Back to results

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

Primary Purpose

Metastatic Melanoma

Status

Recruiting

Phase

Phase 1

Locations

Denmark

Study Type

Interventional

Intervention

Nivolumab

PD-L1/IDO peptide vaccine

About this trial

This is an interventional treatment trial for Metastatic Melanoma

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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:

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

Sites / Locations

Herlev HospitalRecruiting
National Center for Cancer Immune Therapy, Dept. of OncologyRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Patient group

Arm Description

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.

Outcomes

Primary Outcome Measures

Number and type of reported 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.

Secondary Outcome Measures

Treatment related immune responses

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

Clinical response will be evaluated by RECIST and PERCIST 1.1 and irRC

Overall Survival

Overall Survival (OS), defined as time from treatment initiation to death, will be described with use of Kaplan Meier curve.

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, will be described with Kaplan Meier curve.

Full Information

NCT ID

NCT03047928

First Posted

February 6, 2017

Last Updated

September 2, 2022

Sponsor

Inge Marie Svane

1. Study Identification

Unique Protocol Identification Number

NCT03047928

Brief Title

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

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

September 2022

Overall Recruitment Status

Recruiting

Study Start Date

February 22, 2018 (Actual)

Primary Completion Date

April 1, 2023 (Anticipated)

Study Completion Date

April 1, 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor-Investigator

Name of the Sponsor

Inge Marie Svane

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Product Manufactured in and Exported from the U.S.

Data Monitoring Committee

Yes

5. Study Description

Brief 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.

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Metastatic Melanoma

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1, Phase 2

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

50 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Patient group

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

Nivolumab

Other Intervention Name(s)

Opdivo

Intervention Description

Nivolumab 3 mg/kg is administered biweekly as long as there is clinical benefit.

Intervention Type

Biological

Intervention Name(s)

PD-L1/IDO peptide vaccine

Other Intervention Name(s)

IO102/IO103 peptide vaccine

Intervention Description

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.

Primary Outcome Measure Information:

Title

Number and type of reported adverse events

Description

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

0-55 weeks

Secondary Outcome Measure Information:

Title

Treatment related immune responses

Description

Time Frame

Up to 24 months

Title

Objective response rate

Description

Clinical response will be evaluated by RECIST and PERCIST 1.1 and irRC

Time Frame

Up to 24 months

Title

Overall Survival

Description

Overall Survival (OS), defined as time from treatment initiation to death, will be described with use of Kaplan Meier curve.

Time Frame

Up to 24 months

Title

Progression free survival

Description

Time Frame

Up to 24 months

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

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: AST and ALT ≤2,5 X ULN or ≤5 X ULN with liver metastases Serum total bilirubin ≤1,5 X ULN or direct bilirubin ≤ ULN for patient with total bilirubin level > 1,5 ULN Serum creatinine ≤1,5 X ULN ANC (Absolute Neutrophil Count) ≥1,000/mcL Platelets ≥ 75,000 /mcL Hemoglobin ≥ 9 g/dL eller ≥ 5.6 mmol/L Signed declaration of content after oral and written information about the protocol. 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

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Inge Marie Svane, Prof., MD

Phone

+4538683868

inge.marie.svane@regionh.dk

First Name & Middle Initial & Last Name or Official Title & Degree

Cathrine Lund Lorentzen, MD

Phone

+4538683868

cathrine.lund.lorentzen@regionh.dk

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Inge Marie Svane, Prof., MD

Organizational Affiliation

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

Official's Role

Study Director

First Name & Middle Initial & Last Name & Degree

Cathrine Lund Lorentzen, MD

Organizational Affiliation

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

Official's Role

Principal Investigator

Facility Information:

Facility Name

Herlev Hospital

City

Herlev

ZIP/Postal Code

2730

Country

Denmark

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Cathrine L Lorentzen, MD

Facility Name

National Center for Cancer Immune Therapy, Dept. of Oncology

City

Herlev

ZIP/Postal Code

2730

Country

Denmark

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Inge Marie Svane, Prof., MD

Phone

+4538683868

inge.marie.svane@regionh.dk

First Name & Middle Initial & Last Name & Degree

Cathrine Lund Lorentzen, MD

Phone

+4538683868

cathrine.lund.lorentzen@regionh.dk

12. IPD Sharing Statement

Citations:

PubMed Identifier

34887574

Citation

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.

Results Reference

derived

Learn more about this trial

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

We'll reach out to this number within 24 hrs