A phase II trial of the proteasome inhibitor bortezomib in patients with advanced biliary tract cancers.

BACKGROUND: Patients with advanced biliary tract cancers have limited therapeutic options. Preclinical data suggest that proteasome inhibition may be an effective therapeutic strategy. We thus evaluated the clinical efficacy of bortezomib in advanced biliary tract cancers. PATIENTS AND METHODS: Patients with locally advanced or metastatic cholangiocarcinoma or gallbladder adenocarcinoma who had received 0 to 2 previous therapies received bortezomib 1.3 mg/m(2) on days 1, 4, 8, and 11 of a 21-day cycle. The primary end point was objective response rate. A Simon 2-stage design was used (null response rate of < 5% and response rate of ≥ 20% of interest). RESULTS: Twenty patients enrolled (bile duct/gallbladder cancer [14/6] and previous treatments 0/1/2 [10/6/3]). The trial was discontinued early because of lack of confirmed partial responses. No unanticipated adverse events were noted. There was 1 unconfirmed partial response. Ten patients achieved stable disease as best response. Median time to progression was 5.8 months (95% confidence interval [CI], 0.7-77.6 months). Median survival was 9 months (95% CI, 4.6-18.5 months). The 6-month and 1-year survival rates were 70% and 38%, respectively. There was no difference in survival based on primary disease site. CONCLUSION: Single-agent bortezomib does not result in objective responses in biliary tract cancers. However, the rate of stable disease and time to progression benchmark is encouraging. Further development of bortezomib in combination with other therapies in this disease setting should be considered.

A phase 1b study of humanized KS-interleukin-2 (huKS-IL2) immunocytokine with cyclophosphamide in patients with EpCAM-positive advanced solid tumors.

BACKGROUND: Humanized KS-interleukin-2 (huKS-IL2), an immunocytokine with specificity for epithelial cell adhesion molecule (EpCAM), has demonstrated favorable tolerability and immunologic activity as a single agent. METHODS: Phase 1b study in patients with EpCAM-positive advanced solid tumors to determine the maximum tolerated dose (MTD) and safety profile of huKS-IL2 in combination with low-dose cyclophosphamide. Treatment consisted of cyclophosphamide (300 mg/m2 on day 1), and escalating doses of huKS-IL2 (0.5-4.0 mg/m2 IV continuous infusion over 4 hours) on days 2, 3, and 4 of each 21-day cycle. Safety, pharmacokinetic profile, immunogenicity, anti-tumor and biologic activity were evaluated. RESULTS: Twenty-seven patients were treated for up to 6 cycles; 26 were evaluable for response. The MTD of huKS-IL2 in combination with 300 mg/m2 cyclophosphamide was 3.0 mg/m2. At higher doses, myelosuppression was dose-limiting. Transient lymphopenia was the most common grade 3/4 adverse event (AE). Other significant AEs included hypotension, hypophosphatemia, and increase in serum creatinine. All patients recovered from these AEs. The huKS-IL2 exposure was dose-dependent, but not dose-proportional, accumulation was negligible, and elimination half-life and systemic clearance were independent of dose and time. Most patients had a transient immune response to huKS-IL2. Immunologic activity was observed at all doses. Ten patients (38%) had stable disease as best response, lasting for ≥ 4 cycles in 3 patients. CONCLUSION: The combination of huKS-IL2 with low-dose cyclophosphamide was well tolerated. Although no objective responses were observed, the combination showed evidence of immunologic activity and 3 patients showed stable disease for ≥ 4 cycles.

A Phase I trial of the kinesin spindle protein (Eg5) inhibitor AZD4877 in patients with solid and lymphoid malignancies.

