PR-104 a bioreductive pre-prodrug combined with gemcitabine or docetaxel in a phase Ib study of patients with advanced solid tumours.

BACKGROUND: The purpose of this phase Ib clinical trial was to determine the maximum tolerated dose (MTD) of PR-104 a bioreductive pre-prodrug given in combination with gemcitabine or docetaxel in patients with advanced solid tumours. METHODS: PR-104 was administered as a one-hour intravenous infusion combined with docetaxel 60 to 75 mg/m2 on day one given with or without granulocyte colony stimulating factor (G-CSF) on day two or administrated with gemcitabine 800 mg/m2 on days one and eight, of a 21-day treatment cycle. Patients were assigned to one of ten PR-104 dose-levels ranging from 140 to 1100 mg/m2 and to one of four combination groups. Pharmacokinetic studies were scheduled for cycle one day one and 18F fluoromisonidazole (FMISO) positron emission tomography hypoxia imaging at baseline and after two treatment cycles. RESULTS: Forty two patients (23 females and 19 males) were enrolled with ages ranging from 27 to 85 years and a wide range of advanced solid tumours. The MTD of PR-104 was 140 mg/m2 when combined with gemcitabine, 200 mg/m2 when combined with docetaxel 60 mg/m2, 770 mg/m2 when combined with docetaxel 60 mg/m2 plus G-CSF and ≥770 mg/m2 when combined with docetaxel 75 mg/m2 plus G-CSF. Dose-limiting toxicity (DLT) across all four combination settings included thrombocytopenia, neutropenic fever and fatigue. Other common grade three or four toxicities included neutropenia, anaemia and leukopenia. Four patients had partial tumour response. Eleven of 17 patients undergoing FMISO scans showed tumour hypoxia at baseline. Plasma pharmacokinetics of PR-104, its metabolites (alcohol PR-104A, glucuronide PR-104G, hydroxylamine PR-104H, amine PR-104M and semi-mustard PR-104S1), docetaxel and gemcitabine were similar to that of their single agents. CONCLUSIONS: Combination of PR-104 with docetaxel or gemcitabine caused dose-limiting and severe myelotoxicity, but prophylactic G-CSF allowed PR-104 dose escalation with docetaxel. Dose-limiting thrombocytopenia prohibited further evaluation of the PR104-gemcitabine combination. A recommended dose was identified for phase II trials of PR-104 of 770 mg/m2 combined with docetaxel 60 to 75 mg/m2 both given on day one of a 21-day treatment cycle supported by prophylactic G-CSF (NCT00459836).

Disease progression increases the risk of skeletal-related events in patients with bone metastases from castration-resistant prostate cancer, lung cancer, or other solid tumors.

Baseline and disease progression characteristics may predict the risk of skeletal-related events (SREs) in patients with bone metastases from various solid tumors. Exploratory analysis of phase III trials compared zoledronic acid with placebo in patients with bone metastases from castration-resistant prostate cancer (N = 643) and lung cancer or other solid tumors (N = 773), adjusted for baseline and time-dependent disease parameters. In all models, more than three bone lesions at baseline correlated with the increased SRE risk. Bone and overall disease progression correlated with increased SRE risk. Overall, cancer progression correlated with increased SRE risks and zoledronic acid was associated with reduced SRE risks versus placebo.

A pilot trial of CTLA-4 blockade with human anti-CTLA-4 in patients with hormone-refractory prostate cancer.

PURPOSE: Blockade of the T-cell inhibitory receptor CTL-associated antigen-4 (CTLA-4) augments and prolongs T-cell responses and is a strategy to elicit antitumor immunity. The objectives of this pilot study were to establish the pharmacokinetic and safety profile for a single dose of 3 mg/kg of the anti-CTLA-4 antibody Ipilimumab (MDX-010, BMS-734016) and to assess if this therapy resulted in prostate-specific antigen (PSA) modulation and the development of polyclonal T-cell activation and/or clinical autoimmunity in patients with hormone-refractory prostate cancer treated with Ipilimumab. EXPERIMENTAL DESIGN: Patients with metastatic hormone-refractory prostate cancer received a single 3 mg/kg i.v. dose of Ipilimumab. Serologic measures of autoimmunity were obtained, and T-cell activation was evaluated by flow cytometry. Pharmacokinetic sampling of plasma for MDX-CTLA-4, PSA measurement, and diagnostic imaging were also undertaken. RESULTS: Fourteen patients were treated: 12 patients received a single dose of Ipilimumab, and 2 patients were re-treated with a second dose upon PSA progression. Two patients showed PSA declines of > or =50%. Treatment was well tolerated with clinical autoimmunity limited to one patient who developed grade 3 rash/pruritus requiring systemic corticosteroids. The mean +/- SD Ipilimumab terminal elimination half-life was 12.5 +/- 5.3 days. CONCLUSIONS: A single dose of 3 mg/kg Ipilimumab, an anti-CTLA-4 antibody, given to patients with prostate cancer is safe and does not result in significant clinical autoimmunity. PSA-modulating effects observed warrant further investigation.

