| CTRI Number |
CTRI/2015/01/005385 [Registered on: 12/01/2015] Trial Registered Prospectively |
| Last Modified On: |
12/01/2015 |
| Post Graduate Thesis |
No |
| Type of Trial |
Interventional |
|
Type of Study
|
Other (Specify) [Timing of chemotherapy] |
| Study Design |
Randomized, Parallel Group Trial |
|
Public Title of Study
|
A study comparing chemotherapy given before or after radiation in patients with rectal cancer |
|
Scientific Title of Study
|
INNOVA: INterval or NeOadjuVAnt chemotherapy in rectal cancer. A phase II randomized study comparing interval versus neoadjuvant chemotherapy in magnetic resonance imaging-defined high risk rectal cancer |
| Trial Acronym |
INNOVA |
|
Secondary IDs if Any
|
| Secondary ID |
Identifier |
| U1111-1165-0578 |
UTN |
|
|
Details of Principal Investigator or overall Trial Coordinator (multi-center study)
|
| Name |
Ramakrishnan A S |
| Designation |
Additional Professor |
| Affiliation |
Cancer Institute (WIA) |
| Address |
Dept. of Surgical Oncology, Cancer Institute (WIA), Dr.S.Krishnamurthy Campus, No.18, Sardar Patel road, Guindy, Chennai
Chennai
TAMIL NADU
600036
India |
| Phone |
044-22209150 |
| Fax |
|
| Email |
ram_a_s@yahoo.com |
|
Details of Contact Person
Scientific Query
|
| Name |
Ramakrishnan A S |
| Designation |
Additional Professor |
| Affiliation |
Cancer Institute (WIA) |
| Address |
Dept. of Surgical Oncology, Cancer Institute (WIA), Dr.S.Krishnamurthy Campus, No.18, Sardar Patel road, Guindy, Chennai
Chennai
TAMIL NADU
600036
India |
| Phone |
044-22209150 |
| Fax |
|
| Email |
ram_a_s@yahoo.com |
|
Details of Contact Person
Public Query
|
| Name |
Ramakrishnan A S |
| Designation |
Additional Professor |
| Affiliation |
Cancer Institute (WIA) |
| Address |
Dept. of Surgical Oncology, Cancer Institute (WIA), Dr.S.Krishnamurthy Campus, No.18, Sardar Patel road, Guindy, Chennai
Chennai
TAMIL NADU
600036
India |
| Phone |
044-22209150 |
| Fax |
|
| Email |
ram_a_s@yahoo.com |
|
|
Source of Monetary or Material Support
|
|
|
Primary Sponsor
|
| Name |
Cancer Institute WIA |
| Address |
Dr.S.Krishnamurthy Campus, NO.18, Sardar Patel road, Guindy, Chennai-600036 |
| Type of Sponsor |
Research institution and hospital |
|
|
Details of Secondary Sponsor
|
|
|
Countries of Recruitment
|
India |
|
Sites of Study
|
| No of Sites = 1 |
| Name of Principal
Investigator |
Name of Site |
Site Address |
Phone/Fax/Email |
| Ramakrishnan A S |
Cancer Institute (WIA) |
Dept. of Surgical Oncology (GI ncology division), Cancer Institute (WIA), Dr.S.Krishnamurthy campus, No.18, Sardar Patel road, Guindy, Chennai-600036
Chennai
TAMIL NADU |
044-22209150
ram_a_s@yahoo.com |
|
|
Details of Ethics Committee
|
| No of Ethics Committees= 1 |
| Name of Committee |
Approval Status |
| Cancer Institute (WIA) Institutional Ethics Committee |
Approved |
|
|
Regulatory Clearance Status from DCGI
|
|
|
Health Condition / Problems Studied
|
| Health Type |
Condition |
| Patients |
Carcinoma Rectum, |
|
|
Intervention / Comparator Agent
|
| Type |
Name |
Details |
| Intervention |
Interval chemotherapy |
