Phase Ib study of codrituzumab in combination with sorafenib in patients with non-curable advanced hepatocellular carcinoma (HCC).

PURPOSE: Codrituzumab, a humanized antibody against glypican-3, is highly expressed in HCC. A phase I study evaluated the combination with sorafenib in HCC. PATIENTS AND METHODS: In a 3 + 3 design, codrituzumab was given intravenously in various doses with sorafenib 400 mg twice daily to patients with advanced HCC, age ≥18, ECOG 0-1, Child-Pugh A and B7, adequate organ functions, and no prior systemic therapy, with tumor assessment by RECIST 1.0 and safety by CTCAE 3.0. PK and pre, during, and post-therapy 124I radiolabeled codrituzumab PET scan imaging were performed. RESULTS: 41 patients were enrolled: 2.5 mg/kg weekly (qw) (12), 5 mg/kg qw (12), 10 mg/kg qw (3), 1600 mg every 2 weeks (q2w) (6), and 1600 mg qw (7). Two drug limiting toxicities occurred: grade 3 hyponatremia at 5 mg/kg and grade 3 hyponatremia and hyperglycemia at 1600 mg q2w. Adverse events occurred in 80% of patients, including at least one ≥grade 3: ten (25%) increased AST, three (7.5%) increased ALT, and ten (25%) increased lipase. There were no responses and nine (25.7%) had stable disease. PK C max and AUCt of codrituzumab and sorafenib were comparable to single-agent data. Thirteen out of 14 patients showed 124I radiolabeled codrituzumab uptake in tumor. In all three patients who underwent a post-progression PET, glypican-3 remained expressed. CONCLUSION: Codrituzumab plus sorafenib were tolerated at 1600 mg q2w and 400 mg bid, respectively, with no responses. Codrituzumab exerts selective distribution to HCC cells, and GPC3 does not show any down-regulation post-progression (NCT00976170).

Clinical management and case reports for the treatment of hepatocellular carcinoma with sorafenib.

Hepatocellular carcinoma (HCC) is one of the most common solid organ malignancies worldwide, and its incidence is rising in industrialized nations. Sorafenib, an oral multikinase inhibitor, is effective for the treatment of advanced HCC, and is the only systemic drug indicated for the treatment of unresectable HCC. Patients with HCC often have cirrhosis due to viral infection, chronic alcohol consumption, or other causes of liver damage, resulting in reduced liver function of variable severity. Because of the heterogeneity of HCC cases, physicians must consider the benefits and risks associated with sorafenib treatment on a patient-by-patient basis. California Pacific Medical Center (PMC) has established a clinical protocol, discussed here, for treatment of HCC with sorafenib, and for management of treatment-associated adverse effects. In addition, 3 case reports are presented as examples of the use of sorafenib in patient populations not represented in the phase 3 trials: as an adjuvant treatment after a surgical procedure and as effective treatment for stabilizing recurrent and metastatic HCC.

Relative rates of missed diagnosis for colonoscopy, barium enema, and flexible sigmoidoscopy in 379 patients with colorectal cancer.

BACKGROUND: Failures of diagnosis of colorectal cancer by colonoscopy, barium enema, and flexible sigmoidoscopy have been demonstrated using various techniques. A relative assessment of these diagnostic tests for patients with colorectal cancer has not been reported. This study was designed to determine relative rates of failures for these tests when applied to diagnosis of colorectal cancer. METHODS: We created a database of patients with colorectal cancer diagnosed between 2000 and 2005. Records were reviewed for the results of colonoscopy, barium enema, and flexible sigmoidoscopy in the 3 years prior to diagnosis. An examination that was negative for cancer with no immediate follow-up was defined as a failure of diagnosis, either from inaccurate observation, failure to examine the entire colon, or failure of timely follow-up. The failure rates were compared. RESULTS: Three hundred seventy-nine patients, who had 421 examinations, were analyzed. The diagnosis of colorectal cancer failed in 60 of 379 patients (16%). These 60 patients had 71 examinations that failed to make the diagnosis: 25 of 282 colonoscopies (9%), 16 of 79 barium enemas (20%), and 30 of 60 flexible sigmoidoscopies (50%). These differences were statistically significant. CONCLUSIONS: Failure rates for colonoscopy, barium enema, and flexible sigmoidoscopy were 9%, 20%, and 50%.