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ABSTRACT: Introduction: Vascular-disrupting agents (VDAs) are a new class of oncology drugs, which specifically target established tumor neovasculature and have a relatively low toxicity profile. VDAs generally have non-overlapping side effects when concomitantly used with conventional cytotoxics. Several members of the VDA class have recently progressed through mid-to-late stages of clinical trials. Areas covered: We examined recent publications on preclinical findings and Phase I/II/III clinical trial data on mechanisms of actions, toxicities, and optimal use of VDA class drugs. It is becoming apparent that VDAs should be used in combination with other classes of cytotoxic agents for the optimization of their effect in treating various cancers. In this article we describe doses, timing of delivery, and sequence of combined therapy. We also address the combined mechanisms of actions of VDAs and conventional cytotoxic medications. Expert opinion: Vascular-disrupting agents represent a new class of promising anticancer agents, which exhibit synergistic and/or additive effects in combination with many conventional cytotoxics. Pharmacological evaluation of the optimal combinations of VDAs with agents of other classes and drug interactions need to be continued. Further clinical and preclinical studies are required for distinguishing cancer patients' subpopulations that would most benefit from VDAs, identifying tumor biomarkers predictive of response as well as reliable and reproducible imaging and/or biological assays indicative of pharmacodynamic effects, and establishing clinical algorithms for treatment.
Expert Opinion on Investigational Drugs 01/2013; · 5.27 Impact Factor
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ABSTRACT: The taxanes are recognized as a major class of chemotherapeutic agents; however, mechanisms of innate and acquired resistance can limit their usefulness. Cabazitaxel, a novel taxane with microtubule-stabilizing potency similar to docetaxel, exhibits activity against tumor cell lines resistant to paclitaxel and docetaxel. Cabazitaxel demonstrated linear pharmacokinetics and a terminal elimination half-life comparable to that of docetaxel, findings which support dosing as a single infusion in 3-week treatment cycles. Dose-ranging studies recommended doses of 20 or 25 mg/m2 every 3 weeks. Antitumor activity was demonstrated in patients with advanced cancer and chemotherapy failure (including taxane failure). Other early studies investigated the efficacy of cabazitaxel in pretreated metastatic breast cancer, either as a single agent or in combination with capecitabine. Objective antitumor response rates of up to 24%, and sustained tumor stabilizations were also observed. The TROPIC phase III study, performed in patients with metastatic, castrate-resistant prostate cancer previously treated with docetaxel, established cabazitaxel as the first chemotherapeutic agent to offer a survival advantage in this patient population. Across these studies, the dose-limiting hematologic toxicity was neutropenia (including febrile neutropenia), usually controllable with colony-stimulating factor/granulocyte-colony stimulating factor support.
Clinical Cancer Research 10/2012; · 7.74 Impact Factor
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Razelle Kurzrock,
Nash Gabrail,
Chandtip Chandhasin,
Stacy Moulder,
Carrie Smith,
Andrew Brenner,
Kamalesh Sankhala, Alain Mita,
Kelly Elian,
Danielle Bouchard,
John Sarantopoulos
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ABSTRACT: GRN1005 is a novel peptide-drug conjugate composed of paclitaxel covalently linked to a peptide, angiopep-2, that targets the low-density lipoprotein receptor-related protein 1. This first-in-human study evaluated the safety, tolerability, pharmacokinetics, and efficacy of GRN1005 in patients with advanced solid tumors. Patients in sequential cohorts (one patient per cohort until grade 2 toxicity, then 3 + 3 design) received intravenous GRN1005 at escalating doses between 30 and 700 mg/m(2) once in every 21 days. In the maximum tolerated dose (MTD) expansion group, patients were required to have brain metastases. Fifty-six patients received GRN1005, including 41 with brain metastases (median number of prior therapies = 4). MTD was 650 mg/m(2); the main dose-limiting toxicity was myelosuppression. Sixteen of 20 patients dosed at the MTD had brain metastases. Pharmacokinetics was dose linear and the mean terminal-phase elimination half-life was 3.6 hours. No evidence of accumulation was observed after repeat dosing. No anti-GRN1005 antibodies were detected. Five of the 20 patients (25%) dosed at 650 mg/m(2) (MTD), three of whom had previous taxane therapy, achieved an overall partial response (breast, n = 2; non-small cell lung cancer, n = 2; and ovarian cancer, n = 1); responses in all five patients were also accompanied by shrinkage of brain lesions (-17% to -50%). In addition, six patients (11%; doses 30-700 mg/m(2)) experienced stable disease that lasted 4 months or more. GRN1005 was well tolerated and showed activity in heavily pretreated patients with advanced solid tumors, including those who had brain metastases and/or failed prior taxane therapy.
Molecular Cancer Therapeutics 12/2011; 11(2):308-16. · 5.23 Impact Factor
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ABSTRACT: Heat shock proteins (Hsp) are highly conserved proteins and their expression is dependent on the level of various cellular stresses. Hsp work as a molecular chaperon for several cellular proteins and have cytoprotective roles. Their function is essential for normal cell viability and growth. Hsp90 interacts with proteins mediating cell signaling involved in essential processes such as proliferation, cell cycle control, angiogenesis and apoptosis. The naturally occurring Hsp90 inhibitor geldanamycin (GA) was the first to demonstrate anticancer activity but its significant toxicity profile in pre-clinical models precluded its clinical development. Subsequent, several Hsp90 inhibitors have been developed and underwent clinical development with favorable safety profiles. Several initial clinical studies have shown promising anticancer activity of Hsp90 inhibitors mainly in breast cancer, non small cell lung carcinoma (NSCLC), gastrointestinal stromal tumors (GIST) and various hematological malignancies. The universal involvement of Hsp90 in multiple oncogenic processes makes Hsp90 inhibitors ideal compounds to be explored as a single agent or in combination with other anticancer therapies.
Current drug targets 07/2011; 12(14):2001-8. · 3.93 Impact Factor
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ABSTRACT: The phosphatidylinositol 3-kinase (PI3K)-Akt-mammalian target of rapamycin (mTOR) pathway is vital for cell metabolism, growth, and proliferation. mTOR is frequently upregulated in many tumor types and hence has become an important target in cancer treatment. Sirolimus and its derivatives (rapalogs) interact with the intracellular receptor FK506 binding protein 12 (FKBP12), forming a complex with high affinity for mTOR and thus disrupting its activity. Rapalogs are being evaluated extensively in cancer patients with different formulations and schedules. Significant clinical activity has led to their approval for the treatment of kidney cancer, mantle cell lymphoma, and subependymal giant cell astrocytoma; however, despite increasing knowledge about cancer cell biology, their activity in other malignancies is unclear. Further research is needed to identify optimal dosage, administration and targeted combination as well as the subset of patients likely to respond to mTOR/PI3K inhibition. This review focuses on a discussion of the pathway, its implications in cancer biology and results of clinical trials of rapalogs alone or in combination, organizing them by common malignancy type.
Targeted Oncology 05/2011; 6(2):69-94. · 3.61 Impact Factor
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ABSTRACT: To characterize the cardiovascular profile of sorafenib, a multitargeted kinase inhibitor, in patients with advanced cancer.
Fifty-three patients with advanced cancer received oral sorafenib 400 mg bid in continuous 28-day cycles in this open-label study. Left ventricular ejection fraction (LVEF) was evaluated using multigated acquisition scanning at baseline and after 2 and 4 cycles of sorafenib. QT/QTc interval on the electrocardiograph (ECG) was measured in triplicate with a Holter 12-lead ECG at baseline and after 1 cycle of sorafenib. Heart rate (HR) and blood pressure (BP) were obtained in duplicate at baseline and after 1 and 4 cycles of sorafenib. Plasma pharmacokinetic data were obtained for sorafenib and its 3 main metabolites after 1 and 4 cycles of sorafenib.
