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Summary Cancer evolves dynamically as clonal expansions supersede one another driven by shifting selective pressures, mutational processes, and disrupted cancer genes. These processes mark the genome, such that a cancer's life history is encrypted in the somatic mutations present. We developed algorithms to decipher this narrative and applied them to 21 breast cancers. Mutational processes evolve across a cancer's lifespan, with many emerging late but contributing extensive genetic variation. Subclonal diversification is prominent, and most mutations are found in just a fraction of tumor cells. Every tumor has a dominant subclonal lineage, representing more than 50% of tumor cells. Minimal expansion of these subclones occurs until many hundreds to thousands of mutations have accumulated, implying the existence of long-lived, quiescent cell lineages capable of substantial proliferation upon acquisition of enabling genomic changes. Expansion of the dominant subclone to an appreciable mass may therefore represent the final rate-limiting step in a breast cancer's development, triggering diagnosis. PaperClip, Graphical Abstract Highlights ► Genome-wide analyses of mutations emerging through time in 21 breast cancers ► Minimal expansion of subclones occurs until thousands of mutations have accumulated ► Cancer-specific signatures of point mutations and genomic instability emerge late ► ERBB2 amplification begins early but continues to evolve over long molecular time, Newly developed algorithms allow the reconstruction of the genomic history of different breast cancers, tracing the temporal evolution of each tumor and the emergence of the dominant subclones that will eventually trigger diagnosis.

Purpose Current prognostic factors are poor at identifying patients at risk of disease recurrence after surgery for stage II colon cancer. Here we describe a DNA microarray–based prognostic assay using clinically relevant formalin-fixed paraffin-embedded (FFPE) samples. Patients and Methods A gene signature was developed from a balanced set of 73 patients with recurrent disease (high risk) and 142 patients with no recurrence (low risk) within 5 years of surgery. Results The 634–probe set signature identified high-risk patients with a hazard ratio (HR) of 2.62 (P < .001) during cross validation of the training set. In an independent validation set of 144 samples, the signature identified high-risk patients with an HR of 2.53 (P < .001) for recurrence and an HR of 2.21 (P = .0084) for cancer-related death. Additionally, the signature was shown to perform independently from known prognostic factors (P < .001). Conclusion This gene signature represents a novel prognostic biomarker for patients with stage II colon cancer that can be applied to FFPE tumor samples.

There has been a dramatic upsurge in the investigation of molecularly targeted therapy in colorectal cancer over the past two decades, with the first success being bevacizumab, a monoclonal antibody directed at vascular endothelial growth factor (VEGF). The latest additions to our armament are epidermal growth factor receptor (EGFR) inhibitors and the discovery of K-ras mutation’s impact on treatment efficacy. This review summarizes the new therapies targeting established pathways, such as VEGF and EGFR, and introduces tyrosine kinase inhibitors and monoclonal antibodies, as well as exciting novel agents targeting insulin-like growth factor, tumor necrosis factor, the Sonic Hedgehog pathway, Src kinase, mammalian target of rapamycin, and protein kinase C, which already have shown activity in other cancers and are currently being studied in phase 1/2 trials in metastatic colorectal cancer.

John Marshall, MD, is a global leader in the research and development of drugs for colon cancer and other gastrointestinal cancers. He has been the principal investigator of over 150 clinical trials at local, as well as national, levels. Dr Marshall is the clinical director of oncology for Georgetown University Hospital, associate director for clinical care of the Lombardi Comprehensive Cancer Center, and chief of the Division of Hematology-Oncology. In 2009, Dr Marshall became the founding director of the Otto J Ruesch Center for the Cure of Gastrointestinal Cancers. Combining expertise in molecular medicine, translational research, and a patient-centered philosophy, the Ruesch Center is dedicated to realizing the dream of individualized curative therapies through research, care, and advocacy.

Predictive factors for efficacy of vascular endothelial growth factor pathway-targeted therapies have not been identified or confirmed. Hypertension has been observed as a side effect to anti-vascular endothelial growth factor therapy. The goal of our study was to retrospectively assess if hypertension induced during treatment with bevacizumab was associated with clinical outcome in metastatic colorectal cancer patients treated with bevacizumab. We conducted a retrospective chart review of patients with colorectal cancer treated with bevacizumab at Lombardi Comprehensive Cancer Center from 2004 to 2008. Eighty-four patients with metastatic colorectal cancer were eligible. Eighteen patients (21%) developed grades 3 hypertension. Twelve patients (14%) developed grade 2 hypertension. Six patients (7%) developed grade 1 hypertension. Median overall survival (OS) was 29 months and progression-free survival (PFS) was 10 months. Patients with any grade hypertension while on bevacizumab had an adjusted hazard ratio for death of 0.32 (p = 0.03) and adjusted risk of progression of 51% (p = 0.02) compared to those without hypertension (HTN). When stratified by metastatic disease, patients presenting with metastases who developed HTN had better OS and PFS (p = 0.03 and 0.01.) Among patients without metastases at diagnosis, those with HTN on bevacizumab had better OS and PFS but results were not statistically significant (p = 0.60 and 0.62, respectively). Our data indicate that bevacizumab-induced hypertension may represent an interesting prognostic factor for clinical outcome in advanced colorectal cancer patients receiving bevacizumab.

BACKGROUND: Irinotecan-based chemotherapy regimens are 1 option for treatment of metastatic colorectal cancer (mCRC). The authors report the safety and efficacy of such regimens in elderly patients using a large phase III trial (bolus, infusional, or capecitabine with camptostar-celecoxib &n91;BICC-C&n93;) cohort. METHODS: In period 1, 430 previously untreated patients with mCRC were randomized in a 3-by-2 design to receive irinotecan plus infusional 5-fluorouracil, and leucovorin (FOLFIRI), irinotecan plus bolus 5-fluorouracil/leucovorin (mIFL), and irinotecan plus oral capecitabine (CapeIRI). In period 2, an additional 117 patients were randomized to receive FOLFIRI or mIFL and bevacizumab. In both periods patients were also randomized to a double-blind treatment with celecoxib or placebo. A secondary analysis was conducted examining the safety and efficacy of these regimens in elderly (age >70 years) versus nonelderly (age ≤70 years) patients. RESULTS: In period 1, 19.5% of patients were elderly, compared with 24.8% in period 2. Rates of grade 3 and higher toxicity did not differ significantly between age groups in either period by treatment arm, with the exception of asthenia in the FOLFIRI and CapeIRI arms (P = .05 and P = .03, respectively) and dehydration in the CapeIRI arm in period 1 (P = .02). Overall progression-free survival for FOLFIRI in both periods was not statistically different by age. Objective responses and overall survival did not differ by patient age within treatment arms and periods. CONCLUSIONS: Irinotecan/fluoropyrimidine combinations are well tolerated in the elderly population, with similar efficacy to that found in nonelderly patients in first-line mCRC. Cancer 2009. © 2009 American Cancer Society.

