Clinical Evaluation - A Phase IIA Proof of Concept Study of Regorafenib (Bayer 73-4506) in Biopsy-amenable Asian Colorectal Cancer Patients

Clinical Evaluation - A Phase IIA Proof of Concept Study of Regorafenib (Bayer 73-4506) in Biopsy-amenable Asian Colorectal Cancer Patients

1. Primary Endpoints

   • Biomarker data suggestive of regorafenib-mediated inhibition of the RAS-RAF- MEK-ERK signal transduction pathway,of various tyrosine kinase receptors and/or of angiogenesis.
   • Evaluation of potential relationships between biomarker data and clinical activity.
   • Evaluation of a novel biomarker technology (Prometheus COPIA platform)

2. Secondary Endpoints

   • Biomarker data suggestive of regorafenib-mediated effects on circulating rare cells.
   • Comparison of tumor genetic profiles obtained using DNA isolated from plasma, tumor biopsies and circulating tumor cells.
   • Patient safety data
   • Pharmacokinetics of regorafenib
   • Changes in tumor metabolic activity as measured by PET CT scan (optional)

Inclusion Criteria:

• Histologically or cytologically proven metastatic colorectal adenocarcinoma that is refractory to standard therapy and not amenable to surgery with curative intent.

• Tumor characteristics:

  • At least one lesion that is suitable for a repeated biopsy; eg. subcutaneous nodule, skin lesion, rectal tumor, colonic mass easily reached by colonoscopy, peritoneal masses at least 3cm in maximum diameter that are easily assessable by image guided core biopsy.
  • For liver lesions, more superficially located lesions at least 3cm in maximum dimension with a rim of normal liver tissue, assessable safely by image guided core biopsy as determined by an experienced interventional radiologist.

• Eastern Cooperative Oncology Group ECOG performance status of 0 or 1 (see Appendix 10.4).

• Adequate bone marrow function (absolute neutrophil count =1,500/mm3; platelet count =100000/mm3; hemoglobin =9g/dl

• Adequate liver and renal function as assessed by the following laboratory requirements conducted within 7 days of starting to study treatment:

  • Total bilirubin < 1.5 x the upper limit of normal (ULN).
  • Alanine transaminase (ALT) and aspartate aminotransferase (AST) < 2.5 x ULN (< 5 x ULN for patients with liver involvement of their cancer).
  • Amylase and lipase < 1.5 x the ULN
  • Serum creatinine < 1.5 x the ULN.
  • Glomerular filtration rate (GFR) = 30 ml/min/1.73 m2 according to the MDRD (Modified diet in renal disease) abbreviated formula

• Prothrombin time, international normalized ratio (INR) and partial thromboplastin time less than or equal to 1.2 times the ULN.

• Male or female at least 21 years of age.

• A female subject is eligible to enter and participate in the study if she is:

  • Non-childbearing potential (ie. physiologically incapable of becoming pregnant) including any women who:
  • Has had a hysterectomy or
  • Has bilateral oophorectomy (ovariectomy) or
  • Has bilateral tubal ligation or
  • Is postmenopausal (demonstrate total cessation of menses for greater than or
  • Childbearing potential, has a negative serum or urine pregnancy test at screening, agrees to one of the following: double barrier contraception or abstinence.

• Predicted life expectancy of at least 12 weeks.

• Resting oxygen saturation greater than 92% on room air.

• Written informed consent.

• Able to swallow and retain oral medication.

• Prothrombin time (PT), International Normalized Ratio for PT (PT INR), and partial thromboplastin time (PTT) or activated partial thromboplastin time (aPTT) within normal limits.

Exclusion Criteria: