Nab-Paclitaxel to Paclitaxel in Advanced Urothelial Cancer Progressing on or After Platinum Containing Regimen.

A Multicentre Randomized Phase II Trial Comparing Nab-Paclitaxel to Paclitaxel in Patients With Advanced Urothelial Cancer Progressing on or After a Platinum Containing Regimen.

The purpose of this study is to compare the effects on urothelial cancer of nab-paclitaxel compared to paclitaxel to treat this disease.

This research is being done because currently there is no effective treatment for urothelial cancer that has progressed after prior chemotherapy.

Nab-paclitaxel is a formulation of the chemotherapeutic drug paclitaxel that is combined with a human protein called albumin. In Canada, nab-paclitaxel is currently approved for the treatment of metastatic breast cancer. This drug has been tested in other cancers and has shown promising activity in lung cancer, melanoma and pancreatic cancer. Information from research studies suggests that nab-paclitaxel may be a useful treatment for urothelial cancer.

Inclusion Criteria:

• Histologically or cytologically confirmed diagnosis of TCC of the urinary tract (bladder, urethra, ureter, renal pelvis) and metastatic or locally advanced inoperable disease extent (T4, N2, N3 or M1 disease)

Note: Mixed histologies (except small cell) permitted if predominately TCC by IHC.

• Patients must have evidence of metastatic disease, but measurable disease is not mandatory. To be considered evaluable for the overall response rate (complete and partial response), patients must have at least one measurable lesion as follows:

  • X-ray, physical exam ≥ 20 mm
  • Conventional CT scan, MRI ≥ 20 mm
  • Spiral CT scan ≥ 10 mm

• Male or female, 18 years of age or older.

• ECOG performance status ≤ 2 at study entry

• Adequate hematological, renal and hepatic functions as defined by the following required laboratory values obtained within 14 days prior to randomization. If anemic, patients should be asymptomatic and should not be decompensated.

  • Absolute neutrophil count (ANC) ≥ 1.5 x10^9/L (1,500 cells/mm3)
  • Platelet count ≥ 90 x10^9/L (100,000/mm3)
  • Hemoglobin ≥ 90 g/L
  • Calculated creatinine clearance > 25 mL/min (Cockcroft and Gault formula)
  • Total bilirubin ≤ 1.5 times the upper limit of normal (≤ 2.5X if Gilbert's disease)
  • ALT (SGPT) ≤ 3 x ULN or ≤ 5 x ULN if hepatic metastases are present

• Patients may have had prior neoadjuvant or adjuvant therapy for completely resected disease, provided it was completed at least 12 months prior to randomization. Patients must have recovered from any acute toxic effects to ≤ Grade 2 from any prior treatments. Neoadjuvant or adjuvant chemotherapy will be considered to have been first line therapy in the metastatic setting if the patient progressed within 12 months of the last dose.

• Patients must have received one and only one prior chemotherapeutic regimen which included a platinum (at least one cycle) for metastatic/recurrent disease. Treatment must have been discontinued at least 4 weeks prior to randomization in this study. Patients must have recovered from any acute toxic effects to ≤ Grade 2 from any prior treatments

• Patients may not have had any prior therapy with a taxane in any setting.

• Patients may have had prior investigational agents but these must have been discontinued at least 4 weeks prior to randomization. Patients must have recovered from any acute toxic effects to ≤ Grade 2 from any prior treatments.

• Prior treatments with radiation therapy in the adjuvant and/or metastatic setting are permitted provided that at least 2 weeks have elapsed since the last fraction of radiation therapy and all treatment related adverse events are ≤ Grade 1 at the time of randomization.

• Patients may have had prior surgery provided that at least 4 weeks elapsed between the end of surgery and randomization onto the study. Patients must have recovered from any acute toxic effects to ≤ Grade 2 from any prior treatments.

• Patients may have peripheral neuropathy from previous treatments providing that it is ≤ Grade 1.

• Patient is able (i.e. sufficiently fluent) and willing to complete the health and demographic, quality of life, and health utilities questionnaires in either English or French. The baseline assessment must be completed within required timelines, prior to registration/randomization. Inability (illiteracy in English or French, loss of sight, or other equivalent reason) to complete the questionnaires will not make the patient ineligible for the study. However, ability but unwillingness to complete the questionnaires will make the patient ineligible.

• Patient consent must be appropriately obtained in accordance with applicable local and regulatory requirements. Each patient must sign a consent form prior to enrollment in the trial to document their willingness to participate.

• Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test within 7 days prior to randomization. In addition to routine contraceptive methods, "effective contraception" also includes heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy, bilateral tubal ligation or vasectomy/vasectomized partner. However, if at any point a previously celibate patient chooses to become heterosexually active during the time period for use of contraceptive measures outlined in the protocol, he/she is responsible for beginning contraceptive measures.

• Patients must be accessible for treatment and follow up. Patients registered on this trial must be treated and followed at the participating centre. This implies there must be reasonable geographical limits (for example: 1 ½ hour's driving distance) placed on patients being considered for this trial. Investigators must assure themselves the patients registered on this trial will be available for complete documentation of the treatment, adverse events, response assessment and follow-up.

• In accordance with CCTG policy, protocol treatment is to begin within 5 working days of patient randomization.

Exclusion Criteria:

• A candidate for potentially curative surgery or radiotherapy.

• Patients with brain metastases are ineligible if they meet at least one of the following criteria:

  1. diagnosis within 3 months from randomization

  2. untreated brain metastases

  3. unstable brain metastasis as defined by:

     • cavitation or hemorrhage in the brain lesion
     • symptomatic state
     • daily prednisone or equivalent use greater than 10 mg

Patients do not need CT/MRI scans to rule out brain metastases unless there is a clinical suspicion of CNS metastases.

• Patients with serious illness or medical condition which would not permit the patient to be managed according to the protocol including, but not limited to:

  1. . any evidence of severe or uncontrolled systemic disease (i.e. known cases of hepatitis B or C or human immunodeficiency virus (HIV)).

  2. patients with active or uncontrolled infections.

     Screening for chronic conditions is not required, although patients known to have such conditions at screening should not be included.

• Women who are pregnant or breastfeeding.

• Patients with history of allergic or hypersensitivity reactions to any study drug or their excipients or with a history of allergic reactions attributed to compounds with similar chemical composition to any of the study drugs.

• Planned concomitant participation in another clinical trial of an experimental agent, vaccine or device. Concomitant participation in observational studies is acceptable.

• Patients with a history of other malignancies, except: adequately treated non-melanoma skin cancer, curatively treated in-situ cancer of the cervix, or other solid tumours curatively treated with no evidence of disease for ≥ 5 years. Prior prostate cancer is allowed provided that it is an incidental finding at cystoprostatectomy with a PSA <0.5 ng/mL at randomization or a prior diagnosis of low risk prostate cancer at any time as defined by ≤T2, a Gleason Score of 6 or less and PSA <10 ng/mL.