Infliximab for refractory sarcoidosis

BACKGROUND AND AIM OF WORK: Tumor necrosis factor-alpha (TNF-alpha) appears to be an important cytokine in the inflammation of sarcoidosis. Infliximab is a chimeric monoclonal antibody which specifically inhibits TNF-alpha. We investigated the efficacy of infliximab for the therapy of chronic, resistant sarcoidosis. METHODS: Patients with persistent symptomatic sarcoidosis despite corticosteroids and immunosuppressive agents were selected for treatment with infliximab. Patients were treated initially and at 2, 4, and 12 weeks with 5 mg/kg of infliximab at each treatment. Index lesions, which had progressed despite corticosteroid therapy, were reevaluated at 16 weeks. RESULTS: Three patients were treated. In two patients, the index lesion was lupus pernio, which significantly improved with infliximab. The third patient had restrictive lung disease. At week 16, there was a 26% improvement in the vital capacity from pretreatment values. All patients tolerated the treatments well. CONCLUSIONS: Infliximab was associated with significant improvement in chronic sarcoidosis.     

Serum levels of leptin and proinflammatory cytokines in advanced-stage non-small cell lung cancer

In this study, we aimed to investigate the diagnostic and prognostic roles and the effects of chemotherapy of serum proinflammatory cytokines consisting of IL-6, TNF-alpha, CRP, and leptin levels in patients with advanced-stage non-small cell lung cancer. Twenty-eight patients newly diagnosed of non-surgical advanced non-small cell lung cancer and 15 healthy controls were included. All patients with good performance status were treated with combination therapy consisting of cisplatin plus vinorelbine chemotherapy. Blood samples were obtained in fasting conditions before chemotherapy first and after two cycles of chemotherapy. IL-6 and TNF-alpha immunoassays employ the quantitative sandwich enzyme immunoassay technique. Leptin (Sandwich) ELISA is a solid-phase enzyme-linked immunosorbent assay based on the sandwich principle. CRP is a photometric immunoturbidimetric test. Most of the patients were elderly, male predominance, good performance status, and no or less than 10% weight loss. Higher serum TNF-alpha (p < 0.001) and CRP (p < 0.001), and lower leptin (p = 0.021) levels in patients than in controls. Serum IL-6 cytokine (p = 0.693) levels were not significantly different. No statistically significant relationships between investigated serum parameters and various characteristics of patient and disease. Likewise, serum levels of leptin, IL-6, TNF-alpha, and CRP were all similar in lung cancer patients independently from severity of weight loss (p > 0.05). A direct relationship was found between serum IL-6 and TNF-alpha levels (r = 0.530, p = 0.004). We found that both serum leptin (p = 0.046) and IL-6 (p = 0.002) levels were decreased owing to the chemotherapy effect independently from chemotherapy response. However, serum TNF-alpha and CRP levels were not changed by the chemotherapy effect. The stage of the disease, serum LDH levels, performance status, and responsiveness to chemotherapy yielded prognostic value. Only serum IL-6 levels out of the parameters showed a trend (p = 0.06) related to a worse prognosis.     

Quantitative evaluation of oxidative stress, chronic inflammatory indices and leptin in cancer patients: correlation with stage and performance status

In advanced cancer patients, the oxidative stress could take place either at the onset of disease or as a function of disease progression. To test this hypothesis, the following parameters were investigated: the erythrocyte activity of the enzymes superoxide dismutase (SOD) and glutathione peroxidase (GPx), the serum activity of glutathione reductase (GR) and the serum total antioxidant status (TAS). The total antioxidant capacity of plasma LMWA was evaluated by the cyclic voltammetry methodology. We further determined the serum levels of proinflammatory cytokines (IL-6 and TNFalpha), IL-2, leptin and C-reactive protein (CRP). All of these parameters have been correlated with the most important clinical indices of patients such as Stage of disease, ECOG PS and clinical response. Eighty-two advanced stage cancer patients and 36 healthy individuals used as controls were included in the study. Our findings show that SOD activity was significantly higher in cancer patients than in controls and GPx activity was significantly lower in cancer patients than in controls. Serum values of IL-6, TNFalpha and CRP were significantly higher in patients than in controls. Serum leptin values of cancer patients were significantly lower than controls. SOD activity increased significantly from Stage II/ECOG 0-1 to Stage IV/ECOG 0-1, whereas it decreased significantly in Stage IV/ECOG 3. GPx activity decreased significantly in Stage IV/ECOG 2-3. An inverse correlation between ECOG PS and serum leptin levels was found. Serum levels of IL-2 decreased from Stage II/ECOG 0-1 to Stage IV/ECOG 2-3. A direct correlation between Stage/ECOG PS and serum levels of both IL-6 and CRP was observed. Cisplatin administration induced a significant increase of GPx after 24 hr. In conclusion, this is the first study that shows that several "biological" parameters of cancer patients such as antioxidant enzyme activity, cytokines, leptin and CRP strictly correlate with the most important clinical parameters of disease such as Stage and ECOG PS.     

