Mohammed M. Dar

Targeted anti-mitotic therapies: can we improve on tubulin agents?

The advent of molecularly targeted drug discovery has facilitated the identification of a new generation of anti-mitotic therapies that target proteins with specific functions in mitosis. The exquisite selectivity for mitosis and the distinct ways in which these new agents interfere with mitosis provides the potential to not only overcome certain limitations of current tubulin-targeted anti-mitotic drugs, but to expand the scope of clinical efficacy that those drugs have established. The development of these new anti-mitotic drugs as targeted therapies faces significant challenges; nevertheless, these potential therapies also serve as unique tools to dissect the molecular mechanisms of the mitotic-checkpoint response.

Phase I Study of GSK461364, a Specific and Competitive Polo-like Kinase 1 Inhibitor, in Patients with Advanced Solid Malignancies

Purpose: GSK461364 is an ATP-competitive inhibitor of polo-like kinase 1 (Plk1). A phase I study of two schedules of intravenous GSK461364 was conducted. Experimental Design: GSK461364 was administered in escalating doses to patients with solid malignancies by two schedules, either on days 1, 8, and 15 of 28-day cycles (schedule A) or on days 1, 2, 8, 9, 15, and 16 of 28-day cycles (schedule B). Assessments included pharmacokinetic and pharmacodynamic profiles, as well as marker expression studies in pretreatment tumor biopsies. Results: Forty patients received GSK461364: 23 patients in schedule A and 17 in schedule B. Dose-limiting toxicities (DLT) in schedule A at 300 mg (2 of 7 patients) and 225 mg (1 of 8 patients) cohorts included grade 4 neutropenia and/or grade 3–4 thrombocytopenia. In schedule B, DLTs of grade 4 pulmonary emboli and grade 4 neutropenia occurred at 7 or more days at 100 mg dose level. Venous thrombotic emboli (VTE) and myelosuppression were the most common grade 3–4, drug-related events. Pharmacokinetic data indicated that AUC (area under the curve) and C max (maximum concentration) were proportional across doses, with a half-life of 9 to 13 hours. Pharmacodynamic studies in circulating tumor cells revealed an increase in phosphorylated histone H3 (pHH3) following drug administration. A best response of prolonged stable disease of more than 16 weeks occurred in 6 (15%) patients, including 4 esophageal cancer patients. Those with prolonged stable disease had greater expression of Ki-67, pHH3, and Plk1 in archived tumor biopsies. Conclusions: The final recommended phase II dose for GSK461364 was 225 mg administered intravenously in schedule A. Because of the high incidence (20%) of VTE, for further clinical evaluation, GSK461364 should involve coadministration of prophylactic anticoagulation. Clin Cancer Res; 17(10); 3420–30. ©2011 AACR.

Clinical and Biological Effects of Recombinant Human Interleukin-18 Administered by Intravenous Infusion to Patients with Advanced Cancer

Purpose: Interleukin-18 (IL-18) is an immunostimulatory cytokine with antitumor activity in preclinical animal models. A phase I study of recombinant human IL-18 (rhIL-18) was done to determine the toxicity, pharmacokinetics, and biological activities of rhIL-18 in patients with advanced cancer. Experimental Design: Cohorts of patients were given escalating doses of rhIL-18, each administered as a 2-hour i.v. infusion on 5 consecutive days. Toxicities were graded using standard criteria. Serial blood samples were obtained for pharmacokinetic and pharmacodynamic measurements. Results: Twenty-eight patients (21 with renal cell cancer, 6 with melanoma, and 1 with Hodgkins lymphoma) were given rhIL-18 in doses ranging from 3 to 1,000 μg/kg. Common side effects included chills, fever, nausea, headache, and hypotension. Common laboratory abnormalities included transient, asymptomatic grade 1 to 2 neutropenia, thrombocytopenia, anemia, hypoalbuminemia, hyponatremia, and elevations in liver transaminases. One patient in the 100 μg/kg cohort experienced transient grade 3 hypotension and grade 2 bradycardia during the first infusion of rhIL-18. No other dose-limiting toxicities were observed. Plasma concentrations of rhIL-18 increased with increasing dose, and 2.5-fold accumulation was observed with repeated dosing. Biological effects of rhIL-18 included transient lymphopenia and increased expression of activation antigens on lymphocytes and monocytes. Increases in serum concentrations of IFN-γ, granulocyte macrophage colony-stimulating factor, IL-18 binding protein, and soluble Fas ligand were observed. Two patients experienced unconfirmed partial responses after rhIL-18 treatment. Conclusions: rhIL-18 can be safely given in biologically active doses to patients with advanced cancer. A maximum tolerated dose of rhIL-18 was not determined. Further clinical studies of rhIL-18 are warranted.