BACKGROUND: This Phase I study assessed the safety and maximum tolerated dose (MTD) of the kinesin spindle protein inhibitor AZD4877 in patients with relapsed/refractory solid tumors and lymphoma. METHODS: In this multicenter study, a standard 3 + 3 dose-escalation design was used. AZD4877 was given as an intravenous infusion on days 1, 4, 8 and 11 of each 21-day cycle. Responses were assessed with CT scans +/- PET after 6 and 12 weeks, then every 12 weeks while on therapy. An additional four patients with lymphoma were enrolled at the MTD. RESULTS: 29 patients were enrolled and 22 patients received at least one dose of AZD4877 and were evaluable for safety. The MTD was 11 mg. Dose-limiting toxicity was neutropenia (n = 2 patients, 15 mg cohort). The most common adverse events were grade 1/2 fatigue, nausea, neutropenia and dyspnea. AZD4877 exposure generally increased with dose, with mean elimination half-life approximately 16 h at the MTD. Pharmacodynamic analyses demonstrated moderate correlation between plasma drug concentrations at 6 or 24 h and monoaster formation in peripheral blood mononuclear cells (PBMCs). CONCLUSIONS: AZD4877 is generally well-tolerated with pharmacodynamic evidence of target inhibition in circulating PBMCs.

A Phase I, open-label, dose escalation study of afatinib, in a 3-week-on/1-week-off schedule in patients with advanced solid tumors.

BACKGROUND: A Phase I study to determine the maximum tolerated dose (MTD) and pharmacokinetics of afatinib (BIBW 2992), a novel irreversible ErbB Family Blocker, administered orally once daily in a 3-week-on/1-week-off dosing schedule. METHODS: Patients with advanced solid tumors received single-agent afatinib at 10, 20, 40, 55 or 65 mg/day. Safety, antitumor activity, pharmacokinetics and pharmacodynamic modulation of biomarkers were assessed. RESULTS: Forty-three patients were enrolled. Dose-limiting toxicities (DLTs) occurred in five patients in the dose escalation phase (1/8 at 40 mg/day; 1/6 at 55 mg/day; 3/6 at 65 mg/day). The MTD was established at 55 mg/day. In the expansion cohort at the MTD, 6 patients experienced a DLT in the first 28-day treatment period. The most frequent DLT was diarrhea. The most common adverse events were diarrhea, rash, nausea, vomiting and fatigue. Overall, the afatinib safety profile in a 3-week-on/1-week-off dose schedule was similar to that of our daily-continuous schedule. Afatinib displayed dose-dependent pharmacokinetics at doses up to and including 55 mg/day, with a terminal half-life suitable for once-daily dosing. Signs of clinical antitumor activity were observed. In biopsies taken from clinically normal forearm skin, afatinib caused a reduced proliferation rate, with a concomitant increase in differentiation of epidermal keratinocytes. CONCLUSION: Afatinib in a 3-week-on/1-week-off schedule showed a good safety profile. The MTD was 55 mg/day, although excess DLTs in the expansion cohort indicated that the 40 mg/day dose would have an acceptable safety profile for future studies. Dose cohorts between 40 and 55 mg/day were not examined in this study.

Phase I pharmacologic and biologic study of ramucirumab (IMC-1121B), a fully human immunoglobulin G1 monoclonal antibody targeting the vascular endothelial growth factor receptor-2.

PURPOSE To evaluate the safety, maximum-tolerated dose (MTD), pharmacokinetics (PKs), pharmacodynamics, and preliminary anticancer activity of ramucirumab (IMC-1121B), a fully human immunoglobulin G(1) monoclonal antibody targeting the vascular endothelial growth factor receptor (VEGFR)-2. PATIENTS AND METHODS Patients with advanced solid malignancies were treated once weekly with escalating doses of ramucirumab. Blood was sampled for PK studies throughout treatment. The effects of ramucirumab on circulating vascular endothelial growth factor-A (VEGF-A), soluble VEGFR-1 and VEGFR-2, tumor perfusion, and vascularity using dynamic contrast-enhanced magnetic resonance imaging were assessed. Results Thirty-seven patients were treated with 2 to 16 mg/kg of ramucirumab. After one patient each developed dose-limiting hypertension and deep venous thrombosis at 16 mg/kg, the next lower dose (13 mg/kg) was considered the MTD. Nausea, vomiting, headache, fatigue, and proteinuria were also noted. Four (15%) of 27 patients with measurable disease had a partial response (PR), and 11 (30%) of 37 patients had either a PR or stable disease lasting at least 6 months. PKs were characterized by dose-dependent elimination and nonlinear exposure consistent with saturable clearance. Mean trough concentrations exceeded biologically relevant target levels throughout treatment at all dose levels. Serum VEGF-A increased 1.5 to 3.5 times above pretreatment values and remained in this range throughout treatment at all dose levels. Tumor perfusion and vascularity decreased in 69% of evaluable patients. CONCLUSION Objective antitumor activity and antiangiogenic effects were observed over a wide range of dose levels, suggesting that ramucirumab may have a favorable therapeutic index in treating malignancies amenable to VEGFR-2 inhibition.

