RTA 408 Capsules in Patients With Melanoma - REVEAL

NCT02259231 | Completed Phase 1 Results FDA Drug

• 1 other identifier: RTA 408-C-1401
• Study Type: interventional
• Target: 41
• Locations: 1 country
• Sites: 10

Brief Summary

Malignant melanoma is a leading cause of death from cutaneous malignancies, accounting for approximately three-fourths of all skin cancer deaths. For metastatic or unresectable melanomas, standard treatment options include immune checkpoint inhibitors (e.g., ipilimumab and nivolumab) and other therapies, however, approved therapies are rarely curative. It is now well accepted that tumors are able to evade detection and eradication by the immune system, even though many tumor types, particularly melanoma, are capable of eliciting a strong immune response (Swann, 2007). Substantial mechanistic work in recent years has revealed the key role of myeloid-derived suppressor cells (MDSCs) in masking cancer cells from the immune system, promoting both tumor progression and resistance to cancer immunotherapy. The immune-suppressive effect of MDSCs is dependent on the production of reactive oxygen species (ROS) and reactive nitrogen species (RNS). High levels of these reactive molecules and their by-products, such as nitrotyrosine, have been correlated with poor clinical outcomes in melanoma. Currently available melanoma therapies do not target MDSCs. In animals, RTA 408 significantly reduces tumor nitrotyrosine burden, inhibits the activity of MDSCs, and augments T-cell anticancer activity at relevant doses. Thus, through inhibition of MDSC activity and suppression of tumor ROS/RNS, RTA 408 may work in combination with T-cell-activating therapeutics such as ipilimumab to enhance the natural immune anticancer response. RTA 408 also has direct anticancer effects via inhibition of NF-kappa B. Chronic activation of NF-kappa B is associated with tumor progression, metastasis, and resistance to therapy. This proposed study is designed to assess the safety, efficacy, pharmacodynamics, and pharmacokinetics of omaveloxolone (RTA 408) in combination with ipilimumab or nivolumab in patients with unresectable or metastatic melanoma. In this open-label, multicenter, dose-escalation, Phase 1b/2 study, patients who qualify will receive omaveloxolone (RTA 408) at the assigned dose level in combination with ipilimumab or nivolumab. Patients will receive omaveloxolone (RTA 408) orally once daily for 1 week prior to initiation of ipilimumab or nivolumab. For patients treated with ipilimumab , the run-in period will be followed by omaveloxolone (RTA 408) orally once daily in combination with ipilimumab administered at Weeks 1, 4, 7, and 10. After Week 10, patients will receive maintenance treatment with omaveloxolone (RTA 408) alone once daily. For patients treated with nivolumab, the run-in period will be followed by omaveloxolone (RTA 408) orally once daily in combination with nivolumab administered approximately every two weeks as clinically indicated. Each patient will continue at the assigned omaveloxolone (RTA 408) dose level until disease progression occurs, toxicity requiring discontinuation from study drug (i.e., RTA 408) is experienced, the patient has completed approximately 72 weeks of treatment, the patient is discontinued from the study drug for another reason, or the patient withdraws consent. Patients will return 4 weeks after omaveloxolone (RTA 408) treatment completion for a follow-up visit. The starting omaveloxolone (RTA 408) dose level for the first dose-escalation cohort in this study has been selected based on available safety and pharmacodynamic data from a Phase 1 study of RTA 408 (NCT02029729). Subsequent cohorts will be enrolled at dose levels based on available safety and PD data from this study, but they will not be greater than 2-fold above the prior dose level. Phase 1b (dose-escalation): In the phase 1b/2 portion of this study, 12 patients will be enrolled in each dose cohort, with six patients administered omaveloxolone (RTA 408) plus ipilimumab and the remaining six administered rTA 408 plus nivolumab. Subsequent cohorts will assess escalating the doses of omaveloxolone (RTA 408) administered in combination with ipilimumab or nivolumab. Dose escalation decisions will be based on ongoing review of all available safety information for enrolled patients. Phase 2: The Phase 2 portion of the study may include separate expansion cohorts consisting of patients treated with either of the combination therapies. Each expansion cohort will include an additional 24 patients enrolled at the selected Phase 2 dose level to achieve a total of 30 patients at that omaveloxolone (RTA 408) dose in combination with ipilimumab or nivolumab.

Conditions

Melanoma; Unresectable (Stage III) Melanoma; Metastatic (Stage IV) Melanoma

Keywords

RTA 408; RTA 408 Capsules; Myeloid-derived suppressor cells (MDSDs); iNOS; Melanoma; Checkpoint inhibitor; omaveloxolone

Outcome Measures

Primary Outcomes (1)

• Measure of Efficacy of the Phase 2 Dose of RTA 408 in Combination With Nivolumab Using Overall Response Rate (ORR; Complete Plus Partial Responses) According to RECIST Version 1.1 Criteria

  Best overall response rate (ORR) is defined as the proportion of patients with complete or partial tumor size reduction according to RECIST v1.1 criteria. Stable disease is not a component of ORR. Complete response: Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. Partial reduction: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. The first occurrence of a response is considered an unconfirmed response. A CR or PR which persists to the next tumor burden assessment is then considered a confirmed response. Confirmed plus unconfirmed best overall response are presented. A subject may be counted twice if best unconfirmed response and best confirmed response are different.

  From enrollment up to the time of disease progression, up to 172 weeks for participants receiving Omaveloxolone in combination with Ipilimumab and 173 weeks for participants receiving Omaveloxolone combination with Nivolumab

Study Arms (7)

Omaveloxolone 5 mg & ipilimumab

EXPERIMENTAL

Omaveloxolone (RTA 408) capsules, Dose1 taken orally once daily for 168 weeks, plus ipilimumab (3 mg/kg) administered at weeks 1, 4, 7, and 10.

Drug: Omaveloxolone Capsules (2.5 mg/capsule); Drug: Ipilimumab (3 mg/kg)

Omaveloxolone 10 mg & ipilimumab

EXPERIMENTAL

Omaveloxolone (RTA 408) capsules, 10 mg taken orally once daily for 168 weeks, plus ipilimumab (3 mg/kg) administered at weeks 1, 4, 7, and 10.

Drug: Ipilimumab (3 mg/kg); Drug: Omaveloxolone Capsules (10 mg/capsule)

Omaveloxolone 5 mg & nivolumab

EXPERIMENTAL

Omaveloxolone (RTA 408) capsules, 5 mg taken orally once daily for 168 weeks, plus nivolumab (240 mg) administered every two weeks as clinically indicated.

Drug: Omaveloxolone Capsules (2.5 mg/capsule); Drug: Nivolumab (240 mg)

Omaveloxolone 10 mg & nivolumab

EXPERIMENTAL

Omaveloxolone (RTA 408) capsules, 10 mg taken orally once daily for 168 weeks, plus nivolumab (240 mg) administered every two weeks as clinically indicated.

Drug: Nivolumab (240 mg); Drug: Omaveloxolone Capsules (10 mg/capsule)

Omaveloxolone 20 mg & nivolumab

EXPERIMENTAL

Omaveloxolone (RTA 408) capsules, 20 mg taken orally once daily for 168 weeks, plus nivolumab (240 mg) administered every two weeks as clinically indicated.

Drug: Nivolumab (240 mg); Drug: Omaveloxolone Capsules (10 mg/capsule)

Omaveloxolone 100 mg & nivolumab

EXPERIMENTAL

Omaveloxolone (RTA 408) capsules, 100 mg taken orally once daily for 168 weeks, plus nivolumab (240 mg) administered every two weeks as clinically indicated.

Drug: Nivolumab (240 mg); Drug: Omaveloxolone Capsules (50 mg/capsule)

Omaveloxolone 150 mg & nivolumab

EXPERIMENTAL

Omaveloxolone (RTA 408) capsules, 150 mg taken orally once daily for 168 weeks, plus nivolumab (240 mg) administered every two weeks as clinically indicated.

