Regorafenib Assessment in Refractory Advanced Colorectal Cancer(RegARd-C) (RegARd-C)

Regorafenib Assessment in Refractory Advanced Colorectal Cancer

The general objectives are to evaluate activity and the safety of regorafenib in a population of patients bearing advanced, refractory colorectal cancers and to explore the different downstream molecular pathways to identify tumor response and resistance mechanisms.

Study Overview

• Status: Completed
• Conditions: Advanced Chemorefractory Colorectal Adenocarcinoma
• Intervention / Treatment: Drug: regorafenib

Detailed Description

The primary objective is to identify in a population of patients bearing advanced, refractory colorectal cancers, those who draw no benefit from treatment with regorafenib. There is no specific hypothesis underlying sample size and the study is therefore to be seen as exploratory.

Secondary objectives:

• To analyze PFS and response rate (RR) in relationship with the same covariates as for OS
• To assess regorafenib efficacy (OS, PFS, RR) and safety profile in this study population.
• To assess the Disease control rate (DCR = Complete response [CR] + partial response [PR] + stable disease [SD])
• To compare the relative benefit (OS, PFS) of regorafenib according to history of treatment with bevacizumab.

• Study Type: Interventional
• Enrollment (Actual): 141
• Phase: Phase 2

Contacts and Locations

Study Locations

• Belgium
  • Brussels, Belgium, 1000
    • Jules Bordet Institute
  • Brussels, Belgium, 1070
    • Hopital Erasme
  • Brussels, Belgium
    • Cliniques Universitaires Saint Luc
  • Charleroi, Belgium, 6000
    • Grand Hôpital de Charleroi
  • Ghent, Belgium
    • UZ Ghent
  • Kortrijk, Belgium, 8500
    • AZ Groeninge
  • Liège, Belgium, 4000
    • Centre Hospitalier Universitaire de Liège
  • Liège, Belgium, 4000
    • Clinique St Joseph
  • Lobbes, Belgium, 6540
    • Centre Hospitalier de Jolimont
  • Mons, Belgium, 7000
    • CHU Ambroise Pare
  • Namur, Belgium, 5000
    • Centre Hospitalier Regional De Namur
  • Namur, Belgium, 5000
    • Clinique et Maternite Sainte Elisabeth
  • Ottignies, Belgium, 1340
    • Clinique Saint Pierre
  • Roeselare, Belgium, 8800
    • Hartziekenhuis Roeselare-Menen (HHRM)
  • Turnhout, Belgium, 2300
    • AZ Turnhout
  • Yvoir, Belgium, 5530
    • Cliniques Universitaires UCL de Mont-Godinne
  • Edegem
    • Antwerpen, Edegem, Belgium, 2650
      • UZA

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Histologically proven colorectal adenocarcinoma that is metastatic or unresectable and for which standard treatments do not exist or are no longer effective.
2. Age ≥ 18 years.
3. Life expectancy of greater than 12 weeks.
4. ECOG performance status ≤ 1.

5. Participants must have normal organ and bone marrow function as defined below:

   • Leukocytes >3,000/mcL,with an absolute neutrophil count >1,500/mcL, platelets >100,000/mcL, Hb >or=9g/dl.
   • Total bilirubin≤1.5×institutional ULN.
   • AST/ALT/P-Alk levels ≤ 2.5 × institutional ULN (≤5x institutional ULN in case of liver metastatic involvement).
   • Lipase ≤1.5 institutional ULN.
   • coagulation tests ≤ 1.5 x institutional ULN.
   • Creatinine ≤ 1.5× institutional ULN or creatinine clearance >30mL/min according to the Modified Diet in Renal Disease (MDRD) abbreviated formula.
6. Women of childbearing potential and men must agree to use adequate contraception prior to study entry, until at least 3 months after the last study drug administration.
7. Signed Written Informed Consent (IC).
8. Presence of a previously collected or freshly obtained at the time of study entry frozen metastatic tumor biopsy in a FDG-PET targetable lesion.
9. Presence of at least one metabolically measurable tumoral lesion on FDG PET-CT

Exclusion Criteria:

