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Neoadjuvant Treatment With Regorafenib and Capecitabine Combined With Radiotherapy in Locally Advanced Rectal Cancer (RECAP)

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ClinicalTrials.gov Identifier: NCT02910843
Recruitment Status : Recruiting
First Posted : September 22, 2016
Last Update Posted : May 21, 2019
Sponsor:
Information provided by (Responsible Party):
Swiss Group for Clinical Cancer Research

Brief Summary:
Despite treatment of locally advanced rectal cancer relapses are frequent. Several attempts to improve these results with therapy intensification have shown modest effect on disease free survival (DFS) and overall survival (OS). Recent studies with addition of sorafenib and cediranib revealed promising effect on tumor response with acceptable toxicity. Regorafenib is a multi tyrosine kinase inhibitor (TKI) with a broad mechanism of action. Therefore this trial investigates if similar results can be achieved as with sorafenib or cediranib.

Condition or disease Intervention/treatment Phase
Rectal Cancer Drug: Regorafenib Drug: Capecitabine Radiation: Radiotherapy Procedure: Surgery Phase 1

Detailed Description:

Despite treatment of locally advanced rectal cancer relapses are frequent. Several attempts to improve these results with therapy intensification have shown modest effect on disease free survival (DFS) and overall survival (OS). Recent studies with addition of sorafenib and cediranib revealed promising effect on tumor response with acceptable toxicity. Regorafenib is a multi tyrosine kinase inhibitor (TKI) with a broad mechanism of action. Therefore this trial investigates if similar results can be achieved as with sorafenib or cediranib.

The objective of the dose escalation part is to determinate safety, tolerability and the recommended dose. The objective of the expansion cohort is to assess the efficacy and to further characterize safety and tolerability of the therapy.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 24 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Neoadjuvant Treatment With Regorafenib and Capecitabine Combined With Radiotherapy in Locally Advanced Rectal Cancer. A Multicenter Phase Ib Trial (RECAP)
Actual Study Start Date : February 22, 2017
Estimated Primary Completion Date : December 2019
Estimated Study Completion Date : December 2022

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Regorafenib & Capecitabine
  • Regorafenib dose level 1-3: day 1 to 14 and day 22 to 35 (2 weeks on 1 week off, 2 weeks on, including Saturday and Sunday) at a daily dose according to the escalation table.
  • Regorafenib dose level -1: day 1 to 5, day 8 to 12, day 22 to 26 and day 29 to 33 (5 days on and 2 days off during week 1, 2, 4 and 5; week 3 off) at a daily dose according to the escalation table.
  • Capecitabine: day 1 to 38 (5 weeks and 3 days, including Saturday and Sunday) according to dose escalation table. The intake stops in the evening of the last day of RT.
  • External beam Radiotherapy
  • Surgery
Drug: Regorafenib
  • Regorafenib dosel level 1-3: day 1 to 14 and day 22 to 35 (2 weeks on 1 week off, 2 weeks on, including Saturday and Sunday) at a daily dose according to the escalation table.
  • Regorafenib dosel level -1: day 1 to 5, day 8 to 12, day 22 to 26 and day 29 to 33 (5 days on and 2 days off during week 1, 2, 4 and 5; week 3 off) at a daily dose according to the escalation table.
Other Name: BAY 73-4506

Drug: Capecitabine
• Capecitabine: day 1 to 38 (5 weeks and 3 days, including Saturday and Sunday) according to dose escalation table. The intake stops in the evening of the last day of RT.
Other Name: XELODA

Radiation: Radiotherapy
Monday through Friday for 5 weeks and 3 days (d1-38) starting on day 1 (daily fraction 1.8 Gy, final dose 50.4 Gy).

Procedure: Surgery
6-12 weeks (± 1 week) after radio-chemotherapy (RCT) has been completed (42-84 days after last day of RCT).




Primary Outcome Measures :
  1. Dose limiting toxicity (DLTs) [ Time Frame: up to 4 weeks after the last administration of RCT ]
    In the dose escalation part the dose limiting toxicity (DLTs) is observed during and up to 4 weeks after the last administration of RCT.

  2. Pathological near complete or complete tumor response (npCR or pCR) [ Time Frame: up to 2 months after end of treatment ]
    In the dose escalation part the pathological near complete or complete tumor response (npCR or pCR) is specified.


