- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT03043729
mFOLFOX6 vs. mFOLFOX6 + Aflibercept as Neoadjuvant Treatment in MRI-defined T3-rectal Cancer
mFOLFOX6 vs. mFOLFOX6 + Aflibercept as Neoadjuvant Treatment in MRI-defined T3-rectal Cancer: a Randomized Phase-II-trial
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
Study Type
Enrollment (Actual)
Phase
- Phase 2
Contacts and Locations
Study Locations
-
-
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Mannheim, Germany, 68167
- Tagestherapiezentrum am ITM & III. Med. Klinik
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
- Age ≥ 18 years on day of signing informed consent
- Signed and dated informed consent, and willing and able to comply with protocol requirements
- WHO/ECOG Performance Status (PS) 0-1
- Diagnosis of rectal adenocarcinoma
- Candidate for sphincter-sparing surgical resection prior to neoadjuvant therapy according to the primary surgeon, i.e. no patient will be included for whom surgeon indicates need for abdomino-perineal resection (APR) at baseline.
Clinical staging is based on the combination of the following assessments:
- Physical examination by the primary surgeon
- CT scan of the chest/abdomen
- Pelvic MRI
- Rigid rectoscopy / endoscopic ultrasound (ERUS).
- Both examinations (i.e. MRI and ERUS) are mandatory.
The tumor has to fulfill the following criteria:
- No symptomatic bowel obstruction
- Locally advanced rectal and rectosigmoid cancer, i.e. lower border of tumor > 5 cm and < 16 cm from anal verge as determined by rigid rectoscopy
MRI criteria:
- Lower border of tumor below a line defined by promontorium and symphysis, regardless of the criterion "< 16 cm from anal verge as determined by rigid rectoscopy".
- No evidence that tumor is adjacent to (defined as within 2 mm of) the mesorectal fascia on MRI (i.e. CRM > 2 mm)
- Only T3-tumors are included, i.e infiltration into perirectal fat < 10 mm provided CRM > 2 mm
- Note: MRI criteria are used for the definition of T3 tumor (i.e. exclusion of T2 and T4 situation).
Hematological status:
- Neutrophils (ANC) ≥ 2 x 10^9/L
- Platelets ≥ 100 x 10^9/L
- Hemoglobin ≥ 9 g/dL (previous transfusion of packed blood cells allowed)
Adequate renal function:
- Serum creatinine level ≤ 1.5 x upper limit normal (ULN) or ≤ 1.5 mg/dl
- Creatinine clearance ≥ 30 ml/min
Adequate liver function:
- Serum bilirubin ≤ 1.5 x upper limit normal (ULN)
- Alkaline phosphatase < 3 x ULN
- AST and ALT < 3 x ULN
- Proteinuria < 2+ (dipstick urinalysis) or ≤ 1 g/24hour or ≤ 500mg/dl
- Regular follow-up feasible
- For female patients of childbearing potential, negative pregnancy test within 1 week (7 Days) prior of starting study treatment
- Female patients of childbearing potential (i.e. did not undergo surgical sterilization - hysterectomy, bilateral tubal ligation, or bilateral oophorectomy - and is not post-menopausal for at least 24 consecutive months) must commit to using high effective and appropriate methods of contraception until at least 6 months after the end of study treatment such as combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation, progestogen-only hormonal contraception associated with inhibition of ovulation, intrauterine device (IUD), intrauterine hormone-releasing system (IUS), bilateral tubal occlusion, vasectomized partner, sexual abstinence. If an oral contraception is used, a barrier method of contraception (e.g. male condom, female condom, cervical cap, diaphragm, contraceptive sponge) has to be applied additionally
- Fertile male patients with a partner of childbearing potential must commit to using high effective and appropriate methods of contraception (details see above) until at least 9 months after the end of study treatment.
Exclusion Criteria:
- Distant metastases (CT scans of thorax and abdomen are mandatory)
- cT2 and cT4 tumors (defined by MRI criteria)
- Exclusion of potentially compromised CRM as defined by MRI criteria (i.e. > 2 mm distance from CRM)
- Prior antineoplastic therapy for rectal cancer
- History or evidence upon physical examination of CNS metastasis
- Uncontrolled hypercalcemia
- Pre-existing permanent neuropathy (NCI-CTCAE grade ≥ 2)
- Uncontrolled hypertension (defined as systolic blood pressure > 150 mmHg and/or diastolic blood pressure > 100 mmHg), or history of hypertensive crisis, or hypertensive encephalopathy
- Concomitant protocol unplanned antitumor therapy (e.g. chemotherapy, molecular targeted therapy, immunotherapy, radiotherapy)
- Treatment with any other investigational medicinal product within 28 days prior to study entry
- Known dihydropyrimidine dehydrogenase (DPD) deficiency
- Treatment with CYP3A4 inducers unless discontinued > 7 Days prior to randomization
Any of the following in 3 months prior to inclusion:
- Grade 3-4 gastrointestinal bleeding
- Treatment resistant peptic ulcer disease
- Erosive esophagitis or gastritis
- Infectious or inflammatory bowel disease
- Diverticulitis
- Any active infection within 2 weeks prior to study inclusion
- Vaccination with a live, attenuated vaccine within 4 weeks prior to the first administration of the study medication
Other concomitant or previous malignancy, except:
- Adequately treated in-situ carcinoma of the uterine cervix
- Basal or squamous cell carcinoma of the skin
- Cancer in complete remission for > 5 years
- Any other serious and uncontrolled non-malignant disease, major surgery or traumatic injury within the last 28 days prior to study entry
- Pregnant or breastfeeding women
- Patients with known allergy to any constituent to study drugs
- History of myocardial infarction and/or stroke within 6 months prior to randomization, NYHA class III and IV congestive heart failure
- Severe renal insufficiency (creatinin clearance < 30 ml/min)
- Bowel obstruction
- Contra-indication to the assessment by MRI
- Involvement in the planning and/or conduct of the study (applies to both Sanofi staff and/or staff of Sponsor and study site)
- Patient who might be dependent on the sponsor, site or the investigator
- Patient who has been incarcerated or involuntarily institutionalized by court order or by the authorities § 40 Abs. 1 S. 3 Nr. 4 AMG
- Patients who are unable to consent because they do not understand the nature, significance and implications of the clinical trial and therefore cannot form a rational intention in the light of the facts [§ 40 Abs. 1 S. 3 Nr. 3a AMG].
Study Plan
How is the study designed?
Design Details
- Primary Purpose: TREATMENT
- Allocation: RANDOMIZED
- Interventional Model: PARALLEL
- Masking: NONE
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
ACTIVE_COMPARATOR: Arm A
6 cycles chemotherapy with Oxaliplatin 85 mg/m^2 and Leucovorin 350 mg/m^2 i.v. as 2h infusion on Day 1 and 5-FU 400 mg/m^2 i.v. as bolus on Day 1 and 2400 mg/m^2 as 46 h infusion q2w followed by surgery 4 weeks after last neoadjuvant chemotherapy treatment
|
Oxaliplatin 85 mg/m^2, as 2h infusion on Day 1 (Arm A + Arm B)
5-FU 400 mg/m^2 i.v. as bolus on Day 1 and 2400 mg/m^2 as 46 h infusion q2w (Arm A + Arm B)
Leucovorin 350 mg/m^2 i.v. as 2h infusion on Day 1 (Arm A + Arm B)
|
EXPERIMENTAL: Arm B
6 cycles chemotherapy with Oxaliplatin 85 mg/m^2 and Leucovorin 350 mg/m^2 i.v. as 2h infusion on Day 1 and 5-FU 400 mg/m^2 i.v. as bolus on Day 1 and 2400 mg/m^2 as 46 h infusionq2w + Aflibercept 4 mg/kg BW i.v. on Day 1 q2w (6th cycle without Aflibercept) followed by surgery 4 weeks after last neoadjuvant chemotherapy treatment
|
Oxaliplatin 85 mg/m^2, as 2h infusion on Day 1 (Arm A + Arm B)
5-FU 400 mg/m^2 i.v. as bolus on Day 1 and 2400 mg/m^2 as 46 h infusion q2w (Arm A + Arm B)
Leucovorin 350 mg/m^2 i.v. as 2h infusion on Day 1 (Arm A + Arm B)
Aflibercept 4 mg/kg BW i.v. on Day 1 q2w (Arm B, Cycles 1 to 5)
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Pathologic complete response (pCR)
Time Frame: 20 weeks
|
number of patients with a pCR finding divided by the number of patients in the analysis set pCR will be assessed in a standardized manner independently by a central pathology
|
20 weeks
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Dose intensities of study medication
Time Frame: 12 weeks
|
The dose intensities of study medication will be calculated over the whole study duration and will be summarized descriptively by summary statistics.
|
12 weeks
|
Type, incidence and severity of AEs, SAEs
Time Frame: 20 weeks
|
AEs will be coded according to the NCI-CTC Criteria Version 4.03.
For the analysis, all AEs will be classified as related and not related.
AEs will be summarized by presenting the number and percentages of patients having any AE and having an AE in each NCI-CTC category.
Summaries will also be presented for AEs by severity and relationship to study medication.
Tables will be broken down by study arm.
All deaths and serious adverse events will be listed and briefly described.
|
20 weeks
|
Dose reduction or discontinuation of study drug due to adverse events
Time Frame: 20 weeks
|
The dose intensities of study medication will be calculated over the whole study duration and will be summarized descriptively by summary statistics.
|
20 weeks
|
Rate of treatment discontinuation due to toxicity
Time Frame: 20 weeks
|
Summaries will also be presented for AEs by severity and relationship to study medication. Tables will be broken down by study arm. All deaths and serious adverse events will be listed and briefly described. |
20 weeks
|
Type, incidence and severity of laboratory abnormalities
Time Frame: 20 weeks
|
For relevant laboratory parameters, the distribution over time as well as changes from randomization will be calculated and analyzed descriptively.
|
20 weeks
|
Rate of patients with R0-wide resection (according to CRM definitions in S3 guideline-Version 1.1 August 2014)
Time Frame: 20 weeks
|
The R0- and R1 resection as well as downstaging and downsizing using a standardized regression grading (Dworak regression grading) will be analyzed descriptively by means of frequencies and percentages.
|
20 weeks
|
Rate of patients with R0-narrow resection (according to CRM definitions in S3 guideline-Version 1.1 August 2014)
Time Frame: 20 weeks
|
The R0- and R1 resection as well as downstaging and downsizing using a standardized regression grading (Dworak regression grading) will be analyzed descriptively by means of frequencies and percentages.
|
20 weeks
|
Rate of patients with R1 resection (according to CRM definitions in S3 guideline-Version 1.1 August 2014)
Time Frame: 20 weeks
|
The R0- and R1 resection as well as downstaging and downsizing using a standardized regression grading (Dworak regression grading) will be analyzed descriptively by means of frequencies and percentages.
|
20 weeks
|
Rate of patients with locoregional R2 resection (according to CRM definitions in S3 guideline-Version 1.1 August 2014)
Time Frame: 20 weeks
|
The R0- and R1 resection as well as downstaging and downsizing using a standardized regression grading (Dworak regression grading) will be analyzed descriptively by means of frequencies and percentages.
|
20 weeks
|
Rate of number of patients with R0-wide, R0-narrow (according to CRM definitions in S3 guideline-Version 1.1 August 2014), R1 and locoregional R2 resection
Time Frame: 20 weeks
|
The R0- and R1 resection as well as downstaging and downsizing using a standardized regression grading (Dworak regression grading) will be analyzed descriptively by means of frequencies and percentages.
|
20 weeks
|
Disease-free survival (DFS)
Time Frame: 44 weeks
|
Disease-free survival rate will be analyzed using a two-sided Fisher's exact test at a 5% significance level.
