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mFOLFOX6 vs. mFOLFOX6 + Aflibercept as Neoadjuvant Treatment in MRI-defined T3-rectal Cancer

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03043729
Recruitment Status : Recruiting
First Posted : February 6, 2017
Last Update Posted : March 6, 2019
Sponsor:
Collaborators:
Institut für Klinisch-Onkologische Forschung (IKF) Frankfurt
Sanofi
Information provided by (Responsible Party):
AIO-Studien-gGmbH

Brief Summary:
Patients with locally advanced rectal or rectosigmoid cancer staged cT3 CRM-negative with MRI will receive 6 cycles of neoadjuvant treatment with mFOLFOX6 (Arm A) vs. mFOLFOX6 + aflibercept (Arm B) followed by surgery.

Condition or disease Intervention/treatment Phase
Rectal Cancer Rectosigmoid Cancer Drug: Oxaliplatin Drug: 5-FU Drug: Leucovorin Biological: Aflibercept Phase 2

Detailed Description:
Patients with locally advanced rectal cancer are generally recommended to receive preoperative radiotherapy or radiochemotherapy. The advantage of combined-modality therapy in rectal cancer is that it has reduced local pelvic recurrence - a dreaded and morbid event - to rates of about 10%. There is good quality evidence that preoperative radiotherapy reduces local recurrence but there is little if any impact on overall survival. One strategy to reduce the distant recurrence rate, and thereby increase the cure rate, would be to introduce systemic treatment earlier to prevent dissemination of micrometastases. The present trial is designed to compare two neoadjuvant chemotherapy regimens in patients with non-metastatic T3 CRM-negative rectal cancers using quality-controlled MRI of the pelvis as a main inclusion criterion. This strategy is believed to reduce acute and long-term toxicity caused by preoperative radiotherapy and to administer effective systemic chemotherapy early in the course of disease as neoadjuvant chemotherapy.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 209 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: mFOLFOX6 vs. mFOLFOX6 + Aflibercept as Neoadjuvant Treatment in MRI-defined T3-rectal Cancer: a Randomized Phase-II-trial
Actual Study Start Date : March 6, 2017
Estimated Primary Completion Date : August 2021
Estimated Study Completion Date : February 2022

Resource links provided by the National Library of Medicine


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
Drug: Oxaliplatin
Oxaliplatin 85 mg/m^2, as 2h infusion on Day 1 (Arm A + Arm B)

Drug: 5-FU
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)

Drug: Leucovorin
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
Drug: Oxaliplatin
Oxaliplatin 85 mg/m^2, as 2h infusion on Day 1 (Arm A + Arm B)

Drug: 5-FU
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)

Drug: Leucovorin
Leucovorin 350 mg/m^2 i.v. as 2h infusion on Day 1 (Arm A + Arm B)

Biological: Aflibercept
Aflibercept 4 mg/kg BW i.v. on Day 1 q2w (Arm B, Cycles 1 to 5)




Primary Outcome Measures :
  1. 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


Secondary Outcome Measures :
  1. 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.

  2. 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.

  3. 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.

  4. 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.


  5. 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.

  6. 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.

  7. 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.

  8. 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.

  9. 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.

  10. 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.

  11. 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.

  12. 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).

  13. 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.

  14. 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.

  15. 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.

  16. 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.

  17. 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.

  18. Vital signs [ Time Frame: 20 weeks ]
    Vital signs will be analyzed using summary statistics broken down per treatment group and visit.

  19. 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. 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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Age ≥ 18 years on day of signing informed consent
  2. Signed and dated informed consent, and willing and able to comply with protocol requirements
  3. WHO/ECOG Performance Status (PS) 0-1
  4. Diagnosis of rectal adenocarcinoma
  5. 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.
  6. 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.
  7. 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:

      1. 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".
      2. No evidence that tumor is adjacent to (defined as within 2 mm of) the mesorectal fascia on MRI (i.e. CRM > 2 mm)
      3. Only T3-tumors are included, i.e infiltration into perirectal fat < 10 mm provided CRM > 2 mm
      4. Note: MRI criteria are used for the definition of T3 tumor (i.e. exclusion of T2 and T4 situation).
  8. 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)
  9. Adequate renal function:

    • Serum creatinine level ≤ 1.5 x upper limit normal (ULN) or ≤ 1.5 mg/dl
    • Creatinine clearance ≥ 30 ml/min
  10. Adequate liver function:

