Lisa Wang

Phase II trial of the histone deacetylase inhibitor belinostat in women with platinum resistant epithelial ovarian cancer and micropapillary (LMP) ovarian tumours

AIM Micropapillary/borderline (LMP) ovarian tumours are rarely included in clinical trials and are intrinsically resistant to radiation and chemotherapy. Platinum resistant epithelial ovarian cancer (EOC) has a poor prognosis. The histone deacetylase inhibitor belinostat demonstrated antitumour activity in pre-clinical ovarian cancer models. METHODS A phase II study was performed to evaluate the activity of belinostat in two patient populations: women with metastatic or recurrent platinum resistant (progression within 6 months) EOC and LMP ovarian tumours, both groups had received no more than 3 prior lines of chemotherapy. Belinostat 1000 mg/m(2)/d was administered iv days 1-5 of a 21 d cycle. Peripheral blood mononuclear cells (PBMCs) and tumour biopsies, where possible, for correlative studies were obtained prior to and following treatment. RESULTS Eighteen patients with EOC and 14 patients with LMP tumours were enrolled on study. Belinostat was well tolerated with no grade four toxicity (179 cycles). Grade 3 toxicity consisted of thrombosis (3 patients), hypersensitivity (1) and elevated ALP (1). One patient with LMP tumour had a partial response (unconfirmed) and 10 had stable disease (SD), 3 were non-evaluable. Median progression-free survival (PFS) was 13.4 months (95% confidence interval (CI), 5.6--not reached). Best response in patients with EOC was SD (nine patients) and median PFS was 2.3 months (95% CI, 1.2-5.7 months). An accumulation of acetylated histones H3 and H4 was noted in PBMCs and in tumour tissue. CONCLUSIONS Belinostat is well tolerated in both patient groups and shows some activity in patients with micropapillary (LMP) disease.

Reporting of Serious Adverse Drug Reactions of Targeted Anticancer Agents in Pivotal Phase III Clinical Trials

PURPOSE Oncologists prescribe anticancer drugs based on results of phase III randomized clinical trials (RCTs), but some safety concerns appear only later in updated drug labels. Here, we analyze adverse drug reactions (ADRs) of targeted anticancer agents from updated drug labels and their reporting in corresponding pivotal RCTs. METHODS We searched the US Food and Drug Administration (FDA) Web site for approved targeted anticancer drugs with updates of their labels related to safety in 2008 and 2009 and at least one RCT referenced in the updated drug label. For each drug, serious ADRs, including potentially fatal ADRs, were identified from the updated label. Published reports of RCTs referenced in the label were searched to determine whether they described these ADRs. RESULTS We identified 12 eligible targeted anticancer agents with 36 corresponding RCTs referenced in updated drug labels. There were 76 serious ADRs reported in updated drug labels, and 50% (n = 38) were potentially fatal. Of these, 39% (n = 30) of all serious ADRs and 39% (n = 15) of potentially fatal ADRs were not described in any published report of RCTs, whereas 49% and 58%, respectively, were not described in initial drug labels. After a median 4.3 years between initial approval and update of drug labels, 42% (n = 5) of targeted cancer agents acquired one or more boxed warnings (the highest level of FDA alert). CONCLUSION Published reports of pivotal RCTs and initial drug labels contain limited information about serious ADRs of targeted anticancer agents. Rare but serious ADRs may be important causes of morbidity and mortality in general oncologic practice.

Phase I Study of Decitabine in Combination with Vorinostat in Patients with Advanced Solid Tumors and Non-Hodgkin's Lymphomas

