PRONTO Trial (PRophylactic Versus ON-demand Use of TOcilizumab) (PRONTO)

July 4, 2024 updated by: Insel Gruppe AG, University Hospital Bern

Prospective Comparison Between Prophylactic and On-demand Use of Tocilizumab in CAR-T Recipients - a Randomized, Two Arm, Open-label, Single-center Trial

Despite the consequent use of Tocilizumab together with conventional antipyretics at early/first signs of emerging CRS, CRS (and eventually the subsequent development of ICANS) remain a major concern for patients.

This study aims to identify safety and efficacy of prophylactic Tocilizumab treatment. In particular, to explore whether prophylactic Tocilizumab treatment can decrease the incidence and severity of CRS (and subsequent eventual neurotoxicity) following CAR-T-treatment.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Recruiting

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Detailed Description

Adoptive immunotherapy with CD19 (cluster of differentiation antigen 19) targeting chimeric antigen-receptor (CAR-)T cells is an effective therapeutic strategy against relapsed or refractory B-cell malignancies, including B-cell lymphomas, B-ALL (acute lymphoblastic leukemia) and myeloma. Currently, up to 50 commercial CAR-T-cell treatments are performed annually at the Inselspital in Bern, making it by far the largest center for CAR-T cell treatment in Switzerland.

CAR-T treatment is associated with well-described acute adverse events, including cytokine release syndrome (CRS) and neurotoxicity, termed immune effector cell associated neurologic syndrome (ICANS). CRS (at all grades) occurs in between 42 to 93% of all patients with variations among available products, and ICANS can occur (at all grades) in 21% up to 64%.

Acute complications of CAR-T cell therapy are the result of rapid CAR-T cell expansion and of a hyper-inflammatory state related to cell activation. Interleukin (IL-6) is a central mediator of cytokine-responses in CRS and ICANS together with other cytokines and chemokines involved. IL-6 interacts with its receptor (IL-6R) in either membrane-bound form, leading to "classic" IL-6 signaling after interacting with GP130, or soluble in plasma, where the IL-6 / IL-6R complex interacts with GP130 expressing cells in "trans" IL-6 signaling.

Tocilizumab is a humanized monoclonal antibody that binds the IL-6R in both its soluble and membrane-bound forms. Tocilizumab treatment has become the standard of care for patients presenting with CRS (at all grades), together with antipyretic treatment (grades 1 or 2 at the regular ward) or with vasoactive and/or ventilation support at the intensive care unit (grades 3 and 4).

The study aims to assess the incidence of CRS of all grades, as well as the incidence of ICANS of all grades, the duration of hospitalisation and the need of platelet and erythrocyte transfusion within the first three months after CAR-T treatment in patients receiving prophylactic Tocilizumab compared to patients receiving on-demand Tocilizumab.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Estimated)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
100

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact

The name and contact information for the person who can answer enrollment questions for a clinical study. Each location where the study is being conducted may also have a specific contact, who may be better able to answer those questions.

Study Locations

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • Patients planned to receive commercial CAR-T treatment for all registered indications comprising lymphomas, leukemias or myeloma at a single academic center (Bern Inselspital)
  • With written informed consent
  • Considered by the investigator to be clinically fit for this treatment
  • Patients aged ≥18 years

Exclusion Criteria:

  • Previous Tocilizumab treatment within 3 months prior to CAR-T infusion
  • Patients with treatment with an investigational compound within 8 weeks prior to CAR-T infusion
  • Women who are pregnant or breast feeding, or women intending to become pregnant during the study period; or participants lacking safe contraception, defined as: Female participants of childbearing potential, not using and not willing to continue using a medically reliable method of contraception for the entire study duration, such as oral, injectable, or implantable contraceptives, or intrauterine contraceptive devices, or who are not using any other method considered sufficiently reliable by the investigator in individual cases during study treatment and for a total of 12 months; Female participants who are surgically sterilised / hysterectomised or post-menopausal for longer than 2 years are not considered as being of child bearing potential.
  • Inability to follow the procedures of the study, e.g. due to language problems, psychological disorders, dementia, etc. of the participant
  • Previous enrolment into the current study
  • Enrolment of the investigator, his/her family members, employees and other dependent persons