Phase I study of the safety, tolerability, and pharmacokinetics of oral CP-868,596, a highly specific platelet-derived growth factor receptor tyrosine kinase inhibitor in patients with advanced cancers.

PURPOSE: This phase I, first-in-human study evaluated the safety, tolerability, pharmacokinetics, and maximum-tolerated dose (MTD) of an oral platelet-derived growth factor receptor inhibitor, CP-868,596. PATIENTS AND METHODS: Patients with advanced solid tumors were eligible. Dose escalations were performed in three groups with two formulations: uncoated on an empty stomach (UES), uncoated with food (UFED), and film-coated (FC) without food. Initial dose escalation in the UES group was followed by parallel escalations in the UFED and FC groups. RESULTS: Fifty-nine patients enrolled. CP-868,596 was escalated from 100 mg to 340 mg daily in the UES group, from 60 mg to 100 mg twice daily in the UFED group, and from 100 mg once daily to 140 mg twice daily in the FC group. MTDs were 200 mg daily in the UES group and 100 mg twice daily in the FC group; MTD was not reached at 100 mg twice daily in the UFED group. Dose-limiting toxicities included hematuria, increased gamma-glutamyltransferase or ALT, insomnia, and nausea/vomiting. Most treatment-related AEs were of grades 1 to 2 severity; nausea, vomiting, and diarrhea were reported most frequently. Administration with food generally improved tolerability. CP-868,596 was absorbed slowly; systemic exposure parameters appeared to increase greater than proportionally with dose. Mean serum concentrations exceeded the preclinically predicted minimal efficacious concentration (ie, 16 ng/mL) at all dosages. Food and film coating apparently increased interpatient variability of the maximum observed plasma concentration and the area under the concentration-time curve. No objective responses were reported, and eight patients achieved stable disease (mean duration, 5.7 months). CONCLUSION: CP-868,596 potentially demonstrated greater than dose-proportional pharmacokinetics. The recommended dosage of 100 mg twice daily with food was well tolerated. Additional development as a single agent in selected populations or in combination with chemotherapy in broader populations is warranted.

The effect of stretching on muscle responses and postural sway responses during computerized dynamic posturography in women and men.

OBJECTIVE: To evaluate the effect of stretching on the parameters of postural sway and on the kinematic variables associated with balance control in women and men. DESIGN: Mixed repeated measures design with 2 levels. SETTING: Research laboratory. PARTICIPANTS: Fifteen women and fifteen men (mean age 23.4+/-2.2). INTERVENTION: Two separate sessions of (1) lower extremity stretching and (2) no-stretching, immediately prior to balance testing with simultaneous surface electromyographic (EMG) recordings of muscle responses. MAIN OUTCOME MEASURES: EMG latencies and average amplitudes for 4 lower extremity muscles for the preferred stance limb during computerized dynamic posturography (CDP) tests, specifically the Postural Evoked Response Test, Adaptation Test, Motor Control Test, Sensory Organization Test, and Unilateral Stance Test. RESULTS: Analyses of variance indicated no significant main effect for stretching and 2 significant main effects for gender for the Motor Control Test (P=.021) and latency of tibialis anterior (P=.009). Analyses of covariance with covariants of height and active knee extension revealed no significant main effect of stretching or of gender on muscles responses or CDP performance. CONCLUSIONS: In both women and men, lower extremity stretching did not significantly affect muscle responses or performance during CDP.

Effects of food on the relative bioavailability of lapatinib in cancer patients.

