MelanomaPhase 2NCT04899921
Troriluzole or Placebo Plus Ipi Plus Nivo in Mel Brain Mets
A Phase 2 study testing Ipilimumab, Nivolumab and Troriluzole in people with Melanoma and Metastatic Melanoma, run by Dana-Farber Cancer Institute at 2 sites in United States.
Trial summary
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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Melanoma, Metastatic Melanoma
- What is being tested?
- Ipilimumab, Nivolumab and Troriluzole
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 1 participants
- Where
- 2 sitesUnited States
- Study dates
- 30 Jun 2021to 29 May 2023
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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 magnetic resonance imaging (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 (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:
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- 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.
Who cannot join
- 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.
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- 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
Trial locations and contacts
2 sites in 1 country.
United States2 sites
Massachusetts General Hospital
Boston, Massachusetts, 02114
Dana Farber Cancer Institute
Boston, Massachusetts, 02115
About this study
Official title: A Blinded, Randomized Phase 2 Study of Troriluzole in Combination With Ipilimumab and Nivolumab in Patients With Melanoma Brain Metastases Previously Treated With Anti-PD-1 Therapy
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.
Read the detailed description
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 cytotoxic T-lymphocyte-associated protein-4 (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 programmed death receptor-1 (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.
- Conditions
- Melanoma, Metastatic Melanoma
- Being tested
- Ipilimumab, Nivolumab, Troriluzole, Placebo
- Keywords
- Melanoma, Metastatic Melanoma, Metastatic Melanoma, Brain
- Medical subject headings
- Melanoma
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
IpilimumabDrug
Also called Yervoy
Intravenous injection
NivolumabDrug
Also called Opdivo
Intravenously (IV) into the vein
TroriluzoleDrug
Also called BHV-4157, Trigriluzole, FC-4157
Taken orally
PlaceboDrug
Also called Sugar Pill
Taken orally
| Study group | Role | What they receive |
|---|---|---|
| Ipilimumab + Nivolumab + Troriluzole [Phase I dose level 1] | Experimental | Phase I dose level 1 participants received nivolumab 1 mg/kg and ipilimumab 3 mg/kg intravenously (IV) on day 1 of each 21-day cycle and the original starting troriluzole dose of 140 mg orally in the morning as well as 280 mg orally in the evening every day of each 21-day cycle. Participants were treated until disease progression or unacceptable toxicity. Receives: Drug: Ipilimumab; Drug: Nivolumab; Drug: Troriluzole |
| Ipilimumab + Nivolumab + Troriluzole [Phase II] | Experimental | Participants will be randomly assigned and receive:
12 Week Induction Phase: Nivolumab at pre-determined dose followed by ipilimumab at predetermined dose every 3 weeks, with 21 consecutive days defined as a treatment cycle. Troriluzole self-administered at a predetermined dose orally twice a day
36 Week Maintenance Phase: Nivolumab will be administered every 4 weeks, with 28 consecutive days defined as a treatment cycle. Troriluzole self administered at a predetermined dose orally twice a day. No ipilimumab will be given in the maintenance phase. Receives: Drug: Ipilimumab; Drug: Nivolumab; Drug: Troriluzole |
| Ipilimumab + Nivolumab + Placebo [Phase II] | Experimental | Participants will be randomly assigned and receive:
12 Week Induction Phase: Nivolumab at pre-determined dose followed by ipilimumab at predetermined dose every 3 weeks, with 21 consecutive days defined as a treatment cycle. Placebo self-administered at a predetermined dose orally twice a day
36 Week Maintenance Phase: Nivolumab will be administered every 4 weeks, with 28 consecutive days defined as a treatment cycle. Placebo self administered at a predetermined dose orally twice a day. No ipilimumab will be given in the maintenance phase. Receives: Drug: Ipilimumab; Drug: Nivolumab; Drug: Placebo |
| Ipilimumab + Nivolumab + Troriluzole [Phase I dose level 2] | Experimental | Phase I dose level 2 participants received nivolumab 1 mg/kg and ipilimumab 3 mg/kg intravenously (IV) on day 1 of each 21-day cycle and troriluzole 140 mg twice per day orally. Participants were treated until disease progression or unacceptable toxicity. Receives: Drug: Ipilimumab; Drug: Nivolumab; Drug: Troriluzole |
| Ipilimumab + Nivolumab + Troriluzole [Phase I dose level 3] | Experimental | Phase I dose level 3 participants received nivolumab 1 mg/kg and ipilimumab 3 mg/kg intravenously (IV) on day 1 of each 21-day cycle and troriluzole 140 mg/day orally. Participants were treated until disease progression or unacceptable toxicity. Receives: Drug: Ipilimumab; Drug: Nivolumab; Drug: Troriluzole |
What is being measured
The primary outcome is the main question the study is designed to answer.
