This phase II single-arm trial of docetaxel and capecitabine in previously untreated non-small cell lung cancer (NSCLC) patients was designed to evaluate response rate of this regimen based on promising efficacy data from phase II testing in pre-treated NSCLC patients. The trial also evaluated the correlation between peripheral blood dihydropyrimidine dehydrogenase (DPD) expression and efficacy/toxicity.
Patients with advanced NSCLC (metastatic, including malignant pleural effusion) without prior chemotherapy were enrolled. Baseline DPD screening was performed; patients with baseline DPD level < 0.07 nmol/min/mg protein were considered ineligible for the study. Treatment included a 28-day cycle of docetaxel 36 mg/m2 days 1, 8, 15 and capecitabine 1250 mg/m2/day in divided doses on days 5–18. Overall response rate (RR) was the primary endpoint with a target RR of 50%. Correlative studies included evaluation of DPD activity levels in peripheral blood and correlation with clinical responses.
Twenty-eight patients received 86 cycles of treatment (median 3 cycles) and were evaluable for response. The RR was 18% (5 patients); RR did not meet the pre-specified efficacy endpoint and the trial was stopped. 14 patients had stable disease (SD - 50%) and 4 pts had SD > 12 weeks. Median time to progression was 3.3 months (95% CI 1.5 – 4.6 months). Median overall survival was 10.5 months (95% CI: 3.2 – 15 months). Main toxicities included fatigue, stomatitis and leukopenia. DPD levels ranged from 0.06 to 0.26 nmol/min/mg. The majority of responders (4/5) had DPD levels ≤ 0.1 nmol/min/mg. Most of the responders (4/5) experienced grade 3 toxicities including leukopenia, dehydration, fatigue, and diarrhea. None of the patients (0/4) with higher DPD levels (>0.2 nmol/min/mg) had a response.
The response rate for the regimen did not demonstrate sufficient activity and further study of this regimen in this setting is not indicated. Interestingly, the results suggest that low DPD expression may be associated with response to capecitabine but also with increased toxicity.
non-small cell lung cancer; dihydropyrimidine deficiency; capecitabine
Results of a first-line analysis of the Avastin® Registry: Investigation of Effectiveness and Safety (ARIES) study, a prospective, community-based observational cohort study assessing the impact of chemotherapy choice and treatment duration on outcomes in patients with metastatic colorectal cancer, are reported.
The Avastin® Registry: Investigation of Effectiveness and Safety (ARIES) study is a prospective, community-based observational cohort study that evaluated the effectiveness and safety of first-line treatment patterns, assessing the impact of chemotherapy choice and treatment duration.
The ARIES study enrolled patients with metastatic colorectal cancer (mCRC) receiving first-line chemotherapy with bevacizumab and followed them longitudinally. The protocol did not specify treatment regimens or assessments. Analyses included all patients who initiated bevacizumab in combination with either first-line oxaliplatin with infusional 5-fluorouracil and leucovorin (FOLFOX) or irinotecan with infusional 5-fluorouracil and leucovorin (FOLFIRI). Progression-free survival (PFS) and overall survival (OS) times were estimated using Kaplan–Meier methods. Hazard ratios (HRs) were estimated with multivariate Cox regression analysis, adjusting for potential confounding factors.
In total, 1,550 patients with first-line mCRC were enrolled (median follow-up, 21 months) and most received FOLFOX–bevacizumab (n = 968) or FOLFIRI–bevacizumab (n = 243) as first-line therapy. The baseline characteristics and median treatment duration were generally similar between subgroups. There were no significant differences in the median PFS (10.3 months vs. 10.2 months) or OS (23.7 months vs. 25.5 months) time between the FOLFOX–bevacizumab and FOLFIRI–bevacizumab subgroups, respectively, by unadjusted analyses. Multivariate analyses showed FOLFIRI–bevacizumab resulted in a similar PFS (HR, 1.03; 95% confidence interval [CI], 0.88–1.21) and OS (HR, 0.95; 95% CI, 0.78–1.16) outcome as with FOLFOX–bevacizumab. The incidence proportions of bevacizumab-associated adverse events were similar for FOLFOX- and FOLFIRI-based therapies.
In first-line mCRC patients, the FOLFOX–bevacizumab and FOLFIRI–bevacizumab regimens were associated with similar treatment patterns and clinical outcomes.
