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. The PragmaTIL

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Vall D Hebron Institute Of Oncology

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

15 Jan 2025 → ongoing

Decision date (initial)

2024-07-22

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

European Health and Digital Executive Agency (HADEA)

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Therapy, Efficacy

- To determine whether TIL-ACT using the IL-2 analog ANV419 reduces the number of predefined grade ≥ 3 relevant events non hematological 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) (based on selected PRO-CTCAE) compared to TIL-ACT using HD-IL-2.

Secondary objectives 7

1. To evaluate the safety and the tolerability of TIL-ACT using the IL-2 analog ANV419 compared to TIL-ACT using HD-IL-2.
2. To evaluate short-term efficacy outcomes in patients receiving the IL-2 analog ANV419 or HD-IL-2.
3. To evaluate long-term efficacy outcomes in patients receiving the IL-2 analog ANV419 or HD-IL-2.
4. To evaluate the quality of life (QoL) and symptomatology in patients receiving the IL-2 analog ANV419 or HD-IL-2.
5. To evaluate anxiety and depression in patients receiving the IL-2 analog ANV419 or HD-IL-2
6. 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 optimised and affordable treatments in their healthcare systems.
7. To evaluate patient experience in the two arms of the clinical trial through qualitative interviews

Conditions and MedDRA coding

Advanced selected solid tumors: melanoma, non-small cell lung cancer (NSCLC) and cervical cancer.

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 18

1. 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 a standard anticancer treatment post-progression are also eligible to be included.
2. 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.
3. 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.
4. Patient must be at least 18 years old at the tissue procurement visit.
5. Patient must understand and voluntarily sign an informed consent document before any study-related assessments/procedures being conducted.
6. Patient must be able and willing to comply to the study visit schedule and protocol requirements.
7. Patients must have a clinical performance of Eastern Cooperative Oncology Group 0 or 1.
8. Patients are considered medically fit enough to undergo all study procedures and interventions and adequate hematological, renal, and hepatic functions defined by: a. Haemoglobin ≥9.0 g/dL. b. An absolute neutrophil count ≥ 1.5x10E9/L without the support of filgrastim. c. Platelets ≥100x10E9/L. d. 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. e. AST or ALT ≤3 x ULN. Patients with liver metastases must have AST and ALT ≤5.0 x ULN. f. Total bilirubin <2 mg/dL. Patients with Gilbert’s Syndrome must have a total bilirubin ≤3.0 mg/dL. g. 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).
9. Patients with documented LVEF of ≥45%.
10. Patients with documented FEV1, FVC and DLCO ≥50% tested by a pulmonary function test.
11. 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).
12. 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.
13. Life expectancy ≥3 months.
14. 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.
15. 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: a) Women of non-childbearing potential (WONCBP). b) 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
16. Male Participants: during the treatment period and for at least 2 months after the last dose of study treatment, agreement to: a) 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. b) Refrain from donating sperm during the study. c) Inform if his partner gets pregnant during this time.
17. 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.
18. Patients may have undergone minor surgical procedures within the past 3 weeks, as long as all toxicities have recovered to grade 1 or less.

Exclusion criteria 23

1. 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;
2. Patients with symptomatic brain metastasis.
3. Patients with leptomeningeal carcinomatosis.
4. 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.
5. Patients with an active systemic infection requiring anti-infective treatment within 14 days before preparative lymphodepleting therapy.
6. Patients with active hepatitis B or hepatitis C.
7. Patients with active autoimmune disease requiring immunosuppressive treatments.
8. Patients with a history of organ or bone marrow transplantation.
9. Patients with any form of primary immunodeficiency (such as Severe Combined Immunodeficiency Disease and AIDS).
10. 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.
11. 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.
12. Patients with a history of coronary revascularization or ischemic symptoms within 6 months of first dose of NMA-LD chemotherapy.
13. History of idiopathic pulmonary fibrosis or evidence of active pneumonitis (any origin).
14. Patients with allergies to any of the compounds included in any of the treatment products.
15. Patients with contraindications for cyclophosphamide, fludarabine and IL-2 at per protocol doses (see SmPC for details).
16. Patients who have received any approved anti-cancer cytotoxic, anti-angiogenic and ICB therapy including radiotherapy within 4 weeks before preparative lymphodepleting therapy. a) Exception: palliative radiotherapy for bone metastasis >2 weeks before preparative lymphodepleting therapy, denosumab, bisphosphonates, androgen-deprivation therapy for prostate cancer and hormonal therapy for breast cancer.
17. Patients who have received any non-cytotoxic drug and molecular targeted therapy within 4 weeks before preparative lymphodepleting therapy (or within five half-lives of the investigational product, whichever is shorter).
18. Patients who have received any investigational agent within 4 weeks before preparative lymphodepleting therapy (or within five half-lives of the investigational product, whichever is shorter).
19. Patients who have received a live, attenuated vaccination within the 4 weeks before lymphodepleting therapy.
20. Patients who have undergone major surgery in the previous 3 weeks before lymphodepleting therapy.
21. Patients who have previously received any investigational cell or gene therapies.
22. Women of childbearing potential who are pregnant or breastfeeding.
23. Presence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Mean number of predefined grade ≥3 relevant adverse events per treatment arm during the first two weeks from the first dose of interleukin (IL-2 analog ANV419 or HD-IL-2) administered. Predefined relevant AEs 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 NCI CTCAE v5.0.
2. 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 (within 3 days before TIL infusion) assessment to the first post-treatment evaluation

Secondary endpoints 11

1. 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
2. Overall Response Rate (ORR) per RECIST v1.1 as assessed by investigator.
3. Duration of Response (DOR) per RECIST v1.1 as assessed by investigator.
4. Tumor size calculated as the percentage change from baseline in tumor size (TS) to the time of the best response.
5. Progression Free Survival (PFS)
6. Overall survival (OS)
7. Trajectories of quality of life and symptomatology using the EORTC QLQ-C30 and EQ-5D-5L questionnaires.
8. Patient reported Anxiey and Depression as measured by the Hospital Anxiety and Depression Scale (HADS)
9. Physiological parameters (Heartbeat, mobility, SpO2, and sleep cycle) captured by wearable device (Garmin VivoSmart 5 smartwatch)
10. Qualitative evaluation of patient experience regarding themes around the care journey, expectations and uncertainty whilst undergoing TILs therapy through in-person or virtual qualitative interviews conducted before disease re-evaluation.
11. Direct and indirect costs of TIL-ACT using HD-IL-2 and ANV419

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 4

Comparator 2

Auxiliary 5

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Vall D Hebron Institute Of Oncology

Sponsor organisation

Vall D Hebron Institute Of Oncology

Address

Calle Natzaret 115

City

Barcelona

Postcode

08035

Country

Spain

Scientific contact point

Organisation

Vall D Hebron Institute Of Oncology

Contact name

Early Drug Development Unit (UITM)

Public contact point

Organisation

Vall D Hebron Institute Of Oncology

Contact name

Early Drug Development Unit (UITM)

Third parties 2

Locations

3 EU/EEA countries · 3 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 29 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

3 submissions — initial application plus substantial / non-substantial modifications