PURPOSE: This study was conducted to characterize the effect of food on the relative bioavailability of lapatinib. PATIENTS AND METHODS: A single 1,500-mg, oral dose of lapatinib was administered to 27 patients with advanced solid tumors on each of three occasions that were 1 week apart, in random order: after an overnight fast, with a low-fat breakfast, and with a high-fat breakfast. RESULTS: The low-fat breakfast produced mean increases in lapatinib area under the concentration-time curve (AUC) of 167% (2.67-fold) and maximum concentration (C(max)) of 142% (2.42-fold). The high-fat breakfast produced mean increases in lapatinib AUC of 325% (4.25-fold) and C(max) of 203% (3.03-fold) compared with the fasted state. Increased bioavailability in the fed state did not significantly decrease relative variability. Therefore, absolute variability in systemic exposure was increased. CONCLUSION: These large increases in lapatinib bioavailability and absolute variability support the recommendation for dosing in the fasted state to achieve consistent therapeutic exposure. Prescribers and patients should consider the potential consequences of toxicity or diminished efficacy that might result from dosing without regard to variations in diet.

Phase I study of capecitabine and oxaliplatin in combination with the proteasome inhibitor bortezomib in patients with advanced solid tumors.

PURPOSE: The combination of capecitabine and oxaliplatin has clinical benefit in a variety of gastrointestinal malignancies. The proteasome inhibitor bortezomib enhances the cytotoxic activity of fluoropyrimidines and platinum agents in vivo, and targeting of NF-kappaB may overcome chemotherapy resistance. Thus, we performed this phase I study to document the safety and obtain preliminary efficacy data for the combination of capecitabine, oxaliplatin, and bortezomib. PATIENTS AND METHODS: Patients with advanced solid tumors were treated with oxaliplatin 130 mg/m(2) intravenously on day 1, capecitabine 750-900 mg/m(2) twice daily orally for 14 days, and bortezomib 1.0, 1.3, or 1.6 mg/m(2) intravenously on days 1 and 8 of 21 day cycles. CT scans were repeated every 2 cycles. RESULTS: Thirteen patients received 45 cycles of treatment (median, 2; range, 1-8). No dose-limiting toxicities were noted at all bortezomib dose levels when administered with full dose capecitabine and oxaliplatin. The most common grade 3 nonhematologic toxicities during any cycle of therapy included elevated transaminases (3), vomiting, diarrhea, and dehydration (2 each). Only one patient experienced grade 3 peripheral neuropathy in cycle 8. Three objective tumor responses were noted (squamous cell of anus, adenocarcinoma of unknown primary, adenocarcinoma of rectum). CONCLUSIONS: Weekly bortezomib can be safely combined with full doses of capecitabine and oxaliplatin. As 1.6 mg/m(2) weekly of bortezomib is the maximum tolerated dose in single-agent studies, no further dose escalation was performed in this study. Preliminary evidence of antitumor activity is demonstrated. The further evaluation of this combination in diseases for which capecitabine and oxaliplatin have efficacy should be considered.

The platelet-derived growth factor receptor as a therapeutic target.

Several small molecule tyrosine kinase inhibitors that block the epidermal growth factor receptor and vascular endothelial growth factor receptor function are among the many recently developed targeted anticancer therapeutic agents. Increasing evidence indicates that inhibition of other tumor stromal targets could provide additional and possibly synergistic antitumor effects. This article focuses on the platelet-derived growth factor receptor as one such potential target.

Isolation and characterization of circulating tumor cells in patients with metastatic colorectal cancer.