Bevacizumab; FOLFOX protocol; FOLFIRI protocol; Safety; Treatment outcome
CA19-9 is the most specific biomarker for pancreas cancer. We investigated the prognostic significance of normal (≤37 U/mL) versus elevated (>37 U/mL) CA19-9 levels in patients with resected and advanced pancreas cancer. Relevant data were obtained from patients treated for early-stage or advanced pancreatic adenocarcinoma at our institution. Log-rank tests were used to evaluate relationship between CA19-9 and clinical outcomes of interest for both early- and advanced-stage patients. A total of 123 patients were included (Group A: N = 30 stage I/II; Group B: N = 93 stage III/IV). In group A, elevated preoperative CA19-9 was significantly associated with lymph node involvement (p = 0.031), tumor ≥3 cm (p = 0.011), and lack of tumor differentiation (p = 0.048). Failure of postoperative CA19-9 to normalize predicted significantly worse DFS (p = 0.021). For group B, elevated baseline CA19-9 was associated with shorter OS on chemotherapy (p = 0.0008) and decline in CA19-9 >25 % with treatment was a significant predictor of improved OS (p = 0.0099). Higher than normal CA19-9 level is an adverse prognostic factor in both early and advanced settings and may prove to be useful in the selection of patients for more aggressive therapy in future trials. CA19-9 level decrease of >25 % predicts improved survival in advanced disease on chemotherapy.
CA19-9; Pancreas cancer; Prognostic; Biomarker
Yttrium-90 (90Y) radioembolization is a treatment option for patients with metastatic colorectal cancer with unresectable liver metastases. We conducted a retrospective analysis to evaluate outcomes in 24 such patients who underwent 90Y radioembolization. We concluded that 90Y radioembolization is reasonable for select patients with unresectable hepatic metastases in the absence of other metastatic sites.
Few patients with metastatic colorectal cancer (mCRC) are candidates for resection of their hepatic disease. Yttrium-90 (90Y) radioembolization has promise in the treatment of unresectable mCRC. We conducted retrospective study to assess the efficacy in patients with refractory mCRC who underwent 90Y radioembolization.
Materials and methods
Patients with unresectable mCRC with liver metastases treated at The Ohio State University were included in this analysis. Demographic data, carcinoembryonic antigen (CEA) values, observed toxicities, and information on prior therapies were collected. Response was assessed by RECIST (Response Evaluation Criteria in Solid Tumors) 1.1 criteria. Overall survival (OS) and progression-free survival (PFS) were estimated by the Kaplan-Meier method.
Twenty-four patients (median age, 63 years) were included. Of the patients, 54% had extrahepatic disease; 67% had bilobar involvement. The patients had received a median of 3 prior therapies. No objective responses were observed. Five patients had a CEA response. Median PFS and OS were 3.9 months (95% CI, 2.4–4.8 months) and 8.9 months (95% CI, 4.2–16.7 months), respectively. Patients older than 65 years had improved PFS (4.6 vs. 2.4 months) and OS (14 vs. 5.5 months) vs. younger patients, likely due to receipt of 90Y treatment earlier in their disease course. The presence of extrahepatic disease and the absence of CEA response appeared negatively predictive of efficacy. Toxicities were expected and manageable.
90Y radioembolization is active in select patients with refractory mCRC and with liver metastases, and is safe and well tolerated in the elderly. In patients with extensive extrahepatic disease, 90Y should be used in combination with chemotherapy. CEA may be a predictor of efficacy.
Hepatic; Locoregional; Colorectal cancer; Y-90; Radioembolization
Mutations in the v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) are present in approximately 30% to 40% of colorectal adenocarcinomas. Wild-type (WT) KRAS mutation status is predictive of tumor response with epidermal growth factor receptor-directed therapies, but the results from studies evaluating the prognostic value of KRAS status in localized disease have been contradictory. The prognostic value of KRAS in metastatic disease, specifically according to whether patients have synchronous or metachronous disease at presentation, is less understood.
One-hundred ten consecutive patients with metastatic colorectal adenocarcinoma underwent testing for KRAS exon 2 mutations by polymerase chain reaction amplification and direct nucleotide sequencing. The clinical characteristics, treatments, and outcomes of these patients were then analyzed retrospectively, stratified according to whether patients presented with synchronous or metachronous metastasis and according to KRAS mutation status (WT or mutated).
For the entire cohort, the median overall survival from the date of diagnosis of metastatic disease was 34.3 months (95% confidence interval, 28.3–49.4 months) for patients with WT KRAS (n = 70). The median overall survival for patients with mutated KRAS (n = 40) was 40.3 months (95% confidence interval, 27.9–51.1 months; log-rank P = .91). Kaplan-Meier survival analysis indicated that 3-year overall survival and 5-year overall survival were not statistically different. Within the subgroups of patients with synchronous and metachronous metastatic disease, no significant differences were observed in median overall survival, 3-year overall survival, or 5-year overall survival between the WT KRAS and mutated KRAS groups.
