Lionel D. Lewis

Phase Ia/Ib trial of bispecific antibody MDX-210 in patients with advanced breast or ovarian cancer that overexpresses the proto-oncogene HER-2/neu.

PURPOSE MDX-210 is a bispecific antibody that binds simultaneously to type I Fc receptors for immunoglobulin G (IgG) (Fc gamma RI) and to the HER-2/neu oncogene protein product. MDX-210 effectively directs Fc gamma RI-positive effector cells such as monocytes and macrophages to phagocytose or kill tumor cells that overexpress HER-2/neu. The goals of this phase Ia/Ib trial were to determine the maximum-tolerated dose (MTD) and/or the optimal biologic dose (OBD) of MDX-210. PATIENTS AND METHODS Patients with advanced breast or ovarian cancer that overexpressed HER-2/neu were eligible for treatment. Cohorts of three patients received a single intravenous (IV) infusion of MDX-210 at increasing dose levels from 0.35 to 10.0 mg/m2. RESULTS Treatment was well tolerated, with most patients experiencing transient grade 1 to 2 fevers, malaise, and hypotension only. Two patients experienced transient grade 3 hypotension at 10.0 mg/m2. Transient monocytopenia and lymphopenia developed at 1 to 2 hours, but no other hematologic changes were observed. Doses of MDX-210 > or = 3.5 mg/m2 saturated > or = 80% of monocyte Fc gamma RI and produced peak plasma concentrations > or = 1 microgram/mL, which is greater than the concentration for optimal monocyte/macrophage activation in vitro. Elevated plasma levels of the monocyte products tumor necrosis factor alpha (TNF alpha), interleukin-6 (IL-6), granulocyte colony-stimulating factor (G-CSF), and neopterin were observed with maximal levels at doses > or = 7.0 mg/m2. Localization of MDX-210 in tumor tissue was demonstrated in two patients. One partial and one mixed tumor response were observed among 10 assessable patients. CONCLUSION MDX-210 is immunologically active at well-tolerated doses. The MTD and OBD is 7 to 10 mg/m2.

Phase I and Pharmacokinetic Study of Sorafenib in Patients With Hepatic or Renal Dysfunction: CALGB 60301

PURPOSE We sought to characterize the pharmacokinetics (PK) and determine a tolerable dose of oral sorafenib in patients with hepatic or renal dysfunction. PATIENTS AND METHODS Patients were assigned to one of nine cohorts: cohort 1, bilirubin < or = upper limit of normal (ULN) and AST < or = ULN and creatinine clearance (CC) > or = 60 mL/min; cohort 2, bilirubin more than ULN but < or = 1.5x ULN and/or AST more than ULN; cohort 3, CC between 40 and 59 mL/min; cohort 4, bilirubin more than 1.5x ULN to < or = 3x ULN (any AST); cohort 5, CC between 20 and 39 mL/min; cohort 6, bilirubin more than 3x ULN to 10x ULN (any AST); cohort 7, CC less than 20 mL/min; cohort 8, albumin less than 2.5 mg/dL (any bilirubin/AST); and cohort 9, hemodialysis. Sorafenib was administered as a 400-mg dose on day 1 for PK, and continuous daily dosing started on day 8. RESULTS Of 150 registered patients, 138 patients were treated. With the exception of cohorts 6 and 7, at least 12 patients per cohort were assessable, and the dose level with prospectively defined dose-limiting toxicity in less than one third of patients by day 29 was considered tolerable. No significant associations between the sorafenib PK and cohort were found. CONCLUSION We recommend the following empiric sorafenib starting doses by cohort: cohort 1, 400 mg twice a day; cohort 2, 400 mg twice a day; cohort 3, 400 mg twice a day; cohort 4, 200 mg twice a day; cohort 5, 200 mg twice a day; cohort 6, not even 200 mg every third day tolerable; cohort 7, not defined; cohort 8, 200 mg each day; and cohort 9, 200 mg each day.

Tumor cell targeting by iron oxide nanoparticles is dominated by different factors in vitro versus in vivo.