Involvement of interleukin-6 in the elevation of plasma fibrinogen levels in lung cancer patients

BACKGROUND: Involvements of interleukin-6 (IL-6) and fibrinogen in cancer development have been independently studied. However, the association of these molecules in cancer patients remains uncertain. This study was conducted to clarify the association according to the clinicopathological characteristics of lung cancer patients. METHODS: Serum IL-6 levels assayed in 339 patients without pleural effusion were assessed according to clinical stage, histological type of the cancer and levels of fibrin (ogen) degradation products (FDP), and C-reactive protein (CRP). RESULTS: Elevations of serum IL-6 levels more than 4 pg/ml were found in 37.8% of all patients. According to the clinical stage and histological type, the elevations were significantly more frequent in the advanced stage (44.7%), in squamous cell (49.1%) and large cell carcinomas (63.6%). Similarly, the frequency of the elevated cases (> 400 mg/dl) and the mean value of the fibrinogen level were also higher in the advanced stage (54.2%, 455.0 mg/dl) and large cell carcinoma (54.6%, 459.3 mg/dl), respectively. The elevations of fibrinogen, FDP and CRP levels were found to be related to those of the IL-6 level. CONCLUSION: In lung cancer, serum IL-6 elevations are particularly frequent in the advanced stages of patients with squamous cell and large cell carcinoma, which are associated with the elevated levels of fibrinogen, suggesting a possibility that IL-6 was involved not only directly, but also indirectly, through regulating plasma fibrinogen with promotion of cancer development in vivo.      

Pharmacokinetic and safety study of subcutaneously administered weekly ING-1, a human engineere monoclonal antibody targeting human EpCAM, in patients with advanced solid tumors.

BACKGROUND: ING-1 is a high-affinity, human engineeredtrade mark monoclonal antibody that recognizes a 40 kilodalton epithelial cell adhesion molecule (EpCAM) glycoprotein that is expressed in high levels on most adenocarcinomas and is an attractive target for immunotherapy. METHODS: ING-1 was administered subcutaneously weekly at doses between 0.1 and 2 mg/kg/week. Pharmacokinetic samples were drawn during weeks 1 and 6. RESULTS: Fourteen patients with advanced refractory cancer received a median of 6 (range 1-9) doses of ING-1. At 1 mg/kg, a 62-year-old man with colon cancer developed reversible grade 3 pancreatitis after the third dose. His plasma ING-1 levels were similar to the other two patients dosed at 1 mg/kg. Two patients dosed at 0.6 mg/kg experienced stable disease at 6 weeks. Peak drug levels increased with dose and time, suggesting drug accumulation with repeated dosing. Low human anti-human antibody response was noted in three of the 13 patients assessed and was directed towards the variable region of ING-1. CONCLUSIONS: Weekly ING-1 administered subcutaneously was well tolerated at 0.6 mg/kg/week and further experience at this dose is warranted to demonstrate safety. The risk of pancreatitis and the marginal anti-tumor effect may preclude further monotherapy studies; however, combination studies with chemotherapy are warranted.     

Immunotherapy with subcutaneous low dose interleukin-2 plus melatonin as salvage therapy of heavily chemotherapy-pretreated ovarian cancer

Preliminary results showed that IL-2 immunotherapy may be effective in the treatment of recurring advanced ovarian cancer. The pineal neurohormone melatonin (MLT) has been proven to amplify IL-2 efficacy by counteracting macrophage-mediated immunosuppression. On this basis, a pilot phase II study of low-dose IL-2 plus MLT was performed in advanced ovarian cancer patients progressing after at least 3 previous polychemotherapeutic lines. The study included 12 evaluable patients. IL-2 was injected subcutaneously at 3 million IU/day for 6 days/week for 4 weeks, by repealing the cycle after a al-day rest period in nonprogressing patients. MLT was given orally at 40 mg/day. No complete response was seen. A partial response was achieved in 2/12 (16%) patients. A stable disease was obtained in 5 other patients, whereas the remaining 5 patients progressed. The treatment was well tolerated. This preliminary study suggests that immunotherapy with low-dose IL-2 plus MLT may represent a well tolerated and promising therapy of advanced ovarian cancer progressing on standard medical treatments.     