LVEF (SD) mean change from baseline was -0.8 (±8.6) LVEF(%) after 2 cycles (n = 31) and -1.2 (±7.8) LVEF(%) after 4 cycles of sorafenib (n = 24). The QT/QTc mean changes from baseline observed at maximum sorafenib concentrations (t(max)) after 1 cycle (n = 31) were small (QTcB: 4.2 ms; QTcF: 9.0 ms). Mean changes observed after 1 cycle in BP (n = 31) and HR (n = 30) at maximum sorafenib concentrations (t(max)) were moderate (up to 11.7 mm Hg and -6.6 bpm, respectively). No correlation was found between the AUC and C(max) of sorafenib and its main metabolites and any cardiovascular parameters.
The effects of sorafenib on changes in QT/QTc interval on the ECG, LVEF, BP, and HR were modest and unlikely to be of clinical significance in the setting of advanced cancer treatment.
Cancer Chemotherapy and Pharmacology 04/2011; 67(4):751-64. · 2.83 Impact Factor
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Anthony W Tolcher,
Christopher J Sweeney,
Kyri Papadopoulos,
Amita Patnaik,
Elena G Chiorean, Alain C Mita,
Kamalesh Sankhala,
Eric Furfine,
Jochem Gokemeijer,
Lisa Iacono,
Cheryl Eaton,
Bruce A Silver,
Monica Mita
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ABSTRACT: To determine the maximum tolerated dose (MTD), safety, pharmacokinetics, pharmacodynamics, immunogenicity, and preliminary antitumor activity of CT-322 (BMS-844203), a VEGFR-2 inhibitor and the first human fibronectin domain-based targeted biologic (Adnectin) to enter clinical studies.
Patients with advanced solid malignancies were treated with escalating doses of CT-322 intravenously (i.v.) weekly (qw), or biweekly (q2w). Plasma samples were assayed for CT-322 concentrations, plasma VEGF-A concentrations, and antidrug antibodies.
Thirty-nine patients completed 105 cycles of 0.1 to 3.0 mg/kg CT-322 i.v. either qw or q2w. The most common treatment-emergent grade 1/2 toxicities were fatigue, nausea, proteinuria, vomiting, anorexia, and hypertension. Grade 3/4 toxicities were rare. Reversible proteinuria, retinal artery, and vein thrombosis, left ventricular dysfunction, and reversible posterior leukoencephalopathy syndrome were dose limiting at 3.0 mg/kg. The MTD was 2 mg/kg qw or q2w. CT-322 plasma concentrations increased dose proportionally. Plasma VEGF-A levels increased with dose and plateaued at 2 mg/kg qw. Anti-CT-322 antibodies developed without effects on pharmacokinetics, VEGF-A levels, or safety. Minor decreases in tumor measurements occurred in 4 of 34 evaluable patients and 24 patients had stable disease.
CT-322 can be safely administered at 2 mg/kg i.v. qw or q2w and exhibits promising antitumor activity in patients with advanced solid tumors. The absence of severe toxicities at the MTD, demonstration of plasma drug concentrations active in preclinical models, and clinical pharmacodynamic evidence of VEGFR-2 inhibition warrant further development of CT-322 and suggest strong potential for Adnectin-based targeted biologics.
Clinical Cancer Research 01/2011; 17(2):363-71. · 7.74 Impact Factor
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Monica M Mita,
Matthew A Spear,
Lorrin K Yee, Alain C Mita,
Elisabeth I Heath,
Kyriakos P Papadopoulos,
Kristine C Federico,
Steven D Reich,
Ofelia Romero,
Lisa Malburg,
MaryJo Pilat,
G Kenneth Lloyd,
Saskia T C Neuteboom,
Gillian Cropp,
Edward Ashton,
Patricia M LoRusso
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ABSTRACT: 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.
