Clinical trial NCT03374839: 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
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE1
PHASE2
Conditions: Melanoma
Lead sponsor: Nantes University Hospital
Sponsor class: OTHER
Collaborators: name: Bristol-Myers Squibb
First posted: 2017-12-15
Enrollment: 11
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: Inclusion Criteria:

* over 18 years old 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
* 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 except in the context of adjuvant or neoadjuvant
* 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

Primary outcomes:
measure: Incidence of Treatment (adoptive T cell therapy associated to intravenous injections of Nivolumab) - Emergent Adverse Events
timeFrame: Within 12 months
Secondary outcomes:
measure: Efficacy of adoptive T cell therapy associated to intravenous injections of Nivolumab
timeFrame: At 12 months
measure: Duration of the clinical response
timeFrame: Within 12 months of follow-up
measure: Progression-free survival
timeFrame: 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
measure: Overall survival
timeFrame: From the date of the first infusion of Nivolumab until the date of death, assessed up to 12 months
measure: Specific immune monitoring n°1: Evaluate the fraction of TIL specific to Melan-A and MELOE-1
timeFrame: Week 14 + week 18
measure: Specific immune monitoring n°2: Evaluate the proportion of regulatory T cells
timeFrame: Day 0 (1st Nivolumab injection) + week 14 + week 18 + week 26 + week 38 + at the date of disease progression assessed up to 12 months
measure: Specific immune monitoring n°3: Analyse the expression of tumor antigens
timeFrame: Week 10 + week 38
measure: Specific immune monitoring n°4: Analyse the expression of immunosuppressive cytokines
timeFrame: Week 10 + week 38
measure: Specific immune monitoring n°5: Analyse the expression of indoleamine 2,3-dioxygenase (IDO)
timeFrame: Week 10 + week 38
measure: Specific immune monitoring n°6: Analyse the expression of FoxP3
timeFrame: Week 10 + week 38
measure: Specific immune monitoring n°7: Analyse the expression of regulatory molecules
timeFrame: Week 10 + week 38
measure: Specific immune monitoring n°8: Analyse the mutations of BRAF
timeFrame: Week 10 + week 38
measure: Specific immune monitoring n°9: Analyse the mutations of Neuroblastoma Ras viral oncogene homolog (NRAS)
timeFrame: Week 10 + week 38
measure: Specific immune monitoring n°10: Analyse the mutations of proto-oncogene ckit (cKit)
timeFrame: Week 10 + week 38
measure: Specific immune monitoring n°11: Determine the percentage of reactive T cells in the expanded cells
timeFrame: Week 10
measure: Specific immune monitoring n°12: Determine the phenotype of the expanded T cells
timeFrame: Week 10
measure: Specific immune monitoring n°13: Test TIL reactivity
timeFrame: Week 10
Other outcomes:
Locations:
city: Nantes
country: France
facility: Nantes University Hospital
Study officials:
References: