Efficacy of Pembrolizumab in Progressive Multifocal Leukoencephalopathy in Immunocompromised Patients Excluding HIV and Biologic-Induced Immunosuppression

The primary objective of this study is to evaluate the **efficacy** of Pembrolizumab in achieving at least one negativation of JC virus (JCV) viral load in the cerebrospinal fluid (CSF) within the M0 to M3 period in immunocompromised patients with progressive multifocal leukoencephalopathy (PML). This is clinically relevant as PML is a severe demyelinating disease caused by JCV, and effective treatment options are limited, particularly in patients with irreversible causes of immunosuppression.

Secondary objectives include:

• Cumulative incidence of negativation of JCV viral load in the CSF, considering death as a competing event.
• Evolution of the JCV viral load in CSF.
• In patients achieving negativation of JCV viral load in CSF, cumulative incidence of repositivation of JCV PCR in CSF.
• Evolution of neurological status assessed by the NIH Stroke Scale (NIHSS).
• Evolution of disability and outcome measured by the modified Rankin Scale.
• Evolution of disability and outcome measured by the Glasgow Outcome Scale Extended (GOS-E).
• Relapse after improvement or progression, adjudicated by an adjudication committee.
• Survival rate at 12 months (M12).
• Cause-specific survival rate, related to PML or not.
• Adverse events.

The clinical trial involves **immunocompromised patients** diagnosed with progressive multifocal leukoencephalopathy (PML), excluding those with HIV or those receiving biologics for chronic inflammatory diseases. The study population includes both male and female participants aged 18 years and older. Participants are required to have a confirmed diagnosis of PML for less than two months, as per the American Academy of Neurology, and the presence of JC virus (JCV) in the cerebrospinal fluid (CSF) from the most recent sampling. The trial population is considered vulnerable due to their immunocompromised status. Women of childbearing potential must have a negative pregnancy test and agree to use highly effective contraception methods during the study period and for six months after the experimental treatment. The sponsor has not provided the total number of participants involved in the trial.

The clinical trial is designed to evaluate the efficacy of **pembrolizumab** in immunocompromised patients with progressive multifocal leukoencephalopathy (PML), excluding those with HIV infection or those receiving biologics for chronic inflammatory diseases. This Phase II multicenter, single-arm, two-stage Gehan trial aims to assess the primary endpoint of JCV viral load negativation in cerebrospinal fluid (CSF) within a three-month period. The trial is expected to commence recruitment in September 2023 and conclude by September 2027.

Participants will be administered pembrolizumab intravenously, with a maximum daily dose of 200 mg and a total dose not exceeding 600 mg over a two-month treatment period. The trial will include a series of study visits, beginning with a screening visit to confirm eligibility based on criteria such as age (≥18 years), recent PML diagnosis, and presence of JCV in CSF. Informed consent is required from all participants or their surrogates. Women of childbearing potential must have a negative pregnancy test and agree to use effective contraception for eight months.

Following the inclusion visit, participants will undergo regular follow-up visits at months 1, 2, and 3, where lumbar punctures and JCV PCR tests will be conducted as part of standard care. Secondary endpoints include the cumulative incidence of JCV viral load negativation, evolution of JCV viral load, and various neurological assessments using scales such as the NIH Stroke Scale, Modified Rankin Scale, and Glasgow Outcome Scale Extended. The study will also monitor for relapse, progression, and adverse events classified by the US NCI CTCAE.

The expected duration of participant involvement is up to 12 months, with conditions for early termination including death or significant adverse events. Participants who do not achieve JCV PCR negativation before death will be considered as having failed the primary endpoint. The trial's design ensures rigorous monitoring and assessment to determine the therapeutic potential of pembrolizumab in this patient population.

The clinical trial involves the administration of **Pembrolizumab**, an experimental medication, to assess its efficacy in treating progressive multifocal leukoencephalopathy (PML) in immunocompromised patients without HIV infection. **Pembrolizumab** is provided in the pharmaceutical form of a **concentrate for solution for injection**. The active substance, **Pembrolizumab**, is a protein of other origin. The medication is administered via the **intravenous** route. The dosing regimen includes a maximum daily dose of 200 mg, with a total maximum dose of 600 mg over the treatment period. The maximum treatment period is specified as 2 months. The study does not involve a pediatric formulation of the drug.

In this trial, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are specified. The focus is solely on the administration of **Pembrolizumab**. Participant compliance with the dosing schedule is monitored throughout the study to ensure adherence to the protocol. The trial aims to evaluate the potential of **Pembrolizumab** to achieve at least one negativation of JCV viral load in cerebrospinal fluid within the M0 to M3 period in the specified patient population.

The efficacy of Pembrolizumab in the treatment of **progressive multifocal leukoencephalopathy (PML)** in immunocompromised patients will be assessed primarily through the negativation of JCV viral load in cerebrospinal fluid (CSF). This will be measured using polymerase chain reaction (PCR) tests conducted on CSF samples. The primary endpoint is defined as at least one negative JCV PCR result in the CSF within the M0 to M3 period. Lumbar punctures and JCV PCR on CSF will be performed at Day 0, Month 1, Month 2, and Month 3 as part of standard care. Patients who die before achieving negativation of JCV PCR will be considered as treatment failures.

Secondary endpoints include the cumulative incidence of negative JCV viral load measures by PCR in CSF, with death as a competing event, and the evolution of JCV viral load in the CSF through repeated measures. Additional secondary endpoints involve the repositivation of JCV PCR, neurological status assessed by the NIH Stroke Scale (NIHSS) at Months 1, 2, 3, 6, and 12, and the degree of disability or dependence measured by the Modified Rankin Scale and the Glasgow Outcome Scale Extended (GOS-E) at the same timepoints. The study will also evaluate relapse or progression adjudicated by a committee of specialists, death and cause-specific death related to PML, and any adverse events classified using the US NCI CTCAE.