Chaan Ng

Amgen, Thousand Oaks, California, United States

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Publications (27)199.1 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: To characterize the incidence, onset, management, predictors, and clinical impact of mTOR inhibitor associated noninfectious pneumonitis (NIP) on patients with metastatic renal cell carcinoma. Retrospective review of 310 patients with metastatic renal cell carcinoma who received temsirolimus and/or everolimus between 6/1/2007 and 10/1/2010. Clinical correlations were made with serial radiologic imaging. Fisher's exact, Wilcoxon rank sum, and logistic regression analysis were performed to evaluate the association of NIP with demographic or clinical factors. Log rank and Cox proportional hazards regression analysis were used for the time-to-event analysis. NIP occurred in 6% of temsirolimus and 23% of everolimus treated patients. Symptoms included cough, dyspnea, and fever (median of two and three symptoms per patient, respectively). Median NCI-CTCAE pneumonitis grade was 2 for both groups. Older age and everolimus treatment were predictive of NIP. Patients who developed NIP had significantly longer time on treatment (median 4.1 months vs 2 months) and overall survival (OS) (median 15.4 months vs 7.4 months). NIP was a predictor of improved OS by multivariate analysis. An increased incidence of NIP was observed in everolimus treated patients. Improved OS in patients who developed NIP is an intriguing finding and should be further investigated. Given the incidence, morbidity, and outcomes seen in patients on everolimus who develop NIP, management should include proactive monitoring and treatment of NIP with the goal of preserving mTOR inhibitor therapy.
    BJU International 08/2013; · 3.05 Impact Factor
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    ABSTRACT: The ideal surgical management of hereditary pheochromocytomas includes planning for a potential metachronous bilateral presentation and the possibility of lifelong steroid dependence if bilateral adrenalectomy is needed. An intact and viable cortical remnant after bilateral pheochromocytoma resection can eliminate the necessity for steroid dependency, but can increase the risk of pheochromocytoma recurrence. We retrospectively reviewed outcomes of all patients with a diagnosis of hereditary pheochromocytomas treated at our tertiary cancer institution from 1962-2011, with subset analysis of patients undergoing a cortical-sparing procedure in the setting of bilateral adrenalectomy. Of the ninety-six patients who underwent adrenalectomy for hereditary pheochromocytomas, 47 presented with bilateral disease. In 15 of the 49 patients (30%) who originally underwent unilateral adrenalectomy, pheochromocytoma developed in the contralateral gland at a median of 8.2 years (range 1 to 20 years) after the initial diagnosis. There were 4 recurrences in 55 cortical-sparing remnants (7%) and 3 recurrences in the adrenal bed after 101 intended total adrenal resections (3%) (p = 0.24). Total bilateral adrenalectomy was performed in 25 patients and acute adrenal insufficiency developed in 5 (20%) of those patients. An intended cortical-sparing adrenalectomy was performed in 39 patients and acute adrenal insufficiency developed in 1 (3%). Of these patients with adequate follow-up, 21 of 27 (78%) were steroid independent at 3-year follow-up. Sex, median age, adrenal vein preservation, metachronous adrenal resection, and bilateral cortical-sparing procedures did not predict steroid independence at 3 years. Cortical-sparing adrenalectomy avoids long-term corticosteroid dependence in the majority of patients with hereditary pheochromocytoma with minimal risk of acute adrenal insufficiency. Recurrence occurs in approximately 7% of adrenal remnants.
