CompletedNCT03047928Updated Feb 20, 2025Results posted

Combination Therapy With Nivolumab and PD-L1/IDO Peptide Vaccine to Patients With Metastatic Melanoma

A Phase 1/2 interventional study of Nivolumab and PD-L1/IDO peptide vaccine in Metastatic Melanoma, sponsored by Inge Marie Svane. Completed at 2 sites in Denmark. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2025-02-20.

Sponsored by Inge Marie Svane · Phase 1/2, Interventional, and Treatment

Phase: Phase 1/2
Study type: Interventional
Enrollment: 48
Allocation: Not applicable
Ages: 18 Years and older
Sex: All

Study summary

Combination therapy is becoming more and more general in the treatment of oncological diseases. In this clinical trial combination the standard immunotherapeutic treatment; the programmed death 1 (PD-1) regulatory antibody Nivolumab and a peptide vaccine consisting of programmed death ligand 1 (PD-L1) and Indoleamine 2,3-dioxygenase (IDO) peptides will be tested in patients with metastatic melanoma. Patients will be treated with Nivolumab 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.

Read the detailed description

Background:

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.

Methods:

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.

Conditions studied

Metastatic Melanoma

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Melanoma 3,006

In context

Melanoma

3,006 studies on the registry are indexed under Melanoma; 519 are open to participants now.

This study's enrollment of 48 is above the median of 38 across 2,350 interventional studies indexed under Melanoma.

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Lead sponsor

Inge Marie Svane is the lead sponsor of 25 studies on the registry; 6 are open to participants now.

Counted across the registry records on this site, refreshed daily.

Who can participate

Ages eligible: 18 Years and older
Sexes eligible: All
Accepts healthy volunteers: No

Inclusion criteria

Age ≥ 18
The patient has unrespectable or metastatic melanoma with progressive, persistent or recurrent disease on or following treatment with standard of care agents
Patients belonging to one of the following patient groups will be enrolled:
Cohort A: Anti PD-1/PD-L1 naïve patients (30 patients). The patient is a candidate for Nivolumab monotherapy. Prior anti-PD-1/anti-PD-L1 antibody treatment is not allowed.
OR Cohort B: Extension cohort (10 patients). Progressive disease ON anti-PD-1 monotherapy.Subjects should not have experienced serious and/or life-threatening toxicity to antibody therapy.
OR Cohort C: Extension cohort (10 patients). Progressive disease during follow up OFF anti-PD-1 after clinical benefit (SD/PR/CR) on anti-PD-1 therapy. Subjects should not have discontinued antibody therapy due to serious and/or lifethreatening toxicity
At least one measurable parameter according to RECIST 1.1.
The patient has an ECOG performance status of 0 or 1
The patient is a female of childbearing potential with negative pregnancy test
For women: Agreement to use contraceptive methods with a failure rate of \< 1 % per year during the treatment period and for at least 120 days after the treatment
For men: Agreement to use contraceptive measures and agreement to refrain from donating sperm
The patient has met the following hematological and biochemical criteria:
1. AST and ALT ≤2,5 X ULN or ≤5 X ULN with liver metastases
2. Serum total bilirubin ≤1,5 X ULN or direct bilirubin ≤ ULN for patient with total bilirubin level > 1,5 ULN
3. Serum creatinine ≤1,5 X ULN
4. ANC (Absolute Neutrophil Count) ≥1,000/mcL
5. Platelets ≥ 75,000 /mcL
6. Hemoglobin ≥ 9 g/dL eller ≥ 5.6 mmol/L
Signed declaration of content after oral and written information about the protocol.

Exclusion criteria

Exclusion Criteria:

The patient has not recovered to grade 0-1 from adverse events due to prior chemotherapy, radioactive or biological cancer therapy
The patient has not recovered from surgery or is less than 4 weeks from major surgery
The patient has a history of life-threatening or severe immune related adverse events on treatment with another immunotherapy and is considered to be at risk of not recovering
The patient is expected to require any other form of systemic antineoplastic therapy while receiving the treatment
The patient has a history of severe clinical autoimmune disease
The patient has a history of pneumonitis, organ transplant, human immunodeficiency virus positive, active hepatitis B or hepatitis C
The patient requires systemic steroids for management of immune-related adverse events experienced on another immunotherapy
The patient has active CNS metastases and/or carcinomatous meningitis. However, patients with subclinical brain metastases \< 1 cm can be included (maximum of 4 metastases \< 1 cm). (Patients with previously treated brain metastases may participate provided they are clinically stable. Patients with untreated brain metastasis will be excluded)
The patient has any condition that will interfere with patient compliance or safety (including but not limited to psychiatric or substance abuse disorders)
The patient is pregnant or breastfeeding
The patient is unable to voluntarily agree to participate by signed informed consent or assent
The patient has an active infection requiring systemic therapy
The patient has received a live virus vaccine within 30 days of planned start of therapy
Known side effects to Montanide ISA-51
Significant medical disorder according to investigator; e.g. severe asthma or chronic obstructive lung disease, dysregulated heart disease or dysregulated diabetes mellitus
Concurrent treatment with other experimental drugs
Any active autoimmune diseases e.g. autoimmune neutropenia, thrombocytopenia or hemolytic anemia, systemic lupus erythematosus, scleroderma, myasthenia gravis, autoimmune glomerulonephritis, autoimmune adrenal deficiency, autoimmune thyroiditis etc.
Severe allergy or anaphylactic reactions earlier in life