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.
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.
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.
Clinical Cancer Research 12/2010; 16(23):5892-9. · 7.74 Impact Factor
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Alain C Mita,
Chris H Takimoto,
Monica Mita,
Anthony Tolcher,
Kamalesh Sankhala,
John Sarantopoulos,
Manuel Valdivieso,
Leslie Wood,
Erik Rasmussen,
Yu-Nien Sun,
Z Don Zhong,
Michael B Bass,
NgocDiep Le,
Patricia LoRusso
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ABSTRACT: To evaluate the safety, pharmacokinetics, and antitumor activity of AMG 386, an investigational selective angiopoietin 1/2-neutralizing peptibody, in combination with FOLFOX-4 (F), carboplatin/paclitaxel (C/P), or docetaxel (D), in adult patients with advanced solid tumors.
Three cohorts of patients (F, n = 6; C/P, n = 8; D, n = 12) received one full cycle of chemotherapy alone during the pretreatment phase, followed by administration of AMG 386 10 mg/kg i.v. weekly in combination with chemotherapy until disease progression or intolerance. Safety and tolerability, tumor response, pharmacokinetic profiles, and biomarkers were assessed.
Twenty-six patients were enrolled; 22 received treatment with AMG 386. No dose-limiting toxicities or grade 3 or 4 adverse events related to AMG 386 were reported. The most common adverse events were diarrhea and hypomagnesemia (n = 3 each). One patient developed grade 2 hypertension and one had grade 1 subconjunctival eye hemorrhage. No neutralizing antibodies to AMG 386 were detected. There were no pharmacokinetic interactions between AMG 386 and F, C/P, or D. One patient receiving AMG 386 plus C/P for bladder cancer refractory to gemcitabine/cisplatin had a complete response at week 8. The remaining best tumor responses were partial response (n = 3, one from each cohort), stable disease > or =8 weeks (n = 13), and progressive disease (n = 1).
Weekly administration of AMG 386 in combination with three common chemotherapy regimens was well tolerated in patients with advanced solid tumors. No pharmacokinetic interactions between AMG 386 and any of the tested chemotherapy regimens were noted. Promising antitumor activity was observed with all three treatment combinations.
Clinical Cancer Research 06/2010; 16(11):3044-56. · 7.74 Impact Factor
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Devalingam Mahalingam,
Ernest C Medina,
Juan A Esquivel,
Claudia M Espitia,
Sabrina Smith,
Kelli Oberheu,
Ronan Swords,
Kevin R Kelly,
Monica M Mita, Alain C Mita,
Jennifer S Carew,
Francis J Giles,
Steffan T Nawrocki
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ABSTRACT: The mammalian target of rapamycin (mTOR) inhibitor temsirolimus has exhibited promising anticancer activity for the treatment of renal cell cancers (RCC). Survivin expression has been implicated in drug resistance and reducing its levels with the histone deacetylase (HDAC) inhibitor vorinostat may enhance the anticancer activity of temsirolimus.
The sensitivity of RCC cell lines to the combination of temsirolimus and vorinostat was determined by measuring cell viability, clonogenic survival, and apoptosis. The effects of this combination on survivin levels were determined in vitro and in vivo. Survivin expression was silenced using small interfering RNA to evaluate its role in determining sensitivity to temsirolimus and vorinostat. The effect of the combination on angiogenesis was also determined in RCC xenograft models.
Vorinostat synergistically improved the anticancer activity of temsirolimus in a panel of RCC cell lines in vitro and in two xenograft models in vivo. While each single agent led to a modest decrease in survivin levels, the combination dramatically reduced its expression, which correlated with an induction of apoptosis. Silencing survivin levels induced apoptosis and significantly improved the efficacy of temsirolimus and vorinostat. In addition, the temsirolimus/vorinostat combination led to a strong reduction in angiogenesis.
