Monoclonal Antibody Ch14.18, Sargramostim, Aldesleukin, and Isotretinoin After Autologous Stem Cell Transplant in Treating Patients With Neuroblastoma

A Comprehensive Safety Trial of Chimeric Antibody 14.18 (Ch14.18) With GM-CSF, IL-2 and Isotretinoin in High-Risk Neuroblastoma Patients Following Myeloablative Therapy

This phase III trial is studying the side effects of giving monoclonal antibody Ch14.18 together with sargramostim, aldesleukin, and isotretinoin after autologous stem cell transplant in treating patients with neuroblastoma. Monoclonal antibodies, such as Ch14.18, may find tumor cells and help kill them. Colony-stimulating factors, such as sargramostim, may increase the number of immune cells found in bone marrow or peripheral blood. Aldesleukin may stimulate the white blood cells to kill tumor cells. Isotretinoin may help neuroblastoma cells become more like normal cells, and to grow and spread more slowly. Giving monoclonal antibody Ch14.18 with sargramostim, aldesleukin, and isotretinoin after autologous stem cell transplant may be an effective treatment for neuroblastoma.

Study Overview

• Status: Completed
• Conditions: High Risk Neuroblastoma
• Intervention / Treatment: Other: Diagnostic Laboratory Biomarker Analysis; Biological: Aldesleukin; Drug: Isotretinoin; Biological: Dinutuximab; Biological: Sargramostim

Detailed Description

PRIMARY OBJECTIVES:

I. To comprehensively define the safety profile of ch14.18 when administered with cytokines and isotretinoin in high-risk neuroblastoma patients after autologous stem cell transplant (ASCT).

SECONDARY OBJECTIVES:

I. To further describe and refine the event-free survival (EFS) and overall survival (OS) estimates and baseline characteristics for subjects receiving chl4.18 + cytokines + isotretinoin.

II. To further describe the safety and toxicity of chl4.18 + cytokines + isotretinoin with focus on: a) number of courses delivered per patient; b) number of dose reductions or stoppage (ch14.18 and/or interleukin [IL]-2 [aldesleukin]); and c) number of toxic deaths.

III. To further describe the immune reconstitution of patients following ASCT, based on laboratory data obtained just prior to, during, and after treatment with this regimen.

IV. To obtain correlative laboratory data to evaluate and describe mechanisms related to response, toxicity of immune activation, and allergic phenomena.

OUTLINE:

Patients receive sargramostim subcutaneously (SC) or intravenously (IV) over 2 hours on days 0-13 of courses 1, 3, and 5; monoclonal antibody Ch14.18 IV over 10 hours on days 3-6 of courses 1, 3, and 5 and on days 7-10 of courses 2 and 4; and isotretinoin orally (PO) twice daily (BID) on days 11-24 of course 1, on days 14-27 of courses 2, 4, and 6, and on days 10-23 of courses 3 and 5. Patients also receive aldesleukin IV continuously on days 0-3 and on days 7-10 of courses 2 and 4. Treatment repeats every 24-32 days for 6 courses in the absence of disease progression or unacceptable toxicity.

After completion of study therapy, patients are followed up every 3 months for 1 year, every 6 months for 4 years, and then annually thereafter.

• Study Type: Interventional
• Enrollment (Actual): 105
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • California
    • Loma Linda, California, United States, 92354
      • Loma Linda University Medical Center
    • Los Angeles, California, United States, 90027
      • Children's Hospital Los Angeles
    • Orange, California, United States, 92868
      • Children's Hospital of Orange County
    • Palo Alto, California, United States, 94304
      • Lucile Packard Children's Hospital Stanford University
    • San Diego, California, United States, 92123
      • Rady Children's Hospital - San Diego
    • San Francisco, California, United States, 94115
      • UCSF Medical Center-Mount Zion
    • San Francisco, California, United States, 94143
      • UCSF Medical Center-Parnassus
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Children's Hospital Colorado
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University Hospital/Winship Cancer Institute
    • Atlanta, Georgia, United States, 30322
      • Children's Healthcare of Atlanta - Egleston
  • Illinois
    • Chicago, Illinois, United States, 60637
      • University of Chicago Comprehensive Cancer Center
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University/Melvin and Bren Simon Cancer Center
    • Indianapolis, Indiana, United States, 46202
      • Riley Hospital for Children
  • Louisiana
    • New Orleans, Louisiana, United States, 70118
      • Children's Hospital New Orleans
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Dana-Farber Cancer Institute
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • C S Mott Children's Hospital
  • Minnesota
    • Minneapolis, Minnesota, United States, 55404
      • Children's Hospitals and Clinics of Minnesota - Minneapolis
    • Minneapolis, Minnesota, United States, 55455
      • University of Minnesota/Masonic Cancer Center
  • Missouri
    • Kansas City, Missouri, United States, 64108
      • Children's Mercy Hospitals and Clinics
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine
  • New York
    • New York, New York, United States, 10032
      • NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center
    • Valhalla, New York, United States, 10595
      • New York Medical College
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center
  • Ohio
    • Cincinnati, Ohio, United States, 45229
      • Cincinnati Children's Hospital Medical Center
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Children's Hospital of Philadelphia
  • Tennessee
    • Memphis, Tennessee, United States, 38105
      • Saint Jude Children's Research Hospital
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University/Ingram Cancer Center
  • Texas
    • Dallas, Texas, United States, 75390
      • UT Southwestern/Simmons Cancer Center-Dallas
    • Fort Worth, Texas, United States, 76104
      • Cook Children's Medical Center
    • Houston, Texas, United States, 77030
      • Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center
  • Washington
    • Seattle, Washington, United States, 98105
      • Seattle Children's Hospital
  • Wisconsin
    • Madison, Wisconsin, United States, 53792
      • University of Wisconsin Hospital and Clinics

