SAKK 41/16-RECAP Präoperative Behandlung mit Regorafenib und Capecitabine zusammen mit Radiotherapie in lokal fortgeschrittenem Enddarmkrebs. Eine multizentrische Phase Ib Studie.

Drug: Regorafenib;Drug: Capecitabine;Radiation: Radiotherapy;Procedure: Surgery

Inclusion Criteria:

- Written informed consent according to Swiss law and ICH/GCP regulations before any
trial specific procedures.

- Histologically confirmed and clinically advanced adenocarcinoma. pStage 2 and 3
according AJCC 2012, mrT3/4 N0, mrTx N1-2 cM0 (assessed by mandatory CT scan
thorax/abdomen, MRI pelvis). TNM classification; recommended MRI quality assurance.

- Tumor is located in the lower and middle rectum (caudal end is defined at maximum of
12 cm from anal verge measured by endoscopy).

- A multi-disciplinary tumor board recommends neoadjuvant radio-chemotherapy and
surgery.

- No DPD deficiency (Dihydro-pyrimidine-dehydrogenase DPD deficiency test mandatory).
Carrier status of a predefined risk allele of the dihydro-pyrimidine-dehydrogenase
gene (DPYD), defined as the presence of at least one of the following mutations:
c.1679T>G, c.1905+1G>A, c.2846A>T, c.1129-5923C>G.

- Age 18 to 75 years.

- WHO performance status 0-1.

- Adequate bone marrow function: neutrophils = 1.5 x 109/L, platelets = 100 x 109/L,
hemoglobin = 100 g/L.

- Adequate hepatic and pancreatic function: bilirubin = 1.5 x ULN, AST/ALT/AP = 2.5 x
ULN, Lipase = 1.5 x the ULN.

- Adequate renal function (calculated creatinine clearance > 50 mL/min, according to the
formula of Cockcroft-Gault).

- INR = 1.5 or PTT = 1.5 x ULN (patients who are being therapeutically anticoagulated
are not allowed to participate in the trial). If anti coagulation is indicated during
trial treatment, low molecular weight heparin must be used.

- Women with child-bearing potential are using effective contraception, are not pregnant
and agree not to become pregnant during trial treatment and during the 8 weeks
thereafter. A negative pregnancy test before inclusion into the trial is required for
all women with child-bearing potential.

- Men agree to use effective contraception during trial treatment and 8 weeks
thereafter.

Exclusion Criteria:

- History of hematologic or primary solid tumor malignancy, unless in remission for at
least 3 years from registration with the exception of adequately treated cervical
carcinoma in situ or localized non-melanoma skin cancer.

- Concurrent or recent (within 30 days of registration) treatment with any other
experimental drug.

- Any prior treatment for rectal cancer.

- Major surgery or significant traumatic injury within 28 days before registration
(colostomy accepted).

- Concomitant strong CYP3A4 inhibitors (e.g. clarithromycin, indinavir, itraconazole,
ketoconazole, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir,
telithromycin, voriconazole) or strong CYP3A4 inducers (e.g. carbamazepine,
phenobarbital, phenytoin, rifampin, St. John's Wort) within 28 days or 5 drug
half-lives (if drug half-life in patients is known), whichever is shorter, before
start of trial treatment (see http://medicine.iupui.edu/).

- Severe or uncontrolled cardiovascular disease (congestive heart failure NYHA II-IV),
unstable angina pectoris, history of myocardial infarction within the last six months,
serious arrhythmias requiring medication (with exception of atrial fibrillation or
paroxysmal supraventricular tachycardia), significant QT-prolongation (QTc interval
>460 msec), uncontrolled hypertension (sustained systolic blood pressure > 150 mm Hg
and/or diastolic > 100 mm Hg despite antihypertensive therapy).

- Patients with evidence or history of any bleeding diathesis, irrespective of severity.

- Any hemorrhage or bleeding event = Grade 3, NCI-CTCAE v4.03 within 4 weeks prior to
the start of trial medication.

- Significant proteinuria: Positive dipstick 2+ and greater if proteinuria = 3.5g/24 h
measured by urine protein-creatinine ratio is confirmed (= Grade 3, NCI-CTCAE v4.0).

- Patients with known hepatopathy as cirrhosis or diseases like Morbus Gilbert
Meulengracht.

- Interstitial lung disease with ongoing signs and symptoms at the time of informed
consent.

- Known history of human immunodeficiency virus (HIV) or active chronic Hepatitis C or
Hepatitis B Virus infection or any uncontrolled active systemic infection requiring
intravenous (iv) antimicrobial treatment.

- Lack of physical integrity of the upper gastrointestinal tract or malabsorption
syndrome.

- History of organ allografts.

- Known hypersensitivity to any of the trial drugs, trial drug classes, or excipients in
the formulation.

- Breast-feeding patients.

- Any concomitant drugs contraindicated for use with the trial drugs according to the
Swissmedic approved product information.

- Any other serious underlying medical, psychiatric, psychological, familial or
geographical condition, which in the judgment of the investigator may interfere with
the planned staging, treatment and follow-up, affect patient compliance or place the
patient at high risk from treatment-related complications.