We seek to understand and harness our immune systems almost to the same degree as we have sought the answers of the universe. It is gratifying to see that we are making progress in this area with the result being evidence of clinical benefit and consistent alterations in the immune response. In this review, we will explore just one aspect of our efforts by focusing on vaccines that target carcinoembryonic antigen.

Aiwu Ruth Hea,∗, Jonathan Mendelsonb, Tiffany Blakeb, Lopa Mishrab,c and John L. Marshalla Division of Hematology/Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA Laboratory of Cancer Genetics, Digestive Diseases, and Developmental Molecular Biology, Department of Surgery, Lombardi Cancer Center, Georgetown University, Washington, DC, USA Laboratory of Digestive Diseases, Department of Surgery, DVAMC, Washington, DC, USA

Purpose We investigated dose and pharmacokinetics of erlotinib in patients with hepatic dysfunction or renal dysfunction. Patients and Methods Patients were assigned to one of three cohorts: cohort 1, AST ≥ 3× upper limit of normal; cohort 2, direct bilirubin of 1 to 7 mg/dL; and cohort 3, creatinine of 1.6 to 5.0 mg/dL. Cohort 1a was amended for albumin less than 2.5 g/dL. Erlotinib was administered orally daily to groups of at least three assessable patients in escalating doses of 50, 75, 100, and 150 mg, starting with 50 mg in hepatic dysfunction patients and 75 mg in renal dysfunction patients. Results Between December 2001 and May 2005, 55 patients were accrued. The distribution of assessable patients was: two of three in cohort 1, three of three in cohort 1a, 16 of 30 in cohort 2, and 18 of 18 in cohort 3. Dose-limiting toxicity (DLT) consisted of elevation of both total and direct bilirubin ≥ 1.5× baseline in three patients (cohort 1: one of five patients at 50 mg; cohort 2: two of six patients at 100 mg). In cohort 2, one of seven patients had DLT at 75 mg. No DLT was encountered in cohort 3 with 12 patients at 150 mg. Apparent oral clearance (mean ± standard deviation) was cohort dependent as follows: 1.9 ± 0.2 L/h in cohort 1; 3.7 ± 4.7 L/h in cohort 1a; 2.4 ± 1.1 L/h in cohort 2; and 4.5 ± 2.7 L/h in cohort 3 (Kruskal-Wallis, P < .017). Conclusion Patients with renal dysfunction tolerate 150 mg of erlotinib daily and seem to have an erlotinib clearance similar to patients without organ dysfunction. Patients with hepatic dysfunction should be treated at a reduced dose (ie, 75 mg daily) consistent with their reduced clearance.

Patients exhibiting pancreatic cancer possess poor rates of survival. Therefore, the identification of a biomarker that can be measured non-invasively and be used to predict patient outcomes is required for the successful treatment of pancreatic cancer. The present study evaluated serum microRNA (miRNA/miR) profiles in patients exhibiting pancreatic cancer, who were treated with lapatinib and capecitabine in a phase II trial. Serum samples were collected for the measurement of a panel of miRNAs (miR-21, miR-210, miR-221 and miR-7) associated with the epidermal growth factor receptor (EGFR)1 and human epidermal growth factor receptor (HER)2 pathways. Preclinically, human pancreatic cancer PANC-1, MIA PaCa-2 and BXCP-3 cell lines were utilized for miRNA and drug resistance studies. In total, 6/17 patients treated experienced disease progression following 2 cycles of treatment [non-responders (NRS)], while another 6/17 patients exhibited a stable disease state and received >4 cycles of treatment [responders (RS); range, 4-22 cycles]. Five patients withdrew from the study due to severe toxicity or mortality. The mean overall survival time was 6.5 vs. 10.4 months for NRS and RS, respectively. Significant upregulation of serum miRNAs at earlier time points (3-6 weeks) was observed in NRS. miRNA levels increased with cancer progression, and lapatinib and 5-fluorouracil (5-FU; the active form of capecitabine) treatment increased the miRNA levels (specifically miR-210 and miR-221) in the treatment-resistant pancreatic cancer PANC-1 and MIA PaCa-2 cell lines. However, lapatinib and 5-FU treatment did not increase the miRNA levels in the treatment-sensitive BXPC-3 cell line. Inhibition of miR-221 increased the sensitivity of the PANC-1 cells to treatment. In conclusion, an increase in specific serum miRNAs was associated with resistance to lapatinib and capecitabine treatment. Additional investigation is required with regard to the application of the miRNA panel investigated in the present study as a potential predictor of patient responses to anti-EGFR/HER2 treatment.

Rationale Although metastatic colon cancer is frequently incurable, large studies have confirmed a 25%-30% 5-year survival rate after complete resection of hepatic metastases.1-3 Unfortunately, intraand extrahepatic recurrences are still observed in two thirds of patients after resection of liver metastases. The most effective way to reduce hepatic recurrences that has been reported in randomized studies thus far is to use the combination of hepatic arterial infusion (HAI) and systemic chemotherapy postoperatively. Although Lorenz et al tested HAI with 5-fluorouracil (5-FU) and folinic acid without systemic treatment and showed no benefit over surgery alone,4 Kemeny et al from the Memorial SloanKettering Cancer Center compared HAI of floxuridine plus systemic 5-FU and folinic acid with systemic 5-FU and folinic acid alone after surgery and reported that the combined treatment resulted in a decrease in the hepatic recurrence rate and an improved overall survival but only at 2 years.5 More recently, Kemeny et al reported that HAI with floxuridine combined with intravenous, continuous-infusion 5-FU reduced the risk of recurrence when compared with surgery alone but resulted in no benefit in overall survival.6 Therefore, it has been suggested that surgery plus chemotherapy might reduce the risk of recurrences after surgery for liver metastases7 but that further therapies are clearly needed. Immunotherapy represents a non–cross reactive and potentially less toxic method for improving outcome. Colorectal cancers represent a reasonable target for vaccines because they are known to express tumor-associated and tumor-specific antigens (carcinoembryonic antigen [CEA], melanoma antigen gene family, MUC-1, p53, and others), and T cells specific for these antigens can be detected in the peripheral blood of some patients with colon cancer.8 Colon cancer vaccines have reached phase II/III testing, and trends toward clinical benefit have been reported in patients developing an immune response.9,10 Nonetheless, better vaccine strategies are required in order to improve the immune response against tumor antigens and to improve the clincial activity when the immune response has been activated. Numerous approaches to inducing immune responses against colon cancer have been attempted, including immunization with autologous tumor viral vectors encoding tumor antigens such as CEA, peptides, and dendritic cell–based vaccines.11 Recently, recombinant pox vectors, including vaccinia (rV)– and fowlpox (rF)–encoding CEA have been tested in patients with advanced-stage colon cancers. An intriguing observation was that the group of patients who received the prime boost strategy of rV-encoding CEA followed by rF-encoding CEA had greater CEA-specific T-cell responses and prolonged survival compared with those who received the reverse order of administration. This Submitted: Nov 28, 2005; Accepted: Jan 11, 2006 1Department of Medicine, Duke University Medical Center 2Medical Oncology, Georgetown, Lombardi Cancer Center, Washington, DC 3Medical Oncology, Wake Forest-Baptist Medical Center, WinstonSalem, NC 4Surgical Oncology, Medical University of South Carolina, Charleston 5Gastrointestinal Medical Oncology, University of Texas M. D. Anderson Cancer Center, Houston Emil Lou,1 John Marshall,2 Mebea Aklilu,3 David Cole,4 David Chang,5 Michael Morse1

