Aiwu Ruth He

A phase I study of liposomal-encapsulated docetaxel (LE-DT) in patients with advanced solid tumor malignancies.

BackgroundDocetaxel is a taxane anticancer drug used in a wide variety of solid tumors. Liposomes are versatile drug carriers that may increase drug solubility, serve as sustained release systems, provide protection from drug degradation and toxicities, and help overcome multidrug resistance. This phase I study was conducted to determine the maximum tolerated dose, dose-limiting toxicities (DLTs), pharmacokinetics (PK), and clinical response of liposomal-encapsulated docetaxel (LE-DT) in patients with advanced solid tumor malignancies.MethodsLE-DT was administered using a standard 3xa0+xa03 dose escalation schema with dose levels of 50, 65, 85, 110, and 132xa0mg/m2 IV on a 3-week cycle. Toxicities were assessed using the NCI-CTCAE version 3.0, and response was assessed using RECIST criteria (version 1.0). PK samples were drawn during cycle 1 and analyzed using a non-compartmental analysis.ResultsTwenty-four patients were treated for 1–30 cycles (medianxa0=xa04). No DLTs were experienced through dose levels of 50, 65, 85, and 110xa0mg/m2. Two out of two patients experienced grade 4 neutropenia at the 132xa0mg/m2 dose level. When an additional three patients were treated at the expanded 110xa0mg/m2 dose level, two experienced grade 4 neutropenia. The 85xa0mg/m2 dose level was reassessed with an expanded group of three additional patients, and only one of three patients experienced grade 4 neutropenia. The protocol was amended to allow G-CSF during cycle 1, and an additional three patients were treated at 110xa0mg/m2 with no DLTs experienced. No patient experienced significant neuropathy, even patients treated for 19, 20, and 30 cycles. PK followed a two-compartment elimination pattern; there was no correlation between PK and toxicity. Two patients with thyroid and neuroendocrine cancer had partial responses (PR, 8xa0%), and one patient with non-small-cell lung cancer had an unconfirmed PR. Eight patients (33xa0%) had stable disease lasting more than 3xa0months, for a clinical benefit rate of 41xa0%.ConclusionLE-DT was well tolerated with expected toxicities of neutropenia, anemia, and fatigue, but without neuropathy or edema. Clinical benefit (SDxa0+xa0PR) was observed in 41xa0% of the patients. The recommended phase II dose of LE-DT is 85xa0mg/m2 without G-CSF or 110xa0mg/m2 with G-CSF.

Decrease in blood miR-296 predicts chemotherapy resistance and poor clinical outcome in patients receiving systemic chemotherapy for metastatic colon cancer

Dear Editor: MicroRNA (miRNA) is a new class of small, noncoding RNA that can regulate the expression of multiple genes. miRNAs have been implicated in a diverse number of cellular processes including cell proliferation, apoptosis, regulation of embryonic stem cell development, and cancer cell invasion. Recent studies have shown that, unlike other types of biomarkers, miRNAs in the circulation are remarkably stable making them robust and reliable biomarkers of cancer. We aim to investigate if specific miRNA(s) in the blood can provide a valuable noninvasive tool in predicting clinical outcome of patients enrolled in a phase II clinical trial of Sunitinib and Capecitabine in first-line treatment of metastatic colon cancer. Eight patients were enrolled in the trial and received Sunitinib 37.5 mg orally once daily and Capecitabine 1,000 mg orally twice daily. Serum samples were collected from patients prior to drug administration at baseline and then every 4 weeks. Serum miRNA analysis included 380 miRNAs. Change of miRNAs at 4 weeks compared to baseline (ratio less than 0.5 or larger than 1.5) was calculated and compared to patients’ outcomes. The change in miR-296, one of the 380 miRNAs, demonstrated a statistically significant correlation with patients’ clinical outcome and separated them into two groups. Seven patients were included in the analysis. Three patients had decrease in the level of miR-296 at 4 weeks. Four patients had increase in the level of miR-296 during that time period. Compared to patients with longer survival and better clinical outcome, patients with shorter survival and poor clinical outcome exhibited a decrease in the level of miR-296 at 4 weeks compared to baseline (28 versus 0.43) (P00.035). One patient (not included in the analysis) out of the eight treated had undetectable miRNA-296 levels prior to treatment and remained so at the end of the treatment. This patient had a poor clinical outcome. Recent studies revealed a new function of miR-296 in cancer progression which is interesting and appears to be directly relevant to our results. In this report, miR-296 is progressively lost during tumor progression and correlates with metastatic disease in colorectal cancer. The patients with decrease in miR-296 at 4 weeks may reflect a more aggressive tumor phenotype with increased metastasis and tumor cell invasiveness. The loss of miR-296 may be one of the mechanisms for primary resistance of colorectal cancer to chemotherapy. Additionally, the implication of low serum miR-296 in cancer progression is also supported by the observation that one patient with a poor outcome (not included in the analysis) had undetectable serum miR-296 levels, prior to initiation of treatment and remained so at the end of the treatment. Taken together, our results indicate that the decrease in circulating miR-296 is associated with shorter survival and poor response to treatment with Sunitinib and Capecitabine. Further studies are needed to confirm these findings and evaluate its utility as a predictive and prognostic biomarker.

