Regorafenib in Patients With Metastatic Solid Tumors Who Have Progressed After Standard Therapy

An Open-label Phase II Study of Regorafenib in Patients With Metastatic Solid Tumors Who Have Progressed After Standard Therapy - RESOUND

This is a single arm, single-stage, phase II trial to evaluate the activity of Regorafenib in patients with metastatic solid tumors (pancreatic cancer, ovarian cancer, melanoma, sarcoma, thymoma (type B2 - B3) and thymic carcinoma, who have progressed after standard therapy.

Each tumour will be assessed by itself. Regorafenib 40 mg tablets will be used in the study. Subjects will receive 160 mg regorafenib po every day (qd) for 3 weeks of every 4 week cycle (i.e., 3 weeks on, 1 week off).

Subjects will continue on treatment until at least one of the following occurs (main criteria):

• Progressive Disease (PD) by radiological assessments or clinical progression
• Death
• Unacceptable toxicity
• Subject withdraws consent
• Treating physician determines discontinuation of treatment is in the subject's best interest
• Substantial non-compliance with the protocol

Inclusion Criteria:

1. Signed informed consent
2. Patients older then 18 years.
3. Locally advanced, recurrent or metastatic histologically confirmed malignancy refractory to available standard treatment, included Pancreatic cancer, Ovarian cancer, Melanoma, Sarcoma
4. At least one measurable lesion according to Response Evaluation Criteria In solid tumor
5. Eastern Cooperative Oncology Group Performance Status: 0-1
6. Life expectancy of at least 12 weeks
7. Adequate bone marrow, liver and renal function as assessed by the following laboratory : Hemoglobin > 9.0 g/dl Absolute neutrophil count > 1,500/mm3 Platelet count > 100,000/μl White blood cells >3.0 x 109/L Total bilirubin <1.5 times the upper limit of normal Alanine amino transferase and aspartate amino transferase <2.5 x upper limit of normal (<5 x upper limit of normal for patients with liver involvement) Serum creatinine <1.5 x upper limit of normal Alkaline phosphatase <2.5 x Upper Limit of Normal Prothrombin time / Partial prothrombin time <1.5 x Upper Limit of Normal Lipase ≤ 1.5 x the Upper Limit of Normal
8. Able to swallow and retain oral medication.
9. Estimated creatinine clearance > 30ml/min as calculated using the Cockcroft-Gault equation
10. Resolution of any toxic effects of prior therapy to NCI Common Terminology Criteria for Adverse Event, Version 4.0, grade ≤ 1 .
11. Women of childbearing potential and men must agree to use adequate contraception

Exclusion Criteria:

1. Prior treatment with regorafenib.
2. Major surgical procedure, open biopsy, or significant traumatic injury within 28 days before start of study drug
3. Congestive heart failure >New York Heart Association class 2
4. Unstable angina), new-onset angina.Myocardial infarction less than 6 months before start of study drug
5. Myocardial infarction less than 6 months before start of study drug.
6. Cardiac arrhythmias requiring anti-arrhythmic therapy
7. Uncontrolled hypertension.
8. Pleural effusion or ascites that causes respiratory compromise
9. Ongoing infection > Grade 2
10. Known history of human immunodeficiency virus infection.
11. Active hepatitis B or C, or chronic hepatitis B or C requiring treatment with antiviral therapy.
12. Subjects with seizure disorder requiring medication.
13. History of organ allograft. Subjects with evidence or history of any bleeding diathesis, irrespective of severity.
14. Any hemorrhage or bleeding event > Common Toxicity Criteria for Adverse Effects Grade 3
15. Arterial or venous thrombotic or embolic events within the 6 months before start of study medication
16. Known history or symptomatic metastatic brain or meningeal tumors
17. Suggestive or consistent with central nervous system disease
18. Renal failure requiring hemo-or peritoneal dialysis.
19. Dehydration Common Toxicity Criteria for Adverse Effects v. 4.0 Grade >1.
20. Substance abuse, medical, psychological or social conditions that may interfere with the subject's participation in the study or evaluation of the study results.
21. Known hypersensitivity to any of the study drugs, study drug classes, or excipients in the formulation.
22. Any illness or medical conditions that are unstable or could jeopardize the safety of the subject and his/her compliance in the study.
23. Interstitial lung disease with ongoing signs and symptoms
24. Persistent proteinuria of CTCAE Grade 3
25. Any malabsorption condition.
26. Concomitant participation or participation within the last 30 days in another clinical trial
27. Systemic anticancer therapy including cytotoxic therapy, signal transduction inhibitors, immunotherapy, and hormonal therapy during this trial or within 4 weeks before starting to receive study medication.