Phase I study of pazopanib in combination with Paclitaxel and Carboplatin given every 21 days in patients with advanced solid tumors

Several phase III trials have shown that the addition of an antiangiogenic agent to conventional chemotherapy can improve clinical benefit in patients with advanced solid tumors. This study examined the feasibility of combining pazopanib (Votrient), an oral antiangiogenic agent, with paclitaxel and carboplatin. This 3 + 3 dose-escalation phase I study evaluated the maximum-tolerated regimen (MTR) of daily pazopanib in combination with paclitaxel 175 mg/m(2) and carboplatin [dosed at area under the curve (AUC) 5 or 6] given every 21 days in patients with advanced solid tumors. Plasma samples were collected to evaluate the effect of pazopanib on the pharmacokinetics of paclitaxel and carboplatin. Thirty-four patients were enrolled. The MTR was paclitaxel 175 mg/m(2) and carboplatin AUC5 with pazopanib 200 mg. The most common dose-limiting toxicities were neutropenia and thrombocytopenia. Two patients with esophageal cancer had a complete response and four patients, one each with breast, small-cell lung, pancreatic, and gastroesophageal junction cancer, had partial responses. Pazopanib at 200 mg increased paclitaxel maximal concentration (C(max)) by 43% and carboplatin (AUC5 or AUC6) C(max) by 54%. Paclitaxel and carboplatin given every 21 days at standard doses was not feasible in combination with the monotherapy pazopanib dose of 800 mg daily because of dose-limiting myelosuppression. Coadministration of pazopanib increased exposure to paclitaxel and carboplatin and likely contributed to this effect. Given the antitumor activity of this regimen, further studies are underway to determine a clinically tolerable schedule of pazopanib with paclitaxel and carboplatin. Mol Cancer Ther; 11(8); 1820-8. ?2012 AACR.     

Phase I trial of intravenous IL-4 pseudomonas exotoxin protein (NBI-3001) in patients with advanced solid tumors that express the IL-4 receptor

NBI-3001 is a novel immunotoxin of attenuated Pseudomonas exotoxin fused to circularly permutated IL-4, which has shown some antitumor effects in glioblastoma multiforme with intratumoral administration. The authors evaluated the safety and tolerability of NBI-3001 administered intravenously in a dose-escalation design to patients with renal cell and non-small cell lung carcinoma whose tumors showed at least 10% IL-4 receptor expression. Cohorts of three to six patients were treated at dose levels of 0.008, 0.016, and 0.027 mg/m2 daily x 5 days every 28 days. Neutralizing antibody (NAB) titers, plasma levels of NBI-3001, and patient tolerability were monitored sequentially. 14 patients received a total of 36 cycles of NBI-3001 (range 1-6). No dose-limiting toxicities were noted at dose levels 0.008 and 0.016 mg/m2. At 0.027 mg/m2, two patients developed self-limiting, grade 3 or 4 transaminase elevation during cycle 1. NAB titers of more than 1:100 were detected in five of the seven patients treated with at least two cycles; the median titer after cycle 1 and the median maximum titer in subsequent cycles were 1:50 and approximately 1:1,710, respectively. No objective tumor responses were noted. Eight of 12 evaluable patients with renal cell carcinoma had stable disease; four patients had disease progression. High NAB titers resulted in four patients being withdrawn from the study. The dose-limiting toxicity for intravenous NBI-3001 was transaminase elevation at 0.027 mg/m2. NBI-3001 at 0.016 mg/m2 was well tolerated. Low circulating levels of NBI-3001, coupled with rising NAB titers, may have contributed to the lack of response in tumors that express IL-4R.     

