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

National Cancer Institute (NCI)

Status and phase: Completed; Phase 3

Conditions: High Risk Neuroblastoma

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

Study type: Interventional

Funder types: NIH

Identifiers

NCT01041638

ANBL0931

U10CA098543 (U.S. NIH Grant/Contract)

COG-ANBL0931

CDR0000662673

NCI-2011-01997 (Registry Identifier)

Details and patient eligibility

About

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.

Full 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.

Enrollment: 105 patients

Sex: All

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: N/A

Interventional model: Single Group Assignment

Masking: None (Open label)

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105 participants in 1 patient group

Treatment (Ch14.18, GM-CSF, IL-2, isotretinoin)

Experimental group

Description:

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.

Treatment:

Other: Diagnostic Laboratory Biomarker Analysis

Biological: Aldesleukin

Biological: Sargramostim

Biological: Dinutuximab

Drug: Isotretinoin