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: ADULT; OLDER_ADULT; CHILD
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• All patients must be diagnosed with neuroblastoma, and categorized as high-risk at the time of diagnosis
• At pre-ASCT evaluation, patients must meet the International Neuroblastoma Response Criteria (INRC) for complete response (CR), very good partial response (VGPR), or partial response (PR) for primary site, soft tissue metastases and bone metastases; patients who meet those criteria must also meet the protocol specified criteria for bone marrow response as outlined below: =< 10% tumor (of total nucleated cellular content) seen on any specimen from a bilateral bone marrow aspirate/biopsy; patients who have no tumor seen on the prior bone marrow, and then have =< 10% tumor on any of the bilateral marrow aspirate/biopsy specimens done at pre-ASCT and/or pre-enrollment evaluation will also be eligible; (Note that, per INRC, this would have been defined as an "overall" response of progressive disease [PD])

• Prior to enrollment on ANBL0931, a determination of residual disease must be performed (tumor imaging studies including metaiodobenzylguanidine [MIBG] scan, computed tomography [CT] or magnetic resonance imaging [MRI], bone marrow aspiration and biopsy); this disease assessment is required for eligibility, and should be done preferably within 2 weeks but must be done within a maximum of 4 weeks before enrollment

  • Patients with residual disease are eligible; biopsy is not required
  • Patients must not have progressive disease except for protocol specified bone marrow response
• All patients must have completed therapy including intensive induction chemotherapy followed by ASCT and radiotherapy to be eligible; radiotherapy may be waived for patients who either had a small adrenal mass which was completely resected upfront, or who never had an identifiable primary tumor
• No more than 9 months from the date of starting the first induction chemotherapy after diagnosis to the date of ASCT except for the rare occasions as noted below; for tandem ASCT patients, this will be the date of the FIRST stem cell infusion; Exception: for those who are initially diagnosed as non-high risk neuroblastoma, but later converted (and/ or relapsed) to high risk neuroblastoma, the 9 months restriction should start from the date of induction therapy for high risk neuroblastoma (not from the initial induction therapy for non-high risk disease), to the date of ASCT
• Use Karnofsky for patients > 16 years of age and Lansky for patients =< 16 years of age; required patients must have a Lansky or Karnofsky performance scale score of >= 50%
• Patients must have a life expectancy of >= 2 months (8 weeks)
• Total absolute phagocyte count (APC = neutrophils + monocytes) is at least 1000/uL

• Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 mL/min/1.73 m^2 or a serum creatinine based on age/gender as follows:

  • 1 month to < 6 months: 0.4 mg/dL
  • 6 months to < 1 year: 0.5 mg/dL
  • 1 to < 2 years: 0.6 mg/dL
  • 2 to < 6 years: 0.8 mg/dL
  • 6 to < 10 years: 1 mg/dL
  • 10 to < 13 years: 1.2 mg/dL
  • 13 to < 16 years: 1.5 mg/dL (male), 1.4 mg/dL (female)
  • >= 16 years: 1.7 mg/dL (male), 1.4 mg/dL (female)
• Total bilirubin =< 1.5 x upper limit of normal (ULN) for age
• Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) < 5 x upper limit of normal (ULN) for age
• SOS (sinusoidal obstruction syndrome, formerly known as veno-occlusive disease [VOD]), if present, should be stable or improving
• Shortening fraction of >= 27% by echocardiogram, or ejection fraction of >= 55% by radionuclide angiography
• No evidence of dyspnea at rest
• If pulmonary function tests (PFTs) are performed, forced expiratory volume in one second (FEV1)/forced vital capacity (FVC) > 60% by pulmonary function test
• Patients with seizure disorder may be enrolled if on anticonvulsants and well controlled
• Central nervous system (CNS) toxicity < grade 2

Exclusion Criteria:

