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

• ClinicalTrials.gov Identifier: NCT01041638
• Recruitment Status: Completed
• First Posted: January 1, 2010
• Results First Posted: February 19, 2015
• Last Update Posted: August 17, 2021
• Sponsor: National Cancer Institute (NCI)
• Information provided by (Responsible Party): National Cancer Institute (NCI)

Tracking Information

• First Submitted Date: December 31, 2009
• First Posted Date: January 1, 2010
• Results First Submitted Date: February 3, 2015
• Results First Posted Date: February 19, 2015
• Last Update Posted Date: August 17, 2021
• Actual Study Start Date: December 21, 2009
• Actual Primary Completion Date: December 31, 2013 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: July 30, 2021)

Percentage of Patients Who Experienced a Significant (CTC Grade 3-5) Nonhematologic Toxicity of Interest (Pain, Hypotension, Allergic Reactions, Capillary Leak Syndrome, or Fever). [ Time Frame: Up to 6 courses of therapy ]

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.

• Original Primary Outcome Measures (submitted: December 31, 2009): Safety profile

Current Secondary Outcome Measures (submitted: February 11, 2019)

• Event-free Survival (EFS) [ Time Frame: 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 ]
  Event-free Survival (EFS) for all eligible patients enrolled on the study
• Overall Survival (OS) [ Time Frame: From enrollment until death, or until last contact with the patient, up to 3 years ]
  Overall Survival (OS) for all eligible patients enrolled on the study

Original Secondary Outcome Measures (submitted: December 31, 2009)

• Event-free survival
• Overall survival
• Immune reconstitution as assessed by T-cell recovery, NK-cell recovery, B-cell recovery, absolute neutrophil counts, monocyte counts, and absolute lymphocyte counts
• In vivo immune activation by cytokine components as assessed by sIL2Rα serum levels and ch14.18 serum levels
• Potential for allergic reactions as assessed by C3, C4, CH50, and c1q binding, tryptase, histamine levels, and total IgE
• Genetic factors as assessed by FcR genotyping

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Monoclonal Antibody Ch14.18, Sargramostim, Aldesleukin, and Isotretinoin After Autologous Stem Cell Transplant in Treating Patients With Neuroblastoma
• Official Title: 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
• Brief Summary: 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.

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
• Study Phase: Phase 3
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: High Risk Neuroblastoma

Intervention

• Biological: Aldesleukin
  Given IV
  Other Names:

  • 125-L-Serine-2-133-interleukin 2
  • Proleukin
  • r-serHuIL-2
  • Recombinant Human IL-2
  • Recombinant Human Interleukin-2
• Other: Diagnostic Laboratory Biomarker Analysis
  Correlative studies
• Biological: Dinutuximab
  Given IV
  Other Names:

  • Ch 14.18UTC
  • Ch14.18
  • MOAB Ch14.18
  • monoclonal antibody Ch14.18
  • Unituxin
• Drug: Isotretinoin
  Given PO
  Other Names:

  • 13-cis retinoic acid
  • 13-cis-Retinoate
  • 13-cis-Retinoic Acid
  • 13-cis-Vitamin A Acid
  • 13-cRA
  • Absorica
  • Accure
  • Accutane
  • Amnesteem
  • cis-Retinoic Acid
  • Cistane
  • Claravis
  • Isotretinoinum
  • Isotrex
  • Isotrexin
  • Myorisan
  • Neovitamin A
  • Neovitamin A Acid
  • Oratane
  • Retinoicacid-13-cis
  • Ro 4-3780
  • Ro-4-3780
  • Roaccutan
  • Roaccutane
  • Roacutan
  • Sotret
  • ZENATANE
• Biological: Sargramostim
  Given IV or SC
  Other Names:

  • 23-L-Leucinecolony-Stimulating Factor 2
  • DRG-0012
  • Leukine
  • Prokine
  • rhu GM-CFS
  • Sagramostim
  • Sargramostatin

Study Arms

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.

Interventions:

• Biological: Aldesleukin
• Other: Diagnostic Laboratory Biomarker Analysis
• Biological: Dinutuximab
• Drug: Isotretinoin
• Biological: Sargramostim

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: December 31, 2009): 105
• Original Estimated Enrollment: Same as current
• Actual Study Completion Date: June 30, 2021
• Actual Primary Completion Date: December 31, 2013 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: Child, Adult, Older Adult
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT01041638
• Other Study ID Numbers: NCI-2011-01997; NCI-2011-01997 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); COG-ANBL0931; ANBL0931; CDR0000662673; ANBL0931 ( Other Identifier: Children's Oncology Group ); ANBL0931 ( Other Identifier: CTEP ); U10CA098543 ( U.S. NIH Grant/Contract )
• Has Data Monitoring Committee: Not Provided
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: National Cancer Institute (NCI)
• Original Responsible Party: Gregory H. Reaman, Children's Oncology Group - Group Chair Office
• Current Study Sponsor: National Cancer Institute (NCI)
• Original Study Sponsor: Children's Oncology Group
• Collaborators: Not Provided

Investigators

• Principal Investigator: Mehmet F Ozkaynak; Children's Oncology Group

• PRS Account: National Cancer Institute (NCI)
• Verification Date: June 2021