    • Serum bilirubin ≤ 1.5 x upper limit normal (ULN)
    • Alkaline phosphatase < 3 x ULN
    • AST and ALT < 3 x ULN
  11. Proteinuria < 2+ (dipstick urinalysis) or ≤ 1 g/24hour or ≤ 500mg/dl
  12. Regular follow-up feasible
  13. For female patients of childbearing potential, negative pregnancy test within 1 week (7 Days) prior of starting study treatment
  14. 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
  15. 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:

  1. Distant metastases (CT scans of thorax and abdomen are mandatory)
  2. cT2 and cT4 tumors (defined by MRI criteria)
  3. Exclusion of potentially compromised CRM as defined by MRI criteria (i.e. > 2 mm distance from CRM)
  4. Prior antineoplastic therapy for rectal cancer
  5. History or evidence upon physical examination of CNS metastasis
  6. Uncontrolled hypercalcemia
  7. Pre-existing permanent neuropathy (NCI-CTCAE grade ≥ 2)
  8. Uncontrolled hypertension (defined as systolic blood pressure > 150 mmHg and/or diastolic blood pressure > 100 mmHg), or history of hypertensive crisis, or hypertensive encephalopathy
  9. Concomitant protocol unplanned antitumor therapy (e.g. chemotherapy, molecular targeted therapy, immunotherapy, radiotherapy)
  10. Treatment with any other investigational medicinal product within 28 days prior to study entry
  11. Known dihydropyrimidine dehydrogenase (DPD) deficiency
  12. Treatment with CYP3A4 inducers unless discontinued > 7 Days prior to randomization
  13. 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
  14. Any active infection within 2 weeks prior to study inclusion
  15. Vaccination with a live, attenuated vaccine within 4 weeks prior to the first administration of the study medication
  16. 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
  17. Any other serious and uncontrolled non-malignant disease, major surgery or traumatic injury within the last 28 days prior to study entry
  18. Pregnant or breastfeeding women
  19. Patients with known allergy to any constituent to study drugs
  20. History of myocardial infarction and/or stroke within 6 months prior to randomization, NYHA class III and IV congestive heart failure
  21. Severe renal insufficiency (creatinin clearance < 30 ml/min)
  22. Bowel obstruction
  23. Contra-indication to the assessment by MRI
  24. Involvement in the planning and/or conduct of the study (applies to both Sanofi staff and/or staff of Sponsor and study site)
  25. Patient who might be dependent on the sponsor, site or the investigator
  26. Patient who has been incarcerated or involuntarily institutionalized by court order or by the authorities § 40 Abs. 1 S. 3 Nr. 4 AMG
  27. 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].

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03043729


Contacts
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Contact: Ralf-Dieter Hofheinz, Prof. Dr. med. ralf.hofheinz@umm.de
Contact: Saskia Schulze, M.SC. +49-30-8145-344 31 Saskia.Schulze@aio-studien-ggmbh.de

Locations
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Germany
Tagestherapiezentrum am ITM & III. Med. Klinik Recruiting
Mannheim, Germany, 68167
Contact: Ralf-Dieter Hofheinz, Prof. Dr. med.         
Sponsors and Collaborators
AIO-Studien-gGmbH
Institut für Klinisch-Onkologische Forschung (IKF) Frankfurt
Sanofi
Investigators
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Principal Investigator: Ralf-Dieter Hofheinz, Prof. Dr. Tagestherapiezentrum am ITM & III. Med. Klinik, Universitätsmedizin Mannheim
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Responsible Party: AIO-Studien-gGmbH
ClinicalTrials.gov Identifier: NCT03043729    
Other Study ID Numbers: AIO-KRK-0214
First Posted: February 6, 2017    Key Record Dates
Last Update Posted: March 6, 2019
Last Verified: March 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by AIO-Studien-gGmbH:
neoadjuvant
MRI-defined T3
mFOLFOX6
Aflibercept
Additional relevant MeSH terms:
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Rectal Neoplasms
Colorectal Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Intestinal Diseases
Rectal Diseases
Leucovorin
Oxaliplatin
Antineoplastic Agents
Antidotes
Protective Agents
Physiological Effects of Drugs
Vitamin B Complex
Vitamins
Micronutrients
Nutrients
Growth Substances