Clinical trial NCT00862134: Randomized, Multi-center, Open-label, Study of PR104 Versus PR104/Docetaxel in Non-Small Cell Lung Cancer (NSCLC)
Official title: A Randomized Phase II, Multi-Center, Open-Label Trial of PR104 and Docetaxel in Patients With Advanced Non-Small Cell Lung Cancer
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Non-Small Cell Lung Cancer
Lead sponsor: Proacta, Incorporated
Sponsor class: INDUSTRY
First posted: 2009-03-16
Enrollment: 42
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The current understanding of PR104 justifies the evaluation of PR104 with docetaxel in subjects with Non Small Cell Lung Cancer (NSCLC). These include:

* Aldo-keto reductase 1C3 (AKR1C3). NSCLC has been shown to express high levels of AKR1C3 in about one half of tumors tested. Subjects with high levels of AKR1C3 should have increased activation of PR104 within their tumor.
* Hypoxia. NSCLC has been demonstrated to be a tumor with hypoxia based on both direct tumor measurements (oxygen electrodes) and hypoxic positron emission tomography (PET) imaging. Tumor hypoxia in NSCLC should be sufficient to activate PR104 to its active metabolites PR104H and PR104M.
* Preclinical data. The use of docetaxel and PR104 alone and in combination in preclinical models demonstrates activity of PR104 as a single agent and supraadditive activity when PR104 and docetaxel are used in combination.
* Manageable toxicity. PR104 and docetaxel with Granulocyte Colony-stimulating Factor (G-CSF) have been combined in a prior phase I study. A Maximum Tolerated Dose (MTD) has been identified and the major toxicities of this combination are understood.

The current study will provide an estimate of the activity of PR104 in subjects with NSCLC. This information will prove valuable in defining the future clinical development of PR104, and in determining if PR104 has sufficient activity in NSCLC to warrant a larger phase III registration study in this indication.

Primary objectives

• Estimate the response rate (RR) of PR104/docetaxel

Secondary objectives

* Evaluate survival
* Evaluate progression free survival (PFS)
* Evaluate time to progression (TTP)
* Evaluate safety
* Evaluate the pharmacokinetics of PR104 and its metabolites
* Evaluate the pharmacokinetics of docetaxel
* Evaluate the tumor hypoxia using 18F-fluoromisonidazole (18F-MISO) PET imaging
* Collect diagnostic biopsy samples for the determination of AKR1C3
* Collect plasma samples for assessment of potential biomarkers of tumor hypoxia

Detailed description: A randomized phase II, multi-center, open-label, study of docetaxel versus docetaxel/PR104.

Following informed consent, subjects will undergo baseline evaluation with history, physical exams, blood work and disease assessment. Selected subjects will undergo PET imaging with F18 fluoromisonidazole (F18-FMISO) and Fludeoxyglucose (FDG) for assessment of hypoxia and glucose metabolism, and pharmacokinetics of PR104.

Subjects will be randomized between arm 1 consisting of docetaxel, 75 mg/m\^2, administered intravenously (IV), every 21 days (an approved dose and schedule) and arm 2 consisting of docetaxel, 60 mg/m\^2 with PR104 at 770 mg/m\^2, IV, every 21 days. Subjects randomized to PR104/docetaxel will receive prophylactic G-CSF. One cycle will be 21 days in duration. Subjects will be evaluated weekly. A disease assessment will be performed every six weeks. Subjects with progression will be removed from study. Subjects with a response or stable disease may continue on study if this is considered beneficial by their physician.

Eligibility criteria: Inclusion Criteria:

* Subjects with locally advanced or metastatic NSCLC (stage IIIb/IV) who have relapsed following adjuvant or first line therapy with a platinum containing regimen, and are appropriate candidates for treatment with single agent docetaxel
* Confirmed NSCLC by prior pathological analysis (tissue aspirate or biopsy)
* At least 21 days from prior chemotherapy
* At least 30 days from prior irradiation therapy
* Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1
* Life expectancy of 12 weeks or more
* Adequate hematologic function \[Absolute neutrophil count (ANC) ≥ 1.5 x 10\^9/L; platelet count ≥100x10\^9/L; hemoglobin ≥8.5 g /dL maintained in the absence of red blood cell transfusions; and prothrombin time international normalized ratio ≤1.7; or prothrombin time ≤2 seconds above control)
* Adequate hepatic function (albumin ≥2.8 g/dL; total bilirubin ≤2 mg/dL \[51.3 μmol/L\]; and alanine aminotransferase and aspartate aminotransferase ≤1.5 times the upper limit of the normal range)
* Adequate renal function (serum creatinine ≤2.0 times the upper limit of the normal range or creatinine clearance ≥60 mL/min).
* At least one untreated target lesion that could be measured in one dimension, according to the Response Evaluation Criteria in Solid Tumors (RECIST)

