Thomas Adam Abrams

Efficacy, safety, and potential biomarkers of sunitinib monotherapy in advanced hepatocellular carcinoma: a phase II study.

PURPOSE To assess the safety and efficacy of sunitinib in patients with advanced hepatocellular carcinoma (HCC) and explore biomarkers for sunitinib response. PATIENTS AND METHODS We conducted a multidisciplinary phase II study of sunitinib, an antivascular endothelial growth factor receptor tyrosine kinase inhibitor, in advanced HCC. Patients received sunitinib 37.5 mg/d for 4 weeks followed by 2 weeks of rest per cycle. The primary end point was progression-free survival (PFS). We used functional magnetic resonance imaging to evaluate vascular changes in HCC after sunitinib treatment. Circulating molecular and cellular biomarkers were evaluated before and at six time points after sunitinib treatment. RESULTS Thirty-four patients were enrolled. The objective response rate was 2.9%, and 50% of patients had stable disease. Median PFS was 3.9 months (95% CI, 2.6 to 6.9 months), and overall survival was 9.8 months (95% CI, 7.4 months to not available). Grade 3 or 4 toxicities included leukopenia/neutropenia, thrombocytopenia, elevation of aminotransferases, and fatigue. Sunitinib rapidly decreased vessel leakiness, and this effect was more pronounced in patients with delayed progression. When evaluated early (at baseline and day 14) as well as over three cycles of treatment, higher levels of inflammatory molecules (eg, interleukin-6, stromal-derived factor 1alpha, soluble c-KIT) and circulating progenitor cells were associated with a poor outcome. CONCLUSION Sunitinib shows evidence of modest antitumor activity in advanced HCC with manageable adverse effects. Rapid changes in tumor vascular permeability and circulating inflammatory biomarkers are potential determinants of response and resistance to sunitinib in HCC. Our study suggests that control of inflammation might be critical for improving treatment outcome in advanced HCC.

Oral mTOR Inhibitor Everolimus in Patients With Gemcitabine-Refractory Metastatic Pancreatic Cancer

PURPOSE The PI3K/Akt/mTOR pathway is activated in the majority of pancreatic cancers, and inhibition of this pathway has antitumor effects in preclinical studies. We performed a multi-institutional, single-arm, phase II study of RAD001(everolimus), an oral inhibitor of mTOR, in patients who experienced treatment failure on first-line therapy with gemcitabine. PATIENTS AND METHODS Thirty-three patients with gemcitabine-refractory, metastatic pancreatic cancer were treated continuously with RAD001 at 10 mg daily. Prior treatment with fluorouracil in the perioperative setting was allowed. Patients were observed for toxicity, treatment response, and survival. RESULTS Treatment with single-agent RAD001 was well-tolerated; the most common adverse events were mild hyperglycemia and thrombocytopenia. No patients were removed from the study because of drug-related adverse events. No complete or partial treatment responses were noted, and only seven patients (21%) had stable disease at the first restaging scans performed at 2 months. Median progression-free survival and overall survival were 1.8 months and 4.5 months, respectively. One patient (3%) had a biochemical response, defined as > or = 50% reduction in serum CA19-9. CONCLUSION Although well-tolerated, RAD001 administered as a single-agent had minimal clinical activity in patients with gemcitabine-refractory, metastatic pancreatic cancer. Future studies in metastatic pancreatic cancer should assess the combination of mTOR inhibitors with other agents and/or examine inhibitors of other components of the PI3K/Akt/mTOR pathway.

Efficacy and safety of gemcitabine, oxaliplatin, and bevacizumab in advanced biliary-tract cancers and correlation of changes in 18-fluorodeoxyglucose PET with clinical outcome: a phase 2 study

BACKGROUND Previous phase 2 studies have shown antitumour activity with gemcitabine and oxaliplatin (GEMOX) in patients with advanced biliary-tract cancers (BTCs). In this phase 2 study, we assessed the efficacy and safety of combined bevacizumab with GEMOX (GEMOX-B) in patients with advanced BTCs, and investigated how changes in 18-fluorodeoxyglucose ([(18)F]FDG)-PET correlate with clinical outcome. METHODS Patients with advanced measurable BTCs were given the following treatment on days 1 and 15 of a 28-day cycle: bevacizumab 10 mg/kg, followed by gemcitabine 1000 mg/m(2) (10 mg/m(2) per min) and oxaliplatin 85 mg/m(2) (2-h infusion). [(18)F]FDG-PET scans were obtained at baseline and after completion of the second cycle. The primary endpoint was progression-free survival (PFS). Efficacy and safety analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00361231. FINDINGS 35 patients were enrolled and evaluable for efficacy and toxicity. Median PFS was 7.0 months (95% CI 5.3-10.3), and PFS at 6 months was 63% (47-79), which was below the targeted rate of 70%. Grade 3-4 toxic effects included neutropenia (n=7), raised alanine aminotransferase concentrations (n=5), peripheral neuropathy (n=5), and hypertension (n=5). [(18)F]FDG-PET scans showed a significant decrease in maximum standardised uptake value (SUV(max)) after two cycles of treatment (5.72 [SD 2.01] at baseline; 3.73 [SD 1.88] after two cycles; p<0.0001). These changes were more pronounced in patients with partial response or stable disease than those with progressive disease (24 patients, -2.80 [SD 1.95] vs five patients, 1.41 [SD 3.13]; p=0.009). Change in SUV(max) was a significant predictor of PFS (HR 1.35, 1.14-1.60, p=0.0006) and overall survival (1.25, 1.05-1.50, p=0.01). INTERPRETATION GEMOX-B showed antitumour activity with tolerable safety in patients with advanced BTCs. Decreases in SUV(max) on [(18)F]FDG-PET scans after treatment were associated with disease control and increases in PFS and overall survival. FUNDING Genentech Oncology and Sanofi-Aventis.

Phase 1/2 Study of Everolimus in Advanced Hepatocellular Carcinoma

The phosphoinositide 3‐kinase/Akt/mammalian target of rapamycin pathway plays a critical role in the pathogenesis of hepatocellular carcinoma (HCC). We performed a single‐arm, phase 1/2 study of everolimus in patients with advanced HCC.

First-in-Man Phase I Study of GC33, A Novel Recombinant Humanized Antibody against Glypican-3, in Patients with Advanced Hepatocellular Carcinoma

Purpose: GC33 is a novel recombinant fully humanized monoclonal antibody that binds to human glypican-3 (GPC3). The antitumor activity of GC33 was shown in preclinical models of hepatocellular carcinoma (HCC). This first-in-man clinical trial was conducted to evaluate the safety, pharmacokinetic characteristics, and preliminary efficacy of GC33 in patients with advanced HCC. Experimental Design: Patients with measurable, histologically proven, advanced HCC were enrolled to a dose-escalation study of GC33 (2.5–20 mg/kg) given intravenously weekly. The primary endpoint was to determine the maximum tolerated dose of GC33 for further development. Pharmacokinetic characteristics were measured in serum samples. Immunohistochemistry was conducted on tumor biopsies to evaluate GPC3 expression. Tumor response was assessed every 8 weeks using Response Evaluation Criteria in Solid Tumors criteria. Results: Twenty patients were enrolled and treated with GC33. A maximum tolerated dose was not reached as there were no dose-limiting toxicities (DLT) up to the highest planned dose level. Common adverse events with all grades included fatigue (50%), constipation (35%), headache (35%), and hyponatremia (35%). The incidence of adverse events seemed not to be dose dependent. Trough serum concentrations at steady state were in excess of target concentration at doses of 5 mg/kg or greater. Median time to progression (TTP) was 26.0 weeks in the GPC3 high expression group and 7.1 weeks in the low expression group (P = 0.033). Conclusion: This study shows that GC33 was well tolerated in advanced HCC and provides preliminary evidence that GPC3 expression in HCC may be associated with the clinical benefit to GC33 that warrants prospective evaluation. Clin Cancer Res; 19(4); 920–8. ©2012 AACR.

A multicenter phase II trial of single-agent cetuximab in advanced esophageal and gastric adenocarcinoma

BACKGROUND Epidermal growth factor receptor (EGFR) is overexpressed in a significant proportion of esophageal and gastric carcinomas. Although previous studies have examined tyrosine kinase inhibitors of EGFR, there remains limited data regarding the role of EGFR-directed monoclonal antibody therapy in these malignancies. We carried out a multi-institutional phase II study of cetuximab, a monoclonal antibody against EGFR, in patients with unresectable or metastatic esophageal or gastric adenocarcinoma. PATIENTS AND METHODS Thirty-five patients with previously treated metastatic esophageal or gastric adenocarcinoma were treated with weekly cetuximab, at an initial dose of 400 mg/m(2) followed by weekly infusions at 250 mg/m(2). Patients were followed for toxicity, treatment response, and survival. RESULTS Treatment with cetuximab was well tolerated; no patients were taken off study due to drug-related adverse events. One (3%) partial treatment response was noted. Two (6%) patients had stable disease after 2 months of treatment. Median progression-free survival and overall survival were 1.6 and 3.1 months, respectively. CONCLUSION Although well tolerated, cetuximab administered as a single agent had minimal clinical activity in patients with metastatic esophageal and gastric adenocarcinoma. Ongoing studies of EGFR inhibitors in combination with other agents may define a role for these agents in the treatment of esophageal and gastric cancer.

