Chris R. Garrett

Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial

BACKGROUND No effective therapeutic options for patients with unresectable imatinib-resistant gastrointestinal stromal tumour are available. We did a randomised, double-blind, placebo-controlled, multicentre, international trial to assess tolerability and anticancer efficacy of sunitinib, a multitargeted tyrosine kinase inhibitor, in patients with advanced gastrointestinal stromal tumour who were resistant to or intolerant of previous treatment with imatinib. METHODS Blinded sunitinib or placebo was given orally once daily at a 50-mg starting dose in 6-week cycles with 4 weeks on and 2 weeks off treatment. The primary endpoint was time to tumour progression. Intention-to-treat, modified intention-to-treat, and per-protocol analyses were done. This study is registered at ClinicalTrials.gov, number NCT00075218. FINDINGS 312 patients were randomised in a 2:1 ratio to receive sunitinib (n=207) or placebo (n=105); the trial was unblinded early when a planned interim analysis showed significantly longer time to tumour progression with sunitinib. Median time to tumour progression was 27.3 weeks (95% CI 16.0-32.1) in patients receiving sunitinib and 6.4 weeks (4.4-10.0) in those on placebo (hazard ratio 0.33; p<0.0001). Therapy was reasonably well tolerated; the most common treatment-related adverse events were fatigue, diarrhoea, skin discolouration, and nausea. INTERPRETATION We noted significant clinical benefit, including disease control and superior survival, with sunitinib compared with placebo in patients with advanced gastrointestinal stromal tumour after failure and discontinuation of imatinab. Tolerability was acceptable.

Expression of Epiregulin and Amphiregulin and K-ras Mutation Status Predict Disease Control in Metastatic Colorectal Cancer Patients Treated With Cetuximab

PURPOSE The antiepidermal growth factor receptor (EGFR) antibody cetuximab shows activity in multiple epithelial tumor types; however, responses are seen in only a subset of patients. This study was conducted to identify markers that are associated with disease control in patients treated with cetuximab. PATIENTS AND METHODS One hundred ten patients with metastatic colorectal cancer were enrolled onto a cetuximab monotherapy trial. Transcriptional profiling was conducted on RNA from mandatory pretreatment metastatic biopsies to identify genes whose expression correlates with best clinical responses. EGFR and K-ras mutation analyses and EGFR gene copy number analyses were performed on DNA from pretreatment biopsies. RESULTS Gene expression profiles showed that patients with tumors that express high levels of the EGFR ligands epiregulin and amphiregulin are more likely to have disease control with cetuximab (EREG, P = .000015; AREG, P = .000025). Additionally, patients whose tumors do not have K-ras mutations have a significantly higher disease control rate than patients with K-ras mutations (P = .0003). Furthermore, patients with tumors that have high expression of EREG or AREG also have significantly longer progression-free survival (PFS) than patients with low expression (EREG: P = .0002, hazard ratio [HR] = 0.47, and median PFS, 103.5 v 57 days, respectively; AREG: P < .0001, HR = 0.44, and median PFS, 115.5 v 57 days, respectively). CONCLUSION Patients with tumors that have high gene expression levels of epiregulin and amphiregulin and patients with wild-type K-ras are more likely to have disease control on cetuximab treatment. The identified markers could be developed further to select patients for cetuximab therapy.

Phase I and Pharmacokinetic Study of YM155, a Small-Molecule Inhibitor of Survivin