    Journal of the American College of Surgeons 02/2013; 216(2):280-9. · 4.50 Impact Factor
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    ABSTRACT: Background Sunitinib is a standard-of-care treatment in advanced clear cell renal cell carcinoma (ccRCC). Retrospective and expanded access data suggest sunitinib has activity in advanced non–clear cell renal cell carcinoma (nccRCC).Objective To prospectively determine the clinical efficacy and safety of sunitinib in patients with advanced nccRCC.Design, setting, and participantsThis is a single-arm phase 2 trial with a two-stage design. Eligibility criteria included pathologically confirmed nccRCC or ccRCC with ≥20% sarcomatoid histology, performance status 0–2, measurable disease, a maximum of two prior systemic therapies, and no prior treatment with tyrosine kinase inhibitors directed against the vascular endothelial growth factor receptors.InterventionPatients received sunitinib 50 mg daily on a 4-wk on, 2-wk off schedule.Outcome measurements and statistical analysisPrimary end points were objective response rate (ORR) and progression-free survival (PFS). Secondary end points were safety and overall survival (OS).Results and limitationsFifty-seven patients were eligible (nccRCC histology: papillary, 27; chromophobe, 5; unclassified, 8; collecting duct or medullary carcinoma, 6; sarcomatoid, 7; and others, 4). Median PFS for 55 evaluable patients was 2.7 mo (95% confidence interval [CI], 1.4–5.4). Two patients with chromophobe and one patient with unclassified histology had a confirmed partial response (5% ORR). Median PFS for patients with papillary histology was 1.6 mo (95% CI, 1.4–5.4). Median PFS for patients with chromophobe histology was 12.7 mo (95% CI, 8.5–NA). Median OS for all patients was 16.8 mo (95% CI, 10.7–26.3). Treatment-emergent adverse events were consistent with sunitinib's mechanism of action. The nonrandomized design and small number of patients are limitations of this study.Conclusions The differential response of chromophobe histology to sunitinib suggests a therapeutically relevant biological heterogeneity exists within nccRCC. The low ORR and short PFS with sunitinib in the other nccRCC subtypes underscore the need to enroll patients with these diverse tumors in clinical trials.
    European Urology 12/2012; 62(6):1013–1019. · 10.48 Impact Factor
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    ABSTRACT: RECIST is used to quantify tumor changes during exposure to anticancer agents. Responses are categorized as complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD). Clinical trials dictate a patient's management options based on the category into which his or her response falls. However, the association between response and survival is not well studied in the early trial setting. To study the correlation between response as quantified by RECIST and overall survival (OS, the gold-standard survival outcome), we analyzed 570 participants of 24 phase I trials conducted between October 2004 and May 2009, of whom 468 had quantifiable changes in tumor size. Analyses of Kaplan-Meier estimates of OS by response and null Martingale residuals of Cox models were the primary outcome measures. All analyses are landmark analyses. Kaplan-Meier analyses revealed strong associations between change in tumor size by RECIST and survival (P = 4.5 × 10(-6) to < 1 × 10(-8)). The relationship was found to be near-linear (R(2) = 0.75 to 0.92) and confirmed by the residual analyses. No clear inflection points were found to exist in the relationship between tumor size changes and survival. RECIST quantification of response correlates with survival, validating RECIST's use in phase I trials. However, the lack of apparent boundary values in the relationship between change in tumor size and OS demonstrates the arbitrary nature of the CR/PR/SD/PD categories and questions emphasis placed on this categorization scheme. Describing tumor responses as a continuous variable may be more informative than reporting categoric responses when evaluating novel anticancer therapies.
