RTA 408 Capsules in Patients With Melanoma - REVEAL

Phase 1

Completed

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

• Registration Number: NCT02259231
• Lead Sponsor: Reata, a wholly owned subsidiary of Biogen

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.

Detailed Description

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

Study Timeline

• Study First Submitted: 2014-10-03
• Study First Submitted QC: 2014-10-07
• Study First Posted: 2014-10-08
• Study Start: 2014-10-31
• Primary Completion: 2018-05-09
• Study Completion: 2018-07-23
• Disposition First Submitted: 2019-05-01
• Disposition First Submitted QC: 2019-05-01
• Disposition First Posted: 2019-05-07
• Results First Submitted: 2021-04-30
• Results First Submitted QC: 2021-06-04
• Results First Posted: 2021-06-24
• Status Verified: 2024-02
• Last Update Submitted: 2024-02-01
• Last Update Posted: 2024-02-02

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 41

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Omaveloxolone 100 mg & nivolumab	Omaveloxolone Capsules (50 mg/capsule)	Omaveloxolone (RTA 408) capsules, 100 mg taken orally once daily for 168 weeks, plus nivolumab (240 mg) administered every two weeks as clinically indicated.
Omaveloxolone 5 mg & nivolumab	Omaveloxolone Capsules (2.5 mg/capsule)	Omaveloxolone (RTA 408) capsules, 5 mg taken orally once daily for 168 weeks, plus nivolumab (240 mg) administered every two weeks as clinically indicated.
Omaveloxolone 10 mg & nivolumab	Omaveloxolone Capsules (10 mg/capsule)	Omaveloxolone (RTA 408) capsules, 10 mg taken orally once daily for 168 weeks, plus nivolumab (240 mg) administered every two weeks as clinically indicated.
Omaveloxolone 20 mg & nivolumab	Omaveloxolone Capsules (10 mg/capsule)	Omaveloxolone (RTA 408) capsules, 20 mg taken orally once daily for 168 weeks, plus nivolumab (240 mg) administered every two weeks as clinically indicated.
Omaveloxolone 150 mg & nivolumab	Omaveloxolone Capsules (50 mg/capsule)	Omaveloxolone (RTA 408) capsules, 150 mg taken orally once daily for 168 weeks, plus nivolumab (240 mg) administered every two weeks as clinically indicated.
Omaveloxolone 150 mg & nivolumab	Nivolumab (240 mg)	Omaveloxolone (RTA 408) capsules, 150 mg taken orally once daily for 168 weeks, plus nivolumab (240 mg) administered every two weeks as clinically indicated.
Omaveloxolone 5 mg & ipilimumab	Omaveloxolone Capsules (2.5 mg/capsule)	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.
Omaveloxolone 5 mg & nivolumab	Nivolumab (240 mg)	Omaveloxolone (RTA 408) capsules, 5 mg taken orally once daily for 168 weeks, plus nivolumab (240 mg) administered every two weeks as clinically indicated.
Omaveloxolone 10 mg & nivolumab	Nivolumab (240 mg)	Omaveloxolone (RTA 408) capsules, 10 mg taken orally once daily for 168 weeks, plus nivolumab (240 mg) administered every two weeks as clinically indicated.
Omaveloxolone 10 mg & ipilimumab	Ipilimumab (3 mg/kg)	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.
Omaveloxolone 10 mg & ipilimumab	Omaveloxolone Capsules (10 mg/capsule)	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.
Omaveloxolone 100 mg & nivolumab	Nivolumab (240 mg)	Omaveloxolone (RTA 408) capsules, 100 mg taken orally once daily for 168 weeks, plus nivolumab (240 mg) administered every two weeks as clinically indicated.
Omaveloxolone 5 mg & ipilimumab	Ipilimumab (3 mg/kg)	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.
Omaveloxolone 20 mg & nivolumab	Nivolumab (240 mg)	Omaveloxolone (RTA 408) capsules, 20 mg taken orally once daily for 168 weeks, plus nivolumab (240 mg) administered every two weeks as clinically indicated.

Primary Outcome Measures

Name	Time	Method
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	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	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.

Trial Locations

Locations (10)

University of Colorado Cancer Center, Anschutz Cancer Pavilion; 🇺🇸 Aurora, Colorado, United States

Christiana Hospital Helen F. Graham Cancer Center; 🇺🇸 Newark, Delaware, United States

Highlands Oncology Group; 🇺🇸 Fayetteville, Arkansas, United States

Atlantic Melanoma Center; 🇺🇸 Morristown, New Jersey, United States

Southern Cancer Center; 🇺🇸 Mobile, Alabama, United States

Dana Farber Cancer Institute; 🇺🇸 Boston, Massachusetts, United States

MD Anderson Cancer Center; 🇺🇸 Houston, Texas, United States

Duke Cancer Institute; 🇺🇸 Durham, North Carolina, United States

Goergetown-Lombardi Comprehensive Cancer Center; 🇺🇸 Washington, District of Columbia, United States

H. Lee Moffitt Cancer Center & Research Institute; 🇺🇸 Tampa, Florida, United States