Hepatic safety analysis of trabectedin: results of a pharmacokinetic study with trabectedin in patients with hepatic impairment and experience from a phase 3 clinical trial.

Purpose Trabectedin is metabolized by the liver and has been associated with transient, noncumulative transaminase elevation. Two recent studies further characterize hepatic tolerability with trabectedin therapy: a phase 1 pharmacokinetic study (Study #1004; NCT01273493) in patients with advanced malignancies and hepatic impairment (HI), and a phase 3 study (Study #3007; NCT01343277) of trabectedin vs. dacarbazine in patients with advanced sarcomas and normal hepatic function. Methods In Study #1004, patients received a single 3-h intravenous (IV) infusion of trabectedin: control group, trabectedin 1.3 mg/m2; HI group (baseline total bilirubin >1.5 and ≤3× upper limit of normal [ULN]; AST and ALT ≤2.5× ULN), trabectedin 0.58 or 0.9 mg/m2. In Study #3007, the trabectedin group received 1.5 mg/m2 by 24-h IV infusion every 3 weeks until disease progression or unacceptable toxicity. Results In Study #1004, dose-normalized trabectedin exposure was higher in HI patients (n = 6) versus controls (n = 9) (geometric mean ratios [90% CI] AUClast: 1.97 [1.20; 3.22]). In Study #3007, following trabectedin administration, 90% of patients had elevated ALT (32% grade 3-4) and 84% had elevated AST (17% grade 3-4). Transaminase elevations were transient and noncumulative. Progression-free survival was similar in patients with grade 3-4 hepatotoxicity (n = 109) versus grade 0-2 hepatotoxicity (n = 231) (median [95% CI]: 4.63 [4.01, 5.85] months versus 3.55 [2.73, 4.63] months; P = 0.545, HR = 0.91 [0.68-1.23]). Conclusion Trabectedin treatment of patients with HI results in higher plasma exposures. Hepatotoxicity in patients with normal liver function can be effectively addressed through dose reductions and delays.

TRAIL receptor agonist conatumumab with modified FOLFOX6 plus bevacizumab for first-line treatment of metastatic colorectal cancer: A randomized phase 1b/2 trial.

BACKGROUND: In patients with previously untreated metastatic colorectal cancer (mCRC), we conducted a phase 1b/randomized phase 2 trial to define the safety, tolerability, and efficacy of mFOLFOX6 plus bevacizumab (mFOLFOX6/bev) with conatumumab, an investigational, fully human monoclonal IgG1 antibody that specifically activates death receptor 5 (DR5). METHODS: Twelve patients were enrolled in a phase 1b open-label dose-escalation trial of conatumumab with mFOLFOX6/bev; thereafter, 190 patients were randomized 1:1:1 to receive mFOLFOX6/bev in combination with 2 mg/kg conatumumab, 10 mg/kg conatumumab, or placebo. Therapy cycles were repeated every 2 weeks until disease progression or the occurrence of unacceptable toxicity. RESULTS: In phase 1b, conatumumab with mFOLFOX6/bev was tolerated without apparent added toxicity over mFOLFOX6/bev alone. In phase 2, conatumumab with mFOLFOX6/bev did not confer a benefit in progression-free survival when compared with placebo with mFOLFOX6/bev. Toxicity was similar in all treatment arms. Following treatment, similar increases in circulating caspase-3 levels were observed in all arms. CONCLUSIONS: Conatumumab with mFOLFOX6/bev did not offer improved efficacy over the same chemotherapy with placebo in first-line treatment of patients with mCRC. These data do not support further development of conatumumab in advanced CRC.

Comparison of darbepoetin alfa dosed weekly (QW) vs. extended dosing schedule (EDS) in the treatment of anemia in patients receiving multicycle chemotherapy in a randomized, phase 2, open-label trial.