1. Prior treatment with sorafenib or regorafenib
2. Patients with previous cancer that is not disease-free for at least for 5 years prior to registration, EXCEPT for curatively treated cervical cancer in situ, non-melanoma skin cancer and superficial bladder tumors [Ta (Non-invasive tumor), Tis (Carcinoma in situ) and T1 (Tumor invades lamina propria)].
3. Participants who have had a major surgery, chemotherapy or radiotherapy within 4 weeks prior to entering the study.
4. Unresolved toxicity higher than NCI-CTCAE (version 4.0) Grade 1 attributed to any prior therapy/procedure excluding alopecia and oxaliplatin induced neurotoxicity ≤Grade 2.
5. Participants receiving any experimental agents.
6. Participants with known brain metastases.
7. Bleeding diathesis, history of cardiovascular ischemic disease or cerebrovascular incident within the last six months.
8. Any hemorrhage or bleeding event NCI-CTCAE v.4 Grade >or= 3 within 4 weeks prior to the start of study medication.
9. Uncontrolled concurrent illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure (New York Heart Association (NYHA)class> or=2), unstable angina pectoris, cardiac arrhythmia requiring anti-arrhythmic therapy (beta blockers or digoxin are permitted).
10. Uncontrolled hypertension.
11. Patients with seizure disorder requiring medication.
12. Any history of organ allograft.
13. Pleural effusion or ascites affecting respiration.
14. Uncontrolled diabetes.
15. Non-healing wound, ulcer, or bone fracture.
16. Known history of human immunodeficiency virus (HIV) infection, or active hepatitis B or C, or chronic hepatitis B or C requiring treatment with antiviral therapy.
17. Interstitial lung disease with ongoing signs and symptoms.
18. Renal failure requiring hemo-or peritoneal dialysis.
19. Dehydration NCI-CTCAE v.4 grade >1.
20. Medical,psychological or social conditions that may interfere with the patient's ability to understand informed consent and participation in the study or evaluation of the study results.
21. Known hypersensitivity to the study drug or excipients in the formulation.
22. Any illness or medical conditions that are unstable or could jeopardize the safety of the patient and his/her compliance in the study.
23. Pregnant or lactating women.
24. Subjects unable to swallow oral medications.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Regorafenib; A treatment cycle is defined as a 4 weeks period. Regorafenib will be administered once a day orally at a dose of 160 mg (4 tablets of 40 mg), for 3 weeks.	Drug: regorafenib; Patients will receive 160 mg regorafenib 1/day 3 weeks out of 4.; Other Names: stivarga (registred name)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Overall survival (OS)	2 years from first patient in

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Occurence of Adverse events	Assessment of safety will follow the WHO guidelines and classified according to NCI-CTCAE v. 4.0 and will be performed every 28 days until 28 days (safety follow up visit) after stopping therapy. Reasons for stopping therapy may include progression of disease or unbearable toxicities, or patient's decision.	Every 28 days till 28 days after stopping therapy. An average of 2 months is expected.
Evaluation of tumour response	RECIST 1.1-based radiological assessment (CT or MRI) will be made every 2 cycles, starting at day 28 of the second cycle till demonstration of progressive disease. An average of 2 months is expected.	Every 2 months till progression of the disease. An average of 2 months is expected.
Metabolic response assessed by FDG PET	FDGPET will be done twice during the study course : at baseline (at day 0, before treatment begin) and after 2 weeks.	2 FDGPET will be perfomed : at Baseline (day 0) and at D14
Molecular aberrations	Genetic, epigenetic and molecular aberrations will be investigated using gene expression profiling, RNA and exome sequencing, and methylation profiling on the tumor biopsies and repeated blood samples collected during the trial. The relationship between the molecular aberrations,the patient's outcome (PFS, OS) and with metabolic response after treatment with regorafenib will be studied.	at day 0 (before treatment begins) and at D14, then repeated every 2 months until progression. An average of 2 months is expected.

Collaborators and Investigators

• Sponsor: Jules Bordet Institute
• Investigators: Study Chair: Alain Hendlisz, MD, Jules Bordet Institute

Publications and helpful links

General Publications

• Charette N, Vandeputte C, Ameye L, Bogaert CV, Krygier J, Guiot T, Deleporte A, Delaunoit T, Geboes K, Van Laethem JL, Peeters M, Demolin G, Holbrechts S, Flamen P, Paesmans M, Hendlisz A. Prognostic value of adipose tissue and muscle mass in advanced colorectal cancer: a post hoc analysis of two non-randomized phase II trials. BMC Cancer. 2019 Feb 12;19(1):134. doi: 10.1186/s12885-019-5319-8.
• Hendlisz A, Deleporte A, Vandeputte C, Charette N, Paesmans M, Guiot T, Garcia C, Flamen P. Regorafenib assessment in refractory advanced colorectal cancer: RegARd-C study protocol. BMJ Open. 2015 Mar 9;5(3):e007189. doi: 10.1136/bmjopen-2014-007189.

Study record dates

Study Major Dates

• Study Start: August 1, 2013
• Primary Completion (Actual): May 13, 2016
• Study Completion (Actual): June 17, 2019

Study Registration Dates

• First Submitted: July 28, 2013
• First Submitted That Met QC Criteria: August 21, 2013
• First Posted (Estimate): August 28, 2013

Study Record Updates

• Last Update Posted (Actual): June 25, 2019
• Last Update Submitted That Met QC Criteria: June 21, 2019
• Last Verified: March 1, 2017

More Information

Terms related to this study

• Keywords: adenocarcinoma, colorectal,regorafenib
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Carcinoma; Neoplasms, Glandular and Epithelial; Adenocarcinoma
• Other Study ID Numbers: 2012-005655-16 EUDRACT