Drug: Nivolumab (240 mg); Drug: Omaveloxolone Capsules (50 mg/capsule)

Interventions

Omaveloxolone Capsules (2.5 mg/capsule) DRUG

Capsules containing 2.5 mg of omaveloxolone per capsule to the dosage indicated in the Arm Label

Also known as: RTA 408 Capsules (2.5 mg/capsule)

Omaveloxolone 5 mg & ipilimumab; Omaveloxolone 5 mg & nivolumab

Ipilimumab (3 mg/kg) DRUG

Sterile solution containing ipilimumab to be delivered intravenously at 3mg/kg

Also known as: Yervoy

Omaveloxolone 10 mg & ipilimumab; Omaveloxolone 5 mg & ipilimumab

Nivolumab (240 mg) DRUG

Sterile solution containing nivolumab to be delivered intravenously at 240 mg

Also known as: Opdivo

Omaveloxolone 10 mg & nivolumab; Omaveloxolone 100 mg & nivolumab; Omaveloxolone 150 mg & nivolumab; Omaveloxolone 20 mg & nivolumab; Omaveloxolone 5 mg & nivolumab

Omaveloxolone Capsules (10 mg/capsule) DRUG

Capsules containing 10 mg of omaveloxolone per capsule to the dosage indicated in the Arm Label

Also known as: RTA 408 Capsules (10 mg/capsule)

Omaveloxolone 10 mg & ipilimumab; Omaveloxolone 10 mg & nivolumab; Omaveloxolone 20 mg & nivolumab

Omaveloxolone Capsules (50 mg/capsule) DRUG

Capsules containing 50 mg of omaveloxolone per capsule to the dosage indicated in the Arm Label

Also known as: RTA 408 Capsules (50 mg/capsule)

Omaveloxolone 100 mg & nivolumab; Omaveloxolone 150 mg & nivolumab

Eligibility Criteria

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

You may qualify if:

• Be ≥18 years of age;
• Have advanced, unresectable (Stage III) or metastatic (Stage IV) melanoma;
• Be eligible for commercial receipt of therapy to be used in this study in combination with RTA 408 (i.e., ipilimumab or nivolumab in the Phase 1b portion and nivolumab only in the Phase 2 portion);
• Have discontinued previous treatments for cancer;
• Have discontinued previous experimental therapies and checkpoint inhibitor antibodies at least 28 days prior to the Randomization Visit

You may not qualify if:

• Have received prior treatment with therapy to be used in this study in combination with RTA 408 (i.e., ipilimumab or nivolumab) if enrolling in the Phase 2 portion of the study. This criterion does not apply to patients enrolling in the Phase 1b portion of the study.
• Have prior malignancy active within the previous 2 years;
• Have any active autoimmune disease or a history of known or suspected autoimmune disease;
• History of brain metastases that meet certain conditions;
• History of specific cardiovascular abnormalities;
• Have known active fungal, bacterial, and/or viral infection, including human immunodeficiency virus (HIV) or hepatitis virus (A,B, or C).

Sponsors & Collaborators

• Biogen: lead

Study Sites (10)

Southern Cancer Center

Mobile, Alabama, 36608, United States

Location

Highlands Oncology Group

Fayetteville, Arkansas, 72703, United States

Location

University of Colorado Cancer Center, Anschutz Cancer Pavilion

Aurora, Colorado, 80045, United States

Location

Christiana Hospital Helen F. Graham Cancer Center

Newark, Delaware, 19713, United States

Location

Goergetown-Lombardi Comprehensive Cancer Center

Washington D.C., District of Columbia, 20007, United States

Location

H. Lee Moffitt Cancer Center & Research Institute

Tampa, Florida, 33612, United States

Location

Dana Farber Cancer Institute

Boston, Massachusetts, 02215, United States

Location

Atlantic Melanoma Center

Morristown, New Jersey, 07960, United States

Location

Duke Cancer Institute

Durham, North Carolina, 27710, United States

Location

MD Anderson Cancer Center

Houston, Texas, 77030, United States

Location

MeSH Terms

Conditions

Melanoma; Neoplasm Metastasis

Interventions

omaveloxolone; ORF 50 transactivator; Ipilimumab; Nivolumab

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; Neoplastic Processes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

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

Results Point of Contact

• Title: US Biogen Clinical Trial Center
• Organization: Biogen

clinicaltrials@biogen.com

866-633-4636

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 3, 2014
• First Posted: October 8, 2014
• Study Start: October 31, 2014
• Primary Completion: May 9, 2018
• Study Completion: July 23, 2018
• Last Updated: June 4, 2025
• Results First Posted: June 24, 2021

Record last verified: 2025-05

Data Sharing

• IPD Sharing: Will share

Locations

US (10)