    Journal of Clinical Oncology 06/2012; 30(21):2684-90. · 18.04 Impact Factor
  • Clinical Genitourinary Cancer 08/2011; 9(2):137-9. · 1.43 Impact Factor
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    ABSTRACT: Mammalian target of rapamycin (mTOR) inhibitors mediate AKT activation through a type 1 insulin-like growth factor receptor (IGF-1R)-dependent mechanism. Combining the mTOR inhibitor temsirolimus with cixutumumab, a fully human immunoglobulin G1 monoclonal antibody directed against IGF-1R, was expected to enhance mTOR-targeted anticancer activity by modulating resistance to mTOR inhibition. The objectives of this phase I study were to evaluate the tolerability and activity of temsirolimus and cixutumumab. Patients in sequential cohorts ("3 + 3" design) received escalating doses of temsirolimus with cixutumumab weekly for 28 days. At the maximum tolerated dose (MTD), 21 patients were randomized into three separate drug sequence treatment groups for serial blood draws and 2[18F]fluoro-2-deoxy-d-glucose positron emission tomography combined with X-ray computed tomography (FDG-PET/CT) scans for pharmacodynamic analyses (PD). Forty-two patients with advanced cancer (19 male/23 female, median age = 53, median number of prior therapies = 4) were enrolled. MTD was reached at cixutumumab, 6 mg/kg IV and temsirolimus, 25 mg IV. Dose-limiting toxicities included grade 3 mucositis, febrile neutropenia, and grade 4 thrombocytopenia. The most frequent toxicities were hypercholesterolemia, hypertriglyceridemia, hyperglycemia, thrombocytopenia, and mucositis. Tumor reduction was observed in 2 of 3 patients with Ewing's sarcoma and in 4 of 10 patients with adrenocortical carcinoma. PD data suggest that cixutumumab alone or combined with temsirolimus increased plasma IGF-1 and IGF binding protein 3. FDG-PET/CT showed the odds of achieving stable disease decreased by 58% (P = 0.1213) with a one-unit increase in absolute change of standard uptake value from baseline to day 3. Temsirolimus combined with cixutumumab was well tolerated. We are currently enrolling expansion cohorts at the MTD for Ewing's sarcoma and adrenocortical carcinoma.
    Clinical Cancer Research 07/2011; 17(18):6052-60. · 7.84 Impact Factor
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    ABSTRACT: The purpose of this study was to evaluate poly(L-glutamic acid)-benzyl-DTPA-Gd (PG-Gd), a new biodegradable macromolecular magnetic resonance imaging contrast agent, for its pharmacokinetics and MRI enhancement in nonhuman primates. Studies were performed in rhesus monkeys at intravenous doses of 0.01, 0.02 and 0.08 mmol Gd/kg. T(1)-weighted MR images were acquired at 1.5 T using fast spoiled gradient recalled echo and fast spin echo imaging protocols. The small-molecule contrast agent Magnevist was used as a control. PG-Gd in the monkey showed a bi-exponential disposition. The initial blood concentrations within 2 h of PG-Gd administration were much higher than those for Magnevist. The high blood concentration of PG-Gd was consistent with the MR imaging data, which showed prolonged circulation of PG-Gd in the blood pool. Enhancement of blood vessels and organs with a high blood perfusion (heart, liver, and kidney) was clearly visualized at 2 h after contrast injection at the three doses used. A greater than proportional increase of the area under the blood concentration-time curve was observed when the administered single dose was increased from 0.01 to 0.08 mmol/kg. By 2 days after PG-Gd injection, the contrast agent was mostly cleared from all major organs, including kidney. The mean residence time was 15 h at the 0.08 mmol/kg dose. A similar pharmacokinetic profile was observed in mice, with a mean residence time of 5.4 h and a volume of distribution at steady-state of 85.5 ml/kg, indicating that the drug was mainly distributed in the blood compartment. Based on this pilot study, further investigations on the potential systemic toxicity of PG-Gd in both rodents and large animals are warranted before testing this agent in humans.
    Contrast Media & Molecular Imaging 07/2011; 6(4):289-97. · 2.87 Impact Factor
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    ABSTRACT: Posterior retroperitoneoscopic adrenalectomy (PRA) is an excellent surgical option for adrenal gland removal. The operation requires that surgeons learn a new approach with few similarities to anterior adrenalectomy. This study reports a large series of PRAs incorporated into surgical care using a team-model approach. The prospective endocrine surgery database was queried to identify patients who underwent PRA during a recent 4-year period. Demographic, operative, and pathologic data were recorded. The authors' initial experiences with PRA (group 1) are compared with our contemporary experience (group 2). One hundred and eighteen PRAs were successfully performed (100 unilateral and 9 bilateral). Indications were pheochromocytoma in 21 patients, Cushing's syndrome or Cushing's disease in 22 patients, aldosteronoma in 22 patients, virilizing tumor in 3 patients, isolated metastasis in 28 patients, and nonfunctional mass in 19 patients. Forty-eight percent of patients had undergone earlier abdominal surgery. Forty-eight percent were obese (body mass index [calculated as kg/m(2)] ≥30). No significant differences were found in operative time (110 versus 118 minutes, p = 0.30), tumor size (2.59 versus 2.85 cm, p = 0.44), or body mass index (29.63 versus 29.93, p = 0.82) between groups 1 and 2. Both complications (15.9% versus 7.7%, p = 0.29) and conversion rates (9.5% versus 1.9%, p = 0.19) were lower in group 2, although this was not statistically significant. PRA is a technique safely performed for a variety of adrenal lesions, is ideal for patients who have undergone earlier abdominal surgery, and is feasible in obese patients. Proficiency can be obtained during a short period, leading to low conversion and complication rates. This technique should be incorporated into the armamentarium of the endocrine surgeon. A team approach to learning new surgical techniques is effective.
    Journal of the American College of Surgeons 04/2011; 212(4):659-65; discussion 665-7. · 4.50 Impact Factor
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    ABSTRACT: This pilot clinical trial explored the feasibility, safety, and efficacy of regional hepatic therapy combined with systemic anticancer agents in patients with refractory solid tumors and extensive unresectable liver involvement, including those with compromised hepatic function. Six patients with colorectal (N = 3), ovarian (N = 2), and hepatocellular carcinoma (N = 1) received intra-arterial hepatic oxaliplatin followed by intravenous 5-fluorouracil, leucovorin, and bevacizumab every 2 weeks until disease progression. All had extensive liver metastases; four had elevated baseline serum total bilirubin. Median total bilirubin was 2.8 mg/dL (range, 0.2-5.2 mg/dL). Median Child-Pugh score was 7 (range, 5-10). Thirty treatments were delivered (2-7 per patient). Median age of patients was 57 years (range, 25-69 years). Three patients (1 with colorectal, 1 with hepatocellular, and 1 with ovarian cancer) attained partial responses. Two had failed previous oxaliplatin and cisplatin treatment. Some with elevated bilirubin at baseline had a significant drop in bilirubin with treatment (bilirubin 5.2 → 1 mg/dL, 4.8 → 1.1 mg/dL, and 5.2 → 1.8 mg/dL). The regimen was generally well tolerated; the most common side effects were grade 1 fatigue, anorexia, and/or hypertension. One patient died of enzyme-linked, immunoassay-confirmed, heparin-induced thrombocytopenia during the sixth cycle of therapy. At doses tested, this regimen was safe and demonstrated antitumor activity in patients with advanced refractory malignancies involving the liver, including those with hepatic insufficiency. Further study is warranted.
    Clinical Colorectal Cancer 12/2010; 9(5):311-4. · 1.80 Impact Factor
  • Journal of Clinical Oncology 12/2010; 29(8):e203-5. · 18.04 Impact Factor
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    ABSTRACT: Liver metastases in patients with cancer are associated with poor survival. The authors of this report conducted a phase 1 study of hepatic arterial infusion (HAI) oxaliplatin combination therapy in patients with advanced cancer and liver metastases. Treatment consisted of escalating doses of HAI oxaliplatin 60 mg/m(2) to 175 mg/m(2) and intra-arterial heparin 3000 IU (Day 1); leucovorin 200 mg/m(2) intravenously (iv) and 5-fluorouracil 300 mg/m(2) bolus plus 600 mg/m(2) iv (Days 1 and 2); and bevacizumab 10 mg/kg iv (Day 3). A conventional "3 + 3" design was used. Fifty-seven patients were treated, including 30 women and 27 men. The median age was 57 years, and the patients had received a median of 3 prior therapies (range, 1-7 prior therapies). The most common cancer was colorectal (n = 29). Overall, 204 cycles were administered (median per patient, 2 cycles; range, 1-17 cycles). The maximum tolerated dose (MTD) of HAI oxaliplatin was 140 mg/m(2). Dose-limiting toxicities were grade 4 thrombocytopenia (n = 1) and grade 4 hypokalemia (n = 1) at 150 mg/m(2) (n = 5). Thirty-three patients (58%) had no toxicity greater than grade 1. The most common toxicities were thrombocytopenia (n = 19), fatigue (n = 15), nausea/vomiting (n = 6), constipation (n = 6), and diarrhea (n = 4). Of 55 patients who were evaluable for response (according to Response Evaluation Criteria in Solid Tumors), 4 patients (7%) had a partial response (PR), and 32 patients (58%) had stable disease (SD), including 15 patients (48%) who had SD for >/=4 months. Of 28 patients with colorectal cancer, 3 patients (11%) had a PR, and 9 patients (32%) had SD for >/=4 months. HAI oxaliplatin combined with systemic 5-fluorouracil, leucovorin, and bevacizumab had antitumor activity in patients with advanced cancer and liver metastases, and the current results indicated that this combination warrants further study. Cancer 2010. (c) 2010 American Cancer Society.
