RTA 408 Capsules in Patients With Melanoma - REVEAL

An Open-label, Multicenter, Dose-escalation, Phase 1b/2 Study of the Safety, Efficacy, Pharmacodynamics, and Pharmacokinetics of RTA 408 in Combination With Ipilimumab or Nivolumab in the Treatment of Patients With Unresectable or Metastatic Melanoma

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.

Study Overview

• Status: Completed
• Conditions: Melanoma; Unresectable (Stage III) Melanoma; Metastatic (Stage IV) Melanoma
• Intervention / Treatment: Drug: Omaveloxolone Capsules (2.5 mg/capsule); Drug: Ipilimumab (3 mg/kg); Drug: Omaveloxolone Capsules (10 mg/capsule); Drug: Nivolumab (240 mg); Drug: Omaveloxolone Capsules (50 mg/capsule)

Detailed Description

Study Sponsor, originally Reata Pharmaceuticals, Inc., is now Reata Pharmaceuticals, Inc., a wholly owned subsidiary of Biogen.

• Study Type: Interventional
• Enrollment (Actual): 41
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Mobile, Alabama, United States, 36608
      • Southern Cancer Center
  • Arkansas
    • Fayetteville, Arkansas, United States, 72703
      • Highlands Oncology Group
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado Cancer Center, Anschutz Cancer Pavilion
  • Delaware
    • Newark, Delaware, United States, 19713
      • Christiana Hospital Helen F. Graham Cancer Center
  • District of Columbia
    • Washington, District of Columbia, United States, 20007
      • Goergetown-Lombardi Comprehensive Cancer Center
  • Florida
    • Tampa, Florida, United States, 33612
      • H. Lee Moffitt Cancer Center & Research Institute
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Dana Farber Cancer Institute
  • New Jersey
    • Morristown, New Jersey, United States, 07960
      • Atlantic Melanoma Center
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke Cancer Institute
  • Texas
    • Houston, Texas, United States, 77030
      • MD Anderson Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Be ≥18 years of age;
2. Have advanced, unresectable (Stage III) or metastatic (Stage IV) melanoma;
3. 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);
4. Have discontinued previous treatments for cancer;
5. Have discontinued previous experimental therapies and checkpoint inhibitor antibodies at least 28 days prior to the Randomization Visit

Exclusion Criteria:

1. 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.
2. Have prior malignancy active within the previous 2 years;
3. Have any active autoimmune disease or a history of known or suspected autoimmune disease;
4. History of brain metastases that meet certain conditions;
5. History of specific cardiovascular abnormalities;
6. Have known active fungal, bacterial, and/or viral infection, including human immunodeficiency virus (HIV) or hepatitis virus (A,B, or C).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

7

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Omaveloxolone 5 mg & ipilimumab; 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); Capsules containing 2.5 mg of omaveloxolone per capsule to the dosage indicated in the Arm Label; Other Names: RTA 408 Capsules (2.5 mg/capsule); Drug: Ipilimumab (3 mg/kg); Sterile solution containing ipilimumab to be delivered intravenously at 3mg/kg; Other Names: Yervoy
Experimental: Omaveloxolone 10 mg & ipilimumab; 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); Sterile solution containing ipilimumab to be delivered intravenously at 3mg/kg; Other Names: Yervoy; Drug: Omaveloxolone Capsules (10 mg/capsule); Capsules containing 10 mg of omaveloxolone per capsule to the dosage indicated in the Arm Label; Other Names: RTA 408 Capsules (10 mg/capsule)
Experimental: Omaveloxolone 5 mg & nivolumab; 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); Capsules containing 2.5 mg of omaveloxolone per capsule to the dosage indicated in the Arm Label; Other Names: RTA 408 Capsules (2.5 mg/capsule); Drug: Nivolumab (240 mg); Sterile solution containing nivolumab to be delivered intravenously at 240 mg; Other Names: Opdivo
Experimental: Omaveloxolone 10 mg & nivolumab; 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: Omaveloxolone Capsules (10 mg/capsule); Capsules containing 10 mg of omaveloxolone per capsule to the dosage indicated in the Arm Label; Other Names: RTA 408 Capsules (10 mg/capsule); Drug: Nivolumab (240 mg); Sterile solution containing nivolumab to be delivered intravenously at 240 mg; Other Names: Opdivo
Experimental: Omaveloxolone 20 mg & nivolumab; 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: Omaveloxolone Capsules (10 mg/capsule); Capsules containing 10 mg of omaveloxolone per capsule to the dosage indicated in the Arm Label; Other Names: RTA 408 Capsules (10 mg/capsule); Drug: Nivolumab (240 mg); Sterile solution containing nivolumab to be delivered intravenously at 240 mg; Other Names: Opdivo
Experimental: Omaveloxolone 100 mg & nivolumab; 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); Sterile solution containing nivolumab to be delivered intravenously at 240 mg; Other Names: Opdivo; Drug: Omaveloxolone Capsules (50 mg/capsule); Capsules containing 50 mg of omaveloxolone per capsule to the dosage indicated in the Arm Label; Other Names: RTA 408 Capsules (50 mg/capsule)
Experimental: Omaveloxolone 150 mg & nivolumab; 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); Sterile solution containing nivolumab to be delivered intravenously at 240 mg; Other Names: Opdivo; Drug: Omaveloxolone Capsules (50 mg/capsule); Capsules containing 50 mg of omaveloxolone per capsule to the dosage indicated in the Arm Label; Other Names: RTA 408 Capsules (50 mg/capsule)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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

Collaborators and Investigators

• Sponsor: Reata, a wholly owned subsidiary of Biogen

Study record dates

Study Major Dates

• Study Start (Actual): October 31, 2014
• Primary Completion (Actual): May 9, 2018
• Study Completion (Actual): July 23, 2018

Study Registration Dates

• First Submitted: October 3, 2014
• First Submitted That Met QC Criteria: October 7, 2014
• First Posted (Estimated): October 8, 2014

Study Record Updates

• Last Update Posted (Actual): February 2, 2024
• Last Update Submitted That Met QC Criteria: February 1, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: Checkpoint inhibitor; Melanoma; RTA 408; RTA 408 Capsules; omaveloxolone; iNOS; Myeloid-derived suppressor cells (MDSDs)
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroendocrine Tumors; Nevi and Melanomas; Melanoma; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Nivolumab; Ipilimumab
• Other Study ID Numbers: RTA 408-C-1401

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: In accordance with Biogen's Clinical Trial Transparency and Data Sharing Policy on https://www.biogentrialtransparency.com/

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No