Lee S. Rosen

Irinotecan plus Fluorouracil and Leucovorin for Metastatic Colorectal Cancer

BACKGROUND The combination of fluorouracil and leucovorin has until recently been standard therapy for metastatic colorectal cancer. Irinotecan prolongs survival in patients with colorectal cancer that is refractory to treatment with fluorouracil and leucovorin. In a multicenter trial, we compared a combination of irinotecan, fluorouracil and leucovorin with bolus doses of fluorouracil and leucovorin as first-line therapy for metastatic colorectal cancer. A third group of patients received irinotecan alone. METHODS Patients were randomly assigned to receive irinotecan (125 mg per square meter of body-surface area intravenously), fluorouracil (500 mg per square meter as an intravenous bolus), and leucovorin (20 mg per square meter as an intravenous bolus) weekly for four weeks every six weeks; fluorouracil (425 mg per square meter as an intravenous bolus) and leucovorin (20 mg per square meter as an intravenous bolus) daily for five consecutive days every four weeks; or irinotecan alone (125 mg per square meter intravenously) weekly for four weeks every six weeks. End points included progression-free survival and overall survival. RESULTS Of 683 patients, 231 were assigned to receive irinotecan, fluorouracil, and leucovorin; 226 to receive fluorouracil and leucovorin; and 226 to receive irinotecan alone. In an intention-to-treat analysis, as compared with treatment with fluorouracil and leucovorin, treatment with irinotecan, fluorouracil, and leucovorin resulted in significantly longer progression-free survival (median, 7.0 vs. 4.3 months; P=0.004), a higher rate of confirmed response (39 percent vs. 21 percent, P<0.001), and longer overall survival (median, 14.8 vs. 12.6 months; P=0.04). Results for irinotecan alone were similar to those for fluorouracil and leucovorin. Grade 3 (severe) diarrhea was more common during treatment with irinotecan, fluorouracil, and leucovorin than during treatment with fluorouracil and leucovorin, but the incidence of grade 4 (life-threatening) diarrhea was similar in the two groups (<8 percent). Grade 3 or 4 mucositis, grade 4 neutropenia, and neutropenic fever were less frequent during treatment with irinotecan, fluorouracil, and leucovorin. Adding irinotecan to the regimen of fluorouracil and leucovorin did not compromise the quality of life. CONCLUSIONS Weekly treatment with irinotecan plus fluorouracil and leucovorin is superior to a widely used regimen of fluorouracil and leucovorin for metastatic colorectal cancer in terms of progression-free survival and overall survival.

Long-Term Efficacy and Safety of Zoledronic Acid Compared with Pamidronate Disodium in the Treatment of Skeletal Complications in Patients with Advanced Multiple Myeloma or Breast Carcinoma A Randomized, Double-Blind, Multicenter, Comparative Trial

The goal of the current study was to compare the long‐term (25‐month) safety and efficacy of zoledronic acid with pamidronate in patients with bone lesions secondary to advanced breast carcinoma or multiple myeloma.

Zoledronic Acid Versus Placebo in the Treatment of Skeletal Metastases in Patients With Lung Cancer and Other Solid Tumors: A Phase III, Double-Blind, Randomized Trial—The Zoledronic Acid Lung Cancer and Other Solid Tumors Study Group

PURPOSE To assess the efficacy and safety of zoledronic acid in patients with bone metastases secondary to solid tumors other than breast or prostate cancer. PATIENTS AND METHODS Patients were randomly assigned to receive zoledronic acid (4 or 8 mg) or placebo every 3 weeks for 9 months, with concomitant antineoplastic therapy. The 8-mg dose was reduced to 4 mg (8/4-mg group). The primary efficacy analysis was proportion of patients with at least one skeletal-related event (SRE), defined as pathologic fracture, spinal cord compression, radiation therapy to bone, and surgery to bone. Secondary analyses (time to first SRE, skeletal morbidity rate, and multiple event analysis) counted hypercalcemia as an SRE. RESULTS Among 773 patients with bone metastases from lung cancer or other solid tumors, the proportion with an SRE was reduced in both zoledronic acid groups compared with the placebo group (38% for 4 mg and 35% for 8/4 mg zoledronic acid v 44% for the placebo group; P =.127 and P =.023 for 4-mg and 8/4-mg groups, respectively). Additionally, 4 mg zoledronic acid significantly increased time to first event (median, 230 v 163 days for placebo; P =.023), an important end point in this poor-prognosis population, and significantly reduced the risk of developing skeletal events by multiple event analysis (hazard ratio = 0.732; P =.017). Zoledronic acid was well tolerated; the most common adverse events in all treatment groups included bone pain, nausea, anemia, and vomiting. CONCLUSION Zoledronic acid (4 mg infused over 15 minutes) is the first bisphosphonate to reduce skeletal complications in patients with bone metastases from solid tumors other than breast and prostate cancer.

