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®)
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.
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