Stereotactic Body Radiation Therapy (sbrt) Combined With Chemotherapy for Unresected Pancreatic Adenocarcinoma.

Objectives: The role of radiation therapy in the management of unresectable pancreatic cancer is controversial. One concern about concurrent chemoradiation relates to the timing of chemotherapy. In contrast to conventional radiation therapy, stereotactic body radiation therapy (SBRT) delivers high doses in a shorter duration resulting in minimal disruption in chemotherapy. Here, we report our results of patients treated with SBRT and chemotherapy for inoperable pancreatic cancer. Materials and Methods: Thirty-eight patients treated with SBRT and chemotherapy for locally advanced, borderline resectable, and medically inoperable pancreatic cancer at our institution from January 2008 to December 2012 were included in this retrospective analysis. Treatment was delivered in 5 fractions of 5 or 6 Gy per fraction over 5 days. Toxicities were scored using the Common Terminology Criteria for Adverse Events version 3. Survival was calculated using the Kaplan-Meier method. Results: The median age was 70 years (range, 45 to 90 y). Eastern Cooperative Oncology Group performance status ranged from 0 to 3. Thirty-four patients received concurrent chemotherapy. Four patients received sequential chemotherapy. Median overall survival was 14.3 months and median progression-free survival was 9.2 months from diagnosis. From radiation, overall survival and progression-free survival were 12.3 and 6.8 months, respectively. The overall local control rate was 79%. Acute toxicity was minimal. Severe late SBRT-related toxicities included 1 grade 3 gastric outlet obstruction, 1 grade 4 biliary stricture, and 1 grade 5 gastric hemorrhage. Conclusions: SBRT combined with chemotherapy for unresectable pancreatic cancer is convenient, feasible, and generally well tolerated. Outcomes of SBRT combined with chemotherapy compare favorably to results obtained with chemotherapy and conventional radiation therapy.

Systemic therapy for advanced hepatocellular carcinoma: an update

Advanced hepatocellular carcinoma (HCC) is a deadly disease with few systemic therapeutic options. Sorafenib is the only agent to be FDA approved for the first-line treatment of patients with HCC. This drug increases overall survival (OS) by 3 months compared with placebo (10.7 months with sorafenib vs. 7.7 months with placebo). More recently, the RESORCE trial demonstrated efficacy of regorafenib in the second-line treatment of HCC: OS was increased from 7.8 months with placebo to 10.6 months with regorafenib after patients experienced disease progression on sorafenib. However, there is still an unmet need for effective systemic therapy of patients with advanced HCC. Numerous genetic pathways have been studied along with drugs to target these pathways but, thus far, drugs targeting cell proliferation, metastasis, angiogenesis, and metabolite use have been studied with minimal success. HCC can be divided into two subclasses: proliferative and non-proliferative, each dependent on separate pathways. HCC can be caused by alcoholic cirrhosis, hepatitis C virus (HCV), and hepatitis B virus (HBV); however no etiology-specific therapies have been demonstrated. Immunotherapy is currently being assessed in clinical trials and is demonstrating some efficacy. More research is needed to determine the most essential pathways to target in the war against this deadly cancer.