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.

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.

Zoledronic acid reduces skeletal-related events in patients with osteolytic metastases: A double-blind, randomized dose-response study

This study evaluated the dose–response relation for zoledronic acid, a new generation high potency bisphosphonate, given as a 5‐minute infusion in patients with malignant osteolytic disease.

Zoledronic acid is superior to pamidronate for the treatment of bone metastases in breast carcinoma patients with at least one osteolytic lesion

Treatment with zoledronic acid (Zol) was compared with a dose of 90 mg of pamidronate (Pam) in breast carcinoma (BC) patients with at least 1 osteolytic lesion based on data from a Phase III, randomized trial.

Safety, Pharmacokinetics, and Antitumor Activity of AMG 386, a Selective Angiopoietin Inhibitor, in Adult Patients With Advanced Solid Tumors

PURPOSE AMG 386 is an investigational peptide-Fc fusion protein (ie, peptibody) that inhibits angiogenesis by preventing the interaction of angiopoietin-1 and angiopoietin-2 with their receptor, Tie2. This first-in-human study evaluated the safety, pharmacokinetics (PK), pharmacodynamics, and antitumor activity of AMG 386 in adults with advanced solid tumors. PATIENTS AND METHODS Patients in sequential cohorts received weekly intravenous AMG 386 doses of 0.3, 1, 3, 10, or 30 mg/kg. Results Thirty-two patients were enrolled on the study and received AMG 386. One occurrence of dose-limiting toxicity was seen at 30 mg/kg: respiratory arrest, which likely was caused by tumor burden that was possibly related to AMG 386. The most common toxicities were fatigue and peripheral edema. Proteinuria (n = 11) was observed without clinical sequelae. Only four patients (12%) experienced treatment-related toxicities greater than grade 1. A maximum-tolerated dose was not reached. PK was dose-linear and the mean terminal-phase elimination half-life values ranged from 3.1 to 6.3 days. Serum AMG 386 levels appeared to reach steady-state after four weekly doses, and there was minimal accumulation. No anti-AMG 386 neutralizing antibodies were detected. Reductions in volume transfer constant (K(trans); measured by dynamic contrast-enhanced magnetic resonance imaging) were observed in 10 patients (13 lesions) 48 hours to 8 weeks after treatment. One patient with refractory ovarian cancer achieved a confirmed partial response (ie, 32.5% reduction by Response Evaluation Criteria in Solid Tumors) and withdrew from the study with a partial response after 156 weeks of treatment; four patients experienced stable disease for at least 16 weeks. CONCLUSION Weekly AMG 386 appeared well tolerated, and its safety profile appeared distinct from that of vascular endothelial growth factor-axis inhibitors. AMG 386 also appeared to impact tumor vascularity and showed antitumor activity in this patient population.

Clinical experience with angiogenesis signaling inhibitors: focus on vascular endothelial growth factor (VEGF) blockers.

Angiogenesis is required for tumor growth and metastasis and, therefore, represents an exciting target for cancer treatment. Angiogenesis is a complex process that is tightly regulated by pro- and anti-angiogenic growth factors. Physiologic angiogenesis takes place during tissue growth and repair, during the female reproductive cycle, and during fetal development. Pathologic angiogenesis is characterized by either excessive (eg, cancer) or inadequate (eg, coronary artery disease) neovascularization. Angiogenesis occurs in a series of complex and interrelated steps that involve the release of pro-angiogenic growth factors, such as vascular endothelial growth factor (VEGF). VEGF regulates both vascular proliferation and permeability, and functions as an anti-apoptotic factor for newly formed blood vessels. The biological effects of VEGF are mediated by two receptors, VEGF-1 and VEGF-2, whose expression is largely limited to the vascular endothelium. VEGF is often expressed in tumors at substantially increased levels. It is expressed in response to hypoxia, oncogenes, and other cytokines, and its expression is associated with poor prognosis in several types of cancer. Several different strategies have been used to inhibit VEGF, including anti-VEGF monoclonal antibodies (eg, bevacizumab) and agents that inhibit the VEGF receptor (eg, SU5416). Both types of agents have tolerable side effects and have shown promise when evaluated in a wide range of tumor types. Angiogenesis, the role of VEGF in angiogenesis and malignancy, and strategies for cancer treatment with VEGF inhibitors are discussed.