Phase II trial of tetrathiomolybdate in patients with advanced kidney cancer.

PURPOSE: Tetrathiomolybdate (TM), a copper-lowering agent, has been shown in preclinical murine tumor models to be antiangiogenic. We evaluated the antitumor activity of TM in patients with advanced kidney cancer in a Phase II trial. EXPERIMENTAL DESIGN: Fifteen patients with advanced kidney cancer were eligible to participate in this trial. TM was initiated p.o. at 40 mg three times a day with meals and 60 mg at bedtime to deplete copper. A target serum ceruloplasmin (CP) level of 5-15 mg/dl was defined as copper depletion. Doses of TM were reduced for grade 3-4 toxicity and to maintain a CP level in the target range. Once copper depletion was attained, patients underwent baseline tumor measurements and then again every 12 weeks for response assessment. Patients not exhibiting progressive disease at 12 weeks after copper depletion continued on treatment. Serum levels of Interleukin (IL)-6, IL-8, vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) were assayed pretreatment and at various time points on treatment. Dynamic contrast enhanced-magnetic resonance imaging (DCE-MRI) was performed on selected patients in an attempt to assess changes in tumor vascularity. RESULTS: All of the patients rapidly became copper depleted. Thirteen patients were evaluable for response. No patient had a complete response or PR. Four patients (31%) had stable disease for at least 6 months during copper depletion (median, 34.5 weeks). TM was well tolerated, with dose reductions most commonly occurring for grade 3-4 granulocytopenia of short duration not associated with febrile episodes. Serum levels of IL-6, IL-8, VEGF, and bFGF did not correlate with clinical activity. Serial DCE-MRI was performed only in four patients, and a decrease in vascularity seemed to correlate with necrosis of a tumor mass associated with tumor growth. CONCLUSIONS: TM is well tolerated and consistently depletes copper as measured by the serum CP level. Clinical activity was limited to stable disease for a median of 34.5 weeks in this Phase II trial in patients with advanced kidney cancer. Serum levels of proangiogenic factors IL-6, IL-8, VEGF, and bFGF may correlate with copper depletion but not with disease stability in this small cohort. TM may have a role in the treatment of kidney cancer in combination with other antiangiogenic therapies.     

Elevations of serum C-reactive protein occur independently of circulating interleukin-6 concentrations in patients with lung-cancer

It has been suggested that a proportion of patients with cancer have an ongoing acute phase response indicated by a raised C-reactive protein (CRP). To examine whether an acute phase protein response is associated with circulating interleukin-6 (IL-6) concentrations in patients with lung cancer, we measured serum levels of CRP and interleukin (IL)-6 in 176 patients with lung cancer and 48 patients with other pulmonary diseases (28 diffuse pulmonary infiltrates, 15 benign lung tumors, and 5 bronchial asthmas). Serum CRP was detectable (greater-than-or-equal-to 2.5 mg/liter) in 57.4% of patients with lung cancer, 78.6% of patients with diffuse pulmonary infiltrates, 46.7% of patients with benign lung tumors, and 40.0% of patients with bronchial asthma. Serum IL-6 was detectable in all patients by a highly sensitive enzyme-immunoassay, the concentration ranging from 0.126 to 35.115 pg/ml. Although there was no significant difference in serum IL-6 levels among the histologic types of lung cancer, the IL-6 concentration was significantly higher in patients with advanced cancers than in those with early ones. Correlation analyses showed that there was no significant relationship between the CRP and IL-6 concentrations in the 176 patients with lung cancer (r=0.212, P=0.1243), while a highly significant correlation between both levels was observed in the 28 patients with diffuse pulmonary infiltrates (r=0.783, P=0.0005). These results indicate that the serum IL-6 level in patients with lung cancer is closely associated with the disease stage, but that a raised CRP concentration occurs independently of circulating IL-6 concentrations in patients with lung cancer.     

