Neoplasms

Symptoms and General Pathology

All Conditions

Skin and Connective Tissue Diseases

Rare Diseases

Neoplasm Metastasis

Melanoma

Neuroendocrine Tumors

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Nerve Tissue

Nevus, Pigmented

Nevus

Nevi and Melanomas

Skin Neoplasms

Skin Diseases

Neuroendocrine Tumor

Neuroepithelioma

Antineoplastic Agents

All Drugs and Chemicals

Nivolumab

Ipilimumab

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

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.

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.

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.

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.

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.

Troriluzole

Placebo

Ann W Silk, MD, MS

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 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.

Troriluzole or Placebo Plus Ipi Plus Nivo in Mel Brain Mets

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 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.

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,

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.

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.

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.

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.

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

The number and proportion of adverse events, graded as defined by CTCAE version 5.0 will be tabulated by type and grade.

Number of induction cycles was defined as the number of induction cycles administered.

Number of maintenance cycles was defined as the number of maintenance cycles administered.

Corticosteroids usage was defined by number of participants who require prednisone ≥1 mg/kg or equivalent.

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.

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.

Biohaven Pharmaceuticals, Inc.

Dana-Farber Cancer Institute

Principal Investigator

Maximum grade toxicity by type was first calculated. Serious AEs were defined as events with treatment attribution of possibly, probably or definitely and grade 3 or higher per CTCAEv4. All remaining events regardless of treatment attribution were classified as Other AEs. Per the source vocabulary (CTCAEv5.0) there is a category "Other, specify" for each system organ class. No further data is available to specify classification beyond this general term.

Ipilimumab + Nivolumab + Troriluzole [Phase I Dose Level 1]

Ipilimumab + Nivolumab + Troriluzole [Phase I Dose Level 2]

Ipilimumab + Nivolumab + Troriluzole [Phase I Dose Level 3]

Total

Age, Categorical

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

Terminated with1 patient enrolled; no data due to patient privacy.

Senior Physician

Terminated with 1 patient enrolled; no data due to patient privacy.

Median Global Progression-Free Survival (PFS)

Median Overall Survival (OS)

Intracranial Response Rate (RR)

Intracranial Progression-free Survival (PFS)

Extracranial Response Rate (RR)

Extracranial Progression-free Survival (PFS)

Number of Participants With Treatment-Related Adverse Events as Assessed by CTCAE Version 5.0

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,

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

Spots Global Cancer Trial Database for metastatic melanoma, brain