Jeffrey A. Silverman

Marqibo (vincristine sulfate liposome injection) improves the pharmacokinetics and pharmacodynamics of vincristine

Vincristine (VCR) is a mainstay of treatment of hematologic malignancies and solid tumors due to its well-defined mechanism of action, demonstrated anticancer activity and its ability to be combined with other agents. VCR is an M-phase cell cycle-specific anticancer drug with activity that is concentration and exposure duration dependent. The pharmacokinetic profile of standard VCR is described by a bi-exponential elimination pattern with a very fast initial distribution half-life followed by a longer elimination half-life. VCR also has a large volume of distribution, suggesting diffuse distribution and tissue binding. These properties may limit optimal drug exposure and delivery to target tissues as well as clinical utility as a single agent or as an effective component of multi-agent regimens. Vincristine sulfate liposome injection (VSLI), Marqibo®, is a sphingomyelin and cholesterol-based nanoparticle formulation of VCR that was designed to overcome the dosing and pharmacokinetic limitations of standard VCR. VSLI was developed to increase the circulation time, optimize delivery to target tissues and facilitate dose intensification without increasing toxicity. In xenograft studies in mice, VSLI had a higher maximum tolerated dose, superior antitumor activity and delivered higher amounts of active drug to target tissues compared to standard VCR. VSLI recently received accelerated FDA approval for use in adults with advanced, relapsed and refractory Philadelphia chromosome-negative ALL and is in development for untreated adult ALL, pediatric ALL and untreated aggressive NHL. Here, we summarize the nonclinical data for VSLI that support its continued clinical development and recent approval for use in adult ALL.

High-Dose Vincristine Sulfate Liposome Injection for Advanced, Relapsed, and Refractory Adult Philadelphia Chromosome–Negative Acute Lymphoblastic Leukemia

PURPOSE Relapsed adult acute lymphoblastic leukemia (ALL) is associated with high reinduction mortality, chemotherapy resistance, and rapid progression leading to death. Vincristine sulfate liposome injection (VSLI), sphingomyelin and cholesterol nanoparticle vincristine (VCR), facilitates VCR dose-intensification and densification plus enhances target tissue delivery. We evaluated high-dose VSLI monotherapy in adults with Philadelphia chromosome (Ph) -negative ALL that was multiply relapsed, relapsed and refractory to reinduction, and/or relapsed after hematopoietic cell transplantation (HCT). PATIENTS AND METHODS Sixty-five adults with Ph-negative ALL in second or greater relapse or whose disease had progressed following two or more leukemia therapies were treated in this pivotal phase II, multinational trial. Intravenous VSLI 2.25 mg/m(2), without dose capping, was administered once per week until response, progression, toxicity, or pursuit of HCT. The primary end point was achievement of complete response (CR) or CR with incomplete hematologic recovery (CRi). RESULTS The CR/CRi rate was 20% and overall response rate was 35%. VSLI monotherapy was effective as third-, fourth-, and fifth-line therapy and in patients refractory to other single- and multiagent reinduction therapies. Median CR/CRi duration was 23 weeks (range, 5 to 66 weeks); 12 patients bridged to a post-VSLI HCT, and five patients were long-term survivors. VSLI was generally well tolerated and associated with a low 30-day mortality rate (12%). CONCLUSION High-dose VSLI monotherapy resulted in meaningful clinical outcomes including durable responses and bridging to HCT in advanced ALL settings. The toxicity profile of VSLI was predictable, manageable, and comparable to standard VCR despite the delivery of large, normally unachievable, individual and cumulative doses of VCR.

Discovery of a potent and selective aurora kinase inhibitor.

This communication describes the discovery of a novel series of Aurora kinase inhibitors. Key SAR and critical binding elements are discussed. Some of the more advanced analogues potently inhibit cellular proliferation and induce phenotypes consistent with Aurora kinase inhibition. In particular, compound 21 (SNS-314) is a potent and selective Aurora kinase inhibitor that exhibits significant activity in pre-clinical in vivo tumor models.