Phase I study of weekly irinotecan combined with weekly cisplatin in patients with advanced solid tumors

BACKGROUND: Previous studies have reported a synergistic effect between irinotecan and cisplatin. We have conducted a phase I trial combining these agents to find the optimal dose of irinotecan in combination with a fixed dose of cisplatin. METHODS: Patients with advanced solid tumors, aged < or =75 years, performance status < or =2, and adequate organ function were enrolled in this study. They were treated at 4-week intervals with irinotecan plus 20 mg/m(2) cisplatin on days 1, 8, and 15. The starting dose of irinotecan of 40 mg/m(2) was escalated in 10 mg/m(2) increments until a maximum dose of 90 mg/m(2) was reached. RESULTS: The recommended dose for phase II studies is 90 mg/m(2) of irinotecan and 20 mg/m(2) of cisplatin on days 1, 8, and 15. Overall response to the chemotherapy was 35% (95% confidential interval, 19.2-54.6%). CONCLUSION: This combination seems to be active against lung cancer with acceptable toxicity. A phase II study is now ongoing.     

The palliative prognostic score and survival in patients with advanced solid tumors receiving chemotherapy

Purpose To evaluate the accuracy of the Palliative Prognostic Score (PaP score) in selecting metastatic gastrointestinal or nonsmall-cell lung cancer patients candidate to palliative chemotherapy. Materials and methods The PaP score was calculated in 173 patients with advanced, pretreated gastrointestinal or nonsmall-cell lung cancer before starting a further line of chemotherapy with palliative aim. Symptom distress score was calculated using the Edmonton Symptom Assessment System (ESAS) before every course of chemotherapy. Univariate analysis of survival was performed using the logrank test; multivariate analysis was performed using the Cox regression model. Symptom distress scores were compared using multivariate analysis of variance test for repeated measures, and overall symptom distress score was compared using analysis of variance test for repeated measures. Results Overall median survival was 26 weeks; in PaP score class A it was 32 weeks, and in class B 8 weeks (p < 0.0001). No patient was classified in class C. The two-class PaP score resulted in an independent prognostic factor (p = 0.022), as well as Karnofsky performance status (p = 0.002) and colorectal cancer (p = 0.017). A trend towards worsening of symptom distress was observed in the entire population and in class A. The high number of missed data did not permit an adequate analysis in class B. Conclusions The PaP score seems to discriminate patients who could benefit by palliative chemotherapy from those who could better benefit by supportive and palliative approach. However, the data are insufficient to validate the use of the PaP score in patients to be treated with palliative chemotherapy, and further trials should be planned to assess its ability to improve the quality of care in oncology and the appropriateness in the choice of palliative chemotherapy.     

Phase I trial of intravenous peptide-pulsed dendritic cells in patients with metastatic melanoma

Sixteen patients with metastatic stage IV melanoma were treated with use of intravenous infusions of dendritic cells (DC) derived by incubation of plastic-adherent peripheral blood mononuclear cells (PBMC) with IL-4 and GM-CSF for 8 days in serumless AIM-V medium, followed by overnight pulsing with peptides. The tyrosinase368-376 (370D) and gp100(209-217 (210M)) peptides restricted to HLA class I A*0201 each differed from wild type by one amino acid modified to increase HLA binding. Median age was 49, with nine men and seven women. All patients, except one, had visceral disease. Patients received escalating doses of peptide-pulsed DCs at 10e7, 3 x 10e7, and 10e8 cells/dose twice at 2 weeks apart, with toxicity and clinical and immune responses as the principal endpoints. The first infusion of DCs was fresh, and frozen DCs were given for the second infusion of each cycle. Mean DC purity by flow cytometry was 49%, with a mean HLA-DR level of 57%, CD86 of 41%, CD58 of 46%, and mean CD14 cells of 0.9%. Toxicity was minimal, with two patients having transient grade III DC-related toxicity. Ten patients received one cycle of treatment and six patients received two cycles of treatment. One patient had a complete remission (CR) of lung and pleural disease after two cycles of DC therapy. Two additional patients had stable disease and two patients had mixed responses. Overall immunity was assessed by recall skin testing with peptides, gamma interferon ELISA assays of peptide specific cytolytic T cell (CTL) stimulated twice with peptide, IL-2, and IL-7 over 24 days, and peptide-specific tetramer assays performed before and after vaccination. Five of 16 patients had an immune response to gp100 or tyrosinase by gamma interferon ELISA assay; four of five were clinically stable or had tumor regression. These data suggest that melanoma antigen peptide-pulsed DC given intravenously are not toxic, and regression or stability of tumor appeared to correlate with the detection of a peptide-specific immune response in the peripheral blood.     

