SYNOPSIS PROTOCOL N UC-0107/1602

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1 SYNOPSIS PROTOCOL N UC-0107/1602 A) TRIAL IDENTIFICATION SPONSOR PROTOCOL CODE NUMBER: UC-0107/1602 VERSION (NR & DATE): 0.1, MARCH 2016 TRIAL TITLE: Extracranial Stereotactic Body Radiation Therapy (SBRT) added to standard treatment versus standard treatment alone in solid tumors patients with 3 bone-only metastasis ABBREVIATED TITLE: STEREO-OS COORDINATING INVESTIGATOR: Dr Sébastien Thureau & Dr Jean-Christophe Faivre NUMBER OF PARTICIPATING CENTERS (ESTIMATE): 20 NUMBER OF PATIENTS: 196 B) SPONSOR IDENTIFICATION NAME: CONTACT PERSON: UNICANCER 101, rue de Tolbiac Paris Cedex 13 (France) MRS NAÏMA BONNET Project Manager R&D UNICANCER Phone: +33 (0) Fax: + 33 (0)1 n-bonnet@unicancer.fr C) TRIAL GENERAL INFORMATION INDICATION: solid tumour patients (histological proof of breast, non-small cell lung or prostate cancer) with 3 bone-only metastases MÉTHODOLOGY: open randomized multicentric phase III study PRIMARY OBJECTIVE: to evaluate the impact of SBRT on Progression-Free Survival (PFS) at 1 year in solid tumour patients with 3 bone-only metastases Synopsis Stéréo-OS -V0.2, April 2016 Page 1 / 5

2 SECONDARY OBJECTIVE(S): - Progression-Free Survival (PFS) at 2 and 3 years - Bone progression-free survival at 1, 2 and 3 years - Local control (LC) at 1, 2 and 3 years - Cancer-specific survival at 1, 2 and 3 years - Overall survival (OS) at 1, 2 and 3 years - Toxicity at 1, 2 and 3 years - Quality of life (QoL) at 1, 2 and 3 years - Variation of CTX serum, ALP - Cost-utility analysis - Cost-effectiveness analysis - Budget impact analysis DIAGNOSIS AND INCLUSION CRITERIA: - Male or female patients, - Age over 18 years and below 75-year old - Good general condition: WHO performance status 1 - Patients with solid tumour (histological proof of breast, non-small cell lung, prostate cancer) - Absence of co-morbidity contra-indicating radio-chemotherapy or surgery - Primary tumour accessible to curative-intent treatment (surgery, chemoradiation ) - Patients with 3 synchronous bone metastasis (1 to 3) as defined by NaF-PET and spinal MRI (if necessary) - Patients with 3 metachronous bone metastasis (1 to 3) as defined by NaF-PET and spinal MRI (if necessary) - Age over 18 years - No visceral metastasis as defined by FDG-PET (or F-Choline-PET for prostate cancer) and cerebral CT or MRI performed less than one month before SBRT - No previous systemic therapy for metastasis (neo- and adjuvant treatment allowed if metachronous metastasis). Prostate cancer patients remain eligible if hormonal treatment has already been initiated. Synopsis Stéréo-OS -V0.2, April 2016 Page 2 / 5

3 NON INCLUSION CRITERIA: - All bone metastasis requiring surgical treatment (spinal cord compression, fracture, ) - Symptoms requiring radiotherapy (pain ) - > 3 bone metastasis as defined by NaF-PET and spinal MRI (if spinal bone metastase on NaF- PET) - visceral metastasis on FDG-PET (F-Choline-PET for prostate cancer) - Previous cancer history within 5 years before inclusion (except basal cell carcinoma of the skin, in situ carcinoma of the uterine cervix) - Previous radiotherapy - Patient enrolled in another therapeutic trial - Pregnant women or women of child-bearing potential or breast feeding mothers, - Hypersensitivity to the active substance (FDG and NaF or F-Choline for prostate cancer) or to any of the excipients - Contraindication to MRI - Patient under protective custody or guardianship - Patient unable to comply with the specific obligations of the study (geographic, social or physical reasons) - Patient unable to understand the purpose of the study (language, etc.). PRIMARY ENDPOINT: 1-year Progression-free survival according to RECIST criteria. SECONDARY ENDPOINT(S): - Local control at 1, 2 and 3 years - Distant bone progression at 1, 3, 6 and 12 months - Cancer-specific survival at 1, 2 and 3 years - Overall survival at 1, 2 and 3 years - Toxicity at 1, 2 and 3 years (CTCAE 4.0) - Quality of life (QoL) with EQ-5D-3L, QLQ-C30, and QLQ-BM22 (specific module for bone metastases), pain score (Visual Analogis Score), KPS and pain medication (opiods or no opioids treatments) - Variation of serum CTX and ALP at 1, 3, 6 and 12 months - Costs assessment - QALY calculation (based on the EQ-5D questionnaire) - Incremental cost-effectiveness ratios (ICERs) - Target and prevalent populations estimations - Cost savings - Overcosts Synopsis Stéréo-OS -V0.2, April 2016 Page 3 / 5

D) THERAPEUTICS REGIMENS THERAPEUTIC REGIMENS: Open randomized multicentric phase III study (ratio 1:1) One hundred ninety-six patients will be randomized between 2 arms: Control group (98 patients):

4 D) THERAPEUTICS REGIMENS THERAPEUTIC REGIMENS: Open randomized multicentric phase III study (ratio 1:1) One hundred ninety-six patients will be randomized between 2 arms: Control group (98 patients): conventional curative treatment to the primary tumor (surgery / radiotherapy / systemic treatment without SBRT to the bone metastases Experimental group (98 patients): conventional curative treatment to the primary tumor and SBRT to the bone metastases. Two SBRT schemes are allowed: 9Gy x 3 fractions or 7Gy x 5 fractions. In case of synchronous metastasis, the patients will be randomized after completion of the primary tumor treatment. The randomization will be stratified on: - Date of metastasis (synchronous vs. metachronous) - Primary tumor site (breast vs. prostate vs. non-small cell lung cancer) Synopsis Stéréo-OS -V0.2, April 2016 Page 4 / 5

5 E) STATISTICAL ANALYSIS PLAN REQUIRED NUMBER OF PATIENTS TO BE SCREENED / INCLUDED: Primary endpoint will be the 1-year Progression Free Survival (PFS). In the control arm, the 1-year PFS probability is expected to be 30%, given the considered population. In the experimental arm with SBRT, we expect an absolute increase of 20%, i.e. a 50% 1-year PFS probability. According to Freedman s method (Stat in Med, 1982), accepting a two-tailed type I error of 5% and a 80% power (type II error of 20%), 178 patients (2 X 89) have to be recruited and 106 events to be observed for the primary analysis. Assuming a 10% withdrawal rate, a total of 196 patients will be included. STATISTICAL ANALYSIS: The primary analysis will take place when 106 events have been observed. This analysis will use the logrank test, stratified on the two stratification factors (date of metastases and primary tumor site). The hazard ratio will be given with its 95% confidence interval. Cox regression model will be used to perform a sensitivity analysis taking into account the usual prognostic factors. A secondary analysis will also be performed, using the Fine and Gray model in order to take into account the competing risks (relapse in the bone, relapse in another site, death), and so to analyse the impact of the different PFS events on the trial results. Other secondary analyses will use the logrank test or the Cox model when appropriate. A p value <= 0.05 will be considered as statistically significant. F) TRIAL DURATIONS INCLUSION PERIOD : 2 YEARS FOLLOW-UP: 3 YEARS DURATION UNTIL PRIMARY ENDPOINT EVALUATION: 3 YEARS OVERALL TRIAL DURATION (INCLUDING FOLLOW-UP): 5 YEARS Synopsis Stéréo-OS -V0.2, April 2016 Page 5 / 5

SYNOPSIS PROTOCOL AFU-GETUG 20/0310

SYNOPSIS PROTOCOL AFU-GETUG 20/0310 A) IDENTIFICATION OF THE CLINICAL TRIAL SPONSOR CODE NUMBER: AFU-GETUG 20/0310 VERSION AND DATE: VERSION DATED MAY, 05 TH 2011 TITLE OF TRIAL: Phase III randomised trial