Neoantigen Vaccine Plus Locally Administered Ipilimumab and Systemic Nivolumab in Advanced Melanoma

Study Overview
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Brief Summary
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This research study is studying a new type of personalized neoantigen vaccine (NeoVax) plus Montanide® in combination with Ipilimumab (Yervoy™) and Nivolumab (Opdivo®) as a possible treatment for melanoma. The drugs involved in this study are: Personalized Neoantigen Vaccine Poly-ICLC (Hiltonol®) Montanide® Ipilimumab (Yervoy™) Nivolumab (Opdivo®)

Detailed Description
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This research study is a Phase I clinical trial, which tests the safety of an investigational personalized neoantigen vaccine consisting of personalized neoantigen peptides and Hiltonol® (NeoVax) plus Montanide® in combination with Nivolumab and Ipilimumab. The study also intends to define the appropriate dose of investigational Ipilimumab administered subcutaneously (under the skin) to use for further studies. Investigational means that the combination is being studied. The FDA (the U.S. Food and Drug Administration) has not approved personalized neoantigen peptides, Hiltonol® or Montanide® a as a treatment for any disease. It is an investigational drug being developed for use in the treatment of metastatic melanoma. The FDA has approved Nivolumab (Opdivo®) and Ipilimumab (Yervoy™) as a treatment option for this disease. The FDA has approved Ipilimumab administered intravenously as a treatment option for this disease. The FDA has not approved Ipilimumab administered subcutaneously (under the skin) as a treatment for any disease. The purpose of this study is to determine if it is possible to administer safely a personalized neoantigen vaccine (NeoVax) + Montanide in combination with Ipilimumab and Nivolumab against melanoma by using information gained from specific characteristics of melanoma. It is known that melanoma cancers have mutations (changes in genetic material) that are specific to an individual patient and tumor. These mutations can cause the tumor cells to produce proteins that appear very different from the body's own cells. It is possible that these proteins used in a vaccine may induce strong immune responses, which may help the body fight any tumor cells that could cause the melanoma to come back in the future. Melanoma cells will be obtained either by tumor surgery or tumor biopsy. The genetic material contained in the melanoma cells will be examined for the presence of tumor-specific mutations. This information will be used to prepare small protein fragments, which are called peptides. The vaccine will consist of up to 20 of these peptides mixed with two drugs that activate the immune system called Poly-ICLC (Hiltonol®) and Montanide®. Poly-ICLC (also called Hiltonol) binds proteins on the surface of certain immune cells to make it appear as if a virus is present. When the cells detect the vaccine, they think it is a virus and turn on the immune system. Poly-ICLC is a compound that has been used to help the body in its fight against cancer. Poly-ICLC will be mixed with neoantigen peptides to create the personalized neoantigen vaccine (NeoVax). Poly-ICLC is an investigational drug, meaning the FDA has not approved it as a treatment for any disease. Montanide® is an activator of immunity that enhances response to vaccination through slow release of the peptides from the injection site and its ability to create an inflammation and stimulate the recruitment of specific cells of the participant's immune system. Montanide® will be mixed with the personalized neoantigen vaccine product and administered as an injection given underneath the skin. Ipilimumab and Nivolumab are antibodies that prevent cancer cells from suppressing immune response so that the body can attack and kill the cancer. An antibody is a common type of protein produced by the body that the immune system (a system that defends the body against potentially harmful particles) uses to find and destroy foreign molecules (particles not typically found in the body) such as bacteria and viruses. Antibodies can also be produced in the laboratory for use in treating patients. There are now several approved antibodies for the therapy of cancer and other diseases. In this research study, the investigators are looking at the effectiveness (how well the drug works), safety, and tolerability of the Personalized NeoAntigen Cancer Vaccine plus Montanide® combined with Ipilimumab and Nivolumab.

