Prevention of Sagopilone-induced Neurotoxicity With Acetyl-L-Carnitine (ALC)

• Efficacy of ALC: incidence of neuropathy of grade 3 or 4, time to onset of neuropathy, duration of neuropathy. [ Time Frame: Start of treatment to safety Follow-up ] [ Designated as safety issue: Yes ]
• Efficacy of ALC: Percentage of discontinuations due to neuropathy. [ Time Frame: Start of treatment to safety Follow-up ] [ Designated as safety issue: No ]
• Safety of Sagopilone in combination with ALC. [ Time Frame: Baseline to Safety follow-up ] [ Designated as safety issue: Yes ]
• Efficacy of Sagopilone: 'best overall response' according to modRECIST criteria [ Time Frame: Start treatment to End of Treatment ] [ Designated as safety issue: No ]
• Efficacy of Sagopilone: 'best overall response' according to CA-125 or PSA response [ Time Frame: Start treatment to End of Treatment ] [ Designated as safety issue: No ]
• Efficacy of Sagopilone: Time to disease progression, Progression-free survival [ Time Frame: Start treatment to Progression or Death ] [ Designated as safety issue: No ]
• Efficacy of Sagopilone: Duration of response [ Time Frame: Start treatment to Progression or Death ] [ Designated as safety issue: No ]
• Efficacy of Sagopilone: WHO performance status. [ Time Frame: Screening to end of Treatment ] [ Designated as safety issue: No ]
• Pharmacokinetic: Sagopilone concentrations (optional) [ Time Frame: Day 1,2,3,5,15 of cycle 1 and day2 ] [ Designated as safety issue: No ]
• Pharmacokinetic: ALC concentrations [ Time Frame: radomisation, day 1 of cycle 1 and 2 ] [ Designated as safety issue: No ]
• Pharmacogenomics (optional): in tumor tissue, blood and ascites [ Time Frame: Blood sample at screening, tissue sample and ascites whenever available ] [ Designated as safety issue: No ]

• Efficacy of ALC: incidence of neuropathy of grade 3 or 4, time to onset of neuropathy neuropathy, duration of neuropathy. [ Time Frame: From day 1 of cycle 1 until safety follow up visit. ] [ Designated as safety issue: Yes ]
• Efficacy of ALC: Percentage of discontinuations due to neuropathy. [ Time Frame: From day 1 of cycle 1 until end of treatment visit. ] [ Designated as safety issue: No ]
• Safety of Sagopilone in combination with ALC. [ Time Frame: At screening, randomization, day 1 of each course and EOT, in addition AE monitoring from time of Informed Consent to either 28-32 days after last tablet. ] [ Designated as safety issue: Yes ]
• Efficacy of Sagopilone: 'best overall response' according to modRECIST criteria [ Time Frame: Screening, day 15-21 of course 2, day 15-21 of course 4, day 15-21 of course 6 and at EOT ] [ Designated as safety issue: No ]
• Efficacy of Sagopilone: 'best overall response' according to CA-125 or PSA response [ Time Frame: Screening, day 15 of course 1 and 2, from course 3 onward between day 15-21 and at EOT ] [ Designated as safety issue: No ]
• Efficacy of Sagopilone: Time to disease progression, Progression-free survival [ Time Frame: Randomization until end of treatment visit ] [ Designated as safety issue: No ]
• Efficacy of Sagopilone: Duration of response [ Time Frame: Day 1 of course 1 until end of treatment visit ] [ Designated as safety issue: No ]
• Efficacy of Sagopilone: WHO performance status. [ Time Frame: Screening, day 1 of all 6 courses and EOT ] [ Designated as safety issue: No ]
• Pharmacokinetic: Sagopilone concentrations (optional) [ Time Frame: Day 1, 2, 3, 5, 15 of cycle 1 and day 1 of cycle 2 ] [ Designated as safety issue: No ]
• Pharmacokinetic: ALC concentrations [ Time Frame: Randomisation, day 1 of cycle 1 and 2 ] [ Designated as safety issue: No ]
• Pharmacogenomics (optional): in tumor tissue, blood and ascites [ Time Frame: Blood sample at screening, tissue sample and ascites whenever available ] [ Designated as safety issue: No ]

This study investigates the safety and efficacy of Acetyl-L-Carnitine and compares it to the safety and efficacy of a placebo (inactive) tablet in the prevention of Sagopilone-induced peripheral neuropathy. Patients will receive intravenous infusion of sagopilone for 3 hours on day 1 of a 3-weeks cycle. Treatment with Sagopilone will be given as long as the patient is benefitting. In addition patients will receive ALC or placebo, starting 1 week before first sagopilone infusion and ending 30-33 days after the last infusion with sagopilone. Safety will be determined by laboratory and other evaluations. Efficacy of ALC will be determined by the incidence of all grades of peripheral neuropathy with the results of a patient questionnaire. Efficacy of the combination of ALC and Sagopilone will be determined by the tumor response.