A Phase I/II Trial of Pazopanib in Combination with Lapatinib in Adult Patients with Relapsed Malignant Glioma

Purpose: Increased mitogenic signaling and angiogenesis, frequently facilitated by somatic activation of EGF receptor (EGFR; ErbB1) and/or loss of PTEN, and VEGF overexpression, respectively, drive malignant glioma growth. We hypothesized that patients with recurrent glioblastoma would exhibit differential antitumor benefit based on tumor PTEN/EGFRvIII status when treated with the antiangiogenic agent pazopanib and the ErbB inhibitor lapatinib. Experimental Design: A phase II study evaluated the antitumor activity of pazopanib 400 mg/d plus lapatinib 1,000 mg/d in patients with grade 4 malignant glioma and known PTEN/EGFRvIII status not receiving enzyme-inducing anticonvulsants (EIAC). The phase II study used a two-stage Green–Dahlberg design for futility. An independent, parallel phase I component determined the maximum-tolerated regimen (MTR) of pazopanib and lapatinib in patients with grade 3/4 glioma receiving EIACs. Results: The six-month progression-free survival (PFS) rates in phase II (n = 41) were 0% and 15% in the PTEN/EGFRvIII-positive and PTEN/EGFRvIII-negative cohorts, respectively, leading to early termination. Two patients (5%) had a partial response and 14 patients (34%) had stable disease lasting 8 or more weeks. In phase I (n = 34), the MTR was not reached. On the basis of pharmacokinetic and safety review, a regimen of pazopanib 600 mg plus lapatinib 1,000 mg, each twice daily, was considered safe. Concomitant EIACs reduced exposure to pazopanib and lapatinib. Conclusions: The antitumor activity of this combination at the phase II dose tested was limited. Pharmacokinetic data indicated that exposure to lapatinib was subtherapeutic in the phase II evaluation. Evaluation of intratumoral drug delivery and activity may be essential for hypothesis-testing trials with targeted agents in malignant glioma. Clin Cancer Res; 19(4); 900–8. ©2012 AACR.

Response to a Novel Multitargeted Tyrosine Kinase Inhibitor Pazopanib in Metastatic Merkel Cell Carcinoma

A 69-year-old woman presented with a 2-year history of gradually increasing scalp swelling in December 2001. The patient was in good general condition, but physical examination revealed a 5-cm fleshy tumor on the right scalp, with pathology consistent with Merkel cell carcinoma on excisional biopsy. A metastatic work-up, including computed tomography (CT) of the thorax and abdomen, mammography, and gastroscopy, was negative, and the patient underwent a subsequent wide excision with superficial skin graft. No adjuvant radiotherapy was administered at this time. In August 2002, the patient had a local recurrence of a bulky 12-cm mass fixed to the skull, and biopsies of the right upper deep cervical and supraclavicular lymph nodes were inconclusive for involvement. The tumor was inoperable, and the patient underwent radical radiotherapy for a total of 70 Gy, with excellent response at all tumor sites. In March 2003, two small nodules developed in the field, which were believed to represent either soft tissue radionecrosis or possibly a second local recurrence. In October 2003, the patient underwent repeat wide excision with right level II to V neck dissection for nodal and scalp tumor recurrence. Histopathologic examination of the tissue revealed Merkel cell carcinoma with eight of 19 positive lymph nodes and negative margins. The tissue was strongly positive for neuron-specific enolase, with cytoplasmic and perinuclear dot positive for AE1/3, CAM5.2, and epithelial membrane antigen (Fig 1A). Synaptophysin was focally positive, whereas S-100 protein was weakly staining, and chromogranin was negative. CT of the thorax/abdomen revealed multiple pulmonary lesions consistent with metastatic disease. The patient was given six cycles of carboplatin with etoposide, and achieved a partial response. In July 2004, a 1.6 1.2 cm right neck mass developed just deep to the flap with a necrotic center at C2-C3, and the pulmonary metastases also showed progression on follow-up CT. The patient underwent repeat wide excision of the neck mass, and postoperative chemotherapy was begun with weekly paclitaxel. Stable disease was maintained until December 2004, when pulmonary metastases progressed, and a 2.3-cm subcarinal lymph node was noted on CT. The patient enrolled onto a clinical trial of tegafur, 5-chloro-2,4dihydroxypyridine, and oxonic acid (S1) at 30 mg/m twice daily. A partial response of the pulmonary metastases was achieved, and the patient continued to receive S1 for 35 cycles until relapse occurred in December 2006, with a 1.5-cm nodule above the right ear. Fine-needle aspiration of the nodule was consistent with Merkel cell carcinoma. The patient was observed closely until April 2007, when the right ear mass had grown to 3.5 cm, and pulmonary metastases had progressed on CT imaging. The patient was enrolled onto a clinical trial of a novel multitargeted tyrosine kinase inhibitor pazopanib at 800 mg daily after written informed consent was provided according to institutional guidelines. Consent to use her data for this report was obtained and A B

A phase I trial of ispinesib, a kinesin spindle protein inhibitor, with docetaxel in patients with advanced solid tumours.