PurposeOur previous clinical experience with vaccinia and replication-defective avipox recombinant carcinoembryonic antigen (CEA) vaccines has demonstrated safety and clinical activity with a correlation between CEA-specific immune response and survival. Preclinical evidence demonstrated that the addition of the transgenes for three T-cell costimulatory molecules (B7-1, ICAM-1, LFA-3, designated TRICOM) results in a significant improvement in antigen-specific T-cell responses and antitumor activity. We describe here the first trial in humans of the CEA-TRICOM vaccines (also including an enhancer agonist epitope within the CEA gene).Patients and MethodsFifty-eight patients with advanced CEA-expressing cancers were accrued to eight cohorts that involved vaccinations with the following: replication-defective fowlpox recombinant (rF)-CEA(6D)-TRICOM; primary vaccination with recombinant vaccinia (rV)-CEA(6D)-TRICOM plus rF-CEA(6D)-TRICOM booster vaccinations; and rV-CEA(6D)-TRICOM and then rF-CEA(6D)-TRICOM, plus granulocyte-macrophage colony-stimulating factor (GM-CSF) with vaccines, or with divided doses of vaccine with GM-CSF. Vaccines were administered every 28 days for six doses and then once every 3 months. Reverting to treatments every 28 days was allowed if patients progressed on the 3-month schedule.ResultsIn this phase I study, no significant toxicity was observed. Twenty-three patients (40%) had stable disease for at least 4 months, with 14 of these patients having prolonged stable disease (> 6 months). Eleven patients had decreasing or stable serum CEA, and one patient had a pathologic complete response. Enhanced CEA-specific T-cell responses were observed in the majority of patients tested.ConclusionWe demonstrated that the CEA-TRICOM vaccines are safe and can generate significant CEA-specific immune responses, and they seem to have clinical benefit in some patients with advanced cancer.

This phase II study was designed to characterize the clinical activity of ISIS 3521 in patients with metastatic colorectal cancer (CRC). Sixteen patients with pretreated or refractory CRC were treated with ISIS 3521. Eleven patients were given a dose of 2.0 mg/kg per day, and 5 patients received 3.0 mg/kg per day given over 21 days followed by a 7-day rest period. Patients continued with study until evidence of disease progression or unacceptable toxicity was detected. Patients underwent baseline tumor biopsies followed by a second biopsy during the last week of the first 21-day infusion. All 16 patients underwent baseline tumor biopsies, and 12 of the 16 patients underwent on-study tumor biopsies. No evidence of tumor response was observed. One patient had stable disease after 2 cycles and remained on for 1 additional cycle only to demonstrate progression of disease at that time. No dose-limiting or other significant toxicities were observed at both dosages, which could not be explained by progression of disease. Fatigue was common in all patients treated but was not dose limiting, and there was no evidence of coagulopathy. Analysis of the tumor biopsies obtained from the 11 evaluable samples showed marked uptake of ISIS 3521 in the normal liver parenchyma. However, there was minimal uptake within the tumor cells. In addition, no evidence of any alteration in protein kinase C-a within the tumors or any downstream effects leading to apoptosis were observed. ISIS 3521 demonstrated no clinical activity or target modulation in refractory metastatic CRC.

Purpose: Rapid cleavage in vivo and inefficient cellular uptake limit the clinical utility of antisense oligonucleotides (AON). Liposomal formulation may promote better intratumoral AON delivery and inhibit degradation in vivo. We conducted the first clinical evaluation of this concept using a liposomal AON complementary to the c-raf-1 proto-oncogene (LErafAON). Experimental Design: A dose escalation study was done to determine the maximum tolerated dose and to characterize the toxicities of LErafAON given as weekly intravenous infusion for 8 weeks to adults with advanced solid tumors. Pharmacokinetic analysis and evaluation of c-raf-1 target suppression in peripheral blood mononuclear cells were included. Results: Twenty-two patients received LErafAON (median 7 infusions; range 1–27) at doses of 1, 2, 4, and 6 mg/kg/week. Across all dose cohorts patients experienced infusion-related hypersensitivity reactions including flushing, dyspnea, hypoxia, rigors, back pain, and hypotension. Prolonged infusion duration and pretreatment with acetaminophen, H1- and H2-antagonists, and corticosteroids reduced the frequency and severity of these reactions. Progressive thrombocytopenia was dose-limiting at 6 mg/kg/week. No objective responses were observed. Two patients treated at the maximum tolerated dose of 4 mg/kg/week had evidence of stable disease, with dosing extended beyond 8 weeks. Pharmacokinetic analysis revealed persistence of detectable circulating rafAON at 24 hours in 7 of 10 patients in the highest 2 dose cohorts. Suppression of c-raf-1 mRNA was noted in two of five patients analyzed. Conclusions: Dose-independent hypersensitivity reactions and dose-dependent thrombocytopenia limited tolerance of LErafAON. Future clinical evaluation of this approach will depend on modification of the liposome composition.

