A Study Of Naxitamab , Granulocyte Macrophage Colony Stimulating Factor For Patients With Relapsed /Refractory , Soft Tissue or Anti GD2 Immunotherapy Refractory Neuroblastoma

Refractory Neuroblastoma Clinical Trial

— NICE  

Official title:

A Phase II Single Center Study Of Naxitamab , Granulocyte Macrophage Colony Stimulating Factor (GM CSF and Ifosfamide Carboplatin Etoposide) For Patients With Relapsed Refractory , Soft Tissue or Anti GD2 Immunotherapy Refractory Neuroblastoma

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT06438614
• Other study ID #: HSJD HR NB.2 2019
• Status: Completed
• Phase: Phase 2
• Start date: August 20, 2020
• Est. completion date: October 24, 2023

Study information

• Verified date: March 2024
• Source: Fundació Sant Joan de Déu
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to evaluate safety and efficacy of naxitamab, granulocyte macrophage Colony Stimulating Factor (GM CSF) and Isofosfamide/Carboplatin/Etoposide (NICE) for Patients With Relapsed /Refractory, soft tissue or anti GD2 immunotherapy refractory Neuroblastoma

Description:

The anti-GD2 monoclonal antibody Naxitamab (also known as hu3F8) in combination with macrophage colony-stimulating factor (GM-CSF) is currently under pivotal phase 3 investigation for the treatment of High-Risk Neuroblastoma Patients with Primary or Secondary Refractory Osteomedullary Disease.

A subset of patients with high-risk, resistant disease, i.e., relapsed or refractory Neuroblastoma with soft tissue involvement as measured by 123I-MIBG, 18F-FDG avid or measurable CT/MRI tumors outside of the bone marrow, or disease refractory to Naxitamab in combination with GM-CSF has shown significant response rates to a chemoimmunotherapy combination of Naxitamab, GM-CSF, irinotecan and temozolomide (HITS- Hu3F8, irinotecan, temozolomide and sargramostim) (NCT03189706). Treatment is administered on an outpatient basis and toxicities include those expected from I/T (myelosuppression and diarrhea) as well as pain and hypertension expected with Naxitamab. No other greater than grade 2 related toxicities occurred in this study (n=46). Early responses, assessed after 2 cycles, were documented in 18 (39%) patients and here complete (n = 9), partial (n = 8), and mixed (n = 1) and 13 patients had stable disease. Responses were achieved in refractory (3/7;43%) and progressive disease (15/39;38%) subgroups, in patients who had previously received I/T (12/34;35%) and/or anti-GD2 MoAb (14/36;39%), and in soft tissue (6/22; 27%) MIBG-avid skeletal sites (20/36;56%) and on bone marrow histology (9/12;75%). While encouraging, new strategies are warranted to further treat resistant disease.

A high-dose combination of ifosfamide, carboplatin, and etoposide (ICE) has activity against Neuroblastoma without cross-resistance to widely used chemotherapy regimens.

Through compassionate use, 4 patients with progression of disease or refractory disease after HITS therapy, have been further treated with two cycles of a combination of naxitamab, Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF) and ifosfamide/Carboplatin/Etoposide (NICE). The first patient showed a complete response.

Toxicity included G2 prolonged aplasia and G3 hypertension, both expected from the chemotherapy agents and hu3F8. One patient progressed after the 2 cycles and the other 2 showed stable disease, according to the revised (2017) INRC criteria.

In this formal trial, we will investigate whether the combination of Naxitamab and GM-CSF with ICE has a synergistic treatment effect in relapsed or refractory disease. The safety and efficacy of NICE (Naxitamab, Ifosfamide/Carboplatin/Etoposide) in patients that have not achieved complete remission with HITS chemo-immunotherapy will be assessed.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 47
• Est. completion date: October 24, 2023
• Est. primary completion date: July 20, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Months and older

Eligibility

Inclusion Criteria:

1. Diagnosis of NB as defined per INRC as

1. histopathology of tumor biopsy, or

2. BM aspirate or biopsy indicative of NB by histology plus high blood or urine catecholamine metabolite levels or MYCN amplification, or

3. FDG, MIBG avid lesion(s)

2. High-risk NB as defined as any of the following:

1. Stage 4 with MYCN amplification

2. Stage 4 without MYC amplification >1.5 y of age

3. Stage 3 with MYCN amplification

3. Relapsed/refractory Neuroblastoma with

1. Evidence of soft tissue disease or

2. Progessive disease/incomplete response/relapsed to previous treatment with Naxitamab plus GM-CSF

4. Prior treatment with murine and hu3F8 is allowed

5. Prior treatment with irinotecan or temozolomide or ICE is permitted

6. Evaluable (microscopic marrow metastasis, elevated tumor markers, positive MIBG or PET scans) or measurable (CT, MRI) disease documented after completion of prior systemic therapy

7. Age =18 months

8. Acceptable hematological status defined as:

1. Hemoglobin =8 g/dL (5.0 mmol/L)

2. White blood cell count =1000/µL

3. ANC =500/µL

4. Platelet count =50,000/µL

9. Acceptable liver function defined as:

1. ALT and AST =5 times ULN

2. Bilirubin =1.5 x ULN

10. Acceptable kidney function defined as:

a. eGFR >60 mL/min/1.73 m2 calculated by the 2009 revised Bedside Schwartz Equation

11. Written informed consent from legal guardian(s) and/or patient in accordance with local regulations. Children must provide assent as required by local regulations (= 12 years old).

