MelanomaPhase 1/2Nivo-TILNCT03374839
Combined Therapy of Nivolumab and Adoptive T Cell Therapy in Metastatic Melanoma Patients
A Phase 1/2 study testing TIL + IL-2 + Nivolumab in people with Melanoma, run by Nantes University Hospital at 1 site in France.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 75 years
- Conditions the study is for
- Melanoma
- What is being tested?
- TIL + IL-2 + Nivolumab
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 11 participants
- Where
- 1 siteFrance
- Study dates
- 12 Feb 2018to Jan 2024
- 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 to 75 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Show all 35Show fewer
- 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")
Who cannot join
- Positive viral serology for HIV (human immunodeficiency virus) 1/2, p24 Ag, HTLV1, HTLV2, B and C hepatitis or syphilis
Trial locations and contacts
1 site in 1 country.
Brigitte Dréno, MD, PhD contact
France1 site, 1 recruiting
- Recruiting
Nantes University Hospital
Nantes, 44000
Amir Khammari, PhD, amir.khammari@chu-nantes.fr
Brigitte Dréno, MD, PhD
About this study
Official title: Combined Therapy of Nivolumab and Adoptive T Cell Therapy in Metastatic Melanoma Patients: Pilot Study Phase I/II
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.
- Conditions
- Melanoma
- Being tested
- TIL + IL-2 + Nivolumab
- Medical subject headings
- Melanoma
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
TIL + IL-2 + NivolumabDrug
The patients will receive Nivolumab (at a dose of 3 mg per kilogram of body weight) every 2 weeks from day0 until week52.
Two TIL (Tumor Infiltrating Lymphocytes) injections will be performed: at week 14 and at week 18.
The TIL injections are systematically followed by subcutaneous injections of Proleukin® (IL-2) at a concentration of 6 million international unit (IU) per day for 5 days.
| Study group | Role | What they receive |
|---|---|---|
| TIL + IL-2 + Nivolumab | Experimental | A 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. Receives: Drug: TIL + IL-2 + Nivolumab |
What is being measured
The primary outcome is the main question the study is designed to answer.
Incidence of Treatment (adoptive T cell therapy associated to intravenous injections of Nivolumab) - Emergent Adverse Events
Clinical and biological criteria defined by the NCI (Common Terminology Criteria for Adverse Events - version 4.0, may 2009, http://ctep.cancer.gov)
Measured: Within 12 months
Secondary outcomes (17)
Efficacy of adoptive T cell therapy associated to intravenous injections of Nivolumab
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)
Measured: At 12 months
Duration of the clinical response
Time interval between the evaluation of the first objective response and the first evaluation of disease progression or death, whichever occurs first
Measured: Within 12 months of follow-up
Progression-free survival
Evaluation of the progression-free survival of patients treated with adoptive T cell therapy in combination with intravenous injections of Nivolumab
Measured: 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
Overall survival
Evaluation of the overall survival of patients treated with adoptive T cell therapy in combination with intravenous injections of Nivolumab
Measured: From the date of the first infusion of Nivolumab until the date of death, assessed up to 12 months
Specific immune monitoring n°1: Evaluate the fraction of TIL specific to Melan-A and MELOE-1
Evaluation of the fraction of TIL specific to two Human Leukocyte Antigen (HLA)-peptide complexes (Melan-A and MELOE-1)
Measured: Week 14 + week 18
Specific immune monitoring n°2: Evaluate the proportion of regulatory T cells
Evaluation of the proportion of regulatory T cells
Measured: Day 0 (1st Nivolumab injection) + week 14 + week 18 + week 26 + week 38 + at the date of disease progression assessed up to 12 months
Specific immune monitoring n°3: Analyse the expression of tumor antigens
Analysis of the expression of tumor antigens
Measured: Week 10 + week 38
Specific immune monitoring n°4: Analyse the expression of immunosuppressive cytokines
Analysis of the expression of immunosuppressive cytokines
Measured: Week 10 + week 38
Specific immune monitoring n°5: Analyse the expression of indoleamine 2,3-dioxygenase (IDO)
Analysis of the expression of IDO
Measured: Week 10 + week 38
Specific immune monitoring n°6: Analyse the expression of FoxP3
Analysis of the expression of FoxP3
Measured: Week 10 + week 38
Specific immune monitoring n°7: Analyse the expression of regulatory molecules
Analysis of the expression of regulatory molecules
Measured: Week 10 + week 38
Specific immune monitoring n°8: Analyse the mutations of BRAF
Analysis of BRAF mutations
Measured: Week 10 + week 38
Specific immune monitoring n°9: Analyse the mutations of Neuroblastoma Ras viral oncogene homolog (NRAS)
Analysis of NRAS mutations
Measured: Week 10 + week 38
Specific immune monitoring n°10: Analyse the mutations of proto-oncogene ckit (cKit)
Analysis of cKit mutations
Measured: Week 10 + week 38
Specific immune monitoring n°11: Determine the percentage of reactive T cells in the expanded cells
Produce tumor cell line and determine the percentage of reactive T cells in the expanded cells
Measured: Week 10
Specific immune monitoring n°12: Determine the phenotype of the expanded T cells
Produce tumor cell line and determine the phenotype of the expanded T cells
Measured: Week 10
Specific immune monitoring n°13: Test TIL reactivity
Produce tumor cell line and test TIL reactivity
Measured: Week 10
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted15 Dec 2017
- Study start12 Feb 2018
- Primary completionJan 2024 (estimated)
- Study completionJan 2024 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for MelanomaStudies of the same condition, open and under way.