Official Title
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A Phase Ib Study of Neoantigen Vaccine (NeoVax Plus Montanide) in Combination With Nivolumab and Locally Administered Ipilimumab in Patients With Advanced Melanoma

Conditions
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Melanoma

Intervention / Treatment
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* Drug: Nivolumab
* Biological: NeoVax plus Montanide
* Drug: Ipilimumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participant is willing and able to give written informed consent Participants must have histologically confirmed melanoma that is unresectable stage III or stage IV; at least one site of disease must be resectable, partially-resectable, or amenable to core biopsies to provide tumor tissue for sequence analysis Participants must have measurable disease by RECIST v1.1 that has not been treated with local therapy within the last 12 months of study treatment. The measurable lesion and the lesion used for surgical or core biopsies can be identical as long as it remains measurable after biopsy Age ≥ 18 years ECOG performance status of 0 or 1 Recovered from all toxicities associated with prior treatment, to acceptable baseline status (as to Lab toxicity see below limits for inclusion) or a National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4, Grade of 0 or 1, except for toxicities not considered a safety risk, such as alopecia or vitiligo Participants must have normal organ and marrow function as defined below: WBC ≥3,000/µL ANC ≥1,500/µL Platelets ≥100,000/µL Hemoglobin ˃ 9.0 g/dL Total Bilirubin ≤ 1.5 x ULN (except subjects with Gilbert Syndrome, who can have total bilirubin < 3.0 mg/dL) AST(SGOT)/ALT(SGPT) ≤ 3 x ULN Creatinine ≤ 1.5 x ULN OR Creatinine clearance ≥40 mL/min/1.73 m2 for participants with creatinine levels above institutional normal (if using the Cockcroft-Gault formula below): Female CrCl = (140 - age in years) x weight in kg x 0.85 72 x serum creatinine in mg/dL Male CrCl = (140 - age in years) x weight in kg x 1.00 72 x serum creatinine in mg/dL Women of childbearing potential (WOCBP) should have a negative serum pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of Nivolumab, because the effects of NeoVax plus Montanide and Nivolumab on the developing human fetus are unknown Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with study agents, breastfeeding should be discontinued if the mother is treated with Ipilimumab, Nivolumab and Personalized Neoantigen vaccine + Montanide. Female participants enrolled in the study, who are not free from menses for >2 years, post hysterectomy / oophorectomy, or surgically sterilized, should be willing to use either 2 adequate barrier methods or a barrier method plus a hormonal method of contraception to prevent pregnancy or to abstain from sexual activity throughout the study, starting with visit 1 through 23 weeks (30 days plus the time required for Nivolumab to undergo five half-lives) after the last dose of study therapy. Approved contraceptive methods include for example: intra uterine device, diaphragm with spermicide, cervical cap with spermicide, male condoms, or female condom with spermicide. Spermicides alone are not an acceptable method of contraception. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Male participants should agree to use an adequate method of contraception starting with visit 1 through 31 weeks after the last dose of study therapy Eligibility Criteria for Secondary Registration ECOG performance status of 0 or 1 Screening laboratory values must meet the following criteria and should be obtained within 7 days prior to registration WBC ≥ 3000/μL Neutrophils ≥ 1500/μL Platelets ≥ 100 x103/μL Hemoglobin > 9.0 g/dL Serum creatinine ≤ 1.5 x ULN or creatinine clearance (CrCl) ≥ 40 mL/min (if using the Cockcroft-Gault formula below): Female CrCl = (140 - age in years) x weight in kg x 0.85 72 x serum creatinine in mg/dL Male CrCl = (140 - age in years) x weight in kg x 1.00 72 serum creatinine in mg/dL AST/ALT ≤ 3 x ULN Total Bilirubin ≤ 1.5 x ULN (except subjects with Gilbert Syndrome, who can have total bilirubin < 3.0 mg/dL) Women of childbearing potential (WOCBP) should have a negative serum pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of Nivolumab, because the effects of NeoVax plus Montanide and Nivolumab on the developing human fetus are unknown Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with study agents, breastfeeding should be discontinued if the mother is treated with Ipilimumab, Nivolumab and Personalized Neoantigen vaccine + Montanide. Female participants enrolled in the study, who are not free from menses for >2 years, post hysterectomy / oophorectomy, or surgically sterilized, should be willing to use either 2 adequate barrier methods or a barrier method plus a hormonal method of contraception to prevent pregnancy or to abstain from sexual activity throughout the study, starting with visit 1 through 23 weeks (30 days plus the time required for Nivolumab to undergo five half-lives) after the last dose of study therapy. Approved contraceptive methods include for example: intra uterine device, diaphragm with spermicide, cervical cap with spermicide, male condoms, or female condom with spermicide. Spermicides alone are not an acceptable method of contraception Male participants should agree to use an adequate method of contraception starting with visit 1 through 31 weeks after the last dose of study therapy Exclusion Criteria: Prior immunotherapy for metastatic melanoma except anti-CTLA-4 Concomitant therapy with any anti-cancer agents, other investigational anti-cancer therapies, or immunosuppressive agents including but not limited to methotrexate, chloroquine, azathioprine, etc. within six months of study participation Active brain metastases or leptomeningeal metastases Use of a non-oncology vaccine therapy for prevention of infectious diseases during the 4 week period prior to first dose of Nivolumab. Participants may not receive any non-oncology vaccine therapy during the period of Nivolumab or NeoVax plus Montanide administration and until at least 8 weeks after the last dose of study therapy History of severe allergic reactions attributed to any vaccine therapy for the prevention of infectious diseases Active, known or suspected autoimmune disease. Subjects are permitted to enroll if they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger A condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of 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 test positive for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS) Uncontrolled intercurrent illness including, but not limited to ongoing or active infection requiring treatment, symptomatic Any underlying medical condition, psychiatric condition or social situation that in the opinion of the investigator would compromise study administration as per protocol or compromise the assessment of AEs Planned major surgery Pregnant women are excluded from this study because Nivolumab, personalized neoantigen peptides and poly-ICLC are agents with unknown risks to the developing fetus. Because there is an unknown but potential risk of adverse events in nursing infants secondary to treatment of the mother with Nivolumab, personalized neoantigen peptides and poly-ICLC, nursing women are excluded from this study Individuals with a history of an invasive malignancy are ineligible except for the following circumstances: a) individuals with a history of invasive malignancy are eligible if they have been disease-free for at least 3 years and are deemed by the investigator to be at low risk for recurrence of that malignancy; b) individuals with the following cancers are eligible if diagnosed and treated - carcinoma in situ of the breast, oral cavity or cervix, localized prostate cancer, basal cell or squamous cell carcinoma of the skin