In this study, KRAS mutation status did not influence overall survival in either synchronous or metachronous metastatic colorectal adenocarcinoma and, as such, had no prognostic role in this disease setting.
metastatic colorectal adenocarcinoma; KRAS; mutation; prognosis
This study evaluated the tolerability, pharmacokinetics (PK), and preliminary antitumor activity of EZN-2208, a water-soluble, poly(ethylene) glycol conjugate of SN38.
Patients with advanced malignancies were enrolled in dose-escalating cohorts (3 + 3 design). EZN-2208 was administered as a 1-hour intravenous infusion given weekly for 3 weeks per each 4-week cycle. Doses ranged from 1 to 12 mg/m2.
Forty-one patients received EZN-2208. All patients had received prior cancer therapy (median = 2, range = 1–11). Twenty patients (49%) had received prior irinotecan, and one patient had received prior topotecan. One patient in the 9-mg/m2 cohort had dose-limiting toxicity (grade 3 febrile neutropenia), and one patient in the 12-mg/m2 cohort had grade 3 neutropenia that resulted in the inability to deliver the third dose of EZN-2208. The most commonly reported drug-related adverse events were nausea (51%), diarrhea (46%), fatigue (41%), alopecia (29%), neutropenia (24%), and vomiting (22%). Administration of EZN-2208 results in prolonged exposure to SN38. Stable disease, sometimes prolonged and associated with tumor shrinkage, was observed as best response.
EZN-2208 has an acceptable safety profile in previously treated patients with advanced malignancies. The recommended phase II dose of EZN-2208 administered according to this schedule was 9 mg/m2.
topoisomerase-1 inhibitors; SN-38; polyethylene glycol; Phase 1 clinical trials
Triapine (Vion Pharmaceuticals), a novel inhibitor of the M2 subunit of ribonucleotide reductase (RR), is a potent radiosensitizer. This NCI/CTEP-sponsored phase I study assessed the safety/tolerability of triapine in combination with radiation (RT) in patients with locally advanced pancreas cancer (LAPCA).
METHODS AND MATERIALS
We evaluated 3 dose levels of triapine (24 mg/m2, 48 mg/m2, 72 mg/m2) administered with 50.4 Gy of RT in 28 fractions. Patients with LAPCA received triapine thrice weekly, every other week during the course of RT. Dose-limiting toxicity (DLT) was assessed during and for 4 weeks following completion of RT. Dynamic contrast enhanced (DCE)-MRI and serum RR levels were evaluated as potential predictors for early response.
Twelve patients were treated. Four patients (1 non-evaluable [NE]) were enrolled at dose level 1 (DL1), three patients at DL2, and five patients (2NE) at DL3. No DLTs were observed and the MTD was not reached. Two patients (17%) achieved PR and 6 patients (50%) had SD. One patient underwent R0 resection following therapy. 92% of patients (100% on DL3) experienced freedom from local tumor progression. 75% of patients who eventually progressed developed metastases without local progression. RR levels did not appear to predict outcome. In 4 patients with available data, DCE-MRI may predict early response or resistance to therapy.
The combination of triapine at 72 mg/m2 three times weekly every other week and standard RT is tolerable with interesting activity in patients with LAPCA.
Triapine; radiation; pancreas cancer
Colorectal cancer remains one of the most common causes of cancer diagnoses and mortality in the United States. The treatment of metastatic colorectal cancer has evolved significantly over the last decade with near-tripling of patient survival rate. A significant contribution to this outcome was the advent of novel targeted agents, such as the epidermal growth factor (EGFR) inhibitors. In an era of emphasis on refining therapy, the presence of KRAS mutation will predict for resistance and limit exposure to patients who are more likely to benefit. In contrast, the presence of BRAF mutations does not seem to have a predictive value. Agents that are thought to reverse resistance to EGFR inhibitors such as those targeting PI3K, c-MET or IGF-1R are currently under study.
EGFR inhibitors have exhibited single agent activity, and seem to synergize very well with standard chemotherapy except for cetuximab and 5-fluorouracil, leucovorin, oxaliplatin (FOLFOX). Preliminary data suggests that EGFR inhibitors have similar effectiveness to vascular endothelial growth factor (VEGF) inhibitors in the first line setting. Skin toxicity remains the main limiting factor for the utilization of EGFR inhibitors, but strategies including the use of agents such as minocycline or doxycycline added to topical care seem to limit the severity of the rash.
Epidermal growth factor inhibitors (EGFR inhibitor); metastatic colorectal cancer (mCRC); cetuximab; panitumumab; KRAS; targeted therapy
Based on the promising activity and tolerability of flavopiridol administered with a pharmacokinetically-derived dosing schedule in chronic lymphocytic leukemia (CLL), we conducted a phase I study using this schedule in patients with advanced solid tumors.