Safety, Pharmacokinetics, and Efficacy of AMG 706, an Oral Multikinase Inhibitor, in Patients With Advanced Solid Tumors

PURPOSE AMG 706 is an investigational, orally bioavailable inhibitor of vascular endothelial growth factor receptors 1, 2, and 3, platelet-derived growth factor receptor, and stem-cell factor receptor. This phase I, dose-finding study evaluated the safety, pharmacokinetics, and pharmacodynamics of AMG 706 in patients with refractory advanced solid tumors. PATIENTS AND METHODS AMG 706 was administered at escalating doses of 50 to 175 mg once daily or 25 mg bid for the first 21 days of a 28-day cycle. The 125-mg once-daily dose was also administered continuously. The maximum-tolerated dose (MTD), safety, pharmacokinetics, tumor response, and serum levels of proangiogenic markers were determined. RESULTS Seventy-one patients received AMG 706. The MTD was 125 mg once daily administered continuously. The most frequent adverse events were fatigue (55%), diarrhea (51%), nausea (44%), and hypertension (42%). Plasma AMG 706 concentrations increased in a dose-proportional manner with no accumulation after multiple doses. Five patients (7%) had a partial response, 35 patients (49%) had stable disease (at least through day 50), and 31 patients (44%) had progressive disease. Changes in tumor size correlated significantly with an increase in placental growth factor (P = .003) and a decrease in soluble kinase domain receptor (P = .001). CONCLUSION In this study of patients with advanced refractory solid tumors, AMG 706 was well tolerated and displayed favorable pharmacokinetics and evidence of antitumor activity. Additional studies of AMG 706 as monotherapy and in combination with various agents are ongoing.

The new bisphosphonate, Zometa (zoledronic acid), decreases skeletal complications in both osteolytic and osteoblastic lesions: a comparison to pamidronate.

Bisphosphonates are the treatment of choice for lytic bone lesions associated with breast cancer. In contrast, bone lesions associated with prostate cancer are predominately osteoblastic. Zoledonic acid (Zol) is a new-generation bisphosphonate that is approximately 2–3 orders of magnitude more potent than pamidronate (Pam) in preclinical models and has demonstrated clinical efficacy in patients with both lytic and blastic lesions. Zoledonic acid (4 mg via 15 min infusion) every 3–4 weeks was directly compared to Pam (90 mg via 2 hr infusion) in 767 patients with breast cancer and bone metastases. The primary endpoint was the proportion of patients experiencing a skeletal-related event (SRE) over 13 months. Zoledonic acid was as effective as Pam, and the proportion of Zol-treated patients with an SRE (42% in the hormonal therapy strata and 44% in the chemotherapy strata) was comparable to the original studies comparing Pam to placebo. Among 371 breast cancer patients receiving hormonal therapy, the proportion of patients with an SRE was 47% for Pam vs. 57% for placebo (P=0.057), and among 380 patients treated with chemotherapy, the proportions with an SRE were 43% for Pam vs. 56% for placebo (P=0.008) at 12 months. Zoledronic acid (4 mg) has been compared to placebo in a randomized Phase III trial involving 422 men with hormone-refractory prostate cancer metastatic to bone. Zoledonic acid demonstrated a significant advantage over placebo for median time to first SRE (median not reached for Zol vs. 321 days for placebo; P=0.011), the proportion of patients with an SRE over 15 months (33 vs. 44% for placebo; P=0.021), and mean skeletal morbidity rate (number of SREs/time, 0.08 vs. 1.49 for placebo; P=0.006). In addition, the effects of Zol were apparent early. At 3 months, only 12% of Zol-treated patients had an SRE vs. 23% for placebo (P=0.003), and at 6 months, the proportions were 21 vs. 31% for placebo (P=0.025). In contrast, a previous study of Pam in 236 prostate cancer patients found that Pam was no more effective than placebo in reducing bone pain or SREs over 6 months. In these studies, Zol was well tolerated with a safety profile similar to other IV bisphosphonates. In conclusion, Zol is the first bisphosphonate to demonstrate efficacy in both lytic and blastic disease. The unique properties of this novel agent should be further explored in future clinical trials.