Interleukin-18 in multiple myeloma patients: serum levels in relation to response to treatment and survival

Interleukin-18 (IL-18) plays a role in the host's response to tumours and angiogenesis. We determined serum levels of IL-18, vascular endothelial growth factor (VEGF), angiogenin (ANG), tumor necrosis factor (TNF-alpha) and CRP in 65 newly diagnosed myeloma patients. IL-18, VEGF, angiogenin, TNF-alpha and CRP were significantly higher at stage III in comparison to stages II and I. These cytokines (measured in 27 patients) significantly decreased after treatment. In survival analysis, higher levels of IL-18 were associated with a poorer prognosis. We conclude that increased serum IL-18 in myeloma patients correlates with advanced disease, increased levels of angiogenic cytokines and worse survival.     

A phase II study of etanercept (Enbrel), a tumor necrosis factor alpha inhibitor in patients with metastatic breast cancer.

PURPOSE: Tumor necrosis factor (TNF) alpha is a key player in the tumor microenvironment and is involved in the pathogenesis of breast cancer. Etanercept is a recombinant human soluble p75 TNF receptor that binds to TNF-alpha and renders it biologically unavailable. In the current study, we sought to determine the toxicity, biological activity, and therapeutic efficacy of Etanercept in metastatic breast cancer. EXPERIMENTAL DESIGN: We initiated a Phase II, nonrandomized, open-labeled study in patients with progressive metastatic breast cancer refractory to conventional therapy (Phase I toxicity data were available in patients with rheumatoid arthritis). Etanercept was administered subcutaneously at a dose of 25 mg twice weekly until disease progression. RESULTS: Sixteen patients were recruited [median age 53 years (range, 34 to 74)]. A total of 141.6 weeks of therapy was administered (median of 8.1 weeks). Seven patients received > or =12 weeks of therapy. The most common side effects were injection site reactions (6), fatigue (5), loss of appetite (2), nausea (1), headache (1), and dizziness (1). Brief period of disease stabilization was seen in 1 patient lasting for 16.4 weeks. Immunoreactive TNF-alpha was elevated within 24 hours of therapy and persisted until the end of treatment (days 7, 28, 56, and 84). Phytohemagglutinin stimulates the production of interleukin-6 and CCL2 in peripheral blood cells, and the ability of Etanercept to modulate this response was assessed in a cytokine release assay. A consistent decrease in interleukin-6 and CCL2 level was seen compared with pretreatment values in serial blood samples (days 1, 7, 28, 56, and 84). CONCLUSIONS: Our study shows the safety and biological activity of Etanercept in breast cancer and provides data to assess pharmacodynamic endpoints of different schedules of Etanercept and combinations with chemotherapy or other biological therapies.     

Combination antiangiogenesis therapy with marimastat, captopril and fragmin in patients with advanced cancer

Marimastat, low molecular weight heparins and captopril have antiangiogenic activity in vitro and in animal models. We studied the safety and efficacy of the combination of these drugs in patients with advanced cancer. In all, 50 patients were enrolled. Captopril was given orally at a dose of 50 mg bd daily. Fragmin was administered as a daily subcutaneous injection of 200 units kg(-1) for the first 28 days and 5000 units thereafter. Marimastat was given at 10 mg bd orally. Serum, plasma and urinary angiogenic factors were measured at baseline and after 1 month of treatment. Inhibition of release of tumour necrosis factor alpha (TNF-alpha) from peripheral lymphocytes was used as a surrogate pharmacodynamic end point. There was one case of haemorrhagic stroke and one upper gastrointestinal haemorrhage. The commonest toxicity was myalgia. One of 10 patients with renal cancer had a partial response, and three patients had a prolonged period of stable disease. The treatment significantly inhibited phytohaemagglutinin (PHA)-stimulated TNF-alpha release from patient's lymphocytes. The combination of marimastat, fragmin and captopril is well tolerated and has in vivo activity. Inhibition of PHA-stimulated TNF-alpha release from lymphocytes is a surrogate pharmacodynamic marker of metalloprotease inhibition.     