Flavopiridol was given IV as a 30-min loading dose followed by a 4-hr infusion weekly for 4 weeks repeated every 6 weeks. Dose-escalation was in cohorts of three patients using the standard 3+3 phase I study design. Blood samples were obtained for pharmacokinetic and pharmacodynamic studies.
Thirty-four eligible patients with advanced solid tumors received a total of 208 doses (median 7, range 1–24). Total doses ranged from 40 – 105 mg/m2. The primary dose limiting toxicity was cytokine release syndrome (CKRS). No antitumor responses were observed. The mean peak plasma concentration across all doses was 1.65 ± 0.86 µM. Area under the concentration-versus-time curve (AUC0–∞) ranged from 4.31 to 32.2 µM·hr with an overall mean of 13.6 ± 7.0 µM·hr. Plasma flavopiridol concentrations and AUC increased proportionally with dose. There was no correlation between cytokine levels and clinical outcomes.
The maximum-tolerated dose of flavopiridol is 20 mg/m2 bolus followed by 20 mg/m2 infusion over 4 hours given weekly for 4 weeks on a 6-week cycle in patients with advanced solid tumors. Flavopiridol PK was notably different, and there was a higher frequency of CKRS, despite prophylactic steroids, seen in this patient group compared to previous studies with CLL using a similar dosing schedule.
Flavopiridol; CDK inhibitor; Phase I trial; Solid tumors
A phase I study to determine the maximum tolerated dose (MTD) of bortezomib (B) when combined with weekly paclitaxel in patients with advanced solid tumors.
Patients and methods
Eligible patients received escalating doses of intravenous (IV) bortezomib (0.6–2 mg/m2) on days 2 and 9 and IV paclitaxel at 100 mg/m2 on days 1 and 8 of a 21-day cycle. Dose escalation was based on two end-points: not exceeding 80% 20S-proteasome inhibition (20-S PI) and the development of dose-limiting toxicity defined as grade 3 or greater non-hematologic or grade 4 hematologic toxicities.
Forty-five patients with advanced solid tumors and a median of 3 prior chemotherapy regimens (range 0– 9), received 318 doses (median 5, range 1–34) of bortezomib and paclitaxel. Dose-related inhibition of 20-S PI was observed with a maximum inhibition of 70–80% at the MTD of 1.8 mg/m2 of bortezomib. At the MTD (N = 9) the following toxicities were observed: grade 4 neutropenia without fever (n = 2) and cerebrovascular ischemia (n = 1); grade 3 neutropenia (n = 3), diarrhea (n = 2), nausea (n = 1), and fatigue (n = 1); grade 2 fatigue (n = 5), diarrhea (n = 4), and dyspnea (n = 2). There was one partial response in a patient with an eccrine porocarcinoma. Stabilization of disease was observed in 7 (16%) patients, 3 of whom had advanced pancreatic cancer.
Sequential paclitaxel and bortezomib in previously treated patients with advanced solid tumors resulted in acceptable toxicity and no evidence of interaction. The recommended phase II dose of bortezomib in combination with weekly paclitaxel was 1.8 mg/m2.
Bortezomib; Phase I; Solid tumors; Paclitaxel
Interferon-alpha (IFN-α) promotes anti-tumor immunity through its actions on immune cells. We hypothesized that elevated percentages of myeloid-derived suppressor cells (MDSC) and increased pro-inflammatory cytokines in peripheral blood would be associated with impaired response to IFN-α in patients with gastrointestinal (GI) malignancies. This study evaluated relationships between plasma IL-6, IL-10, circulating MDSC subsets, and IFN-α-induced signal transduction in 40 patients with GI malignancies. Plasma IL-6 and IL-10 were significantly higher in patients versus normal donors. CD33+HLADR−CD11b+CD15+ and CD33+HLADR−/low CD14+ MDSC subsets were also elevated in patients versus normal donors (P < 0.0001). Plasma IL-6 was correlated with CD33+HLADR−CD15+ MDSC (P = 0.008) and IL-10 with CD33+HLADR−CD15− MDSC (P = 0.002). The percentage of CD15+ and CD15− but not CD14+ MDSC subsets were inversely correlated with IFN-α-induced STAT1 phosphorylation in CD4+ T cells, while co-culture with in vitro generated MDSC led to reduced IFN-α responsiveness in both PBMC and the CD4+ subset of T cells from normal donors. Exploratory multivariable Cox proportional hazards models revealed that an increased percentage of the CD33+HLADR−CD15− MDSC subset was associated with reduced overall survival (P = 0.049), while an increased percentage of the CD33+HLADR−/lowCD14+ subset was associated with greater overall survival (P = 0.033). These data provide evidence for a unique relationship between specific cytokines, MDSC subsets, and IFN-α responsiveness in patients with GI malignancies.
Myeloid-derived suppressor cell; Immune suppression; Interleukin-6; Interleukin-10
Pyrazoloacridine (PZA) is an investigational nucleic acid binding agent that inhibits the activity of topoisomerases 1 and 2. We conducted a phase II clinical study to determine the efficacy and toxicities of PZA in patients with metastatic breast cancer (MBC).
In this phase II multicenter study, patients who were treated with no more than one prior chemotherapy for MBC were treated with 750 mg/m2 of PZA given as a 3-hour intravenous infusion every 3 weeks. Treatment cycles were continued until disease progression or unacceptable toxicities. The study was designed to distinguish between a response rate of <15% vs >30% (alpha=0.10, beta=0.10) using Simons optimal 2-stage design. At least 2 responses were required in the first 12 patients in the 1st stage and 6 of 35 in the 2nd stage to recommend the agent for further study.
Two patients in the first stage had a response allowing accrual to second stage. A total of 15 patients (out of 35 planned) were treated on the study prior to premature closure. Three patients had a partial response (20%) lasting 4.5–6 months. Two patients had stable disease for 3 and 5 months. The dose limiting toxicity was granulocytopenia with ten patients requiring dose reduction or dose delay for grade 4 neutropenia. Other grade 3 and 4 toxicities include vomiting (n=2), nausea (n=2), neurotoxicity (n=1), fatigue (n=1), anemia (n=1), dyspnea 9n=1) and renal (n=1).
Pyrazoloacridine demonstrated modest activity in patients with metastatic breast cancer.
pyrazoloacridine; metastatic breast cancer; Phase II
Venous thromboembolism (VTE) is a frequent complication of gastrointestinal cancers that increases morbidity and may impact mortality. Low-molecular-weight heparins (LMWHs) and vitamin K antagonists (VKAs) are standard anticoagulation options for the ambulatory gastrointestinal cancer patient with VTE, but both of these agents are challenging to use for various reasons. Novel oral anticoagulants (NOAs) are new, orally available anticoagulants designed to be easier to administer with more reliable pharmacokinetics that eliminate the need for frequent monitoring of various laboratory parameters. This paper reviews the existing efficacy and safety data for the use of NOAs dabigatran etexilate, rivaroxaban, and apixaban and discusses the potential role of these agents in the management of gastrointestinal cancer-related VTE.
There have been significant developments in colon cancer research over the last few years, enabling us to better characterize tumors individually and classifying them according to certain molecular or genetic features. Currently, we are able to use KRAS mutational status as a guide to therapy with anti-epidermal growth factor receptor antibodies. Other molecular features under research include BRAF mutation, microsatellite instability, and CpG island methylation. These three molecular features are often associated with tumors that have overlapping phenotypes and can be present simultaneously in the same tumor. However, they carry different prognostic and predictive qualities, making analysis of their interaction relatively complex. Much research thus far has examined the clinical relevance of microsatellite instability in helping determine prognosis and the predictive value of adjuvant 5-fluorouracil chemotherapy in stages II and III colon cancers. BRAF mutation appears to be a biomarker for poor prognosis. CpG island methylation is tightly associated with microsatellite instable tumors and BRAF mutation, but its clinical utility remains uncertain. Hereby, we examine preclinical and clinical data that supports the utilization of all three phenotypes in future research applied to clinical practice.
Hepatocellular carcinoma (HCC) is a common and deadly malignancy with few systemic therapy options. The RAF/mitogen-activated protein kinase kinase (MEK)/extracellular signal-related kinase (ERK) pathway is activated in approximately 50% to 60% of HCCs and represents a potential target for therapy. Selumetinib is an orally available inhibitor of MEK tyrosine kinase activity.
Patients and Methods
Patients with locally advanced or metastatic HCC who had not been treated with prior systemic therapy were enrolled on to the study. Patients were treated with selumetinib at its recommended phase II dose of 100 mg twice per day continuously. Cycle length was 21 days. Imaging was performed every two cycles. Biopsies were obtained at baseline and at steady-state in a subset of patients, and pharmacokinetic (PK) analysis was performed on all patients.
Nineteen patients were enrolled, 17 of whom were evaluable for response. Most (82%) had Child-Pugh A cirrhosis. Toxicity was in line with other studies of selumetinib in noncirrhotic patients. PK parameters were also comparable to those in noncirrhotic patients. No radiographic response was observed in this group, and the study was stopped at the interim analysis. Of 11 patients with elevated α-fetoprotein, three (27%) had decreases of 50% or more. Median time to progression was 8 weeks. Inhibition of ERK phosphorylation was demonstrated by Western blotting.
In this study of selumetinib for patients with HCC, no radiographic responses were seen and time to progression was short, which suggests minimal single-agent activity despite evidence of suppression of target activation.
Biliary cancers (BCs) carry a poor prognosis, but targeting the RAS/RAF/mitogen-activated protein kinase kinase (MEK)/extracellular signal-related kinase (ERK) pathway is of significance. Selumetinib is an inhibitor of MEK1/2, so this trial was designed to determine the safety and efficacy of selumetinib in BC.
Patients and Methods
This was a multi-institutional phase II study of selumetinib at 100 mg given orally twice per day to patients with advanced BC. The primary end point was response rate. All patients were required to provide tissue before enrolling. The levels of phosphorylated ERK (pERK) and AKT (pAKT) were assessed by immunohistochemistry. Tumors were genotyped for the presence of BRAF- and/or RAS-activating mutations.
Twenty-eight eligible patients with a median age of 55.6 years were enrolled. Thirty-nine percent of patients had received one prior systemic therapy. Three patients (12%) had a confirmed objective response. Another 17 patients (68%) experienced stable disease (SD), 14 of whom (56%) experienced prolonged SD (> 16 weeks). Patients gained an average nonfluid weight of 8.6 pounds. Median progression-free survival was 3.7 months (95% CI, 3.5 to 4.9) and median overall survival was 9.8 months (95% CI, 5.97 to not available). Toxicities were mild, with rash (90%) and xerostomia (54%) being most frequent. Only one patient experienced grade 4 toxicity (fatigue). All patients had tissue available for analysis. No BRAF V600E mutations were found. Two patients with short-lived SD had KRAS mutations. Absence of pERK staining was associated with lack of response.
Selumetinib displays interesting activity and acceptable tolerability in patients with metastatic BC. Our results warrant further evaluation of selumetinib in patients with metastatic BC.
This paper reports a trial performed by a National Cancer Institute–funded cooperative group evaluating the antitumor efficacy and safety of sunitinib malate in patients with previously treated pancreas adenocarcinoma.
The Cancer and Leukemia Group B (CALGB) conducted a phase II study evaluating sunitinib in patients with progressive metastatic pancreas adenocarcinoma following prior gemcitabine-based therapy (trial CALGB 80603; ClinicalTrials.gov identifier, NCT00397787). The primary endpoint was to determine the disease control rate (DCR) as measured by the Response Evaluation Criteria in Solid Tumors (complete response, partial response [PR], and stable disease) at 6 weeks.
Patients and Methods.
Patients aged ≥18 years with an Eastern Cooperative Oncology Group (ECOG) performance status score of 0–2 and with progressive pancreas adenocarcinoma following treatment with gemcitabine were eligible. Sunitinib was dosed at 50 mg orally days 1–28, every 42 days (1 cycle). The statistical plan called for a three-stage design. A DCR ≥15% was considered worthy of further study.
In total, 77 patients were enrolled. Forty-two (54.6%) enrollees were male. The median age was 65 years. The ECOG performance status score distribution was: 0, 39%; 1, 50%; 2, 11%. The DCR was 21.6%; one patient (1.4%) had a PR and 15 patients (20.3%) had stable disease as their best response. The progression-free survival time was 1.31 months (95% confidence interval [CI] 1.25–1.38 months) and overall survival time was 3.68 months (95% CI, 3.06–4.24 months).
The study met its primary endpoint; however sunitinib had minimal activity and moderate toxicity in a population of gemcitabine-refractory pancreas adenocarcinoma patients. For future studies, limiting enrollment to patients with an ECOG performance status score of 0–1 is recommended.
Sunitinib; Phase II; Refractory; Pancreas adenocarcinoma; CALGB 80603
In preclinical models, non-cytotoxic suramin (concentrations <50 μM) potentiates the activity of multiple chemotherapeutic agents. The present study evaluated the safety and tolerability of suramin in combination with docetaxel or gemcitabine in previously chemotherapy-treated patients with advanced non-small cell lung cancer.
Patients received suramin intravenously in combination with either docetaxel on day 1 or gemcitabine on days 1 and 8, of each 21-day treatment cycle. After 3 cycles, patients with partial response (PR) or better continued on the same combination, whereas patients with stable disease (SD) or worse crossed-over to the other combination. Pharmacokinetic analyses were performed before and after each treatment.