The aim of this study is to define the maximum tolerated dose (MTD), safety, pharmacokinetics (PKs) and efficacy of ispinesib (SB-715992) in combination with docetaxel. Patients with advanced solid tumours were treated with ispinesib (6–12u2009mgu2009m−2) and docetaxel (50–75u2009mgu2009m−2). Docetaxel was administered over 1u2009h followed by a 1-h infusion of ispinesib on day 1 of a 21-day schedule. At least three patients were treated at each dose level. Blood samples were collected during cycle 1 for PK analysis. Clinical response assessments were performed every two cycles using RECIST guidelines. Twenty-four patients were treated at four dose levels. Prolonged neutropaenia and febrile neutropaenia were dose limiting in six and two patients, respectively. The MTD was ispinesib 10u2009mgu2009m−2 with docetaxel 60u2009mgu2009m−2. Pharmacokinetic assessment demonstrated concentrations of ispinesib and docetaxel, consistent with published data from single agent studies of the drugs. Seven patients (six hormone refractory prostate cancer (HRPC), one renal cancer) had a best response of stable disease (⩾18 weeks). One patient with HRPC had a confirmed >50% prostatic-specific antigen decrease. The MTD for ispinesib and docetaxel was defined and the combination demonstrated an acceptable toxicity profile. Preliminary PK data suggest no interaction between ispinesib and docetaxel.

A Dose-Escalation Study of Recombinant Human Interleukin-18 Using Two Different Schedules of Administration in Patients with Cancer

Purpose: Interleukin-18 (IL-18) is an immunostimulatory cytokine with antitumor activity in preclinical models. A phase I study of recombinant human IL-18 (rhIL-18) was done to determine the toxicity, pharmacokinetics, and biological activities of rhIL-18 administered at different doses in two different schedules to patients with advanced cancer. Experimental Design: Cohorts of three to four patients were given escalating doses of rhIL-18 as a 2-h i.v. infusion either on 5 consecutive days repeated every 28 days (group A) or once a week (group B) for up to 6 months. Toxicities were graded using standard criteria. Blood samples were obtained for safety, pharmacokinetic, and pharmacodynamic measurements. Results: Nineteen patients (10 melanoma and 9 renal cell cancer) were given rhIL-18 in doses of 100, 500, or 1,000 μg/kg (group A) or 100, 1,000, or 2,000 μg/kg (group B). Common side effects included chills, fever, headache, fatigue, and nausea. Common laboratory abnormalities included transient, asymptomatic grade 1 to 3 lymphopenia, grade 1 to 4 hyperglycemia, grade 1 to 2 anemia, neutropenia, hypoalbuminemia, liver enzyme elevations, and serum creatinine elevations. No dose-limiting toxicities were observed. Biological effects of rhIL-18 included transient lymphopenia and increased expression of activation antigens on lymphocytes. Increases in serum concentrations of IFN-γ, granulocyte macrophage colony-stimulating factor, and IL-18–binding protein were observed following dosing. Conclusions: rhIL-18 can be given in biologically active doses by either weekly infusions or daily infusions for 5 days repeated every 28 days to patients with advanced cancer. Toxicity was generally mild to moderate, and a maximum tolerated dose of rhIL-18 by either schedule was not determined.

A first in human study of SB-743921, a kinesin spindle protein inhibitor, to determine pharmacokinetics, biologic effects and establish a recommended phase II dose

PurposeTo determine the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), safety, pharmacokinetics, and pharmacodynamics of SB-743921 when administered as a 1-h infusion every 21xa0days to patients with advanced solid tumors or relapsed/refractory lymphoma.MethodsPatients who failed prior standard therapy or those without any standard options were eligible. Forty-four patients were enrolled using an initial accelerated dose-escalation phase followed by a standard dose-escalation phase. An additional 20 patients were enrolled at the recommended phase II dose to obtain additional safety and pharmacokinetic data. The doses evaluated ranged from 2 to 8xa0mg/m2. The pharmacokinetics of SB-743921 was evaluated at 19 time-points over 48xa0h following during administration during cycle 1. Toxicity was assessed by the NCI Common Terminology Criteria version 3.0. Response evaluation was performed every 6xa0weeks.ResultsThe most common and consistent DLT was neutropenia. Other DLTs observed included hypophosphatemia, pulmonary emboli, SVC syndrome, transaminitis, hyponatremia, and hyperbilirubinemia. The MTD of SB-743921 as a 1-h infusion every 21xa0days was established as 4xa0mg/m2. The maximum plasma concentration and area under the plasma concentration time curve appeared to increase proportionally to dose. One durable objective response was seen in a patient with metastatic cholangiocarcinoma who was on treatment 11xa0months and 6 patients had stable disease for over four cycles.ConclusionsThe recommended phase II dose of SB-743921 on this specific schedule of a 1-h infusion every 3xa0weeks is 4xa0mg/m2. The promising efficacy and lack of severe toxicities in this study warrant the continued development of SB-743921.

