## Protocol Section
### Identification Module
**NCT ID:** NCT06430736

**Acronym:** PRONTO

**Brief Title:** PRONTO Trial (PRophylactic Versus ON-demand Use of TOcilizumab)

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

#### Organization Study ID Info
**ID:** PRONTO
#### Organization
**Class:** OTHER
**Full Name:** Insel Gruppe AG, University Hospital Bern
### Status Module
#### Completion Date
**Date:** 2027-06

**Type:** ESTIMATED

#### Expanded Access Info
#### Last Update Post Date
**Date:** 2024-05-28

**Type:** ACTUAL

**Last Update Submit Date:** 2024-05-21

**Overall Status:** NOT_YET_RECRUITING

#### Primary Completion Date
**Date:** 2026-12

**Type:** ESTIMATED

#### Start Date
**Date:** 2024-06

**Type:** ESTIMATED

**Status Verified Date:** 2024-05

#### Study First Post Date
**Date:** 2024-05-28
**Type:** ACTUAL
**Study First Submit Date:** 2024-05-21
**Study First Submit QC Date:** 2024-05-21
### Sponsor Collaborators Module

#### Lead Sponsor

**Class:** OTHER

**Name:** Insel Gruppe AG, University Hospital Bern

#### Responsible Party

**Type:** SPONSOR

### Oversight Module

**Is FDA Regulated Device:** False

**Is FDA Regulated Drug:** False

**Oversight Has DMC:** False

### Description Module

**Brief Summary:** 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.

**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.

### Conditions Module

**Conditions:**

- Myeloma

- Lymphoma

- Leukemia

**Keywords:**

- Tocilizumab

- Myeloma

- Leukemia

- Lymphoma

- CRS

- ICANS

### Design Module

#### Design Info

**Allocation:** RANDOMIZED

**Intervention Model:** PARALLEL

**Intervention Model Description:** Randomized, two arm, open-label, single-center trial.

##### Masking Info

**Masking:** NONE

**Primary Purpose:** TREATMENT

#### Enrollment Info

**Count:** 100

**Type:** ESTIMATED

**Phases:**

- PHASE2

**Study Type:** INTERVENTIONAL

### Arms Interventions Module

#### Arm Group 1

**Description:** 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.

**Intervention Names:**

- Drug: Tocilizumab before CAR-T cell infusion

**Label:** Tocilizumab prophylactic

**Type:** EXPERIMENTAL

#### Arm Group 2

**Description:** 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.

**Intervention Names:**

- Drug: Tocilizumab at emerging CRS

**Label:** Tocilizumab on demand

**Type:** ACTIVE_COMPARATOR

### Interventions

#### Intervention 1

**Arm Group Labels:**

- Tocilizumab prophylactic

**Description:** 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.

**Name:** Tocilizumab before CAR-T cell infusion

**Other Names:**

- Prophylactic

**Type:** DRUG

#### Intervention 2

**Arm Group Labels:**

- Tocilizumab on demand

**Description:** 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.

**Name:** Tocilizumab at emerging CRS

**Other Names:**

- On demand

**Type:** DRUG

### Outcomes Module

#### Primary Outcomes

**Description:** 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

**Measure:** Incidence of CRS of all grades

**Time Frame:** 30 days

#### Secondary Outcomes

**Description:** 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

**Measure:** Incidence of ICANS of all grades

**Time Frame:** 30 days

**Description:** Number of days from admission to discharge from hospital

**Measure:** Hospitalization duration

**Time Frame:** 30 days

**Description:** Number of transfusion (erythrocyte) given

**Measure:** Erythrocyte transfusion needs

**Time Frame:** 90 days

**Description:** Number of transfusion (platelet) given

**Measure:** Platelet transfusion needs

**Time Frame:** 90 days

**Description:** Number of admissions to the intensive care unit

**Measure:** Incidence of admissions to the intensive care unit

**Time Frame:** 30 days

**Description:** Number of infections per patient

**Measure:** Incidence of infections

**Time Frame:** 90 days

**Description:** Overall survival assessment are based on physician's reporting of the assessments of the various disease types involved at day 90 and day 180

**Measure:** Overall survival rates

**Time Frame:** 180 days

**Description:** Relapse assessment are based on physician's reporting of the assessments of the various disease types involved at day 90 and day 180

**Measure:** Progression-free survival rates

**Time Frame:** 180 days

**Description:** daily assessment of IL-6 during the hospitalisation and at day 90 and day 180

**Measure:** IL-6 to monitor CRS

**Time Frame:** 180 days

**Description:** Peripheral molecular DNA CAR-T level measurement performed at day 0, day 8 and once a month during months 2 to 6

**Measure:** Peripheral molecular CAR-T levels

**Time Frame:** 180 days

### Eligibility Module

**Eligibility Criteria:** 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

**Minimum Age:** 18 Years

**Sex:** ALL

**Standard Ages:**

- ADULT

- OLDER_ADULT

### Contacts Locations Module

#### Central Contacts

**Contact 1:**

**Email:** thomas.pabst@insel.ch

**Name:** Thomas Pabst, Prof.

**Phone:** +41 31 632 84 30

**Role:** CONTACT

#### Locations

**Location 1:**

**City:** Bern

**Contacts:**

***Contact 1:***

- **Email:** thomas.pabst@insel.ch

- **Name:** Thomas Pabst, Prof.

- **Phone:** 0041316328430

- **Role:** CONTACT

**Country:** Switzerland

**Facility:** Insel Gruppe AG

**State:** BE

**Zip:** 3010

#### Overall Officials

**Official 1:**

**Affiliation:** Insel Gruppe AG Bern Switzerland

**Name:** Thomas Pabst, Prof.

**Role:** STUDY_CHAIR

### IPD Sharing Statement Module

**Access Criteria:** email contact: thomas.pabst@insel.ch

**Info Types:**

- STUDY_PROTOCOL

- SAP

- ICF

**IPD Sharing:** YES

**Time Frame:** 24 months

## Derived Section

### Condition Browse Module - Ancestors

- ID: D000009370

- Term: Neoplasms by Histologic Type

- ID: D000009369

- Term: Neoplasms

- ID: D000008232

- Term: Lymphoproliferative Disorders

- ID: D000008206

- Term: Lymphatic Diseases

- ID: D000007160

- Term: Immunoproliferative Disorders

- ID: D000007154

- Term: Immune System Diseases

- ID: D000006402

- Term: Hematologic Diseases

### Condition Browse Module - Browse Branches

- Abbrev: BC04

- Name: Neoplasms

- Abbrev: BC15

- Name: Blood and Lymph Conditions

- Abbrev: BC20

- Name: Immune System Diseases

- Abbrev: All

- Name: All Conditions

- Abbrev: BC14

- Name: Heart and Blood Diseases

- Abbrev: Rare

- Name: Rare Diseases

### Condition Browse Module - Browse Leaves

- ID: M11220

- Name: Lymphoma

- Relevance: HIGH

- As Found: Lymphoma

- ID: M12058

- Name: Multiple Myeloma

- Relevance: LOW

- As Found: Unknown

- ID: M27588

- Name: Neoplasms, Plasma Cell

- Relevance: LOW

- As Found: Unknown

- ID: M10945

- Name: Leukemia

- Relevance: HIGH

- As Found: Leukemia

- ID: M12315

- Name: Neoplasms by Histologic Type

- Relevance: LOW

- As Found: Unknown

- ID: M11225

- Name: Lymphoproliferative Disorders

- Relevance: LOW

- As Found: Unknown

- ID: M11203

- Name: Lymphatic Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M10206

- Name: Immunoproliferative Disorders

- Relevance: LOW

- As Found: Unknown

- ID: M10200

- Name: Immune System Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M9490

- Name: Hematologic Diseases

- Relevance: LOW

- As Found: Unknown

- ID: T3543

- Name: Lymphosarcoma

- Relevance: LOW

- As Found: Unknown

- ID: T3947

- Name: Multiple Myeloma

- Relevance: LOW

- As Found: Unknown

### Condition Browse Module - Meshes

- ID: D000008223

- Term: Lymphoma

- ID: D000007938

- Term: Leukemia

### Intervention Browse Module - Browse Branches

- Abbrev: Antipy

- Name: Antipyretics

- Abbrev: All

- Name: All Drugs and Chemicals

### Intervention Browse Module - Browse Leaves

- ID: M29176

- Name: Antipyretics

- Relevance: LOW

- As Found: Unknown

### Misc Info Module

- Version Holder: 2024-05-31