Resource utilisation and time commitment associated with correction of anaemia in cancer patients using epoetin alfa.

OBJECTIVE: This study set out to identify the resource use and time commitment associated with treatment of anaemia with erythropoietic therapy, for both haematology/oncology clinics and patients. METHODS: The study was carried out at three haematology/oncology clinics in the US, and included 124 cancer patients with anaemia. Stages in the administration of epoetin alfa were identified (preparation, injection and documentation). At each site a trained researcher observed medical staff and recorded the time taken for each stage, in minutes, using a stopwatch. The supplies used for each stage were also recorded. Travel times, waiting times and demographics for patients and caregivers attending the clinic were obtained from self-report questionnaires during the clinic visit. In total, 177 injections of epoetin alfa were administered. MAIN OUTCOME MEASURE: Total mean time clinic staff and patients spent on treatment visits. RESULTS: The total mean time expended by clinic staff for each injection, including preparation, administration, documentation and phlebotomy, was 25.5 minutes (range 18.6-31.2 at individual centres). The total mean time requirement for patients (time spent travelling to and from the clinic, time spent waiting for the epoetin alfa injection) was 83 minutes. CONCLUSION: Treatments that may reduce the time burden of anaemia management should be considered.

Clinical benefit of zoledronic acid in patients with lung cancer and other solid tumors: analysis based on history of skeletal complications.

The results of a retrospective exploratory analysis of a phase III trial of zoledronic acid in patients with bone metastases secondary to lung cancer or other solid tumors are reported herein to assess the risk of skeletal-related events (SREs) and the efficacy of 4 mg zoledronic acid compared with placebo. The study is based on patient SRE history before study entry. Patients were stratified based on SRE history (eg, pathologic fracture, spinal cord compression, radiation therapy or surgery to bone, or hypercalcemia) before study entry, and SRE incidence over 21 months was analyzed. Of 507 patients randomized to 4 mg zoledronic acid or placebo, 131 completed the 9-month core phase and 69 entered the 12-month extension phase. Before study entry, 347 of 503 patients who were evaluable for efficacy (69%) experienced >/= 1 SRE; these patients had a higher risk of developing an SRE on study than patients with no prior SRE (odds ratio, 1.41). Among patients with an SRE before study entry, zoledronic acid reduced the risk of SREs by 31% (P = 0.009), reduced the mean skeletal morbidity rate (1.96 vs. 2.81 SREs per year for placebo; P = 0.030), and prolonged the median time to first SRE by nearly 4 months (215 days vs. 106 days for placebo; P = 0.011). Among patients with no SRE before study entry (n = 156), zoledronic acid reduced the risk of SREs by 23% (P = 0.308), reduced the mean skeletal morbidity rate (1.34 vs. 2.53 SREs per year for placebo; P = 0.332), and prolonged the median time to first SRE by 2.5 months (P = 0.534). This exploratory analysis demonstrates that patients with a history of SREs are at high risk for subsequent SREs, but zoledronic acid reduces skeletal morbidity regardless of SRE history.

Role of dendritic cell phenotype, determinant spreading, and negative costimulatory blockade in dendritic cell-based melanoma immunotherapy.

MART-1(27-35)-peptide-pulsed immature dendritic cells (DCs) resulted in immunologic and clinical activity in a prior phase 1 trial. A phase 2 cohort expansion was initiated to further characterize the phenotype and cytokine milieu of the DC vaccines and their immunologic activity in vitro and to further examine a possible link between clinical activity and determinant spreading. In an open-label phase 2 trial, 10(7) autologous ex vivo generated DCs pulsed with the HLA-A*0201 immunodominant peptide MART-1(27-35) were administered to 10 subjects with stage II-IV melanoma. The experimental vaccines were administered intradermally in a biweekly schedule for a total of three injections, and blood for immunologic assays was obtained before each administration and at three time points after. DC vaccine preparations had wide intra- and interpatient variability in terms of cell surface markers and preferential cytokine milieu, but they did not correlate with the levels of antigen-specific T cells after vaccination. Of four patients with measurable disease, one had stable disease for 6 months and another has a continued complete response for over 2 years, which is confounded by receiving a closely sequenced CTLA4 blocking antibody. The DC vaccines induced determinant spreading in this subject, and CTLA4 blockade reactivated T cells with prior antigen exposure. The DC phenotype and cytokine profile do not correlate with the ability to induce antigen-specific T cells, while determinant spreading after DC immunization may be a marker of an efficient antitumor response. Sequential CTLA4 blockade may enhance the immune activity of DC-based immunotherapy.