Median Global Progression-Free Survival (PFS)
Global PFS is defined as the time from random assignment to the earlier of death or documented disease progression in the intracranial or extracranial compartments. The follow-up of patients who have neither died nor progressed will be censored at the date of the last follow-up visit. Disease assessment was based on RECIST 1.1 for all extracranial lesions and modified RECIST 1.1 for all brain lesions. Per RECIST 1.1 for target lesions: PD is at least a 20% increase in sum LD, taking as reference the smallest sum on study with at least 5 mm absolute increase. For non-target lesions, progression-free means no new lesions or unequivocal progression on existing non-target lesions or not evaluated,
Measured: Participants would be followed up to 5 years.
Secondary outcomes (11)
Median Overall Survival (OS)
OS was defined as the time from randomization (or registration) to death due to any cause, or censored at date last known alive. Estimates of OS would be from a PHMC model.
Measured: Participants were followed up to 5 years.
Intracranial Response Rate (RR)
Intracranial response rate was defined as the proportion of participants who have achieved complete response (CR) or partial response (PR) based on modified RECIST 1.1.
Measured: From enrollment to end of treatment up to 5 years
Intracranial Progression-free Survival (PFS)
Intracranial PFS was defined as the time from first dose of study therapy to documented intracranial progression or death, whichever occurs first. Per modified RECIST 1.1 for target lesions: PD is at least a 20% increase in sum LD, taking as reference the smallest sum on study with at least 5 mm absolute increase. For non-target lesions, progression-free means no new lesions or unequivocal progression on existing non-target lesions or not evaluated.
Measured: From date of randomization until the date of first documented intracranial progression or date of death from any cause, whichever came first, assessed up to 5 years.
Extracranial Response Rate (RR)
The extracranial response rate was defined as the proportion of participants who have achieved complete response or partial response based on Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1) for all extracranial lesions.
Measured: From enrollment to end of treatment up to 5 years
Extracranial Progression-free Survival (PFS)
Extracranial PFS is defined as the time from first dose of study therapy to documented extracranial progression (per RECIST) or death, whichever occurs first. Evaluated using the international criteria proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1)39 for all extracranial lesions and modified RECIST 1.1 for all brain lesions
Measured: From date of randomization until the date of first documented extracranial progression or date of death from any cause, whichever came first, assessed up to 5 years.
Number of Participants With Treatment-Related Adverse Events as Assessed by CTCAE Version 5.0
The number and proportion of adverse events, graded as defined by CTCAE version 5.0 will be tabulated by type and grade.
Measured: From enrollment to end of treatment up to 5 years
Number of Induction
Number of induction cycles was defined as the number of induction cycles administered.
Measured: From enrollment to end of treatment up to 5 years
Number of Maintenance Cycles
Number of maintenance cycles was defined as the number of maintenance cycles administered.
Measured: From enrollment to end of treatment up to 5 years
Corticosteroids Usage
Corticosteroids usage was defined by number of participants who require prednisone ≥1 mg/kg or equivalent.
Measured: From enrollment to end of treatment up to 5 years
Frequency of Clinically-indicated Stereotactic Radiation Therapy to the Brain
Frequency of clinically-indicated stereotactic radiation therapy to the brain was defined as the number of participants who received on-study brain-directed stereotactic radiation.
Measured: From enrollment to end of treatment up to 5 years
Frequency of Clinically-indicated Surgical Intervention to the Brain
Frequency of clinically-indicated surgical intervention to the brain was defined as the number of participants who received on-study surgical intervention to the brain.
Measured: From enrollment to end of treatment up to 5 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted25 May 2021
- Study start30 Jun 2021
- Primary completion29 May 2023
- Study completion29 May 2023
Why it stopped: Due to poor enrollment
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for MelanomaStudies of the same condition, open and under way.
- More trials run by Dana-Farber Cancer InstituteThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind
- Who is masked
- Participant, Investigator
- Enrolment
- 1 participants (actual)
Sponsor and investigators
- Lead sponsor
- Dana-Farber Cancer Institute
- Sponsor type
- University, hospital or other
- Collaborators
- Biohaven Pharmaceuticals, Inc.
- Responsible party
- Principal investigator, Ann W. Silk, MD MS, Dana-Farber Cancer Institute
- Investigators
- Ann W Silk, MD, MS, Principal investigator, Dana-Farber Cancer Institute
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04899921
- Sponsor's protocol ID
- 20-675
- Status last verified
- Mar 2024
- First submitted
- 16 Apr 2021
- Last updated
- 26 Mar 2024
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes: The Dana-Farber / Harvard Cancer Center encourages and supports the responsible and ethical sharing of data from clinical trials. De-identified participant data from the final research dataset used in the published manuscript may only be shared under the terms of a Data Use Agreement. Requests may be directed to: \[contact information for Sponsor Investigator or designee\]. The protocol and statistical analysis plan will be made available on Clinicaltrials.gov only as required by federal regulation or as a condition of awards and agreements supporting the research.
