TIL Therapy in Metastatic Melanoma and IL2 Dose Assessment (METILDA)

A Randomised Phase II Study in Metastatic Melanoma to Evaluate the Efficacy of Adoptive Cellular Therapy With Tumour Infiltrating Lymphocytes (TIL) and Assessment of High Versus Low Dose Interleukin-2

This is a two arm, open-labelled phase II randomised trial of Tumour Infiltrating Lymphocytes (TIL) in metastatic melanoma patients given with preconditioning chemotherapy and Interleukin-2 (IL2). Eligible patients will undergo surgical tumour excision from which TIL will be derived, cultured and expanded. Patients will receive preconditioning chemotherapy with cyclophosphamide (60mg/kg) day -7 and day -6, followed by fludarabine (25mg/m2) day -5 to day -1. The autologous TILs will be re-infused on day 0 and the patients will receive up to 12 doses of intravenous High Dose Interleukin-2 (HD-IL2) or Low Dose Interleukin-2 (LD-IL2) depending on the randomised arm.

The primary objectives are response rate assessed and compared by CT scans carried out at week 6, week 12 and at 12 weekly intervals thereafter and the evaluation of feasibility and tolerability of TIL therapy with HD-IL2 versus LD-IL2.

Study Overview

• Status: Terminated
• Conditions: Metastatic Melanoma
• Intervention / Treatment: Drug: Cyclophosphamide; Drug: Fludarabine; Drug: Interleukin-2; Genetic: Tumour Infiltrating Lymphocytes

• Study Type: Interventional
• Enrollment (Actual): 2
• Phase: Phase 2

Contacts and Locations

Study Locations

• United Kingdom
  • Greater Manchester
    • Manchester, Greater Manchester, United Kingdom, M20 4BX
      • The Christie NHS Foundation Trust

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Patients must have histologically confirmed malignant melanoma with confirmed evidence of progressive metastatic disease and to have failed / refused standard therapies.
• They must have resectable metastatic lesion(s) of at least 2cm in diameter.
• There must be measurable / evaluable disease after the surgical resection.
• Patients may have had any previous systemic therapies including anti-CTLA4 (Ipilimumab) agent provided they are otherwise fit for treatment.
• Tumour samples may be taken prior to other systemic therapy if patients wish to store the sample for possible future use.
• Age equal to or greater than 18 years.
• World Health Organisation (WHO) performance status of 0 or 1.
• Life expectancy >3months.
• LVEF > 50% as measured by ECHO/MUGA and satisfactory stress ECHO (if over 60 or had previous cardiotoxic therapy).
• Haemoglobin (Hb) ≥ 9.0 g/dL
• Neutrophils ≥ 1.0 x 109/L
• Platelets (Plts) ≥ 100 x 109/L
• serum bilirubin ≤ 1.5 x ULN
• alanine aminotransferase (ALT) ≤ 5 x ULN
• aspartate aminotransferase (AST) ≤ 5 x ULN
• alkaline phosphatase (ALP) ≤ 5 x ULN
• Serum creatinine ≤ 0.15 mmol/L
• Female patients of child-bearing potential must have a negative serum or urine pregnancy test prior treatment and agree to use appropriate medically approved contraceptive precautions for four weeks prior to entering the trial, during the trial and for six months afterwards.
• Male patients must agree to use barrier method contraception during the TIL treatment and for six months afterwards.
• Full written informed consent

Exclusion Criteria:

