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)

NCT06630611 | Recruiting Phase 2

• 1 other identifier: VHIO23002
• Study Type: interventional
• Target: 40
• Locations: 1 country
• Sites: 1

Brief 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. 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. 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

Keywords

Immune checkpoint blockade (ICB) resistant tumors; Tumor-Infiltrating Lymphocyte; Adoptive Cell Therapy; Interleukin-2 (IL-2)

Outcome Measures

Primary Outcomes (2)

• Predefined grade ≥3 relevant adverse events

  Mean number of predefined grade ≥3 relevant adverse events per treatment arm during the first two weeks from the first dose of interleukin administered. Predefined relevant adverse events are rash, fatigue, myalgia, chills, fever, hypotension, arrhythmia, hypoxia, dyspnea, pulmonary distress, oliguria, edema, weight gain, diarrhea, confusion, headache, anxiety, ALT increase, AST increase, bilirubin increase, and serum creatinine increase according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v5.0.

  During the first two weeks from the first dose of interleukin administered

• PRO CTCAE

  Change of PRO CTCAE composite score (score 0-3 for each symptom) of selected events (diarrhea, fatigue, shortness of breath, rash, swelling, chills, heart palpitations, insomnia, anxious, sad, headache and muscle pain) from the baseline assessment (within 3 days before TIL infusion) to the first post-treatment evaluation.

  From the baseline assessment (within 3 days before TIL infusion) to the first post-treatment evaluation (at week 6 after TIL infusion).

Secondary Outcomes (15)

• Incidence of Adverse Events (AEs)

  From lymphodepleting chemotherapy start through 30 days after the last dose of IL-2, or until the first dose of the subsequent anti-cancer therapy, whichever occurs first.

• Overall Response Rate (ORR)

  From the date of baseline until the date of disease progression, assessed up to 60 months.

• Duration of Response (DOR)

  From the time measurement criteria are met for CR or PR until the first date that recurrent or progressive disease is objectively documented, assessed up to 60 months.

• Percentage change of tumor size

  From the date of baseline until the date of best response, assessed up to 60 months.

• Progression Free Survival (PFS)

  From the date of baseline until the date of disease progression, assessed up to 60 months.

Study Arms (2)

Control Arm (Arm A)

ACTIVE COMPARATOR

Patients will receive standard high dose of IL2 (HD-IL-2) after receiving standard lymphodepleting chemotherapy and TIL product. In the control arm, the first i.v. dose of HD-IL2 will be administered within 3-24 hours after TIL infusion, and thereafter every 8 hours to tolerance up to a maximum of 6 doses.

Biological: NMA-LD regimen; Biological: Tumor infiltrating lymphocytes adoptive cell therapy (TIL-ACT) infusion; Biological: High dose IL-2

Experimental Arm (Arm B)

EXPERIMENTAL

Patients will receive IL2 analog (ANV419) after receiving standard lymphodepleting chemotherapy and TIL product. In the experimental arm, ANV419 (one dose) will be administered within 3-24 hours after TIL infusion.

Biological: NMA-LD regimen; Biological: Tumor infiltrating lymphocytes adoptive cell therapy (TIL-ACT) infusion; Biological: IL-2 analog

Interventions

NMA-LD regimen BIOLOGICAL

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

Also known as: Cyclophosphamide and Fludarabine

Control Arm (Arm A); Experimental Arm (Arm B)

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

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.

Control Arm (Arm A); Experimental Arm (Arm B)

High dose IL-2 BIOLOGICAL

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.

Control Arm (Arm A)

IL-2 analog BIOLOGICAL

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.

Experimental Arm (Arm B)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients must have histologically or cytologically proven metastatic or unresectable cutaneous melanoma, NSCLC, or cervical cancer. The disease must have progressed to at least one standard systemic anticancer therapy, regardless whether in the adjuvant or metastatic setting, or the patient is unable/unwilling to receive standard therapy. Patients who are receiving an anticancer treatment post-progression are also eligible to be included, at the investigator's discretion, always respecting the wash-out period for starting NMA-LD chemotherapy.
• Patients must have at least one adequate lesion (primary tumor or metastasis) for resection or biopsy (with minimal morbidity, preferentially using imaging-guided minimally invasive procedures) for TIL generation.
• Note: If this lesion was previously irradiated, the lesion must have demonstrated progression prior to resection/biopsy.
• Patients must have a remaining measurable disease as defined by RECIST v. 1.1 criteria following tumor resection/biopsy for TIL manufacturing.
• Note: Lesions previously irradiated should not be selected as target lesions unless there has been demonstrated progression in those lesions.
• Patient must be at least 18 years old at the tissue procurement visit.
• Patient must understand and voluntarily sign an informed consent document before any study-related assessments/procedures being conducted.
• Patient must be able and willing to comply to the study visit schedule and protocol requirements.
• Patients must have a clinical performance of Eastern Cooperative Oncology Group 0 or 1.
• Patients are considered medically fit enough to undergo all study procedures and interventions and adequate hematological, renal, and hepatic functions defined by:
• Haemoglobin ≥9.0 g/dL.
• An absolute neutrophil count ≥ 1.5x10E9/L without the support of filgrastim.
• Platelets ≥100x10E9/L.
• PT and aPTT ≤1.5 x ULN (unless receiving therapeutic anticoagulation).
• \- subjects receiving therapeutic anticoagulation (such as low-molecular-weight heparin or warfarin) should be on a stable dose.

