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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.
Full 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.
Enrollment
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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:
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:
Hematological status:
Adequate renal function:
Adequate liver function:
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:
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:
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].
Primary purpose
Allocation
Interventional model
Masking
119 participants in 2 patient groups
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Data sourced from clinicaltrials.gov
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