Vorinostat augmented the anticancer activity of temsirolimus in both in vitro and in vivo models of RCC. The effectiveness of the combination was due to a decrease in survivin levels and corresponding induction of apoptosis, and enhanced inhibition of angiogenesis. Targeting survivin may be a promising therapeutic strategy to improve RCC therapy.
Clinical Cancer Research 12/2009; 16(1):141-53. · 7.74 Impact Factor
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Jennifer S Carew,
Ernest C Medina,
Juan A Esquivel,
Devalingam Mahalingam,
Ronan Swords,
Kevin Kelly,
Hui Zhang,
Peng Huang, Alain C Mita,
Monica M Mita,
Francis J Giles,
Steffan T Nawrocki
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ABSTRACT: Autophagy is an evolutionarily conserved cell survival pathway that enables cells to recoup ATP and other critical biosynthetic molecules during nutrient deprivation or exposure to hypoxia, which are hallmarks of the tumour microenvironment. Autophagy has been implicated as a potential mechanism of resistance to anticancer agents as it can promote cell survival in the face of stress induced by chemotherapeutic agents by breaking down cellular components to generate alternative sources of energy. Disruption of autophagy with chloroquine (CQ) induces the accumulation of ubiquitin-conjugated proteins in a manner similar to the proteasome inhibitor bortezomib (BZ). However, CQ-induced protein accumulation occurs at a slower rate and is localized to lysosomes in contrast to BZ, which stimulates rapid buildup of ubiquitinated proteins and aggresome formation in the cytosol. The histone deacetylase (HDAC) inhibitor vorinostat (VOR) blocked BZ-induced aggresome formation, but promoted CQ-mediated ubiquitinated protein accumulation. Disruption of autophagy with CQ strongly enhanced VOR-mediated apoptosis in colon cancer cells. Accordingly, knockdown of the essential autophagy gene Atg7 also sensitized cells to VOR-induced apoptosis. Knockdown of HDAC6 greatly enhanced BZ-induced apoptosis, but only marginally sensitized cells to CQ. Subsequent studies determined that the CQ/VOR combination promoted a large increase in superoxide generation that was required for ubiquitinated protein accumulation and cell death. Finally, treatment with the CQ/VOR combination significantly reduced tumour burden and induced apoptosis in a colon cancer xenograft model. Collectively, our results establish that inhibition of autophagy with CQ induces ubiquitinated protein accumulation and VOR potentiates CQ-mediated aggregate formation, superoxide generation and apoptosis.
Journal of Cellular and Molecular Medicine 08/2009; 14(10):2448-59. · 4.13 Impact Factor
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Sanjay Goel, Alain C Mita,
Monica Mita,
Eric K Rowinsky,
Quincy S Chu,
Nancy Wong,
Christopher Desjardins,
Fang Fang,
Mendel Jansen,
Dale E Shuster,
Sridhar Mani,
Chris H Takimoto
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ABSTRACT: Eribulin mesylate (E7389), a non-taxane microtubule dynamics inhibitor, is a structurally simplified, synthetic analogue of halichondrin B that acts via a mechanism distinct from conventional tubulin-targeted agents. This phase I study determined the maximum tolerated dose (MTD) and pharmacokinetics of eribulin administered on a 3 of 4 week schedule in patients with advanced solid malignancies.
Patients received eribulin mesylate (1-hour i.v. infusion) on days 1, 8, and 15 of a 28-day cycle. Dosing began at 0.25 mg/m(2) with escalation guided by dose-limiting toxicities (DLT). MTD, DLTs, safety, pharmacokinetics, and antitumor activity were characterized.
