Assessment of the Safety and Tolerability of ex Vivo Next-generation Neoantigen-selected Tumor-infiltrating Lymphocyte (TIL) Therapy in Advanced Epithelial Tumors and Immune Checkpoint Blockade (ICB) Resistant Solid Tumors

NCT05141474 | Recruiting Early Phase 1

• 1 other identifier: VHIO20001
• Study Type: interventional
• Target: 10
• 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. Adoptive cell therapy using tumor-infiltrating lymphocytes product (TIL-ACT) is a well-established combination therapy currently under study in several world reference centers, using an autologous cell product without genetic modifications. This cell product consists of tumor-infiltrating lymphocytes (TIL), which are collected from the patient and expanded in the lab under specific conditions to enhance its antitumoral efficacy before reinfusion in the same patient. However, this cell product alone does not achieve adequate efficacy, and a combination of both previous non-myeloablative lymphodepleting (NMA-LD) chemotherapy and subsequent cytokine therapy (specifically IL-2) is needed to support the expansion of the infused cells. The investigators hypothesize that TILs enriched for neoantigen recognition are superior to unselected TILs at mediating tumor regression in patients with epithelial tumors and even other solid tumors where immune checkpoint blockade (ICB) is approved and used as part of standard therapy. The investigators propose to manufacture a T-cell product composed of TILs that are selected based on their ability to recognize patient-specific neoantigens and to use these to treat patients with metastatic, refractory, epithelial cancers, as well as ICB-resistant solid tumors. Furthermore, it also proposed to study the tumor and T cells at baseline and after treatment to investigate whether specific phenotypic and functional traits may be associated with clinical outcome. Primary objective: To evaluate the safety and the tolerability of ex vivo next generation neoantigen-selected Tumor-infiltrating Lymphocyte (TIL) in patients with metastatic or unresectable epithelial tumors and immune checkpoint blockade (ICB) resistant solid tumors. Secondary objectives:

• To determine the success in producing active specific TILs from our target patients.
• To evaluate the initial clinical activity of the NEXTGEN-TIL products in our target patients.

Conditions

Epithelial Tumors, Malignant; Malignant Solid Tumor

Keywords

Immune checkpoint blockade resistant tumors; Tumor-infiltrating Lymphocyte; Adoptive Cell Therapy

Outcome Measures

Primary Outcomes (8)

• Incidence of Adverse Events (AE)

  Nature and frequency of AE, graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v5.0.

  From baseline through 6 months from the last dose of IL-2 or until the first dose of the next anticancer therapy, whichever occurs first

• Incidence of Serious Adverse Events (SAE)

  Nature and frequency of SAE, graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v5.0.

  From baseline through 6 months from the last dose of IL-2 or until the first dose of the next anticancer therapy, whichever occurs first

• Treatment-limiting Toxicity (TLT)

  Toxicities related to treatment administration that, if recurrent at high enough frequency (≥2 patients treated), should trigger review by the Independent Data Safety Monitoring Board (IDSMB), which could lead to recommendations for treatment modifications for subsequent patients.

  From the first dose of study treatment (Day -5) to 30 days after

• Incidence of alterations in clinical laboratory test results

  Nature and frequency of abnormalities found in clinical laboratory test results

  From baseline through study completion, an average of 2 years

• Incidence of alterations in electrocardiogram assessment

  Nature and frequency of abnormalities found in electrocardiogram

  From baseline through study completion, an average of 2 years

• Incidence of alterations in vital signs measurements

  Nature and frequency of abnormalities found in vital signs.

  From baseline through study completion, an average of 2 years

• Incidence of physical examination findings

  Nature and frequency of abnormalities found in the physical examination.

  From baseline through study completion, an average of 2 years

• Assessment of performance status

  Patient performance status assessed as per Eastern Cooperative Oncology Group (ECOG) score, where grade 0 is for fully active and capable patient and grade 5 is death.

  From baseline through study completion, an average of 2 years

Secondary Outcomes (4)

• Neoantigen-selected TIL analysis

  At baseline

• Overall Response Rate (ORR)

  From baseline through disease progression, assessed up to 36 months after last dose of IL-2

• Duration of Response (DOR)

  From baseline through disease progression, assessed up to 36 months after last dose of IL-2

• Progression-Free Survival (PFS)

  From baseline through disease progression, assessed up to 36 months after last dose of IL-2

Study Arms (1)

NEXTGEN-TIL

EXPERIMENTAL

Subjects will receive a therapy based on Tumor-infiltrating Lymphocyte (NEXTGEN-TIL product) preceded by a preparative non-myeloablative lymphodepleting (NMA-DL) regimen and followed by IL-2 infusion. Patients will be followed-up for 2 years, assessed at weeks 2, 3, 4, 6, 9, 12, 18, 24, 30, 36 (9 months), and then at 1 year, 1,5 and 2 years.