Publications
Aden D, Sureka N, Zaheer S, Chaurasia JK, Zaheer S. Metabolic Reprogramming in Cancer: Implications for Immunosuppressive Microenvironment. Immunology. 2025 Jan;174(1):30-72. doi: 10.1111/imm.13871. Epub 2024 Oct 27.
PubMed 39462179
Study at a glance
From the registry record, last updated by the sponsor on 26 Mar 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Blinded, Randomized Phase 2 Study of Troriluzole in Combination With Ipilimumab and Nivolumab in Patients With Melanoma Brain Metastases Previously Treated With Anti-PD-1 Therapy
- ClinicalTrials.gov ID
- NCT04899921
- Acronym / sponsor ID
- 20-675
- Conditions
- Melanoma, Metastatic Melanoma
- Keywords
- Melanoma, Metastatic Melanoma, Metastatic Melanoma, Brain
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: Due to poor enrollment
- Enrolment
- 1 participants (actual)
- Lead sponsor
- Dana-Farber Cancer InstituteUniversity, hospital or other
- Collaborators
- Biohaven Pharmaceuticals, Inc.
- Study start
- 30 Jun 2021 (actual)
- Primary completion
- 29 May 2023 (actual)
- Study completion
- 29 May 2023 (actual)
- First posted
- 25 May 2021 (actual)
- Results
- Posted 13 Dec 2023
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
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 cytotoxic T-lymphocyte-associated protein-4 (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 programmed death receptor-1 (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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind (participant, investigator)
- Number of arms
- 5
| Arm | Type | Receives |
|---|---|---|
| Ipilimumab + Nivolumab + Troriluzole [Phase I dose level 1] | Experimental | Drug: Ipilimumab, Drug: Nivolumab, Drug: TroriluzolePhase I dose level 1 participants received nivolumab 1 mg/kg and ipilimumab 3 mg/kg intravenously (IV) on day 1 of each 21-day cycle and the original starting troriluzole dose of 140 mg orally in the morning as well as 280 mg orally in the evening every day of each 21-day cycle. Participants were treated until disease progression or unacceptable toxicity. |
| Ipilimumab + Nivolumab + Troriluzole [Phase II] | Experimental | Drug: Ipilimumab, Drug: Nivolumab, Drug: TroriluzoleParticipants will be randomly assigned and receive: 12 Week Induction Phase: Nivolumab at pre-determined dose followed by ipilimumab at predetermined dose every 3 weeks, with 21 consecutive days defined as a treatment cycle. Troriluzole self-administered at a predetermined dose orally twice a day 36 Week Maintenance Phase: Nivolumab will be administered every 4 weeks, with 28 consecutive days defined as a treatment cycle. Troriluzole self administered at a predetermined dose orally twice a day. No ipilimumab will be given in the maintenance phase. |
| Ipilimumab + Nivolumab + Placebo [Phase II] | Experimental | Drug: Ipilimumab, Drug: Nivolumab, Drug: PlaceboParticipants will be randomly assigned and receive: 12 Week Induction Phase: Nivolumab at pre-determined dose followed by ipilimumab at predetermined dose every 3 weeks, with 21 consecutive days defined as a treatment cycle. Placebo self-administered at a predetermined dose orally twice a day 36 Week Maintenance Phase: Nivolumab will be administered every 4 weeks, with 28 consecutive days defined as a treatment cycle. Placebo self administered at a predetermined dose orally twice a day. No ipilimumab will be given in the maintenance phase. |
| Ipilimumab + Nivolumab + Troriluzole [Phase I dose level 2] | Experimental | Drug: Ipilimumab, Drug: Nivolumab, Drug: TroriluzolePhase I dose level 2 participants received nivolumab 1 mg/kg and ipilimumab 3 mg/kg intravenously (IV) on day 1 of each 21-day cycle and troriluzole 140 mg twice per day orally. Participants were treated until disease progression or unacceptable toxicity. |
| Ipilimumab + Nivolumab + Troriluzole [Phase I dose level 3] | Experimental | Drug: Ipilimumab, Drug: Nivolumab, Drug: TroriluzolePhase I dose level 3 participants received nivolumab 1 mg/kg and ipilimumab 3 mg/kg intravenously (IV) on day 1 of each 21-day cycle and troriluzole 140 mg/day orally. Participants were treated until disease progression or unacceptable toxicity. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (16 listed)
- 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 magnetic resonance imaging (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 (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).
