Safety Study of Dinutuximab Combined With Immunotherapy to Treat Neuroblastoma

Phase II Single Arm Study to Assess Dinutuximab (Ch 14.18) Combined With the Cytokines Granulocyte-macrophage Colony Stimulating Factor (GM-CSF) and IL-2 in Patients With High-risk Neuroblastoma Not Eligible to Other Immunotherapy Trials

The purpose of this study is to evaluate safety of the triple COG schema with the monoclonal antibody Dinutuximab + cytokines (GM-CSF and IL2) and isotretinoin (13-cis-retinoic acid, or RA) in patients with high-risk neuroblastoma.

Study Overview

• Status: Completed
• Conditions: Effects of Immunotherapy; Neuroblastoma; Neoplasm, Residual
• Intervention / Treatment: Drug: Dinutuximab. Immunotherapy

Detailed Description

Assess toxicity and safety of subcutaneous GM-CSF and iv IL-2 in enhancing Dinutuximab-mediated ablation of Bone Marrow (BM) disease in patients with high-risk neuroblastoma who have achieved a Complete Response or Very Good Partial Response of the macroscopic disease in the investigators institution.

Assess response of minimal residual disease (MRD) of the anti-GD2 monoclonal antibody Dinutuximab combined with granulocyte-macrophage colony stimulating factor (GM-CSF) and IL-2 in patients with high-risk neuroblastoma (NB). More precisely, to apply real-time quantitative RT-PCR to test the hypothesis that minimal residual disease content of BM after the first treatments with dinutuximab/GM-CSF has significant prognostic impact on relapse-free survival.

• Study Type: Interventional
• Enrollment (Actual): 24
• Phase: Phase 2

Contacts and Locations

Study Locations

• Spain
  • Barcelona, Spain
    • Hospital Sant Joan de Deu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Diagnosis of neuroblastoma as defined by international criteria by histopathology or bone marrow metastases. Patients age must be less than 18 years at the time of initial diagnosis.

2. Neuroblastoma, as defined by risk-related treatment guidelines and the International Neuroblastoma Staging System, stage 4 with (any age) or without (>18 months) MYCN-amplification, or MYCN-amplified neuroblastoma other than stage 1, or high-risk neuroblastoma defined based on the 3-gene molecular profile developed at our institution (Garcia I, et al. CCR 2012).

   • Group 1 patients have neuroblastoma (as defined above) resistant to standard therapy, as evidenced by incomplete response in bone marrow, but no MIBG-avid soft tissue or bone tumor and no progressive disease.

   • Group 2 patients have no evidence of measurable disease

     3 - Patients must have a Lansky or Karnofsky Performance Scale score of > 50% and patients must have a life expectancy of > 2 months.

4- Pre-enrollment tumor survey: Prior to enrollment a determination of residual disease must be Performed (Tumor imaging studies including CT or MRI, MIBG scan, bone marrow aspiration & biopsy, and blood and bone marrow samples). This disease assessment is required for eligibility.

5 - Patients must have adequate organ functions at the time of registration:

• Hematological: Total absolute phagocyte count (APC = neutrophils + monocytes) is at least 1000/microL
• Renal: Adequate Renal Function Defined As: Creatinine clearance or radioisotope GFR > 70 mL/min/1.73 m2 or serum creatinine based on age/gender.
• Hepatic- total bilirubin < 1.5 x normal, and SGPT (ALT) < 5 x normal. Veno-occlusive disease, if present, should be stable or improving.
• Cardiac- shortening fraction of > 30% by echocardiogram, or if shortening fraction abnormal, ejection fraction of > 55% by gated radionuclide study.
• Pulmonary- FEV1 and FVC > 60% of predicted by pulmonary function test. For children who are unable to do PFTs, no evidence of dyspnea at rest, no exercise intolerance.

• Central nervous system- Patients with seizure disorder may be enrolled if on anticonvulsants and wellcontrolled. CNS toxicity < Grade 2.

  6 - 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.

