TIL and Anti-PD1 in Metastatic Melanoma

NCT03638375 | Unknown Phase 1 DMC

• 1 other identifier: NL64805.000.18
• Study Type: interventional
• Target: 34
• Locations: 1 country
• Sites: 1

Brief Summary

The ACTME study is an investigator initiated, single center phase I/II clinical trial for patients with progressive unresectable stage III or stage IV melanoma. The trial consists of both a phase I part to determine safety and feasibility and a phase II part to evaluate first clinical activity of IFN-alpha, nivolumab and TIL. The treatment with IFN-alpha will be added after the combination of TIL and nivolumab has proven to be safe.

Conditions

Toxicity, Drug; Adverse Drug Event; Effects of Immunotherapy

Keywords

Metastatic melanoma; anti-PD1; TIL; interferon-alpha; adoptive cell therapy; nivolumab

Outcome Measures

Primary Outcomes (1)

• Incidence of treatment-related serious adverse events as assessed by CTCAE 4.0 criteria

  To evaluate the safety and toxicity of ACT with nivolumab, followed by evaluating the safety and toxicity of IFN-alpha, and nivolumab plus ACT according to the common terminology criteria of adverse events (CTCAE) 4.0 criteria. Treatment related adverse events grade 3 or less and SAE related to treatment that do not result in treatment termination are considered acceptable for continuation of the study. * Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. * Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL * Grade 3: Severe or medically significant but not immediately life-threatening hospitalization or prolongation of hospitalization indicated; disabling; limiting self care ADL * Grade 4: Life-threatening consequences; urgent intervention indicated * Grade 5: Death related to AE

  14 weeks after start of treatment

Secondary Outcomes (7)

• Evaluation of disease control rate according to RECIST 1.1 criteria

  14 weeks after first nivolumab infusion

• Evaluation of disease control rate according to immune RECIST response criteria

  14 weeks after first nivolumab infusion

• To study the potential working mechanisms of the different treatment compounds. Therefore, blood will be drawn to analyse changes in circulating immune cells and their function during treatment.

  Within 5 years after first inclusion

• To establish a possible prognostic biomarker profile in patients tumor material, blood, serum and TILs used for infusion

  Within 5 years after first inclusion

• To characterize the infusion product

  Within 5 years after first inclusion

Study Arms (2)

Treatment with nivolumab plus TIL

EXPERIMENTAL

In the first cohort the subcutaneous IFN-alpha injections will be omitted and the combination of nivolumab and TIL is given. * Nivolumab is given 3mg/kg i.v. once every two weeks and starts 4 weeks before the first TIL infusion * TILs are given at a dose ranging between 2.5-7.5x10\^8 T cells i.v. once every three weeks, three times per cycle.

Drug: Nivolumab & Tumor Infiltrating Lymphocytes with/without Interferon-Alpha

Treatment with Nivolumab plus TIL and IFN-alpha

EXPERIMENTAL

In the second cohort of the first phase and the second phase of the trial patients will be treated with subcutaneous IFN-alpha injections in combination with TIL and nivolumab. * IFN-alpha is given at a fixed dose of 3 million IU s.c. every day, for 11 weeks, starting one week before the first TIL infusion * Nivolumab is given 3mg/kg i.v. once every two weeks and starts 4 weeks before the first TIL infusion * TILs are given at a dose ranging between 2.5-7.5x10\^8 T cells i.v. once every three weeks, three times per cycle.

Drug: Nivolumab & Tumor Infiltrating Lymphocytes with/without Interferon-Alpha

Interventions

Nivolumab & Tumor Infiltrating Lymphocytes with/without Interferon-Alpha DRUG

During 15 weeks patients will be treated with nivolumab (3mg/kg i.v.) once every two weeks. Four weeks after starting nivolumab, patients will receive their first TIL infusion (2.5-7.5x10\^8 T cells i.v.) once every three weeks for three infusions. In the second group treatment with IFN-alpha (3 million IU s.c.) daily will be added one week before the first TIL infusion and will be continued for 11 weeks.

Treatment with Nivolumab plus TIL and IFN-alpha; Treatment with nivolumab plus TIL

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age ≥ 18 years
• Histologically or cytologically proven metastatic skin melanoma
• Melanoma must be at one of the following AJCC 2009 stages:
• Unresectable (or residual) regional metastatic melanoma, i.e. in terms of AJCC 2009 classification unresectable stage III melanoma, or
• Stage IV melanoma, i.e. distant metastatic disease (any T, any N, M1a, M1b or M1c), and normal LDH
• Patients have failed on standard treatment options
• Patients with brain metastases have to be neurologically stable for at least 2 months and should not use dexamethasone
• Presence of measurable progressive disease according to RECIST version 1.1
• Expected survival of at least 3 months
• WHO performance status ≤1
• Within the last 2 weeks prior to study day 1, vital laboratory parameters should be within normal range, except for the following laboratory parameters, which should be within the ranges specified:
• Lab Parameter Range Hemoglobin ≥ 6,0 mmol/l Granulocytes ≥ 1,500/µl Lymphocytes ≥ 700/µl Platelets ≥ 100,000/µl Creatinine clearance ≥ 60 min/ml Serum bilirubin ≤ 40 µmol/l ASAT and ALAT ≤ 5 x the normal upper limit LDH ≤ 2 x the normal upper limit
• Viral tests must be performed at least 30 days before surgery:
• Negative for HIV type 1/2, HTLV and TPHA
• No HBV (hepatitis B virus) antigen or antibodies against HBc in the serum

You may not qualify if:

• Patients with brain metastases who are neurologically unstable and/or use dexamethasone
• Clinically significant heart disease (NYHA Class III or IV)
• Other serious acute or chronic illnesses, e.g. active infections requiring antibiotics, bleeding disorders, or other conditions requiring concurrent medications not allowed during this study
• Subjects with a condition requiring systemic chronic steroid therapy (≥ 10mg/day prednisone or equivalent) or any immunosuppressive therapy within 14 days prior to planned date for first dose of study treatment. Topical, inhaled, nasal and ophthalmic steroids, and adrenal replacement therapy are allowed.
• Other malignancy within 2 years prior to entry into the study, except for treated non-melanoma skin cancer and in situ cervical carcinoma
• Mental impairment that may compromise the ability to give informed consent and comply with the requirements of the study
• Any serious or uncontrolled medical disorder or active infection that, in the opinion of the investigator, may increase the associated with the participation, study drug administration, or would impair the ability of the patient to receive protocol therapy
• Lack of availability for follow-up assessments
• Pregnancy or breastfeeding
• Known allergy to penicillin or streptomycin (used during the culturing of T cells)

Sponsors & Collaborators

• Leiden University: lead
• Bristol-Myers Squibb: collaborator

Study Sites (1)

Leiden University Medical Center

Leiden, 2333 ZA, Netherlands

Location

Related Publications (1)

• van der Kooij MK, Verdegaal EME, Visser M, de Bruin L, van der Minne CE, Meij PM, Roozen ICFM, Jonker MA, van den Bosch S, Liefers GJ, Speetjens FM, van der Burg SH, Kapiteijn E. Phase I/II study protocol to assess safety and efficacy of adoptive cell therapy with anti-PD-1 plus low-dose pegylated-interferon-alpha in patients with metastatic melanoma refractory to standard of care treatments: the ACTME trial. BMJ Open. 2020 Nov 24;10(11):e044036. doi: 10.1136/bmjopen-2020-044036.

  PMID: 33234662 DERIVED

MeSH Terms

Conditions

Drug-Related Side Effects and Adverse Reactions; Melanoma

Interventions

Nivolumab

Condition Hierarchy (Ancestors)

Chemically-Induced Disorders; Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Nerve Tissue; Nevi and Melanomas; Skin Neoplasms; Neoplasms by Site; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Ellen Kapiteijn, Dr.

  LUMC

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Model Details: The ACTME trial consists of both a phase I part to determine safety and feasibility and a phase II part to evaluate first clinical activity of IFN-alpha, nivolumab and TIL. The treatment with IFN-alpha will be added after the combination of TIL and nivolumab has proven to be safe. Phase 1, Cohort 1: Adding TIL therapy to anti-PD1 immunotherapy. Phase 1, Cohort 2: Adding IFN-alpha to the treatment with TIL and anti-PD1 immunotherapy. Phase 2: Patients will be treated with TIL, IFN-alpha and anti-PD1 according to the same schedule as used in phase 1 cohort 2.

Study Record Dates

• First Submitted: July 5, 2018
• First Posted: August 20, 2018
• Study Start: July 31, 2018
• Primary Completion: November 29, 2025
• Study Completion: November 29, 2025
• Last Updated: December 12, 2023

Record last verified: 2023-12

Data Sharing

• IPD Sharing: Will not share

Locations

NL (1)