BACKGROUND To ascertain if hepatic or renal dysfunction or prior pelvic radiation (XRT) leads to increased toxicity at a given dose of irinotecan and to characterize the pharmacokinetics of irinotecan and its major metabolites in patients with hepatic or renal dysfunction. PATIENTS AND METHODS Adults with tumors appropriate for irinotecan therapy and who had abnormal liver or renal function tests or had prior radiation to the pelvis were eligible. Patients were assigned to one of four treatment cohorts: I, aspartate aminotransferase (AST) > or = 3x upper limit of normal and direct bilirubin

Purpose: To describe and compare the perceptions of cancer patients and their physicians regarding phase I clinical trials. Methods: Eligible patients had been offered phase I trial participation and had decided to participate but had not yet begun treatment. Each patient’s physician also served as a study subject. Patients and physicians completed questionnaires with domains including perceptions of potential benefit and harm from treatment (experimental and standard), relative value of quality and length of life, and perceived content of patient-physician consultations. Results: Three hundred twenty-eight patients and 48 physicians completed surveys. Patients had high expectations regarding treatment outcomes (eg, median 60% benefit from experimental therapy), with those choosing to participate in a phase I trial being more optimistic than those declining phase I participation. Patients predicted a higher likelihood of both benefit and adverse reactions from treatment (experimental and standard) than their physicians (P < .0001 for all comparisons). Although 95% of patients reported that quality of life was at least as important as length of life, only 28% reported that changes in quality of life with treatment were discussed with their physicians. In contrast, 73% of physicians reported that this topic was discussed (P < .0001). Conclusion: Cancer patients offered phase I trial participation have expectations for treatment benefit that exceed those of their physicians. The discordant perceptions of patients and physicians may possibly be explained by patient optimism and confidence; however, the discrepancies in reports of consultation content, particularly given patients’ stated values regarding quality of life, raise the possibility that communication in this context is suboptimal.

BACKGROUND Patients in Phase I clinical trials sometimes report high expectations regarding the benefit of treatment. The authors examined a range of patient characteristics to determine which factors were associated with greater expectations of benefit from Phase I trials. METHODS Participants were adult patients with cancer who had been offered participation in Phase I studies and had decided to participate. Patients completed interviewer-administered surveys before initiation of treatment. Physicians assessed Eastern Cooperative Oncology Group performance status for each patient. Statistical analyses (Pearson product moment correlation and t tests) used multiple imputation to account for missing data. RESULTS Overall, 593 patients who were offered participation in Phase I trials were contacted, and 328 patients agreed to participate in a study of decision making by cancer patients. Of these, 260 patients (79%) enrolled in a Phase I trial. Patients' expectations regarding the chance that their disease would be controlled with experimental therapy were unrelated to age, gender, living situation, education level, or functional status. Expectations were correlated positively with beliefs about the benefit of standard therapy and the maximum benefit patients may experience from experimental therapy. Greater expectations of benefit were associated with better health-related quality of life, stronger religious faith, optimism, relative health stock, monetary risk seeking, and poorer numeracy. CONCLUSIONS Expectations expressed as beliefs in personal outcomes may be related more to quality of life and personality variables than to patients' knowledge or functional status. Whether such expectations are accurate reflections of knowledge has important implications for evaluating the informed consent process. Cancer 2003;98:166–75. © 2003 American Cancer Society. DOI 10.1002/cncr.11483

Purpose: Bryostatin-1 is a compound known to inhibit protein kinase C expression. Clinical trials have focused on administration schedules ranging from 1 hour to 72 hour infusions. Preclinical data suggest that the down regulation of the target PKC occurs only as long as the drug is being infused. Therefore we performed a phase 1 clinical trial to determine the safety and recommended dose of prolonged infusion Bryostatin-1. Experimental Design: Patients with advanced metastatic cancer were enrolled in this traditional phase 1 clinical trial utilizing prolonged infusion Bryostatin-1. The administration of Bryostatin-1 was initially begun at 96 hours and extended to 14 days. Doses were escalated using the 96 hour infusion time and then duration of infusion was increased. All patients underwent extensive sampling for determination of PKC levels as well as other key biologic end points. The determination of maximum tolerated dose and recommended phase two dose were based on toxicity. Results: 38 patients were...

Capecitabine is a synthetic oral fluoropyrimidine carbamate that is sequentially activated in a three-step process, which results in the preferential production of 5-fluorouracil in tumours, rather than in the normal surrounding tissue. Capecitabine is proven to be as effective as the combination of 5-fluorouracil and leucovorin administered on the Mayo clinic schedule in patients with metastatic colorectal cancer. It has also been proven to be effective in patients with metastatic breast cancer that has progressed despite prior anthracyclines and taxoids. More recently, it has also been shown to increase survival in combination with docetaxel in patients with metastatic breast cancer in comparison to docetaxel alone. This article reviews the pharmacology and clinical activity of capecitabine, as well as combinations of capecitabine with other chemotherapeutic agents and future directions of investigation with this convenient and widely active antitumour therapy.

PURPOSE: PV701, a replication-competent strain of Newcastle disease virus, causes regression of tumor xenografts after intravenous administration. This phase I study was designed to define the maximum-tolerated dose (MTD) and safety of single and multiple intravenous doses of PV701 as a single agent in patients with cancer.PATIENTS AND METHODS: Seventy-nine patients with advanced solid cancers that were unresponsive to standard therapy were enrolled. Four PV701 intravenous dosing regimens were evaluated: (1) single dose: one dose every 28 days; (2) repeat dose: three doses in 1 week every 28 days; (3) desensitizing: one lower dose followed by two higher doses in 1 week every 28 days; and (4) two week: one lower dose followed by five higher doses over 2 weeks every 21 days.RESULTS: A 100-fold dose intensification was achieved over 195 cycles. A first-dose MTD of 12 × 109plaque-forming units (PFU)/m2was established for outpatient dosing. After an initial dose of 12 × 109PFU/m2, patients tolerated an MTD for subsequent doses of 120 × 109PFU/m2. The most common adverse events were flu-like symptoms that occurred principally after the first dose and were decreased in number and severity with each subsequent dose. Tumor site–specific adverse events and acute dosing reactions were also observed but not cumulative toxicity. Objective responses occurred at higher dose levels, and progression-free survival ranged from 4 to 31 months. Tumor tissue from one patient was obtained after 11 months of therapy and showed evidence of PV701 particles budding from the tumor cell membrane by electron microscopy and a pronounced lymphoplasmacytic infiltrate by histologic examination.CONCLUSION: PV701 warrants further study as a novel therapeutic agent for cancer patients.

