Pembrolizumab in Progressive Multifocal Leukoencephalopathy (PML) in Immunocompromised Patients Without HIV Infection (PENALTY)

This study aims to assess the efficacy and safety of pembrolizumab in immunocompromised patients with progressive multifocal leukoencephalopathy (PML). This phase II, multicenter, single-arm study includes patients with an underlying cause of immunosuppression hardly reversible, i.e. not the patients with HIV nor those receiving biologics for chronic inflammatory diseases. Patients will receive intravenous pembrolizumab (2 mg/kg, maximum 200 mg) at month 0, 1 and 2 (total of three doses). The primary endpoint will be achieving at least one negative result of JCV viral load in cerebrospinal fluid (CSF) within the M0 to M3 period.

Study Overview

• Status: Not yet recruiting
• Conditions: Progressive Multifocal Leukoencephalopathy
• Intervention / Treatment: Drug: Pembrolizumab, 25 mg/ml solution for intravenous (IV) injection

• Study Type: Interventional
• Enrollment (Estimated): 33
• Phase: Phase 2; Phase 3

Contacts and Locations

• Study Contact: Name: Valérie POURCHER, Pr; Phone Number: +33 (0)1 42 16 02 62; Email: valerie.martinez@aphp.fr
• Study Contact Backup: Name: TUBACH Florence, Pr; Phone Number: +33 (0)1 42 16 05 05; Email: urc.pslcfx.psl@aphp.fr

Study Locations

• France
  • Paris, France, 75013
    • Hôpital Pitié-Salpêtrière - Médecine Intensive Réanimation
    • Contact: Nicolas WEISS, Pr; Phone Number: +33 (0)1 42 16 27 70; Email: nicolas.weiss@aphp.fr
  • Paris, France, 75013
    • Hôpital Pitié-Salpêtrière - Service d'hématologie clinique
    • Contact: Damien ROOS-WEIL, Dr; Phone Number: +33 (0)1 42 16 15 96; Email: damien.roosweil@aphp.fr
  • Paris, France, 75013
    • Hôpital Pitié-Salpêtrière - Service des Maladies infectieuses et tropicales
    • Contact: Valérie POURCHER, Pr; Phone Number: +33 (0)1 42 16 02 62; Email: valerie.martinez@aphp.fr

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. Age ≥ 18 years old
2. Diagnosis of definite PML since less than 2 months according to American Academy of Neurology
3. Presence of JCV in the CSF in the last CSF sampling.
4. Signed informed consent (from the patient, or if unable to consent, from a surrogate)
5. For women of childbearing potential: negative serum or urine b-HCG test and agree to use a highly effective contraception methods during 8 months (i.e. until 6 months after end of experimental treatment)

Exclusion Criteria:

1. Patients in whom immune reconstitution is achievable (HIV infection - Multiple sclerosis - Auto-immune and inflammatory diseases)
2. Patients who have received solid organ transplantation
3. Hypersensitivity to the active substance or to any of the excipients
4. Life expectancy less than 1 month
5. Pregnancy or lactating women or planning birth during the study period
6. Having previously been treated by anti-PD1mAb
7. Patient receiving IL-2 or IL-7 for the treatment of PML at inclusion
8. Patient whose weight is > 100kg

9. Participation in other interventional study [a patient already included in another interventional study for which the treatment can lead to an immunodepression can be included if:

   • the investigational treatment has been completed and there is no risk of drug interaction with the administration of Pembrolizumab as defined in PENALTY study
   • if this does not alter the study's ability to evaluate the effect of Pembrolizumab in terms of safety and efficacy (from the investigator's point of view)]
10. Patient without national health insurance, and patient on AME (state medical aid)
11. Patient under guardianship or curatorship
12. Patient deprived of their 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: Pembrolizumab; Pembrolizumab (commercial name: KEYTRUDA; MSD), 25 mg/ml solution for intravenous (IV) injection	Drug: Pembrolizumab, 25 mg/ml solution for intravenous (IV) injection; Pembrolizumab administration at D0, M1 and M2

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Negativation of JCV viral load in the CSF as assessed by PCR: at least one JCV PCR in the CSF negative in the Day 0 to Month 3 period	At baseline (Day 0), 1 month, 2 months and 3 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Negativation of JCV PCR viral load in the CSF: cumulative incidence of negative JCV viral load measures by PCR in CSF, with death as competing event		At baseline (Day 0), 1 month, 2 months and 3 months
Evolution of the JCV viral load in the CSF (repeated measures JCV PCR in CSF)		At baseline (Day 0), 1 month, 2 months and 3 months
Repositivation of JCV PCR: at least a positive result following at least a negative result		At baseline (Day 0), 1 month, 2 months and 3 months
Evolution of National Institutes of Health Stroke Scale (NIHSS) score	Repeated measures of neurological status	At baseline (Day 0), 1 month, 2 months, 3 months, 6 months, and 12 months
Evolution of 6-item Modified Rankin Scale score (includes death as most severe state)	Repeated measures of degree of disability or dependence in the daily activities in neurological conditions	At baseline (Day 0), 1 month, 2 months, 3 months, 6 months, and 12 months
Evolution of Glasgow Outcome Scale Extended (GOS-E) score	Repeated measures of neurological outcome and degree of disability in neurological conditions	At baseline (Day 0), 1 month, 2 months, 3 months, 6 months, and 12 months
Relapse or progression	Adjudication by a dedicated committee ; based on clinical evolution, JCV PCR in CSF, brain MRI	From baseline to end of participation, a maximum of 12 months
Death (and date of death)		From baseline to end of participation, a maximum of 12 months
Cause specific death: death related to PML	Adjudication by a dedicated committee	From baseline to end of participation, a maximum of 12 months
Any adverse event classified by using US NCI CTCAE		From baseline to end of participation, a maximum of 12 months

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris

Study record dates

Study Major Dates

• Study Start (Estimated): April 1, 2024
• Primary Completion (Estimated): April 1, 2028
• Study Completion (Estimated): April 1, 2028

Study Registration Dates

• First Submitted: February 14, 2024
• First Submitted That Met QC Criteria: February 21, 2024
• First Posted (Estimated): February 26, 2024

Study Record Updates

• Last Update Posted (Estimated): February 26, 2024
• Last Update Submitted That Met QC Criteria: February 21, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: Pembrolizumab; Progressive Multifocal Leukoencephalopathy; Checkpoint inhibitors
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; Immunologic Deficiency Syndromes; Immune System Diseases; Demyelinating Diseases; Encephalitis, Viral; Central Nervous System Viral Diseases; Central Nervous System Infections; Infectious Encephalitis; DNA Virus Infections; Slow Virus Diseases; Encephalitis; Polyomavirus Infections; Neuroinflammatory Diseases; Urogenital Diseases; Genital Diseases; HIV Infections; Leukoencephalopathy, Progressive Multifocal; Leukoencephalopathies; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Pembrolizumab
• Other Study ID Numbers: APHP211001; 2023-503520-31-00 (Other Identifier: EU CT number)

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