NCT06630611

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)

Phase II Randomized Study Evaluating 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

• Status: Recruiting
• Phase: Phase 2
• Study type: Interventional
• Enrollment: 40 (estimated)
• Sponsor: Vall d'Hebron Institute of Oncology · Academic / Other
• Sex: All
• Age: 18 Years
• Healthy volunteers: Not accepted

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

Detailed description

This is a an open-label, randomized, pragmatic multicenter phase II clinical trial to compare the safety, quality of life and efficacy of current protocols of adoptive cell therapy based on tumorinfiltrating lymphocytes (TIL-ACT) established at each institution facility through the randomization between two types of following interleukin used for engrafting and in vivo expansion of TILs: standard high-dose (HD) IL-2(600.000 IU/kg) or ANV419. Total number of patients included in the trial will be 40. Of the total 40 patients, the first 10 patients recruited in the study will be metastatic melanoma patients. The melanoma and non-melanoma cohorts will be equally distributed between the two arms. Patients will be randomized to start treatment with either HD-IL-2 (Control arm) or with ANV419 (Experimental arm). The objectives of this study are the following: Primary objectives: * 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. * To determine whether TIL-ACT using the IL-2 analog improves patient´s reported outcomes (PRO) compared to TIL-ACT using HD-IL-2 Secondary objectives: * To evaluate the safety and the tolerability of TIL-ACT using the IL-2 analog ANV419 compared to TIL-ACT using HD-IL-2. * To evaluate short-term efficacy outcomes in patients receiving the IL-2 analog ANV419 or HD-IL-2. * To evaluate long-term efficacy outcomes in patients receiving the IL-2 analog ANV419 or HD-IL-2. * To evaluate the quality of life (QoL) and symptomatology in patients receiving the IL-2 analog ANV419 or HD-IL-2. * To evaluate anxiety and depression in patients receiving the IL-2 analog ANV419 or HD-IL-2. * To develop the health technology assessment (HTA) of TIL-ACT using ANV419, via the analysis of cost-effectiveness, budget impact, reimbursement strategies, user acceptance, and technical feasibility. This assessment, together with a social return of investment (SROI) analysis, will provide relevant information to participant member states regarding the possibility of implementing optimized and affordable treatments in their healthcare systems. Exploratory objectives: * To evaluate the impact of the different cytokine regimens on CD8+, NK and Treg proliferation, cytokine secretion profile, as well as the persistence and transcriptomic/phenotypic profile of the infused TIL product at different times following TIL infusion. * To correlate the presence and persistence of tumor- and neoantigen- reactive TIL and their transcriptomic/phenotypic profile with clinical outcome. * To evaluate the influence of tumor and neoantigen heterogeneity measured through tumor and cell free DNA sequencing prior to and during treatment. * To evaluate biometric physiological parameters (mobility, heart rate, SpO2 and sleep cycle) through wearable devices during and after treatmen

Conditions

• Melanoma
• Non Small Cell Lung Cancer
• Cervical Cancer

Interventions

Type	Name	Description
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.

Timeline

• Start date: 2025-01-15
• Primary completion: 2029-09-01
• Completion: 2029-09-01
• First posted: 2024-10-08
• Last updated: 2025-01-28

Locations

1 site across 1 country: Spain