PURPOSE: Development of targeted therapeutic agents in colorectal cancer (CRC) is impeded by the lack of a noninvasive surrogate of drug effect. This pilot study evaluated the ability of immunomagnetic separation to isolate circulating tumor cells (CTCs) and of the fluorescent microscope system and flow cytometry to enumerate and characterize CTCs from patients with metastatic CRC. PATIENTS AND METHODS: Fifty patients with metastatic CRC contributed 50 mL of blood at treatment initiation and disease evaluation timepoints. Fresh tumor specimens were obtained from 17 patients for comparison of circulating and in situ tumor cell characteristics. Epithelial cells were magnetically isolated from whole blood targeting the antiepithelial cell adhesion molecule (EpCAM). Circulating tumor cells were defined as EpCAM isolated, cytokeratin positive, nuclear stain positive, and CD45 negative. Total RNA was isolated from EpCAM-enriched CTCs and multigene reverse-transcriptase polymerase chain reaction analyses were performed. RESULTS: The median number of CTCs detected by flow cytometry was 2/7.5 mL blood. Mean change in cell count was significantly different for patients with tumor progression versus nonprogression (+6.7 vs. +0.2/7.5 mL; P = 0.001). A correlation was noted between mean fluorescence intensity (flow cytometry) of cytokeratin in CTC and matched tumor specimens (r = 0.79, P = 0.06). Nearly 80% (15 of 19) of samples with >or= 2 CTCs expressed >or= 1 epithelial marker gene (CK19, CK20, carcinoembryonic antigen, or epidermal growth factor receptor). CONCLUSION: Isolating and characterizing CTCs from patients with metastatic CRC is feasible. Change in the CTC number might reflect clinical status, and flow cytometric and gene expression data suggest similarity of circulating and in situ tumor cells. Further evaluation of CTCs for pharmacodynamic and clinical monitoring in patients with CRC is warranted.

Phase I and pharmacokinetic study of the farnesyltransferase inhibitor R115777 in combination with irinotecan in patients with advanced cancer.

PURPOSE: R115777 is a selective, nonpeptidomimetic inhibitor of farnesyltransferase (FTase), an enzyme responsible for the post-translational modification of several proteins, including Ras. Given the high frequency of K-Ras mutations in malignancies commonly treated with irinotecan, the broad preclinical antiproliferative activity of R115777 and its largely non-overlapping toxicity profile with irinotecan, this phase I study of the combination of R115777 and irinotecan in patients with advanced cancer was undertaken. PATIENTS AND METHODS: Enrolled onto the study were 14 patients (eight male, six female; median age 63 years, range 48-72 years). Five patients had an ECOG performance status (PS) of 0, eight patients PS 1, and one patient PS 2. The patients were treated with R115777 orally twice daily for 28 days and irinotecan 100 mg/m(2) as an intravenous infusion on days 1, 8, 15, and 22 of each 42-day cycle. Seven patients received R115777 100 mg twice daily and seven received R115777 200 mg twice daily. RESULTS: Dose-limiting toxicity (DLT) was experienced by one of seven patients treated with R115777 100 mg (grade 3 fatigue), and two of seven patients treated with R115777 200 mg (grade 3 diarrhea, grade 4 neutropenia lasting >5 days). The maximum tolerated dose (MTD) was R115777 100 mg twice daily and irinotecan 100 mg/m(2) weekly. Non-DLTs were primarily rash, fatigue, diarrhea, and neutropenia. R115777 demonstrated linear pharmacokinetics without interaction with irinotecan and achieved serum levels required for antitumor activity in vitro. CONCLUSIONS: Serum levels of R115777 exceeded those necessary for FTase inhibition in vitro without evidence of interaction with irinotecan. However, the MTD of R115777 in this study was lower than that obtained with an alternate schedule. Thus, further development of this schedule is not recommended.

Phase II and pharmacodynamic study of the farnesyltransferase inhibitor R115777 as initial therapy in patients with metastatic pancreatic adenocarcinoma.