Purpose: This phase I study evaluated the safety, tolerability, pharmacokinetics, and preliminary efficacy of the combination of decitabine with vorinostat. Patients and Methods: Patients with advanced solid tumors or non-Hodgkins lymphomas were eligible. Sequential and concurrent schedules were studied. Results: Forty-three patients were studied in 9 different dose levels (6 sequential and 3 concurrent). The maximum tolerated dose (MTD) on the sequential schedule was decitabine 10 mg/m2/day on days 1 to 5 and vorinostat 200 mg three times a day on days 6 to 12. The MTD on the concurrent schedule was decitabine 10 mg/m2/day on days 1 to 5 with vorinostat 200 mg twice a day on days 3 to 9. However, the sequential schedule of decitabine 10 mg/m2/day on days 1 to 5 and vorinostat 200 mg twice a day on days 6 to 12 was more deliverable than both MTDs with fewer delays on repeated dosing and it represents the recommended phase II (RP2D) dose of this combination. Dose-limiting toxicities during the first cycle consisted of myelosuppression, constitutional and gastrointestinal symptoms and occurred in 12 of 42 (29%) patients evaluable for toxicity. The most common grade 3 or higher adverse events were neutropenia (49% of patients), thrombocytopenia (16%), fatigue (16%), lymphopenia (14%), and febrile neutropenia (7%). Disease stabilization for 4 cycles or more was observed in 11 of 38 (29%) evaluable patients. Conclusion: The combination of decitabine with vorinostat is tolerable on both concurrent and sequential schedules in previously treated patients with advanced solid tumors or non-Hodgkins lymphomas. The sequential schedule was easier to deliver. The combination showed activity with prolonged disease stabilization in different tumor types. Clin Cancer Res; 17(6); 1582–90. ©2011 AACR.

The association between EGFR variant III, HPV, p16, c-MET, EGFR gene copy number and response to EGFR inhibitors in patients with recurrent or metastatic squamous cell carcinoma of the head and neck

BackgroundWe examine the potential prognostic and predictive roles of EGFR variant III mutation, EGFR gene copy number (GCN), human papillomavirus (HPV) infection, c-MET and p16INK4Aprotein expression in recurrent or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN).MethodsWe analyzed the archival tumor specimens of 53 patients who were treated in 4 phase II trials for R/M SCCHN. Two trials involved the EGFR inhibitor erlotinib, and 2 trials involved non-EGFR targeted agents. EGFRvIII mutation was determined by quantitative RT-PCR, HPV DNA by Linear Array Genotyping, p16 and c-MET protein expression by immunohistochemistry, and EGFR GCN by FISH.ResultsEGFRvIII mutation, detected in 22 patients (42%), was associated with better disease control, but no difference was seen between erlotinib-treated versus non-erlotinib treated patients. EGFRvIII was not associated with TTP or OS. The presence of HPV DNA (38%), p16 immunostaining (32%), c-MET high expression (58%) and EGFR amplification (27%), were not associated with response, TTP or OS.ConclusionEGFRvIII mutation, present in about 40% of SCCHN, appears to be an unexpected prognostic biomarker associated with better disease control in R/M SCCHN regardless of treatment with erlotinib. Larger prospective studies are required to validate its significance.

Translating clinical trials to clinical practice: outcomes of men with metastatic castration resistant prostate cancer treated with docetaxel and prednisone in and out of clinical trials

BACKGROUND Multiple factors can influence outcomes of patients receiving identical interventions in clinical trials and in routine practice. Here, we compare outcomes of men with metastatic castrate-resistant prostate cancer (mCRPC) treated with docetaxel and prednisone in routine practice and in clinical trials. PATIENTS AND METHODS We reviewed patients with mCRPC treated with docetaxel at Princess Margaret Cancer Centre. Primary outcomes were overall survival and PSA response rate. Secondary outcomes were reasons for discontinuation and febrile neutropenia. Outcomes were compared for men treated in routine practice and in clinical trials, and with data from the TAX 327 study. RESULTS From 2001 to 2011, 438 men were treated, of whom 357 received 3-weekly docetaxel as first-line chemotherapy: 314 in routine practice and 43 in clinical trials. Trial patients were younger and had better performance status. Median survival was 13.6 months [95% confidence interval (95% CI) 12.1-15.1 months] in routine practice and 20.4 months (95% CI 17.4-23.4 months, P = 0.007) within clinical trials, compared with 19.3 months (95% CI 17.6-21.3 months, P < 0.001) in the TAX 327 study. PSA response rates were 45%, 54%, and 53%, respectively (P = NS). Reasons for treatment discontinuation were similar although trial patients received more cycles (median: 6 versus 8 versus 9.5, P < 0.001). Rates of febrile neutropenia were 9.6, 0, and 3% (P < 0.001) while rates of death within 30 days of last dose were 4%, 0%, and 3%, respectively (P = NS). CONCLUSIONS Survival of patients with mCRPC treated with docetaxel in routine practice is shorter than for men included in trials and is associated with more toxicity.