A phase Ia/Ib study of novel anti-ErbB3 monoclonal antibody,barecetamab (ISU104) in refractory solid cancers and monotherapy or in combination with cetuximab in recurrent or metastatic head and neck cancer

We evaluated the safety, tolerability, pharmacokinetics and antitumor activity of barecetamab monotherapy and combination cetuximab therapy in patients with advanced solid cancers, especially head and neck cancer (HNC). Part 1 was a 3 + 3 dose-escalation study in which 15 patients received barecetamab at 1, 3, 5, 10 and 20 mg/kg intravenously (IV) on days 1 and 28 and weekly in patients with advanced solid cancer. Part 2 was a dose-expansion study including two patient groups with advanced HNC, including six patients receiving barecetamab at 20 mg/kg IV every 3 weeks and 12 patients receiving barecetamab and cetuximab (400 mg/m² on day 1 followed by 250 mg/m² every week). No dose-limiting toxicities (DLTs) were observed. Maximum serum target engagement was reached with trough levels of doses ≥3 mg/kg IV weekly. Common adverse drug reactions were diarrhea, stomatitis, dermatitis acneiform and decreased appetite. One durable complete response of more than 17 months was observed, and the overall response and disease control rates were 36.4% (4/11) and 81.1% (9/11), respectively, in the combination therapy group. In conclusion, DLT was not observed in barecetamab at 1 to 20 mg/kg. The recommended phase II dose was determined to be 20 mg/kg triweekly. Barecetamab and in cetuximab combination was well tolerated and demonstrated meaningful antitumor effects.     

A multicenter, phase II study of infliximab plus gemcitabine in pancreatic cancer cachexia

To evaluate the safety and efficacy of infliximab administered with gemcitabine to treat cancer cachexia and to explore a functional measure of clinical benefit, investigators involved in this multicenter, phase II, placebo-controlled study randomized 89 patients with stage II-IV pancreatic cancer and cachexia to receive either placebo or 3 mg/ kg or 5 mg/kg of infliximab at weeks 0, 2, and 4 and then every 4 weeks to week 24; patients also received 1,000 mg/m2 of gemcitabine weekly from weeks 0-6 and then for 3 of every 4 weeks until their disease progressed. The primary endpoint was change in lean body mass (LBM) at 8 weeks from baseline; major secondary endpoints included overall survival, progression-free survival, Karnofsky performance status, and 6-minute walk test distance. In addition, quality of life was measured. The mean change in LBM at 8 weeks was +0.4 kg for patients receiving placebo, +0.3 kg for those receiving 3 mg/kg of infliximab, and +1.7 kg for those receiving 5 mg/kg of infliximab. No statistically significant differences in LBM or secondary endpoints were observed among the groups. Safety findings were similar in all groups. Adding infliximab to gemcitabine to treat cachexia in advanced pancreatic cancer patients was not associated with statistically significant differences in safety or efficacy when compared with placebo.     

Dose and schedule study of panitumumab monotherapy in patients with advanced solid malignancies.

PURPOSE: This phase 1 study evaluated the safety, pharmacokinetics, and activity of panitumumab, a fully human, IgG2 monoclonal antibody that targets the epidermal growth factor receptor in patients with previously treated epidermal growth factor receptor-expressing advanced solid tumors. EXPERIMENTAL DESIGN: Sequential cohorts were enrolled to receive four i.v. infusions of panitumumab monotherapy at various doses and schedules. Safety was continuously monitored. Serum samples for pharmacokinetic, immunogenicity, and chemistry assessments were drawn at preset intervals. Tumor response was assessed at week 8. RESULTS: Ninety-six patients received panitumumab. Median (range) age was 61 years (32-79 years), and 72 (75%) patients were male. Tumor types were 41% colorectal cancer, 22% prostate, 16% renal, 15% non-small cell lung, 3% pancreatic, 3% esophageal/gastroesophageal, and 1% anal. The overall incidence of grade 3 or 4 adverse events was 32% and 7%, respectively. The incidence of skin-related toxicities was dose dependent. No maximum tolerated dose was reached. No human anti-panitumumab antibodies were detected. No investigator-determined panitumumab infusion-related reactions were reported. Serum panitumumab concentrations were similar in the 2.5 mg/kg weekly, 6.0 mg/kg every 2 weeks, and 9.0 mg/kg every 3 weeks dose cohorts. Five of 39 patients (13%) with colorectal cancer had a confirmed partial response, and 9 of 39 patients (23%) with colorectal cancer had stable disease. CONCLUSIONS: Panitumumab was well tolerated with comparable exposure and safety profiles for the weekly, every 2 weeks, and every 3 weeks administration schedules. Rash and dry skin occurred more frequently in the dose cohorts receiving > or =2.5 mg/kg weekly dose. Panitumumab has single-agent antitumor activity, most notably in patients with advanced colorectal cancer.     