PURPOSE: R115777 is a selective nonpeptidomimetic inhibitor of farnesyltransferase (FTase), one of several enzymes responsible for posttranslational modification that is required for the function of p21(ras) and other proteins. Given that RAS mutations are nearly universal in pancreatic cancer and R115777 demonstrated preclinical activity against pancreatic cell lines and xenografts, this phase II study was undertaken to determine its clinical activity and effect on target proteins in patients with measurable metastatic pancreatic adenocarcinoma. PATIENTS AND METHODS: Twenty patients who had not received prior therapy for metastatic disease were treated with 300 mg of R115777 orally every 12 hours for 21 of 28 days. Inhibition of FTase activity in peripheral-blood mononuclear cells was measured using a lamin B C-terminus peptide as substrate. Western blot analysis was performed to monitor farnesylation status of the chaperone protein HDJ-2. RESULTS: No objective responses were seen. Median time to progression was 4.9 weeks, and median survival time was 19.7 weeks. The estimated 6-month survival rate was 25%, with no patients progression-free at 6 months. Grade 3/4 toxicities were liver enzyme elevation, anemia, neutropenia, thrombocytopenia, fatigue, nausea/vomiting, rash, and anorexia. FTase activity (mean +/- SD) decreased by 49.8% +/- 9.8% 4 hours after treatment on day 1 and 36.1% +/- 24.8% before treatment on day 15. HDJ-2 farnesylation (mean +/- SD) decreased by 33.4% +/- 19.8% on day 15. CONCLUSION: Although treatment with R115777 resulted in partial inhibition of FTase activity in mononuclear cells, it did not exhibit single-agent antitumor activity in patients with previously untreated metastatic pancreatic cancer.

Development of new agents for the treatment of advanced colorectal cancer.

During the past decade, there have been several significant advances in the treatment of metastatic colorectal cancer. These include the introduction of the cytotoxic agents capecitabine, irinotecan, and oxaliplatin. Given their diverse mechanisms of action and toxicity profiles, combinations of fluoropyrimidines, irinotecan, and oxaliplatin have proven feasible and have improved patient outcomes compared with 5-fluorouracil alone. Recently, improved understanding of the biology of colorectal cancer has led to the identification of new molecular targets and the development of pharmacologic agents that hold promise for greater tumor selectivity than traditional cytotoxic agents. Two approaches with early indications of clinical activity against colorectal cancer are inhibition of epidermal growth factor receptor signaling and inhibition of the vascular endothelial growth factor pathway. Furthermore, biochemical and genetic profiling of individual tumors, as well as patient genotyping, may ultimately guide clinicians in making rational treatment decisions based on predicted antitumor efficacy or toxicity of selected agents. This article reviews these recent advances in the systemic treatment of colorectal cancer, including discussion of promising agents in clinical development.

Phase I and pharmacokinetic study of irinotecan in combination with raltitrexed.

PURPOSE: To determine the maximum tolerated dose (MTD) of raltitrexed when given with irinotecan and to evaluate the pharmacokinetics of these two agents when given in combination. METHODS: Patients with advanced solid tumors received irinotecan intravenously over 90 min on days 1 and 8 of each 21-day cycle, with raltitrexed given intravenously over 15 min after irinotecan either on day 1 (cohorts 1-7) or day 2 (cohorts 8-9). The 39 patients received irinotecan and raltitrexed in cohorts of three to six patients at the following dose levels (mg/m(2)): 100/1.0, 100/1.5, 100/2.0, 100/2.5, 100/3.0, 100/3.5, 125/3.0, 75/3.0, 100/3.0. Pharmacologic monitoring of irinotecan and raltitrexed was carried out during cycle 1. RESULTS: A total of 39 patients received irinotecan and raltitrexed in cohorts of three to six patients at nine dose levels. The MTD with dosing of irinotecan on days 1 and 8 and raltitrexed on day 1 was 100 mg/m(2) and 3.0 mg/m(2), respectively, every 21 days, with dose-limiting toxicities (DLTs) of fatigue, neutropenia and diarrhea. When raltitrexed was administered 24 h after irinotecan, these doses exceeded the MTD. No pharmacologic interactions were observed between these agents, and no correlations between pharmacokinetic parameters and toxicity were noted. Of 26 patients with colorectal cancer, 6 had objective partial responses (23%). Four of these patients had previously received a 5-FU-based regimen, two for metastatic disease. CONCLUSIONS: Irinotecan can be safely administered with raltitrexed on a day-1 and day-8 schedule at 100 mg/m(2) and 3.0 mg/m(2), respectively, every 21 days. When raltitrexed was given on day 2, these doses were not tolerated, necessitating a dose reduction of the irinotecan to 75 mg/m(2). This regimen possesses clinical activity in patients with colorectal cancer.