    Cancer 09/2010; 116(17):4086-94. · 5.20 Impact Factor
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    ABSTRACT: Tumor-associated macrophages (TAMs) are diverse population containing multiple subtypes. M2 macrophages promote tumor growth and metastasis, in part by secreting a wide range of proangiogenic factors and growth factors. Selective depletion of M2 macrophages has been evaluated as a novel approach to anti-cancer therapy. In this study, a dual magneto-optical imaging probe, PG-Gd-NIR813 was synthesized and evaluated for non-invasive assessment of TAMs after intravenous injection. PG-Gd-NIR813 injected in nude rats bearing C6 tumors showed high uptake of the polymeric contrast agent in the tumor at 1 and 48 h after injection both in vivo and ex vivo optical imaging. T(1)-weighted MR imaging results showed accumulation of PG-Gd-NIR813 into the tumor necrotic area, which was confirmed by TUNEL staining of resected tumors. The uptake of PG-Gd-NIR813 within tumor necrosis decreased after animals were treated by the macrophage-depleting agent. Immunohistochemical staining demonstrated that PG-Gd-NIR813 colocalized with CD68 (marker for macrophages) and CD169 (marker for activated macrophages), but not with CD163 (residential macrophages). Using combined near-infrared fluorescence imaging and magnetic resonance imaging (MRI), we demonstrated that the accumulation of PG-Gd-NIR813 in tumors was mediated through M2 TAMs. Therefore, poly(L-glutamic acid) based reagents could be potentially used to image response to antitumor therapies targeted at M2 TAMs. Furthermore, poly(L-glutamic acid) is a promising carrier for candidate immunotherapeutics targeting M2 TAMs.
    Biomaterials 09/2010; 31(25):6567-73. · 8.31 Impact Factor
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    ABSTRACT: We conducted a phase I study of hepatic arterial infusion (HAI) cisplatin and systemic chemotherapy in patients with advanced cancer and dominant liver involvement. Patients were treated with HAI cisplatin 100-125 mg/m(2) (and 3,000 IU heparin) intraarterially and liposomal doxorubicin (doxil) 20-35 mg/m(2) IV (day 1) every 28 days. A "3 + 3" study design was used. Thirty patients were treated (median age, 56 years). Diagnoses were breast cancer (n = 11), colorectal cancer (n = 8), ocular melanoma (n = 4), and other (n = 7). The median number of prior therapies was 5. The maximum tolerated dose (MTD) was at the 100/35 mg/m(2) level. Dose-limiting toxicities were Grade 4 neutropenia (2 of 4 patients), and Grade 4 thrombocytopenia (n = 1) at the cisplatin 125 mg/m(2) and systemic doxil 35 mg/m(2) dose level. The most common toxicities were nausea/vomiting and fatigue. Of 24 patients evaluable for response, 4 (17%) had a partial response (PR) and 7 (29%) had stable disease (SD) for ≥4 months. Of the 11 patients with breast cancer, 3 (27%) had a PR and 5 (45%) had SD for ≥4 months. Of 4 patients with ocular melanoma, 1 had a PR and 1 SD for 4 months. One patient with hepatocellular carcinoma had SD for 4 months. Of 12 evaluable patients treated at the MTD, 2 (17%) had a PR and 5 (42%) had SD. The MTD was HAI cisplatin 100 mg/m(2) and systemic doxil 35 mg/m(2). This regimen demonstrated antitumor activity, especially in breast cancer.
