Evaluation of a Pragmatic Approach to Adoptive Cell Therapy (ACT) Using an IL2 Analog (ANV419) vs High Dose IL2 After Tumor Infiltrating Lymphocytes (TIL) Therapy in Patients With Melanoma, NSCLC and Cervical Cancer (PragmaTIL)

Summary

Background:

The presence of T-lymphocytes in resected tumor samples derived from long-term survival patients and the fact that reinvigoration of their functionality through the administration of specific immune-therapies can lead to remarkable antitumor responses supports that lymphocytes play a critical role in cancer immunity.

TIL-based ACT (Adoptive cell therapy using tumor-infiltrating lymphocytes product) is a modality of ACT used to treat patients with multiple types of cancer and it consists in the adoptive transfer of ex vivo expanded autologous tumor-infiltrating lymphocytes obtained from tumor resection or tumor biopsies in patients following a non-myeloablative lymphodepleting (NMA-LD) chemotherapy. Ex vivo expansion of TIL relies on the non-specific expansion of lymphocytes present in tumor single cell suspensions or tumor fragments in high dose IL-2.

Although proven efficacy in selected, the HD-IL-2 use remains relatively restricted due to toxicity. Due to the short serum half-life and the need to achieve an immune-modulatory effect in the tissues, IL-2 must be given in doses that induce severe systemic toxicities, including capillary leak syndrome (CLS), pulmonary edema, hypotension, acute renal insufficiency, and rarely myocarditis, limiting its applicability in cancer. Studies comparing HD-IL-2 with lower doses both in renal cell carcinoma and metastatic melanoma to minimize toxicity demonstrated the superiority of the high dose regimens in both diseases. These drawbacks of HD-IL-2 use encouraged the development of improved IL-2-based biologic agents with higher selectivity for effector immune cell subsets, reduced toxicity, and prolonged half-life.

ANV419 is a novel IL-2 agent, which has been developed as a preferentially IL-2Rβγ directed fusion protein with a longer half-life. It has shown high effector selectivity and a favorable safety profile in preclinical testing, including in nonhuman primates, and it has been investigated in an ongoing open-label, dose-escalation Phase I Study in multiple tumor types. he safety profile of ANV419 is characterized by pyrexia, nausea, vomiting, ALT/AST changes and CRS in some patients. Most events are low grade and self-limiting and manageable with standard supportive care. ANV419 was well-tolerated by most patients. No patient discontinued treatment due to treatment related AE.

Taking all the previous information into account, the primary objectives of this study are:

1. To determine whether TIL-ACT using the IL-2 analog ANV419 reduces the mean number of predefined grade ≥3 relevant adverse events related to interleukin use (based on Common Terminology Criteria for Adverse Events v5.0 - CTCAE v5.0) compared to TIL-ACT using HD-IL-2.
2. To determine whether TIL-ACT using the IL-2 analog improves patient´s reported outcomes (PRO) compared to TIL-ACT using HD-IL-2

Conditions

• Melanoma
• Non Small Cell Lung Cancer
• Cervical Cancer

Interventions

BIOLOGICAL

NMA-LD regimen

The use of the NMA-LD regimen (cyclophosphamide and fludarabine) prior to cell administration is expected to lead to myelosuppression in all patients.

BIOLOGICAL

Tumor infiltrating lymphocytes adoptive cell therapy (TIL-ACT) infusion

On Day 0 (at least 24h after the last dose of fludarabine) patients will be hospitalized in a dedicated unit. Autologous TIL infusion will be administered intravenously.

BIOLOGICAL

High dose IL-2

Only for patients in Arm A. IL-2 begins between 3 and 24 hours after the completion of the TIL infusion and is given as a bolus administration every eight hours (minimum interval) to 24 hours (maximum interval) with a maximum of six doses from the beginning of each administration.

BIOLOGICAL

IL-2 analog

Only for patients in Arm B ANV419 will be administered between 3 and 24 hours after the completion of the TIL infusion with a slow IV infusion over 15-30 minutes + 5 minutes once, at 243µg/kg.

Sponsors & Collaborators

• Banc de Sang i Teixits

  collaborator OTHER

• Vall d'Hebron Institute of Oncology

  lead OTHER

Principal Investigators

• Elena Garralda · Vall d'Hebron Institute of Oncology

Study Design

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Model

PARALLEL

Eligibility

Min Age

18 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2025-01-15

Primary Completion

2029-09-30

Completion

2029-09-30

Countries

• Spain

Study Locations