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
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.
• 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.
‣ AST or ALT ≤3 x ULN. Patients with liver metastases must have AST and ALT ≤5.0 x ULN.
‣ Total bilirubin \<2 mg/dL. Patients with Gilbert's Syndrome must have a total bilirubin ≤3.0 mg/dL.
‣ Serum creatinine \<1.5 mg/dL or measured creatinine clearance ≥50 ml/min calculated using the Cockcroft-Gault glomerular filtration rate estimation: (140 - age) × (weight in kg) × (0.85 if female)/72 × (serum creatinine in mg/dL).
• Patients with documented LVEF of ≥ 45%.
⁃ Patients with documented FEV1, FVC and DLCO ≥ 50% tested by a pulmonary function test.
⁃ Patients must be seronegative for HIV antibody (patients who are HIV seropositive may be less responsive and more susceptible to toxicities related to this experimental treatment since they may have a decreased immune competence).
⁃ Patients must be seronegative for active hepatitis B (defined as having a negative hepatitis B surface antigen \[HBsAg\] test), and seronegative for hepatitis C antibody. Patients with a history of hepatitis B virus (HBV) infection and having a negative HBsAg test and a positive antibody to hepatitis B surface antigen (HBsAg) are eligible. Patients with the hepatitis C antibody test positive are eligible only if tested for the presence of antigen by RT-PCR and be HCV RNA negative.
⁃ Life expectancy ≥3 months.
⁃ Patients who are of childbearing potential (postmenarcheal who has not reached a postmenopausal state and has not undergone surgical sterilization) or have partners of childbearing potential must agree to use a highly effective method of contraception during the study and for at least 6 months after the last dose of IL-2.
⁃ Female participants: a female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies:
• Women of non-childbearing potential (WONCBP).
∙ Women of childbearing potential (WOCBP), who:
⁃ i. Agree to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods that result in a failure rate of \<1% per year from screening until 6 months after the infusion of the TIL product. Examples of contraceptive methods with a failure rate of \<1% per year include bilateral tubal occlusion, male sterilization, and copper intrauterine devices.
⁃ ii. Have a negative pregnancy test (blood) within one week before the first study treatment administration (applicable to premenopausal women and women ≤2 years after the start of menopause (menopause is defined as amenorrhea for \<2 years).
⁃ iii. Refrain for donating ovules during the study
⁃ Male Participants: during the treatment period and for at least 2 months after the last dose of study treatment, agreement to:
• Remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures such as a condom or a contraceptive method that result in a failure rate of \<1% per year, with partners who are WOCBP.
∙ Refrain from donating sperm during the study.
∙ Inform if his partner gets pregnant during this time.
⁃ Any toxicity related to prior systemic therapy must have recovered to grade 1 or less according to NCI-CTCAE v5.0 at least 4 weeks before enrollment, except for alopecia, vitiligo, or endocrinopathy managed with replacement therapy, and Grade ≤2 peripheral neuropathy.
⁃ Note: Other Grade 2 AEs that are deemed clinically insignificant by treating physician and in consultation with Medical Monitor are permitted.
⁃ Patients may have undergone minor surgical procedures within the past 3 weeks, as long as all toxicities have recovered to grade 1 or less.