A Phase I clinical trial of the combination of imatinib and paclitaxel in patients with advanced or metastatic solid tumors refractory to standard therapy

PurposePre-clinical data suggest that combining imatinib with traditional cytotoxic chemotherapy may improve imatinib efficacy. We conducted a Phase I study of imatinib in combination with paclitaxel in patients with advanced or metastatic solid tumors.MethodsPatients were accrued to the study in a standard 3xa0+xa03 design. Patients were restaged every two cycles, and those with stable disease (SD), or better, continued study treatment without interruption. Maximally tolerated doses (MTDs) and pharmacokinetic profiles of combination imatinib and paclitaxel were assessed.ResultsFifty-eight patients were enrolled, including 40 in the Phase I dose escalation portion. Alternating dose escalation of imatinib and paclitaxel on a 28-day cycle resulted in MTDs of 800xa0mg imatinib daily, on days 1–4, 8–11, 15–18, and 22–25, and 100xa0mg/m2 paclitaxel weekly, on days 3, 10, and 17. Two expansion cohorts, comprising 10 breast cancer patients and 8 patients with soft-tissue sarcomas, were enrolled at the MTDs. The most common adverse events were flu-like symptoms (64xa0%) and nausea/vomiting (71xa0%). The most common Grade 3/4 toxicities were neutropenia (26xa0%), flu-like symptoms (12xa0%), and pain (12xa0%). There were no relevant differences in the pharmacokinetic profiles of either drug when given in combination compared with alone. Thirty-eight subjects were evaluable for response, 18 (47.4xa0%) of whom experienced clinical benefit. Five patients (13.2xa0%) had a partial response (PR) and 13 patients (34.2xa0%) had SD; the average time to progression in those with clinical benefit was 17xa0weeks (range: 7–28xa0weeks).ConclusionsThis combination of imatinib and paclitaxel was reasonably safe and tolerable, and demonstrated evidence of anti-tumor activity. Further exploration in disease-specific Phase II trials is warranted.

Biologic therapies for advanced pancreatic cancer

Patients with metastatic pancreatic cancer have poor prognosis and short survival due to lack of effective therapy and aggressiveness of the disease. Pancreatic cancer has widespread chromosomal instability, including a high rate of translocations and deletions. Upregulated EGF signaling and mutation of K-RAS are found in most pancreatic cancers. Therefore, inhibitors that target EGF receptor, K-RAS, RAF, MEK, mTOR, VEGF and PDGF, for example, have been evaluated in patients with pancreatic cancer. Although significant activities of these inhibitors have not been observed in the majority of pancreatic cancer patients, an enormous amount of experience and knowledge has been obtained from recent clinical trials. With a better inhibitor or combination of inhibitors, and improvement in the selection of patients for available inhibitors, better therapy for pancreatic cancer is on the horizon.

A phase 1 study of cetuximab and lapatinib in patients with advanced solid tumor malignancies

Acquired resistance to antiepidermal growth factor receptor (anti‐EGFR) therapy may be caused by EGFR–v‐erb‐b2 avian erythroblastic leukemia viral oncogene homolog 2 (ErbB2) heterodimerization and pathway reactivation. In preclinical studies, inhibiting ErbB2 blocked this resistance mechanism and resensitized cells to anti‐EGFR therapy. Cetuximab targets EGFR, whereas lapatinib inhibits both EGFR and ErbB2. The objective of this phase 1 trial was to assess the safety, dose‐limiting toxicities (DLTs), and maximum tolerated doses (MTDs) of cetuximab and lapatinib in patients with solid tumors.

A phase I study of intravenous artesunate in patients with advanced solid tumor malignancies