• Prostate Cancer
• Ovarian Cancer

• Drug: Sagopilone 16 mg/m^2 i.v., Acetyl-L-Carnitine (ALC) 1000 mg tid, HRPC only: Prednisone or Prednisolone 5 mg bid
  Subjects will receive intravenous (i.v.) infusion of Sagopilone for 3 hours on day 1 of a 3-weeks cycle. In addition, subjects will receive Acetyl-L-Carnitine (ALC) 1000 mg tid. Treatment with Sagopilone and ALC will be continued as long as there is benefit. Subjects with HRPC will also receive Prednisone or Prednisolone 5 mg bid, throughout the treatment with Sagopilone.
• Drug: Sagopilone 16 mg/m^2 i.v. and placebo 1000 mg tid, HRPC only: Prednisone or Prednisolone 5 mg bid
  Subjects will receive intravenous (i.v.) infusion of Sagopilone for 3 hours on day 1 of a 3-weeks cycle. Treatment will be continued as long as there is benefit. In addition, subjects will receive 21 weeks of placebo 1000 mg tid. After all patients have completed 6 cycles of treatment, an analysis will be performed to see whether ALC was better than placebo. If this is the case, patients still under placebo treatment will be offered to switch to ALC. Subjects with HRPC will also receive Prednisone or Prednisolone 5 mg bid, throughout the treatment with Sagopilone.

• Experimental: Arm 1
  Intervention: Drug: Sagopilone 16 mg/m^2 i.v., Acetyl-L-Carnitine (ALC) 1000 mg tid, HRPC only: Prednisone or Prednisolone 5 mg bid
• Placebo Comparator: Arm 2
  Intervention: Drug: Sagopilone 16 mg/m^2 i.v. and placebo 1000 mg tid, HRPC only: Prednisone or Prednisolone 5 mg bid

Inclusion Criteria:

• Males or females aged >/= 18 years
• Epithelial ovarian, peritoneal cavity or Fallopian tube cancer (except mucinous or clear cell tumors) or Adenocarcinoma of the prostate
• At least 1 unidimensional measurable lesion (suitable for RECIST evaluation) or for patients without measurable disease, CA 125 levels >/= 2 times the upper limit of normal (ULN) within 3 months and confirmed within 2 weeks prior to first infusion (ovarian cancer) or PSA value >/= 5 ng/mL (HRPC).
• Progression of disease (HRPC) despite adequate androgen-inhibiting hormone therapy.
• Progression of disease (Ovarian Cancer) or symptomatic relapse after previous therapy (elevated CA125 levels alone are insufficient for inclusion) WHO performance status 0 to 1
• No clinical residual neuropathy (CTCAE Grade 0 at baseline)
• Adequate recovery from previous surgery, radiation, and chemotherapy (excluding alopecia)
• Adequate function of major organs and systems.
• Survival expectation =3 months

• Histologically or cytologically proven:

  1. Epithelial ovarian, peritoneal cavity or Fallopian tube cancer (except mucionous cell tumors or clear cell tumors that have a clear cell component of >33%)

Exclusion Criteria:

• Symptomatic brain metastases requiring whole- brain irradiation
• Any concomitant malignancy: the following exceptions are allowed: Non-melanoma skin cancer, Carcinoma in situ of the cervix, Malignancy with definitive treatment >/= 5 years ago without relapse.
• Diabetes mellitus (even if controlled only by special diet)
• History of chronic hepatitis B or C, or known HIV infection
• Seizure disorder requiring medication (such as steroids or anti-epileptics)
• Inability to swallow oral medications
• Prior treatment with epothilones
• Concomitant use of neurotoxic drugs
• Concomitant use of compounds that have potentially positive effects towards symptoms of neuropathy