Population pharmacokinetic and adverse event analysis of topotecan in patients with solid tumors

OBJECTIVE: Our objective was to describe the pharmacokinetics and pharmacodynamics of topotecan in patients. METHODS: Data were pooled from 9 clinical trials. Topotecan, as a single-agent therapy, was administered as a daily 30-minute intravenous infusion for 5 days on a 3-week cycle. Doses of 0.2 to 2.0 mg/m(2) were studied; concentration and neutropenic event data were obtained on multiple occasions. The pharmacokinetics were characterized with use of hierarchical nonlinear regression. The relationship between severity of neutropenia and exposure was characterized with use of logistic regression. RESULTS: The pharmacokinetics of topotecan were described with a linear 2-compartment model. Compromised renal function, low body weight, and poor Eastern Cooperative Oncology Group performance status were determinants of lower clearance, resulting in elevated exposure. Application of covariates reduced interpatient variability in clearance. Logistic regression showed that topotecan area under the concentration-time curve from 0 to 24 hours was predictive of the severity of neutropenia; the only other significant covariate was the number of courses of previous treatment with platinum-based regimens. CONCLUSIONS: Patients with compromised renal function, low body weight, or poor performance status had low topotecan clearance. Patients with high topotecan AUC had an increased probability of experiencing severe neutropenia, which was greater if the patient had been pretreated with platinum-based agents. The use of covariates to individualize dose would result in less variability in exposure, reducing the likelihood of severe neutropenia and potentially improving treatment benefit.     

Safety and dose escalation of the targeted oncolytic adenovirus OBP-301 for refractory advanced liver cancer: Phase I clinical trial

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Phase I-II trial of ONYX-015 in combination with MAP chemotherapy in patients with advanced sarcomas

ONYX-015 is a provisionally replication competent adenovirus with oncolytic activity in cells with malfunctioning p53. Sarcomas represent a rational target for this approach given the high frequency of p53 mutations (40-75%) and MDM-2 amplification (10-30%). We, therefore, undertook a phase I/II study of ONYX-015, days 1-5 every month administered intratumorally under radiographic guidance, in combination with MAP (mitomycin-C, doxorubicin, cisplatin) chemotherapy in patients with advanced sarcoma. Six patients were treated. Injected lesions included liver metastases in four patients and chest wall metastases in two patients. Sarcoma histologies were gastrointestinal stromal tumors (GIST, two patients), leiomyosarcoma (two patients), liposarcoma (one patient), and malignant peripheral nerve sheath tumor (1 patient). Dose escalation was performed from 10(9) plaque forming units (PFU)/dose (total dose of 5 x 10(9) PFU/cycle) to 10(10) PFU/dose (total dose of 5 x 10(10) PFU/cycle) without dose-limiting toxicity being encountered. Immunohistochemistry of the metastatic lesions prior to treatment showed that five out of six patients were positive for p53, while two patients also had mdm-2 overexpression. Adenoviral replication was detected in two out of six patient biopsies on day 5 of the first cycle, by in situ hybridization (ISH). Both patients were treated at the highest dose level. ONYX-015 viral DNA was detected by quantitative PCR in the plasma of 5/6 patients on day 5 of the first cycle, and up to day 12 (7 days after the last viral dose) in one patient who had extended sampling for viral kinetics performed, suggesting viral replication in sarcoma tissue. One patient with p53 mutation and MDM-2 amplification achieved a partial response to treatment that lasted 11 months. In conclusion, intratumoral administration of ONYX-015 in combination with MAP chemotherapy is well tolerated with no significant toxicity due to ONYX-015 being encountered. Detection of viral DNA in post treatment tumor specimens by ISH and detection of the ONYX-015 genome in the peripheral blood by quantitative PCR, up to 7 days after the last viral dose provide evidence for adenoviral replication. There was evidence of antitumor activity in one out of six patients. Further investigation of this approach in patients with recurrent sarcomas is warranted.     