Patients will receive concurrent chemoradiation (5040cGy at a daily fractin of 180 cGy, 5 days a week)with capecitabine (825 mg/sqm) for 5-6 weeks. An MRI scan will be done on week 10. If there is stable disease or partial/ complete response, they will receive 3 cycles of interval chemotherapy (CAPOX) for 9 weeks. A restaging will be done at week 19. In the absence of metastatic disease, surgery will be performed immediately. Patient will then receive adjuvant 3 cycles of chemotherapy (CAPOX) not later than 4-8 weeks after surgery. If there is progressive disease on the MRI done on week 10, then the patients will proceed to surgery immediately and will be taken off protocolChemotherapy will consist of CAPOX regimen- intravenous oxaliplatin 130mg/m2 on Day 1 along with oral Capecitabine 2000mg/m2 per day in 2 divided doses for 14 days followed by a 7 day rest. This cycle will be repeated every 3 weeks. In Arm A, 3 neoadjuvant cycles will be given at the start of treatment and the remaining 3 adjuvant cycles will be given after surgery. |
| Comparator Agent |
Neoadjuvant chemotherapy |
Patients receive 3 cycles of neoadjuvant chemotherapy (CAPOX) for 9 weeks. At week 9, an MRI scan of the pelvis will be done to assess response followed by concurrent chemoradiation (5040 cGy at a fraction of 180cGy per day, 5 days a week)with capecitabine 825 mg/sqm for 5-6 weeks. A restaging will be done at week 19 (4 weeks after completion of chemoradiation). In the absence of metastatic disease, surgery will be done on week 21. Patient will then receive adjuvant 3 cycles of chemotherapy (CAPOX) not later than 4-8 weeks after surgery.
Chemotherapy will consist of CAPOX regimen- intravenous oxaliplatin 130mg/m2 on Day 1 along with oral Capecitabine 2000mg/m2 per day in 2 divided doses for 14 days followed by a 7 day rest. This cycle will be repeated every 3 weeks. In this arm (Arm A), 3 neoadjuvant cycles will be given at the start of treatment and the remaining 3 adjuvant cycles will be given after surgery |
|
|
Inclusion Criteria
|
| Age From |
18.00 Year(s) |
| Age To |
70.00 Year(s) |
| Gender |
Both |
| Details |
â—Histopathologically confirmed adenocarcinoma of the lower and middle third rectum, with the lower edge of the tumor within 12 cm from the anal verge
â—Age 18 to 70 years
â—ECOG performance status 0-2
â—Locally advanced tumor defined as presence of any one of the following on high-resolution thin slice (3mm) MRI:
- Involved or threatened CRM (tumor or node extends to ≤2mm of or beyond the mesorectal fascia)
- Any T3 tumor in the lower rectum (within 6 cm from anal verge), T3c or T3d in mid rectum (ie-tumor extending >5mm beyond the muscularis propria)
- Resectable T4
- T3/T4 N1 or T1-T4 N2
- Extramural vascular invasion
â—No evidence of established distant metastasis
â—Adequate haematological, liver and renal function (WBC >3 x 109/L, neutrophils >1.5 x 109/l and platelets >100 x 109/L; serum creatinine ≤1 x upper limit of normal or creatinine clearance >50ml/min; serum bilirubin <1.5 x upper limit normal and liver transaminases and alkaline phosphatase <3 x upper limit normal)
â—Normal clinical cardiovascular assessment
â—Willing and able to give informed consent and comply with treatment schedule
|
|
| ExclusionCriteria |
| Details |
â—Disease outside the mesorectal envelope (internal iliac/ lateral pelvic lymph nodes)
â—Previous radiotherapy to the pelvis
â—Previously received chemotherapy for the currently diagnosed cancer
â—Synchronous colorectal or other malignancies
â—Active stable or unstable angina, NYHA class 2 congestive cardiac failure, myocardial infarction in the past 1 year, acute coronary syndrome even if controlled, arrhythmias
â—Serious uncontrolled intercurrent illness including uncontrolled hypertension or poorly controlled diabetes mellitus
â—Patients with a history of previous malignancy in the past 5 years, excepting basal or squamous cell skin cancer or cervical carcinoma-in-situ.