Sorafenib in combination with gemcitabine in recurrent epithelial ovarian cancer: a study of the Princess Margaret Hospital Phase II Consortium.

Objectives: Antiangiogenic strategies have demonstrated efficacy in epithelial ovarian cancer (EOC). Sorafenib is a novel multitargeted kinase inhibitor with antiangiogenic activity. Gemcitabine has known activity against EOC. A phase 1 clinical trial of this combination suggested activity in ovarian cancer with no dose-limiting toxicity. This phase 2 study was designed to examine the safety and efficacy of gemcitabine and sorafenib in patients with recurrent EOC. Methods: Patients with recurrent EOC after platinum-based chemotherapy and who had subsequently received up to 3 prior chemotherapy regimens were eligible. Gemcitabine (1000 mg/m2 intravenous [IV]) was administered weekly for 7 of 8 weeks in the first cycle, then weekly for 3 weeks of each subsequent 4-week cycle. Sorafenib (400 mg p.o. bid) was given continuously. The primary end point for this trial was objective response rate by the Response Evaluation Criteria in Solid Tumors. Secondary endpoints included Gynecologic Cancer Intergroup (GCIG) CA-125 response, time to progression, overall survival, and toxicity. Results: Forty-three patients were enrolled, and 33 completed at least 1 cycle. Two patients had a partial response (Response Evaluation Criteria in Solid Tumors objective response rate = 4.7%). Ten patients (23.3%) maintained response or stable disease for at least 6 months. GCIG CA-125 response was 27.9%. The median time to progression was 5.4 months, and the median overall survival was 13.0 months. Hematologic toxicity was common but manageable. The most common nonhematologic adverse events were hand-foot syndrome, fatigue, hypokalemia, and diarrhea. Conclusion: This trial of gemcitabine and sorafenib in recurrent EOC did not meet its primary efficacy end point, but the combination was associated with encouraging rates of prolonged stable disease and CA-125 response.

A phase II study of sunitinib in recurrent and/or metastatic adenoid cystic carcinoma (ACC) of the salivary glands: current progress and challenges in evaluating molecularly targeted agents in ACC

BACKGROUND Vascular endothelial growth factor (VEGF) and c-kit are highly expressed in adenoid cystic carcinoma (ACC) and associated with biologic aggressiveness. This study aimed to assess the antitumor activity of sunitinib, a multi-targeted inhibitor of vascular endothelial growth factor receptor, c-kit, platelet-derived growth factor receptor, ret proto-oncogene (RET) and FMS-like tyrosine kinase 3 (FLT3), in ACC of the salivary gland. PATIENTS AND METHODS Patients with progressive, recurrent and/or metastatic ACC were treated with sunitinib 37.5 mg daily in this single-arm, two-stage phase II trial. Response was assessed every 8 weeks. RESULTS Fourteen patients were enrolled on to the study. Among 13 assessable patients, there were no objective responses, 11 patients had stable disease (SD), 8 patients had SD ≥ 6 months and 2 patients had progressive disease as best response. Median time to progression was 7.2 months. Median overall survival was 18.7 months. Toxic effects occurring in at least 50% of patients included fatigue, oral mucositis and hypophosphatemia usually of mild to moderate severity. CONCLUSIONS Although no responses were observed, sunitinib was well tolerated, with prolonged tumor stabilization of ≥ 6 months in 62% of assessable patients. The lack of responses is comparable with other trials of molecularly targeted agents in ACC and highlights the need for novel strategies in phase II clinical trial design.

Phase II clinical and pharmacokinetic study of aflibercept in patients with previously treated metastatic colorectal cancer