- More trials run by Nantes University HospitalThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
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
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 11 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Nantes University Hospital
- Sponsor type
- University, hospital or other
- Collaborators
- Bristol-Myers Squibb
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03374839
- Sponsor's protocol ID
- RC15_0247
- Acronym
- Nivo-TIL
- Status last verified
- May 2022
- First submitted
- 29 Nov 2017
- Last updated
- 6 May 2022
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
Study at a glance
From the registry record, last updated by the sponsor on 6 May 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Combined Therapy of Nivolumab and Adoptive T Cell Therapy in Metastatic Melanoma Patients: Pilot Study Phase I/II
- ClinicalTrials.gov ID
- NCT03374839
- Acronym / sponsor ID
- Nivo-TIL / RC15_0247
- Conditions
- Melanoma
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 11 participants (estimated)
- Lead sponsor
- Nantes University HospitalUniversity, hospital or other
- Collaborators
- Bristol-Myers Squibb
- Study start
- 12 Feb 2018 (actual)
- Primary completion
- Jan 2024 (estimated)
- Study completion
- Jan 2024 (estimated)
- First posted
- 15 Dec 2017 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| TIL + IL-2 + Nivolumab | Experimental | Drug: TIL + IL-2 + NivolumabA 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. |
Who may qualify
- Ages
- 18 to 75 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (35 listed)
- 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
Key exclusion criteria (1 listed)
- Positive viral serology for HIV (human immunodeficiency virus) 1/2, p24 Ag, HTLV1, HTLV2, B and C hepatitis or syphilis
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| TIL + IL-2 + NivolumabThe patients will receive Nivolumab (at a dose of 3 mg per kilogram of body weight) every 2 weeks from day0 until week52. Two TIL (Tumor Infiltrating Lymphocytes) injections will be performed: at week 14 and at week 18. The TIL injections are systematically followed by subcutaneous injections of Proleukin® (IL-2) at a concentration of 6 million international unit (IU) per day for 5 days. | Drug | TIL + IL-2 + Nivolumab |
Primary outcome
Incidence of Treatment (adoptive T cell therapy associated to intravenous injections of Nivolumab) - Emergent Adverse Events
Time frame: Within 12 months
Clinical and biological criteria defined by the NCI (Common Terminology Criteria for Adverse Events - version 4.0, may 2009, http://ctep.cancer.gov)
17 secondary outcomes
Efficacy of adoptive T cell therapy associated to intravenous injections of Nivolumab
Time frame: At 12 months
Duration of the clinical response
Time frame: Within 12 months of follow-up
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
Overall survival
Time frame: From the date of the first infusion of Nivolumab until the date of death, assessed up to 12 months
Specific immune monitoring n°1: Evaluate the fraction of TIL specific to Melan-A and MELOE-1
Time frame: Week 14 + week 18
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
Specific immune monitoring n°3: Analyse the expression of tumor antigens
Time frame: Week 10 + week 38
Specific immune monitoring n°4: Analyse the expression of immunosuppressive cytokines
Time frame: Week 10 + week 38
Specific immune monitoring n°5: Analyse the expression of indoleamine 2,3-dioxygenase (IDO)
Time frame: Week 10 + week 38
Specific immune monitoring n°6: Analyse the expression of FoxP3
Time frame: Week 10 + week 38
Specific immune monitoring n°7: Analyse the expression of regulatory molecules
Time frame: Week 10 + week 38
Specific immune monitoring n°8: Analyse the mutations of BRAF
Time frame: Week 10 + week 38
Specific immune monitoring n°9: Analyse the mutations of Neuroblastoma Ras viral oncogene homolog (NRAS)
Time frame: Week 10 + week 38
Specific immune monitoring n°10: Analyse the mutations of proto-oncogene ckit (cKit)
Time frame: Week 10 + week 38
Specific immune monitoring n°11: Determine the percentage of reactive T cells in the expanded cells
Time frame: Week 10
Specific immune monitoring n°12: Determine the phenotype of the expanded T cells
Time frame: Week 10
Specific immune monitoring n°13: Test TIL reactivity
Time frame: Week 10
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 6 May 2022.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Brigitte Dréno, MD, PhD contact
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing TIL + IL-2 + Nivolumab in people with Melanoma, run by Nantes University Hospital at 1 site in France.
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 35 inclusion and 1 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 6 May 2022. 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 France. 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?
Contact Amir Khammari, PhD ((+33) (0)2 40 08 32 80, amir.khammari@chu-nantes.fr), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Incidence of Treatment (adoptive T cell therapy associated to intravenous injections of Nivolumab) - Emergent Adverse Events (time frame: Within 12 months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
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 6 May 2022.