Study With Gemcitabine and RTA 402 for Patients With Unresectable Pancreatic Cancer

Study Overview
=================
Brief Summary
-----------------
This study assesses the safety and efficacy of RTA 402 in combination with gemcitabine in patients with unresectable pancreatic cancer.

Detailed Description
-----------------
Phase I will be conducted to determine the MTD of RTA 402 (administered orally Days 1-21 or Days 1-28 of a 28-day cycle) in combination with gemcitabine (1000 m/m2). Gemcitabine will be administered as an intravenous infusion on Days 1, 8, and 15 of each 28-day cycle. The phase II portion of the study will be randomized, and double-blinded. Phase II will utilize the RTA 402 MTD determined in Phase I; Arm 1 will consist of gemcitabine + RTA 402. RTA 402 capsules will administered orally Days 1-21 of each 28-day cycle (or Days 1-28 if appropriate, based on phase I results); gemcitabine (1000 mg/m2) will be administered as an intravenous infusion on Days 1, 8, and 15 of each 28-day cycle in each Arm. Arm 2 will consist of gemcitabine + placebo, placebo capsules will be taken orally Days 1-21 of each 28-day cycle (or Days 1-28 if appropriate, based on phase I results). Both treatment arms are 4-weeks in length. The study was conceived with both a Phase I and Phase II portion as described above; however, only the Phase I portion was completed. The trial was terminated in 2009 before the Phase II portion could begin. This study was previously posted by Reata Pharmaceuticals. In September 2023, sponsorship of the trial was transferred to Biogen.

Official Title
-----------------
A Randomized Phase I/II Study With Gemcitabine and RTA 402 or Gemcitabine and Placebo for Patients With Unresectable Pancreatic Cancer

Conditions
-----------------
Pancreatic Neoplasms, Pancreatic Cancer

Intervention / Treatment
-----------------
* Drug: Bardoxolone methyl
* Drug: Bardoxolone methyl
* Drug: Bardoxolone methyl
* Drug: Bardoxolone methyl
* Drug: Bardoxolone methyl
* Drug: Bardoxolone methyl
* Drug: Bardoxolone methyl
* Drug: Gemcitabine
* Drug: Placebo
* Drug: Bardoxolone methyl