Purpose: Aflibercept is a recombinant fusion protein of the VEGF receptor (VEGFR) 1 and VEGFR2 extracellular domains. We assessed the safety and efficacy of aflibercept in patients with metastatic colorectal cancer (MCRC) who had received at least one prior palliative regimen. Experimental Design: Seventy-five patients were enrolled onto this two-stage phase II trial in two cohorts, bevacizumab naïve (n = 24) and prior bevacizumab (n = 51). Aflibercept was administered at 4 mg/kg i.v. in two-week cycles. The primary endpoint was a combination of objective response rate and 16-week progression-free survival (PFS). Results: In the bevacizumab-naïve cohort (n = 24), the best response was stable disease for 16 weeks or more in five of 24 patients. In the prior bevacizumab cohort (n = 50), one patient achieved a partial response and six patients had stable disease for 16 weeks or more. The median PFS in the bevacizumab-naïve and prior bevacizumab cohorts was two months [95% confidence interval (CI): 1.7–8.6 months] and 2.4 months (95% CI: 1.9–3.7 months), respectively. Median overall survival (OS) was 10.4 months (95% CI: 7.6–15.5) and 8.5 months (95% CI: 6.2–10.6), respectively. The most common grade 3 or higher treatment-related adverse events were hypertension, proteinuria, fatigue, and headache. Ten patients discontinued study treatment due to toxicity. Mean free to VEGF-bound aflibercept ratio was 1.82, suggesting that free aflibercept was present in sufficient amount to bind endogenous VEGF. Conclusion: Aflibercept showed limited single-agent activity in patients with pretreated MCRC with moderate toxicity. Further study of aflibercept with chemotherapy is ongoing. Clin Cancer Res; 18(21); 6023–31. ©2012 AACR.

A Phase II Study of Pazopanib in Patients with Recurrent or Metastatic Invasive Breast Carcinoma: A Trial of the Princess Margaret Hospital Phase II Consortium

PURPOSE Angiogenesis is an important hallmark of breast cancer growth and progression. Pazopanib, an oral small molecule inhibitor of vascular endothelial growth factor receptor, platelet-derived growth factor receptor, and KIT, has activity across a range of solid tumors. We evaluated the activity of single-agent pazopanib in recurrent or metastatic breast cancer (MBC). PATIENTS AND METHODS Patients with recurrent breast cancer or MBC, treated with up to two prior lines of chemotherapy, were eligible to receive pazopanib, 800 mg daily until progression. The primary endpoint was the objective response rate as measured by Response Evaluation Criteria in Solid Tumors. Secondary endpoints included time to progression, the stable disease rate, and toxicity. Using a two-stage design, confirmed response in three of 18 patients was required to proceed to stage 2. RESULTS Twenty evaluable patients were treated, with a median age of 56 years; 70% were estrogen receptor positive, all were human epidermal growth factor receptor 2 negative. The majority had one or two prior lines of chemotherapy. One patient (5%) had a partial response, 11 (55%) had stable disease (SD) [four (20%) with SD > or = 6 months], and seven (35%) had progressive disease as their best response. One (5%) was not evaluable. The median time to progression was 5.3 months. Pazopanib did not cause significant severe toxicity aside from grade 3-4 transaminitis, hypertension, and neutropenia in three patients each (14% each) and grade 3 gastrointestinal hemorrhage in one patient (5%). CONCLUSION Pazopanib provides disease stability in advanced breast cancer. The activity seen is comparable with that of other antiangiogenic agents in this setting. Pazopanib may be of interest for future studies in breast cancer, including in combination with other systemic agents.

A multicenter phase II clinical trial of lapatinib (GW572016) in hormonally untreated advanced prostate cancer.

Objectives:Lapatinib (GW572016) is a selective and potent dual tyrosine kinase inhibitor of the epidermal growth factor 1 (EGFR) and 2 (HER2), approved in the treatment of HER2 positive breast cancer. Since EGFR and HER2 overexpression has also been seen in prostate cancer and appears to correlate with a worse clinical outcome, Lapatinib may represent a novel therapeutic strategy in prostate cancer. This Phase II multicenter clinical trial is the first to evaluate Lapatinib in early stage, hormonally untreated recurrent or metastatic prostate cancer. Methods:Eligible patients received lapatinib 1500 mg PO daily until progression. The primary end point was prostate specific antigen (PSA) response. Archival tumor tissue was collected for EGFR and HER2 analysis. Results:A total of 23 patients, median age 67, ECOG PS 0–2, mean baseline PSA 7.5, were evaluable for response. In total, 125 cycles were administered. The most frequent adverse events were lymphopenia, fatigue, rash, dyspepsia, and diarrhea. Grade 3+ increased alanine aminotransferase (ALT) was reported in 2 patients, and grade 4 blurry vision in 1 patient. No PSA responses were seen. Median time to progression (TTP) was 4.6 months and 6 months progression-free estimate was 44.5%. Conclusions:Lapatinib was well tolerated but like other EGFR- and HER2-targeted agents in advanced HRPC failed to show significant antitumor activity even in this very early stage hormonally untreated population.