ClinicalTrials.gov
ClinicalTrials.gov Menu

RTA 408 Capsules in Patients With Melanoma - REVEAL

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT02259231
Recruitment Status : Completed
First Posted : October 8, 2014
Last Update Posted : September 6, 2018
Sponsor:
Information provided by (Responsible Party):
Reata Pharmaceuticals, Inc.

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.


Condition or disease Intervention/treatment Phase
Melanoma Unresectable (Stage III) Melanoma Metastatic (Stage IV) Melanoma Drug: Omaveloxolone Capsules (2.5 mg/capsule) Drug: Ipilimumab (3 mg/kg) Drug: Nivolumab (240 mg) Phase 1 Phase 2

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 41 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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
Study Start Date : October 2014
Actual Primary Completion Date : May 9, 2018
Actual Study Completion Date : July 23, 2018

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Melanoma

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 Name: RTA 408 Capsules (2.5 mg/capsule)

Drug: Ipilimumab (3 mg/kg)
Sterile solution containing ipilimumab to be delivered intravenously at 3mg/kg
Other Name: 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: Omaveloxolone Capsules (2.5 mg/capsule)
Capsules containing 2.5 mg of omaveloxolone per capsule to the dosage indicated in the Arm Label
Other Name: RTA 408 Capsules (2.5 mg/capsule)

Drug: Ipilimumab (3 mg/kg)
Sterile solution containing ipilimumab to be delivered intravenously at 3mg/kg
Other Name: Yervoy

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 Name: RTA 408 Capsules (2.5 mg/capsule)

Drug: Nivolumab (240 mg)
Sterile solution containing nivolumab to be delivered intravenously at 240 mg
Other Name: 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 (2.5 mg/capsule)
Capsules containing 2.5 mg of omaveloxolone per capsule to the dosage indicated in the Arm Label
Other Name: RTA 408 Capsules (2.5 mg/capsule)

Drug: Nivolumab (240 mg)
Sterile solution containing nivolumab to be delivered intravenously at 240 mg
Other Name: 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 (2.5 mg/capsule)
Capsules containing 2.5 mg of omaveloxolone per capsule to the dosage indicated in the Arm Label
Other Name: RTA 408 Capsules (2.5 mg/capsule)

Drug: Nivolumab (240 mg)
Sterile solution containing nivolumab to be delivered intravenously at 240 mg
Other Name: 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: Omaveloxolone Capsules (2.5 mg/capsule)
Capsules containing 2.5 mg of omaveloxolone per capsule to the dosage indicated in the Arm Label
Other Name: RTA 408 Capsules (2.5 mg/capsule)

Drug: Nivolumab (240 mg)
Sterile solution containing nivolumab to be delivered intravenously at 240 mg
Other Name: Opdivo

Experimental: Omaveloxolone Dose5 TBD & nivolumab
Omaveloxolone (RTA 408) capsules, Dose5 TBD 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 Name: RTA 408 Capsules (2.5 mg/capsule)

Drug: Nivolumab (240 mg)
Sterile solution containing nivolumab to be delivered intravenously at 240 mg
Other Name: Opdivo

Experimental: Omaveloxolone Dose6 TBD & nivolumab
Omaveloxolone (RTA 408) capsules, Dose6 TBD 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 Name: RTA 408 Capsules (2.5 mg/capsule)

Drug: Nivolumab (240 mg)
Sterile solution containing nivolumab to be delivered intravenously at 240 mg
Other Name: Opdivo




Primary Outcome Measures :
  1. Measure of overall response rate using RECIST (Response Evaluation Criteria in Solid Tumors) of the Phase 2 dose of omaveloxolone with nivolumab [ Time Frame: 169 weeks ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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).

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02259231


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

Responsible Party: Reata Pharmaceuticals, Inc.
ClinicalTrials.gov Identifier: NCT02259231     History of Changes
Other Study ID Numbers: RTA 408-C-1401
First Posted: October 8, 2014    Key Record Dates
Last Update Posted: September 6, 2018
Last Verified: September 2018

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Reata Pharmaceuticals, Inc.:
RTA 408
RTA 408 Capsules
Myeloid-derived suppressor cells (MDSDs)
iNOS
Melanoma
Checkpoint inhibitor
omaveloxolone

Additional relevant MeSH terms:
Melanoma
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Nerve Tissue
Nevi and Melanomas
Nivolumab
Antibodies, Monoclonal
Antineoplastic Agents
Immunologic Factors
Physiological Effects of Drugs