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
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.
Patients must have a remaining measurable disease as defined by RECIST v. 1.1 criteria following tumor resection/biopsy for TIL manufacturing.
Patient must be at least 18 years old at the tissue procurement visit.
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.
Parallel
NMA-LD regimen
Biological/VaccineThe use of the NMA-LD regimen (cyclophosphamide and fludarabine) prior to cell administration is expected to lead to myelosuppression in all patients.
Tumor infiltrating lymphocytes adoptive cell therapy (TIL-ACT) infusion
Biological/VaccineOn 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.
High dose IL-2
Biological/VaccineOnly 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.
IL-2 analog
Biological/VaccineOnly 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.
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.
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.
Incidence of Adverse Events (AEs)
Nature, frequency, and severity of treatment related adverse events according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) per treatment arm.
Overall Response Rate (ORR)
Overall Response Rate (ORR) per RECIST v1.1 as assessed by investigator.
Duration of Response (DOR)
Duration of Response (DOR) per RECIST v1.1 as assessed by investigator.
Percentage change of tumor size
Tumor size calculated as the percentage change
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Vall d'Hebron Institute of Oncology
Lead sponsor
Banc de Sang i Teixits
Collaborator
