Arginase-1 Peptide Vaccine in Patients With Metastatic Solid Tumors

Study Overview
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Brief Summary
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In this phase I first-in-humans-study a vaccine consisting of arginase-1 (ARG1) peptides and the adjuvant Montanide ISA-51 will be tested in ten patients with metastatic solid tumors. Patients will be treated with an ARG1 vaccine every third week for 45 weeks.

Detailed Description
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Arginase-1 (ARG1) is an enzyme that converts the amino acid arginine into urea and ornithine. ARG1 is mainly expressed in hepatocytes but different myeloid cells are also capable of ARG1-expression. An ARG1-induced arginine depletion suppresses T cell function through the impairment of the T cell receptor (TCR)-complex. A research group from the Center for Cancer Immune Therapy (CCIT) have identified spontaneous T cell reactivity against ARG1 peptides in peripheral blood mononuclear cells of cancer patients and healthy donors. The theoretic background for an ARG1 peptide vaccine is to activate ARG1-specific T cells to infiltrate the tumor microenvironment and eliminate ARG1-expressing immunosuppressive cells. The aim is to treat 10 patients with progressive solid tumors following treatment with standard of care agents. Patients will receive ARG1 vaccinations administered subcutaneously every third week for 45 weeks. The primary endpoint is to evaluate safety and toxicity. Immune responses will be assessed using blood- and tumor tissue samples and clinical responses are evaluated using RECIST 1.1.

Official Title
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Arginase-1 Peptide Vaccine in Patients With Metastatic Solid Tumors

Conditions
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Non Small Cell Lung Cancer, Urothelial Carcinoma, Malignant Melanoma, Ovarian Cancer, Colorectal Cancer, Breast Cancer, Squamous Cell Carcinoma of the Head and Neck, Metastatic Cancer

Intervention / Treatment
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* Biological: ARG1-18,19,20


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 18 The patient has metastatic solid tumors (NSCLC, colorectal cancer, urothelial cancer, breast cancer, ovarian cancer, malignant melanoma or HNSCC); progressive or recurrent disease on or following treatment with standard of care agents At least one measurable parameter according to RECIST 1.1. The patient has an ECOG performance status of 0 or 1 Life expectancy of at least 3 months Prior PD1/PD-L1 allowed The patient is a female of childbearing potential with negative pregnancy test For fertile women: Agreement to use contraceptive methods with a failure rate of < 1 % per year during the treatment period and for at least 150 days 12 weeks after the treatment. Safe contraceptive methods for women are birth control pills, intrauterine device, contraceptive injection, contraceptive implant, contraceptive patch or contraceptive vaginal ring. 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 or ≥ 5.6 mmol/L Mandatory provision of archival tissue and blood for biomarker testing at baseline Mandatory provision of blood for biomarker testing during the study Signed declaration of consent after oral and written information about the protocol Exclusion Criteria: 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 or radiation therapy while receiving the treatment. However, radiation therapy treatment of non target lesion is allowed. 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 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 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 Concurrent treatment with Valproate or Xanthin Oxidase inhibitors Known side effects to Montanide ISA-51 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ARG1-18,19,20 peptide vaccine<br>One ARG1-vaccine every third week for 45 weeks. | Biological: ARG1-18,19,20<br>* 300 ug ARG1-18,19,20 peptide in water mixed with 500ul montanide<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse Events Evaluated by CTCAE 4.0 | Patients were evaluated according to Common Terminology Criteria for Adverse Events (CTCEA). An adverse event (AE) is an abnormal clinical finding. Each participant was assessed from start of treatment until 6 months after the last vaccine. | 0 - 75 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Immune Responses | To evaluate the immunological impact of the ARG1-18,19,20 peptide vaccines using blood samples and tumor biopsies. | project blood samples were taken at baseline and every 3 months for a maximum of 1,5 year. Tumor biopsies were taken at baseline and after 3 months if possible. | 
| Overall Survival | Overall Survival (OS) defined as time from treatment initiation to death, will be described with use of Kaplan Meier curve. | 0 - 75 weeks | 
| 4.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. 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. | 0 - 75 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Arginase 1