    Cancer Chemotherapy and Pharmacology 03/2010; 66(6):1087-93. · 2.80 Impact Factor
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    ABSTRACT: To compare nondestructive in vivo and ex vivo micro-computed tomography (muCT) and ex vivo dual-energy-X-ray-absorptiometry (DXA) in characterizing mineralized cortical and trabecular bone response to prostate cancer involving the skeleton in a mouse model. In vivo microCT was performed before and 10 weeks after implantation of human prostate cancer cells (MDA-PCa-2b) or vehicle into SCID mouse femora. After resection, femora were imaged by nondestructive ex vivo specimen microCT at three voxel sizes (31 micro, 16 micro, 8 micro) and DXA, and then sectioned for histomorphometric analysis of mineralized bone. Bone mineral density (BMD), trabecular parameters (number, TbN; separation, TbSp; thickness, TbTh) and mineralized bone volume/total bone volume (BV/TV) were compared and correlated among imaging methods and histomorphometry. Statistical tests were considered significant if P<0.05. Ten weeks post inoculation, diaphyseal BMD increased in the femur with tumor compared to the opposite femur by all modalities (p<0.005, n = 11). Diaphyseal BMD by in vivo microCT correlated with ex vivo 31 and 16 microm microCT and histomorphometry BV/TV (r = 0.91-0.94, P<0.001, n = 11). DXA BMD correlated less with bone histomorphometry (r = 0.73, P<0.001, n = 11) and DXA did not distinguish trabeculae from cortex. By in vivo and ex vivo microCT, trabecular BMD decreased (P<0.05, n = 11) as opposed to the cortex. Unlike BMD, trabecular morphologic parameters were threshold-dependent and when using "fixed-optimal-thresholds," all except TbTh demonstrated trabecular loss with tumor and correlated with histomorphometry (r = 0.73-0.90, P<0.05, n = 11). Prostate cancer involving the skeleton can elicit a host bone response that differentially affects the cortex compared to trabeculae and that can be quantified noninvasively in vivo and nondestructively ex vivo.
    PLoS ONE 01/2010; 5(3):e9854. · 3.73 Impact Factor
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    ABSTRACT: Thyroid cancer is the most common endocrine malignancy. The outcomes of patients with relapsed thyroid cancer treated on early-phase clinical trials have not been systematically analyzed. We reviewed the records of consecutive patients with metastatic thyroid cancer referred to the Phase I Clinical Trials Program from March 2006 to April 2008. Best response was assessed by Response Evaluation Criteria in Solid Tumors. Fifty-six patients were identified. The median age was 55 yr (range 35-79 yr). Of 49 patients evaluable for response, nine (18.4%) had a partial response, and 16 (32.7%) had stable disease for 6 months or longer. The median progression-free survival was 1.12 yr. With a median follow-up of 15.6 months, the 1-yr survival rate was 81%. In univariate analysis, factors predicting shorter survival were anaplastic histology (P = 0.0002) and albumin levels less than 3.5 g/dl (P = 0.05). Among 26 patients with tumor decreases, none died (median follow-up 1.3 yr), whereas 52% of patients with any tumor increase died by 1 yr (P = 0.0001). The median time to failure in our phase I clinical trials was 11.5 months vs. 4.1 months for the previous treatment (P = 0.04). Patients with advanced thyroid cancer treated on phase I clinical trials had high rates of partial response and prolonged stable disease. Time to failure was significantly longer on the first phase I trial compared with the prior conventional treatment. Patients with any tumor decrease had significantly longer survival than those with any tumor increase.