Thirty-two patients received eribulin mesylate (0.25, 0.5, 0.7, 1.0, or 1.4 mg/m(2)). Neutropenia was the principal DLT: At 1.4 mg/m(2), two patients experienced grade 4 neutropenia, one of whom also developed grade 3 fatigue; three additional patients experienced grade 3 neutropenia and were not treated during cycle 1 on day 15. Therefore, the MTD was 1.0 mg/m(2). Fatigue (53% overall, 13% grade 3, no grade 4), nausea (41%, all grade 1/2), and anorexia (38% overall, 3% grade 3, no grade 4) were the most common eribulin-related adverse events. Eight patients reported grade 1/2 neuropathy (no grade 3/4). Eribulin pharmacokinetics were dose-proportional over the dose range studied. One patient (cervical cancer) achieved an unconfirmed partial response lasting 79 days. Ten patients reported stable disease.
Eribulin mesylate, given on days 1, 8, and 15 of a 28-day cycle, exhibits manageable tolerability at 1.0 mg/m(2) with further dose escalation limited by neutropenia and fatigue.
Clinical Cancer Research 07/2009; 15(12):4207-12. · 7.74 Impact Factor
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Alain C Mita,
Louis J Denis,
Eric K Rowinsky,
Johann S Debono,
Andrew D Goetz,
Leonel Ochoa,
Bahram Forouzesh,
Muralidhar Beeram,
Amita Patnaik,
Kathleen Molpus,
Dorothée Semiond,
Michèle Besenval,
Anthony W Tolcher
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ABSTRACT: To assess the feasibility of administering XRP6258, a new taxane with a low affinity for the multidrug resistance 1 protein, as a 1-hour i.v. infusion every 3 weeks. The study also sought to determine the maximum tolerated dose and the recommended dose, to describe the pharmacokinetic (PK) behavior of the compound, and to seek preliminary evidence of anticancer activity.
Twenty-five patients with advanced solid malignancies were treated with 102 courses of XRP6258 at four dose levels ranging from 10 to 25 mg/m(2). Dose escalation was based on the occurrence of dose-limiting toxicity (DLT) at each dose level, provided that PK variables were favorable. The maximum tolerated dose was defined as the dose at which at least two patients developed a DLT at the first course.
Neutropenia was the principal DLT, with one patient experiencing febrile neutropenia and two others showing prolonged grade 4 neutropenia at the 25 mg/m(2) dose level. Nonhematologic toxicities, including nausea, vomiting, diarrhea, neurotoxicity, and fatigue, were generally mild to moderate in severity. XRP6258 exhibited dose-proportional PK, a triphasic elimination profile, a long terminal half-life (77.3 hours), a high clearance (mean CL, 53.5 L/h), and a large volume of distribution (mean V(ss), 2,034 L/m(2)). Objective antitumor activity included partial responses in two patients with metastatic prostate carcinoma, one unconfirmed partial response, and two minor responses.
The recommended phase II dose of XRP6258 on this schedule is 20 mg/m(2). The general tolerability and encouraging antitumor activity in taxane-refractory patients warrant further evaluations of XRP6258.
Clinical Cancer Research 02/2009; 15(2):723-30. · 7.74 Impact Factor
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ABSTRACT: Survivin, a member of the family of inhibitor of apoptosis proteins, functions as a key regulator of mitosis and programmed cell death. Initially, survivin was described as an inhibitor of caspase-9. However, over the last years, research studies have shown that the role of survivin in cancer pathogenesis is not limited to apoptosis inhibition but also involves the regulation of the mitotic spindle checkpoint and the promotion of angiogenesis and chemoresistance. Survivin gene expression is transcriptionally repressed by wild-type p53 and can be deregulated in cancer by several mechanisms, including gene amplification, hypomethylation, increased promoter activity, and loss of p53 function. This article reviews the multiple functions of survivin in the regulation of apoptosis, the promotion of tumorigenesis, and the development of survivin inhibitors as a novel anticancer therapeutic strategy.
