A phase 2, Multicenter Study of TILs Treatment in Germ Cell tumors: the ARES Study

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Fundacio Institut D'Investigacio Biomedica De Bellvitge IDIBELL

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Decision date (initial)

2025-11-04

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Instituto de Salud Carlos III mediante el proyecto ICI23/00065 y cofinanciado por la Unión Europea

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Therapy, Safety

• To evaluate selected short-term efficacy outcomes of autologous TIL (VHIO-TIL-01) as a single therapy in the target population.

Secondary objectives 2

1. To characterize the safety profile of TIL (VHIO-TIL-01) as a single therapy in the target population.
2. To evaluate short and long-term efficacy outcomes of autologous TIL (VHIO-TIL-01) as a single therapy in the target population

Conditions and MedDRA coding

Germ Cell Tumors refractory to salvage chemotherapy

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 14

1. Patients must have histologically or pathologically confirmed diagnosis of advanced Germ Cell Tumors refractory to salvage chemotherapy
2. Patients must be ≥ 18 years at the time of consent
3. Patients must have at least one resectable lesion (or aggregate lesions) of a minimum 1.5 cm in diameter post-resection for TIL investigational product production or if tumor resection can not be performed, TILs could be isolated from at least 6 core-biopsies. a. If the lesion considered for resection for TIL generation is within a previously irradiated field, the lesion must have demonstrated radiographic progression prior to resection. b. Patient must have an adequate histopathology specimen for protocol-required testing (see Section 5.6).
4. Patients must have evidence of progressive or recurrent GCT (measurable or non- measurable) following two lines of platinum-based chemotherapy. This is defined by at least one of the follow criteria: o Tumor biopsy of new or growing or unresectable lesions demonstrating viable non- teratomatous GCT (no adjuvant treatment after macroscopically complete resection of viable GCT is allowed). In the event of an incomplete gross resection where viable GCT is found, patients will be considered eligible for the study. o Elevated serum tumor markers (B-hCG or FP) are increasing. Increase of an elevated LDH alone does not constitute progressive disease. o Development of new or enlarging lesions in the setting of persistently elevated B-hCG or FP after two lines of platinum-based chemotherapy, even if the B-hCG and FP are not continuing to increase.
5. Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and an estimated life expectancy of ≥3 months in the opinion of the Investigator.
6. Patients of childbearing potential or those with partners of childbearing potential must be willing to practice an approved method of highly effective birth control during treatment and for 12 months after receiving all protocol related therapy (Note: Females of reproductive potential are to use effective contraception during treatment and for 12 months after their last dose of IL-2). Males may not donate sperm, and female may not donate ovules during the study or for 12 months after treatment discontinuation, whichever occurs later. Approved methods of birth control are as follows: - Combined (estrogen and progesterone containing) hormonal birth control associated with inhibition of ovulation: oral, intravaginal, transdermal progesterone-only hormonal birth control associated with inhibition of ovulation: oral, injectable, implantable intrauterine device (IUD), intrauterine hormone-releasing system (IUS), bilateral tubal occlusion. - Vasectomized partner. - True absolute sexual abstinence when this is in line with the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar ovulation, symptothermal, post-ovulation methods) is not acceptable.
7. Patients must have the following hematologic parameters: a. Absolute neutrophil count (ANC) ≥1x109/L b. Hemoglobin ≥9.0 g/dL c. Platelet count ≥100x109/L
8. Patients must have adequate organ function: a. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤3 times the upper limit of normal (ULN), or ≤5 times ULN in patients with liver metastasis; b. An estimated creatinine clearance ≥40 mL/min using the Cockcroft Gault formula at Screening; c. Total bilirubin ≤2 mg/dL: i. Patients with Gilbert’s Syndrome must have a total bilirubin ≤3 mg/dL
9. Patients must be seronegative for the human immunodeficiency virus (HIV1 and HIV2). Patients with positive serology for hepatitis B virus surface antigen (HBsAg), hepatitis B core antibody (anti-HBc), or hepatitis C virus (anti-HCV) indicating acute or chronic infection may be enrolled if the viral load by polymerase chain reaction (PCR) is undetectable with/without active treatment. Additional serology testing may be required depending on local prevalence of certain viral exposures.
10. Patients must have a washout period from prior anticancer therapy(ies) of a minimum duration, as detailed below prior to the first study treatment (ie, start of NMA-LD): a. Chemotherapy: the washout is a minimum of 14 days, prior to the start of treatment. b. Immunotherapy, prior checkpoint-targeted therapy, other monoclonal antibodies (mAbs), or vaccines are allowed if disease progression is confirmed prior to or within the washout period of ≥21 days prior to the start of NMA-LD. c. Palliative radiation therapy: prior external beam radiation is allowed provided all radiation-related toxicities are resolved to Grade 1 or baseline, excluding alopecia, skin pigmentation change, or other clinically insignificant events, e.g., small area radiation dermatitis or rectal or urinary urgency. d. Surgery/pre-planned procedure: previous surgical procedure(s) is permitted provided that wound healing has occurred, all complications have resolved, and at least 14 days have elapsed (for major operative procedures) prior to the tumor resection
11. Patients must have recovered from all prior anticancer treatment-related adverse events (TRAEs) to Grade ≤ 1 (per Common Terminology Criteria for Adverse Events [CTCAE], version 5.0 [v5.0]), except for alopecia or vitiligo.
12. Patients with stable Grade ≥ 2 toxicity from prior anticancer therapy may be considered on a case-by-case basis after consultation with the Medical Monitor.
13. Patients must have provided written authorization for use and disclosure of protected health information.
14. In the opinion of the Investigator, the patient must be able to complete all study required procedures and has the ability to understand the requirements of the study and freely give consent to participate. Specifically, the patient has to provide written informed consent (as evidenced by signature on an ICF approved by an Institutional Review Board/Independent Ethics Committee [IRB/IEC]) and has to agree to abide by the study restrictions and return to the site for required assessments.

