Early Immunotherapy with Intravenous Immunoglobulin, Cyclophosphamide and Methylprednisolone in Patients with Anti-Hu-associated Paraneoplastic Sensory Neuronopathy (NESPA)

Paraneoplastic Neurological Syndromes are rare autoimmune complications linked to the presence of systemic cancer. Despite their autoimmune origin, they have historically shown little response to immunotherapy. The reason for this failure is probably related to too late administration of immunotherapy, at a stage where the inflammation has already disappeared and irreversible neuronal loss has occurred. The protocol focuses on patients with anti-Hu antibody sensory neuronopathy. This single arm trial consists of an early immunotherapy combining Intravenous Immunoglobulin (IVIG) for 3 months, cyclophosphamide and methylprednisolone for 6 months, at the rate of 1 cycle per month. The percentage of patients with clinical improvement will be evaluated (ONLS) at 3 months. The tolerance of the treatment will also be evaluated as well as other functional scales at 3 and 6 months.

Study Overview

• Status: Recruiting
• Conditions: Paraneoplastic Sensory Neuronopathy
• Intervention / Treatment: Drug: Immunoglobulins IV (CLAYRIG); Drug: Cyclophosphamide IV; Drug: Methylprednisolone IV

• Study Type: Interventional
• Enrollment (Estimated): 21
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Dimitri Psimaras, MD; Phone Number: +33 1 42 16 04 35; Email: dimitri.psimaras@aphp.fr
• Study Contact Backup: Name: Alice LEPRINCE-LAURENGE, MD; Phone Number: +33 1 42 16 03 86; Email: alice.laurenge@aphp.fr

Study Locations

• France
  • Paris, France, 75013
    • Recruiting
    • Hôpital Pitié-Salpêtrière
    • Contact: Dimitri Psimaras, MD; Email: dimitri.psimaras@aphp.fr
    • Contact: Alice LEPRINCE-LAURENGE, MD; Email: alice.laurenge@aphp.fr

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Age ≥ 18 years old
• "Possible" sensory neuronopathy according to the criteria of Camdessanché et al. [2] with ONLS score ≥ 1
• Dominant picture of sensory ataxia (damage to the central nervous system and/or the neuromuscular junction is allowed, provided that it has a minor impact on the patient's disability)
• Positive anti-Hu antibodies in blood and/or cerebrospinal fluid
• Outpatient (modified Rankin Score (mRS) 2 or 3)
• Onset of neurological symptoms less than 3 months ago
• Free, informed, written and signed consent
• Affiliation to a social security or beneficiary scheme (except AME)

Exclusion Criteria:

• Known hypersensitivity to one of the treatments under study, to their metabolites, or to one of the excipients
• Absolute contraindications to IVIg: selective IgA deficiency, known thrombophilia, patients suffering from type I or II hyperprolinemia, hypersensitivity to human immunoglobulins
• Absolute contraindications to cyclophosphamide: vaccination against yellow fever in the 3 months preceding inclusion, acute urinary infection, pre-existing hemorrhagic cystitis, urinary tract obstruction, acute bone marrow failure
• Contraindication to methylprednisolone: live vaccines, or live attenuated vaccines within 3 months, infectious state or evolving virus (hepatitis, herpes, chickenpox, shingles)
• More than two courses of IVIg administered within 3 months before recruitment
• Other concomitant immunotherapy
• Other cause of immunosuppression (acquired or congenital)
• Treatment with checkpoint inhibitors in progress or completed less than 3 months previously
• Woman or man without effective contraception
• Pregnant or breastfeeding woman
• History of psychiatric or general illnesses that may contraindicate treatment
• Patients unable to complete the follow-up required by the study
• Patients under guardianship or curatorship
• Patient deprived of liberty by a judicial or administrative decision

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: Early immunotherapy; Early immunotherapy with intravenous immunoglobulin, cyclophosphamide and methylprednisolone

Drug: Immunoglobulins IV (CLAYRIG); Patients will be treated with cycles of : - Intravenous (IV) immunoglobulins: 2 g/kg per cycle, over 3 to 5 days (D1 to D3 or D5). Cycles will be administered every 4 weeks for a total of 3 first cycles; Drug: Cyclophosphamide IV; Patients will be treated with cycles of : - Cyclophosphamide IV: 1 g on the first day (D1). Cycles will be administered every 4 weeks for a total of 6 cycles; Drug: Methylprednisolone IV; Patients will be treated with cycles of : Methylprednisolone IV: 1 g/day for 3 days (D1 to D3). Cycles will be administered every 4 weeks for a total of 6 cycles

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Percentage of patients with clinical improvement on the ONLS (Overall Neuropathy Limitations Scale) at 3 months	At 3 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of patients with clinical improvement on the ONLS (Overall Neuropathy Limitations Scale) at 3 and 6 months		At 3 months and at 6 months
Percentage of patients with improvement in the ataxic component on the Score of Ataxia scale at 3 and 6 months		At 3 months and at 6 months
Percentage of patients with improvement in neuropathic pain on the Numeric Rating Scale (NRS) at 3 and 6 months		At 3 months and at 6 months
Percentage of patients with functional improvement on the modified Rankin Score (mRS) at 3 and 6 months		At 3 months and at 6 months
Percentage of patients with functional improvement on the Barthel Index (BI) at 3 and 6 months		At 3 months and at 6 months
Percentage of patients alive and without tumor progression at 6 months		At 6 months
Tolerance to treatment	Will be assessed by the frequency and severity of expected and unexpected adverse effects recorded during treatment	Through study completion, a maximum of 36 months

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Investigators: Principal Investigator: Dimitri Psimaras, MD, Assistance Publique - Hopitaux de Paris

Study record dates

Study Major Dates

• Study Start (Actual): January 10, 2025
• Primary Completion (Estimated): June 1, 2028
• Study Completion (Estimated): June 1, 2028

Study Registration Dates

• First Submitted: April 15, 2024
• First Submitted That Met QC Criteria: April 17, 2024
• First Posted (Actual): April 18, 2024

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: February 13, 2025
• Last Verified: February 1, 2025

More Information

Terms related to this study

• Keywords: Sensory neuronopathy; Paraneoplastic syndrome; Early immunotherapy
• Additional Relevant MeSH Terms: Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Inflammatory Agents; Antiemetics; Autonomic Agents; Peripheral Nervous System Agents; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antirheumatic Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Protective Agents; Neuroprotective Agents; Cyclophosphamide; Immunoglobulins; Methylprednisolone
• Other Study ID Numbers: APHP230701; 2023-506942-22-01 (Other Identifier: CTIS)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: The procedures carried out with the French data privacy authority (CNIL, Commission nationale de l'informatique et des libertés) do not provide for the transmission of the database, nor do the information and consent documents signed by the patients. Consultation by the editorial board or interested researchers of individual participant data that underlie the results reported in the article after deidentification may nevertheless be considered, subject to prior determination of the terms and conditions of such consultation and in respect for compliance with the applicable regulations.
• IPD Sharing Time Frame: Beginning 3 months and ending 3 years following article publication. Requests out of these time frame can also be submitted to the sponsor
• IPD Sharing Access Criteria: Researchers who provide a methodologically sound proposal.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No