BACKGROUND: Chemotherapy-induced anemia (CIA) is responsive to treatment with erythropoiesis-stimulating agents (ESAs) such as darbepoetin alfa. Administration of ESAs on a synchronous schedule with chemotherapy administration could benefit patients by reducing clinic visits and potentially enhancing on-time chemotherapy delivery. METHODS: This phase 2, 25-week, open-label study evaluated the noninferiority of darbepoetin alfa administered weekly vs. as an extended dosing schedule (every 2 or 3 weeks) in patients with CIA. Patients were randomized 1:1 to an extended dosing schedule (EDS: darbepoetin alfa 300 µg Q2W if chemotherapy was QW, Q2W, or Q4W or darbepoetin alfa 500 µg Q3W if chemotherapy was Q3W) or weekly (150 µg QW regardless of chemotherapy schedule). Stratification factors included chemotherapy cycle length, screening hemoglobin (<10 g/dL vs. ≥10 g/dL), and tumor type (lung/gynecological vs. other nonmyeloid malignancies). The primary endpoint was change in hemoglobin from baseline to Week 13. RESULTS: Seven hundred fifty-two patients (374 QW patients; 378 EDS patients) received ≥1 dose of darbepoetin alfa and were included in the analysis. Demographics and disease state were similar between groups. Seventy-one percent of patients in the EDS group and 76% in the QW group achieved the target hemoglobin of ≥11.0 g/dL. There was a minimal difference in the primary endpoint of mean change in hemoglobin (baseline to Week 13) between the QW and the EDS groups (-0.04 g/dL; 95% confidence interval: -0.26, 0.17 g/dL). The upper limit of the 95% confidence interval was less than the prespecified limit of <0.75 g/dL, supporting noninferiority of the EDS dosing schedule. Reported adverse events were similar between groups. A slight increase in transfusions was reported in the QW group. CONCLUSION: Darbepoetin alfa, when administered synchronously with chemotherapy, on an EDS appears to be similarly efficacious to darbepoetin alfa weekly dosing with no unexpected adverse events. This study provides prospective data on how multiple dosing regimens available with darbepoetin alfa can be synchronized with chemotherapy administered across a range of dosing schedules. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT00144131.

Effect of the cytochrome P450 2C19 inhibitor omeprazole on the pharmacokinetics and safety profile of bortezomib in patients with advanced solid tumours, non-Hodgkin's lymphoma or multiple myeloma.

BACKGROUND AND OBJECTIVE: Bortezomib, an antineoplastic for the treatment of relapsed multiple myeloma and mantle cell lymphoma, undergoes metabolism through oxidative deboronation by cytochrome P450 (CYP) enzymes, primarily CYP3A4 and CYP2C19. Omeprazole, a proton-pump inhibitor, is primarily metabolized by and demonstrates high affinity for CYP2C19. This study investigated whether coadministration of omeprazole affected the pharmacokinetics, pharmacodynamics and safety profile of bortezomib in patients with advanced cancer. The variability of bortezomib pharmacokinetics with CYP enzyme polymorphism was also investigated. PATIENTS AND METHODS: This open-label, crossover, pharmacokinetic drug-drug interaction study was conducted at seven institutions in the US and Europe between January 2005 and August 2006. Patients who had advanced solid tumours, non-Hodgkin's lymphoma or multiple myeloma, were aged >/=18 years, weighed >/=50 kg and had a life expectancy of >/=3 months were eligible. Patients received bortezomib 1.3 mg/m2 on days 1, 4, 8 and 11 for two 21-day cycles, plus omeprazole 40 mg in the morning of days 6-10 and in the evening of day 8 in either cycle 1 (sequence 1) or cycle 2 (sequence 2). On day 21 of cycle 2, patients benefiting from therapy could continue to receive bortezomib for six additional cycles. Blood samples for pharmacokinetic/pharmacodynamic evaluation were collected prior to and at various timepoints after bortezomib administration on day 8 of cycles 1 and 2. Blood samples for pharmacogenomics were also collected. Pharmacokinetic parameters were calculated by noncompartmental analysis of plasma concentration-time data for bortezomib administration on day 8 of cycles 1 and 2, using WinNonlin version 4.0.1.a software. The pharmacodynamic profile was assessed using a whole-blood 20S proteasome inhibition assay. RESULTS: Twenty-seven patients (median age 64 years) were enrolled, 12 in sequence 1 and 15 in sequence 2, including eight and nine pharmacokinetic-evaluable patients, respectively. Bortezomib pharmacokinetic parameters were similar when bortezomib was administered alone or with omeprazole (maximum plasma concentration 120 vs 123 ng/mL; area under the plasma concentration-time curve from 0 to 72 hours 129 vs 135 ng . h/mL). The pharmacodynamic parameters were also similar (maximum effect 85.8% vs 93.7%; area under the percent inhibition-time curve over 72 hours 4052 vs 3910 % x h); the differences were not statistically significant. Pharmacogenomic analysis revealed no meaningful relationships between CYP enzyme polymorphisms and pharmacokinetic/pharmacodynamic parameters. Toxicities were generally similar between patients in sequence 1 and sequence 2, and between cycle 1 and cycle 2 in both treatment sequences. Among 26 evaluable patients, 13 (50%) were assessed as benefiting from bortezomib at the end of cycle 2 and continued to receive treatment. CONCLUSION: No impact on the pharmacokinetics, pharmacodynamics and safety profile of bortezomib was seen with coadministration of omeprazole. Concomitant administration of bortezomib and omeprazole is unlikely to cause clinically significant drug-drug interactions and is unlikely to have an impact on the efficacy or safety of bortezomib.