Secondary Outcome Measures :
  1. Quality of the mesorectal excision including details of the circumferential resection margin (CRM)/surface [ Time Frame: up to 2 months after end of treatment ]
    Quality of the mesorectal excision including details of the circumferential resection margin (CRM)/surface according to Nagtegaal.

  2. Sphincter preservation [ Time Frame: up to 2 months after end of treatment ]
    Sphincter preservation is defined as preservation of the rectal sphincter or part of it.

  3. Pathological response [ Time Frame: up to 2 months after end of treatment ]
    Dworak tumor regression grading (TRG) system.

  4. Circumferential resection margin (CRM) status [ Time Frame: up to 2 months after end of treatment ]

    Negative (clear) circumferential margins are defined by an invasion front which is at a > 1mm distance from the lateral resection margin; circumferential resection margins of ≤ 1 mm are considered positive (involved).

    CRM negative (clear) ≤ 1mm and CRM positive (involved) ≤ 1mm.


  5. Downstaging of primary tumor and/or lymph nodes (comparison between mrT/N and ypT/N) [ Time Frame: up to 2 months after end of treatment ]
    Downstaging of primary tumor and/or lymph nodes (comparison between mrT/N and ypT/N)

  6. Postoperative complications [ Time Frame: within 8 weeks after surgery ]

    Surgical complications within 8 weeks after surgery. A surgical local complication is defined as either:

    • insufficiency of anastomosis
    • fistula
    • severe local infection requiring antibiotics
    • bladder dysfunction
    • erectile dysfunction
    • additional interventions / operation needed (e.g. drainage of hematoma/abscess)



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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

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): NCT02910843


Contacts
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Contact: Daniela Bärtschi +41 31 389 91 91 trials@sakk.ch

Locations
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Switzerland
St. Claraspital Basel Recruiting
Basel, Switzerland, 4016
Contact: Dieter Köberle, MD    +41 61 685 85 85    dieter.koeberle@claraspital.ch   
Principal Investigator: Dieter Köberle, MD         
Universitätsspital Basel Recruiting
Basel, Switzerland, 4031
Contact: Viviane Hess, Prof    +41 61 265 50 74    viviane.hess@usb.ch   
Principal Investigator: Viviane Hess, Prof         
Inselspital Bern Recruiting
Bern, Switzerland, 3010
Contact: Martin D. Berger, MD    +41 31 632 41 14    martin.berger@insel.ch   
Principal Investigator: Martin D. Berger, MD         
Kantonsspital Graubünden Recruiting
Chur, Switzerland, 7000
Contact: Ioannis Metaxas, MD    +41 81 256 66 46    ioannis.metaxas@ksgr.ch   
Principal Investigator: Ioannis Metaxas, MD         
Kantonsspital Luzern Recruiting
Luzern, Switzerland, 6000
Contact: Ralph Winterhalder, MD    +41 41 205 58 75    ralph.winterhalder@ksl.ch   
Principal Investigator: Ralph Winterhalder, MD         
Kantonsspital St. Gallen Withdrawn
St. Gallen, Switzerland, 9007
UniversitätsSpital Zürich Recruiting
Zurich, Switzerland, 8091
Contact: Bernhard Pestalozzi, Prof    +41 (0)44 255 34 40    bernhard.pestalozzi@usz.ch   
Principal Investigator: Bernhard Pestalozzi, Prof         
Sponsors and Collaborators
Swiss Group for Clinical Cancer Research
Investigators
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Study Chair: Sara Bastian, MD Kantonsspital Graubünden, Chur

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Responsible Party: Swiss Group for Clinical Cancer Research
ClinicalTrials.gov Identifier: NCT02910843     History of Changes
Other Study ID Numbers: SAKK 41/16 - RECAP
First Posted: September 22, 2016    Key Record Dates
Last Update Posted: May 21, 2019
Last Verified: May 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 Swiss Group for Clinical Cancer Research:
rectal cancer
Neoadjuvant treatment
Regorafenib
Capecitabine
locally advanced rectal cancer
Phase Ib trial
Additional relevant MeSH terms:
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Rectal Neoplasms
Colorectal Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Rectal Diseases
Digestive System Diseases
Gastrointestinal Diseases
Intestinal Diseases
Capecitabine
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents