Hepatic Arterial Infusion of Autologous Tumor Infiltrating Lymphocytes in Patients With Melanoma and Liver Metastases (HAITILS)

A Phase I Study Using Hepatic Arterial Infusion of Autologous Tumor Infiltrating Lymphocytes in Patients With Melanoma and Liver Metastases

The purpose of this study is to evaluate the feasibility, safety and tolerability of treatment with autologous tumor infiltrating lymphocytes (TIL) administered via hepatic arterial infusion in patients with liver metastases (including but not restricted to) of malignant melanoma.

Study Overview

• Status: Recruiting
• Conditions: Metastatic Cutaneous Melanoma; Metastatic Uveal Melanoma
• Intervention / Treatment: Drug: Autologous Tumor Infiltrating Lymphocytes; Drug: Melphalan; Drug: Interleukin-2

• Study Type: Interventional
• Enrollment (Anticipated): 6
• Phase: Phase 1

Contacts and Locations

Study Locations

• Sweden
  • Gothenburg, Sweden
    • Recruiting
    • Department of Oncology, Sahlgrenska University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Patients 18-75 years of age on the day of signing informed consent.
2. Patient is willing and able to provide written informed consent and comply with study procedures. Written informed consent must be signed and dated before the start of specific protocol procedures.

3. Patient must have a histologically/cytologically confirmed diagnosis of:

   • stage IV uveal melanoma with or without any previous systemic therapy OR
   • stage IV cutaneous melanoma with confirmed progression following at least one or two prior systemic therapies including a programmed cell death protein-1 (PD-1) inhibitor with or without a CTLA-4 inhibitor; and if BRAF V600 mutation-positive, also a BRAF inhibitor or a BRAF inhibitor in combination with a MEK inhibitor.
4. Measurable disease by computed tomography (CT) per RECIST 1.1 criteria with at least one target lesion identified in the liver and where the distribution pattern of metastasis is predominantly engaging the liver as judged by the investigator.
5. At least one resectable lesion in the liver (or aggregate of lesions resected) of a minimum size of 0.5 cm in diameter post- resection to generate TILs.
6. ECOG performance status of 0 - 2.
7. Female patient of childbearing potential should have a negative urine or serum pregnancy test within 72 hours prior to receiving the first treatment. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
8. Female patients of childbearing potential must be willing to use a highly efficient method of contraception (Pearl index <1), for the course of the study through 120 days after the last dose of study medication.
9. Male patients with women of childbearing potential partners must agree to use a condom for contraception, starting with the first dose of study therapy through 120 days after the last dose of study therapy.

Exclusion Criteria:

1. Life expectancy of less than 3 months.
2. History of interstitial lung disease (ILD) or (non-infectious) pneumonitis.
3. Reduced renal function defined as S- Creatinine >=1.5xULN or Creatinine Clearance < 40 mL/min, calculated using the Cockroft and Gault formula.
4. Reduced hepatic function (defined as ASAT, ALAT, bilirubin > 3*ULN and PK- INR > 1.5) or medical history of liver cirrhosis or portal hypertension.
5. Hemoglobin <90 g/L or platelets <100x109/L or neutrophils <1.5x109/L
6. Use of live vaccines four weeks before or after the start of study.
7. History of severe hypersensitivity reactions to monoclonal antibodies.
8. Active infection.
9. Infection of human immunodeficiency virus (HIV), acquired immunodeficiency syndrome (AIDS), hepatitis B or hepatitis C.
10. Active autoimmune disease or a history of known or suspected autoimmune disease.
11. A condition requiring systemic treatment with either corticosteroids (>10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids and adrenal replacement doses >10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.
12. Concomitant therapy with any other anti- cancer therapy, concurrent medical conditions requiring use of immunosuppressive medications or use of other investigational drugs.
13. Has a known additional malignancy of other diagnosis that is progressing or requires active treatment.
14. Pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of study drug.
15. A history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the patient's participation for the full duration of the study, or is not in the best interest of the patient to participate, in the opinion of the treating Investigator.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SEQUENTIAL
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Autologous tumor infiltrating lymphocytes (TIL); Autologous TIL administered via hepatic arterial infusion followed by low dose Interleukin-2 after preconditioning chemotherapy with Melphalan.	Drug: Autologous Tumor Infiltrating Lymphocytes; Administered via hepatic arterial infusion; Drug: Melphalan; Melphalan will be administered once as an intravenous infusion.; Drug: Interleukin-2; After TIL infusion, Interleukin-2 will be administered subcutaneously once daily for up to 14 days.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence and severity of adverse events (AEs) and serious adverse events (SAEs)	Adverse events are graded according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0	5 years from start of chemotherapy

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective response rate (ORR)	Defined by RECIST 1.1	2 years from start of chemotherapy
Clinical benefit rate (CBR)	Defined by RECIST 1.1	18 weeks
Progression free survival (PFS)	Evaluation of progression-free survival	2 years
hepatic Progression free survival (hPFS)	Evaluation of hepatic progression-free survival	2 years
Duration of objective response (DOR)	Evaluation of duration of response	2 years
Overall Survival (OS)	Evaluation of overall survival	5 years
Evaluation of feasibility of an automated production of TILs	Defined as the proportion of patients included that receive treatment with the TIL product.	2 years

Collaborators and Investigators

• Sponsor: Vastra Gotaland Region
• Collaborators: Miltenyi Biomedicine GmbH

Study record dates

Study Major Dates

• Study Start (ACTUAL): February 6, 2023
• Primary Completion (ANTICIPATED): February 1, 2025
• Study Completion (ANTICIPATED): February 1, 2030

Study Registration Dates

• First Submitted: March 5, 2021
• First Submitted That Met QC Criteria: March 22, 2021
• First Posted (ACTUAL): March 23, 2021

Study Record Updates

• Last Update Posted (ACTUAL): February 10, 2023
• Last Update Submitted That Met QC Criteria: February 7, 2023
• Last Verified: January 1, 2023

More Information

Terms related to this study

• Keywords: Antineoplastic Agents, Immunological; Melphalan; Interleukin-2; Adoptive Cell Transfer; Lymphocytes, Tumor-Infiltrating; Hepatic arterial infusion; bioreactor
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroendocrine Tumors; Nevi and Melanomas; Melanoma; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Analgesics, Non-Narcotic; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Melphalan; Interleukin-2
• Other Study ID Numbers: 2020-006126-31

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No