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
Overview
- Phase
- Phase 2
- Intervention
- Ipilimumab
- Conditions
- Melanoma
- Sponsor
- Dana-Farber Cancer Institute
- Enrollment
- 1
- Locations
- 2
- Primary Endpoint
- Median Global Progression-Free Survival (PFS)
- Status
- Terminated
- Last Updated
- 2 years ago
Overview
Brief 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.
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.
Investigators
Ann W. Silk, MD MS
Principal Investigator
Dana-Farber Cancer Institute
Eligibility Criteria
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 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:
- •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.
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.
Arms & Interventions
Ipilimumab + Nivolumab + Troriluzole [Phase I dose level 1]
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.
Intervention: Ipilimumab
Ipilimumab + Nivolumab + Troriluzole [Phase I dose level 1]
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.
Intervention: Nivolumab
Ipilimumab + Nivolumab + Troriluzole [Phase I dose level 1]
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.
Intervention: Troriluzole
Ipilimumab + Nivolumab + Troriluzole [Phase II]
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.
Intervention: Ipilimumab
Ipilimumab + Nivolumab + Troriluzole [Phase II]
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.
Intervention: Nivolumab
Ipilimumab + Nivolumab + Troriluzole [Phase II]
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.
Intervention: Troriluzole
Ipilimumab + Nivolumab + Placebo [Phase II]
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.
Intervention: Ipilimumab
Ipilimumab + Nivolumab + Placebo [Phase II]
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.
Intervention: Nivolumab
Ipilimumab + Nivolumab + Placebo [Phase II]
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.
Intervention: Placebo
Ipilimumab + Nivolumab + Troriluzole [Phase I dose level 2]
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.
Intervention: Ipilimumab
Ipilimumab + Nivolumab + Troriluzole [Phase I dose level 2]
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.
Intervention: Nivolumab
Ipilimumab + Nivolumab + Troriluzole [Phase I dose level 2]
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.
Intervention: Troriluzole
Ipilimumab + Nivolumab + Troriluzole [Phase I dose level 3]
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.
Intervention: Ipilimumab
Ipilimumab + Nivolumab + Troriluzole [Phase I dose level 3]
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.
Intervention: Nivolumab
Ipilimumab + Nivolumab + Troriluzole [Phase I dose level 3]
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.
Intervention: Troriluzole
Outcomes
Primary Outcomes
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,
Secondary Outcomes
- Median Overall Survival (OS)(Participants were followed up to 5 years.)
- Intracranial Response Rate (RR)(From enrollment to end of treatment up to 5 years)
- Number of Participants With Treatment-Related Adverse Events as Assessed by CTCAE Version 5.0(From enrollment to end of treatment up to 5 years)
- Number of Induction(From enrollment to end of treatment up to 5 years)
- Number of Maintenance Cycles(From enrollment to end of treatment up to 5 years)
- Intracranial Progression-free Survival (PFS)(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)(From enrollment to end of treatment up to 5 years)
- Extracranial Progression-free Survival (PFS)(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.)
- Corticosteroids Usage(From enrollment to end of treatment up to 5 years)
- Frequency of Clinically-indicated Stereotactic Radiation Therapy to the Brain(From enrollment to end of treatment up to 5 years)
- Frequency of Clinically-indicated Surgical Intervention to the Brain(From enrollment to end of treatment up to 5 years)