Metabolism of (+)-1,4-Dihydro-7-(trans-3-methoxy-4-methylamino-1-pyrrolidinyl)-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic Acid (Voreloxin; Formerly SNS-595), a Novel Replication-Dependent DNA-Damaging Agent

(+)-1,4-Dihydro-7-(trans-3-methoxy-4-methylamino-1-pyrrolidinyl)-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acid (voreloxin; formerly SNS-595 or AG-7352) is currently under investigation for the treatment of platinum-resistant ovarian cancer and acute myeloid leukemia. In vitro voreloxin undergoes minimal cytochrome P450 (P450) and UDP glucuronosyltransferase (UGT)-mediated metabolism, and in vivo excretion of unchanged voreloxin as the major species is consistent with the slow rate of metabolism observed in vitro. The objective of the present study was to examine the cross-species metabolic profile of voreloxin and to identify and characterize the metabolites formed in rats. We also investigated baculovirus-expressed human P450s and UGTs to determine which isoforms participated in voreloxin metabolism. Incubations using human, monkey, and rat liver microsomes showed monkey and rat metabolism is similar to human. Voreloxin and metabolites collected from plasma, bile, and urine from rats administered radiolabeled voreloxin were separated by high-performance liquid chromatography, and their structures were elucidated by liquid chromatography/tandem mass spectrometry. Activity of metabolites was determined with authentic reference standards in cell-based cytotoxicity assays. The proposed structures of metabolites suggest that metabolic pathways for voreloxin include glucuronide conjugation, oxidation, N-dealkylation, and O-dealkylation.

Discovery and Development of Potent LFA-1/ICAM-1 Antagonist SAR 1118 as an Ophthalmic Solution for Treating Dry Eye

LFA-1/ICAM-1 interaction is essential in support of inflammatory and specific T-cell regulated immune responses by mediating cell adhesion, leukocyte extravasation, migration, antigen presentation, formation of immunological synapse, and augmentation of T-cell receptor signaling. The increase of ICAM-1 expression levels in conjunctival epithelial cells and acinar cells was observed in animal models and patients diagnosed with dry eye. Therefore, it has been hypothesized that small molecule LFA-1/ICAM-1 antagonists could be an effective topical treatment for dry eye. In this letter, we describe the discovery of a potent tetrahydroisoquinoline (THIQ)-derived LFA-1/ICAM-1 antagonist (SAR 1118) and its development as an ophthalmic solution for treating dry eye.

2-Aminobenzimidazoles as potent Aurora kinase inhibitors

This Letter describes the discovery and key structure-activity relationship (SAR) of a series of 2-aminobenzimidazoles as potent Aurora kinase inhibitors. 2-Aminobenzimidazole serves as a bioisostere of the biaryl urea residue of SNS-314 (1c), which is a potent Aurora kinase inhibitor and entered clinical testing in patients with solid tumors. Compared to SNS-314, this series of compounds offers better aqueous solubility while retaining comparable in vitro potency in biochemical and cell-based assays; in particular, 6m has also demonstrated a comparable mouse iv PK profile to SNS-314.

Voreloxin, a first-in-class anticancer quinolone derivative, in relapsed/refractory solid tumors: a report on two dosing schedules.

Purpose: Voreloxin, a novel replication-dependent DNA-damaging agent, intercalates DNA and inhibits topoisomerase II. Voreloxin induces site-selective DNA double-strand breaks and apoptosis. We report the phase 1 experience of voreloxin in patients with relapsed/refractory solid tumors, including dose-limiting toxicity (DLT), maximum-tolerated dose (MTD), pharmacokinetics, and clinical activity. Experimental Design: Two dose-escalation studies evaluated voreloxin administered i.v. every 3 weeks (SPO-0001) or weekly for 3 weeks every 28 days (SPO-0002). In SPO-0001, patients were classified as heavily pretreated (HP) or minimally pretreated (MP) based on therapeutic history. Results: In the SPO-0001 study, 41 patients (24 HP/17 MP) were treated in eight dose cohorts (3-75 mg/m2). At 60 mg/m2, four HP patients experienced DLTs: grade 4 neutropenia (n = 3, one with fever) and grade 3 febrile neutropenia/pneumonia (n = 1). At 75 mg/m2, two MP patients experienced DLTs: grade 4 neutropenia/thrombocytopenia (n = 1) or grade 2 oral thrush for >29 days (n = 1). Therefore, the MTD was 48 mg/m2 (HP patients) and 60 mg/m2 (MP patients). In the SPO-0002 study, 21 patients were treated in six dose cohorts (3-24 mg/m2). At 18 mg/m2, two patients experienced DLTs: grade 3 neutropenia, one with pleural effusion (>14 days each). The MTD was 15 mg/m2. Voreloxin exhibited low clearance (2 L/h/m2), a long terminal half-life (22 hours), and dose-proportional exposure. Overall, 31 of 62 patients had stable disease and 1 patient (ovarian cancer) had a partial response per Rustin criteria. Conclusions: Voreloxin showed an acceptable safety profile with clinical activity in patients with relapsed/refractory solid tumors. The MTD was schedule-dependent. Voreloxin is currently in clinical studies of ovarian cancer and acute myeloid leukemia. Clin Cancer Res; 16(7); 2167–75. ©2010 AACR.

