Logistical problems impacting the speed of enrolment

Randomized phase III multicenter study investigating the role of letrozole in heavily pretreated recurrent ovarian cancer.

This is a randomized, open-label, phase III, multicenter, global study evaluating the efficacy and safety of Letrozole in heavily pretreated recurrent ovarian cancer patients in comparison to physician' choice chemotherapy.

Subjects who meet all the inclusion criteria and none of the exclusion criteria will be randomized in a 1:1 ratio to one of the two arms, as follow:

Arm A: Letrozole 1 tablet (2,5 mg) orally once a day in 28-day cycles Arm B: Pegylated Liposomal Doxorubicin 40 mg/m2 d1q28 or Topotecan 4 mg/m2 d1,8,15q28 or Gemcitabine 1000 mg/m2 d1,8,15q28 or Paclitaxel 80 mg/m2 d1,8,15q28 In case of objective response and acceptable toxicity, no maximum number of cycles of treatment is defined.

The aim of the study is to assess the activity of Letrozole in women with recurrent epithelial ovarian cancer, heavily pretreated.

Inclusion Criteria:

• Female of 18 years of age or older

• Histologically or cytologically documented invasive epithelial ovarian cancer, primary peritoneal carcinoma, or fallopian tube cancer

• Platinum resistant or refractory disease (patients who did not respond to last platinumbased therapy or with last relapse occurred < 6 months from the last dose of platinum) or patients not amenable of platinum treatment

• >3 previous chemotherapy lines

• ECOG performance status 0 -2

• Measurable and evaluable disease according to RECIST criteria confirmed by radiological imaging: at least one lesion of ≥ 1.0 cm for non-lymph nodes or ≥ 1.5 cm in short-axis diameter for lymph nodes at CT scan (Subjects with isolated rising CA-125 without radiologically visible disease are excluded)

• Left Ventricular Ejection Fraction (LVEF) ≥ institutional lower limit normal

• Estimated life expectancy ≥ 16 weeks

• Adequate functions evidenced by:

  • Hemoglobin ³10.0 g/dl
  • Absolute neutrophil count ³1.5 x 109/L
  • White blood cells >3x109/L
  • Platelet >100 x109/L
  • AST and ALT £ 2.5 x Upper limit of normal, unless liver metastasis, in which case AST and ALT < or = 5 x Upper limit of normal will be accepted
  • Bilirubin ≤ 1.5 times the upper limit of normal (ULN)
  • Estimated glomerular filtration ³ 60mL/min using the Cockcroft-Gault equation.

• Patient able to comply with the treatment

• Evidence of not pregnancy status as documented by a negative beta-human chorionic gonadotropin (ß-hCG) test

• Not breastfeeding women

• Patients with child-bearing potential using (or willing to use) effective contraception during treatment and 3 months ahead unless they are postmenopausal (at least 12 months consecutive amenorrhea, in the appropriate age group and without other known or suspected cause), or have been sterilized surgically.

• Comprehension and signature of the informed consent

Exclusion Criteria:

• Subjects with borderline ovarian cancer
• Subject with low malignant potential tumors
• Less than 3 lines of previous therapies
• Platinum sensitive disease (last relapse occurred > 6 months from the last dose of platinum)
• Less than 4 weeks from last dose of therapy with any investigational agent, or chemotherapy
• History of another neoplastic disease (except basal cell carcinoma or cervical carcinoma in situ adequately treated) unless in remission for 3 years or longer
• Breastfeeding women
• Pregnant women
• Prior therapy with letrozole.
• Severe osteoporosis documented by BMD (Bone Mineral Density) T-score ≤ -2.5 with existing fragility fracture(s)
• Patients with a known hypersensitivity to Paclitaxel , PLD, Topotecan, Gemcitabine or Letrozole or any case of severe toxicity related to them. Also Patients with a known hypersensitivity to any of the ingredients or excipients of the IMPs (e.g. macrogolglycerol ricinoleate (polyoxyl castor oil), ethanol, anhydrous, citric acid, anhydrous, sodium chloride hydrochloric acid, mannitol, sodium acetate, sodium hydroxide, tartaric acid, lactose monohydrate, maize starch, hypromellose Type 2910, cellulose microcrystalline, sodium starch glycolate type A, colloidal anhydrous silica, magnesium stearate, hypromellose 6 cp E464, titanium dioxide E171, Iron oxide yellow E172, Macrogol 400, talc E553b)
• Prior resistance to Paclitaxel, PLD, Topotecan, Gemcitabine
• Patients with active hepatic disease (HCV or HBV infections), hepatic severe impairment or cirrhosis
• Bowel obstruction, sub-occlusive disease, prior gastrectomy, symptomatic brain metastases.
• Myocardial infarct within six months before enrolment , NYHA Class II or worse heart failure, unstable angina, serious cardiac arrhythmia or cardiac arrhythmia requiring treatment.
• Any serious concomitant illness requiring treatment
• Pre-existing peripheral neuropathy > CTCAE Grade 2.
• Concomitant use of strong CYP3A4 inhibitors (e.g. ketoconazole, itraconazole, voriconazole, ritonavir, clarithromycin, and telithromycin) or strong CYP2A6 inhibitors (e.g. methoxsalen) because they may increase exposure to letrozole.
• Concomitant use of inducers of CYP3A4 (e.g. phenytoin, rifampicin, carbamazepine, phenobarbital, and St. John's Wort) which may reduce exposure to letrozole.
• Concomitant use of medicinal products with a narrow therapeutic index that are substrates for CYP2C19 (e.g. phenytoin, clopidrogel) that may have their systemic serum concentrations altered by letrozole.