Phase I trial using weekly administration of gemcitabine and docetaxel in patients with advanced pancreatic carcinoma

BACKGROUND: In advanced pancreatic carcinoma, no effective chemotherapy has been found yet due to the lack of appropriate response. The frequent use of gemcitabine is based on the fact that there is a significant improvement in the quality of life, but neither an effect on remission nor a detectable increase in survival rates could be observed. Therefore, the hypothesis was that the combination of gemcitabine with other drugs can result in a better outcome of patients. The aim of this study was to determine the maximally tolerable dosage of gemcitabine and docetaxel using a weekly administration regimen. PATIENTS AND METHODS: Twenty-five patients with advanced or metastatic pancreatic carcinoma received combination chemotherapy using gemcitabine and docetaxel in a weekly administration regimen, beginning with 800 mg/m2 of gemcitabine and 25 mg/m2 of docetaxel. Four patients were originally enrolled for each of the seven different dosages of both drugs. Side effects were assessed according to the WHO standard. Quality of life was evaluated according to the Core Quality of Life Questionnaire (QLQ-C30) of the European Organization for Research and Treatment of Cancer. RESULTS: Using the two maximal dosages of gemcitabine and docetaxel (gemcitabine, 800 and 1,000 mg/m2, and docetaxel, 45 and 40 mg/m2; respectively), only 3 and 2 patients were enrolled, respectively, because of toxic side effects > or = grade III according to WHO grading. Maximal dosages with tolerable side effects were 1,000 mg/m2 of gemcitabine and 35 mg/m2 of docetaxel given in weekly intervals. Main side effects of this combination chemotherapy were gastrointestinal symptoms and hematologic toxicity. CONCLUSION: Combination therapy with gemcitabine and docetaxel in advanced or metastatic pancreatic carcinoma is a well-tolerated and acceptable alternative treatment option with regard to the severity of side effects and its positive impact on quality of life and tumor-associated pain. According to the study endpoint, dosages of 1,000 mg/m2 of gemcitabine and 35 mg/m2 of docetaxel are recommended as maximum-tolerated doses (given in weekly intervals) for a future phase II trial.     

Randomized controlled trial of standardized education and telemonitoring for pain in outpatients with advanced solid tumors

Purpose

Previous studies have not defined the role of telemonitoring with educational tools in outpatients with advanced cancers. We tested the effectiveness of standardized education and telemonitoring for improving pain, distress, anxiety, depression, quality of life (QoL), and performance in outpatients with advanced cancers.

Methods

A total of 108 patients were randomly assigned to receive pain education alone (control arm) or pain education plus telemonitoring (experimental arm). Nursing specialists provided video-assisted educational material in both arms and daily telemonitoring for the first week in the experimental arm. Assessment was performed at baseline and 1 week and included evaluations of pain (Brief Pain Inventory, BPI), distress (Distress Thermometer, DT), anxiety, and depression (Hospital Anxiety and Depression Scale, HADS), QoL (QLQ-C30), and a Karnofsky score.

Results

Overall (n?=?108), pain intensity was significantly improved at 1 week, including worst pain (7.3 to 5.7, P?<?0.01) and average pain (4.6 to 3.8, P?<?0.01). Additionally, anxiety (HADS score?≥?11, 75 % to 56 %, P?<?0.01), depression (HADS score?≥?11, 73 % to 51 %, P?<?0.01), QoL (fatigue and insomnia), and the Karnofsky score (32 to 66, P?<?0.01) were also significantly improved at 1 week. However, the level of distress did not improve. The telemonitoring plus standardized education group showed more significant improvement in portion of pain >4 on VAS scale (35 % vs. 19 %, P?=?0.02).