Realizing the full potential of iron oxide nanoparticles (IONP) for cancer diagnosis and therapy requires selective tumor cell accumulation. Here, we report a systematic analysis of two key determinants for IONP homing to human breast cancers: (i) particle size and (ii) active vs passive targeting. In vitro, molecular targeting to the HER2 receptor was the dominant factor driving cancer cell association. In contrast, size was found to be the key determinant of tumor accumulation in vivo, where molecular targeting increased tumor tissue concentrations for 30 nm but not 100 nm IONP. Similar to the in vitro results, PEGylation did not influence in vivo IONP biodistribution. Thus, the results reported here indicate that the in vitro advantages of molecular targeting may not consistently extend to pre-clinical in vivo settings. These observations may have important implications for the design and clinical translation of advanced, multifunctional, IONP platforms.

Immune response in patients with newly diagnosed glioblastoma multiforme treated with intranodal autologous tumor lysate-dendritic cell vaccination after radiation chemotherapy.

Patients with glioblastoma multiforme (GBM) are profoundly immunosuppressed and may benefit from restoration of an antitumor immune response in combination with conventional radiation therapy and temozolomide (TMZ). The optimal strategies to evaluate clinically relevant immune responses to treatment have yet to be determined. The primary objective of our study was to determine immunologic response to cervical intranodal vaccination with autologous tumor lysate-loaded dendritic cells (DCs) in patients with GBM after radiation therapy and TMZ. We used a novel hierarchical clustering analysis of immune parameters measured before and after vaccination. Secondary objectives were to assess treatment feasibility and to correlate immune response with progression-free survival (PFS) and overall survival. Ten eligible patients received vaccination. Tumor-specific cytotoxic T-cell response measured after vaccination was enhanced for the precursor frequency of CD4+ T and CD4+ interferon &ggr;-producing cells. Hierarchical clustering analysis of multiple functional outcomes discerned 2 groups of patients according to their immune response, and additionally showed that patients in the top quintile for at least one immune function parameter had improved survival. There were no serious adverse events related to DC vaccination. All patients were alive at 6 months after diagnosis and the 6-month PFS was 90%. The median PFS was 9.5 months and overall survival was 28 months. In patients with GBM, immune therapy with DC vaccination after radiation and TMZ resulted in tumor-specific immune responses that were associated with prolonged survival. Our data suggest that DC vaccination in combination with radiation and chemotherapy in patients with GBM is feasible, safe, and may induce tumor-specific immune responses.

Effects of Food on the Relative Bioavailability of Lapatinib in Cancer Patients

PURPOSE This study was conducted to characterize the effect of food on the relative bioavailability of lapatinib. PATIENTS AND METHODS A single 1,500-mg, oral dose of lapatinib was administered to 27 patients with advanced solid tumors on each of three occasions that were 1 week apart, in random order: after an overnight fast, with a low-fat breakfast, and with a high-fat breakfast. RESULTS The low-fat breakfast produced mean increases in lapatinib area under the concentration-time curve (AUC) of 167% (2.67-fold) and maximum concentration (C(max)) of 142% (2.42-fold). The high-fat breakfast produced mean increases in lapatinib AUC of 325% (4.25-fold) and C(max) of 203% (3.03-fold) compared with the fasted state. Increased bioavailability in the fed state did not significantly decrease relative variability. Therefore, absolute variability in systemic exposure was increased. CONCLUSION These large increases in lapatinib bioavailability and absolute variability support the recommendation for dosing in the fasted state to achieve consistent therapeutic exposure. Prescribers and patients should consider the potential consequences of toxicity or diminished efficacy that might result from dosing without regard to variations in diet.

