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

NCT02910843 | Terminated Phase 1 DMC

• 1 other identifier: SAKK 41/16 - RECAP
• Study Type: interventional
• Target: 25
• Locations: 1 country
• Sites: 7

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.

Conditions

Rectal Cancer

Keywords

rectal cancer; Neoadjuvant treatment; Regorafenib; Capecitabine; locally advanced rectal cancer; Phase Ib trial

Outcome Measures

Primary Outcomes (2)

• Dose limiting toxicity (DLTs)

  In the dose escalation part the dose limiting toxicity (DLTs) is observed during and up to 4 weeks after the last administration of RCT.

  up to 4 weeks after the last administration of RCT

• Pathological near complete or complete tumor response (npCR or pCR)

  In the dose escalation part the pathological near complete or complete tumor response (npCR or pCR) is specified.

  up to 2 months after end of treatment

Secondary Outcomes (6)

• Quality of the mesorectal excision including details of the circumferential resection margin (CRM)/surface

  up to 2 months after end of treatment

• Sphincter preservation

  up to 2 months after end of treatment

• Pathological response

  up to 2 months after end of treatment

• Circumferential resection margin (CRM) status

  up to 2 months after end of treatment

• Downstaging of primary tumor and/or lymph nodes (comparison between mrT/N and ypT/N)

  up to 2 months after end of treatment

Study Arms (1)

Regorafenib & Capecitabine

EXPERIMENTAL

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

Interventions

Regorafenib DRUG

* 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.

Also known as: BAY 73-4506

Regorafenib & Capecitabine

Capecitabine DRUG

• 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.

Also known as: XELODA

Regorafenib & Capecitabine

Radiotherapy RADIATION

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).

Regorafenib & Capecitabine

Surgery PROCEDURE

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

Regorafenib & Capecitabine

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

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

You may not qualify if:

• 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.

Sponsors & Collaborators

• Swiss Cancer Institute: lead

Study Sites (7)

St. Claraspital Basel

Basel, 4016, Switzerland

Location

Universitätsspital Basel

Basel, 4031, Switzerland

Location

Inselspital Bern

Bern, 3010, Switzerland

Location

Kantonsspital Graubünden

Chur, 7000, Switzerland

Location

Kantonsspital Luzern

Lucerne, 6000, Switzerland

Location

Kantonsspital St. Gallen

Sankt Gallen, 9007, Switzerland

Location

UniversitätsSpital Zürich

Zurich, 8091, Switzerland

Location

MeSH Terms

Conditions

Rectal Neoplasms

Interventions

regorafenib; Capecitabine; Radiotherapy; Surgical Procedures, Operative

Condition Hierarchy (Ancestors)

Colorectal Neoplasms; Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Intestinal Diseases; Rectal Diseases

Intervention Hierarchy (Ancestors)

Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Fluorouracil; Uracil; Pyrimidinones; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Therapeutics

Study Officials

• Sara Bastian, MD

  Kantonsspital Graubünden, Chur

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 14, 2016
• First Posted: September 22, 2016
• Study Start: February 22, 2017
• Primary Completion: December 31, 2021
• Study Completion: December 31, 2021
• Last Updated: January 10, 2023

Record last verified: 2023-01

Data Sharing

• IPD Sharing: Will not share

Locations

CH (7)