Eighteen patients received a total of 79 courses (37 suramin plus docetaxel, 42 suramin plus gemcitabine). The dose-limiting toxicity (DLT) was febrile neutropenia, observed in three of six patients treated with suramin and docetaxel 75 mg/m2. No DLTs were observed with suramin plus docetaxel 56 mg/m2 or suramin plus gemcitabine 1,250 mg/m2. Common adverse events included neutropenia, thrombocytopenia, anemia, fatigue, nausea, vomiting, skin rash, hyperglycemia, and electrolyte abnormalities. The target plasma suramin concentration range of 10–50 μM was achieved in 90% of treatments. Discernable antitumor activity was noted in 11 patients (2 PR, 9 SD).
Non-cytotoxic suramin, in combination with docetaxel 56 mg/m2 or gemcitabine 1,250 mg/m2, was reasonably well-tolerated with a manageable toxicity profile. Target plasma concentrations were correctly predicted by our previously described dosing nomogram. The observed preliminary evidence of antitumor activity encourages evaluation of this strategy in efficacy trials.
Suramin; Docetaxel; Gemcitabine; Chemosensitizer; Modulator; Non-small cell lung cancer
Patients with metastatic gastric cancer have a poor outcome. The development of new combinations of chemotherapy has led to steady but only modest gains in overall survival with largest effects reported with two- and three-drug regimens. Trastuzumab, a fully humanized monoclonal antibody directed at the human epidermal growth factor receptor-2 (HER2), has been found to improve response rate and survival in patients with advanced gastric cancer. This update will review the role of HER2 and summarize therapeutic advances in the use of trastuzumab in advanced gastric cancer.
gastric; gastroesophageal; adenocarcinoma; chemotherapy; trastuzumab
Our preclinical work showed a dramatic synergy between interleukin-12 (IL-12) and trastuzumab for stimulation of natural killer cell cytokine secretion. We aimed to determine the safety profile of IL-12 when given in combination with trastuzumab and paclitaxel to patients with meta-static HER2-overexpressing cancers. Paclitaxel was given i.v. at 175 mg/m2 every 3 weeks. Trastuzumab was given on day 1 each week (4 mg/kg initially and 2 mg/kg thereafter) in combination with injections of IL-12 on days 2 and 5 starting in cycle 2. This trial accrued 21 patients with metastatic HER2-positive tumors (breast, 7; colon, 6; esophagus, 4; stomach, 2; pancreas, 1; thyroid, 1). The IL-12 component was dose-escalated in cohorts of three patients. The dose-limiting toxicity was grade 3 fatigue at the 300 ng/kg dose level in two patients. The recommended phase II dose was 200 ng/kg administered s.c. There was one complete response in a patient with breast cancer, partial responses in 4 patients (breast, 2; esophageal, 2), and stabilization of disease lasting 3 months or greater (SD) in 6 other patients. All but one response occurred in patients with HER2 3+ disease. Two SD patients completed 1 year of therapy. Ten patients had progressive disease. There was increased activation of extracellular signal–regulated kinase in peripheral blood mononuclear cells and increased levels of IFN-γ and several chemokines in patients with clinical benefit (complete response, partial response, or SD), but not in patients with progressive disease. IL-12 in combination with trastuzumab and paclitaxel therefore exhibits an acceptable toxicity profile and has activity in patients with HER2-overexpressing cancers.
To evaluate the maximum-tolerated dose (MTD), safety profile, and immunogenicity of two chimeric, B-cell epitopes derived from the human epidermal growth factor receptor (HER2) extracellular domain in a combination vaccine with a promiscuous T-cell epitope (ie, MVF) and nor-muramyl-dipeptide as adjuvant emulsified in SEPPIC ISA 720.
Patients and Methods
Eligible patients with metastatic and/or recurrent solid tumors received three inoculations on days 1, 22, and 43 at doses of total peptide that ranged from 0.5 to 3.0 mg. Immunogenicity was evaluated by enzyme-linked immunosorbent assay, flow cytometry, and HER2 signaling assays.
Twenty-four patients received three inoculations at the intended dose levels, which elicited antibodies able to recognize native HER2 receptor and inhibited both the proliferation of HER2-expressing cell lines and phosphorylation of the HER2 protein. The MTD was determined to be the highest dose level of 3.0 mg of the combination vaccine. There was a significant increase from dose level 1 (0.5 mg) to dose level 4 (3.0 mg) in HER2-specific antibodies. Four patients (one each with adrenal, colon, ovarian, and squamous cell carcinoma of unknown primary) were judged to have stable disease; two patients (one each with endometrial and ovarian cancer) had partial responses; and 11 patients had progressive disease. Patients with stable disease received 6-month boosts, and one patient received a 20-month boost.