A double-blinded, randomized, placebo-controlled trial of infliximab in subjects with active pulmonary sarcoidosis

STUDY OBJECTIVES: To evaluate the safety and tolerability of infliximab in the treatment of active pulmonary sarcoidosis, and to provide an initial assessment of the efficacy of infliximab in the treatment of active pulmonary sarcoidosis. DESIGN: Double-blind, randomized, placebo-controlled phase II study. SETTING: Multicenter. PATIENTS: Active Radiographic Stage II, III, and IV active pulmonary sarcoidosis despite corticosteroids or previous intolerance to corticosteroids. INTERVENTION: Infliximab 5mg/kg (group I) or placebo (group II) at weeks 0 and 2 and open-label infliximab 5mg/kg for all subjects at weeks 6 and 14. MEASUREMENTS: Pulmonary function, chest radiographs, dyspnea stage, SF-36. RESULTS: Mean vital capacity (VC) at wk 0 was 2.47 +/- 0.2 (group I) and 2.37 +/- 0.31 (group II). At 6 weeks the mean +/- SD relative change in VC compared to baseline was 15.22 +/- 9.91% for group I (n=13) and 8.39 +/- 3.33% for group II (n=6) (p=0.65). Four patients had serious adverse events, including decreased WBC and elevated CPK (1 patient), pneumonia (1 patient), cellulitis, acute renal failure, pulmonary embolus and death (1 patient), and visual field defect (1 patient). CONCLUSIONS: Infliximab may improve VC in patients with active PS resistant to steroids. Larger scale, longer term studies will be needed to assess both safety and efficacy.     

Immunotherapy with subcutaneous low-dose interleukin-2 and the pineal indole melatonin as a new effective therapy in advanced cancers of the digestive tract.

The advanced tumours of the digestive tract are generally less responsive to conventional chemotherapies. Moreover, preliminary results with IL-2 immunotherapy also seem to show a low efficacy. On the basis of our previous studies suggesting s synergistic action between IL-2 and some neurohormones, such as the pineal indole MLT, a clinical trial was performed to investigate the clinical efficacy and tolerability of an immunotherapy with IL-2 plus MLT in patients with advanced neoplasms of the digestive tract. The study included 35 patients (colorectal cancer: 14; gastric cancer: 8; hepatocarcinoma: 6; pancreas adenocarcinoma: 7). Distant organ metastases were present in 31/35 patients. MLT was given orally at a daily dose of 50 mg at 8.00 p.m., starting 7 days before IL-2, which was given subcutaneously at a dose of 3 million IU/day at 8.00 p.m. for 6 days/week for 4 weeks, corresponding to one cycle of immunotherapy. In nonprogressed patients, a second cycle was given after a 21-day rest period. A complete response was achieved in two patients (gastric cancer: 1; hepatocarcinoma: 1). Six other patients obtained a partial response: (gastric cancer: 2; hepatocarcinoma: 2; colon cancer: 1; pancreas cancer: 1). Therefore, the overall response rate was 8/35 (23%). Stable disease was obtained in 11/35 (31%) patients, whereas the remaining 16 patients (46%) progressed. The response rate was significantly higher in untreated patients than in those previously treated with chemotherapy. Toxicity was low in all patients, who received the treatment as a home therapy. This study shows that the immunotherapy with low-dose IL-2 plus the pineal hormone MLT is a new well tolerated and effective therapy of advanced tumours of the digestive tract, mainly in gastric cancer and hepatocarcinoma.     

Efficacy, safety, and biomarkers of single-agent bevacizumab therapy in patients with advanced hepatocellular carcinoma