Chemotherapy remains the primary mode of treatment for metastatic carcinoma of the esophagus. The efficacy of various chemotherapeutic regimens has been studied predominantly in patients with squamous cell carcinoma of the esophagus. In light of the increasing incidence of adenocarcinoma of the esophagus, studies evaluating newer chemotherapy agents, such as docetaxel, in this patient population are necessary. The objective of this trial was to determine the complete and partial response rate of docetaxel in patients with incurable adenocarcinoma of the esophagus.Eligible patients had histologically confirmed metastatic adenocarcinoma of the esophagus or locally extensive disease not curable with surgery or radiation therapy. Patients were either chemotherapy naive or previously treated with chemotherapy (including paclitaxel). Docetaxel was administered at a dose of 75 mg/m2 every three weeks intravenously. Appropriate imaging studies/examinations were obtained after every two cycles to evaluate response.A total of 22 patients were enrolled in the trial. Chemotherapy-naive patients achieved a response rate of 18% (95% CI = 2.3 to 51.8) while patients who received prior chemotherapy achieved a 0% response rate (95% CI = 0 to 25). There were no complete responses. The overall median survival time is 3.4 months and the one-year survival rate is 21%. The toxicities included febrile neutropenia (32%) as well as grade 3 and 4 fatigue (14%) and anorexia (9%).Although chemotherapy naive patients achieved an 18% response rate and no responses were seen in previously treated patients, the limitations of this trial does not allow for any definitive conclusions to be made about the efficacy of single agent docetaxel chemotherapy in patients with incurable esophageal cancer.

522 Background: Recent analysis of CALGB 80405 showed that left sided colon tumors (LT) respond differently to biologics compared with right-sided tumors, likely due to molecular differences. Molecular variations between LT and rectal tumors remain undefined. Herein, we report our exploration of these variations. Methods: Tumors with origins clearly defined as splenic flexure to descending colon (SFT), sigmoid colon (SgT), or rectum (RT) were included. Protein expression, gene amplification and NextGen sequencing was tested. Microsatellite instability (MSI) was measured by PCR. Tumor mutational load (TML) was calculated using only somatic nonsynonymous missense mutations. Chi-square tests were used for comparative analyses. Results: In total, 1,457 primary tumors (SFT 125; SgT 460, and RT 872) were examined. When compared with SFT, RT had a higher frequency of TP53 (71% vs. 57%, p = 0.03) and APC (66% vs. 49%, p = 0.01); a lower frequency of PIK3CA (11% vs. 22%, p = 0.02), BRAF (3% vs. 15% p = 0.0001), GNAS (0.9% vs. 4%, p = 0.04), HNF1A (0.7% vs. 5%, p = 0.01), and CTNNB1(0.3% vs. 4%, p = 0.003); and a higher expression of TOPO1 (52% vs. 31%, p = 0.0001), ERCC1 (29% vs. 15%, p = 0.03), and MGMT (64% vs. 53%, p = 0.048). When compared with SgT, RT had higher expression of TLE3 (33% vs. 23%, p = 0.007), TOPO1 (52% vs. 35%, p < 0.001), TUBB3 (41% vs. 28%, p = 0.003), and MGMT (64% vs. 54%, p = 0.003). There were no differences between SFT, SgT, and RT in the frequency of PD-L1 expression (5%, 2%, and 2%) on tumor cells, PD-1 expression on tumor-infiltrating lymphocytes (54%, 42%, and 42%), or Her-2 expression (1%, 2%, and 3%) and amplification (3%, 3%, and 5%). MSI was seen in 7% of SFT, 4% of SgT, and 0.7% of RT (total LT vs. RT, p = 0.01). Mean TML was 23, 6.5, and 7 mutations (mut)/MB (332 tumors), and the portion of tumors carrying a TML of > 17mut/MB was 9%, 1.6%, and 4% for SFT, SgT, and RT, respectively. In all 3 cohorts, a TML > 17 mut/MB was highly concordant with MSI. There was a correlation between PD-1 and TML in RT (p = 0.04) but not in SFT or SgT. There were no correlations between PD-L1 and TML. Conclusions: Tumors arising in the rectum may carry genetic alterations that are distinct from LT. A better understanding of disease biology may help to identify therapeutic targets and advance precision medicine

TPS507 Background: No effective therapy is available for patients (pts) with advanced cholangiocarcinoma (CC) after disease progression on first-line chemotherapy. In Phase I studies, pembrolizumab (pem) showed activity in pts with advanced CC. Interferon alpha-2b was shown to increase tumor immune infiltrates. In order to improve the response rate (RR) of pts with CC to pem, we propose to combine sylatron with pem in an open-label, single-arm, multicenter Phase II study. Methods: To be eligible for study, pts must have CC, manifesting as either intrahepatic, extrahepatic or gallbladder cancer that is unresectable, metastatic, and has either failed to respond to or demonstrated progression on frontline chemotherapy. Forty-four pts will be enrolled on study to receive SC sylatron (200 mg) weekly for 12 weeks, and IV pem (200mg) once every 3 weeks, starting on week 4 (at the same time as the 4th dose of sylatron), until pts experience disease progression or unacceptable toxicity, or withdraw consent. CT scans will be performed every 9 weeks. The primary endpoints are overall RR (ORR) and the safety and tolerability of combined pem and sylatron therapy. Secondary endpoints include OS, PFS, and ORR by irRECIST. An initial 3-week window will exist in which to evaluate the effect of sylatron alone (following prior chemotherapy) on the tumor microenvironment: one biopsy (biopsy 1) will be obtained before the start of sylatron therapy, and another (biopsy 2) after the third but before the fourth injection of sylatron (and the initiation of pem plus sylatron combination therapy). The effect of sylatron on the CC immune microenvironment will be studied by comparing biopsies 1 and 2. Immune microenvironment in pem + sylatron responders will be compared with non-responders. The study will assess whether the addition of sylatron improves the RR of pem from 17% to 35% in pts with advanced CC. Simon’s two-stage optimum design will be used to test the null hypothesis that P ≤ 0.17 vs. the alternative hypothesis that P ≥ 0.350. This study design provides 80% power (one-sided significance level of 0.05). The time-to-event endpoints (PFS, OS) will be estimated using Kaplan-Meier methodology.

675 Background: Recent retrospective analysis of CALGB/SWOG 80405 showed that left-sided colon cancers (LCC) respond differently to biological therapy compared with right-sided tumors. However, differences between rectal cancers (RC) and LCC remain undefined. Herein, we report our exploration of differences between these two groups. Methods: Individual patient data from 4182 patients (pts) with metastatic colorectal cancers, enrolled onto 8 first-line randomized trials, were pooled. Only pts with tumor locations that were clearly defined as LCC (splenic flexure to sigmoid) or RC were included in this analysis. Differences in pt characteristics and disease factors according to LCC vs. RC were identified. The prognostic effect of primary tumor location on OS and PFS was quantified via multivariable Cox proportional hazards modeling stratified by treatment arm within each study and adjusting for age, sex, performance status, and prior surgery. Results: In total, 2,479 (59%) pts with LCC and 1,703 (41%) pts with RC were identified. Pts with RC, compared with LCC, were more likely to be male (68% vs. 62%, p < 0.001), have lung metastases (mets) (56% vs. 37%, p < 0.001), and have 2 or more metastatic sites (64% vs. 60%, p < 0.02), whereas pts with LCC were more likely to have liver mets (84% vs. 76%, p < 0.001). RC had a greater frequency of KRAS mutations (41% vs. 37%, p = 0.04) than LCC but there were no differences in the frequency of BRAF mutations (5% vs. 4%, p = 0.2). In multivariable analysis, no differences in OS or PFS were observed between pts with LCC vs. RC. While risk of death did not differ by primary tumor location, across all pts with LCC or RC, those with liver mets had a 17% increased risk of death compared to those with lung mets (HR = 1.17, p = 0.03) after adjusting for effects of other variables. Forthcoming prognostic analysis of LCC vs. RC within grouped backbone treatments (e.g., FOLFOX and FOLFIRI) is underway. Conclusions: Tumors arising in the rectum may carry clinical and molecular features that are distinct from LCC. Further investigations are warranted to determine whether RC should be treated with the same chemo backbone and biological therapy as LCC.

530 Background: GI cancers are generally insensitive to immune checkpoint inhibitors (ICIs). Response to ICIs has been shown to correlate with TMB. Herein, we attempt to quantify TMB in GI cancers and its correlation with PD-1/PDL-1 expression. Methods: Tumor from various GI sites: right-sided and left-sided colon cancers (RT and LT), rectal cancer (RC), small bowel adenocarcinoma (SBA), gastric adenocarcinoma (GA), anal cancer (SCCA), hepatocellular carcinoma (HCC), esophageal adenocarcinoma and squamous cell carcinoma (EA and E-SCC), biliary cancer (BC), pancreatic adenocarcinoma (PA), and pancreatic neuroendocrine tumors (PNET), were analyzed by NextGen sequencing. TMB was calculated using only somatic nonsynonymous missense mutations sequenced with a 592-gene panel. MSI was assessed by fragment analysis. Correlation of PD-1/PD-L1 expression with TMB was calculated by student’s t test. Results: In total, 1375 tumors were examined. Among the different GI cancer types, RT and LT had the highest TMB (mean: 11.6 and 9.9 mutations [mut]/megabase [MB]), whereas BC and PA had the lowest levels (mean: 5.7 and 4.9 mut/MB) (Table). Overall primary tumors had higher TMB than metastases (mean: 8.3 vs. 6.5 mut/MB, p = 0.037). Using a cut-off of 17 mut/MB to define high vs. low TMB, high TMB was seen in all 24 MSI-H and 2 MSS colon tumors with POLE mutations, but not in other MSS colon tumors (n = 325, p < 0.0001). Similarly, among 6 GA tumors tested for MSI, high TMB was seen in 2 MSI-H while low TMB was seen in the 4 MSS tumors. Overall high TMB was seen most frequently in RT (12%), GA (11%), and SCCA (8%), and least frequently in PA (1.3%) and E-SCC (0%). PD-1 correlated with TMB in some tumor types (RT and RC), as did PD-L1 (RT and HCC). Conclusions: TMB varies among GI cancers. Forthcoming prognostic analysis to assess the correlation between TMB and response to ICIs in GI cancers is underway. [Table: see text]

538 Background: Nivolumab has shown promising results in SCCA patients. The majority of SCCA cases have been linked to prior human papillomavirus (HPV) infection. However, HPV negative tumors are frequently TP53 mutated and often resistant to therapy. Molecular characteristics of SCCA are largely undefined. Here we explored the underlying biology of SCCA and the differences between TP53-wild type ( TP53-WT) and TP53-mutated ( TP53-MT) tumors. Methods: SCCA specimens underwent multiplatform testing with protein expression (IHC), gene amplification (ISH), and sequencing (NGS). Tumor mutational burden (TMB) was calculated using only somatic nonsynonymous missense mutations. Chi-square tests were used for comparative analyses. Results: In total, 253 tumors were studied. The most frequently mutated genes included PIK3CA (24%), BRCA2 (14%), FBXW7 (12.4%), TP53 (9.7%), and PTEN (8.9%). In a subset of 23 tumors subjected to Illumina NextSeq (592 gene) testing, the most common mutations were NOTCH2 (30%), NOTCH1 (27.3%), POLE (21.7%) , TSC2 (17.4%), PTEN (14.3%), BRAF (13.6%), BRCA2 (13.0%), PIK3CA (13.0%), and FBXW7 (9.5%). Tumors frequently expressed MRP1 (97.6%), EGFR (92.7%), TOP2A (88.5%), TOPO1 (69.5%), MGMT (67.8%), and RRM1 (59.9%). Expression of PD-1 was seen in 55.8% (24/43) of tumors, and PD-L1 in 15.4% (9/34). HER2 was amplified in 2% (3/147) of samples, which has not been previously described in SCCA. When compared with TP53-WT (n = 93) tumors, T P53-MT (n = 10) had higher rates of BRAF (22% vs. 1%, p < 0.001) and RB1 mutations (44% vs. 0%, p < 0.001), whereas TP53-WT had higher expression of TOPO1 (76% vs. 40%, p = 0.01) and TUBB3 (19% vs. 50%, p = 0.02). There were no differences between the two groups in the frequency of PD-1 or PD-L1 expression. Mean TMB was 8.6 mutations/megabase and, using a TMB cut-off > 17 mutations/megabase to define high vs. low TMB, 6.7% of tumors were TMB-High. High TMB did not correlate with PD-1 (p = 0.50) or PD-L1 status (p = 0.52). Conclusions: Molecular profiling differences between TP53-MT and TP53-WT SCCA indicate different carcinogenic pathways and biology, which may influence response to therapy. Low frequency mutations in several druggable genes may provide therapeutic opportunities for patients with SCCA.