• Those receiving radiotherapy, targeted therapy, immunotherapy, systemic steroids, or chemotherapy during the previous four weeks (six weeks for nitrosoureas and Mitomycin-C) prior to treatment or during the course of the treatment.
• All toxic manifestations of previous treatment must have resolved. Exceptions to this are alopecia or certain Grade 1 toxicities, which an investigator considers should not exclude the patient.
• Previous radiotherapy treatment to the resectable metastatic site(s) within 1 year and no other suitable metastatic sites.
• Participation in any other clinical trial within the previous 30 days or during the course of this treatment.
• Previous allogeneic transplant.
• Patient with ocular melanoma.
• Clinically significant cardiac disease. Examples would include unstable coronary artery disease, myocardial infarction within 6 months or Class III or IV AHA criteria for heart disease (see Appendix 6)
• Patients who are high medical risks because of non-malignant systemic disease, including those with, uncontrolled cardiac or respiratory disease, or other serious medical or psychiatric disorders which in the lead clinicians opinion would not make the patient a good candidate for this therapy.
• Concurrent systemic infections (CTCAE Grade 3 or more) within the 28 days prior to treatment.
• Prior history of malignancies at other sites, with the exception of adequately treated cone-biopsied in situ carcinoma of the cervix uteri and basal or squamous cell carcinoma of the skin.
• Patients known or found to be serologically positive for Hepatitis B, C, HIV or HTLV.
• History of systemic autoimmune disease which could be life-threatening if reactivation occurred (for example hypothyroidism would be permissible, prior rheumatoid arthritis or SLE would not).
• Patients with more than 3 brain metastases.
• Patients with symptomatic brain metastasis measuring more than 10mm in diameter or evidence of significant surrounding oedema on MRI will not be eligible until after treatment demonstrating no clinical or radiologic CNS progression for at least 2 months. Patient must be able to wean off any steroid use 3 weeks before treatment commencement.
• Patients who are likely to require long-term systemic steroids or other immunosuppressive therapy.
• Pregnant and lactating women.
• Radiotherapy to >25% skeleton.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: ARM A: High Dose Interleukin-2 (HD IL2); Eligible participants will undergo surgical tumour excision from which TIL will be derived, cultured and expanded. Participants will receive preconditioning chemotherapy with cyclophosphamide (60mg/kg) day -7 and day -6, followed by fludarabine (25mg/m2) day -5 to day -1. The autologous TILs will be re-infused on day 0 and the patients will receive up to 12 doses of intravenous HD IL2	Drug: Cyclophosphamide; Drug: Fludarabine; Drug: Interleukin-2; Other Names: IL2; Genetic: Tumour Infiltrating Lymphocytes; Other Names: TIL
Active Comparator: ARM B: Low Dose Interleukin-2 (LD IL2); Eligible participants will undergo surgical tumour excision from which TIL will be derived, cultured and expanded. Participants will receive preconditioning chemotherapy with cyclophosphamide (60mg/kg) day -7 and day -6, followed by fludarabine (25mg/m2) day -5 to day -1. The autologous TILs will be re-infused on day 0 and the patients will receive up to 12 doses of intravenous LD-IL2	Drug: Cyclophosphamide; Drug: Fludarabine; Drug: Interleukin-2; Other Names: IL2; Genetic: Tumour Infiltrating Lymphocytes; Other Names: TIL

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Disease response according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria	Subject will have CT scan at 6,12,24 weeks post treatment to compare with baseline CT scan in order to assess disease response to therapy	Best response

Collaborators and Investigators

• Sponsor: The Christie NHS Foundation Trust
• Collaborators: National Institute for Health Research, United Kingdom
• Investigators: Principal Investigator: Paul Lorigan, MD, The Christie NHS Foundation Trust; Principal Investigator: Robert E Hawkins, MD, The University of Manchester

Study record dates

Study Major Dates

• Study Start: March 1, 2014
• Primary Completion (Actual): July 24, 2015
• Study Completion (Actual): July 24, 2015

Study Registration Dates

• First Submitted: November 21, 2013
• First Submitted That Met QC Criteria: November 21, 2013
• First Posted (Estimate): November 26, 2013

Study Record Updates

• Last Update Posted (Actual): April 20, 2023
• Last Update Submitted That Met QC Criteria: April 18, 2023
• Last Verified: April 1, 2023

More Information

Terms related to this study

• 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; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Cyclophosphamide; Fludarabine; Interleukin-2
• Other Study ID Numbers: 11_DOG14_12; 2013-001071-20 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No