Study design

Phase: Phase 1 / Phase 2
Primary purpose: Treatment
Allocation: Not applicable
Intervention model: Single group
Masking: None (open label)
Enrollment: 48 participants (actual)

Study arms

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.
Drug: Nivolumab · Biological: PD-L1/IDO peptide vaccine

Interventions

DrugNivolumab
Nivolumab 3 mg/kg is administered biweekly as long as there is clinical benefit.
Also known as: Opdivo
BiologicalPD-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.
Also known as: IO102/IO103 peptide vaccine

What researchers measure

Primary outcomes

Number of Participants With Adverse Events
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.
Time frame: 0 - 75 weeks

Secondary outcomes

Objective Response Rate
Clinical response will be evaluated by RECIST and PERCIST 1.1. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by PET-CT scans: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.
Time frame: The patients were evaluated every 12 weeks until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 58 months
Overall Survival
Overall survival (OS) defined as the time from treatment until death or end of follow-up
Time frame: The patients were evaluated from the date of first study treatment until the date of death from any cause, assessed up to 58 months
Progression Free Survival
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. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.
Time frame: The patients were evaluated from date of first study treatment until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 58 months
Evaluation of Vaccine-specific Responses in Peripheral Blood Mononuclear Cells (PBMCs)
Number of patients with a significant increase of vaccine-specific T cells in the blood during vaccination, assessed by the presence of vaccine-specific responses in peripheral blood mononuclear cells (PBMCs) before, on and after vaccination using a modified interferon (IFN)-γ enzyme-linked immune absorbent spot (ELISPOT) assay.
Time frame: At baseline and up to 24 months after inclusion

Results

Posted Feb 20, 2025

Participant flow

Participant flow — Overall Study
Milestone	Arm A	Arm B	Arm C
Started	30	14	4
Completed	30	10	4
Not completed	0	4	0
Withdrew: Adverse event	0	2	0
Withdrew: Protocol violation	0	1	0
Withdrew: Included in another protocol	0	1	0

Outcome measures

PrimaryNumber of Participants With Adverse Events

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.

Time frame:: 0 - 75 weeks
Reported as:: Count of participants · Participants

Number of Participants With Adverse Events
Participants	Arm A	Arm B	Arm C
Number of Participants With Adverse Events	30	10	4

SecondaryObjective Response Rate

Clinical response will be evaluated by RECIST and PERCIST 1.1. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by PET-CT scans: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.

Time frame:: The patients were evaluated every 12 weeks until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 58 months
Reported as:: Count of participants · Participants

Objective Response Rate
Participants	Arm A	Arm B	Arm C
Objective Response Rate	24	0	2

SecondaryOverall Survival

Overall survival (OS) defined as the time from treatment until death or end of follow-up

Time frame:: The patients were evaluated from the date of first study treatment until the date of death from any cause, assessed up to 58 months
Reported as:: Median · months

Overall Survival
months	Arm A	Arm B	Arm C
Overall Survival	NA (36.4 to NA)	16.7 (4.13 to NA)	NA (NA to NA)

SecondaryProgression Free Survival

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. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.

Time frame:: The patients were evaluated from date of first study treatment until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 58 months
Reported as:: Median · months

Progression Free Survival
months	Arm A	Arm B	Arm C
Progression Free Survival	25.5 (8.8 to 39)	2.4 (1.38 to 2.52)	NA (NA to NA)

SecondaryEvaluation of Vaccine-specific Responses in Peripheral Blood Mononuclear Cells (PBMCs)

Number of patients with a significant increase of vaccine-specific T cells in the blood during vaccination, assessed by the presence of vaccine-specific responses in peripheral blood mononuclear cells (PBMCs) before, on and after vaccination using a modified interferon (IFN)-γ enzyme-linked immune absorbent spot (ELISPOT) assay.

Time frame:: At baseline and up to 24 months after inclusion
Reported as:: Count of participants · Participants

Evaluation of Vaccine-specific Responses in Peripheral Blood Mononuclear Cells (PBMCs)
Participants	Arm A	Arm B	Arm C
Evaluation of Vaccine-specific Responses in Peripheral Blood Mononuclear Cells (PBMCs)	28	2	1

Adverse events

Collected over All-Cause Mortality, Serious Adverse Events and Other Adverse Events were assessed every 2nd week during treatment and every 3 months during follow-up. All-Cause Mortality was assessed up to 58 months. Serious and Other Adverse Events were assessed up to 75 weeks. Non-serious events are listed at a 0% frequency threshold.