Infusion of palonosetron plus dexamethasone for the prevention of chemotherapy-induced nausea and vomiting.

Serotonin (5-HT3) receptor antagonists are the foundation of standard antiemetic care for cancer patients receiving emetogenic chemotherapy. To enhance the efficacy of these supportive care agents, dexamethasone is routinely admixed with the 5-HT3 receptor antagonist, which is administered by intravenous infusion before chemotherapy begins. This phase II study evaluated the safety and efficacy of intravenous palonosetron admixed with dexamethasone to prevent chemotherapy-induced nausea and vomiting (CINV) in patients receiving moderately emetogenic chemotherapy. Cancer patients received palonosetron 0.25 mg plus dexamethasone 8 mg admixed in 50 mL of infusion solution before receiving at least one qualifying chemotherapeutic agent (cyclophosphamide < or = 1,500 mg/m2, doxorubicin > or = 20 mg/m2, carboplatin, or oxaliplatin). Patients used diaries to record nausea and emesis experienced and rescue medications used. Of 32 participants, 27 (84%) had a complete response (no emesis and no rescue medication) during the acute (0-24 hours) interval posttherapy, 19 (59%) had a complete response during the delayed (> 24-120 hours) posttherapeutic interval, and 19 (59%) had a complete response during the overall (0-120 hours) posttreatment interval. A total of 23 patients (72%) had no emetic episodes, 16 (50%) had no nausea, and 21 (66%) used no rescue medication throughout the overall 5-day interval. The combination was well tolerated. Palonosetron plus dexamethasone given as a pretreatment infusion is effective and safe in preventing acute and delayed CINV in patients receiving moderately emetogenic chemotherapy.

Treatment of chemotherapy-induced anemia in breast cancer: results of a randomized controlled trial of darbepoetin alfa 200 microg every 2 weeks versus epoetin alfa 40,000 U weekly.

BACKGROUND: Current chemotherapy regimens for breast cancer result in high incidences of anemia, which can be treated with erythropoietic agents. The relative efficacy of darbepoetin alfa and epoetin alfa was explored in this phase II, open-label, randomized, multicenter trial in anemic patients with breast cancer receiving chemotherapy. PATIENTS AND METHODS: Patients were randomized at a 1:1 ratio to receive darbepoetin alfa 200 microg every 2 weeks (n = 72) or epoetin alfa 40,000 U weekly (n = 69) for < or = 16 weeks. Clinical and hematologic endpoints and validation of a novel patient satisfaction questionnaire for anemia treatment were evaluated for all patients randomized to receive > or = 1 dose of study drug. RESULTS: Baseline characteristics were generally similar between treatment groups. Mean changes in hemoglobin (Hb) level from baseline were similar at 1.9 g/dL for darbepoetin alfa and 1.7 g/dL for epoetin alfa. Hematopoietic responses (> or = 2 g/dL increase in Hb level from baseline or Hb level > or = 12 g/dL) were also similar between groups (88% for darbepoetin alfa and 81% for epoetin alfa). The proportions of patients who received a transfusion during treatment were 6% (95% CI, 0-11%) for darbepoetin alfa and 16% (95% CI, 7%-25%) for epoetin alfa. Most patients (67 patients receiving darbepoetin alfa [93%]; 61 patients receiving epoetin alfa [90%]) exhibited a clinically meaningful target Hb level > or = 11 g/dL. No differences in safety were observed. CONCLUSION: These results suggest that, in patients with breast cancer, darbepoetin alfa 200 microg every 2 weeks and epoetin alfa 40,000 U weekly result in comparable clinical outcomes for the treatment of chemotherapy-induced anemia.

