Troriluzole or Placebo Plus Ipi Plus Nivo in Mel Brain Mets

NCT04899921 | Terminated Phase 2 Results DMC FDA Drug

• 1 other identifier: 20-675
• Study Type: interventional
• Target: 1
• Locations: 1 country
• Sites: 2

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.

Conditions

Melanoma; Metastatic Melanoma

Keywords

Melanoma; Metastatic Melanoma; Metastatic Melanoma, Brain

Outcome Measures

Primary Outcomes (1)

• 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,

  Participants would be followed up to 5 years.

Secondary Outcomes (11)

• 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

• 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.

Study Arms (5)

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.

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.

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.

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.

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.

Drug: Ipilimumab; Drug: Nivolumab; Drug: Troriluzole

Interventions

Ipilimumab DRUG

Intravenous injection

Also known as: Yervoy

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]

Nivolumab DRUG

Intravenously (IV) into the vein

Also known as: Opdivo

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]

Troriluzole DRUG

Taken orally

Also known as: BHV-4157, Trigriluzole, FC-4157

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]

Placebo DRUG

Taken orally

Also known as: Sugar Pill

Ipilimumab + Nivolumab + Placebo [Phase II]

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• 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.

You may not qualify if:

• 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).

Sponsors & Collaborators

• Dana-Farber Cancer Institute: lead
• Biohaven Pharmaceuticals, Inc.: collaborator

Study Sites (2)

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

Location

Dana Farber Cancer Institute

Boston, Massachusetts, 02115, United States

Location

Related Publications (1)

• 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.

  PMID: 39462179 DERIVED

MeSH Terms

Conditions

Melanoma

Interventions

Ipilimumab; Nivolumab; Sugars

Condition Hierarchy (Ancestors)

Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Nerve Tissue; Nevi and Melanomas; Skin Neoplasms; Neoplasms by Site; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Carbohydrates

Results Point of Contact

• Title: Senior Physician
• Organization: Dana-Farber Cancer Institute

ann_silk@dfci.harvard.edu

6176326836

Study Officials

• Ann W Silk, MD, MS

  Dana-Farber Cancer Institute

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: April 16, 2021
• First Posted: May 25, 2021
• Study Start: June 30, 2021
• Primary Completion: May 29, 2023
• Study Completion: May 29, 2023
• Last Updated: March 26, 2024
• Results First Posted: December 13, 2023

Record last verified: 2024-03

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: Data can be shared no earlier than 1 year following the date of publication
• Access Criteria: Contact the Belfer Office for Dana-Farber Innovations (BODFI) at innovation@dfci.harvard.edu

Locations

US (2)