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Rectal CancerPhase 2NCT03043729

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

A Phase 2 study testing Oxaliplatin, 5-FU and Leucovorin in people with Rectal Cancer and Rectosigmoid Cancer, run by AIO-Studien-gGmbH at 1 site in Germany.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Rectal Cancer, Rectosigmoid Cancer
What is being tested?
Oxaliplatin, 5-FU and Leucovorin
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
119 participants
Where
1 siteGermany
Study dates
6 Mar 2017to 1 Jun 2022
Phase
Phase 2
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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:
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  • 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.

Who cannot join

  • 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
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  • 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].

Trial locations and contacts

1 site in 1 country.

Germany1 site

  • Tagestherapiezentrum am ITM & III. Med. Klinik

    Mannheim, 68167

Other trials in Germany

About this study

Official title: mFOLFOX6 vs. mFOLFOX6 + Aflibercept as Neoadjuvant Treatment in MRI-defined T3-rectal Cancer: a Randomized Phase-II-trial

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.

Read the 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.

Being tested
Oxaliplatin, 5-FU, Leucovorin, Aflibercept
Keywords
neoadjuvant, MRI-defined T3, mFOLFOX6, Aflibercept
Medical subject headings
Rectal Neoplasms

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • OxaliplatinDrug

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

  • 5-FUDrug

    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)

  • LeucovorinDrug

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

  • AfliberceptBiological

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

Study groups in NCT03043729
Study groupRoleWhat they receive
Arm AActive comparator6 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
Receives: Drug: Oxaliplatin; Drug: 5-FU; Drug: Leucovorin
Arm BExperimental6 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
Receives: Drug: Oxaliplatin; Drug: 5-FU; Drug: Leucovorin; Biological: Aflibercept

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Pathologic complete response (pCR)

    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

    Measured: 20 weeks

Secondary outcomes (20)

  1. Dose intensities of study medication

    The dose intensities of study medication will be calculated over the whole study duration and will be summarized descriptively by summary statistics.

    Measured: 12 weeks

  2. Type, incidence and severity of AEs, SAEs

    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.

    Measured: 20 weeks

  3. Dose reduction or discontinuation of study drug due to adverse events

    The dose intensities of study medication will be calculated over the whole study duration and will be summarized descriptively by summary statistics.

    Measured: 20 weeks

  4. Rate of treatment discontinuation due to toxicity

    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.

    Measured: 20 weeks

  5. Type, incidence and severity of laboratory abnormalities

    For relevant laboratory parameters, the distribution over time as well as changes from randomization will be calculated and analyzed descriptively.

    Measured: 20 weeks

  6. Rate of patients with R0-wide resection (according to CRM definitions in S3 guideline-Version 1.1 August 2014)

    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.

    Measured: 20 weeks

  7. Rate of patients with R0-narrow resection (according to CRM definitions in S3 guideline-Version 1.1 August 2014)

    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.

    Measured: 20 weeks

  8. Rate of patients with R1 resection (according to CRM definitions in S3 guideline-Version 1.1 August 2014)

    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.

    Measured: 20 weeks

  9. Rate of patients with locoregional R2 resection (according to CRM definitions in S3 guideline-Version 1.1 August 2014)

    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.

    Measured: 20 weeks

  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

    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.

    Measured: 20 weeks

  11. Disease-free survival (DFS)

    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.

    Measured: 44 weeks

  12. Relapse-free survival (RFS) in resected patients

    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).

    Measured: 44 weeks

  13. Overall survival (OS) rate

    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.

    Measured: 44 weeks

  14. Downstaging ability in resected patients using a standardized regression grading (Dworak regression grading)

    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.

    Measured: 20 weeks

  15. Downsizing ability in resected patients using a standardized regression grading (Dworak regression grading)

    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.

    Measured: 20 weeks

  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

    Perioperative medical events as well as mortality within 28 days after surgery will be summarized by frequencies and percentages broken down per treatment arm.

    Measured: 20 weeks

  17. Mortality after surgery

    Perioperative medical events as well as mortality within 28 days after surgery will be summarized by frequencies and percentages broken down per treatment arm.

    Measured: 20 weeks

  18. Vital signs

    Vital signs will be analyzed using summary statistics broken down per treatment group and visit.

    Measured: 20 weeks

  19. Physical examination

    Physical examination as well as WHO/ECOG will be analyzed by calculating frequencies and percentages broken down per treatment group and visit.

    Measured: 20 weeks

  20. ECOG

    Physical examination as well as WHO/ECOG will be analyzed by calculating frequencies and percentages broken down per treatment group and visit.

    Measured: 20 weeks

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted6 Feb 2017 (estimated)
  2. Study start6 Mar 2017
  3. Primary completion11 Jan 2021
  4. Study completion1 Jun 2022

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
119 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03043729
Sponsor's protocol ID
AIO-KRK-0214
Status last verified
Feb 2023
First submitted
31 Jan 2017
Last updated
6 Feb 2023
Results posted
No
Data monitoring committee
No
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
No

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Oxaliplatin, 5-FU and Leucovorin in people with Rectal Cancer and Rectosigmoid Cancer, run by AIO-Studien-gGmbH at 1 site in Germany.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 35 inclusion and 35 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 6 Feb 2023. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in Germany. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Pathologic complete response (pCR) (time frame: 20 weeks). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03043729.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 6 Feb 2023.

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