Carlumab, an anti-C-C chemokine ligand 2 monoclonal antibody, in combination with four chemotherapy regimens for the treatment of patients with solid tumors: an open-label, multicenter phase 1b study.

C-C chemokine ligand 2 (CCL2) stimulates tumor growth, metastasis, and angiogenesis. Carlumab, a human IgG1κ anti-CCL2 mAb, has shown antitumor activity in preclinical and clinical trials. We conducted a first-in-human phase 1b study of carlumab with one of four chemotherapy regimens (docetaxel, gemcitabine, paclitaxel + carboplatin, and pegylated liposomal doxorubicin HCl [PLD]). Patients had advanced solid tumors for which ≥1 of these regimens was considered standard of care or for whom no other treatment options existed. Dose-limiting toxicities included one grade 4 febrile neutropenia (docetaxel arm) and one grade 3 neutropenia (gemcitabine arm). Combination treatment with carlumab had no clinically relevant pharmacokinetic effect on docetaxel (n = 15), gemcitabine (n = 12), paclitaxel or carboplatin (n = 12), or PLD (n = 14). Total serum CCL2 concentrations increased post-treatment with carlumab alone, consistent with carlumab-CCL2 binding, and continued increase in the presence of all chemotherapy regimens. Free CCL2 declined immediately post-treatment with carlumab but increased with further chemotherapy administrations in all arms, suggesting that carlumab could sequester CCL2 for only a short time. Neither antibodies against carlumab nor consistent changes in circulating tumor cells (CTCs) or circulating endothelial cells (CECs) enumeration were observed. Three of 19 evaluable patients showed a 30 % decrease from baseline urinary cross-linked N-telopeptide of type I collagen (uNTx). One partial response and 18 (38 %) stable disease responses were observed. The most common drug-related grade ≥3 adverse events were docetaxel arm-neutropenia (6/15) and febrile neutropenia (4/15); gemcitabine arm-neutropenia (2/12); paclitaxel + carboplatin arm-neutropenia, thrombocytopenia (4/12 each), and anemia (2/12); and PLD arm-anemia (3/14) and stomatitis (2/14). Carlumab could be safely administered at 10 or 15 mg/kg in combination with standard-of-care chemotherapy and was well-tolerated, although no long-term suppression of serum CCL2 or significant tumor responses were observed.

Phase I study of U3-1287, a fully human anti-HER3 monoclonal antibody, in patients with advanced solid tumors.

PURPOSE: HER3 is a key dimerization partner for other HER family members, and its expression is associated with poor prognosis. This first-in-human study of U3-1287 (NCT00730470), a fully human anti-HER3 monoclonal antibody, evaluated its safety, tolerability, and pharmacokinetics in patients with advanced solid tumor. EXPERIMENTAL DESIGN: The study was conducted in 2 parts: part 1--sequential cohorts received escalating doses (0.3-20 mg/kg) of U3-1287 every 2 weeks, starting 3 weeks after the first dose; part 2--additional patients received 9, 14, or 20 mg/kg U3-1287 every 2 weeks, based on observed tolerability and pharmacokinetics from part 1. Recommended phase II dose, adverse event rates, pharmacokinetics, and tumor response were determined. RESULTS: Fifty-seven patients (part 1: 26; part 2: 31) received U3-1287. As no dose-limiting toxicities were reported, the maximum-tolerated dose was not reached. The maximum-administered dose was 20 mg/kg every 2 weeks. The most frequent adverse events related to U3-1287 were fatigue (21.1%), diarrhea (12.3%), nausea (10.5%), decreased appetite (7.0%), and dysgeusia (5.3%). No patient developed anti-U3-1287 antibodies. In these heavily pretreated patients, stable disease was maintained 9 weeks or more in 19.2% in part 1 and 10 weeks or more in 25.8% in part 2. CONCLUSION: U3-1287 treatment was well tolerated, and some evidence of disease stabilization was observed. Pharmacokinetic data support U3-1287 dosing of 9 to 20 mg/kg every 2 to 3 weeks. Combination studies of U3-1287 are ongoing.

A phase Ib study of AMG 102 in combination with bevacizumab or motesanib in patients with advanced solid tumors.

PURPOSE: This phase Ib study evaluated the safety, pharmacokinetics, pharmacodynamics, and antitumor activity of AMG 102, a fully human monoclonal antibody against hepatocyte growth factor/scatter factor (HGF/SF), in combination with bevacizumab or motesanib in patients with advanced solid tumors. EXPERIMENTAL DESIGN: Patients with treatment-refractory advanced solid tumors were sequentially enrolled into four cohorts (3, 10, or 20 mg/kg AMG 102 plus 10 mg/kg bevacizumab i.v. every 2 weeks, or 3 mg/kg AMG 102 i.v. every 2 weeks plus 75 mg motesanib orally once daily). RESULTS: Fourteen patients were enrolled and received AMG 102. The combination of AMG 102 with bevacizumab (n = 12) seemed to have acceptable toxicity. The number of patients (n = 2) who received AMG 102 plus motesanib was insufficient to adequately assess safety. No dose-limiting toxicities were reported. Enrollment in the motesanib cohort was suspended because of reports of cholecystitis in other motesanib studies. Treatment-emergent adverse events among patients receiving AMG 102 plus bevacizumab were generally mild and included fatigue (75%), nausea (58%), constipation (42%), and peripheral edema (42%). No anti-AMG 102 antibodies were detected. Bevacizumab did not seem to affect AMG 102 pharmacokinetics. Circulating total HGF/SF increased from baseline throughout the study. Eight of 10 evaluable patients had reductions in tumor dimensions, and stable disease at > or =8, > or =16, and > or =24 weeks occurred in 9, 7, and 4 patients, respectively. Progression-free survival ranged from 7.9 to 121.9 weeks. CONCLUSIONS: AMG 102 in combination with bevacizumab was well tolerated. Further evaluation of AMG 102 in combination with antiangiogenic agents is warranted.

Phase 1 first-in-human trial of the vascular disrupting agent plinabulin(NPI-2358) in patients with solid tumors or lymphomas.

PURPOSE: Plinabulin (NPI-2358) is a vascular disrupting agent that elicits tumor vascular endothelial architectural destabilization leading to selective collapse of established tumor vasculature. Preclinical data indicated plinabulin has favorable safety and antitumor activity profiles, leading to initiation of this clinical trial to determine the recommended phase 2 dose (RP2D) and assess the safety, pharmacokinetics, and biologic activity of plinabulin in patients with advanced malignancies. EXPERIMENTAL DESIGN: Patients received a weekly infusion of plinabulin for 3 of every 4 weeks. A dynamic accelerated dose titration method was used to escalate the dose from 2 mg/m² to the RP2D, followed by enrollment of an RP2D cohort. Safety, pharmacokinetic, and cardiovascular assessments were conducted, and Dynamic contrast-enhanced MRI (DCE-MRI) scans were performed to estimate changes in tumor blood flow. RESULTS: Thirty-eight patients were enrolled. A dose of 30 mg/m² was selected as the RP2D based on the adverse events of nausea, vomiting, fatigue, fever, tumor pain, and transient blood pressure elevations, with DCE-MRI indicating decreases in tumor blood flow (Ktrans) from 13.5 mg/m² (defining a biologically effective dose) with a 16% to 82% decrease in patients evaluated at 30 mg/m². Half-life was 6.06 ± 3.03 hours, clearance was 30.50 ± 22.88 L/h, and distributive volume was 211 ± 67.9 L. CONCLUSIONS: At the RP2D of 30 mg/m², plinabulin showed a favorable safety profile, while eliciting biological effects as evidenced by decreases in tumor blood flow, tumor pain, and other mechanistically relevant adverse events. On the basis of these results additional clinical trials were initiated with plinabulin in combination with standard chemotherapy agents.