Exclusion Criteria:

* Previous treatment with docetaxel (prior treatment with paclitaxel permitted)
* Receipt of more than one prior systemic chemotherapy regimen
* Active concomitant malignancy likely to effect any of the primary or secondary outcome measures in the current study
* Women who are pregnant, breast-feeding or planning to become pregnant during the study
* Men or women of reproductive-potential who are unwilling to use an effective method of contraception during the study and for 30 days following the last dose
* Evidence of a significant medical disorder or laboratory finding that, in the opinion of the Investigator, compromises the subject's safety during study participation
* Active Central Nervous System (CNS) metastatic disease requiring intervention
* Less than 4 weeks since major surgery
* Known human immunodeficiency virus (HIV) positivity

Primary outcomes:
measure: Number of Participants That Achieved a Response (Complete or Partial) After Receiving PR104/Docetaxel Versus Docetaxel Alone
timeFrame: Participants were followed for the duration on study, an average of 4 months
Secondary outcomes:
measure: Safety and Tolerability: Serious Adverse Events
timeFrame: 30 days following last administration of study treatment
measure: Positive Aldo-keto Reductase 1C3 (AKR1C3) Expression in Participating Patients
timeFrame: Within 1 year of enrollment
Other outcomes:
Locations:
city: San Diego
country: United States
facility: Sharp Clinical Oncology Research
state: California
city: Miami
country: United States
facility: University of Miami/Sylvester Comprehensive Cancer Center
state: Florida
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Skokie
country: United States
facility: Orchard Research, LLC
state: Illinois
city: Zion
country: United States
facility: Midwestern Regional Medical Center
state: Illinois
city: Beech Grove
country: United States
facility: St. Francis Health Services
state: Indiana
city: Ames
country: United States
facility: McFarland Clinic/William R. Bliss Cancer Center
state: Iowa
city: Cedar Rapids
country: United States
facility: Iowa Blood & Cancer Care
state: Iowa
city: Wichita
country: United States
facility: Cancer Center of Kansas
state: Kansas
city: Mt. Sterling
country: United States
facility: Montgomery Cancer Center
state: Kentucky
city: Baton Rouge
country: United States
facility: Baton Rouge General/Penington
state: Louisiana
city: Annapolis
country: United States
facility: Annapolis Oncology Center
state: Maryland
city: Baltimore
country: United States
facility: Lapidus Cancer Center/Sinai Hospital
state: Maryland
city: Kalamazoo
country: United States
facility: Kalamazoo Hematology & Oncology
state: Michigan
city: Reno
country: United States
facility: VA Sierra Nevada Health Care System
state: Nevada
city: Durham
country: United States
facility: VA Medical Center
state: North Carolina
city: Winston-Salem
country: United States
facility: Piedmont Hematology Oncology Associates, PLLC
state: North Carolina
city: Cincinnati
country: United States
facility: Cincinnati VA Medical Center
state: Ohio
city: Philadelphia
country: United States
facility: University of Pennsylvania
state: Pennsylvania
city: Columbia
country: United States
facility: WJB Dorn VA Medical Center
state: South Carolina
city: Memphis
country: United States
facility: ACORN
state: Tennessee
city: Dallas
country: United States
facility: Mary Crowley Medical Research Center
state: Texas
city: Fort Worth
country: United States
facility: The Center for Cancer and Blood Disorders
state: Texas
city: Midland
country: United States
facility: Texas Oncology - Allison Cancer Center
state: Texas
city: Temple
country: United States
facility: Scott & White Memorial Hospital
state: Texas
city: Montreal
country: Canada
facility: McGill University
state: Quebec
city: Hamilton
country: New Zealand
facility: Waikato District Health Board
Study officials:
References: