Clinical Trials /

Combined Therapy of Nivolumab and Adoptive T Cell Therapy in Metastatic Melanoma Patients

NCT03374839

Description:

To improve the efficacy of immunotherapy for cancer, recent studies focused on specific targets to redirect the immune network toward eradicating a variety of tumors and ameliorating the self-destructive process. A clinically relevant immune escape mechanism in melanoma is the activation of the Programmed cell Death-1 (PD-1) receptor on infiltrating T cells. By blocking PD-1 receptors with anti-PD-1 monoclonal antibodies (mAbs), T-cells are unaffected by the PD-L1 expressed on tumor cells and the patients T cells are free to respond to melanoma antigens and attack tumor cells. So the objective of this trial is to evaluate the safety and the efficacy of a combined therapy Nivolumab and adoptive T cell therapy in metastatic melanoma patients.

Related Conditions:
  • Melanoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Combined Therapy of Nivolumab and Adoptive T Cell Therapy in Metastatic Melanoma Patients
  • Official Title: Combined Therapy of Nivolumab and Adoptive T Cell Therapy in Metastatic Melanoma Patients: Pilot Study Phase I/II

Clinical Trial IDs

  • ORG STUDY ID: RC15_0247
  • NCT ID: NCT03374839

Conditions

  • Melanoma

Interventions

DrugSynonymsArms
TIL + IL-2 + NivolumabTIL + IL-2 + Nivolumab

Purpose

To improve the efficacy of immunotherapy for cancer, recent studies focused on specific targets to redirect the immune network toward eradicating a variety of tumors and ameliorating the self-destructive process. A clinically relevant immune escape mechanism in melanoma is the activation of the Programmed cell Death-1 (PD-1) receptor on infiltrating T cells. By blocking PD-1 receptors with anti-PD-1 monoclonal antibodies (mAbs), T-cells are unaffected by the PD-L1 expressed on tumor cells and the patients T cells are free to respond to melanoma antigens and attack tumor cells. So the objective of this trial is to evaluate the safety and the efficacy of a combined therapy Nivolumab and adoptive T cell therapy in metastatic melanoma patients.

Trial Arms

NameTypeDescriptionInterventions
TIL + IL-2 + NivolumabExperimentalA first cohort of 3 patients will be done to ensure that the combined treatment (TIL + IL-2 + Nivolumab) would not cause severe autoimmunity pathologies. For this first cohort, a dose of 0.5 billion of TILs per injection will be administered. After the opinion of the Data and Safety Monitoring Committee (DSMC), the sponsor will make the decision of the second cohort of 8 patients who will receive between 1 and 20 billion of TIL.
  • TIL + IL-2 + Nivolumab

Eligibility Criteria

        Inclusion Criteria:

          -  18 to 75 years with a weight ≥ 40 kg

          -  Patients must have signed informed consent

          -  Patients with stage IIIb, IIIc or IV metastatic melanoma (AJCC 6th edition) with at
             least two lesions (lymph nodes relapse, or in transit metastasis, or unresectable
             cutaneous metastases, or visceral metastases except bone and brain metastases)
             including one easily accessible and no more than 2 lines of treatment of melanoma at
             the metastatic stage.

          -  Patients with a melanoma expressing a Braf V600 mutation can be included only in case
             of targeted biotherapy (BRAF inhibitor +/- mitogen-activated protein kinase kinase
             enzymes (MEK) inhibitor) failure

          -  Measurable/assessable disease in 28 days which precede the first administration of the
             treatment

          -  A negative pregnancy test for women with childbearing potential

          -  Eastern Cooperative Oncology Group (ECOG) of 0-1, Karnofsky > 80%

          -  Laboratory results:

        Haemoglobin ≥ 10 g/dl or ≥ 6,25 mmol/l; Neutrophils ≥ 1500/μl; Leukocytes ≥ 4000/μl;
        Lymphocytes ≥ 700/μl; Blood platelet ≥ 100.000/μl; Serum creatinine ≤ 1.5 x superior normal
        value or creatinine clearance (CrCl) ≥ 40 mL/min (if using the Cockcroft-Gault formula);
        Serum bilirubin ≤ 2.0 mg/dl or ≤ 34.2 mol/l; Total bilirubin ≤ 1.5 x superior normal value
        (except subjects with Gilbert Syndrome, who can have total bilirubin < 3mg/dL); Aspartate
        aminotransferase (AST) and Alanine aminotransferase (ALT) ≤ 2 x superior normal value;
        Lactate dehydrogenase (LDH) ≤ 1.5 x superior normal value