Conclusions

Standardized pain education using nursing specialists is an efficient way to improve not only pain itself but also anxiety, depression, performance, and QoL. The addition of telemonitoring helps to improve pain management in the outpatient setting.     

Phase I/II trial of formoterol fumarate combined with megestrol acetate in cachectic patients with advanced malignancy

Purpose

The aim of this study was to test the safety, tolerability and efficacy of a novel combination of an anabolic β₂-agonist and an appetite stimulant in patients with cancer cachexia.

Methods

Thirteen patients (M/F 5:8) with advanced malignancy and involuntary weight loss received oral formoterol (80 μg/day) and megestrol acetate (480 mg/day) for up to 8 weeks. Quadriceps size (MRI), quadriceps and hand-grip strength, lower limb extensor power, physical activity and quality of life were measured at baseline and at 8 weeks. Response criteria were specified pre-trial, with a major response defined as an increase in muscle size ≥4 % or function ≥10 %.

Results

Six patients withdrew before 8 weeks, reflecting the frail, comorbid population. In contrast, six out of seven (86 %) patients completing the course achieved a major response for muscle size and/or function. In the six responders, mean quadriceps volume increased significantly (left 0.99 vs. 1.05 L, p?=?0.012; right 1.02 vs. 1.06 L, p?=?0.004). There was a trend towards an increase in quadriceps and handgrip strength (p?>?0.05). The lack of appetite symptom score declined markedly (76.2 vs. 23.8; p?=?0.005), indicating improvement. Adverse reactions were few, the commonest being tremor (eight reports), peripheral oedema (three), tachycardia (two) and dyspepsia (two).

Conclusions

In this frail cohort with advanced cancer cachexia, an 8-week course of megestrol and formoterol in combination was safe and well tolerated. Muscle mass and/or function were improved to a clinically significant extent in most patients completing the course. This combination regimen warrants further investigation in larger, randomized trials.     

Oral mucositis in patients treated with chemotherapy for solid tumors: a retrospective analysis of 150 cases

 The incidence and the severity of chemotherapy-associated oral mucositis were determined in a retrospective analysis of 150 patients with various solid tumors. In addition, possible risk factors for the development of mucositis were identified. Patients were treated with chemotherapeutic regimens appropriate to tumor type and disease stage on an in- or outpatient basis. Mucositis was scored using the World Health Organization (WHO) criteria. Eighty-seven episodes of mucositis occurred in 47 (31%) patients. Twenty-six patients each experienced only one episode, whereas 21 patients had up to eight episodes of mucositis. The 1,281 chemotherapy cycles that have been analyzed included 87 cycles in which mucositis was observed. In 16 patients (11%) only slight oral mucosal changes were recorded (maximum WHO score 1), while 25 patients (17%) experienced mild to moderate mucositis (maximum WHO score 2), and in 6 patients (4%) mucositis was moderate to severe (maximum WHO score 3). No grade 4 mucositis developed. In 24 of the 47 patients with mucositis (51%) clinical features of acute pseudomembranous candidiasis were present. Leukopenia, leukopenic fever, and use of corticosteroids and central venous catheters were associated with the chemotherapy cycles with mucositis. Multivariate analysis identified the administration of paclitaxel, doxorubicin, or etoposide as independent risk factor (adjusted rate ratios 8.06, 7.35, and 6.70, respectively), whereas low body mass was associated with a slightly increased risk (adjusted rate ratio 0.92) for the development of mucositis. In conclusion, almost one-third of patients receiving chemotherapy for solid tumors experienced one or more episodes of mild to more severe oral mucositis, indicating that this is a frequent complication in such patients. Published online: 7 March 2000     

Drug monitoring of sunitinib in patients with advanced solid tumors: a monocentric observational French study

