Phase II Study of Up-front Chemotherapy and Neo-adjuvant Short-course Radiotherapy for Resectable Rectal Carcinoma
Overview
- Phase
- Phase 2
- Intervention
- FOLFOX4
- Conditions
- Rectal Carcinoma
- Sponsor
- Istituto Scientifico Romagnolo per lo Studio e la cura dei Tumori
- Enrollment
- 52
- Locations
- 2
- Primary Endpoint
- Toxicity events
- Status
- Completed
- Last Updated
- last year
Overview
Brief 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:
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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.
-
Restaging (week 11)
-
Surgery (week 12-16) with Total Mesorectal Excision (TME)
-
End Of Treatment (week 16-32)
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Adjuvant therapy (The maximum interval between surgery and start of adjuvant therapy should be 8 weeks):
-
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.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Patients with histologically or cytologically confirmed diagnosis of adenocarcinoma of the mid-low rectum (within 12 cm from the anal verge)
- •Stage: lowT2N0, T2N+M0, T3-4 N-/+M0 (N+ = ≥ 3 nodes \>0,5 cm diameter or ≥ 1 nodes \> 1 cm diameter)
- •Age ≥18 and ≤ 80 years
- •ECOG performance status 0-1
- •Patients must have normal organ and marrow function as defined below:
- •Leukocytes ≥ 3,000/mL
- •Absolute neutrophil count ≥ 1,500/mL
- •Platelets ≥ 100,000/mL
- •Total bilirubin ≤ 1.5 X ULN
- •AST (SGOT)/ALT (SGPT) ≤ 2.5 X ULN
Exclusion Criteria
- •Metastatic disease
- •Patients who have had any chemotherapy or radiotherapy prior to entering the study
- •Acute or sub-acute gastrointestinal occlusion
- •Participation in another clinical trial, with any investigational agent within 30 days prior the study screening
- •Other known malignant neoplastic diseases in the patient's medical history with a disease-free interval of less than 5 years (except for previously treated basal cell carcinoma, superficial bladder tumor and in situ carcinoma of the uterine cervix)
- •History of allergic reactions attributed to compounds of similar chemical or biological composition to drugs used in the study
- •Uncontrolled concomitant illness, including but not limited to: ongoing or active infections; congestive heart failure; unstable angina pectoris; cardiac arrhythmia; or psychiatric illness/social situations that would limit compliance to study requirements
Arms & Interventions
Single Arm
* Neoadjuvant therapy: FOLFOX4 2 cycles + Tomotherapy + FOLFOX4 2 cycles * Surgery * Adjuvant therapy: FOLFOX4 8 cycles * TME (Total Mesorectal Excision)
Intervention: FOLFOX4
Single Arm
* Neoadjuvant therapy: FOLFOX4 2 cycles + Tomotherapy + FOLFOX4 2 cycles * Surgery * Adjuvant therapy: FOLFOX4 8 cycles * TME (Total Mesorectal Excision)
Intervention: Tomotherapy
Single Arm
* Neoadjuvant therapy: FOLFOX4 2 cycles + Tomotherapy + FOLFOX4 2 cycles * Surgery * Adjuvant therapy: FOLFOX4 8 cycles * TME (Total Mesorectal Excision)
Intervention: TME (Total Mesorectal Excision)
Outcomes
Primary Outcomes
Toxicity events
Time Frame: 15 months
6 evaluable patients are needed to assess toxicity. If one toxicity resulting in discontinuation of treatment will be observed in 6 patients, we can conclude that the true probability of toxicity is less than 45% with a confidence \>90% and the treatment can be considered safe. If 2 or more toxicity resulting in discontinuation of treatment on 6 patients we can conclude that the true probability of toxicity is greater than 10% with a confidence \>90%, and the study will be stopped because not safe and another type of radiotherapy schedule must be designed.
The Simon optimal two-stage design (Richard Simon, Controlled Clinical Trials 1989)
Time Frame: 15 months
It's a two-stage design that use for P1(the proportion of pCR with the new radio-chemotherapeutic treatment) - P0 (the expected proportion of pCR) =0.15. It's used to understand if a treatment is active or not.
Complete pathological response (pCR)
Time Frame: 3 years
According to pathological response criteria, a total regression is considered a complete response. This parameter is used to understand if a treatment is active or not ( if at least 7 patients out of 50 enrolled will achieve a pCR, the treatment could be considered active).
Secondary Outcomes
- Overall survival time (OS)(5 years)
- Disease-free survival time (DFS)(5 years)
- Objective tumor response rate (ORR)(5 years)
- Pathological Downstaging Rate(5 years)
- Intention-to-treat (ITT) population(5 years)