The purpose of this research is to test the safety and effectiveness of the investigational
combination of Troriluzole, ipilimumab, and nivolumab, and to learn whether this combination
works in treating melanoma that has spread to the brain.
This is a multi-center, double-blind, randomized, phase II signal-detection trial with a
non-randomized safety run-in to assess the efficacy and safety of adding troriluzole to
ipilimumab/nivolumab induction and nivolumab maintenance in patients with melanoma that has
metastasized to the brain. Measuring the shrinking or growth of melanoma in participants will
allow researchers to learn about these study drugs and provide information on the safety and
effectiveness of this combination in treating melanoma.
The U.S. Food and Drug Administration (FDA) has not approved Troriluzole as a treatment for
any disease. The U.S. Food and Drug Administration (FDA) has approved nivolumab, ipilimumab,
and the combination of these two drugs as treatment options for melanoma that has
metastasized to the brain.
Ipilimumab and nivolumab are drugs that treat cancer by blocking certain molecules in the
body. This blocking action prevents other molecules from binding to cells involved in the
immune system. With these changes, the immune system is more likely to become active, and
will react more intensely when activated. The immune system is able to destroy cancer cells
and reduce the size of tumors, so activating the immune system is an important part of cancer
treatment. Ipilimumab blocks a molecule called CTLA-4, which normally decreases the
activation of the immune system by binding to T-Cells, which are important immune system
cells that can attack cancer cells. Nivolumab blocks a molecule called PD-1, which also
normally decreases the activation of the immune system.
Troriluzole is a drug that modulates glutamate, the most abundant excitatory neurotransmitter
in the human body. The primary mode of action of Troriluzole is reducing synaptic levels of
glutamate. This may change parts of the immune system in the brain, which is could improve
treatment outcomes with anti-cancer drugs such as ipilimumab and nivolumab that can work in
the brain. This study is testing Troriluzole's ability to increase the effectiveness of
ipilimumab and nivolumab treatment in melanoma that has spread to the brain, as well as
testing the safety of the combination of these three drugs.
Participation in this research is expected to last up to 4 years: 1 year of treatment and 3
years of follow up.
About 108 subjects will take part in this research.
Inclusion Criteria:
- Participants must have histologically or cytologically confirmed melanoma. All
melanoma subtypes are included, except for ocular melanoma.
- Participants must have measurable disease in the brain (intraparenchymal brain
metastases), defined as at least one lesion that can be accurately measured by MRI in
at least one dimension as ≥5 mm and ≤ 3 cm in longest diameter. See Section 11
(Measurement of Effect) for the evaluation of measurable disease. Measurable disease
in the extracranial compartment (body) is not required. Measurable lesions may not
have received previous treatment with radiation therapy. Prior stereotactic radiation
therapy or SRT (e.g. GammaKnife, CyberKnife) is allowed for lesions other than the
lesions selected as measurable target lesions. Prior craniotomy with resection of
brain metastases is allowed.
- Participants must have received prior systemic treatment with anti-PD-1 therapy (e.g.
pembrolizumab, or nivolumab) in any setting (neoadjuvant, adjuvant or metastatic).
Prior anti-CTLA-4 monotherapy is allowed (e.g. ipilimumab). Prior targeted therapy
(e.g. BRAF inhibitors, MEK inhibitors) is allowed.
- Age ≥18 years. Because no dosing or adverse event data are currently available on the
use of troriluzole in participants <18 years of age, children are excluded from this
study, but will be eligible for future pediatric trials.
- ECOG performance status 0 or 1 (see Appendix A).
- Participants must have adequate organ and marrow function as defined below:
- absolute neutrophil count ≥1,000/mcL
- total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN), or in the case
of Gilbert's disease ≤ 3x ULN
- AST(SGOT)/ALT(SGPT) ≤3 × institutional ULN
- Human immunodeficiency virus (HIV)-infected participants on effective anti-retroviral
therapy with undetectable viral load within 6 months are eligible for this trial.
