RANDOMIZED PHASE II STUDY OF NABPACLITAXEL, IN RECURRENT ADVANCED OR METASTATIC CERVICAL CANCER MITO CER-NAB Enrica Mazzoni, MD Medical Oncology & Breast Unit Perrino Hospital, Brindisi

MITO - 23 Recurrent advanced or metastatic carcinoma of the uterine cervix Recurrent advanced or metastatic carcinoma of the uterine cervix II-III line chemotherapy Treatment physician choice: - Topotecan 4 mg/mq d1,8,15 q 28 - Weekly Paclitaxel 80 mg/mq d1,8,15 q28 - -Gemcitabine 1000 mg/mq gg1,8,15 q28 - -Weekly Cisplatin 30 mg/mq - -Carboplatin AUC 5 g 1 q 21 II-III line chemotherapy Treatment physician choice: - Topotecan 4 mg/mq d1,8,15 q 28 - Weekly Paclitaxel 80 mg/mq d1,8,15 q28 - -Gemcitabine 1000 mg/mq gg1,8,15 q28 - -Weekly Cisplatin 30 mg/mq - -Carboplatin AUC 5 g 1 q 21 Randomized phase II Nab-paclitaxel 125 mg/mq d1,8,15 q 28 R 1:1 STRATIFICATION CRITERIA: PS (0 vs 1 vs2) PFI ( 6 months) number of previous platinum-based (1 vs 2 vs 3) previous taxanes-based treatment (yes/no) study design

Primary: Progression Free Survival Rates (PFR) at 6 months. Secondary : Overall Survival (OS), Progresion free survival (PFS) Safety profile. Objective Response Rate (ORR), Correlation between serum SPARC levels and response to nab-paclitaxel treatment. end points

Patients with histologically confirmed advanced or metastatic, FIGO stage IIB-IV, carcinoma (squamous or not) of the uterine cervix. Female patients ≥18 years of age. At least previous chemotherapy platinum-based (also with radiotherapy concomitant to the pelvis). Previous treatment with taxanes is allowed. Patients not candidate to further platinum-based treatment because PFI<6 months (“platinum-resistant”) or already treated with 2 platinum- based therapy lines. Measurable disease by RECIST 1.1 ECOG Performance Status of 0–2. Signed informed consent. Life expectancy of at least 12 weeks. Adequate bone marrow function: ANC: > 2,0 x 109/L, or platelet count >100 x 109/L, Haemoglobin > 10 g/dL. Adequate liver and renal function: serum total bilirubin < 1,2 mg/dL, serum creatinin < 1,5 mg/dL. inclusion criteria

Grade 2, or more, residual peripheral neurotoxicity (CTCAE v3.0) and any ongoing grade 2 toxicity associated with prior anticancer therapy. Another primary malignancy within the past five years (except for non- melanoma skin cancer and cervical carcinoma in situ). Clinically significant cardiovascular disease, congestive heart failure. Symptomatic brain or other central nervous system metastases. Serious active infection or metabolic disease. Positive serum pregnancy test within 7 days prior to study enrollment. Serious cardiac arrhythmia requiring medication. Myocardial infarction within 12 months. Unability to comply with treatment and follow up assessments and procedure. exclusion criteria

MITO - 23 statistical analysis Study Design Randomised 1:1 phase II trial Primary endpoint: PFR at 6 mos Sample size Literature data PFR 6 mos = 25% PFR 6 mos = 45% Two-side error alpha = 0,2 Statistical power of 80% Sample Size = 102 patients in 2 years

Failed first-line cytotoxic drug treatment 35 pts 125 mg/m(2) IV over 30 minutes on days 1, 8, and 15 of each 28 day cycle 10 ( 28.6%; CI 14.6%-46.3%) = PR 15 patients (42.9%) = SD

PFR at 6 months = 50% Median PFS = 5.0 months Median OS = 9.4 months

RANDOMIZED PHASE II STUDY OF NABPACLITAXEL, IN RECURRENT ADVANCED OR METASTATIC CERVICAL CANCER MITO CER-NAB Enrica Mazzoni, MD Medical Oncology & Breast Unit Perrino Hospital, Brindisi