Exclusion criteria 13

1. Patients who have received an organ allograft. High-dose chemotherapy followed by autologous stem cell transplantation as treatment of germ-cell cancer is allowed.
2. Patient with symptomatic and/or untreated brain metastases: Patients with definitively-treated brain metastases will be considered for enrollment if, prior to the start of treatment the patient is clinically stable for ≥ 2 weeks, there are no new brain lesions via magnetic resonance imaging (MRI) post-treatment, and the patient does not require ongoing corticosteroid treatment.
3. Patient who is on a systemic steroid therapy within 21 days of enrollment.
4. Patients who have an active medical illness(es), which in the opinion of the Investigator, would pose increased risks for study participation; such as systemic infections (e.g., syphilis or any other infection requiring antibiotics), coagulation disorders, or other active major medical illnesses of the cardiovascular, respiratory, or immune systems.
5. Patient with active or prior documented autoimmune or inflammatory disorders (including pneumonitis, inflammatory bowel disease [e.g., colitis or Crohn’s disease], diverticulitis [with the exception of diverticulosis], systemic lupus erythematosus, sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves’ disease, rheumatoid arthritis, hypophysitis, uveitis, etc.]). The following are exceptions to this criterion: a. Patients with vitiligo or alopecia; b. Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement; c. Any chronic skin condition that does not require systemic therapy; or d. Patients with celiac disease controlled by diet alone
6. Patients who have received a live or attenuated vaccination within 28 days prior to the start of treatment.
7. Patients who have any form of primary immunodeficiency (such as severe combined immunodeficiency disease [SCID] or acquired immune deficiency syndrome [AIDS]).
8. Patients with a history of hypersensitivity to any component of the study drugs or with known hypersensitivity to any component of TIL product formulation including, but not limited to any of the following: a. NMA-LD (cyclophosphamide, mesna, and fludarabine) b. IL-2/ aldesleukin (Proleukin®) c. Antibiotics of the aminoglycoside group (ie, streptomycin, gentamicin [excluding those who are skin-test negative for gentamicin hypersensitivity]) d. Any component of the TIL product formulation including dimethyl sulfoxide [DMSO], human serum albumin [HSA], IL-2, and dextran-40
9. Patients who have a left ventricular ejection fraction (LVEF) <45% or who are New York Heart Association (NYHA) Class II or higher.
10. Patients who have obstructive or restrictive pulmonary disease and have a documented FEV1 (forced expiratory volume in 1 second) ≤60% of predicted normal. If a patient is not able to perform reliable spirometry due to abnormal upper airway anatomy (ie, tracheostomy), a 6-minute walk test may be used to assess pulmonary function. Patients who are unable to walk a distance of at least 80% predicted for age and sex or demonstrates evidence of hypoxia at any point during the test (SpO2 <90%) are excluded.
11. Patients who have had another primary malignancy within the previous 3 years (except for those which do not require treatment or have been curatively treated >1 year ago, and in the judgment of the Investigator, does not pose a significant risk of recurrence including, but not limited to, non-melanoma skin cancer, DCIS, LCIS, prostate cancer Gleason score ≤6 or bladder cancer).
12. Participation in another clinical study with an investigational product the previous 21 days.
13. Patients protected by the following constraints: a. Hospitalized persons without consent, or persons deprived of liberty because of a judiciary or administrative decision; Sponsor’s Medical Monitor. b. Adult persons with a legal protection measure, or persons who cannot express their consent, or patients in emergency situations who cannot consent to participate in the trial.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Favorable response rate defined as a complete response per RECIST v1.1 with negative tumor markers (aFP, bHCG, LDH); or a partial response per RECIST v1.1 with a 50% decrease in tumor markers; or stable disease per RECIST v1.1 with negative tumor markers; or growing teratoma as assessed by the investigator.

Secondary endpoints 7

1. Incidence of Grade ≥3 treatment emergent adverse events (TEAE) according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v5.0.
2. Complete Response (CR) Rate per RECIST v1.1 as assessed by investigator with negative tumor markers.
3. Partial response (PR) per RECIST v1.1 with at least 50% decrease in tumor markers.
4. Growing teratoma rate.
5. Duration of response (DOR) per RECIST v1.1 assessed by investigator and tumor markers.
6. Progression-free survival (PFS) defined as the time from the date of treatment administration to the date of first documentation of disease progression or death due to any cause, whichever occurs first. For a patient who has not progressed and is last known to be alive, PFS will be censored at the last response assessment that is stable disease or better.
7. Overall survival (OS) defined from the date of treatment administration to the date of death.

Investigational products

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

Test 1

Auxiliary 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Fundacio Institut D'Investigacio Biomedica De Bellvitge IDIBELL

Sponsor organisation

Fundacio Institut D'Investigacio Biomedica De Bellvitge IDIBELL

Address

Avinguda De La Gran Via De L'hospitalet 199

City

L'Hospitalet De Llobregat

Postcode

08908

Country

Spain

Scientific contact point

Organisation

Fundacio Institut D'Investigacio Biomedica De Bellvitge IDIBELL

Contact name

Clinical trial coordinator

Public contact point

Organisation

Fundacio Institut D'Investigacio Biomedica De Bellvitge IDIBELL

Contact name

Clinical trial coordinator

Locations

1 EU/EEA country · 3 investigational sites

By country

Investigational sites

Results and documents

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

Documents 7 files

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

Application history

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