Combination Therapy With Nivolumab and PD-L1/IDO Peptide Vaccine to Patients With Metastatic Melanoma
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|ClinicalTrials.gov Identifier: NCT03047928|
Recruitment Status : Recruiting
First Posted : February 9, 2017
Last Update Posted : October 31, 2018
|Condition or disease||Intervention/treatment||Phase|
|Metastatic Melanoma||Drug: Nivolumab Biological: PD-L1/IDO peptide vaccine||Phase 1 Phase 2|
Huge advances have been made in the treatment of metastatic melanoma (MM) the past 5 years. Especially immunotherapy has shown promising results.
Cancer cells are naturally attacked by cells of the immune system, but can induce a state of tolerance whereby they escape from immune attack. This escape is brought about by many mechanisms. An important one is the programmed death pathway (PD-1/PD-L1). PD-L1 is commonly overexpressed on cancer cells. Interaction of PD-1 on activated T cells and PD-L1 on cancer cells lead to inhibition of the cytotoxic T cells. Another important mechanism is through overexpression of the metabolic enzyme IDO on cancer cells. Activation of IDO also inhibits cytotoxic T cells.
Investigators have recently identified spontaneous T cell reactivity against PD-L1 and IDO in the tumor microenvironment and in the peripheral blood of patients with MM and healthy donors. Both IDO and PD-L1 reactive CD8 T cells are cytotoxic and can kill cancer cells and immune regulatory cells in vitro.. Thus boosting specific T cells that recognize immune regulatory proteins such as IDO and PD-L1 may directly modulate immune regulation.
Due to distinct mechanisms of action, the combination of treatment with a monoclonal antibody targeting PD-1 (Nivolumab) and a vaccine with peptides against PD-L1 and IDO may have a synergistic effect.
Investigators have previously reported a phase I trial where, the IDO peptide was tested in 15 patients with MM in combination with Ipilimumab, and no grade 3-4 toxicity was seen. The PD-L1 peptide is currently being tested in a first-in-man study in patients with multiple myeloma.
A two-step clinical phase I/II trial design will be used, starting out with a pilot study including 6 patients with MM to test feasibility and tolerability. If the treatment is found feasible the study will be extended to a phase II study with 24 patients. The objective is to describe anti-tumor immune responses and objective responses using RECIST 1.1.
Patients will be treated with Nivolumab in accordance with standard regimen, which involves outpatient IV infusions every second week as long as there is clinical benefit. The PD-L1/IDO peptide vaccine is given from start of Nivolumab and every second week for the first 6 vaccines and thereafter every fourth week up to 1 year. 15 vaccines will be administered in total.
Patients will be followed with clinical controls and diagnostic imaging every 12 weeks. Patients who receive all vaccines will have follow up after 3 and 6 months in parallel with standard of care treatment for Nivolumab.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||50 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||Combination Therapy With Nivolumab and PD-L1/IDO Peptide Vaccine to Patients With Metastatic Melanoma|
|Actual Study Start Date :||February 22, 2018|
|Estimated Primary Completion Date :||April 1, 2019|
|Estimated Study Completion Date :||April 1, 2020|
Experimental: Patient group
All patients receive the same treatment. Patients included in the protocol are treated with Nivolumab according to usual guidelines, implying outpatient IV infusions of 3 mg/kg biweekly until progression.
The vaccine is administered on the same day as the administration start of Nivolumab. The vaccination is given biweekly for a total of 6 times, then every fourth week up to week 47, whereupon no additional vaccines will be given. In total, 15 vaccines will be administered. A vaccine consist of 100 μg IDO long peptide, 100 μg PD-L1 long1 peptide and 500 microliters Montanide as adjuvant.
Patients who complete all vaccines will continue Nivolumab treatment after standard guidelines.
Nivolumab 3 mg/kg is administered biweekly as long as there is clinical benefit.
Other Name: Opdivo
Biological: PD-L1/IDO peptide vaccine
The vaccine is administered biweekly for a total of 6 times, then every fourth week up to 47 weeks, whereupon no additional vaccinations will be given. A total of 15 vaccines will be administered. A vaccine consists of 100 μg PD-L1 long1 peptide, 100 μg IDO long peptide and 500 μl Montande as adjuvant.
Other Name: IO102/IO103 peptide vaccine
- Number and type of reported adverse events [ Time Frame: 0-55 weeks ]Determine the safety of the combination therapy of Nivolumab and the PD-L1/IDO peptide vaccine for patients with metastatic melanoma by reporting adverse events according to CTCAE v. 4.0.
- Treatment related immune responses [ Time Frame: Up to 24 months ]To evaluate the immunological impact of the combination therapy with Nivolumab and PD-L1/IDO peptide vaccine for patients with metastatic melanoma. ELISPOT and tetramer staining methods will be applied to identify PD-L1 and IDO specific T cells in the blood over time.
- Objective response rate [ Time Frame: Up to 24 months ]Clinical response will be evaluated by RECIST and PERCIST 1.1 and irRC
- Overall Survival [ Time Frame: Up to 24 months ]Overall Survival (OS), defined as time from treatment initiation to death, will be described with use of Kaplan Meier curve.
- Progression free survival [ Time Frame: Up to 24 months ]Progression free survival (PFS), defined as the time from treatment initiation to disease progression, relapse or death due to any cause, which ever comes first, will be described with Kaplan Meier curve.
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): NCT03047928
|Contact: Inge Marie Svane, Prof., MDfirstname.lastname@example.org|
|Contact: Julie Westerlin Kjeldsen, MDemail@example.com|
|Center for Cancer Immune Therapy, Dept. of Oncology/Hematology||Recruiting|
|Herlev, Denmark, 2730|
|Contact: Inge Marie Svane, Prof., MD +4538683868 firstname.lastname@example.org|
|Contact: Julie Westerlin Kjeldsen, MD +4538683868 email@example.com|
|Herlev, Denmark, 2730|
|Contact: Julie W Kjeldsen, MD|
|Study Director:||Inge Marie Svane, Prof., MD||Center for Cancer Immune Therapy, Dept. of Oncology/Hematology, Copenhagen University Hospital Herlev, Herlev Ringvej 75, DK-2730|
|Principal Investigator:||Julie Westerlin Kjeldsen, MD||Center for Cancer Immune Therapy, Dept. of Oncology/Hematology, Copenhagen University Hospital Herlev, Herlev Ringvej 75, DK-2730|