A randomized comparison of every-2-week darbepoetin alfa and weekly epoetin alfa for the treatment of chemotherapy-induced anemia in patients with breast, lung, or gynecologic cancer.

An important clinical question is the relative efficacy of the most common dosages of darbepoetin alfa (Aranesp; Amgen Inc.; Thousand Oaks, CA) 200 microg every 2 weeks (Q2W) and epoetin alfa (Procrit; Ortho Biotech Products, LP; Raritan, NJ) 40,000 U weekly (QW) for the treatment of chemotherapy-induced anemia. We designed three concurrent randomized, open-label, multicenter, identical trials (with the exception of tumor type criteria of breast, gynecologic, or lung cancer) of darbepoetin alfa and epoetin alfa in patients with chemotherapy-induced anemia to validate the Patient Satisfaction Questionnaire for Anemia (PSQ-An) treatment tool and to compare the efficacies and safety profiles of these two agents. In each trial, patients were randomized 1:1 to receive either darbepoetin alfa at a dose of 200 microg Q2W or epoetin alfa at a dose of 40,000 U QW for up to 16 weeks. The PSQ-An was assessed for validity, feasibility, and reliability. Secondary clinical endpoints were analyzed using the primary analysis set. Both individual trial analyses and a protocol-specified combined analysis of data from all three trials were conducted. Overall, 312 patients (157 darbepoetin alfa; 155 epoetin alfa) were randomized and received study drug. Baseline characteristics were similar in both treatment groups in each trial and overall. The PSQ-An was valid, feasible, and reliable. In general, no difference between treatment groups was observed for hemoglobin- and transfusion-based endpoints in each individual trial or in the combined analysis. From exploratory analyses, achievement and maintenance of a hemoglobin target range (11-13 g/dl) were similar in both groups. No differences in safety were observed. With the PSQ-An, formal comparisons of the impact of anemia therapies on patients and caregivers can be made in future prospective studies. Further, darbepoetin alfa (200 microg Q2W) and epoetin alfa (40,000 U QW) appear to achieve comparable clinical and hematologic outcomes.

A randomized controlled trial of darbepoetin alfa administered as a fixed or weight-based dose using a front-loading schedule in patients with anemia who have nonmyeloid malignancies.

BACKGROUND: The effect of using fixed versus weight-based doses for erythropoietic agents has not been reported previously. To investigate this issue, the authors conducted a randomized Phase II study of darbepoetin alfa administered as either a fixed dose or a weight-based dose using an accelerated correction and maintenance dosing regimen (front-loading). METHODS: During the correction phase, patients with anemia (hemoglobin < 11.0 g/dL) who had nonmyeloid malignancies and who were receiving chemotherapy were given darbepoetin alfa at a fixed dose of 325 microg (n = 122) or at a weight-based dose of 4.5 microg/kg (n = 120) once weekly until they achieved a hemoglobin concentration > or = 12.0 g/dL. Patients then received darbepoetin alfa (325 microg or 4.5 microg/kg) once every 3 weeks for the remainder of the 16-week treatment period (maintenance phase). RESULTS: Darbepoetin alfa resulted in high Kaplan-Meier rates of hematopoietic response (> or = 2 g/dL increase from the baseline level or a hemoglobin level > or = 12 g/dL) in both the fixed-dose group (86%; 95% confidence interval [95% CI], 78- 94%) and the weight-based dose group (84%; 95% CI, 76-92%). The median time to hematopoietic response was 34 days (95% CI, 28-44 days) for the fixed-dose group and 36 days (95% CI, 30-45 days) for the weight-based dose group. Hemoglobin concentrations were maintained at target levels for up to 16 weeks in both groups. Darbepoetin alfa was well tolerated, and no clinically significant differences between fixed doses and weight-based doses were observed. CONCLUSIONS: Darbepoetin alfa was effective when administered as either a fixed dose or a weight-based dose using a front-loading approach to rapidly correct anemia and effectively maintain hemoglobin levels in patients with anemia who had malignant disease.