â—Known HIV, HBV or HCV infection
â—Pregnant or lactating women or premenopausal women not using adequate contraception
â—Patients with any other condition or concurrent medical or psychiatric disease who, in the opinion of the investigator, is not eligible to enter the study
|
|
|
Method of Generating Random Sequence
|
Computer generated randomization |
|
Method of Concealment
|
Centralized |
|
Blinding/Masking
|
Open Label |
|
Primary Outcome
|
| Outcome |
TimePoints |
| pathological complete response (pCR) [defined as absence of any detectable residual tumor cells in the resected specimen] |
completion of surgery |
|
|
Secondary Outcome
|
| Outcome |
TimePoints |
| Frequency and severity of adverse events (AE) during chemotherapy [National Cancer Institute’s common toxicity criteria] and chemoradiation [using Radiation Therapy Oncology Group’s toxicity criteria] |
end of chemoradiation and end of chemotherapy |
| Surgical complications: intra-operative and 30-day postoperative [according to Dindo score] |
during surgery and till 30 days after surgery |
Microscopic R0 resection rate [defined as negative resection margins including circumferential margin (CRM)]
-Circumferential margin (CRM) involvement [defined as tumor ≤1mm from the inked circumferential margin]
-Tumor downstaging [defined as reduction of at least one level in T or N stage between the baseline MRI and histological stage]
-Tumor regression grade (TRG)
|
completion of surgery |
| Complicance to treatment |
at end of treatment |
|
|
Target Sample Size
|
Total Sample Size="94"
Sample Size from India="94"
Final Enrollment numbers achieved (Total)= "Applicable only for Completed/Terminated trials"
Final Enrollment numbers achieved (India)="Applicable only for Completed/Terminated trials" |
|
Phase of Trial
|
Phase 2 |
|
Date of First Enrollment (India)
|
15/01/2015 |
| Date of Study Completion (India) |
Applicable only for Completed/Terminated trials |
| Date of First Enrollment (Global) |
Date Missing |
| Date of Study Completion (Global) |
Applicable only for Completed/Terminated trials |
|
Estimated Duration of Trial
|
Years="3"
Months="0"
Days="0" |
|
Recruitment Status of Trial (Global)
|
Not Applicable |
| Recruitment Status of Trial (India) |
Not Yet Recruiting |
|
Publication Details
|
|
|
Individual Participant Data (IPD) Sharing Statement
|
Will individual participant data (IPD) be shared publicly (including data dictionaries)?
|
|
Brief Summary
|
Patients with locally advanced rectal cancers who are at a high risk of distant metastases are not exposed to systemic doses of chemotherapy until very late in the treatment schedule using the current standard of care of neoadjuvant chemoradiation followed by surgery and adjuvant chemotherapy. Hence, earlier incorporation of chemotherapy either in the neoadjuvant or interval setting may improve tumor response and as a consequence, the overall survival.
The INNOVA trial (Interval or NeOadjuVAnt chemotherapy in rectal cancer) is designed to evaluate two pre-operative regimens in locally advanced high-risk rectal cancers (neoadjuvant and interval chemotherapy with capecitabine plus oxaliplatin) in a single-center randomized open-label phase II trial. We seek to evaluate the efficacy of these two pre-operative regimens as determined by the primary end-point, pCR rate and to evaluate the toxicity of these regimens. The regimen with a better pCR rate could be considered for comparison with the current standard of care in a future randomized phase III trial. If both the regimens have an identical pCR rate, then the one with a favourable toxicity profile would be considered for further evaluation.
An optimal Simon’s two-stage design will be used to calculate sample size in order to terminate an ineffective arm early in the study. The pCR rates for the current standard of chemoradiation with capecitabine varies from 7% to 14% (14,27,55). Hence, the experimental regimens, a pCR of 5% is considered unacceptable (p0) whereas a pCR of 20% is considered acceptable (p1). In the first stage, 21 patients will be recruited in each arm. If ≤1 pCR is observed in any arm, then that arm of the study will be terminated and it will be concluded that that arm should not be pursued. If ≥2 pCR is observed in both arms, then both arms will be carried to the second stage where an additional 20 patients will be recruited in each arm. Thus, with a sample size of 41 patients per arm, the Type I error amounts to 5% and Type II error will be 10%. If ≥5 pCR is observed in any arm, then that arm will be considered suitable for further investigation. This design ensures a 90% probability of correctly selecting the more effective treatment when there is an absolute difference in the pCR rates of at least 15% between the two experimental treatment arms. If both arms have similar responses, then other factors like adverse effects, compliance and feasibility will be considered to select a regimen to pursue for further investigation. After accounting for a 15% drop-out rate, a total sample size of 94 patients (47 per arm) would be targeted. |