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: Nivolumab+Ipilimumab+NeoVax plus Montanide<br>Run in period will begin within 2 weeks of metastatic tissue biopsy, once the following criteria Patients will receive Nivolumab at a flat dose I.V. infusion every 4 weeks (28 days) Patients will receive Ipilimumab injection on weeks 12, 15, 18, and 21 Patients will receive NeoVax plus Montanide injection on weeks 12, 15, 18, and 21 | Drug: Nivolumab<br>* Nivolumab is an antibody that prevent cancer cells from suppressing the immune response so that the body can attack and kill the cancer<br>* Other names: Opdivo;Biological: NeoVax plus Montanide<br>* Montanide® is an activator of immunity that enhances response to vaccination through slow release of the peptides from the injection site and its ability to create an inflammation and stimulate the recruitment of specific cells of your immune system. Montanide® will be mixed with the personalized neoantigen vaccine<br>Drug: Ipilimumab<br>* Ipilimumab is an antibody that prevent cancer cells from suppressing the immune response so that the body can attack and kill the cancer<br>* Other names: Yervoy;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of DLT | Assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 | 7 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assess the induction of IFN-γ T-cell response or tetramer staining to the assay peptides | The proportion of patients who achieve more than 55 SFU/106 PBMC or 3 times their baseline level | 16 weeks | 
| Rate of objective responses | Assessed by RECIST1.1 | 24 weeks | 
| Rate of participants with clinical benefit | Assessed by RECIST1.1 | 24 weeks | 
| Rate of participants with response conversion | Assessed by RECIST1.1 | 24 weeks | 
| Rate of complete responses | Assessed by RECIST1.1 | 24 weeks | 
| Rate of partial responses | Assessed by RECIST1.1 | 24 weeks | 
| Rate of participants with progressive disease | Assessed by RECIST1.1 | 24 weeks | 
| Rate of participants with stable disease | Assessed by RECIST1.1 | 24 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Melanoma