RTA 408 Capsules in Patients With Melanoma - REVEAL

NCT02259231 — Phase 1 / Phase 2, Completed, 41 participants, Biogen

ClinicalTrials Daily · Areas · Conditions · Drugs · Sponsors ·

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

Registry	NCT02259231
Status	Completed
Phase	Phase 1 / Phase 2
Study type	Interventional; non randomized, sequential, masking: none, treatment
Enrollment	41 (Actual)
Sponsor	Biogen (Industry)
Conditions	Melanoma, Unresectable (Stage III) Melanoma, Metastatic (Stage IV) Melanoma
Interventions	Omaveloxolone Capsules (2.5 mg/capsule), Ipilimumab (3 mg/kg), Nivolumab (240 mg), Omaveloxolone Capsules (10 mg/capsule), Omaveloxolone Capsules (50 mg/capsule) (Drug)
Dates	start 2014-10-31, primary completion 2018-05-09, completion 2018-07-23, first posted 2014-10-08, last updated 2025-06-04
Locations	10 sites in United States

-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.

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+Arms and interventions

Arm	Type	Interventions	Description
Omaveloxolone 5 mg & ipilimumab	Experimental	Drug: Omaveloxolone Capsules (2.5 mg/capsule); Drug: 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 10 mg & ipilimumab	Experimental	Drug: Ipilimumab (3 mg/kg); Drug: 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 5 mg & nivolumab	Experimental	Drug: Omaveloxolone Capsules (2.5 mg/capsule); Drug: 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	Experimental	Drug: Nivolumab (240 mg); Drug: 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	Experimental	Drug: Nivolumab (240 mg); Drug: 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 100 mg & nivolumab	Experimental	Drug: Nivolumab (240 mg); Drug: 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 150 mg & nivolumab	Experimental	Drug: Nivolumab (240 mg); Drug: 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 Capsules (2.5 mg/capsule) (Drug), also known as RTA 408 Capsules (2.5 mg/capsule): Capsules containing 2.5 mg of omaveloxolone per capsule to the dosage indicated in the Arm Label
Ipilimumab (3 mg/kg) (Drug), also known as Yervoy: Sterile solution containing ipilimumab to be delivered intravenously at 3mg/kg
Nivolumab (240 mg) (Drug), also known as Opdivo: Sterile solution containing nivolumab to be delivered intravenously at 240 mg
Omaveloxolone Capsules (10 mg/capsule) (Drug), also known as RTA 408 Capsules (10 mg/capsule): Capsules containing 10 mg of omaveloxolone per capsule to the dosage indicated in the Arm Label
Omaveloxolone Capsules (50 mg/capsule) (Drug), also known as RTA 408 Capsules (50 mg/capsule): Capsules containing 50 mg of omaveloxolone per capsule to the dosage indicated in the Arm Label

+Outcome measures

Primary outcomes

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.

+Eligibility

Sex: All, ages: 18 Years to any

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).

+Posted results

Participant flow

Milestone	Omaveloxolone 5 mg & Ipilimumab	Omaveloxolone 10 mg & Ipilimumab	Omaveloxolone 5 mg & Nivolumab	Omaveloxolone 10 mg & Nivolumab	Omaveloxolone 20 mg & Nivolumab	Omaveloxolone 100 mg & Nivolumab	Omaveloxolone 150 mg & Nivolumab
Started	6	6	6	6	6	6	5
Completed	0	0	0	0	0	0	0
Not completed	6	6	6	6	6	6	5

Outcome results

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 (Primary), Count of participants, Participants: Omaveloxolone 5 mg & Ipilimumab 6; Omaveloxolone 10 mg & Ipilimumab 0; Omaveloxolone 5 mg & Nivolumab 5; Omaveloxolone 10 mg & Nivolumab 2; Omaveloxolone 20 mg & Nivolumab 3; Omaveloxolone 100 mg & Nivolumab 3; Omaveloxolone 150 mg & Nivolumab 4

Adverse events

Time frame: Adverse events were reported from time of the first dose of study drug 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.

