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

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: Recruiting
• Conditions: Lymphoma; Leukemia; Myeloma
• Intervention / Treatment: Drug: Tocilizumab before CAR-T cell infusion; Drug: Tocilizumab at emerging CRS

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: Interventional
• Enrollment (Estimated): 100
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Thomas Pabst, Prof.; Phone Number: +41 31 632 84 30; Email: thomas.pabst@insel.ch

Study Locations

• Switzerland
  • BE
    • Bern, BE, Switzerland, 3010
      • Recruiting
      • Insel Gruppe AG
      • Contact: Thomas Pabst, Prof.; Phone Number: 0041316328430; Email: thomas.pabst@insel.ch

Participation Criteria

Eligibility Criteria

• 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

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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

Outcome Measure	Measure Description	Time Frame
Incidence of CRS of all grades	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

Outcome Measure	Measure Description	Time Frame
Incidence of ICANS of all grades	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	Number of days from admission to discharge from hospital	30 days
Erythrocyte transfusion needs	Number of transfusion (erythrocyte) given	90 days
Platelet transfusion needs	Number of transfusion (platelet) given	90 days
Incidence of admissions to the intensive care unit	Number of admissions to the intensive care unit	30 days
Incidence of infections	Number of infections per patient	90 days
Overall survival rates	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	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	daily assessment of IL-6 during the hospitalisation and at day 90 and day 180	180 days
Peripheral molecular CAR-T levels	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

• Sponsor: Insel Gruppe AG, University Hospital Bern
• Investigators: Study Chair: Thomas Pabst, Prof., Insel Gruppe AG Bern Switzerland

Study record dates

Study Major Dates

• Study Start (Actual): July 1, 2024
• Primary Completion (Estimated): December 1, 2026
• Study Completion (Estimated): June 1, 2027

Study Registration Dates

• First Submitted: May 21, 2024
• First Submitted That Met QC Criteria: May 21, 2024
• First Posted (Actual): May 28, 2024

Study Record Updates

• Last Update Posted (Actual): July 8, 2024
• Last Update Submitted That Met QC Criteria: July 4, 2024
• Last Verified: July 1, 2024

More Information

Terms related to this study

• Keywords: Lymphoma; Tocilizumab; Leukemia; Myeloma; CRS; ICANS
• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Hematologic Diseases; Lymphoma; Leukemia
• Other Study ID 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