Key exclusion criteria (19 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| IpilimumabAlso: YervoyIntravenous injection | Drug | Ipilimumab + Nivolumab + Placebo [Phase II], Ipilimumab + Nivolumab + Troriluzole [Phase I dose level 1], Ipilimumab + Nivolumab + Troriluzole [Phase I dose level 2], Ipilimumab + Nivolumab + Troriluzole [Phase I dose level 3], Ipilimumab + Nivolumab + Troriluzole [Phase II] |
| NivolumabAlso: OpdivoIntravenously (IV) into the vein | Drug | Ipilimumab + Nivolumab + Placebo [Phase II], Ipilimumab + Nivolumab + Troriluzole [Phase I dose level 1], Ipilimumab + Nivolumab + Troriluzole [Phase I dose level 2], Ipilimumab + Nivolumab + Troriluzole [Phase I dose level 3], Ipilimumab + Nivolumab + Troriluzole [Phase II] |
| TroriluzoleAlso: BHV-4157, Trigriluzole, FC-4157Taken orally | Drug | Ipilimumab + Nivolumab + Troriluzole [Phase I dose level 1], Ipilimumab + Nivolumab + Troriluzole [Phase I dose level 2], Ipilimumab + Nivolumab + Troriluzole [Phase I dose level 3], Ipilimumab + Nivolumab + Troriluzole [Phase II] |
| PlaceboAlso: Sugar PillTaken orally | Drug | Ipilimumab + Nivolumab + Placebo [Phase II] |
Primary outcome
Median Global Progression-Free Survival (PFS)
Time frame: Participants would be followed up to 5 years.
Global PFS is defined as the time from random assignment to the earlier of death or documented disease progression in the intracranial or extracranial compartments. The follow-up of patients who have neither died nor progressed will be censored at the date of the last follow-up visit. Disease assessment was based on RECIST 1.1 for all extracranial lesions and modified RECIST 1.1 for all brain lesions. Per RECIST 1.1 for target lesions: PD is at least a 20% increase in sum LD, taking as reference the smallest sum on study with at least 5 mm absolute increase. For non-target lesions, progression-free means no new lesions or unequivocal progression on existing non-target lesions or not evaluated,
11 secondary outcomes
Median Overall Survival (OS)
Time frame: Participants were followed up to 5 years.
Intracranial Response Rate (RR)
Time frame: From enrollment to end of treatment up to 5 years
Intracranial Progression-free Survival (PFS)
Time frame: From date of randomization until the date of first documented intracranial progression or date of death from any cause, whichever came first, assessed up to 5 years.
Extracranial Response Rate (RR)
Time frame: From enrollment to end of treatment up to 5 years
Extracranial Progression-free Survival (PFS)
Time frame: From date of randomization until the date of first documented extracranial progression or date of death from any cause, whichever came first, assessed up to 5 years.
Number of Participants With Treatment-Related Adverse Events as Assessed by CTCAE Version 5.0
Time frame: From enrollment to end of treatment up to 5 years
Number of Induction
Time frame: From enrollment to end of treatment up to 5 years
Number of Maintenance Cycles
Time frame: From enrollment to end of treatment up to 5 years
Corticosteroids Usage
Time frame: From enrollment to end of treatment up to 5 years
Frequency of Clinically-indicated Stereotactic Radiation Therapy to the Brain
Time frame: From enrollment to end of treatment up to 5 years
Frequency of Clinically-indicated Surgical Intervention to the Brain
Time frame: From enrollment to end of treatment up to 5 years
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 26 Mar 2024.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 39462179Aden D, Sureka N, Zaheer S, Chaurasia JK, Zaheer S. Metabolic Reprogramming in Cancer: Implications for Immunosuppressive Microenvironment. Immunology. 2025 Jan;174(1):30-72. doi: 10.1111/imm.13871. Epub 2024 Oct 27.
- Individual participant dataSharing planned: Yes. The Dana-Farber / Harvard Cancer Center encourages and supports the responsible and ethical sharing of data from clinical trials. De-identified participant data from the final research dataset used in the published manuscript may only be shared under the terms of a Data Use Agreement. Requests may be directed to: [contact information for Sponsor Investigator or designee]. The protocol and statistical analysis plan will be made available on Clinicaltrials.gov only as required by federal regulation or as a condition of awards and agreements supporting the research.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Ann W Silk, MD, MS principal investigator
Dana-Farber Cancer Institute
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Ipilimumab, Nivolumab and Troriluzole in people with Melanoma and Metastatic Melanoma, run by Dana-Farber Cancer Institute at 2 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 16 inclusion and 19 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 26 Mar 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 13 Dec 2023). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Median Global Progression-Free Survival (PFS) (time frame: Participants would be followed up to 5 years.). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04899921, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 26 Mar 2024.