Phase I study of twice-weekly gemcitabine and concomitant external-beam radiotherapy in patients with adenocarcinoma of the pancreas

PURPOSE To determine the maximum tolerated dose and dose-limiting toxicity associated with twice-weekly gemcitabine and concomitant external-beam radiotherapy in patients with adenocarcinoma of the pancreas. METHODS AND MATERIALS Twenty-one patients with biopsy-proven adenocarcinoma of the pancreas were treated with external-beam radiotherapy to a dose of 50.4 Gy in 28 fractions, concurrent with gemcitabine, infused over 30 min before irradiation on a Monday and Thursday schedule. The dose of gemcitabine was escalated in 5 cohorts of 3--6 patients each. Initial gemcitabine dose was 10 mg/m(2), with dose escalation until dose-limiting toxicity was observed. RESULTS The maximum tolerated dose of gemcitabine was 50 mg/m(2), when given in a twice-weekly schedule with radiation. Dose-limiting toxicity was seen in 2 patients at 60 mg/m(2), and consisted of severe upper gastrointestinal bleeding approximately 1 month after completion of treatment. Six patients had radiographic evidence of response to treatment, and 5 of these underwent complete surgical resection. Three patients who underwent complete resection had been deemed to have unresectable tumors before enrollment on trial. Four patients are alive, including 2 without evidence of disease more than 1 year after resection. CONCLUSION The combination of external-beam radiation and twice-weekly gemcitabine at a dose of 50 mg/m(2) is well tolerated and shows promising activity for the treatment of pancreatic cancer. Our data suggest a higher maximum tolerated dose and different dose-limiting toxicity than previously reported. Further investigation of this regimen is warranted.

Modulation of Cell Cycle Progression in Human Tumors: A Pharmacokinetic and Tumor Molecular Pharmacodynamic Study of Cisplatin Plus the Chk1 Inhibitor UCN-01 (NSC 638850)

Background: UCN-01, a Chk1 inhibitor, abrogates S and G2 arrest and enhances cancer cell killing by DNA-damaging drugs in preclinical models. UCN-01 avidly binds α1-acid glycoprotein in plasma; whether sufficient drug concentrations are achieved in human tumors is unknown. A phase I trial tested the hypothesis that UCN-01 abrogates cisplatin-induced cell cycle arrest (in tumors) at tolerable doses. Methods: Patients with advanced cancer received i.v. cisplatin, followed 22 hours later by UCN-01 (3-day continuous i.v. infusion of a 28-day cycle). Platinum was measured by atomic absorption, UCN-01 by high-performance liquid chromatography, and cell cycle progression in tumor biopsies by geminin immunostaining (biomarker for S/G2 phases of cell cycle). Results: The first two patients treated with cisplatin (20 mg/m2 plus UCN-01 45 mg/m2/d) experienced dose-limiting toxicities (subarachnoid hemorrhage, hyperglycemia, hypoxia, cardiac ischemia, and atrial fibrillation). Following 25% UCN-01 dose reduction, no toxicities greater than grade 2 were seen. Median plasma UCN-01 half-life (T1/2) was 405 hours. Salivary UCN-01 concentrations showed a rapid initial decline (median T1/2α, 29.9 hours), followed by a terminal decay parallel to that in plasma. UCN-01 pharmacokinetics, and the timing of clinical toxicities, suggests that UCN-01 is bioavailable despite α1-acid glycoprotein binding. Marked suppression of cells in S/G2 in tumor biopsies was seen by geminin immunohistochemistry, suggesting that UCN-01 is bioavailable at concentrations sufficient to inhibit Chk1. Conclusions: Cisplatin (30 mg/m2), followed 22 hours later by UCN-01 (34 mg/m2/d for 3 days), is well tolerated clinically and yields UCN-01 concentrations sufficient to affect cell cycle progression in tumors.