Arm	Deaths	Serious adverse events	Other adverse events
Omaveloxolone 5 mg & Ipilimumab	0/6 (0.0%)	2/6 (33.3%)	6/6 (100.0%)
Omaveloxolone 10 mg & Ipilimumab	0/6 (0.0%)	2/6 (33.3%)	6/6 (100.0%)
Omaveloxolone 5 mg & Nivolumab	1/6 (16.7%)	1/6 (16.7%)	6/6 (100.0%)
Omaveloxolone 10 mg & Nivolumab	1/6 (16.7%)	3/6 (50.0%)	6/6 (100.0%)
Omaveloxolone 20 mg & Nivolumab	2/6 (33.3%)	2/6 (33.3%)	6/6 (100.0%)
Omaveloxolone 100 mg & Nivolumab	0/6 (0.0%)	2/6 (33.3%)	6/6 (100.0%)
Omaveloxolone 150 mg & Nivolumab	1/5 (20.0%)	2/5 (40.0%)	5/5 (100.0%)

Serious adverse events by term

Term	Organ system	Omaveloxolone 5 mg & Ipilimumab	Omaveloxolone 10 mg & Ipilimumab	Omaveloxolone 5 mg & Nivolumab	Omaveloxolone 10 mg & Nivolumab	Omaveloxolone 20 mg & Nivolumab	Omaveloxolone 100 mg & Nivolumab	Omaveloxolone 150 mg & Nivolumab
Lung Infection	Infections and infestations	1/6	0/6	0/6	0/6	0/6	0/6	0/5
Soft tissue infection	Infections and infestations	1/6	0/6	0/6	0/6	0/6	0/6	1/5
Clostridial infection	Infections and infestations	0/6	0/6	0/6	0/6	0/6	1/6	0/5
Colitis	Gastrointestinal disorders	0/6	1/6	0/6	0/6	0/6	0/6	0/5
Abdominal pain	Gastrointestinal disorders	0/6	0/6	0/6	0/6	0/6	1/6	0/5
Oesophageal disorder	Gastrointestinal disorders	0/6	0/6	0/6	1/6	0/6	0/6	0/5
Abdominal pain lower	Gastrointestinal disorders	0/6	0/6	0/6	1/6	0/6	0/6	0/5
Cerebral thrombosis	Nervous system disorders	0/6	1/6	0/6	0/6	0/6	0/6	0/5
Hemiparesis	Nervous system disorders	0/6	0/6	0/6	1/6	0/6	0/6	0/5
Transient ischaemic attack	Nervous system disorders	0/6	0/6	0/6	0/6	0/6	0/6	1/5
Dyspnoea	Respiratory, thoracic and mediastinal disorders	0/6	1/6	0/6	0/6	0/6	0/6	0/5
Disease progression	General disorders	0/6	0/6	0/6	1/6	2/6	0/6	0/5
Pyrexia	General disorders	0/6	0/6	0/6	0/6	0/6	1/6	0/5
Anaemia	Blood and lymphatic system disorders	0/6	0/6	0/6	0/6	0/6	1/6	0/5
Blood creatinine phosphokinase increased	Investigations	0/6	0/6	1/6	0/6	0/6	0/6	0/5
Troponin increased	Investigations	0/6	0/6	1/6	0/6	0/6	0/6	0/5
Dehydration	Metabolism and nutrition disorders	0/6	0/6	1/6	0/6	0/6	0/6	0/5
Neoplasm malignant	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	0/6	0/6	0/6	0/6	0/6	0/6	1/5
Hypotension	Vascular disorders	0/6	0/6	0/6	0/6	0/6	1/6	0/5