Background The folate receptor alpha is selectively over-expressed in a number of human cancers. BMS-753493 is a folate conjugate of the epothilone analog BMS-748285 that was designed to selectively target folate receptor expressing cancer cells. Methods BMS-753493 was investigated in two parallel multi-institutional first-in-human phase I/IIa studies in patients with advanced solid tumors. In Study 1, patients were treated on a schedule of once daily dosing of BMS-753493 administered on Days 1, 4, 8 and 11 every 21 days with a starting dose of 5 mg daily and in Study 2, patients were treated once daily on Days 1-4 every 21 days, with a starting dose of 2.5 mg daily. Results A total of 65 patients were treated across the two studies. The maximum tolerated dose (MTD) was 26 mg in Study 1 and 15 mg in Study 2. Fatigue, transaminitis, gastrointestinal toxicity, and mucositis were dose-limiting toxicities. One patient in Study 2 developed Stevens-Johnson syndrome attributed to BMS-753493. Plasma exposures of both the conjugated and free epothilone increased in a dose related fashion in both studies and the half-life of the conjugated epothilone was 0.2-0.6 h across dose levels. No objective tumor responses were seen in either study. Conclusions BMS-753493 was generally tolerable and toxicities known to be associated with epothilone class of anticancer agents were common, although peripheral neuropathy and neutropenia appear to have been less frequent and less severe as compared to epothilones. Antitumor activity was not demonstrated and further development of BMS-753493 has been discontinued.

Introduction 131I-CLR1404 is a small molecule that combines a tumor-targeting moiety with a therapeutic radioisotope. The primary aim of this phase 1 study was to determine the administered radioactivity expected to deliver 400 mSv to the bone marrow. The secondary aims were to determine the pharmacokinetic (PK) and safety profiles of 131I-CLR1404. Methods Eight subjects with refractory or relapsed advanced solid tumors were treated with a single injection of 370 MBq of 131I-CLR1404. Whole body planar nuclear medicine scans were performed at 15–35 minutes, 4–6, 18–24, 48, 72, 144 hours, and 14 days post injection. Optional single photon emission computed tomography imaging was performed on two patients 6 days post injection. Clinical laboratory parameters were evaluated in blood and urine. Plasma PK was evaluated on 127I-CLR1404 mass measurements. To evaluate renal clearance of 131I-CLR1404, urine was collected for 14 days post injection. Absorbed dose estimates for target organs were determined using the RADAR method with OLINDA/EXM software. Results Single administrations of 370 MBq of 131I-CLR1404 were well tolerated by all subjects. No severe adverse events were reported and no adverse event was dose-limiting. Plasma 127I-CLR1404 concentrations declined in a bi-exponential manner with a mean t½ value of 822 hours. Mean Cmax and AUC(0-t) values were 72.2 ng/mL and 15753 ng•hr/mL, respectively. An administered activity of approximately 740 MBq is predicted to deliver 400 mSv to marrow. Conclusions Preliminary data suggest that 131I-CLR1404 is well tolerated and may have unique potential as an anti-cancer agent. Trial Registration ClinicalTrials.gov NCT00925275

KRN330 is a recombinant, fully-human monoclonal antibody directed against A33, a surface differentiation antigen that is uniformly expressed in 95 % of colorectal cancers. A previous Phase 1 study of single-agent KRN330 identified a maximum tolerated dose (MTD) of 3 mg/kg q2w and preliminary evidence of clinical activity among patients with advanced and metastatic colorectal cancer (mCRC). This Phase 1/2 trial sought to assess the safety and activity of second-line KRN330 plus irinotecan in patients with mCRC. Patients with mCRC who showed disease progression after FOLFOX/CapOx received intravenous doses of KRN330 (0.5 or 1.0 mg/kg qw or q2w) plus irinotecan (180 mg/m(2)) in a standard 3 + 3 dose escalation. The MTD of KRN330 with irinotecan in 19 patients was 0.5 mg/kg qw in the Phase 1 study with gastrointestinal effects and neutropenia being the predominant dose-limiting toxicities. In the Phase 2 study, the most frequent treatment-related Grade ≥3 toxicities in 44 patients were fatigue (15.9 %), neutropenia (13.6 %), leukopenia (6.8 %), diarrhea (4.5 %), and dehydration (4.5 %). Objective response rate (ORR) was 4.5 % and disease control rate was 45.5 % for the intent-to-treat population. Median progression-free survival was 87 days (95 % CI, 43-136 days). The prespecified ORR of KRN330 plus irinotecan was not met. Further investigation of KRN330 plus other agents may be warranted.

A MESSAGE FROM ASCO'S PRESIDENT Since its founding in 1964, the American Society of Clinical Oncology (ASCO) has been committed to improving cancer outcomes through research and the delivery of quality care. Research is the bedrock of discovering better treatments—providing hope to the millions of individuals who face a cancer diagnosis each year. The studies featured in “Clinical Cancer Advances 2013: Annual Report on Progress Against Cancer From the American Society of Clinical Oncology” represent the invaluable contributions of thousands of patients who participate in clinical trials and the scientists who conduct basic and clinical research. The insights described in this report, such as how cancers hide from the immune system and why cancers may become resistant to targeted drugs, enable us to envision a future in which cancer will be even more controllable and preventable. The scientific process is thoughtful, deliberate, and sometimes slow, but each advance, while helping patients, now also points toward new research questions and unexplored opportunities. Both dramatic and subtle breakthroughs occur so that progress against cancer typically builds over many years. Success requires vision, persistence, and a long-term commitment to supporting cancer research and training. Our nation's longstanding investment in federally funded cancer research has contributed significantly to a growing array of effective new treatments and a much deeper understanding of the drivers of cancer. But despite this progress, our position as a world leader in advancing medical knowledge and our ability to attract the most promising and talented investigators are now threatened by an acute problem: Federal funding for cancer research has steadily eroded over the past decade, and only 15% of the ever-shrinking budget is actually spent on clinical trials. This dismal reality threatens the pace of progress against cancer and undermines our ability to address the continuing needs of our patients. Despite this extremely challenging economic environment, we continue to make progress. Maintaining and accelerating that progress require that we keep our eyes on the future and pursue a path that builds on the stunning successes of the past. We must continue to show our policymakers the successes in cancer survival and quality of life (QOL) they have enabled, emphasizing the need to sustain our national investment in the remarkably productive US cancer research enterprise. We must also look to innovative methods for transforming how we care for—and learn from—patients with cancer. Consider, for example, that fewer than 5% of adult patients with cancer currently participate in clinical trials. What if we were able to draw lessons from the other 95%? This possibility led ASCO this year to launch CancerLinQ, a groundbreaking health information technology initiative that will provide physicians with access to vast quantities of clinical data about real-world patients and help achieve higher quality, higher value cancer care. As you read the following pages, I hope our collective progress against cancer over the past year inspires you. More importantly, I hope the pride you feel motivates you to help us accelerate the pace of scientific advancement. Clifford A. Hudis, MD, FACP President American Society of Clinical Oncology