    The Journal of clinical endocrinology and metabolism 10/2009; 94(11):4423-32. · 6.50 Impact Factor
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    ABSTRACT: The objective of this study was to independently evaluate the objective response rate of sorafenib and sorafenib plus low-dose interferon-alfa 2b (IFN) as frontline therapy in patients with metastatic renal cell carcinoma (mRCC). Untreated patients with clear cell mRCC were randomized to receive sorafenib 400 mg orally twice daily or sorafenib 400 mg orally twice daily plus subcutaneous IFN 0.5 million U (MU) twice daily. Primary endpoints included the objective response rate (ORR) and safety. Secondary endpoints included progression-free survival (PFS) and overall survival (OS). Exploratory endpoints included the predictive value of tumor tissue biomarkers. Eighty patients were enrolled. The median follow-up was 19.7 months (range, 0-34.2 months). The ORR was 30% (95% confidence interval [CI], 16.6%-46.5%) in the sorafenib arm and 25% (95% CI, 12.7%-41.2%) in the combination arm. The median PFS was 7.39 months in the sorafenib-alone arm (95% CI, 5.52-9.20 months) and 7.56 months in the sorafenib plus IFN arm (95% CI, 5.19-11.07 months). The median OS was 27.04 months in the combination arm (95% CI, from 22.31 to not attained) and was not reached in the sorafenib arm. Toxicities were comparable in both arms. In a multivariate model, increased phosphorylated protein kinase B (pAKT) levels were associated with poorer PFS (hazard ratio, 1.04; 95% CI, 1.00-1.08; P = .0411) and OS (hazard ratio, 1.15; 95% CI, 1.02-1.29; P = .0173). The addition of low-dose IFN to sorafenib resulted in efficacy outcomes that were comparable to those achieved with sorafenib monotherapy. The current results indicated that pAKT levels may predict for clinical outcome, but further mechanistic study is required.
    Cancer 10/2009; 116(1):57-65. · 5.20 Impact Factor
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    ABSTRACT: Darinaparsin, an organic arsenic, targets essential cell survival pathways. We determined the dose-limiting toxicity (DLT) and maximum tolerated dose of darinaparsin in patients with advanced cancer. Patients with solid malignancies refractory to conventional therapies were treated with i.v. darinaparsin daily for 5 days every 4 weeks. The starting dose (78 mg/m(2)) escalated to 109, 153, 214, 300, 420, and 588 mg/m(2). A conventional "3 + 3" design was used. Forty patients (median age, 61.5 years; median number of prior therapies, 5) received therapy; 106 cycles were given (median, 2; range, 1-12). Twenty patients reported no drug-related toxicities. No DLTs were reported at a dose of <420 mg/m(2). At 588 mg/m(2), two of four patients developed DLTs, including grade 3 altered mental status and ataxia. Of four patients treated at the de-escalated dose of 500 mg/m(2), one developed similar toxicities. De-escalating the dose to 420 mg/m(2) (n = 8) resulted in two neurologic DLTs. Further de-escalation to 300 mg/m(2) (n = 3) resulted in no drug-related toxicities. Arsenic plasma levels peaked on treatment day 3, plateaued on day 5, and returned to baseline on day 7. Plasma levels varied within cohorts but increased with increasing doses. The median plasma arsenic half-life was 16.2 hours. Seven (17.5%) patients had stable disease for > or =4 months (median, 6; range, 4-11), including 4 of 17 with colorectal and 2 of 3 with renal cancer. The recommended dose for phase II trials is 300 mg/m(2) i.v. given daily for 5 days every 4 weeks.