Other adverse events by term

Term	Organ system	Omaveloxolone 5 mg & Ipilimumab	Omaveloxolone 10 mg & Ipilimumab	Omaveloxolone 5 mg & Nivolumab	Omaveloxolone 10 mg & Nivolumab	Omaveloxolone 20 mg & Nivolumab	Omaveloxolone 100 mg & Nivolumab	Omaveloxolone 150 mg & Nivolumab
Anaemia	Blood and lymphatic system disorders	1/6	2/6	2/6	0/6	0/6	1/6	2/5
Bone marrow failure	Blood and lymphatic system disorders	1/6	0/6	1/6	0/6	0/6	0/6	0/5
Leukopenia	Blood and lymphatic system disorders	0/6	0/6	1/6	0/6	0/6	0/6	0/5
Thrombocytopenia	Blood and lymphatic system disorders	0/6	1/6	0/6	0/6	0/6	0/6	0/5
Cardiac failure	Cardiac disorders	0/6	1/6	0/6	0/6	0/6	0/6	0/5
Palpitations	Cardiac disorders	0/6	0/6	1/6	0/6	0/6	0/6	0/5
Sinus bradycardia	Cardiac disorders	0/6	0/6	0/6	1/6	0/6	0/6	0/5
Sinus tachycardia	Cardiac disorders	1/6	1/6	0/6	0/6	0/6	0/6	0/5
Multiple lentigines syndrome	Congenital, familial and genetic disorders	0/6	1/6	0/6	0/6	0/6	0/6	0/5
Ear pain	Ear and labyrinth disorders	0/6	0/6	0/6	0/6	2/6	0/6	0/5
Vertigo	Ear and labyrinth disorders	1/6	0/6	0/6	0/6	1/6	0/6	0/5
Adrenal insufficiency	Endocrine disorders	0/6	1/6	0/6	0/6	0/6	0/6	0/5
Hypophysitis	Endocrine disorders	2/6	0/6	1/6	0/6	0/6	0/6	0/5
Hypothyroidism	Endocrine disorders	1/6	0/6	0/6	0/6	0/6	0/6	0/5
Inappropriate antidiuretic hormone secretion	Endocrine disorders	0/6	0/6	1/6	0/6	0/6	0/6	0/5
Conjunctivitis	Eye disorders	0/6	0/6	1/6	0/6	0/6	0/6	0/5
Dry eye	Eye disorders	0/6	0/6	1/6	0/6	0/6	0/6	0/5
Eye disorder	Eye disorders	0/6	0/6	1/6	0/6	0/6	0/6	0/5
Eye irritation	Eye disorders	0/6	0/6	1/6	0/6	0/6	0/6	0/5
Mydriasis	Eye disorders	0/6	0/6	0/6	0/6	1/6	0/6	0/5
Photophobia	Eye disorders	0/6	0/6	0/6	0/6	0/6	0/6	1/5
Vision blurred	Eye disorders	0/6	0/6	1/6	0/6	0/6	0/6	0/5
Vitreous floaters	Eye disorders	0/6	0/6	1/6	0/6	0/6	0/6	1/5
Abdominal distension	Gastrointestinal disorders	0/6	0/6	0/6	0/6	0/6	1/6	1/5
Abdominal pain	Gastrointestinal disorders	0/6	3/6	2/6	2/6	1/6	1/6	0/5
Abdominal pain upper	Gastrointestinal disorders	1/6	0/6	1/6	0/6	2/6	0/6	0/5
Ascites	Gastrointestinal disorders	0/6	1/6	0/6	0/6	0/6	0/6	1/5
Colitis	Gastrointestinal disorders	0/6	1/6	0/6	0/6	0/6	0/6	0/5
Constipation	Gastrointestinal disorders	1/6	2/6	3/6	3/6	3/6	0/6	1/5
Diarrhoea	Gastrointestinal disorders	3/6	3/6	1/6	1/6	2/6	4/6	2/5
Dry mouth	Gastrointestinal disorders	0/6	1/6	0/6	0/6	1/6	0/6	1/5
Dyspepsia	Gastrointestinal disorders	0/6	2/6	0/6	2/6	2/6	0/6	1/5
Dysphagia	Gastrointestinal disorders	0/6	0/6	1/6	0/6	0/6	0/6	0/5
Faecal incontinence	Gastrointestinal disorders	0/6	0/6	0/6	1/6	0/6	0/6	0/5