  7 - Signed informed consent indicating awareness of the investigational nature of this program.

Exclusion Criteria:

1. - Existing severe major organ dysfunction, i.e., renal., cardiac, hepatic, neurologic, pulmonary, or gastrointestinal toxicity ≥ grade 3.
2. - Progressive disease or MIBG-avid soft tissue/bone tumor.
3. - Active life-threatening infection.
4. - Inability to comply with protocol requirements.
5. - Patient is eligible for SIOP HR-NB-01 protocol (= newly diagnosed high-risk neuroblastoma patient in a center where the SIOP protocol is open for enrollment).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Dinutuximab. Immunotherapy; Dinutuximab will be administered at 17.5 mg/m2/day for 4 days up to 5 courses. Each dose should be infused IV over approximately 10 hours. Immunotherapy (sargramostim + isotretinoin + interleukin2) Sargramostim will be administered at 250 micrograms/m2/d by subcutaneous (SC) injection daily from Day 0 through 13 (daily with the infusion of Dinutuximab and for 3 days before and 7 days afterward). Isotretinoin (13-cis-retinoic acid, or RA) (160mg/m2/day or 5.33mg/kg/day if < 12kg) PO divided into 2 doses daily x 14 days. Interleukin-2 (IL-2) 3 MIU/m2/day will be given by continuous infusion for 4 days during the first week of each course 2 and 4 given on Days 0 - 3

Drug: Dinutuximab. Immunotherapy; Patients will receive 5 courses of Dinutuximab + GM-CSF + IL2 at intervals of 28 days for all courses. In addition, all patients will receive isotretinoin (13-cis-retinoic acid, or RA) at 160 mg/m2/dose twice a day for 14 days every 28 days, for 6 courses. Patients come off study if progressive disease develops at any time after cycle 1 or life-threatening grade 4 toxicity occurs clearly attributable to Immunotherapy.; Other Names: Sargramostim; GM-CSF; Ch14.18; Isotretinoin; 13-cis-retinoic acid, or RA; Interleukin-2 (IL-2)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants with Serious and Non-Serious Adverse Events	Type, incidence, severity, timing, seriousness, and relatedness; of reported AEs, physical examinations, and laboratory tests. Toxicity will be graded and tabulated by the NCI-CTCAE v 4.0.	Expected, 7 months from treatment initiation. From IC signature, every day during immunotherapy treatment (Cycles 1 to 5), day 1 of cycle 6. From patient consent signature up to 30 days after administration of the last dose of study drug.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Relapse-free survival	Rate of BM response for patients with detectable minimal residual disease in the BM after the first treatments with Dinutuximab/GM-CSF and relation with relapse-free survival.	Anticipated, 2 years from study treatment initiation. From IC signature, every 3 months, up to 2 years (anticipated).

Collaborators and Investigators

• Sponsor: Fundació Sant Joan de Déu
• Investigators: Principal Investigator: Jaume Mora, MD, Hospital Sant Joan de Deu, Barcelona

Study record dates

Study Major Dates

• Study Start (Actual): November 26, 2014
• Primary Completion (Actual): December 26, 2016
• Study Completion (Actual): December 31, 2018

Study Registration Dates

• First Submitted: June 12, 2014
• First Submitted That Met QC Criteria: June 18, 2014
• First Posted (Estimated): June 23, 2014

Study Record Updates

• Last Update Posted (Actual): April 22, 2024
• Last Update Submitted That Met QC Criteria: April 19, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: Immunotherapy; Neuroblastoma; Dinutuximab
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neoplastic Processes; Neuroectodermal Tumors, Primitive; Neuroectodermal Tumors, Primitive, Peripheral; Neuroblastoma; Neoplasm, Residual; Physiological Effects of Drugs; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Analgesics, Non-Narcotic; Antineoplastic Agents; Immunologic Factors; Dermatologic Agents; Sargramostim; Dinutuximab; Interleukin-2; Isotretinoin
• Other Study ID Numbers: HSJD-HR-NB-Ch14.18