Objective. Hepatocellular carcinoma (HCC) is a highly vascularized tumor in which neoangiogenesis contributes to growth and metastasis. We assessed the safety, efficacy, and potential biomarkers of activity of bevacizumab in patients with advanced HCC. Methods. In this phase II trial, eligible patients received bevacizumab, 5 mg/kg or 10 mg/kg every 2 weeks. The disease-control rate at 16 weeks (16W-DCR) was the primary endpoint. Circulating endothelial cells (CECs) and plasma cytokines and angiogenic factors (CAFs) were measured at baseline and throughout treatment. Results. The 16W-DCR was 42% (95% confidence interval, 27%-57%). Six of the 43 patients who received bevacizumab achieved a partial response (objective response rate [ORR], 14%). Grade 3-4 asthenia, hemorrhage, and aminotransferase elevation occurred in five (12%), three (7%), and three (7%) patients, respectively. During treatment, placental growth factor markedly increased, whereas vascular endothelial growth factor (VEGF)-A dramatically decreased (p < .0001); soluble VEGF receptor-2 (p < .0001) and CECs (p = .03) transiently increased on day 3. High and increased CEC counts at day 15 were associated with the ORR (p = .04) and the 16W-DCR (p = .02), respectively. Lower interleukin (IL)-8 levels at baseline (p = .01) and throughout treatment (p ≤ .04) were associated with the 16W-DCR. High baseline IL-8 and IL-6 levels predicted shorter progression-free and overall survival times (p ≤ .04). Conclusion. Bevacizumab is active and well tolerated in patients with advanced HCC. The clinical value of CECs, IL-6, and IL-8 warrants further investigation.     

Phase I clinical study of pertuzumab, a novel HER dimerization inhibitor, in patients with advanced cancer.

PURPOSE: Pertuzumab, a recombinant humanized monoclonal antibody (2C4), binds to extracellular domain II of the HER-2 receptor and blocks its ability to dimerize with other HER receptors. Pertuzumab represents a new class of targeted therapeutics known as HER dimerization inhibitors. A clinical study was conducted to investigate safety and pharmacokinetics of pertuzumab and to perform a preliminary assessment of HER dimerization inhibition as a treatment strategy. PATIENTS AND METHODS: Patients with incurable, locally advanced, recurrent or metastatic solid tumors that had progressed during or after standard therapy were recruited to a dose-escalation study of pertuzumab (0.5 to 15 mg/kg) given intravenously every 3 weeks. Results: Twenty-one patients received pertuzumab and 19 completed at least two cycles. Pertuzumab was well tolerated. Overall, 365 adverse events were reported and 122 considered to be possibly drug related. Of these, 116 were of grade 1 to 2 intensity. The pharmacokinetics of pertuzumab were similar to other humanized immunoglobulin G antibodies, supporting a 3-week dosing regimen. Trough plasma concentrations were in excess of target concentrations at doses greater than 5 mg/kg. Two patients, one with ovarian cancer (5.0 mg/kg) and one with pancreatic islet cell carcinoma (15.0 mg/kg), achieved a partial response. Responses were documented by Response Evaluation Criteria in Solid Tumors after 1.5 and 6 months of pertuzumab therapy, and lasted for 11 and 10 months, respectively. Stable disease lasting for more than 2.5 months (range, 2.6 to 5.5 months) was observed in six patients. CONCLUSION: These results demonstrate that pertuzumab is well tolerated, has a pharmacokinetic profile which supports 3-week dosing, and is clinically active, suggesting that inhibition of dimerization may be an effective anticancer strategy.     

Interleukin 12 immunotherapy after autologous stem cell transplantation for hematological malignancies.

PURPOSE: To determine the safety, maximum tolerated dose,and biological effects of recombinant human IL-12 after autologous stem cell transplantation for cancer. EXPERIMENTAL DESIGN: Twelve patients with hematological malignancies (8 non-Hodgkin's lymphoma, 2 Hodgkin's disease, and 2 plasma cell myeloma) began interleukin (IL)-12 therapy at a median of 66 days after transplantation. Recombinant human IL-12 was given by bolus i.v. injection in doses of 30, 100, or 250 ng/kg once as an inpatient and then, after a 2-week hiatus, once daily for 5 consecutive days every 3 weeks on an outpatient basis. RESULTS: Common side effects included fever, chills, fatigue, nausea or vomiting, and asymptomatic elevation in serum liver function tests. Transient neutropenia and thrombocytopenia were also common, but no patient required platelet transfusion or had a neutropenic fever. Dose-limiting toxicities (diarrhea and elevated liver function tests) occurred in 2 of 3 patients treated in the 250 ng/kg cohort. Biological effects, including increases in serum IFN-gamma levels and transient lymphopenia involving CD4 T cells, CD8 T cells, B cells, and NK cells, were seen at all three dose levels. CONCLUSIONS: Biologically active doses of IL-12 can be given safely to patients after autologous stem cell transplantation for high-risk hematological malignancies. Further studies are indicated to assess the efficacy of IL-12 in this setting.