PurposeThe artemisinin class of anti-malarial drugs has shown significant anti-cancer activity in pre-clinical models. Proposed anti-cancer mechanisms include DNA damage, inhibition of angiogenesis, TRAIL-mediated apoptosis, and inhibition of signaling pathways. We performed a phase I study to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of intravenous artesunate (IV AS).MethodsPatients were enrolled in an accelerated titration dose escalation study with planned dose levels of 8, 12, 18, 25, 34 and 45xa0mg/kg given on days 1 and 8 of a 21-day cycle. Toxicities were assessed using the NCI CTCAE (ver. 4.0), and response was assessed using RECIST criteria (version 1.1). Pharmacokinetic (PK) studies were performed during cycle 1.ResultsA total of 19 pts were enrolled, 18 of whom were evaluable for toxicity and 15 were evaluable for efficacy. DLTs were seen at dosages of 12 (1 of 6 patients), 18 (1 of 6) and 25xa0mg/kg (2 of 2), and were neutropenic fever (Gr 4), hypersensitivity reaction (Gr 3), liver function test abnormalities (Gr 3/4) along with neutropenic fever, and nausea/vomiting (Gr 3) despite supportive care. The MTD was determined to be 18xa0mg/kg. No responses were observed, while four patients had stable disease, including three with prolonged stable disease for 8, 10, and 11 cycles, for a disease control rate of 27%. PK parameters of AS and its active metabolite, dihydroartemisinin (DHA), correlated with dose.ConclusionThe MTD of intravenous artesunate is 18xa0mg/kg on this schedule. Treatment was well tolerated. Modest clinical activity was seen in this pre-treated population.ClinicalTrials.gov IdentifierNCT02353026.

Detection of a lipid peroxidation-induced DNA adduct across liver disease stages

BackgroundnOxidative stress and chronic inflammation can increase cellular levels of reactive oxygen species and lipid peroxidation (LPO) when associated with the pathogenesis of hepatocellular carcinoma (HCC), which can develop following the progression of steatosis, fibrosis and cirrhosis. Using a monoclonal antibody for cyclic γ-hydroxy-1, N2 -propanodeoxyguanosine (γ-OHPdG), a promutagenic DNA adduct formed endogenously by LPO, we examined its formation across liver disease stages to understand its potential role in HCC development.nnnMethodsnFormalin-fixed paraffin embedded (FFPE) liver tissue samples from 49 patients representing normal, steatosis, fibrosis, cirrhosis and HCC were stained for γ-OHPdG and 8-hydroxydeoxyguanosine (8-oxo-dG), an oxidative damage biomarker. Quantification of immunohistochemical (IHC) staining was performed using histological scoring of intensity and distribution. Using primary human hepatocytes (HH) and a stellate cell (SC) co-culture, immunocytochemical staining of γ-OHPdG and Nile Red was performed to determine if the formation of γ-OHPdG was consistent between the clinical sample disease stages and the in vitro steatotic and fibrotic conditions.nnnResultsnγ-OHPdG levels varied significantly between the stages of normal and steatosis, steatosis and fibrosis, and steatosis and cirrhosis (P≤0.005). There was a trend, although not significant, of increased levels of γ-OHPdG in HCC compared to the other groups. A strong correlation was observed (Pearsons, R2 =0.85) between levels of γ-OHPdG and 8-oxo-dG across the disease spectrum. The increase of γ-OHPdG in steatosis and decrease in fibrosis was a pattern confirmed in an in vitro model using primary HH co-cultured with human SCs.nnnConclusionsnγ-OHPdG was detected in FFPE liver tissues of patients with different stages of liver disease and in vitro studies, demonstrating that its formation is consistent with LPO in early stages of liver disease and suggesting that it may be a source of mutagenic DNA damage in liver disease progression.

Diverse clinical outcome and predictors for clinical outcome in patients with HCC treated with TACE.

442 Background: Hepatocellular carcinoma (HCC) is the sixth most common cancer, and the second leading cause of cancer-related death, worldwide. This reflects the challenges facing HCC treatment. Methods: Patients (pts) with HCC receiving TACE treatment (n = 96) were examined retrospectively for clinical outcome and its possible predictors. The number of TACE treatments and the time elapsed between each treatment were assessed and correlated with overall survival (OS) using the log rank test of Kaplan Meier curves. T-stage, level of differentiation, vascular invasion, and Child Pugh score at the time of HCC diagnosis were compared among pts who received different numbers of TACE treatments (Kaplan-Meier survival analysis, ANOVA and student T test). Results: TACE treated pts had a median OS of 46 month (mo) and progression free survival of 12 mo (difference in time between the date of first progression and the date of diagnosis). Pts received 1-2 (n = 52), 3-4 (n = 28), or 5-6 (n = 16) TACE treatments. We ...