• Females of childbearing potential must have a negative pregnancy test
• Patients of childbearing potential must agree to use an effective birth control method
• Female patients who are lactating must agree to stop breast-feeding
• Patients must not have received prior anti-GD2 antibody therapy
• Patients must not have received prior vaccine therapy administered as treatment of neuroblastoma not routine infectious disease vaccinations

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

EXPERIMENTAL: Treatment (Ch14.18, GM-CSF, IL-2, isotretinoin); Patients receive sargramostim SC or IV over 2 hours on days 0-13 of courses 1, 3, and 5; monoclonal antibody Ch14.18 IV over 10 hours on days 3-6 of courses 1, 3, and 5 and on days 7-10 of courses 2 and 4; and isotretinoin PO BID on days 11-24 of course 1, on days 14-27 of courses 2, 4, and 6, and on days 10-23 of courses 3 and 5. Patients also receive aldesleukin IV continuously on days 0-3 and on days 7-10 of courses 2 and 4. Treatment repeats every 24-32 days for 6 courses in the absence of disease progression or unacceptable toxicity.

Other: Diagnostic Laboratory Biomarker Analysis; Correlative studies; Biological: Aldesleukin; Given IV; Other Names: Proleukin; 125-L-Serine-2-133-interleukin 2; r-serHuIL-2; Recombinant Human IL-2; Recombinant Human Interleukin-2; Drug: Isotretinoin; Given PO; Other Names: Amnesteem; Cistane; Claravis; Sotret; 13-cis retinoic acid; 13-cis-Retinoate; 13-cis-Retinoic Acid; 13-cis-Vitamin A Acid; 13-cRA; Absorica; Accure; Accutane; cis-Retinoic Acid; Isotretinoinum; Isotrex; Isotrexin; Myorisan; Neovitamin A; Neovitamin A Acid; Oratane; Retinoicacid-13-cis; Ro 4-3780; Ro-4-3780; Roaccutan; Roaccutane; Roacutan; ZENATANE; Biological: Dinutuximab; Given IV; Other Names: Ch14.18; Ch 14.18UTC; MOAB Ch14.18; monoclonal antibody Ch14.18; Unituxin; Biological: Sargramostim; Given IV or SC; Other Names: 23-L-Leucinecolony-Stimulating Factor 2; DRG-0012; Leukine; Prokine; rhu GM-CFS; Sagramostim; Sargramostatin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Patients Who Experienced a Significant (CTC Grade 3-5) Nonhematologic Toxicity of Interest (Pain, Hypotension, Allergic Reactions, Capillary Leak Syndrome, or Fever).	Designed to collect comprehensive safety/toxicity data, as well as additional efficacy data for the immunotherapy. To address the primary objective, descriptive analyses summarizing the number and type of AEs will be performed. The percentage of patients reporting each unacceptable (Grade 3 or higher) CTC toxicity code, tabulated by course, are reported.	Up to 6 courses of therapy

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Event-free Survival (EFS)	Event-free Survival (EFS) for all eligible patients enrolled on the study	From enrollment until the first occurrence of relapse, progressive disease, secondary malignancy, or death, or until last contact if no event occurred, up to 3 years
Overall Survival (OS)	Overall Survival (OS) for all eligible patients enrolled on the study	From enrollment until death, or until last contact with the patient, up to 3 years

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Mehmet F Ozkaynak, Children's Oncology Group

Publications and helpful links

Helpful Links

• Data Available: Select individual patient-level data from this trial can be requested from the NCTN/NCORP Data Archive.

Study record dates

Study Major Dates

• Study Start (ACTUAL): December 21, 2009
• Primary Completion (ACTUAL): December 31, 2013
• Study Completion (ACTUAL): June 30, 2021

Study Registration Dates

• First Submitted: December 31, 2009
• First Submitted That Met QC Criteria: December 31, 2009
• First Posted (ESTIMATE): January 1, 2010

Study Record Updates

• Last Update Posted (ACTUAL): August 17, 2021
• Last Update Submitted That Met QC Criteria: July 30, 2021
• Last Verified: June 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroectodermal Tumors, Primitive; Neuroectodermal Tumors, Primitive, Peripheral; Neuroblastoma; Physiological Effects of Drugs; Anti-Infective Agents; Peripheral Nervous System Agents; Antiviral Agents; Anti-HIV Agents; Anti-Retroviral Agents; Analgesics; Sensory System Agents; Analgesics, Non-Narcotic; Antineoplastic Agents; Immunologic Factors; Dermatologic Agents; Micronutrients; Vitamins; Keratolytic Agents; Aldesleukin; Sargramostim; Dinutuximab; Tretinoin; Interleukin-2; Isotretinoin; Vitamin A
• Other Study ID Numbers: NCI-2011-01997 (REGISTRY: CTRP (Clinical Trial Reporting Program)); U10CA098543 (U.S. NIH Grant/Contract); COG-ANBL0931; ANBL0931 (OTHER: CTEP); CDR0000662673