You may not qualify if:

• Patients with more than two brain metastases. Note: Patients with brain metastases \> 1cm in diameter or perilesional edema on MRI scan must be definitively-treated and stable for at least 4 weeks, and the patient must not require corticosteroid treatment \>10 mg prednisone or equivalent per day to be considered for enrollment;
• Patients with symptomatic brain metastasis.
• Patients with leptomeningeal carcinomatosis.
• Patients with an active concurrent or history within the past 3 years of invasive malignancy, except for non-melanoma skin cancer, cervical and bladder carcinoma in situ, good prognosis ductal carcinoma in situ of the breast, or prostate carcinoma that is in remission under androgen deprivation therapy for \>2 years. Other exceptions may apply and require discussion between the Investigator and the Medical Monitor.
• Patients with an active systemic infection requiring anti-infective treatment within 14 days before preparative lymphodepleting therapy.
• Patients with active hepatitis B or hepatitis C.
• Patients with active autoimmune disease requiring immunosuppressive treatments.
• Patients with a history of organ or bone marrow transplantation.
• Patients with any form of primary immunodeficiency (such as Severe Combined Immunodeficiency Disease and AIDS).
• Patients requiring regular treatment with steroids at a dose higher than prednisone 10 mg/day (or equivalent).
• Note: use of inhaled, topical steroids and use of systemic physiologic corticosteroid replacement therapy are permitted.
• Patients with current or history within the last 6 months, as determined by the Investigator, of clinically significant, progressive, and/or uncontrolled renal, hepatic, hematological, endocrine, pulmonary, cardiac, gastroenterological or neurological disease.
• Patients with a history of coronary revascularization or ischemic symptoms within 6 months of first dose of NMA-LD chemotherapy.
• History of idiopathic pulmonary fibrosis or evidence of active pneumonitis (any origin).
• Patients with allergies to any of the compounds included in any of the treatment products.

Sponsors & Collaborators

• Vall d'Hebron Institute of Oncology: lead
• Banc de Sang i Teixits: collaborator

Study Sites (1)

Vall d'Hebron Institute of Oncology

Barcelona, Spain

RECRUITING

MeSH Terms

Conditions

Melanoma; Carcinoma, Non-Small-Cell Lung; Uterine Cervical Neoplasms

Interventions

Cyclophosphamide; fludarabine; Interleukin-2

Condition Hierarchy (Ancestors)

Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Nerve Tissue; Nevi and Melanomas; Skin Neoplasms; Neoplasms by Site; Skin Diseases; Skin and Connective Tissue Diseases; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Lung Diseases; Respiratory Tract Diseases; Uterine Neoplasms; Genital Neoplasms, Female; Urogenital Neoplasms; Uterine Cervical Diseases; Uterine Diseases; Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases

Intervention Hierarchy (Ancestors)

Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds; Interleukins; Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Lymphokines; Proteins; Biological Factors

Study Officials

• Elena Garralda

  Vall d'Hebron Institute of Oncology

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Elena Garralda

CONTACT

34 93 489 30 00; egarralda@vhio.net

Susana Muñoz

CONTACT

smuñoz@vhio.net

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Patients will be randomized 1:1 over the two study arms. Randomization will be stratified by cancer type (melanoma and non-melanoma) and center following a block randomization. Of the total 40 patients, the first 10 patients recruited in the study will be metastatic melanoma patients. Of the remaining 30 patients 10 of them must be melanoma patients (20 in total) and the other 20 patients will be preferably NSCLC or cervical cancer, but additional patients with melanoma can also be included.

Study Record Dates

• First Submitted: July 26, 2024
• First Posted: October 8, 2024
• Study Start: January 15, 2025
• Primary Completion (Estimated): September 1, 2029
• Study Completion (Estimated): September 1, 2029
• Last Updated: January 28, 2025

Record last verified: 2025-01

Data Sharing

• IPD Sharing: Will not share

Locations

ES (1)