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Trial record 60 of 283 for:    Tumor infiltrating lymphocytes

TIL and Anti-PD1 in Metastatic Melanoma (ACTME)

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ClinicalTrials.gov Identifier: NCT03638375
Recruitment Status : Recruiting
First Posted : August 20, 2018
Last Update Posted : August 20, 2018
Sponsor:
Collaborator:
Bristol-Myers Squibb
Information provided by (Responsible Party):
HW Kapiteijn, Leiden University Medical Center

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.

Condition or disease Intervention/treatment Phase
Toxicity, Drug Adverse Drug Event Effects of Immunotherapy Drug: Nivolumab & Tumor Infiltrating Lymphocytes with/without Interferon-Alpha Phase 1 Phase 2

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 34 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Intervention 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)
Primary Purpose: Treatment
Official Title: Adoptive TIL Therapy With Low-dose IFN-alpha Plus Anti-PD1 in Metastatic Melanoma
Actual Study Start Date : July 31, 2018
Estimated Primary Completion Date : May 9, 2022
Estimated Study Completion Date : May 9, 2023

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Melanoma

Arm Intervention/treatment
Experimental: Treatment with nivolumab plus TIL

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

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.


Experimental: Treatment with Nivolumab plus TIL and IFN-alpha

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

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.





Primary Outcome Measures :
  1. Incidence of treatment-related serious adverse events as assessed by CTCAE 4.0 criteria [ Time Frame: 14 weeks after start of treatment ]

    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


Secondary Outcome Measures :
  1. Evaluation of disease control rate according to RECIST 1.1 criteria [ Time Frame: 14 weeks after first nivolumab infusion ]

    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


  2. Evaluation of disease control rate according to immune RECIST response criteria [ Time Frame: 14 weeks after first nivolumab infusion ]

    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


  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. [ Time Frame: Within 5 years after first inclusion ]
    The investigators will analyse the patients their tumor material, blood, serum and the TILs used for infusion

  4. To establish a possible prognostic biomarker profile in patients tumor material, blood, serum and TILs used for infusion [ Time Frame: Within 5 years after first inclusion ]
    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.

  5. To characterize the infusion product [ Time Frame: Within 5 years after first inclusion ]
    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.

  6. To analyse potential correlations between the clinical response and hypothesis related immune parameters [ Time Frame: Within 5 years after first inclusion ]
  7. To analyse the overall survival following treatment [ Time Frame: Within 5 years after first inclusion ]
    The overall survival of all patients entering the study will be monitored



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Age ≥ 18 years
  2. Histologically or cytologically proven metastatic skin melanoma
  3. 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
  4. Patients with brain metastases have to be neurologically stable for at least 2 months and should not use dexamethasone
  5. Presence of measurable progressive disease according to RECIST version 1.1
  6. Expected survival of at least 3 months
  7. WHO performance status ≤1
  8. 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

  9. 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
  10. Able and willing to give valid written informed consent.
  11. 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.

Exclusion Criteria:

  1. Patients with brain metastases who are neurologically unstable and/or use dexamethasone
  2. Clinically significant heart disease (NYHA Class III or IV)
  3. 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
  4. Active immunodeficiency disease, autoimmune disease requiring immune suppressive drugs or autoimmune adverse events following treatment with checkpoint inhibitors. Vitiligo is not an exclusion criterion
  5. 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.
  6. Other malignancy within 2 years prior to entry into the study, except for treated non-melanoma skin cancer and in situ cervical carcinoma
  7. Mental impairment that may compromise the ability to give informed consent and comply with the requirements of the study
  8. 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
  9. Lack of availability for follow-up assessments
  10. Pregnancy or breastfeeding
  11. Known allergy to penicillin or streptomycin (used during the culturing of T cells)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03638375


Contacts
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Contact: Ellen Kapiteijn, Dr. 071 526 9111 H.W.kapiteijn@lumc.nl
Contact: Monique K. van der Kooij, Drs. 071 526 9111 m.k.van_der_kooij@lumc.nl

Locations
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Netherlands
Leiden University Medical Center Recruiting
Leiden, Netherlands, 2333 ZA
Contact: Ellen Kapiteijn, Dr.    +3371 526 9111    h.w.kapiteijn@lumc.nl   
Principal Investigator: Ellen Kapiteijn, Dr.         
Sponsors and Collaborators
Leiden University Medical Center
Bristol-Myers Squibb
Investigators
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Principal Investigator: Ellen Kapiteijn, Dr. LUMC

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Responsible Party: HW Kapiteijn, Principal Investigator, Leiden University Medical Center
ClinicalTrials.gov Identifier: NCT03638375     History of Changes
Other Study ID Numbers: NL64805.000.18
First Posted: August 20, 2018    Key Record Dates
Last Update Posted: August 20, 2018
Last Verified: August 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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

Keywords provided by HW Kapiteijn, Leiden University Medical Center:
Metastatic melanoma
anti-PD1
TIL
interferon-alpha
adoptive cell therapy
nivolumab

Additional relevant MeSH terms:
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Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Nerve Tissue
Melanoma
Drug-Related Side Effects and Adverse Reactions
Nevi and Melanomas
Chemically-Induced Disorders
Nivolumab
Interferons
Interferon alpha-2
Interferon-alpha
Antineoplastic Agents, Immunological
Antineoplastic Agents
Antiviral Agents
Anti-Infective Agents
Immunologic Factors
Physiological Effects of Drugs