Therapeutic drug monitoring (TDM) could be helpful in oral targeted therapies. Data are sparse to evaluate its impact on treatment management. This study aimed to determine a threshold value of plasma drug exposure associated with the occurrence of grade 3–4 toxicity, then the potential impact of TDM on clinical decision. Consecutive outpatients treated with sunitinib were prospectively monitored between days 21 and 28 of the first cycle, then monthly until disease progression. At each consultation, the composite AUC_?,ss (sunitinib + active metabolite SU12662) was assayed. The decisions taken during each consultation were matched with AUC_?,ss and compared to the decisional algorithm based on TDM. A total of 105 cancer patients and 288 consultations were matched with the closest AUC_?,ss measurement. The majority (60%) of the patients had metastatic renal clear‐cell carcinoma (mRCC). Fifty‐five (52%) patients experienced grade 3–4 toxicity. Multivariate analysis identified composite AUC_?,ss as a parameter independently associated with grade 3–4 toxicity (P < 0.0001). Using the ROC curve, the threshold value of composite AUC_?,ss predicting grade ≥3 toxicity was 2150 ng/mL/h (CI 95%, 0.6–0.79%; P < 0.0001). At disease progression in patients with mRCC, AUC_?,ss tended to be lower than the one assayed during the first cycle (1678 vs. 2004 ng/mL/h, respectively, P = 0.072). TDM could have changed the medical decision for sunitinib dosing in 30% of patients at the first cycle of treatment, and in 46% of the patients over the whole treatment course. TDM is routinely feasible and may both contribute to improve toxicity management and to identify sunitinib underexposure at the time of disease progression.     

Phase I clinical trial of MPC-6827 (Azixa), a microtubule destabilizing agent, in patients with advanced cancer

MPC-6827 (Azixa) is a small-molecule microtubule-destabilizing agent that binds to the same (or nearby) sites on β-tubulin as colchicine. This phase I study was designed to determine the dose-limiting toxicities (DLT), maximum tolerated dose (MTD), and pharmacokinetics (PK) of MPC-6827 in patients with solid tumors. Patients with advanced/metastatic cancer were treated with once-weekly, 1- to 2-hour intravenous administration of MPC-6827 for 3 consecutive weeks every 28 days (1 cycle). Dose escalation began with 0.3, 0.6, 1, and 1.5 mg/m(2), with subsequent increments of 0.6 mg/m(2) until the MTD was determined. A 3 + 3 design was used. Pharmacokinetics of MPC-6827 and its metabolite MPI-0440627 were evaluated. Forty-eight patients received therapy; 79 cycles were completed (median, 1; range, 1-10). The most common adverse events were nausea, fatigue, flushing, and hyperglycemia. The DLT was nonfatal grade 3 myocardial infarction at 3.9 mg/m(2) (1/6 patients) and at 4.5 mg/m(2) (1/7 patients). The MTD was determined to be 3.3 mg/m(2) (0/13 patients had a DLT). Five (10.4%) of the 48 patients achieved stable disease (Response Evaluation Criteria in Solid Tumors) for 4 months or greater. MPC-6827 has a high volume of distribution and clearance. Half-life ranged from 3.8 to 7.5 hours. In conclusion, MPC-6827 administered intravenously over 2 hours at a dose of 3.3 mg/m(2) once weekly for 3 weeks every 28 days was safe in patients with heavily pretreated cancer. Clinical trials with MPC-6827 and chemotherapy are ongoing.     

Phase I trial of valaciclovir, the L-valyl ester of acyclovir, in patients with advanced human immunodeficiency virus disease.