The combination vaccines were safe and effective in eliciting antibody responses in a subset of patients (62.5%) and were associated with no serious adverse events, autoimmune disease, or cardiotoxicity. There was preliminary evidence of clinical activity in several patients.
Hepatocellular carcinoma (HCC) is on the rise worldwide. HCC responds poorly to chemotherapy. Lapatinib is an inhibitor of EGFR and HER2/NEU both implicated in hepatocarcinogenesis. This trial was designed to determine the safety and efficacy of lapatinib in HCC.
A Fleming phase II design with a single stage of 25 patients with a 90% power to exclude a true response rate of < 10% and detect a true response rate of ≥30% was utilized. The dose of lapatinib was 1,500 mg/d administered orally in 28-day cycles. Tumor and blood specimens were analyzed for expression of HER2/NEU/CEP17 and status of downstream signal pathway proteins.
Twenty-six patients with HCC enrolled on this study. 19% had one prior therapy. Most common toxicities were diarrhea (73%), nausea (54%) and rash (42%). No objective responses were observed. Ten (40%) patients had stable disease (SD) as their best response including 6 (23%) with SD lasting > 120 days. Median progression-free-survival was 1.9 months and median overall survival 12.6 months. Patients who developed a rash had a borderline statistically significant longer survival. Tissue and blood specimens were available on >90% of patients. No somatic mutations in EGFR (exons 18–21) were found. In contrast to our previous findings, we did not find evidence of HER2/NEU somatic mutations. PTEN, P-AKT and P70S6K expression did not correlate with survival.
Lapatinib is well-tolerated but appears to benefit only a subgroup of patients for whom predictive molecular or clinical characteristics are not yet fully defined.
Curcumin, a yellow pigment and the active component of turmeric, has been shown to protect against carcinogenesis and prevent tumor development in several types of cancer. However, its low bioavailability and potency prevent it from being effective in most chemotherapeutic applications. One potential means of circumventing this problem has been the creation of synthetic curcumin analogues. We tested the efficacy of two such analogues, known as FLLL11 and FLLL12, in human pancreatic cancer cell lines. We compared the impact of curcumin with FLLL11 and FLLL12 on cell viability in five different pancreatic cancer cell lines. Although all three compounds were capable of lowering viability in all cell lines tested, FLLL11 and FLLL12 (IC50 values between 0.28–3.2 and 0.91–3.43λμmol/l, respectively) were substantially more potent than curcumin (IC50 values between 8.67 and 20.35λμmol/l). In addition, FLLL11 and FLLL12 inhibited phosphorylation of signal transducer and activator of transcription 3 and AKT, two cell signaling pathways frequently found persistently active in many forms of cancer. Furthermore, FLLL11 and FLLL12 were found to be more effective than curcumin in inducing apoptosis as evidenced by increased cleavage of PARP and caspase-3 in pancreatic cancer cell lines. These results indicate that the curcumin analogues, FLLL11 and FLLL12, are more effective than curcumin in inhibiting cell viability and inducing apoptosis, and may have translational potential as chemopreventive or therapeutic agents for pancreatic cancer.
AKT; curcumin; pancreatic cancer; signal transducer and activator of transcription 3
Hepatocellular carcinoma is rare, but increasing in prevalence in the United States. Recent studies have shown that sorafenib, a multikinase inhibitor, can reduce tumor progression in patients with this cancer. However, complete remission has not been observed. We report a case of a 78-year old patient with unresectable metastatic hepatocellular carcinoma who had a rapid and complete clinical response following therapy with sorafenib for six months. No evidence of disease recurrence has been noted for 6 months after discontinuation of therapy.
Several studies showed that gain-of-function somatic mutations affecting the catalytic domain of EGFR in non-small cell lung carcinomas were associated with response to gefitinib and erlotinib, both EGFR-tyrosine kinase inhibitors. In addition, 4% of non-small cell lung carcinomas were shown to have ERBB2 mutations in the kinase domain. In our study, we sought to determine if similar respective gain-of-function EGFR and ERBB2 mutations were present in hepatoma and/or biliary cancers.
We extracted genomic DNA from 40 hepatoma (18) and biliary cancers (22) samples, and 44 adenocarcinomas of the lung, this latter as a positive control for mutation detection. We subjected those samples to PCR-based semi-automated double stranded nucleotide sequencing targeting exons 18–21 of EGFR and ERBB2. All samples were tested against matched normal DNA.
We found 11% of hepatoma, but no biliary cancers, harbored a novel ERBB2 H878Y mutation in the activating domain.
These newly described mutations may play a role in predicting response to EGFR-targeted therapy in hepatoma and their role should be explored in prospective studies.