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Phase I patients should have treatment naïve pancreatic cancer; however , Phase I patients who have had 1 prior regimen consisting of adjuvant chemo-radiation or adjuvant gemcitabine - as defined within the NCCN guidelines may be enrolled. Phase II patients must have metastatic disease (Stage IV only). Karnofsky performance status of >70% Adequate liver function. (total bilirubin ≤ 1.5 mg/dL and AST(SGOT) and ALT(SGPT) of < 2.5 ULN ( ≤ 5 ULN for Phase II patients with liver metastases), Serum Creatinine < 1.5 ULN Adequate bone marrow function as documented by the following laboratory test results within 14 days of starting therapy. platelets ≥100,000/mm3, absolute neutrophil count (ANC) ≥1500/mm3, hemoglobin ≥9.0 g/dL, white blood cell (WBC) count ≥3000 /mm3 Practice effective contraception during the entire study period. Life expectancy of more than 3 months. Able and willing to sign the informed consent form. Willing and able to self-administer orally and document all doses of RTA 402 ingested. Exclusion Criteria: Prior treatment for current malignancy outside of the adjuvant setting for Phase I Inability to swallow tablets or capsules Active brain metastases or primary central nervous system (CNS) malignancies. (Patients with a previously treated brain metastasis may be included.) Active second malignancy Ten percent or greater weight loss over the 6 weeks before study entry. Pregnant or breast feeding Clinically significant illnesses which could compromise participation in the study, including, but not limited to: Uncontrolled diabetes; Active or uncontrolled infection; Acute or chronic liver disease; Confirmed diagnosis of Human immunodeficiency virus (HIV) infection; Uncontrolled hypertension, symptomatic congestive heart failure, unstable angina pectoris, myocardial infarction within the past 6 months, or uncontrolled cardiac arrhythmia. Psychiatric illness that would limit compliance with study requirements.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1 Cohort 1<br>Bardoxolone methyl 150 mg/day x 21 days and gemcitabine (1000 mg/m2 by intravenous infusion on Days 1, 9, and 15) | Drug: Bardoxolone methyl<br>* Bardoxolone methyl capsules (150 mg/day) for 21 days<br>* Other names: RTA 402;Drug: Gemcitabine<br>* 1,000 mg/m2 administered as an intravenous infusion on days 1, 8, and 15<br>* Other names: Gemzar;|
| Experimental: Phase 1 Cohort 2<br>Bardoxolone methyl 300 mg /day for 21 days and gemcitabine (1000 mg/m2 by intravenous infusion on Days 1, 9, and 15) | Drug: Bardoxolone methyl<br>* Bardoxolone methyl capsules (300 mg/day) for 21 days<br>* Other names: RTA 402;Drug: Gemcitabine<br>* 1,000 mg/m2 administered as an intravenous infusion on days 1, 8, and 15<br>* Other names: Gemzar;|
| Experimental: Phase 1 Cohort 3<br>Bardoxolone methyl 150 mg/day for 28 days and gemcitabine (1000 mg/m2 by intravenous infusion on Days 1, 9, and 15) | Drug: Bardoxolone methyl<br>* Bardoxolone methyl capsules (150 mg/day) for 28 days<br>* Other names: RTA 402;Drug: Gemcitabine<br>* 1,000 mg/m2 administered as an intravenous infusion on days 1, 8, and 15<br>* Other names: Gemzar;|
| Experimental: Phase 1 Cohort 4<br>Bardoxolone methyl 200 mg/day for 28 days and gemcitabine (1000 mg/m2 by intravenous infusion on Days 1, 9, and 15) | Drug: Bardoxolone methyl<br>* Bardoxolone methyl capsules (200 mg/day) for 28 days<br>* Other names: RTA 402;Drug: Gemcitabine<br>* 1,000 mg/m2 administered as an intravenous infusion on days 1, 8, and 15<br>* Other names: Gemzar;|
| Experimental: Phase 1 Cohort 5<br>Bardoxolone methyl 250 mg/day for 28 days and gemcitabine (1000 mg/m2 by intravenous infusion on Days 1, 9, and 15) | Drug: Bardoxolone methyl<br>* Bardoxolone methyl capsules (250 mg/day) for 28 days<br>* Other names: RTA 402;Drug: Gemcitabine<br>* 1,000 mg/m2 administered as an intravenous infusion on days 1, 8, and 15<br>* Other names: Gemzar;|
| Experimental: Phase 1 Cohort 6<br>Bardoxolone methyl 300 mg/day x 28 days and gemcitabine (1000 mg/m2 by intravenous infusion on Days 1, 9, and 15) | Drug: Bardoxolone methyl<br>* Bardoxlone methyl capsules (300 mg/day) x 28 days<br>* Other names: RTA 402;Drug: Gemcitabine<br>* 1,000 mg/m2 administered as an intravenous infusion on days 1, 8, and 15<br>* Other names: Gemzar;|
| Experimental: Phase 1 Cohort 7<br>Bardoxolone methyl 350 mg/day x 28 days and gemcitabine (1000 mg/m2 by intravenous infusion on Days 1, 9, and 15) | Drug: Bardoxolone methyl<br>* Bardoxolone methyl capsules (350 mg/day) x 28 days<br>* Other names: RTA 402;Drug: Gemcitabine<br>* 1,000 mg/m2 administered as an intravenous infusion on days 1, 8, and 15<br>* Other names: Gemzar;|
| Experimental: Phase 2 Cohort 1<br>Bardoxolone methyl maximum tolerated dose(as determined in the Phase 1 portion of the study)/day x 28 days and gemcitabine (1000 mg/m2 by intravenous infusion on Days 1, 9, and 15) | Drug: Gemcitabine<br>* 1,000 mg/m2 administered as an intravenous infusion on days 1, 8, and 15<br>* Other names: Gemzar;Drug: Bardoxolone methyl<br>* Bardoxolone methyl maximum tolerated dose (as determined in the Phase 1 portion of the study)/day x 28 days<br>* Other names: RTA 402;|
| Placebo Comparator: Phase 2 Cohort 2<br>Placebo capsules/day x 28 days and gemcitabine (1000 mg/m2 by intravenous infusion on Days 1, 9, and 15) | Drug: Gemcitabine<br>* 1,000 mg/m2 administered as an intravenous infusion on days 1, 8, and 15<br>* Other names: Gemzar;Drug: Placebo<br>* Placebo capsules x 28 days<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase I - To determine the maximum tolerated dose (MTD) of RTA 402 in combination with gemcitabine in patients with locally advanced or metastatic pancreatic cancer. |  | End of trial | 
| Phase II - To determine if treatment with RTA 402 in combination with gemcitabine can increase the progression-free survival versus gemcitabine plus placebo in patients with unresectable metastatic pancreatic cancer. |  | End of Trial | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase I - To document any preliminary antitumor activity of RTA 402 in this patient population. |  | End ofTrial | 
| Phase I - To characterize the pharmacokinetics (PK) of RTA 402 in this population. |  | End of Trial | 
| Phase II - To determine the overall response rate in patients treated with RTA 402 + gemcitabine and in patients treated with gemcitabine + placebo. |  | End of Trial | 
| Phase II - To determine the 1-year survival in this patient population. |  | End of Trial | 
| Phase II - To determine the toxicities of these regimens. |  | End of Trial | 
| Phase II - To determine the changes in quality of life (Functional Assessment of Chronic Illness Therapy (Fatigue), [FACIT-F]). |  | End of Trial | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
pancreatic cancer, gemcitabine