Valaciclovir, the L-valyl ester of acyclovir, is rapidly and extensively converted in humans to acyclovir after oral administration by first-pass metabolism. A phase I study was conducted in two cohorts of volunteers with advanced human immunodeficiency virus (HIV) disease (absolute CD4 lymphocyte count of < 150 cells per microliters) who received oral valaciclovir at dosages of 1,000 or 2,000 mg four times daily for 30 days. All patients were clinically stable without any changes in underlying HIV-related medications for > or = 6 weeks prior to entry in study; these medications were continued throughout the study. Multiple-dose administration of valaciclovir showed a generally favorable safety profile. Nausea, vomiting, diarrhea, and abdominal pain each were reported in < or = 31% of the patients; of these symptoms, only one episode of diarrhea was considered causally related to valaciclovir exposure. Four patients developed neutropenia (two at each dose level) which was not clinically significant. There were no renal or neurologic adverse events. Valaciclovir was rapidly absorbed and converted to acyclovir, with plasma valaciclovir levels generally undetectable or levels of < or = 0.4 microgram/ml. After 3 h postdosing, valaciclovir was not detectable in plasma. Acyclovir was measurable in plasma as early as 15 min following valaciclovir dosing, and plasma concentrations of acyclovir greatly exceeded those of valaciclovir. The mean values for the maximum concentration of drug in plasma, time to maximum concentration of drug in plasma, area under the concentration-time curve from 0 h to infinity, and apparent half-life of acyclovir obtained after single- and multiple-dose valaciclovir administration in HIV-infected patients were similar to those reported in normal healthy volunteers. The time to maximum concentration in serum and half-life of acyclovir after valaciclovir administration were approximately 2 and 3 h, respectively, which were similar to those reported after oral administration of acyclovir itself. The mean trough and peak acyclovir concentrations and the daily area under the concentration-time curve acyclovir values at steady state were 2.5 and 8.4 micrograms/ml and 120 h micrograms/ml, respectively, after a dosage of 2,000 mg of valaciclovir four times daily. These values were approximately fivefold greater than those achieved with high dosages of oral acyclovir (800 mg, five times daily) and were not affected by continued use of medications necessary for management of advanced HIV disease. Thus, 2,000 mg of valaciclovir given orally four times daily should be evaluated for its potential efficacy in suppressing cytomegalovirus and other herpes group virus infections not optimally managed with current oral acyclovir therapy.     

A phase I clinical trial of a ribozyme-based angiogenesis inhibitor targeting vascular endothelial growth factor receptor-1 for patients with refractory solid tumors

PURPOSE: This study intended to determine the maximum tolerated dose, safety, pharmacokinetic variables, clinical response, and pharmacodynamic markers of daily s.c. administration of Angiozyme. PATIENTS AND METHODS: Patients with refractory solid tumors were enrolled in a dose escalation and expanded cohort design. Dose escalation involved cohorts of patients at doses of 10, 30, 100, or 300 mg/m(2)/d for 29 days. A second component enrolled 15 additional patients at a daily dose of 100 mg/m(2). Patients were eligible to continue on therapy until disease progression. RESULTS: Thirty-one patients were enrolled and 28 were evaluable (range, 29-505 days; median, 89.5 days). A maximum tolerated dose was not defined by toxicity but rather by the maximal deliverable dose of 300 mg/m(2)/d. Grade 1 to 2 injection site reactions were the most common toxicities. One patient in the 300 mg/m(2) group experienced a reversible grade 3 injection site reaction. Angiozyme showed dose-dependent plasma concentrations with good bioavailability. Surrogate markers showed Angiozyme localization in tumor biopsies and a significant increase in serum von Willebrand factor antigen, a marker for endothelial cell dysfunction. Although Angiozyme-reactive antibody production was noted for some patients, no antibody-related adverse events were noted. Seven of 28 (25%) evaluable patients had stable disease for >or =6 months, with the longest treatment duration of > or =16 months. Two patients (nasopharyngeal carcinoma and melanoma) showed minor responses. CONCLUSION: Angiozyme was well tolerated with satisfactory pharmacokinetic variables for daily s.c. dosing. Results have provided the basis for subsequent clinical trials of this first-of-class biologically targeted therapeutic.     