Faeces discoloured	Gastrointestinal disorders	0/6	0/6	0/6	0/6	0/6	1/6	0/5
Flatulence	Gastrointestinal disorders	0/6	1/6	1/6	1/6	0/6	1/6	0/5
Frequent bowel movements	Gastrointestinal disorders	0/6	0/6	1/6	0/6	0/6	0/6	0/5
Gastric ulcer	Gastrointestinal disorders	1/6	0/6	0/6	0/6	0/6	0/6	0/5
Gastrooesophageal reflux disease	Gastrointestinal disorders	2/6	0/6	0/6	0/6	0/6	0/6	0/5
Haemorrhoidal haemorrhage	Gastrointestinal disorders	0/6	0/6	0/6	0/6	1/6	0/6	0/5
Haemorrhoids	Gastrointestinal disorders	0/6	0/6	0/6	0/6	0/6	1/6	0/5
Hiatus hernia	Gastrointestinal disorders	0/6	0/6	0/6	0/6	0/6	1/6	0/5
Melaena	Gastrointestinal disorders	0/6	0/6	0/6	0/6	0/6	1/6	0/5
Mucous stools	Gastrointestinal disorders	0/6	0/6	0/6	1/6	0/6	0/6	0/5
Nausea	Gastrointestinal disorders	4/6	4/6	4/6	1/6	2/6	4/6	0/5
Oesophageal disorder	Gastrointestinal disorders	0/6	0/6	0/6	0/6	0/6	1/6	0/5
Oral disorder	Gastrointestinal disorders	0/6	0/6	0/6	0/6	1/6	0/6	0/5
Rectal haemorrhage	Gastrointestinal disorders	1/6	0/6	0/6	0/6	0/6	0/6	0/5
Toothache	Gastrointestinal disorders	0/6	0/6	1/6	0/6	0/6	0/6	1/5
Vomiting	Gastrointestinal disorders	1/6	0/6	1/6	0/6	1/6	2/6	0/5
Asthenia	General disorders	0/6	0/6	1/6	0/6	0/6	0/6	0/5
Chills	General disorders	1/6	0/6	0/6	0/6	0/6	1/6	0/5
Early satiety	General disorders	0/6	0/6	0/6	0/6	0/6	0/6	1/5
Face oedema	General disorders	0/6	0/6	1/6	0/6	0/6	0/6	0/5
Fatigue	General disorders	5/6	5/6	5/6	1/6	6/6	1/6	3/5
Gait disturbance	General disorders	0/6	0/6	1/6	1/6	0/6	0/6	0/5
Influenza like illness	General disorders	0/6	0/6	1/6	0/6	0/6	0/6	0/5
Localised oedema	General disorders	0/6	0/6	0/6	0/6	0/6	0/6	1/5
Malaise	General disorders	0/6	0/6	1/6	0/6	0/6	0/6	0/5
Mucosal inflammation	General disorders	0/6	0/6	0/6	0/6	0/6	0/6	1/5

169 more terms not shown.

+Locations (10)

Facility	City	Country
Southern Cancer Center	Mobile, Alabama	United States
Highlands Oncology Group	Fayetteville, Arkansas	United States
University of Colorado Cancer Center, Anschutz Cancer Pavilion	Aurora, Colorado	United States
Christiana Hospital Helen F. Graham Cancer Center	Newark, Delaware	United States
Goergetown-Lombardi Comprehensive Cancer Center	Washington D.C., District of Columbia	United States
H. Lee Moffitt Cancer Center & Research Institute	Tampa, Florida	United States
Dana Farber Cancer Institute	Boston, Massachusetts	United States
Atlantic Melanoma Center	Morristown, New Jersey	United States
Duke Cancer Institute	Durham, North Carolina	United States
MD Anderson Cancer Center	Houston, Texas	United States

+Study documents

Study Protocol (PDF, 2016-11-29)
Statistical Analysis Plan (PDF, 2019-10-25)