PURPOSE: This trial sought to determine, for the first time, the validity in human vaccinations of using two different recombinant vaccines in diversified prime-and-boost regimens to enhance T-cell responses to a tumor antigen. PATIENTS AND METHODS: Eighteen patients with advanced tumors expressing carcinoembryonic antigen (CEA) were randomized to receive either recombinant vaccinia (rV)-CEA followed by three avipox-CEA vaccinations, or avipox-CEA (three times) followed by one rV-CEA vaccination. Subsequent vaccinations in both cohorts were with avipox-CEA. Immunologic monitoring was performed using a CEA peptide and the enzyme-linked immunospot assay for interferon gamma production. RESULTS: rV-CEA followed by avipox-CEA was superior to the reverse order in the generation of CEA-specific T-cell responses. Further increases in CEA-specific T-cell precursors were seen when local granulocyte-macrophage colony-stimulating factor (GM-CSF) and low-dose interleukin (IL)-2 were given with subsequent vaccinations. The treatment was extremely well tolerated. Limited clinical activity was seen using vaccines alone in this patient population. Antibody production against CEA was also observed in some of the treated patients. CONCLUSION: rV-CEA was more effective in its role as a primer of the immune system; avipox-CEA could be given up to eight times with continued increases in CEA T-cell precursors. Future trials should use rV-CEA first followed by avipox-CEA. Vaccines specific to CEA are able to generate CEA-specific T-cell responses in patients without significant toxicity. T-cell responses using vaccines alone may be inadequate to generate significant anticancer objective responses in patients with advanced disease. Cytokines such as GM-CSF and IL-2 may play a key role in generating such responses.

Aims To examine the relationship between cytochrome P450 2C19 (CYP2C19) genotype and expressed metabolic activity in 16 patients with advanced metastatic cancer. Methods Individual CYP2C19 genotypes were determined by PCR-based amplification, followed by restriction fragment length analysis, and compared with observed CYP2C19 metabolic activity, as determined using the log hydroxylation index of omeprazole. Results All 16 patients had an extensive metabolizer genotype. However, based on the antimode in a distribution of log omeprazole hydroxylation indices from healthy volunteers, four of the patients had a poor metabolizer phenotype and there was a general shift of the remaining 12 patients towards a slower metabolic phenotype. This suggests a reduction in metabolic activity for all patients relative to healthy volunteers. A careful analysis of patient medical records failed to reveal any drug interactions or other source for the observed discordance between genotype and phenotype. Conclusions There are no previous reports of a ‘discordance’ between genotype and expressed enzyme activity in cancer patients. Such a decrease in enzyme activity could have an impact on the efficacy and toxicity of chemotherapeutic agents and other drugs, used in standard oncology practice.

The 5-year survival of pancreatic adenocarcinoma with surgery and adjuvant chemotherapy is below 25%. The original Gastrointestinal Tumor Study Group (GITSG) adjuvant study demonstrated a survival benefit attributed to weekly intravenous boluses of 5-fluorouracil (5-FU) for 2 years in addition to chemoradiation compared to surgery alone. In theory, the prolonged exposure to therapy could maintain pressure on dormant cancer cells that remain in G0 arrest and kill them as they infrequently enter the G1/S phase. We retrospectively evaluated outcomes in patients who were treated with adjuvant chemotherapy and maintenance capecitabine compared with those who received only adjuvant chemotherapy.Patients who had undergone surgical resection with curative intent and received adjuvant chemotherapy were analyzed. Those who subsequently received maintenance capecitabine therapy were compared to those who received adjuvant chemotherapy only. The primary end points were disease recurrence and all-cause mortality.The median overall survival (OS) of patients receiving maintenance capecitabine was greater than 48.4 months (the exact estimate was not available, since the survival probability curve does not cross 0.5). It was 22.0 months (95% confidence interval [CI], 16.6-29.2) in patients who received adjuvant chemotherapy only (P.001 by log-rank test). The median recurrence-free survival (RFS) was also longer in the maintenance capecitabine group: 54.3 (95% CI, 22.2-Inf) compared to 14.1 (95% CI, 11.6-16.7) months (P.001, by log-rank test).In this retrospective study, patients with resected pancreatic adenocarcinoma who received adjuvant chemotherapy had improved OS and RFS with additional maintenance therapy with capecitabine. These findings should be confirmed with a randomized, controlled trial.

Aims: To determine the maximum tolerated dose (MTD), safety and anti-tumor activity of afatinib combined with docetaxel in advanced cancer. Patients & methods: The MTD was determined from dose-limiting toxicities in the first cycle. Results: Thirty-one patients received 10, 20 and 30 mg oral afatinib, plus 60 and 75 mg/m2 intravenous docetaxel (six cohorts; 3-week cycles). The MTD of afatinib was 20 mg/day (days 2–21) with 75 mg/m2 docetaxel (day 1). Dose-limiting toxicities were grade 3/4 diarrhea (n = 3) and febrile neutropenia (n = 6). Most frequently occurring adverse events were diarrhea, neutropenia and rash. Disease stabilization occurred in 14 patients. Conclusion: Afatinib 20 mg/day plus docetaxel was suboptimal and the study could not yield Phase II dose recommendations. The combination resulted in a manageable safety profile.

Degradation of basement membrane and extracellular matrix by matrix metalloproteinases (MMPs) is believed to be required for tumor invasion, tumor-induced angiogenesis and vascular invasion. A synthetic hydroxamate, batimastat (also known as BB-94), inhibits MMPs by binding the zinc ion in the active site of the MMP. Batimastat inhibits at least 50% of MMP activity at concentrations less than or equal to 10 ng/ml in vitro. Batimastat retarded ascites accumulation and increased survival in mice with human ovarian tumor xenografts. Acute and long-term toxicological studies revealed no major toxicity in animals. Batimastat is poorly soluble and was administered intraperitoneally (i.p.) as a suspension. Previous studies in patients with malignant ascites have shown no major toxicities at doses as high as 1350 mg/m2.