A phase I study of the pharmacokinetic and safety profiles of oral pazopanib with a high-fat or low-fat meal in patients with advanced solid tumors

Pazopanib is an oral angiogenesis inhibitor of vascular endothelial growth factor (VEGF) receptor, platelet-derived growth factor receptor, and cytokine receptor. This open-label, randomized, crossover, phase I study evaluated the effect of low- and high-fat meals on the pharmacokinetics (PK) of pazopanib in patients with advanced solid tumors. Patients participated in either the lead-in cohort or randomized food-effect cohort. Patients in the lead-in cohort were administered a single dose of pazopanib 400 mg with a high-fat meal. Patients in the food-effect cohort were randomized to receive single doses of pazopanib 800 mg in fed condition (high- or low-fat meal) or fasting condition, in random sequence 14 days apart. After completion of the study, patients were given the opportunity to continue treatment with daily pazopanib 800 mg. Administration of pazopanib with both low- and high-fat meals increased maximum observed plasma concentration (C(max)) and area under the plasma concentration-time curve (AUC) by approximately twofold as compared with the corresponding values when administered to patients in the fasted condition. Therefore, pazopanib should be administered to patients in the fasted state so as to minimize within- and between-day variability in the systemic exposure to pazopanib in patients with cancer.     

Phase I/II trial of outpatient PEG-interferon with interleukin-2 in advanced renal cell carcinoma: a cytokine working group study

A phase I/II trial was undertaken to determine the maximum tolerated dose of polyethylene glycol interferon-alpha-2b (PEG-IFN) with interleukin-2 (IL-2), and to evaluate the efficacy and toxicity in patients with metastatic renal cell carcinoma. Patients initially received subcutaneous PEG-IFN, 3.0 mcg/kg/wk, combined with IL-2, but owing to unexpected toxicity a revised phase I schedule ensued. Patients received 1.0, 1.5, 2.0, or 3.0 mcg/kg/wk of PEG-IFN on days 1, 8, 15, and 22; subcutaneous IL-2 was given at a dose of 5 x 10 IU/m2 every 8 hours x 3 on day 1, followed daily at 5 x 10 IU/m2 days 2, 3, 4, and 5 of week 1, then 5 times per week for 3 weeks, followed by 2 weeks off. The maximum tolerated dose of PEG-IFN was 2.0 mcg/kg/wk. Fifty-four patients were enrolled. Frequent grade III/IV cardiac and neurologic toxicities led to an expanded phase I trial. Eleven serious events in 33 patients in the phase II portion led to early termination. No patient died from treatment. The overall response rate in 53 evaluable patients was 30.2% (95% confidence interval 20.5-39.9), with 2 complete responses and 14 partial responses and at least 1 response at each dose level. The median duration of response was 11 months (range, 2 to 65+ mo); median survival was 20 months (range, 2 to 71+ mo); median time to progression was 4 months. Despite clinical efficacy, the study was closed prematurely owing to excess toxicity. Although all serious adverse events resolved, this degree of toxicity is unacceptable for an outpatient treatment regimen.     

Phase I trial of anti-B4-blocked ricin in pediatric patients with leukemia and lymphoma.

Monoclonal antibodies, specific for antigens expressed on lymphoid malignancies, which have been conjugated to toxins such as ricin, hold promise in the therapy of childhood leukemia and lymphoma. Anti-B4-blocked ricin (anti-B4-bR) is such an agent, and a phase I study of this agent was conducted in children with relapsed or refractory B-lineage leukemia and lymphoma. Anti-B4-bR was given as two 7-day continuous infusions separated by 7 days. Twenty patients were enrolled and 19 received the drug. Two dosage levels (30 and 40 microg/kg per day) were evaluated. Forty micrograms per kilogram per day was the maximally tolerated dose. Dose-limiting toxicity was capillary leak syndrome. Grade 3 reversible elevation in transaminases was also encountered. Human antimouse antibodies or human antiricin antibodies were detected in five patients. No complete remissions or partial remissions were seen.