Exclusion Criteria:

1. Existing major organ dysfunction > grade 2, with the exception of hearing loss and hematologic toxicity (defined as suppression of all subtypes of WBCs, RBCs, and platelets).

2. Active life-threatening infection.

3. Pregnant women or women who are breast-feeding.

4. Inability to comply with protocol requirements, including genetic studies.

5. History of allergy to GM-CSF = G4 (CTCAE) or does not respond to treatment.

6. ANC < 500/uL .

7. Platelet count <50,000/uL.

8. Patients with relapsed/refractory Neuroblastoma with solely bone marrow/bone involvement. Only patients with B/BM compartiment disease who show progressive disease/incomplete response/relapsed to previous treatment with Naxitamab plus GM-CSF may be eligible (inclusion critèrium #3).

Related Conditions & MeSH terms

• Neuroblastoma
• Refractory Neuroblastoma
• Sarcoma
• Soft Tissue Cancer

Intervention

Drug:
• HITS
Four doses of hu3F8, five doses each of irinotecan and temozolomide and five doses of GM-CSF. Irinotecan 50mg/m2/day IV will be administered from day 1-5concurrently with temozolomide 150mg/m2/day orally. Hu3F8 2.25mg/kg IV will be administered on days 2, 4, 9and11. GM-CSF 250mcg/m2/day SC will be administered on days 7-11
• Naxitamab + GM-CSF cycles
Patients that achieve CR after 2 or 4 cycles of HITS will move on to 5 cycles of Naxitamab + GM-CSF cycles.
• NICE
Patients that do not have an objective response (CR/PR) will receive NICE within 3 weeks from last dose. Each cycle of NICE consists of four doses of hu3F8, five doses of GM-CSF, one dose of carboplatin, and 3 doses each of ifosfamide and etoposide (table 2). Hu3F8 2.25mg/kg IV will be administered on days 2, 4, 9and 11. GM-CSF 250mcg/m2/day SC will be administered on days 7-11. Ifosfamide 1.5 gr/m2/day IV will be administered from day 1-3 concurrently with etoposide 100 mg/m2/day IV. Carboplatin 400 mg/m2/day IV will be administered on day 1

Locations

Country	Name	City	State
Spain	Hospital Sant Joan de Déu	Esplugues De Llobregat	Barcelona

Sponsors (1)

Lead Sponsor	Collaborator
Fundació Sant Joan de Déu

Country where clinical trial is conducted

Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Participants with Serious and Non-Serious Adverse Events	The safety and tolerability of the treatment will be determined by means of type, incidence, severity, timing, seriousness, and relatedness of reported AEs, physical examinations, and laboratory tests. Toxicity will be graded and tabulated by the NCI CTCA E v 5 .0	14 months after ICF signature
Primary	Best Overall Response (at the end of HITS treatment)	Best Overall Response is defined as the best response recorded from the start of the study treatment	From first day of treatment with HITS until completion of HITS (39 days).
Primary	Best Overall Response of Complete Response (CR) (at the end of HITS treatment)	The number and proportion of patients with CR as Best Overall Response at the end of HITS treatment	From first day of treatment with HITS until completion of HITS(39 days).
Primary	Objective Response Rate (at the end of HITS treatment)	Objective Response Rate is defined as the proportion of patients with Best Overall Response of CR (complete response) or PR (partial response).	From first day of treatment with HITS until completion of HITS (39 days).
Primary	Clinical Benefit Rate (at the end of HITS treatment)	Clinical Benefit Rate is defined as the proportion of patients with Best Overall Response of CR (complete response) or PR (partial response) or SD (stable disease) = 24 w	From first day of treatment with HITS until completion of HITS (39 days).
Primary	Best Overall Response (at the end of NICE treatment)	Best Overall Response is defined as the best response recorded from the start of the study treatment	From first day of treatment with NICE until completion of NICE (39 days).
Primary	Best Overall Response of Complete Response (CR) (at the end of NICE treatment)	The number and proportion of patients with CR as Best Overall Response at the end of NICE treatment	From first day of treatment with NICE until completion of NICE (39 days).
Primary	Objective Response Rate (at the end of NICE treatment)	Objective Response Rate is defined as the proportion of patients with Best Overall Response of CR (complete response) or PR (partial response).	From first day of treatment with NICE until completion of NICE (39 days).
Primary	Clinical Benefit Rate (at the end of NICE treatment)	Clinical Benefit Rate is defined as the proportion of patients with Best Overall Response of CR (complete response) or PR (partial response) or SD (stable disease) = 24 w	From first day of treatment with NICE until completion of NICE (39 days).
Secondary	To evaluate serum cytokines in patients receiving NICE		From first day of treatment with NICE, until day 11 post administration.
Secondary	To measure MRD after HITS	Minimal residual disease for NB will be evaluated using the Revised International NB Response Criteria (JCO August 1, 2017)	From first day of treatment with HITS until completion of HITS (39 days).
Secondary	To measure MRD after NICE	Minimal residual disease for NB will be evaluated using the Revised International NB Response Criteria (JCO August 1, 2017)	From first day of treatment with NICE until completion of NICE (39 days).