Adverse event summary by group
Group	Deaths	Serious	Other
Arm A	12/30 (40%)	11/30 (36.7%)	30/30 (100%)
Arm B	6/14 (42.9%)	2/14 (14.3%)	13/14 (92.9%)
Arm C	2/4 (50%)	1/4 (25%)	4/4 (100%)

Most frequent serious events

Showing 10 of 19

Most frequent serious events
Event	Arm A	Arm B	Arm C
MelaenaGastrointestinal disorders	0/30	0/14	1/4
Staphylococcal infectionInfections and infestations	1/30	0/14	1/4
HypophysitisEndocrine disorders	1/30	1/14	0/4
BacteraemiaInfections and infestations	0/30	1/14	0/4
pneumonitisRespiratory, thoracic and mediastinal disorders	2/30	0/14	0/4
PneumoniaRespiratory, thoracic and mediastinal disorders	2/30	0/14	0/4
MyocarditisCardiac disorders	1/30	0/14	0/4
Tonsillar disorderNeoplasms benign, malignant and unspecified (incl cysts and polyps)	1/30	0/14	0/4
Pulmonary embolismRespiratory, thoracic and mediastinal disorders	1/30	0/14	0/4
VasculitisVascular disorders	1/30	0/14	0/4

Most frequent other events

Showing 10 of 35

Most frequent other events
Event	Arm A	Arm B	Arm C
Injection related reactionSkin and subcutaneous tissue disorders	23/30	5/14	2/4
FatigueGeneral disorders	17/30	3/14	3/4
Granuloma skinSkin and subcutaneous tissue disorders	20/30	5/14	1/4
Rash maculo-papularSkin and subcutaneous tissue disorders	16/30	1/14	1/4
Injection site erythemaSkin and subcutaneous tissue disorders	7/30	1/14	2/4
ArthralgiaMusculoskeletal and connective tissue disorders	11/30	0/14	1/4
DiarrhoeaGastrointestinal disorders	9/30	2/14	1/4
NauseaGastrointestinal disorders	8/30	3/14	1/4
PruritusSkin and subcutaneous tissue disorders	8/30	2/14	0/4
Dry skinSkin and subcutaneous tissue disorders	8/30	3/14	1/4

Baseline characteristics

Age, Categorical
Age, Categorical(Participants)	Arm A	Arm B	Arm C	Total
<=18 years	0	0	0	0
Between 18 and 65 years	7	5	1	13
>=65 years	23	9	3	35

Sex: Female, Male
Sex: Female, Male(Participants)	Arm A	Arm B	Arm C	Total
Female	14	8	2	24
Male	16	6	2	24

Race and Ethnicity Not Collected
Race and Ethnicity Not Collected(Participants)	Arm A	Arm B	Arm C	Total
Count of participants	—	—	—	0

Region of Enrollment
Region of Enrollment(Participants)	Arm A	Arm B	Arm C	Total
Denmark	30	14	4	48

Study locations

2 sites

Herlev Hospital
Herlev, 2730, Denmark
National Center for Cancer Immune Therapy, Dept. of Oncology
Herlev, 2730, Denmark

References and documents

Publications

Kjeldsen JW, Lorentzen CL, Martinenaite E, Ellebaek E, Donia M, Holmstroem RB, Klausen TW, Madsen CO, Ahmed SM, Weis-Banke SE, Holmstrom MO, Hendel HW, Ehrnrooth E, Zocca MB, Pedersen AW, Andersen MH, Svane IM. A phase 1/2 trial of an immune-modulatory vaccine against IDO/PD-L1 in combination with nivolumab in metastatic melanoma. Nat Med. 2021 Dec;27(12):2212-2223. doi: 10.1038/s41591-021-01544-x. Epub 2021 Dec 9. Erratum In: Nat Med. 2022 Apr;28(4):871. doi: 10.1038/s41591-022-01771-w. PubMed 34887574 ↗

Study documents

Protocol and statistical analysis plan · Oct 4, 2022

Documents are hosted by the registry — open the source record to download them.

Updates

Tracking since Sep 25, 2026

No changes since tracking began. The registry record was last updated on Feb 20, 2025, before this site started recording changes on Sep 25, 2026. Its history is on ClinicalTrials.gov ↗

Registry details

Key details

Study ID: NCT03047928
Lead sponsor: Inge Marie Svane
Responsible party: Inge Marie Svane (MD, Professor, Herlev Hospital) — Sponsor-investigator
First posted: Feb 9, 2017
Start date: Feb 22, 2018
Primary completion: Dec 31, 2022
Completion: Dec 31, 2022
Results posted: Feb 20, 2025
Last update: Feb 20, 2025

Study contacts

Inge Marie Svane, Prof., MD

study director · National Center for Cancer Immune Therapy, Dept. of Oncology, Copenhagen University Hospital Herlev, Borgmester Ib Juuls vej 1, DK-2730

Cathrine Lund Lorentzen, MD

principal investigator · National Center for Cancer Immune Therapy, Dept. of Oncology, Copenhagen University Hospital Herlev, Borgmester Ib Juuls vej 1, DK-2730

Oversight

Data monitoring committee: Yes
FDA-regulated drug: No
FDA-regulated device: No

View the source record on ClinicalTrials.gov ↗

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