Randomized, Multi-center, Open-label, Study of PR104 Versus PR104/Docetaxel in Non-Small Cell Lung Cancer (NSCLC)

Non-Small Cell Lung Cancer Clinical Trial

Official title:

A Randomized Phase II, Multi-Center, Open-Label Trial of PR104 and Docetaxel in Patients With Advanced Non-Small Cell Lung Cancer

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT00862134
• Other study ID #: PR104-2003
• Status: Terminated
• Phase: Phase 2
• First received: March 12, 2009
• Last updated: January 8, 2013
• Start date: March 2009
• Est. completion date: May 2010

Study information

• Verified date: January 2013
• Source: Proacta, Incorporated
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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

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.

Other known NCT identifiers

• NCT00840021

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 42
• Est. completion date: May 2010
• Est. primary completion date: January 2010
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Carcinoma, Non-Small-Cell Lung
• Lung Neoplasms
• Non-Small Cell Lung Cancer

Intervention

Drug:
• PR104
770 mg/m^2, IV, every 21 days. Number of Cycles: until progression or unacceptable toxicity develops.
• docetaxel
75 mg/m^2, IV, every 21 days. Number of Cycles: until progression or unacceptable toxicity develops.
• docetaxel
60 mg/m^2, IV, every 21 days. Number of Cycles: until progression or unacceptable toxicity develops.
• Granulocyte colony-stimulating factor
Subjects randomized to PR104/docetaxel will receive prophylactic G-CSF per package insert administration recommendations. Number of Cycles: until progression or unacceptable toxicity develops.

Locations

Country	Name	City	State
Canada	McGill University	Montreal	Quebec
New Zealand	Waikato District Health Board	Hamilton
United States	McFarland Clinic/William R. Bliss Cancer Center	Ames	Iowa
United States	Annapolis Oncology Center	Annapolis	Maryland
United States	Lapidus Cancer Center/Sinai Hospital	Baltimore	Maryland
United States	Baton Rouge General/Penington	Baton Rouge	Louisiana
United States	St. Francis Health Services	Beech Grove	Indiana
United States	Iowa Blood & Cancer Care	Cedar Rapids	Iowa
United States	Northwestern University	Chicago	Illinois
United States	Cincinnati VA Medical Center	Cincinnati	Ohio
United States	WJB Dorn VA Medical Center	Columbia	South Carolina
United States	Mary Crowley Medical Research Center	Dallas	Texas
United States	VA Medical Center	Durham	North Carolina
United States	The Center for Cancer and Blood Disorders	Fort Worth	Texas
United States	Kalamazoo Hematology & Oncology	Kalamazoo	Michigan
United States	ACORN	Memphis	Tennessee
United States	University of Miami/Sylvester Comprehensive Cancer Center	Miami	Florida
United States	Texas Oncology - Allison Cancer Center	Midland	Texas
United States	Montgomery Cancer Center	Mt. Sterling	Kentucky
United States	University of Pennsylvania	Philadelphia	Pennsylvania
United States	VA Sierra Nevada Health Care System	Reno	Nevada
United States	Sharp Clinical Oncology Research	San Diego	California
United States	Orchard Research, LLC	Skokie	Illinois
United States	Scott & White Memorial Hospital	Temple	Texas
United States	Cancer Center of Kansas	Wichita	Kansas
United States	Piedmont Hematology Oncology Associates, PLLC	Winston-Salem	North Carolina
United States	Midwestern Regional Medical Center	Zion	Illinois

Sponsors (1)

Lead Sponsor	Collaborator
Proacta, Incorporated

Countries where clinical trial is conducted

United States,  Canada,  New Zealand, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Participants That Achieved a Response (Complete or Partial) After Receiving PR104/Docetaxel Versus Docetaxel Alone	Defined as the number of subjects with complete response (CR) or partial response (PR) using Response Evaluation Criteria in Solid Tumors (RECIST) criteria	Participants were followed for the duration on study, an average of 4 months	No
Secondary	Safety and Tolerability: Serious Adverse Events	The number of participants with at least one Serious Adverse Event was measured.	30 days following last administration of study treatment	Yes
Secondary	Positive Aldo-keto Reductase 1C3 (AKR1C3) Expression in Participating Patients	AKR1C3 was evaluated on a semi-quantitative scale, and the percentage of cells staining at each of the following four levels was recorded: 0 (unstained), 1+ (weak staining), 2+ (moderate staining) and 3+ (strong staining).; Patients with a strong staining score (3+) were considered to be AKR1C3 positive	Within 1 year of enrollment	No