PURPOSE To determine the maximum-tolerated dose (MTD) and assess the safety, pharmacokinetics, and preliminary evidence of antitumor activity of YM155, a small-molecule inhibitor of survivin. PATIENTS AND METHODS Patients with advanced solid malignancies or lymphoma were treated with escalating doses of YM155 administered by 168-hour continuous intravenous infusion (CIVI). Plasma and urine samples were assayed to determine pharmacokinetic parameters and excretion. RESULTS Forty-one patients received 127 cycles of YM155 at doses ranging from 1.8 to 6.0 mg/m(2)/d by 168-hour CIVI every 3 weeks. Overall, the most common grade 1 to 2 toxicities were stomatitis, pyrexia, and nausea, whereas grade 3 and 4 toxicities were rare. Reversible elevation in serum creatinine in two patients, with one developing acute tubular necrosis, was dose-limiting at 6.0 mg/m(2). The MTD was 4.8 mg/m(2). At the MTD, the mean steady-state concentration, clearance, volume of distribution at steady-state, and terminal elimination half-life were 7.7 ng/mL, 47.7 L/h, 1,763 L, and 26 hours, respectively. One complete and two partial responses lasting 8, 24+ and 48+ months occurred in three patients with non-Hodgkins lymphoma, two patients with hormone- and docetaxel-refractory prostate cancer had prostate-specific antigen responses, and one patient with non-small-cell lung cancer had a minor response. CONCLUSION YM155 can be administered safely at 4.8 mg/m(2)/d 168 hours CIVI every 3 weeks. The absence of severe toxicities, attainment of plasma concentrations active in preclinical models, and compelling antitumor activity warrant further disease-directed studies of this agent alone and in combination with chemotherapy in a broad array of tumors.

Phase I Trial of Histone Deacetylase Inhibition by Valproic Acid Followed by the Topoisomerase II Inhibitor Epirubicin in Advanced Solid Tumors: A Clinical and Translational Study

PURPOSE To determine the safety, toxicity, and maximum-tolerated dose of a sequence-specific combination of the histone deacetylase inhibitor (HDACi), valproic acid (VPA), and epirubicin in solid tumor malignancies and to define the clinical feasibility of VPA as an HDACi. PATIENTS AND METHODS Patients were treated with increasing doses of VPA (days 1 through 3) followed by epirubicin (day 3) in 3-week cycles. The study evaluated pharmacokinetic and pharmacodynamic end points, toxicities, and tumor response. RESULTS Forty-eight patients were enrolled, and 44 received at least one cycle of therapy. Patients (median age, 54 years; range, 39 to 78 years) received the following doses of VPA: 15, 30, 45, 60, 75, 90, 100, 120, 140, and 160 mg/kg/d. Dose-limiting toxicities were somnolence (n = 1), confusion (n = 3), and febrile neutropenia (n = 1). No exacerbation of epirubicin-related toxicities was observed. Partial responses were seen across different tumor types in nine patients (22%), and stable disease/minor responses were seen in 16 patients (39%), despite a median number of three prior regimens (range, zero to 10 prior regimens). Patients received a median number of four treatment cycles (range, one to 10 cycles), and treatment was stopped after reaching maximal epirubicin doses rather than progression in 13 (32%) of 41 patients patients. Total and free VPA plasma concentrations increased linearly with dose and correlated with histone acetylation in peripheral-blood mononuclear cells. CONCLUSION The maximum-tolerated dose and recommended phase II dose was VPA 140 mg/kg/d for 48 hours followed by epirubicin 100 mg/m2. Sustained plasma concentrations of VPA exceeding those required for in vitro synergy were achieved with acceptable toxicity. Noteworthy antitumor activity was observed in heavily pretreated patients and historically anthracycline-resistant tumors.

Malignant Pleural Mesothelioma: A Comprehensive Review

BACKGROUND The incidence of malignant mesothelioma continues to increase, but the disease remains difficult to detect early and treat effectively. METHODS The authors review the pathogenesis, incidence, clinical presentation, diagnosis, pathology, and both standard and experimental treatments for mesothelioma. RESULTS When possible, surgery (video-assisted thoracoscopy, pleurectomy/decortication, or extrapleural pneumonectomy) is utilized. Effects on underlying structures limit application of radiation therapy, but some systemic agents are beginning to enhance survival. CONCLUSIONS The disease is expected to increase in incidence till 2020, so awareness of this entity as a possible diagnosis should be heightened. In patients with advanced disease, several newer antitumor agents are already showing a capability of extending survival so it is not unreasonable to expect further progress in this area.

