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Toxicity, DrugPhase 1/2ACTMENCT03638375

TIL and Anti-PD1 in Metastatic Melanoma

A Phase 1/2 study testing Nivolumab & Tumor Infiltrating Lymphocytes with/without Interferon-Alpha in people with Toxicity, Drug and Adverse Drug Event, run by Leiden University at 1 site in Netherlands.

Unknown status

Status not confirmed. The sponsor has not verified this record for over two years, so it may be out of date.

Official record
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Trial 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… Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
Nivolumab & Tumor Infiltrating Lymphocytes with/without Interferon-Alpha
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
34 participants
Where
1 siteNetherlands
Study dates
31 Jul 2018to 29 Nov 2025
Phase
Phase 1/2
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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
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  • 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
  • No antibodies against HCV (hepatitis C virus) in the serum
  • Able and willing to give valid written informed consent.
  • Progressive disease on prior treatment with f.e. BRAF-inhibitors, MEK-inhibitors or immunotherapy, including anti-PD1 treatment. Systemic therapy must have been discontinued for at least four weeks before start of study treatment.

Who cannot join

  • 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
  • Active immunodeficiency disease, autoimmune disease requiring immune suppressive drugs or autoimmune adverse events following treatment with checkpoint inhibitors. Vitiligo is not an exclusion criterion
  • 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
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  • 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)

Trial locations and contacts

1 site in 1 country.

Netherlands1 site
  • Leiden University Medical Center

    Leiden, 2333 ZA

Other trials in Netherlands

About this study

Official title: Adoptive TIL Therapy With Low-dose IFN-alpha Plus Anti-PD1 in Metastatic Melanoma

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.

Read the detailed description

The ACTME is an investigator initiated, single center phase I/II clinical trial for patients with progressive unresectable stage III or stage IV melanoma.

Patients are conditioned by low-dose IFN-alpha and treated with ACT and PD-1 antibodies. With this approach the investigators hope to solve 4 of the most important aspects curtailing the efficacy of current immunotherapies in metastatic melanoma:

  1. the lack of sufficient numbers of activated tumor-reactive T cells in patients by providing ACT; and
  2. the inhibition of T-cell effector function through PD-1 signalling by administration of nivolumab; as well as
  3. the toxicity of high-dose IL-2, and
  4. long term hospitalization of patients due to the conditioning-regimen used in most ACT protocols by replacing it with low-dose IFN-alpha treatment.

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 in the first cohort of the phase I part of the trial.

Being tested
Nivolumab & Tumor Infiltrating Lymphocytes with/without Interferon-Alpha
Keywords
Metastatic melanoma, anti-PD1, TIL, interferon-alpha, adoptive cell therapy, nivolumab
Medical subject headings
Drug-Related Side Effects and Adverse Reactions, Melanoma

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Nivolumab & Tumor Infiltrating Lymphocytes with/without Interferon-AlphaDrug

    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.

Study groups in NCT03638375
Study groupRoleWhat they receive
Treatment with nivolumab plus TILExperimentalIn 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.
Receives: Drug: Nivolumab & Tumor Infiltrating Lymphocytes with/without Interferon-Alpha
Treatment with Nivolumab plus TIL and IFN-alphaExperimentalIn 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.
Receives: Drug: Nivolumab & Tumor Infiltrating Lymphocytes with/without Interferon-Alpha

What is being measured

The primary outcome is the main question the study is designed to answer.

  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

    Measured: 14 weeks after start of treatment

Secondary outcomes (7)
  1. Evaluation of disease control rate according to RECIST 1.1 criteria

    Disease control is defined by complete response, partial response or stable according to RECIST 1.1 versus no clinical benefit defined as progressive disease.

    Complete response: Disappearance of all target and nontarget lesions, nodes must regress to <10mm short axis, no new lesions, confirmation required Partial response: ≥30% decrease in tumor burden compared with baseline, confirmation required Progressive disease: ≥20% + 5 mm absolute increase in tumor burden compared with nadir, appearance of new lesions or progression of nontarget lesions Stable disease: neither partial response nor progressive disease

    Measured: 14 weeks after first nivolumab infusion

  2. Evaluation of disease control rate according to immune RECIST response criteria

    Disease control is defined by complete response, partial response or stable according to the iRECIST versus no clinical benefit defined as progressive disease.

    Complete response: Disappearance of all lesions Partial response: ≥30% decrease in tumor burden compared with baseline. Progressive disease: ≥20% + 5 mm absolute increase in tumor burden compared with nadir Stable disease: neither progressive disease nor partial response

    Measured: 14 weeks after first nivolumab infusion

  3. 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.

    The investigators will analyse the patients their tumor material, blood, serum and the TILs used for infusion

    Measured: Within 5 years after first inclusion

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

    The investigators will analyse the patients their tumor material, blood, serum and the TILs used for infusion to look at changes in the number and phenotype of circulating immune cells, the cytokines that are produced by these cells and serum/plasma markers of persistence.

    Measured: Within 5 years after first inclusion

  5. To characterize the infusion product

    The expression of co-inhibitory molecules on T cells and regulatory T cells will be measured by flow cytometry. Furthermore, the investigators will assess the fraction of tumor-specific TIL, their cytolytic capacity as well as to analyse their persistence in the circulation. The supernatants of T cell are used for cytokine analysis assays.

    Measured: Within 5 years after first inclusion

  6. To analyse potential correlations between the clinical response and hypothesis related immune parameters

    Measured: Within 5 years after first inclusion

  7. To analyse the overall survival following treatment

    The overall survival of all patients entering the study will be monitored

    Measured: Within 5 years after first inclusion

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted20 Aug 2018
  2. Study start31 Jul 2018
  3. Primary completion29 Nov 2025 (estimated)
  4. Study completion29 Nov 2025 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1/2
Primary purpose
Treatment
Allocation
Non-randomised
Intervention model
Sequential
Model description
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.
Masking
None (open label)
Enrolment
34 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03638375
Sponsor's protocol ID
NL64805.000.18
Acronym
ACTME
Status last verified
Dec 2023
First submitted
5 Jul 2018
Last updated
12 Dec 2023
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
No

Publications

  • 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.

    PubMed 33234662

Questions about this trial

What is this clinical trial studying?

A Phase 1/2 study testing Nivolumab & Tumor Infiltrating Lymphocytes with/without Interferon-Alpha in people with Toxicity, Drug and Adverse Drug Event, run by Leiden University at 1 site in Netherlands.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 18 inclusion and 11 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: status not confirmed, as of the sponsor's last update on 12 Dec 2023. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in Netherlands. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Results are not available in the source record.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Incidence of treatment-related serious adverse events as assessed by CTCAE 4.0 criteria (time frame: 14 weeks after start of treatment). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03638375, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 12 Dec 2023.

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