Howard M. Katzenstein 404-785-0853 email@example.com|
|Principal Investigator: Howard M. Katzenstein|
|United States, Illinois|
|University of Chicago Comprehensive Cancer Center||Recruiting|
|Chicago, Illinois, United States, 60637-1470|
|Contact: Susan L. Cohn 773-702-2571 firstname.lastname@example.org|
|Principal Investigator: Susan L. Cohn|
|United States, Massachusetts|
|Dana-Farber Cancer Institute||Recruiting|
|Boston, Massachusetts, United States, 02115|
|Contact: Suzanne Shusterman 617-632-4901 email@example.com|
|Principal Investigator: Suzanne Shusterman|
|United States, Michigan|
|C S Mott Children's Hospital||Recruiting|
|Ann Arbor, Michigan, United States, 48109|
|Contact: Gregory A. Yanik 734-746-3243 firstname.lastname@example.org|
|Principal Investigator: Gregory A. Yanik|
|United States, North Carolina|
|Duke University Medical Center||Recruiting|
|Durham, North Carolina, United States, 27710|
|Contact: Susan G. Kreissman 919-684-3401 email@example.com|
|Principal Investigator: Susan G. Kreissman|
|United States, Ohio|
|Cincinnati Children's Hospital Medical Center||Recruiting|
|Cincinnati, Ohio, United States, 45229|
|Contact: Brian D. Weiss 513-636-9863 firstname.lastname@example.org|
|Principal Investigator: Brian D. Weiss|
|United States, Pennsylvania|
|Children's Hospital of Philadelphia||Recruiting|
|Philadelphia, Pennsylvania, United States, 19104|
|Contact: Yael P. Mosse 215-590-0965 email@example.com|
|Principal Investigator: Yael P. Mosse|
|United States, Texas|
|Cook Children's Medical Center||Recruiting|
|Fort Worth, Texas, United States, 76104|
|Contact: Mary Meaghan P. Granger 682-885-4007 firstname.lastname@example.org|
|Principal Investigator: Mary Meaghan P. Granger|
|Texas Children's Hospital||Recruiting|
|Houston, Texas, United States, 77030|
|Contact: Peter E. Zage 832-824-4615 email@example.com|
|Principal Investigator: Peter E. Zage|
|United States, Washington|
|Seattle Children's Hospital||Recruiting|
|Seattle, Washington, United States, 98105|
|Contact: Julie R. Park 206-987-1947 firstname.lastname@example.org|
|Principal Investigator: Julie R. Park|
|Hospital for Sick Children||Recruiting|
|Toronto, Ontario, Canada, M5G 1X8|
|Contact: Sylvain Baruchel 416-813-7795 email@example.com|
|Principal Investigator: Sylvain Baruchel|
|Montreal, Quebec, Canada, H3T 1C5|
|Contact: Pierre Teira 514-345-4931 firstname.lastname@example.org|
|Principal Investigator: Pierre Teira|
|Principal Investigator:||Araz Marachelian||New Approaches to Neuroblastoma Therapy Consortium|