Clinical trial NCT00869570: External-Beam Radiation Therapy, Capecitabine, and Sorafenib in Treating Patients With Locally Advanced Rectal Cancer
Official title: Neoadjuvant Radiotherapy Combined With Capecitabine and Sorafenib in Patients With Advanced, K-ras Mutated Rectal Cancer. A Multicenter Phase I/IIa Trial.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Colorectal Cancer
Keywords: adenocarcinoma of the rectum
stage II rectal cancer
stage III rectal cancer
Lead sponsor: Swiss Group for Clinical Cancer Research
Sponsor class: OTHER
First posted: 2009-03-26
Enrollment: 54
Sex: ALL
Minimum age (years): 18
Maximum age (years): 120
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: RATIONALE: Radiation therapy uses high-energy x-rays to kill tumor cells. Drugs used in chemotherapy, such as capecitabine, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Sorafenib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor. Giving radiation therapy together with capecitabine and sorafenib before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed.

PURPOSE: This phase I/II trial is studying the side effects and best dose of capecitabine when given together with sorafenib and external-beam radiation therapy and to see how well it works in treating patients with locally advanced rectal cancer.

Detailed description: OBJECTIVES:

* Determine the recommended dose of neoadjuvant capecitabine when given together with sorafenib tosylate and external-beam radiotherapy in patients with K-ras mutated, locally advanced rectal cancer. (Phase I)
* Assess the efficacy and safety of this regimen in these patients. (Phase II)

OUTLINE: This is a multicenter, phase I, dose-escalation study of capecitabine followed by a phase II study.

Patients receive oral capecitabine twice daily and oral sorafenib tosylate once daily on days 1-33. Patients also undergo external-beam radiotherapy once daily on days 1-5, 8-12, 15-19, 22-26, and 29-33. Approximately 6 weeks after completion of neoadjuvant therapy, patients undergo surgery.

After completion of study therapy, patients are followed at 8 weeks and then periodically for up to 3 years.

Eligibility criteria: DISEASE CHARACTERISTICS:

* Histologically confirmed locally advanced adenocarcinoma of the rectum (with or without nodal involvement) requiring surgery

  * Stage mrT3-4, and/or mrN1-2, M0 disease
* Tumor with K-ras gene mutation as assessed locally
* No distant metastases

PATIENT CHARACTERISTICS:

* WHO performance status 0-1
* Neutrophil count ≥ 1,500/mm\^3
* Platelet count ≥ 100,000/mm\^3
* Hemoglobin ≥ 10.0 g/dL
* Creatinine clearance ≥ 50mL/min
* AST ≤ 2.5 times upper limit of normal (ULN)
* Total bilirubin ≤ 1.5 times ULN
* PT/INR or PTT ≤ 1.5 times ULN
* Not pregnant or nursing
* Negative pregnancy test
* Fertile patients must use effective barrier contraception during and for 12 months after completion of study therapy
* Is compliant and geographic proximity allows for proper staging and follow-up
* No other malignancy within the past 5 years except adequately treated cervical carcinoma in situ or localized nonmelanoma skin cancer
* No psychiatric disorder that would preclude understanding study-related information, giving informed consent, or complying with oral drug intake
* No clinically significant (i.e., active) cardiac disease (e.g., congestive heart failure, symptomatic coronary artery disease, or cardiac arrhythmia \[even if controlled with medication\]) or myocardial infarction within the past 12 months
* No uncontrolled hypertension
* No evidence or history of bleeding diathesis
* No lack of physical integrity of the upper gastrointestinal tract or malabsorption syndrome
* No serious or underlying condition (e.g., active autoimmune disease, uncontrolled diabetes, or uncontrolled infection) that, in the judgement of the investigator, could preclude the ability of the patient to participate in the study
* No known hypersensitivity to study drugs or to any other component of the study drugs

PRIOR CONCURRENT THERAPY:

* No prior treatment for rectal cancer
* No prior organ allografts
* More than 4 weeks since prior major surgery other than colostomy
* More than 30 days since prior treatment in a clinical trial
* No other concurrent experimental drugs or anticancer therapy
* No concurrent brivudine, lamivudine, ribavirin, or any other nucleoside analogue
* No concurrent drugs contraindicated for use with the study drugs
* No other concurrent radiotherapy
* No concurrent anticoagulation therapy other than low molecular weight heparin

Primary outcomes:
measure: Dose-limiting toxicity of the treatment combination (Phase I)
timeFrame: during trial treatment (12 weeks)
measure: Pathological near complete or complete tumor response (Dworak grade 3 and 4) (Phase II)
timeFrame: after trial treatment (approx. 12 weeks).
Secondary outcomes:
measure: R0 and R1 resection
timeFrame: after trial treatment (approx. 12 weeks)
measure: Postoperative complications
timeFrame: within 8 weeks after surgery
measure: Time to distant failure
timeFrame: during 3 years follow-up.
measure: Disease-free survival
timeFrame: during 3 years follow-up.
measure: Adverse events as assessed by NCI CTCAE v3.0
timeFrame: during trial treatment.
Other outcomes:
Locations:
city: Budapest
country: Hungary
facility: Szent Laszlo Korhaz
city: Basel
country: Switzerland
facility: Saint Claraspital AG
city: Basel
country: Switzerland
facility: Universitaetsspital-Basel
city: Bellinzona
country: Switzerland
facility: Istituto Oncologico della Svizzera Italiana - Ospedale Regionale Bellinzona e Valli
city: Bern
country: Switzerland
facility: Inselspital, Bern
city: Biel
country: Switzerland
facility: Spitalzentrum Biel
city: Bruderholz
country: Switzerland
facility: Kantonsspital Bruderholz
city: Chur
country: Switzerland
facility: Kantonsspital Graubuenden
city: Geneva
country: Switzerland
facility: Hopital Cantonal Universitaire de Geneva HUG
city: Luzern
country: Switzerland
facility: Kantonsspital Luzern
city: Luzern
country: Switzerland
facility: OnkoZentrum Luzern at Klinik St. Anna
city: St. Gallen
country: Switzerland
facility: Kantonsspital - St. Gallen
city: Thun
country: Switzerland
facility: SpitalSTS AG Simmental-Thun-Saanenland
city: Winterthur
country: Switzerland
facility: Kantonsspital Winterthur
city: Zurich
country: Switzerland
facility: Onkozentrum - Klinik im Park
city: Zurich
country: Switzerland
facility: Onkozentrum Hirslanden
city: Zurich
country: Switzerland
facility: UniversitaetsSpital Zuerich
city: Zürich
country: Switzerland
facility: Stadtspital Triemli
Study officials:
affiliation: Kantonsspital Graubuenden
name: Roger von Moos, MD
role: STUDY_CHAIR
References:
citation: von Moos R, Koeberle D, Schacher S, Hayoz S, Winterhalder RC, Roth A, Bodoky G, Samaras P, Berger MD, Rauch D, Saletti P, Plasswilm L, Zwahlen D, Meier UR, Yan P, Izzo P, Klingbiel D, Bartschi D, Zaugg K; Swiss Group for Clinical Cancer Research (SAKK). Neoadjuvant radiotherapy combined with capecitabine and sorafenib in patients with advanced KRAS-mutated rectal cancer: A phase I/II trial (SAKK 41/08). Eur J Cancer. 2018 Jan;89:82-89. doi: 10.1016/j.ejca.2017.11.005. Epub 2017 Dec 11.