Panitumumab in Patients with KRAS Wild-Type Colorectal Cancer after Progression on Cetuximab

PURPOSE Cetuximab and panitumumab are monoclonal antibodies that target the epidermal growth factor receptor (EGFR) and are approved for the treatment of patients with KRAS wild-type meta-static colorectal cancer. There are no data that describe the activity of panitumumab in patients with progressive disease on cetuximab. We performed a single-arm phase II trial of panitumumab in patients with KRAS wild-type metastatic colorectal cancer that had progressed on prior cetuximab. PATIENTS AND METHODS We used a two-stage study design to treat patients with panitumumab at 6 mg/kg every 14 days (cycle length = 28 days). Treatment was continued until disease progression, death, inability to tolerate panitumumab, or study withdrawal. The primary endpoint was response rate; secondary endpoints included progression-free survival and overall survival. Twenty patients were treated in the first stage, with plans to treat an additional twelve patients if there was at least one objective response. We collected blood samples at baseline and prior to cycles 2 and 3 to evaluate for the presence of anti-cetuximab and anti-panitumumab antibodies. RESULTS We treated twenty patients for a median of two cycles (range 1-4). No patients responded, and 45% had a best response of stable disease (no progression for at least two cycles). Median progression-free survival was 1.7 months and median overall survival was 5.2 months. Panitumumab was well tolerated. Thirteen patients (65%) had grade 1-2 dry skin or rash, and three patients had treatment-related grade 3 toxicities (one each with hyperglycemia, hyperbilirubinemia, and hypokalemia). No patients had detectable anti-cetuximab antibodies at any time point; one patient developed anti-panitumumab antibodies. CONCLUSIONS Panitumumab has minimal benefit in patients with KRAS wild-type metastatic colorectal cancer that has progressed on prior cetuximab. Discussion Both cetuximab and panitumumab competitively inhibit ligand binding to EGFR, thereby promoting receptor internalization and blocking receptor-mediated signaling. Although the two agents have never been compared directly in a randomized clinical trial, they produce similar response rates when used alone as well as in combination with cytotoxic agents. Cetuximab is a chimeric antibody with approximately 30% murine protein, while panitumumab is a fully human monoclonal antibody. Correspondingly, rates of severe hypersensitivity reactions are somewhat increased with cetuximab (3%) compared to panitumumab (1%). However, the potential efficacy of panitumumab in patients who have developed disease progression on cetuximab has been an open question. Metges et al. (PANERB trial) prospectively treated 32 KRAS wild-type metastatic colorectal cancer patients with cetuximab and irinotecan followed by panitumumab monotherapy after progression. Remarkably, the authors reported an objective response rate of 22% to panitumumab, including a disease control rate (objective response plus stable disease) of 73% in 11 patients who had previously responded to cetuximab and irinotecan. In contrast, we found no responders and a stable disease rate of 45% with a median duration of only 1.7 months in our trial of 20 patients. Moreover, no patients had detectable anti-cetuximab antibodies at baseline. It is not clear to what extent the PANERB trial included patients without objective disease progression on cetuximab or for whom cetuximab-containing regimens may have been ceased due to toxicity in the absence of disease progression. In both circumstances, retreatment with panitumumab may be expected to demonstrate some degree of clinical activity. In our study, disease progression after at least 4 weeks of cetuximab documented radiographically or by increased carcinoembryonic antigen (CEA) levels was required for inclusion in order to ensure that the study population demonstrated unequivocal evidence of progression on cetuximab. While it remains possible that a small subset of patients may benefit from panitumumab after progression on cetuximab, our results suggest that this approach should not be adopted until predictive biomarkers for panitumumab response in this setting have been discovered and validated. Until then, patients who develop progression on cetuximab should be enrolled in trials of novel agents.

Efficacy, safety, pharmacokinetics and biomarkers of cediranib monotherapy in advanced hepatocellular carcinoma: A phase II study

Purpose: We conducted a single-arm phase II study of cediranib, a pan-VEGFR tyrosine kinase inhibitor, in patients with advanced hepatocellular carcinoma (HCC). Experimental Design: Patients with histologically confirmed measurable advanced HCC and adequate hematologic, hepatic, and renal functions received cediranib 30-mg orally once daily (4 weeks/cycle). The primary endpoint was progression-free survival (PFS) rate at 3 months. Other endpoints included response rates, overall survival (OS), pharmacokinetics (PK), and biomarkers for cediranib. Results: Cediranib treatment resulted in an estimated 3-month PFS rate of 77% (60%, 99%). Median PFS was 5.3 (3.5,9.7) months, stable disease was seen in 5/17 patients (29%), and median OS was 11.7 (7.5–13.6) months. Grade 3 toxicities included hypertension (29%), hyponatremia (29%), and hyperbilirubinemia (18%). Cediranib PK were comparable to those seen in cancer patients with normal hepatic function. Plasma levels of VEGF and PlGF increased and sVEGFR1, sVEGFR2, and Ang-2 decreased after cediranib treatment. PFS was inversely correlated with baseline levels of VEGF, sVEGFR2, and bFGF and with on-treatment levels of bFGF and IGF-1, and directly associated with on-treatment levels of IFN-γ. OS was inversely correlated with baseline levels of sVEGFR1, Ang-2, TNF-α, CAIX, and CD34+CD133+CD45dim circulating progenitor cells and on-treatment levels of sVEGFR2. Conclusions: Despite the limitations of primary endpoint selection, cediranib at 30-mg daily showed a high incidence of toxicity and preliminary evidence of antitumor activity in advanced HCC. Hepatic dysfunction did not seem to affect the steady-state PK of cediranib. Exploratory studies suggested proangiogenic and inflammatory factors as potential biomarkers of anti-VEGF therapy in HCC. Clin Cancer Res; 19(6); 1557–66. ©2013 AACR.

Patterns of Adjuvant Chemotherapy Use in a Population-Based Cohort of Patients With Resected Stage II or III Colon Cancer

PURPOSE Previous studies have examined predictors for initiation of adjuvant chemotherapy in stages II and III colon cancer. However, little is known regarding the use of specific chemotherapy regimens or treatment duration. PATIENTS AND METHODS We studied treatment records for 2,560 patients with stage II or III colon cancer who received adjuvant chemotherapy between January 2004 and April 2010 at US cancer care facilities participating in a nationwide, commercially available chemotherapy order entry system that captures patient demographics, stage, and details of chemotherapy treatment. Multivariate analyses of prospectively recorded patient and provider characteristics identified predictors of specific therapeutic approaches. RESULTS The addition of oxaliplatin to fluoropyrimidine-based adjuvant therapy increased during the study period (P trend < .001), and this combination represented 78% and 90% of adjuvant chemotherapy in stage II or III disease, respectively, by 2007. Older patients, those with diminished performance status, and those treated in a private practice setting were significantly less likely to receive oxaliplatin. Thirty percent of patients discontinued adjuvant therapy after less than 3 months. Older age, treatment without oxaliplatin, and receipt of treatment from a physician with a low volume of patients were each independently associated with premature discontinuation [corrected]. Six percent of patients received bevacizumab as part of their adjuvant regimen. CONCLUSION After 2004, oxaliplatin and fluoropyrimidine-based therapy rapidly became the predominant adjuvant treatment for both stage II and stage III colon cancer in this large US cohort. Both increasing patient age and lower volume of an oncologists practice were associated with early termination of adjuvant therapy.

Phase I study of cetuximab, irinotecan, and vandetanib (ZD6474) as therapy for patients with previously treated metastastic colorectal cancer.

Background To determine the maximum tolerated dose (MTD) and safety, and explore efficacy and biomarkers of vandetanib with cetuximab and irinotecan in second-line metastatic colorectal cancer. Methods Vandetanib (an orally bioavailable VEGFR-2 and EGFR tyrosine kinases inhibitor) was combined at 100 mg, 200 mg, or 300 mg daily with standard dosed cetuximab and irinotecan (3+3 dose-escalation design). Ten patients were treated at the MTD and plasma angiogenesis biomarkers (VEGF, PlGF, bFGF, sVEGFR1, sVEGFR2, IL-1β, IL-6, IL-8, TNF-α, SDF1α) were measured before and after treatment. Results Twenty-seven patients were enrolled at 4 dose levels and the MTD. Two dose-limiting toxicities (grade 3 QTc prolongation and diarrhea) were detected at 300 mg of vandetanib with cetuximab and irinotecan resulting in 200 mg being the MTD. Seven percent of patients had a partial response, 59% stable disease and 34% progressed. Median progression-free survival was 3.6 months (95% CI, 3.2–5.6) and median overall survival was 10.5 months (95% CI, 5.1–20.7). Toxicities were fairly manageable with grade 3 or 4 diarrhea being most prominent (30%). Vandetanib and cetuximab treatment induced a sustained increase in plasma PlGF and a transient decrease in plasma sVEGFR1, but no changes in plasma VEGF and sVEGFR2. Conclusions Vandetanib can be safely combined with cetuximab and irinotecan for metastatic colorectal cancer. Exploratory biomarker analyses suggest differential effects on certain plasma biomarkers for VEGFR inhibition when combined with EGFR blockade and a potential correlation between baseline sVEGFR1 and response. However, while the primary endpoint was safety, the observed efficacy raises concern for moving forward with this combination. Trial Registration Clinicaltrials.gov NCT00436072.