Suppression of human tumor cell proliferation through mitochondrial targeting

Intracellular calcium signaling plays a central role in cell proliferation. In leukemic cells, the calcium release‐activated calcium channels provide a major pathway for calcium entry (ICRAC) perpetuating progression through the cell cycle. Although ICRAC is under mitochondrial regulation, targeting mitochondrial function has not been exploited to control malignant cell growth. The benzothiadiazine diazoxide, which depolarized respiration‐dependent mitochondrial membrane potential, reduced the rate of proliferation and arrested human acute leukemic T cells in the G0/G1 phase. Diazoxide did not alter cellular energetics, but rather inhibited the mitochondria‐controlled ICRAC and reduced calcium influx into tumor cells. The antiproliferative action of diazoxide was mimicked by removal of extracellular calcium or by the tyrphostin A9, an ICRAC inhibitor. Deletion of the mitochondrial genome, which encodes essential respiratory chain enzyme subunits, attenuated the inhibitory effect of diazoxide on ICRAC‐mediated calcium influx and cell proliferation. Thus, manipulation of mitochondrial function and associated calcium signaling provides a basis for a novel anticancer strategy.—Holmuhamedov, E., Lewis, L., Bienengraeber, M., Holmuhamedova, M., Jahangir, A., Terzic, A. Suppression of human tumor cell proliferation through mitochondrial targeting. FASEB J. 16, 1010–1016 (2002)

Asymptomatic QTc prolongation associated with quetiapine fumarate overdose in a patient being treated with risperidone

We report a patient who ingested a 2000-mg overdose of quetiapine fumarate (Seroquel3™5). Her maintenance medications also included risperidone, venlafaxine, topiramate, and clonazepam. On presentation, she was drowsy, but had no other significant CNS signs and no cardiac symptoms or abnormal physical signs. Approximately 2 h after the quetiapine ingestion, an electrocardiogram (ECG) showed normal sinus rhythm at 95 beats/min with a corrected QT (QTc) interval of 537 ms (upper limit of normal = 440 ms). Plasma quetiapine concentration at that time was 1800 ng/ml. Continuous ECG monitoring for the subsequent 18 h did not reveal any episode of ventricular tachycardia. A 12-lead ECG 18 h post-overdose was normal with a QTc interval of 401 ms and the corresponding plasma quetiapine concentra-tion was 160 ng/ml. She made an uneventful medical recovery from the toxic ingestion. This case suggests that when patients overdose on quetiapine while taking therapeutic doses of risperidone, such overdoses, even if not massive, can cause considerable QTc interval prolongation. We recommend that quetiapine overdose patients undergo continuous ECG monitoring for 12-18 h post-ingestion.

Phase I Study of the Safety, Tolerability, and Pharmacokinetics of Oral CP-868,596, a Highly Specific Platelet-Derived Growth Factor Receptor Tyrosine Kinase Inhibitor in Patients With Advanced Cancers

PURPOSE This phase I, first-in-human study evaluated the safety, tolerability, pharmacokinetics, and maximum-tolerated dose (MTD) of an oral platelet-derived growth factor receptor inhibitor, CP-868,596. PATIENTS AND METHODS Patients with advanced solid tumors were eligible. Dose escalations were performed in three groups with two formulations: uncoated on an empty stomach (UES), uncoated with food (UFED), and film-coated (FC) without food. Initial dose escalation in the UES group was followed by parallel escalations in the UFED and FC groups. RESULTS Fifty-nine patients enrolled. CP-868,596 was escalated from 100 mg to 340 mg daily in the UES group, from 60 mg to 100 mg twice daily in the UFED group, and from 100 mg once daily to 140 mg twice daily in the FC group. MTDs were 200 mg daily in the UES group and 100 mg twice daily in the FC group; MTD was not reached at 100 mg twice daily in the UFED group. Dose-limiting toxicities included hematuria, increased gamma-glutamyltransferase or ALT, insomnia, and nausea/vomiting. Most treatment-related AEs were of grades 1 to 2 severity; nausea, vomiting, and diarrhea were reported most frequently. Administration with food generally improved tolerability. CP-868,596 was absorbed slowly; systemic exposure parameters appeared to increase greater than proportionally with dose. Mean serum concentrations exceeded the preclinically predicted minimal efficacious concentration (ie, 16 ng/mL) at all dosages. Food and film coating apparently increased interpatient variability of the maximum observed plasma concentration and the area under the concentration-time curve. No objective responses were reported, and eight patients achieved stable disease (mean duration, 5.7 months). CONCLUSION CP-868,596 potentially demonstrated greater than dose-proportional pharmacokinetics. The recommended dosage of 100 mg twice daily with food was well tolerated. Additional development as a single agent in selected populations or in combination with chemotherapy in broader populations is warranted.