Biological: NEXTGEN-TIL; Drug: Non-myeloablative Lymphodepletion (NMA-LD) Regimen; Drug: Interleukin-2

Interventions

NEXTGEN-TIL BIOLOGICAL

NEXTGEN-TIL product is a cellular investigational product comprising a live cell suspension of autologous tumor-infiltrating lymphocytes derived from the patient's own tumor. Each dose contains at least 5 x 10\^8 total viable lymphocytes, and a maximum of 1.11x10\^11. It will be administered IV on Day 0 (24h after the last dose of Fludarabine).

Also known as: Tumor-infiltrating Lymphocyte Adoptive Cell Therapy

NEXTGEN-TIL

Non-myeloablative Lymphodepletion (NMA-LD) Regimen DRUG

Patients will receive a NMA-LD chemotherapy based on Cyclophosphamide 60 mg/kg IV (once daily on Days -5 and -4) and Fludarabine 25 mg/m2 IV (once daily on Days -5 to -1).

Also known as: Cyclophosphamide, Fludarabine

NEXTGEN-TIL

Interleukin-2 DRUG

Patients will receive sequential doses of 720,000 IU/kg IV IL-2 every 8-24 hours depending on patient tolerance. It will be administered on Days 0 to 2, starting between 3 and 24 hours after the completion of NEXTGEN-TIL infusion. IL-2 doses may be skipped in case of toxicity. If 2 sequential doses or more than 2 non-sequential doses of IL-2 are skipped due to patient intolerance or the discretion of the investigator, IL-2 administration must be stopped.

Also known as: IL-2, Aldesleukin

NEXTGEN-TIL

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 solid tumors. The disease must have progressed to at least one standard therapy (including at least one prior line with ICB for the group of patients with tumors where ICB is approved), or the patient is unable/unwilling to receive standard therapy or no standard therapy exists for a particular disease.
• Patients must have at least one adequate lesion (primary tumor or metastasis) for resection or biopsy for TIL generation with minimal morbidity (preferentially using imaging-guided minimally invasive procedures).
• Note: If this lesion was previously irradiated, the lesion must have demonstrated progression prior to resection/biopsy.
• 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 by investigator to undergo all study procedures and interventions.
• Patients with documented left ventricular ejection fraction (LVEF) of ≥45%.
• Patients with documented forced expiratory volume at one second (FEV1), forced vital capacity (FVC) and diffusing capacity of lung for carbon monoxide (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 (HCV) 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 ≥6 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.
• The disease must have progressed to the last standard therapy, including at least one prior line with ICB for the group of patients with tumors where ICB is approved, and no subsequent approved therapy is available, or the patients are unable/unwilling to receive standard therapy, or no standard therapy exists for a particular disease.

You may not qualify if:

• Patients with symptomatic and/or untreated brain metastases. Note: Patients with definitively-treated brain metastases will be considered for enrollment after discussion with Medical Monitor; if, prior to the start of NMA-LD the patient is clinically stable for ≥3 months, there are no new brain lesions via magnetic resonance imaging (MRI) post-treatment, and the patient does not require corticosteroid treatment \>10 mg prednisone or equivalent per day.
• 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.
• 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.
• Patients with contraindications for cyclophosphamide, fludarabine and IL-2 at per protocol doses.

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

Carcinoma

Interventions

Clinical Protocols; Cyclophosphamide; fludarabine; Interleukin-2; aldesleukin

Condition Hierarchy (Ancestors)

Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms

Intervention Hierarchy (Ancestors)

Therapeutics; Epidemiologic Study Characteristics; Health Care Evaluation Mechanisms; Quality of Health Care; Health Care Quality, Access, and Evaluation; 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

0034 93 489 30 00; egarralda@vhio.net

Susana Muñoz

CONTACT

smunoz@vhio.net

Study Design

• Study Type: interventional
• Phase: early phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: First-in-human, open-label, non-controlled, single-centre, phase I trial. Sequential recruitment: The first six patients will be included for safety assessment. If no more than one treatment-limiting toxicity (TLT) is observed, four additional patients will be included for the final safety population analysis (a total of 10 patients).

Study Record Dates

• First Submitted: October 28, 2021
• First Posted: December 2, 2021
• Study Start: October 28, 2021
• Primary Completion (Estimated): January 1, 2027
• Study Completion (Estimated): January 1, 2027
• Last Updated: November 7, 2024

Record last verified: 2024-11

Data Sharing

• IPD Sharing: Will not share

Locations

ES (1)