    Clinical Cancer Research 08/2009; 15(14):4769-76. · 7.84 Impact Factor
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    ABSTRACT: Imexon is an iminopyrrolidone that induces apoptosis and has synergistic activity with docetaxel in preclinical models. This trial was designed to establish the maximum tolerated dose (MTD) of imexon given with docetaxel in breast, prostate and non-small cell lung cancer (NSCLC). 34 patients received protocol therapy. 26 patients received escalating doses of imexon given intravenously over 60 min on days 1-5 every 21 days. Docetaxel was administered intravenously at a fixed dose of 75 mg/m(2) immediately following imexon on day 1 every 21 days. A 3+3 design was used with eight additional patients treated at MTD. Response was measured using RECIST. Seven dose levels of imexon were evaluated (390 mg/m(2) to 1,700 mg/m(2)). The MTD was imexon 1,300 mg/m(2) IV on days 1-5 in combination with docetaxel. Dose limiting toxicities were grade 3 non-cardiac chest pain and grade 3 diarrhea. Activity was seen in 4 patients [2 partial responses (NSCLC (PR=1), prostate cancer (PR=1)), 2 minor responses (MR=breast, NSCLC)]. Eleven patients had stable disease by RECIST (including the patients with MR; prostate cancer=6, NSCLC=3). Six (one with breast cancer, two with prostate cancer and three with NSCLC) demonstrated stable disease (SD) for > or = 3 months. The MTD of combination therapy is imexon 1,300 mg/m(2) IV on days 1-5 with docetaxel 75 mg/m(2) IV on day 1 of a 21 day treatment cycle. Demonstrated responses warrant further investigation in phase II trials of which a phase II trial in NSCLC is planned.
    Investigational New Drugs 06/2009; 28(5):634-40. · 3.50 Impact Factor
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    ABSTRACT: In a search for more effective combination chemotherapy for the treatment of metastatic melanoma, we conducted a phase I trial of a novel combination of docetaxel, temozolomide, and cisplatin. Patients with inoperable or recurrent metastatic melanoma with a Zubrod performance status of 2 or less and adequate organ function were eligible. The dose of docetaxel was escalated between cohorts of patients, and the doses of temozolomide and cisplatin were fixed. A standard 3 + 3 dose escalation design was used to determine the maximum tolerated dose (MTD). Among 23 patients who were enrolled, 21 were evaluable for toxicity. Eighteen patients (78%) had stage IV-M1c disease. The dose-limiting toxicities were myelosuppression and pulmonary embolism. The MTD was 30 mg/m(2) docetaxel on days 1, 8, and 15 when given with 150 mg/m(2) temozolomide on days 1-5, and 20 mg/m(2) cisplatin on days 1-4, repeating every 4 weeks. Among 19 patients evaluated for response, 6 (32%) had partial responses and 5 (26%) had stable disease. Among 14 chemo-naive patients, 6 (43%) had a partial response and 4 (29%) had stable disease. Nine patients developed brain metastases by the time of the last follow-up evaluation, and the median time to brain metastases for all 19 evaluable patients has not been reached. This combination was well tolerated and appears to be a promising treatment for patient with metastatic melanoma.
    Cancer Chemotherapy and Pharmacology 12/2008; 64(1):161-7. · 2.80 Impact Factor
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    ABSTRACT: To evaluate the contribution to scan-rescan coefficient of variation (CV) of patient-specific arterial input function (AIF) measurement in dynamic contrast-enhanced MRI (DCE-MRI) data, and to determine whether any advantage or disadvantage to using a data-derived arterial input function is related to the anatomical location of the target lesion. Two methods are presented for the calculation of perfusion parameters from DCE-MRI data using a two-compartment model. The first method makes use of a single-model AIF across all study data sets, while the second uses an automated process to derive an AIF specific to each data set. Both methods are applied to the analysis of a 25-subject scan-rescan study of patients with advanced solid tumors located in either the lungs or the liver. The parameters of interest in this study are the volume transfer constant between arterial plasma and extracellular extravascular space (Ktrans) and the blood-normalized initial area under the tumor enhancement curve over the first 90 seconds postinjection (IAUCBN90). The use of a data-derived AIF reduces the visit-to-visit CV in both parameters for liver lesions by approximately 70% while the improvement is less than 20% for lung lesions. The use of a data-derived AIF in the analysis of DCE-MRI data provides a substantial reduction in scan-rescan CV in the measurement of vascular parameters such as Ktrans and IAUCBN90. These results show a much larger advantage in the liver than in the lungs. However, this difference is largely driven by a small number of outliers, and may be spurious.
    Journal of Magnetic Resonance Imaging 10/2008; 28(3):791-6. · 2.57 Impact Factor