A Phase 1 Escalating Single-Dose and Weekly Fixed-Dose Study of Cetuximab: Pharmacokinetic and Pharmacodynamic Rationale for Dosing

Purpose: This phase 1 study evaluated the pharmacokinetic and pharmacodynamic effects of cetuximab on patients with epithelial malignancies. Experimental Design: Following a skin and tumor biopsy, patients with advanced epithelial malignancies were randomized to receive a single dose of cetuximab at 50, 100, 250, 400, or 500 mg/m2 i.v. Repeat skin (days 2, 8, 15, and 22) and tumor (day 8) biopsies were obtained. Immunohistochemical expression of epidermal growth factor receptor (EGFR) and its pathway members was done on biopsies. Blood samples were obtained over 22 days for pharmacokinetic analyses. After day 22, all patients received weekly 250 mg/m2 cetuximab until disease progression or unacceptable toxicity. Results: Thirty-nine patients enrolled. Rash was noted in 26 (67%) patients. Three patients (two with colon cancer and one with laryngeal cancer) achieved a partial response and 13 patients had stable disease. Pharmacokinetic data revealed mean maximum observed cetuximab concentrations and mean area under the concentration-time curve from time zero to infinity increased in a dose-dependent manner up to 400 mg/m2 cetuximab. Mean clearance was similar at cetuximab doses ≥100 mg/m2, supporting saturation of EGFR binding at 250 mg/m2. Pharmacodynamic evaluation revealed that patients with partial response/stable disease had a higher-grade rash and higher cetuximab trough levels than those with progressive disease (P = 0.032 and 0.002, respectively). Administration of single doses (250-500 mg/m2) of cetuximab resulted in a dose-dependent decrease in EGFR protein expression levels in skin over time, supporting a minimal dose of cetuximab at 250 mg/m2 for a pharmacodynamic effect. Conclusion: This study provides a pharmacokinetic and pharmacodynamic rationale for the dosing of cetuximab.

Complete Longitudinal Analyses of the Randomized, Placebo-controlled, Phase III Trial of Sunitinib in Patients with Gastrointestinal Stromal Tumor Following Imatinib Failure

Purpose: To analyze final long-term survival and clinical outcomes from the randomized phase III study of sunitinib in gastrointestinal stromal tumor patients after imatinib failure; to assess correlative angiogenesis biomarkers with patient outcomes. Experimental Design: Blinded sunitinib or placebo was given daily on a 4-week-on/2-week-off treatment schedule. Placebo-assigned patients could cross over to sunitinib at disease progression/study unblinding. Overall survival (OS) was analyzed using conventional statistical methods and the rank-preserving structural failure time (RPSFT) method to explore cross-over impact. Circulating levels of angiogenesis biomarkers were analyzed. Results: In total, 243 patients were randomized to receive sunitinib and 118 to placebo, 103 of whom crossed over to open-label sunitinib. Conventional statistical analysis showed that OS converged in the sunitinib and placebo arms (median 72.7 vs. 64.9 weeks; HR, 0.876; P = 0.306) as expected, given the cross-over design. RPSFT analysis estimated median OS for placebo of 39.0 weeks (HR, 0.505, 95% CI, 0.262–1.134; P = 0.306). No new safety concerns emerged with extended sunitinib treatment. No consistent associations were found between the pharmacodynamics of angiogenesis-related plasma proteins during sunitinib treatment and clinical outcome. Conclusions: The cross-over design provided evidence of sunitinib clinical benefit based on prolonged time to tumor progression during the double-blind phase of this trial. As expected, following cross-over, there was no statistical difference in OS. RPSFT analysis modeled the absence of cross-over, estimating a substantial sunitinib OS benefit relative to placebo. Long-term sunitinib treatment was tolerated without new adverse events. Clin Cancer Res; 18(11); 3170–9. ©2012 AACR.

Phase II study of sunitinib malate, a multitargeted tyrosine kinase inhibitor in patients with relapsed or refractory soft tissue sarcomas. focus on three prevalent histologies: leiomyosarcoma, liposarcoma and malignant fibrous histiocytoma

Soft tissue sarcomas (STS) represent a diverse group of histologic subtypes with targetable molecular alterations, often treated as a single disease. Sunitinib malate is a multitargeted receptor tyrosine kinase inhibitor active in other solid tumors carrying similar alterations (i.e., imatinib mesylate‐refractory gastrointestinal stromal tumors). This single‐institution phase II study investigated the safety and efficacy of sunitinib malate in three common STS subtypes. Patients with documented unresectable or metastatic STS (liposarcoma, leiomyosarcoma and malignant fibrous histiocytoma [MFH]), measurable disease, and 3 or less prior lines of therapy were eligible. Treatment consisted of sunitinib malate, 50 mg daily, for 4 weeks every 6 weeks. Forty‐eight patients were enrolled, and 35% were heavily pretreated (≥2 prior lines of chemotherapy). The safety profile resembled previously known sunitinib malate toxicities. Median progression‐free and overall survivals for liposarcoma, leiomyosarcoma, and MFH were 3.9 and 18.6, 4.2 and 10.1 and 2.5 and 13.6 months, respectively. The 3‐month progression‐free rates in the untreated and pretreated (chemotherapy) patients with liposarcoma, leiomyosarcoma and MFH were 75% and 69.2%, 60%, and 62.5% and 25% and 44.4%, respectively. With the caveats that a minority of patients with potentially indolent or low‐grade disease could have been included and the small numbers, a 3‐month progression‐free rate of >40% suggests activity for sunitinib malate at least in liposarcomas and leiomyosarcomas. Thus, we believe that further investigation in these susceptible STS subtypes is warranted.

Phase I Trial of Poly-l-Glutamate Camptothecin (CT-2106) Administered Weekly in Patients with Advanced Solid Malignancies

Purpose: CT-2106 is a 20(S)-camptothecin poly-l-glutamate conjugate. This linkage stabilizes the active lactone form of camptothecin and enhances aqueous solubility. In addition, poly-l-glutamate is postulated to increase tumor delivery of the active compound through enhanced permeability and retention effect in tumor. We studied a weekly schedule of CT-2106 in patients with refractory solid tumor malignancies. Experimental Design: CT-2106 was infused (10 min i.v. infusion) on days 1, 8, and 15 of each 28-day cycle. Plasma and urine were analyzed for total and unconjugated camptothecin by high-performance liquid chromatography equipped with a fluorescence detector. Toxicity and response assessments were done with Common Toxicity Criteria for Adverse Events version 3 and Response Evaluation Criteria in Solid Tumors, respectively. Results: Twenty-six patients were enrolled. Median age was 58 years (range, 36-83) and median number of doses was 6 (range, 1-9). The most frequent tumor type (50%) was melanoma. Dose limiting toxicities were thrombocytopenia and fatigue. A weekly dose of 25 mg/m2 given every 3 of 4 weeks was the maximum tolerated dose. The majority of grade 3 and 4 toxicities were hematologic. The pharmacokinetic profile of conjugated and unconjugated camptothecin showed a polyexponential decline with similar terminal half life (t1/2 range was 44-63 and 31-48 h for conjugated and unconjugated, respectively). Pharmacokinetics of conjugated and unconjugated camptothecin were dose and time independent in the tested dose range. Urinary excretion of conjugated and unconjugated camptothecin accounted for about 30% and 4% of the administered dose, respectively. Conclusions: CT-2106 has a more manageable toxicity profile compared with unconjugated camptothecin. The maximum tolerated dose is 25 mg/m2 weekly given 3 of 4 weeks. This compound results in prolonged release of unconjugated camptothecin.

Clinical and translational results of CALGB 40601: A neoadjuvant phase III trial of weekly paclitaxel and trastuzumab with or without lapatinib for HER2-positive breast cancer.

500 Background: Pts frequently treated with OC in the adjuvant, perioperative, or first-line setting for CRC may be retreated with oxaliplatin at the time of relapse or progression; the efficacy of retreatment is not known. Methods: Under an IRB-approved protocol, the pharmacy records identified 1,166 pts who received OC for CRC at our institution from 1/1/2004-12/30/2009. Pts were categorized as having previously received OC initially for the indication of adjuvant (group A, n=29), unresectable metastatic disease (group B, n=75), or perioperative therapy for metastasectomy (group C, n =22). Results: Four RECIST responses (14%) were seen in group A (2 of these pts received cetuximab in combination), four responses in group B (5%), and no responses in group C. Retreatment with OC following initial oxaliplatin exposure was associated with a low radiographic and biochemical response rate and a short time to progression or withdrawal of OC (Table). Retreatment duration was limited by cumulative neurotoxicity ...