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Experimental: Tocilizumab prophylactic
In the experimental arm, patients will receive a single standard dose of Tocilizumab (Actemra®) 8 mg/kg b.w. intravenously infused over 1 hour in 250 ml NaCl 0.9%, with completion of the infusion 1 hour prior to the infusion of the CAR-T cells. Prior to Tocilizumab administration, no specific premedication is given. The treatment of eventual subsequent CRS will be identical as in patients in the standard arm.
Drug: Tocilizumab before CAR-T cell infusion

Tocilizumab will be given at the standard-dose of 8 mg/kg b.w. intravenously, with completion of the infusion 1 hour prior to infusion of CAR-T cells.

Treatment of eventual subsequent CRS/ICANS will be identical as in patients in the standard arm.

Other Names:
  • Prophylactic
Active Comparator: Tocilizumab on demand
In the standard arm, patients will receive conventional antipyretics and Tocilizumab at first clinical signs (being grade 1 or higher) of emerging CRS. Tocilizumab will be given at the standard-dose of 8 mg/kg b.w. intravenously over one hour in 250 ml NaCl 0.9%, and it will be repeated after 8 hours for a maximum of four administrations in patients with ongoing signs of CRS. Prior to Tocilizumab administration, no specific premedication is given.
Drug: Tocilizumab at emerging CRS
Tocilizumab will be given at the standard-dose of 8 mg/kg b.w. intravenously, and it will be repeated after 8 hours for a maximum of four administrations in patients with ongoing signs of CRS.
Other Names:
  • On demand

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Incidence of CRS of all grades
Time Frame: 30 days
Number of patients with CRS of any grade according to the ASTCT (American Society for Transplantation and Cellular Therapy ) Consensus Grading for Cytokine Release Syndrome and Neurologic Toxicity Associated with Immune Effector Cells ; including use of antipyretics
30 days

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Incidence of ICANS of all grades
Time Frame: 30 days
Number of patients with ICANS of any grade according to the ASTCT Consensus Grading for Cytokine Release Syndrome and Neurologic Toxicity Associated with Immune Effector Cells ; including use of antipyretics
30 days
Hospitalization duration
Time Frame: 30 days
Number of days from admission to discharge from hospital
30 days
Erythrocyte transfusion needs
Time Frame: 90 days
Number of transfusion (erythrocyte) given
90 days
Platelet transfusion needs
Time Frame: 90 days
Number of transfusion (platelet) given
90 days
Incidence of admissions to the intensive care unit
Time Frame: 30 days
Number of admissions to the intensive care unit
30 days
Incidence of infections
Time Frame: 90 days
Number of infections per patient
90 days
Overall survival rates
Time Frame: 180 days
Overall survival assessment are based on physician's reporting of the assessments of the various disease types involved at day 90 and day 180
180 days
Progression-free survival rates
Time Frame: 180 days
Relapse assessment are based on physician's reporting of the assessments of the various disease types involved at day 90 and day 180
180 days
IL-6 to monitor CRS
Time Frame: 180 days
daily assessment of IL-6 during the hospitalisation and at day 90 and day 180
180 days
Peripheral molecular CAR-T levels
Time Frame: 180 days
Peripheral molecular DNA CAR-T level measurement performed at day 0, day 8 and once a month during months 2 to 6
180 days

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Insel Gruppe AG, University Hospital Bern

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Study Chair: Thomas Pabst, Prof., Insel Gruppe AG Bern Switzerland

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
July 1, 2024

Primary Completion (Estimated)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
December 1, 2026

Study Completion (Estimated)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
June 1, 2027

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
May 21, 2024

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
May 21, 2024

First Posted (Actual)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
May 28, 2024

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
July 8, 2024

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
July 4, 2024

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
July 1, 2024

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • PRONTO

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Sharing Time Frame

24 months

IPD Sharing Access Criteria

email contact: thomas.pabst@insel.ch

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

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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