- For participants with evidence of chronic hepatitis B virus (HBV) infection, the HBV
viral load must be undetectable on suppressive therapy, if indicated.
- Participants with a history of hepatitis C virus (HCV) infection must have been
treated and cured. For participants with HCV infection who are currently on treatment,
they are eligible if they have an undetectable HCV viral load.
- Participants with known history or current symptoms of cardiac disease, or history of
treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac
function using the New York Heart Association Functional Classification. To be
eligible for this trial, participants should be class 2B or better.
- The effects of troriluzole on the developing human fetus are unknown. For this reason
and because ipilimumab is a pregnancy category C, women of child-bearing potential and
men must agree to use adequate contraception (hormonal or barrier method of birth
control; abstinence from heterosexual intercourse) prior to study entry, for the
duration of study participation, and 4 months after completion of all study drugs.
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. Men
treated or enrolled on this protocol must also agree to use adequate contraception
prior to the study, for the duration of study participation, and 4 months after
completion of all study drugs.
- Ability to swallow pills.
- Ability to understand and the willingness to sign a written informed consent document.
Exclusion Criteria:
- Ocular subtype of melanoma.
- Cytologically confirmed leptomeningeal metastases, or convincing imaging evidence of
leptomeningeal spread.
- Prior whole brain radiation therapy (WBRT).
- Prior combination therapy with concurrent ipilimumab (3 mg/kg IV) + nivolumab (1 mg/kg
IV) in the 24 months prior to the date of registration.
- Participants who have had systemic therapy (immunotherapy, chemotherapy, or targeted
therapy), radiotherapy, or major surgery within 3 weeks prior to the date of
registration.
- Participants who require immediate local treatment (surgical resection or
radiosurgery) of brain metastases due to neurological symptoms, or brain metastases
located in sensitive areas of the brain requiring immediate local treatment.
- Participants who have required systemic steroids to manage neurologic symptoms
(seizures, cerebral edema, severe headache, nausea/vomiting, etc.) within 1 week prior
to the date of registration.
- Participants who are receiving any other investigational agents for cancer or
neurologic disease.
- Extreme claustrophobia that would interfere with performing brain MRIs or severe
allergy to gadolinium contrast.
- History of severe or life-threatening allergic reactions attributed to compounds of
similar chemical or biologic composition to troriluzole, riluzuole, ipilimumab, or
nivolumab.
- Second primary malignancy that is a competing cause of death in the opinion of the
treating investigator (prognosis < 6 months).
- Patients with a history of solid organ transplant, or allogeneic bone marrow
transplant.
- Active autoimmune disease or any other condition requiring systemic treatment with
either corticosteroids (>10 mg daily prednisone equivalents) or other systemic
immunosuppressive medications within 3 weeks of registration.
- History of grade 4 immune related adverse event from prior cancer treatment, (with the
exception of asymptomatic elevation of serum amylase or lipase).
- History of immune-related adverse event from prior cancer immunotherapy treatment that
has not improved to grade 0-1 (with the exception of patients with ongoing thyroid,
adrenal or gonadal insufficiency requiring continued medical treatment, vitiligo, or
asymptomatic elevation of serum amylase or lipase).
- Participants receiving any medications or substances that are inhibitors or inducers
of the liver enzyme Cytochrome P-450 CYP1A2, including fluvoxamine, cimetidine,
amiodarone, efavirenz, fluoroquinolones (including ciprofloxacin and levofloxacin),
fluvoxamine, furafylline, interferon, methoxsalen, mibefradil, or ticlopidine. These
medications must be discontinued at least 7 days prior to registration.
- Participants with uncontrolled intercurrent illness.
- Participants with psychiatric illness/social situations that would limit compliance
with study requirements.
- Pregnant and nursing (breastfeeding) women are excluded from this study because the
effects of troriluzole on the developing human fetus are unknown, and because
ipilimumab is pregnancy category