Long-term efficacy and safety of zoledronic acid in the treatment of skeletal metastases in patients with nonsmall cell lung carcinoma and other solid tumors: a randomized, Phase III, double-blind, placebo-controlled trial.

BACKGROUND: The authors previously reported the efficacy of a dose of 4 mg of zoledronic acid in reducing skeletal complications in patients with bone metastases secondary to lung carcinoma and other solid tumors (except carcinomas of the breast and prostate). In the current study, they update these results and report the long-term efficacy and safety of 21 months of treatment with zoledronic acid in a randomized, placebo-controlled trial. METHODS: A total of 773 patients were randomized to receive zoledronic acid (4 mg or 8 mg) or placebo via a 15-minute infusion every 3 weeks for 21 months. The 8-mg dose later was reduced to 4 mg (8/4-mg group). The primary efficacy endpoint was the percentage of patients at 21 months with >/= 1 skeletal-related event (SRE) (pathologic fracture, spinal cord compression, radiation therapy to bone, or surgery to bone). Secondary analyses (time to first SRE, annual incidence of SREs, and multiple-event analysis) included hypercalcemia of malignancy. RESULTS: Fewer patients treated with zoledronic acid developed at least 1 SRE at 21 months compared with patients treated with placebo (39% of those treated at the 4-mg dose [P =0.127] and 36% of those treated at the 8/4-mg dose [P = 0.023], compared with 46% of those treated with placebo). Furthermore, 4 mg of zoledronic acid significantly delayed the median time to first SRE (236 days with 4 mg vs. 155 days with placebo; P = 0.009) and significantly reduced the annual incidence of SREs (1.74 per year with the 4-mg dose vs. 2.71 per year with placebo; P = 0.012). Moreover, the 4-mg dose of zoledronic acid was found to reduce the risk of developing a skeletal event by 31% (hazard ratio of 0.693; P = 0.003). Zoledronic acid was found to be well tolerated with long-term use; the most commonly reported adverse events in all treatment groups included bone pain and the transient, acute-phase reactions of nausea, anemia, and emesis. CONCLUSIONS: To the authors' knowledge, zoledronic acid is the first bisphosphonate to demonstrate long-term safety and efficacy in this patient population.

The relationship between psychologic distress and cancer-related fatigue.

BACKGROUND: The authors examined the relationship between changes in depression and anxiety levels with changes in fatigue levels among anemic patients with lung cancer who participated in a randomized, double-blind, placebo-controlled clinical trial of darbepoetin alfa for the treatment of anemia. METHODS: Patients completed the Brief Symptom Inventory (BSI) Depression and Anxiety subscales and the Functional Assessment of Cancer Therapy (FACT) Fatigue subscale during the trial. Pearson correlation coefficients were used to compare changes in the BSI scores with changes in the FACT Fatigue scores. Multiple regression models were used to explore sociodemographic and clinical explanatory variables. RESULTS: At baseline, 25% and 35% of 250 patients reported high levels (normed BSI scores >or= 65) of anxiety and depression, respectively. Correlations of changes in normed BSI Anxiety and Depression subscale scores with changes in FACT Fatigue scores had coefficients of -0.45 (P < 0.001) and -0.44 (P < 0.001), respectively. In the multiple regression models, change in the FACT Fatigue score was the only significant explanatory variable (P < 0.001). For every unit improvement in FACT Fatigue score, there was a corresponding improvement of 0.7 points and 0.8 points in anxiety and depression levels, respectively. CONCLUSIONS: Improvements in fatigue were associated significantly with reductions in anxiety and depression. For patients with anemia, fatigue can be improved or reversed with darbepoetin alfa therapy. Thus, less fatigued patients also may benefit from reduced levels of anxiety and depression.

Hemoglobin increase is associated with improved health-related quality of life in patients with cancer not receiving chemotherapy.

Anemia is becoming recognized as a substantial problem for patients with cancer who are not receiving chemotherapy. Recently, darbepoetin alfa has been shown to provide significant clinical benefits in this patient population. This analysis assesses the effect of change in hemoglobin levels on health-related quality of life (HRQOL) in these patients. Eligible patients had anemia (hemoglobin /= 3 points) were significantly (P < 0.05) associated with improvements in functional, physical, and emotional well-being, depression, anxiety, and global ratings of energy, activity, and overall health. In summary, an increase in hemoglobin was associated with a decrease in fatigue in patients with anemia associated with nonmyeloid malignancies who were not receiving chemotherapy.

