XRP6258 Plus Prednisone Compared to Mitoxantrone Plus Prednisone in Hormone Refractory Metastatic Prostate Cancer (TROPIC)

• Time to Progression Free Survival (PFS) [ Time Frame: From the date of randomization up to 104 weeks (study cut-off) ] [ Designated as safety issue: No ]
  Progression free survival was defined as a composite endpoint evaluated from the date of randomization to the date of tumor progression, PSA progression, pain progression, or death due to any cause, whichever occurred first
• Overall Tumor Response [ Time Frame: From the date of randomization up to 104 weeks (study cut-off) ] [ Designated as safety issue: No ]

  Tumor Overall Response Rate (ORR) (only in patients with measurable disease):

  Objective responses (Complete Response and Partial Response) for measurable disease as assessed by investigators according to RECIST criteria.

  Complete Response (CR) is defined as: Disappearance of all target lesions. Partial Response (PR) is defined as: At least a 30% decrease in the sum of longest diameter (LD) of target lesions taking as reference baseline sum LD.

  Confirmation of objective responses will be performed by repeat tumor imaging (CT scans, MRI, bone scans) after the first documentation of response.

• Time to Tumor Progression [ Time Frame: From the date of randomization up to 104 weeks (study cut-off) ] [ Designated as safety issue: No ]
  Time to tumor progression is defined as the number of months from randomization until evidence of progressive disease (RECIST)
• Time to Prostatic Specific Antigen (PSA) Progression [ Time Frame: at screening, day 1 of every treatment cycle, up to 104 weeks (study cut-off) ] [ Designated as safety issue: No ]

  In PSA non-responders, progression will be defined as a 25% increase over nadir and increase in the absolute value PSA level by at least 5 ng/ml and confirmed by a second value at least 4 weeks later.

  In PSA responders and in patients not evaluable for PSA response at baseline, progression will be defined as a ≥50% increase over nadir, provided that the increase is a minimum of 5 ng/ml and confirmed by a second value at least 1 week later.

• PSA (Prostate-Specific Antigen) Response [ Time Frame: from baseline up to 104 weeks (study cut-off) ] [ Designated as safety issue: No ]
  PSA response was defined as a ≥ 50% reduction in serum PSA, determined only for patients with a serum PSA ≥ 20ng/mL at baseline, confirmed by a repeat PSA ≥ 3 weeks later.
• Time to Pain Progression [ Time Frame: from baseline up to 104 weeks (study cut-off) ] [ Designated as safety issue: No ]

  Pain Progression is defined as an increase of ≥1 point in the median Personal Pain Intensity (PPI) from its nadir noted on 2 consecutive 3-week-apart visits or ≥25 % increase in the mean analgesic score compared with the baseline score & noted on 2 consecutive 3-week-apart visits or requirement for local palliative radiotherapy.

  Evaluation of the PPI & analgesic scores are based on the short-form McGill Pain Questionnaire which consists of 15 descriptors (11 sensory; 4 affective) which are rated on an intensity scale as 0=none (best) 1=mild 2=moderate 3=severe (worst) (TOTAL: 0=best 45=worst)

• Pain Response [ Time Frame: from baseline up to 104 weeks (study cut-off) ] [ Designated as safety issue: No ]
  Pain Response was defined as a two-point or greater reduction from baseline median Present Pain Intensity (PPI) score without an increased Analgesic Score (AS) or a decrease of ≥50% in the AS without an increase in the PPI score, maintained for at least 3 weeks.

• to be evaluated at screening, day 1 of every treatment cycle, end of study treatment, and in follow-up until documented progression: PSA levels
• Anti-tumor activity via Computerized Tomography / Magnetic Resonance Imaging (and bone scans, as indicated)
• Pain via an analgesic consumption score and the Present Pain Index over a one-week period
• Adverse events; laboratory abnormalities; vital signs

This is a randomized, open-label, multi-center study comparing the safety and efficacy of XRP6258 plus prednisone to mitoxantrone plus prednisone in the treatment of hormone refractory metastatic prostate cancer previously treated with a Taxotere®-containing regimen. The primary objective is overall survival. Secondary objectives include progression free survival, overall response rate, prostate-specific antigen (PSA) response/progression, pain response/progression, overall safety, and pharmacokinetics. Patients will be treated until disease progression, death, unacceptable toxicity, or for a maximum of 10 cycles. Patients will have long-term follow-up for a maximum of up to 2 years.

• Neoplasms
• Prostatic Neoplasms

• Drug: cabazitaxel (XRP6258) (RPR116258)
  25 mg/m^2 administered by intravenous (IV) route over 1 hour on day 1 of each 21-day cycle
  Other Name: Jevtana
• Drug: mitoxantrone
  12 mg/m^2 administered by intravenous (IV) route over 15-30 minutes on day 1 of each 21-day cycle
• Drug: prednisone
  10 mg daily administered by oral route

• Active Comparator: Mitoxantrone + Prednisone
  Mitoxantrone + Prednisone
  Interventions:

  • Drug: mitoxantrone
  • Drug: prednisone
• Experimental: Cabazitaxel + Prednisone
  Cabazitaxel + Prednisone
  Interventions:

  • Drug: cabazitaxel (XRP6258) (RPR116258)
  • Drug: prednisone

• Pouessel D, Oudard S, Gravis G, Priou F, Shen L, Culine S. [Cabazitaxel for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: the TROPIC study in France]. Bull Cancer. 2012 Jul-Aug;99(7-8):731-41. French.
• de Bono JS, Oudard S, Ozguroglu M, Hansen S, Machiels JP, Kocak I, Gravis G, Bodrogi I, Mackenzie MJ, Shen L, Roessner M, Gupta S, Sartor AO; TROPIC Investigators. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. Lancet. 2010 Oct 2;376(9747):1147-54.

Inclusion Criteria

1. Histologically or cytologically confirmed adenocarcinoma of the prostate that is refractory to hormone therapy and previously treated with a Taxotere®-containing regimen.
2. Documented progression of disease (demonstrating at least one visceral or soft tissue metastatic lesion, including a new lesion). Patients with non-measurable disease must have documented rising prostate-specific antigen (PSA) levels or appearance of new lesion.
3. Surgical or hormone-induced castration
4. Life expectancy > 2 months
5. Eastern Cooperative Oncology Group (ECOG) performance status 0 - 2

Exclusion criteria

1. Previous treatment with mitoxantrone
2. Previous treatment with <225 mg/m^2 cumulative dose of Taxotere (or docetaxel)
3. Prior radiotherapy to ≥ 40% of bone marrow
4. Surgery, radiation, chemotherapy, or other anti-cancer therapy within 4 weeks prior to enrollment in the study
5. Other prior malignancy, except for adequately treated superficial basal cell skin cancer, or any other cancer from which the patient has been disease-free for less than 5 years
6. Known brain or leptomeningeal involvement
7. Other concurrent serious illness or medical conditions
8. Inadequate organ function evidenced by unacceptable laboratory results

The investigator will evaluate whether there are other reasons why a patient may not participate.