In addition, two-sided 95% confidence intervals for DFS rates and difference in rates between both treatment arms will be calculated.
|
44 weeks
|
Relapse-free survival (RFS) in resected patients
Time Frame: 44 weeks
|
Relapse-free survival: The length of time after completion of primary treatment (neoadjuvant chemotherapy + surgery) until documented relapse (i.e.
local relapse, liver metastasis, systemic metastases).
|
44 weeks
|
Overall survival (OS) rate
Time Frame: 44 weeks
|
Overall survival: Survival will be calculated from the date of subject enrollment until the date of death from any cause.
If no event is observed (e.g.
lost to follow-up) OS is censored at the day of last subject contact.
|
44 weeks
|
Downstaging ability in resected patients using a standardized regression grading (Dworak regression grading)
Time Frame: 20 weeks
|
The R0- and R1 resection as well as downstaging and downsizing using a standardized regression grading (Dworak regression grading) will be analyzed descriptively by means of frequencies and percentages.
|
20 weeks
|
Downsizing ability in resected patients using a standardized regression grading (Dworak regression grading)
Time Frame: 20 weeks
|
The R0- and R1 resection as well as downstaging and downsizing using a standardized regression grading (Dworak regression grading) will be analyzed descriptively by means of frequencies and percentages.
|
20 weeks
|
Type, incidence and severity of perioperative medical events within 28 days after surgery are assessed. Perioperative morbidity is categorized according to the Clavien-Dindo-Classification
Time Frame: 20 weeks
|
Perioperative medical events as well as mortality within 28 days after surgery will be summarized by frequencies and percentages broken down per treatment arm.
|
20 weeks
|
Mortality after surgery
Time Frame: 20 weeks
|
Perioperative medical events as well as mortality within 28 days after surgery will be summarized by frequencies and percentages broken down per treatment arm.
|
20 weeks
|
Vital signs
Time Frame: 20 weeks
|
Vital signs will be analyzed using summary statistics broken down per treatment group and visit.
|
20 weeks
|
Physical examination
Time Frame: 20 weeks
|
Physical examination as well as WHO/ECOG will be analyzed by calculating frequencies and percentages broken down per treatment group and visit.
|
20 weeks
|
ECOG
Time Frame: 20 weeks
|
Physical examination as well as WHO/ECOG will be analyzed by calculating frequencies and percentages broken down per treatment group and visit.
|
20 weeks
|
Collaborators and Investigators
Sponsor
Investigators
- Principal Investigator: Ralf-Dieter Hofheinz, Prof. Dr., Tagestherapiezentrum am ITM & III. Med. Klinik, Universitätsmedizin Mannheim
Study record dates
Study Major Dates
Study Start (ACTUAL)
Primary Completion (ACTUAL)
Study Completion (ACTUAL)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (ESTIMATE)
Study Record Updates
Last Update Posted (ACTUAL)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
- Digestive System Diseases
- Neoplasms
- Neoplasms by Site
- Gastrointestinal Neoplasms
- Digestive System Neoplasms
- Gastrointestinal Diseases
- Intestinal Diseases
- Intestinal Neoplasms
- Rectal Diseases
- Colorectal Neoplasms
- Rectal Neoplasms
- Physiological Effects of Drugs
- Antineoplastic Agents
- Protective Agents
- Angiogenesis Inhibitors
- Angiogenesis Modulating Agents
- Growth Substances
- Growth Inhibitors
- Micronutrients
- Vitamins
- Antidotes
- Vitamin B Complex
- Oxaliplatin
- Leucovorin
- Aflibercept
Other Study ID Numbers
- AIO-KRK-0214
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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