Darbepoetin alfa administered every 2 weeks alleviates anemia in cancer patients receiving chemotherapy.

The objectives of this study were to assess the safety and efficacy of darbepoetin alfa (Aranesp) administered every 2 weeks in anemic patients with solid tumors receiving chemotherapy. This was an open-label, randomized, active-controlled, multicenter dose-finding study evaluating a range of every-2-week darbepoetin alfa doses. The active control arm received epoetin alfa (Epogen, Procrit) at 40,000 U weekly with a dose increase to 60,000 U weekly for subjects with an inadequate response. The lowest clinically effective doses of darbepoetin alfa in this study were 3.0 and 5.0 microg/kg every 2 weeks, with no additional benefit observed at higher doses. The percentage of patients who achieved a hematopoietic response in the 3.0- and 5.0-microg/kg groups was 66% (95% confidence interval [CI] = 46%-86%) and 84% (95% CI = 67%-100%), respectively, compared with 63% (95% CI = 46%-81%) in the epoetin alfa group. Darbepoetin alfa administered at a dose of 3.0 microg/kg every 2 weeks is safe and effective for treating anemia in patients with solid tumors on chemotherapy, and is comparable to epoetin alfa. A dose increase to 5.0 microg/kg of darbepoetin alfa administered every 2 weeks may be appropriate in patients with an inadequate initial response.

Anemia in cancer patients: significance, epidemiology, and current therapy.

Anemia in cancer patients is associated with a decline in energy levels, activity levels, and quality of life, and these variables improve when hemoglobin levels rise. Importantly, the impact of improved hemoglobin levels on response to chemotherapy, radiation therapy, and survival time is under study. This line of research follows favorable preliminary data in clinical studies suggesting improved treatment outcomes with reversal of anemia. It is estimated that there are 10 million people in the United States with cancer. Of the 1.3 million cancer patients who are anemic with hemoglobin levels less than 12 g/dL, about 800,000 are receiving chemotherapy and 500,000 are not. The predominant treatable cause of anemia in these patients is a relative lack of erythropoietin; overall, only 20% of anemic cancer patients receive a trial of erythropoietic therapy. About one-fourth (26%) of patients whose hemoglobin is less than 12 g/dL and who are receiving chemotherapy for cancer are currently receiving erythropoietic therapy. A review of the patients in our oncology practice revealed that 37% were anemic (hemoglobin < 12 g/dL) prior to chemotherapy, and an additional 41% became anemic during chemotherapy. Overall, 63% of our cancer patients on chemotherapy received erythropoietin; 6% of these patients received red cell transfusions. Only 7% of our patients had a hemoglobin level < 10 g/dL before chemotherapy; overall, 80% of our patients maintained hemoglobin levels > or = 10 g/dL at all times. Barriers to the use of erythropoietic agents include cost and reimbursement issues, inconvenience of frequent injections, limitations in efficacy, and indication restrictions. An understanding of the importance of anemia and newer agents requiring less frequent dosing, such as darbepoetin alfa (Aranesp), may help physicians and patients overcome some of these barriers.

Psychological outcomes associated with anemia-related fatigue in cancer patients.

This article examines the relationships between chemotherapy-induced anemia, fatigue, and psychological distress among anemic cancer patients with solid tumors. Patients participating in two randomized clinical trials evaluating the efficacy of darbepoetin alfa (Aranesp) completed a questionnaire at baseline, at the beginning of each chemotherapy cycle, and at the end of the 12-week treatment period. The questionnaire included four psychological distress outcomes: Brief Symptom Inventory (BSI) Depression and Anxiety, Functional Assessment of Cancer Therapy (FACT)-Emotional Well-Being, numeric rating scale of Overall Health, and the FACT-Fatigue subscale. Patients with a hemoglobin response of at least a 2 g/dL increase were more likely to experience meaningful improvements (at least 3 points) in FACT-Fatigue scores than nonresponders (55.0% vs 39.8%; P = .0004). Patients with meaningful improvements in FACT-Fatigue scores reported significantly greater improvements in each of the psychological outcomes relative to those without improved fatigue (P <.0001). For BSI Depression and Anxiety, the differences in mean change scores between patients with and without improved fatigue were 8.2 and 7.7, respectively. Improving the hemoglobin levels of patients undergoing chemotherapy and suffering from anemia-related fatigue has the potential to produce significant positive effects on patients' fatigue, depressive symptoms, anxiety, feelings of helplessness, and overall health.