Randomized, Multi-center, Open-label, Study of PR104 Versus PR104/Docetaxel in Non-Small Cell Lung Cancer (NSCLC)
Condition: Non-Small Cell Lung Cancer
MeSH terms: Lung Neoplasms; Carcinoma, Non-Small-Cell Lung
Intervention: PR104; docetaxel; docetaxel; Granulocyte colony-stimulating factor
Intervention description: 770 mg/m^2, IV, every 21 days. Number of Cycles: until progression or unacceptable toxicity develops.; 75 mg/m^2, IV, every 21 days. Number of Cycles: until progression or unacceptable toxicity develops.; 60 mg/m^2, IV, every 21 days. Number of Cycles: until progression or unacceptable toxicity develops.; Subjects randomized to PR104/docetaxel will receive prophylactic G-CSF per package insert administration recommendations. Number of Cycles: until progression or unacceptable toxicity develops.
Intervention MeSH terms: Docetaxel; Lenograstim
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 42.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

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
    

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