          -  Subjects affiliated to an appropriate health insurance

          -  Women of childbearing potential (WOCBP) must use appropriate method(s) of
             contraception during the clinical trial. Furthermore WOCBP will be instructed to
             adhere to contraception for a period of 5 months after the last dose of Nivolumab.

          -  Men who are sexually active with WOCBP will be instructed to adhere to contraception
             during the clinical trial and for a period of 7 months after the last dose of
             Nivolumab.

          -  Women who are not of childbearing potential (ie, who are postmenopausal or surgically
             sterile) as well as azoospermic men do not require contraception.

        Non inclusion Criteria:

          -  Brain or bone metastases

          -  Ocular melanoma

          -  Chemotherapy or radiotherapy within 4 weeks before baseline (6 weeks for nitroso-ureas
             and mitomycin C)

          -  Contraindication for the use of vasopressor agents

          -  For female: the patient is pregnant or breastfeeding or not using contraception

          -  For men: the patient is sexually active with WOCBP and not using contraception

          -  History or current manifestations of severe progressive heart disease (congestive
             heart failure, coronary artery disease, uncontrolled arterial hypertension, serious
             rhythm disorders or ECG signs of previous myocardial infarction)

          -  Patients should be excluded if they have had prior treatment with an anti-PD-1,
             anti-PD-L1, anti-PD-L2, anti-CTLA4 antibody, or any other antibody or drug
             specifically targeting T-cell costimulation or immune checkpoint pathways

          -  History of allergies and Adverse Drug Reaction:

               -  Hypersensitivity to human albumin, TIL excipient

               -  Hypersensitivity to Nivolumab or related excipients

               -  History of severe hypersensitivity reaction to any monoclonal antibody

               -  Hypersensitivity to aldesleukin or to one of Proleukin excipients

          -  History of chronic autoimmune disease (Addison's disease, multiple sclerosis, Graves'
             disease, rheumatoid arthritis, systemic lupus erythematosus, etc…) except patient with
             active vitiligo or a history of vitiligo.

          -  History of uveitis or melanoma-associated retinopathy

          -  History of inflammatory bowel disease, celiac disease, or other chronic
             gastrointestinal conditions associated with diarrhea.

          -  Presence of a second active cancer, with the exception of an in situ cervical cancer
             or a skin cancer different from the treated melanoma

          -  Unchecked thyroid dysfunction

          -  Any serious, acute or chronic illness id est active infection asking for antibiotics
             administration, coagulation's disorders, or any state asking for an unauthorized
             concomitant treatment described in this study

          -  Patients should be excluded if they have a condition requiring systemic treatment with
             either corticosteroids (> 10 mg daily prednisone equivalents) or other
             immunosuppressive medications within 14 days before 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. Subjects are permitted to
             use topical, ocular, intra-articular, intranasal, and inhalational corticosteroids
             (with minimal systemic absorption). Physiologic replacement doses of systemic
             corticosteroids are permitted, even if > 10 mg/day prednisone equivalents. A brief
             course of corticosteroids for prophylaxis (eg, contrast dye allergy) or for treatment
             of nonautoimmune conditions (eg, delayed-type hypersensitivity reaction caused by
             contact allergen) is permitted.

