Evaluation of Regorafenib in patients with a metastatic colorectal cancer resistant to all other therapies.

Phase 1

• Conditions: Advanced refractory colorectal cancer; MedDRA version: 17.0Level: PTClassification code 10052358Term: Colorectal cancer metastaticSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); Therapeutic area: Diseases [C] - Cancer [C04]

• Registration Number: EUCTR2012-005655-16-BE
• Lead Sponsor: Institut Jules Bordet

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Study Start: 2013-05-28
• Last Update Posted: 21 May 2018

Recruitment & Eligibility

• Status: ot Recruiting
• Sex: All
• Target Recruitment: 140

Inclusion Criteria

1. Histologically proven adenocarcinoma of the colon or the rectum that is metastatic or unresectable and for which standard treatments do not exist or are no longer effective.
2.The tumor should be refractory to all standard chemotherapy agents (fluoropyrimidines, irinotecan, and oxaliplatin) and anti-EGFR monoclonal antibodies in case of wild type K-ras (cetuximab or panitumumab) administered before study entry. Patients treated with oxaliplatin in an adjuvant setting should have progressed during adjuvant therapy or within 6 months of completion of this treatment. Patients who do not meet strictly this criteria, but for whom further treatment with oxaliplatin would be prohibited ( for instance allergic reaction, residual neurotoxicity grade =2) are allowed for inclusion. Prior treatment with bevacizumab and/or aflibercept is allowed but not mandatory.
3. Age = 18 years.
4. Life expectancy of greater than 12 weeks.
5. ECOG performance status = 1.
6. Participants must have normal organ and bone marrow function as defined below:
o Leukocytes > 3,000/mcL, with an absolute neutrophil count > 1,500/mcL, platelets > 100,000/mcL, Hb?9g/dl.
o Total bilirubin = 1.5 × institutional ULN.
bilirubin total can be > 1.5× institutional ULN in case of Gilbert syndrome ( where direct bilirubin only should be = 1.5 × institutional ULN)
o AST/ALT levels = 2.5 × institutional ULN (= 5x institutional ULN in case of liver metastatic involvement).
o P-Alk levels =5 x institutional ULN except in case of bone metastasis (then the liver fraction of P-Alk should be less than 5x institutional ULN).
o International normalized ratio (INR)/ Partial thromboplastin time (PTT) = 1.5 x institutional ULN. Note: Subjects who are therapeutically treated with an agent such as warfarin or heparin will be allowed to participate provided that no prior evidence of underlying abnormality in coagulation parameters exists. Close monitoring of at least weekly evaluations will be performed until INR/PTT is stable based on a measurement that is pre-dose as defined by the local standard of care.
o Creatinine = 1.5× institutional ULN or creatinine clearance >30mL/min according to the Modified Diet in Renal Disease (MDRD) abbreviated formula.
7. Women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control, abstinence) prior to study entry, during regorafenib administration until at least 3 months after the last study drug administration (last day of the last cycle). Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.
8. Signed Written Informed Consent (IC) (approved by an Independent Ethics Committee (IEC) and obtained prior to any study related procedure).
9Presence of a previously collected frozen or FFPE primary or metastatic tumor. Frozen tissue from the primitive tumor is preferred. In addition, the collection of fresh tissue in the primary or a metastatic FDG-PET targetable lesion before study entry is mandatory.
10. Presence of at least one metabolically measurable tumoral lesion on FDG PET-CT, fulfilling following criteria:
o Size = 1.5cm; AND
o FDG uptake above the background liver uptake as described below:
i.e. with a marked accumulation of FDG, at least 1.5-fold greater than liver SUV mean + 2 SDs (in 3-cm spherical ROI in normal right lobe of liver). If liver is

Exclusion Criteria

Participants who exhibit any of the following conditions at screening will not be eligible for admission into the study.
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 ?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? 2), unstable angina pectoris (defined by angina symptoms at rest or new-onset angina started within the last 3 months), cardiac arrhythmia requiring anti-arrhythmic therapy (beta blockers or digoxin are permitted).
10. Uncontrolled hypertension (defined by systolic blood pressure >150 mmHg or diastolic blood pressure >90 mmHg despite optimal medical management).
11. Patients with phaeochromocytoma.
12. Patients with seizure disorder requiring medication.
13 Any history of organ allograft.
14. Pleural effusion or ascites affecting respiration (NCI CTCAEv.4 Grade = 2 dyspnea).
15. Uncontrolled diabetes.
16. Non-healing wound, ulcer, or bone fracture.
17. 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.
18. Interstitial lung disease with ongoing signs and symptoms.
19. Renal failure requiring hemo-or peritoneal dialysis.
20. Dehydration NCI-CTCAE v.4 grade> 1.
21. Substance abuse, 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.
22. Known hypersensitivity to the study drug or excipients in the formulation.
23. Any illness or medical conditions that are unstable or could jeopardize the safety of the patient and his/her compliance in the study.
24. Pregnant or lactating women.
25. Subjects unable to swallow oral medications.
26. Refusal to undergo a PET-targeted fresh biopsy.
27.Subjects with thrombotic, embolic, venous, or arterial events, such as cerebrovascular accident (including transient ischemic attacks) deep vein thrombosis or pulmonary embolism within 6 months of start of study treatment within 6 months of informed consent.
28.Persistent proteinuria > Grade 3 NCI-CTCAE v4.0 (> 3.5 g/24 hours, measured by urine protein: creatinine ratio on a random urine sample).

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified