Phase II Study of Up-front Chemotherapy and Neo-adjuvant Short-course Radiotherapy for Resectable Rectal Carcinoma (COLORE)
Condition: Rectal Carcinoma
MeSH terms: Carcinoma; Rectal Neoplasms
Study type: Interventional
Phase: Phase 2

Summary: 
      Phase II study of up-front chemotherapy and neo-adjuvant shortcourse radiotherapy for
      resectable rectal carcinoma.

      Study Design: Phase II, open-label, single-arm, multi-centre study.

      STUDY PRODUCT,DOSE,ROUTE,REGIMEN AND DURATION OF ADMINISTRATION:

        1. Neoadjuvant Treatment (pre-operative chemo-radiotherapy regimen):

           FOLFOX4* 2 cycles (WK1+WK3) - Tomotherapy** (WK5) - FOLFOX4* 2 cycles (WK7+WK9)

           * Oxaliplatin 85 mg/m2 iv: day 1 Levofolinate 100 mg/m2 iv: day 1-2 5-fluorouracil 400
           mg/m2 iv in bolus and 600 mg/m2 iv infusion over 22h: day 1-2 Every cycle will last 2
           weeks (approximately 48 hours of treatment infusion and 12 days of rest).

           ** 25 Gy in 5 consecutive fractions, one fraction per day in 5 days on CTV (Clinical
           Target Volume) at the isodose of the 95% of the total dose. The treatment plan will be
           elaborated at the work-station dedicated to the Helicoidal Tomotherapy. The treatment
           could be planned also with linear accelerator with IGRT-IMRT technique or VMAT
           technique.

        2. Restaging (week 11)

        3. Surgery (week 12-16) with Total Mesorectal Excision (TME)

        4. End Of Treatment (week 16-32)

        5. Adjuvant therapy (The maximum interval between surgery and start of adjuvant therapy
           should be 8 weeks):

        6. FOLFOX4* 8 cycles (every 2 weeks)

      Study Duration: about 5 years. Enrollment period: 36 months. Treatment period: about 8
      months. Follow-up: 1 year.

      NUMBER OF SUBJECTs:

      · Step A: a maximum of 6 patients. 6 evaluable patients are needed to assess toxicity. If 1
      toxicity resulting in discontinuation of treatment will be observed in 6 patients, the
      treatment can be considered safe (with a confidence > 90%).

      If 2 or more toxicity resulting in discontinuation of treatment on 6 patients, the study will
      be stopped because not safe and another type of radiotherapy schedule must be designed.

      · Step B: a total of 50 patients is required to be recruited in 2 years (including patients
      enrolled in Step A).

      The goal is to achieve a proportion of at least 15% of patients with a complete pathological
      response with the new radiochemotherapeutic treatment.
    

Detailed description: 
      Title: Phase II study of up-front chemotherapy and neo-adjuvant shortcourse radiotherapy for
      resectable rectal carcinoma.

      Short Title/Acronym: COLORE

      Protocol Code: IRST154.01

      Phase: 2

      Study Design: Phase II, open-label, single-arm, multi-centre study.

      STUDY PRODUCT,DOSE,ROUTE,REGIMEN AND DURATION OF ADMINISTRATION:

        1. Neoadjuvant Treatment (pre-operative chemo-radiotherapy regimen):

           FOLFOX4* 2 cycles (WK1+WK3) - Tomotherapy** (WK5) - FOLFOX4* 2 cycles (WK7+WK9)

           * Oxaliplatin 85 mg/m2 iv: day 1 Levofolinate 100 mg/m2 iv: day 1-2 5-fluorouracil 400
           mg/m2 iv in bolus and 600 mg/m2 iv infusion over 22h: day 1-2 Every cycle will last 2
           weeks (approximately 48 hours of treatment infusion and 12 days of rest).

           ** 25 Gy in 5 consecutive fractions, one fraction per day in 5 days on CTV (Clinical
           Target Volume) at the isodose of the 95% of the total dose. The treatment plan will be
           elaborated at the work-station dedicated to the Helicoidal Tomotherapy. The treatment
           could be planned also with linear accelerator with IGRT-IMRT technique or VMAT
           technique.

        2. Restaging (week 11)

        3. Surgery (week 12-16) with Total Mesorectal Excision (TME)

        4. End Of Treatment (week 16-32)

        5. Adjuvant therapy (The maximum interval between surgery and start of adjuvant therapy
           should be 8 weeks):

        6. FOLFOX4* 8 cycles (every 2 weeks)

      Study Duration: about 5 years. Enrollment period: 36 months. Treatment period: about 8
      months. Follow-up: 1 year.

      OBJECTIVES

      Primary objectives:

      Step A: to evaluate the feasibility and safety of the chemoradiotherapy regimen.

      Step B: to evaluate the proportion of patients with pathological complete remission after
      combined radio-chemotherapy.

      Secondary objectives (of Step B):

        -  To evaluate the safety of the neo-adjuvant treatment

        -  To determine pathological down-staging

        -  To evaluate the rate of R0 resection

        -  To evaluate the sphincter saving resection rate

        -  To evaluate median disease free survival and overall survival

        -  To evaluate the correlation between biomarker, pathological response and outcome
           (auxiliary\subsidiary Biological Study)

      NUMBER OF SUBJECT:

      · Step A: a maximum of 6 patients. 6 evaluable patients are needed to assess toxicity. If 1
      toxicity resulting in discontinuation of treatment will be observed in 6 patients, the
      treatment can be considered safe (with a confidence > 90%).

      If 2 or more toxicity resulting in discontinuation of treatment on 6 patients, the study will
      be stopped because not safe and another type of radiotherapy schedule must be designed.

      · Step B: a total of 50 patients is required to be recruited in 2 years (including patients
      enrolled in Step A).

      The goal is to achieve a proportion of at least 15% of patients with a complete pathological
      response with the new radiochemotherapeutic treatment.

      STATISTICAL METHODOLOGY:

      The primary analysis will be performed on the ITT (Intention-To-Treat) population, while the
      secondary analysis will be conducted on the PP (Per Protocol) population.

      The number and percentage of treated patients undergoing grade 1 to 4 adverse events (CTC-AE,
      version 4.0) will be tabulated in the ITT and PP population. No statistical inference will be
      performed.

      Step A: Patients, tumor characteristics and toxicity events observed will be described.

      Step B: The proportion of patients with pathological Complete Response will be calculated.
      Safety profile will be analyzed. OS (Overall Survival) and DFS (Disease Free Survival) will
      be estimated with Kaplan-Meier method (Kaplan El, Meier P., J Am Stat Assoc 1958).

      No interim analysis will be performed. The 95% confidence intervals should also be provided.
    

Intervention name(s): FOLFOX4; Tomotherapy; TME (Total Mesorectal Excision)
Intervention type(s): Drug; Radiation; Procedure
Intervention description(s): FOLFOX4; Tomotherapy; TME (Total Mesorectal Excision)
Other intervention name(s): surgery
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: resectable rectal cancer; up-front chemotherapy; neo-adjuvant short course radiotherapy; short course radiotherapy