          -  Adults under a legal protection regime (guardianship, trusteeship, "sauvegarde de
             justice")

        Exclusion Criteria:

        * Positive viral serology for HIV (human immunodeficiency virus) 1/2, p24 Ag, HTLV1, HTLV2,
        B and C hepatitis or syphilis
      
Maximum Eligible Age:75 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Incidence of Treatment (adoptive T cell therapy associated to intravenous injections of Nivolumab) - Emergent Adverse Events
Time Frame:Within 12 months
Safety Issue:
Description:Clinical and biological criteria defined by the NCI (Common Terminology Criteria for Adverse Events - version 4.0, may 2009, http://ctep.cancer.gov)

Secondary Outcome Measures

Measure:Efficacy of adoptive T cell therapy associated to intravenous injections of Nivolumab
Time Frame:At 12 months
Safety Issue:
Description:The overall tumor response will be evaluated according to the guidelines for Response Evaluation Criteria in Solid Tumors (RECIST1.1) and immune-related Response Criteria (irRC)
Measure:Duration of the clinical response
Time Frame:Within 12 months of follow-up
Safety Issue:
Description:Time interval between the evaluation of the first objective response and the first evaluation of disease progression or death, whichever occurs first
Measure:Progression-free survival
Time Frame:From the date of the first infusion of Nivolumab until the date of the first documented progression or the date of death from any cause, whichever came first, assessed up to 12 months
Safety Issue:
Description:Evaluation of the progression-free survival of patients treated with adoptive T cell therapy in combination with intravenous injections of Nivolumab
Measure:Overall survival
Time Frame:From the date of the first infusion of Nivolumab until the date of death, assessed up to 12 months
Safety Issue:
Description:Evaluation of the overall survival of patients treated with adoptive T cell therapy in combination with intravenous injections of Nivolumab
Measure:Specific immune monitoring n°1: Evaluate the fraction of TIL specific to Melan-A and MELOE-1
Time Frame:Week 14 + week 18
Safety Issue:
Description:Evaluation of the fraction of TIL specific to two Human Leukocyte Antigen (HLA)-peptide complexes (Melan-A and MELOE-1)
Measure:Specific immune monitoring n°2: Evaluate the proportion of regulatory T cells
Time Frame:Day 0 (1st Nivolumab injection) + week 14 + week 18 + week 26 + week 38 + at the date of disease progression assessed up to 12 months
Safety Issue:
Description:Evaluation of the proportion of regulatory T cells
Measure:Specific immune monitoring n°3: Analyse the expression of tumor antigens
Time Frame:Week 10 + week 38
Safety Issue:
Description:Analysis of the expression of tumor antigens
Measure:Specific immune monitoring n°4: Analyse the expression of immunosuppressive cytokines
Time Frame:Week 10 + week 38
Safety Issue:
Description:Analysis of the expression of immunosuppressive cytokines
Measure:Specific immune monitoring n°5: Analyse the expression of indoleamine 2,3-dioxygenase (IDO)
Time Frame:Week 10 + week 38
Safety Issue:
Description:Analysis of the expression of IDO
Measure:Specific immune monitoring n°6: Analyse the expression of FoxP3
Time Frame:Week 10 + week 38
Safety Issue:
Description:Analysis of the expression of FoxP3
Measure:Specific immune monitoring n°7: Analyse the expression of regulatory molecules
Time Frame:Week 10 + week 38
Safety Issue:
Description:Analysis of the expression of regulatory molecules
Measure:Specific immune monitoring n°8: Analyse the mutations of BRAF
Time Frame:Week 10 + week 38
Safety Issue:
Description:Analysis of BRAF mutations
Measure:Specific immune monitoring n°9: Analyse the mutations of Neuroblastoma Ras viral oncogene homolog (NRAS)
Time Frame:Week 10 + week 38
Safety Issue:
Description:Analysis of NRAS mutations
Measure:Specific immune monitoring n°10: Analyse the mutations of proto-oncogene ckit (cKit)
Time Frame:Week 10 + week 38
Safety Issue:
Description:Analysis of cKit mutations
Measure:Specific immune monitoring n°11: Determine the percentage of reactive T cells in the expanded cells
Time Frame:Week 10
Safety Issue:
Description:Produce tumor cell line and determine the percentage of reactive T cells in the expanded cells
Measure:Specific immune monitoring n°12: Determine the phenotype of the expanded T cells
Time Frame:Week 10
Safety Issue:
Description:Produce tumor cell line and determine the phenotype of the expanded T cells
Measure:Specific immune monitoring n°13: Test TIL reactivity
Time Frame:Week 10
Safety Issue:
Description:Produce tumor cell line and test TIL reactivity

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Nantes University Hospital

Last Updated

September 5, 2019