Water-soluble prodrugs of an Aurora kinase inhibitor.

Compound 1 (SNS-314) is a potent and selective Aurora kinase inhibitor that is currently in clinical trials in patients with advanced solid tumors. This communication describes the synthesis of prodrug derivatives of 1 with improved aqueous solubility profiles. In particular, phosphonooxymethyl-derived prodrug 2g has significantly enhanced solubility and is converted to the biologically active parent (1) following iv as well as po administration to rodents.

Pharmacokinetics and Safety of Marqibo (Vincristine Sulfate Liposomes Injection) in Cancer Patients With Impaired Liver Function

Marqibo (vincristine sulfate liposome injection, VSLI) is a novel liposomal formulation of vincristine sulfate (VCR) being developed for the systemic treatment of cancer. This study evaluated the pharmacokinetics (PK) of Marqibo in subjects with melanoma and impaired hepatic function. Calculated PK parameters were similar in subjects with impaired liver function compared with those in subjects with adequate liver function. Subjects with impaired liver function universally had a monoexponential total plasma VCR concentration versus time decline, whereas two thirds of subjects with adequate liver function had a biexponential decline profile. Because one third of subjects with normal hepatic function demonstrated monoexponential disposition, lack of biexponential disposition in the hepatically impaired subjects cannot be clearly attributed to liver impairment. VSLI was generally well tolerated in all subjects.

Long term results of a phase 2 study of vincristine sulfate liposome injection (Marqibo®) substituted for non-liposomal vincristine in cyclophosphamide, doxorubicin, vincristine, prednisone with or without rituximab for patients with untreated aggressive non-Hodgkin lymphomas

Vincristine sulfate liposome injection (VSLI; Marqibo®; M) is active in relapsed and refractory lymphomas, and approved in the United States for relapsed and refractory adult acute lymphocytic leukaemia. We evaluated VSLI (2·0 mg/m2 without dose cap) substituted for non‐liposomal vincristine (VCR) in a cyclophosphamide, doxorubicin, vincristine, prednisone ± ritiximab (CHOP±R) regimen, creating CHMP±R in 72 untreated, aggressive non‐Hodgkin lymphoma patients, including 60 with diffuse large B‐cell lymphoma (DLBCL). The overall response rate was 96% (69/72) including complete response (CR) in 65 (90%) and unconfirmed CR in 2 (3%). Median progression‐free survival (PFS) and overall survival (OS) were not reached at median follow‐up of 8 and 10·2 years, respectively. The 5‐ and 10‐year PFS and OS were 75%, 63%, 87%, and 77%, respectively. Despite VSLI exposure of up to 35 mg, the safety profile of CHMP±R was comparable to that reported for CHOP±R. Grade 3 peripheral neuropathy was reported in 2 (3%) patients; there was no reported Grade 3/4 constipation. CHMP±R was highly active, generally well tolerated, and compared favourably to historical trials with R‐CHOP in DLBCL. This enhanced activity probably reflects VCR dose intensification, pharmacokinetic optimization, and enhanced delivery afforded by VSLI. A Phase 3 trial of R‐CHMP versus R‐CHOP in elderly patients with untreated DLBCL is ongoing.