A randomized, double-blind, placebo-controlled study to evaluate the effect of repeated oral doses of pazopanib on cardiac conduction in patients with solid tumors

PurposeAs tyrosine kinase inhibitors have been associated with cardiotoxicity, we evaluated the effect of pazopanib, an inhibitor of vascular endothelial growth factor receptor, platelet-derived growth factor receptor, and c-Kit, on electrocardiographic parameters in patients with cancer.MethodsThis double-blind, placebo-controlled, parallel-group study randomized patients (Nxa0=xa096) to moxifloxacin (positive control) or placebo on Day 1 followed by pazopanib or placebo 800xa0mg/day (fasted) on Days 2–8 and 1,600xa0mg (with food) on Day 9. Treatment effects were evaluated by baseline-adjusted, time-matched, serial Holter electrocardiograms.ResultsSixty-five patients were evaluable for preplanned analyses. On Day 1, the maximum mean difference in baseline-adjusted, time-matched Fridericia-corrected QT (QTcF) interval in moxifloxacin-treated patients versus placebo was 10.6xa0ms (90xa0% confidence interval [CI]: 4.2, 17.0). The administration scheme increased plasma pazopanib concentrations approximately 1.3- to 1.4-fold versus the recommended 800xa0mg once-daily dose. Pazopanib caused clinically significant increases from baseline in blood pressure, an anticipated class effect, and an unexpected reduction in heart rate from baseline that correlated with pazopanib exposure. On Day 9, the maximum mean difference in baseline-adjusted, time-matched QTcF interval in pazopanib-treated patients versus placebo was 4.4xa0ms (90xa0% CI: −2.4, 11.2). Mixed-effects modeling indicated no significant concentration-dependent effect of pazopanib or its metabolites on QTcF interval.ConclusionsPazopanib as administered in this study achieved supratherapeutic concentrations, produced a concentration-dependent decrease in heart rate, and caused a small, concentration-independent prolongation of the QTcF interval.

Phase I Study of Pazopanib in Combination with Weekly Paclitaxel in Patients with Advanced Solid Tumors

PURPOSEnTo evaluate the maximum tolerated regimen (MTR), dose-limiting toxicities, and pharmacokinetics of pazopanib, an oral small-molecule tyrosine kinase inhibitor of vascular endothelial growth factor receptor, platelet-derived growth factor receptor, and c-Kit, in combination with paclitaxel.nnnPATIENTS AND METHODSnPazopanib was given daily with weekly paclitaxel on days 1, 8, and 15 every 28 days. Dose levels of pazopanib (mg/day)/paclitaxel (mg/m(2)) were 400/15, 800/15, 800/50, and 800/80. An expanded cohort was enrolled at the MTR. Plasma samples were collected to evaluate the effect of pazopanib, an inhibitor of cytochrome P450 (CYP)3A4, on the pharmacokinetics of paclitaxel, a CYP3A4 and CYP2C8 substrate.nnnRESULTSnOf 26 enrolled patients, 17 were treated at the MTR of 800 mg pazopanib and 80 mg/m(2) paclitaxel. Dose-limiting toxicities included a grade 3 abscess and grade 2 hyperbilirubinemia. Other toxicities included elevated liver transaminases and diarrhea. Six patients (23%) had partial responses and 15 patients (58%) had stable disease. Administration of 800 mg pazopanib resulted in a 14% lower paclitaxel clearance and a 31% higher paclitaxel maximal concentration than with administration of paclitaxel alone at 15, 50, and 80 mg/m(2). At the MTR, coadministration of 800 mg pazopanib and 80 mg/m(2) paclitaxel resulted in a 26% higher geometric mean paclitaxel area under the curve.nnnCONCLUSIONnPazopanib, at a dose of 800 mg daily, can be safely combined with a therapeutic dose of paclitaxel at 80 mg/m(2) when administered on days 1, 8, and 15, every 28 days. The observed greater plasma concentrations of paclitaxel given concurrently with pazopanib suggest that pazopanib is a weak inhibitor of CYP3A4 and CYP2C8.