Clinical Cancer Research 09/2008; 14(16):5000-5. · 7.74 Impact Factor
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Monica M Mita, Alain C Mita,
Quincy S Chu,
Eric K Rowinsky,
Gerald J Fetterly,
Michelle Goldston,
Amita Patnaik,
Lesley Mathews,
Alejandro D Ricart,
Theresa Mays,
Heather Knowles,
Victor M Rivera,
Jeff Kreisberg,
Camille L Bedrosian,
Anthony W Tolcher
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ABSTRACT: This phase I trial was conducted to determine the safety, tolerability, pharmacokinetics, and pharmacodynamics of deforolimus (previously known as AP23573; MK-8669), a nonprodrug rapamycin analog, in patients with advanced solid malignancies.
Patients were treated using an accelerated titration design with sequential escalating flat doses of deforolimus administered as a 30-minute intravenous infusion once daily for 5 consecutive days every 2 weeks (QDx5) in a 28-day cycle. Safety, pharmacokinetic, pharmacodynamic, and tumor response assessments were performed.
Thirty-two patients received at least one dose of deforolimus (3 to 28 mg/d). Three dose-limiting toxicity events of grade 3 mouth sores were reported. The maximum-tolerated dose (MTD) was 18.75 mg/d. Common treatment-related adverse events included reversible mouth sores and rash. Whole-blood clearance increased with dose. Pharmacodynamic analyses demonstrated mammalian target of rapamycin inhibition at all dose levels. Four patients (one each with non-small-cell lung cancer, mixed müllerian tumor [carcinosarcoma], renal cell carcinoma, and Ewing sarcoma) experienced confirmed partial responses, and three additional patients had minor tumor regressions.
The MTD of this phase I trial using an accelerated titration design was determined to be 18.75 mg/d. Deforolimus was well tolerated and showed encouraging antitumor activity across a broad range of malignancies when administered intravenously on the QDx5 schedule. On the basis of these overall results, a dose of 12.5 mg/d is being evaluated in phase II trials.
Journal of Clinical Oncology 02/2008; 26(3):361-7. · 18.37 Impact Factor
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Alain C Mita,
Anthony J Olszanski,
Richard C Walovitch,
Raymond P Perez,
Kathleen MacKay,
David P Tuck,
Cecilia Simmons,
Susan Hammond,
Monica M Mita,
Muralidhar Beeram,
Anne J Stone,
Eric K Rowinsky,
Lionel D Lewis
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ABSTRACT: AI-850, paclitaxel in a novel polyoxyethylated castor oil-free hydrophobic microparticle delivery system, is being developed based on its favorable preclinical safety and antitumor activity profiles. The objectives of the study were to assess the feasibility and safety of administering AI-850 as a <30-min i.v. infusion without premedication every 3 weeks, determine the maximum tolerated dose and the phase II recommended dose of AI-850, study the pharmacokinetics of paclitaxel in this new formulation, and seek evidence of anticancer activity.
This was an open-label phase I dose escalation study of AI-850 in patients with advanced solid malignancies. AI-850 doses were escalated according to a modified Fibonacci scheme. Clinical and laboratory toxicity was monitored, and paclitaxel plasma concentrations were measured by liquid chromatography-tandem mass spectrometry.
Twenty-two patients received 56 courses of AI-850 at five dose cohorts ranging from 36 to 250 mg/m(2). Grade 4 neutropenia, either exceeding 5 days or complicated by fever, was dose limiting in two of six patients at 250 mg/m(2) AI-850. Three patients experienced grade 2 to 4 infusion-related adverse reactions. Toxicities, including fatigue, alopecia, nausea and vomiting, neuropathy, anorexia, and myalgia, were mild to moderate, reversible, and not dose related. Pharmacokinetics of free and total paclitaxel showed biexponential plasma decay and dose proportionality for maximum plasma paclitaxel concentration and area under the concentration versus time curve. Antitumor activity was documented in two patients with endometrial and tongue carcinomas.
The administration of AI-850 as a brief infusion once every 3 weeks was feasible at doses up to 205 mg/m(2). The potential of AI-850 as an alternative to other approved paclitaxel formulations requires further clinical evaluation.
Clinical Cancer Research 07/2007; 13(11):3293-301. · 7.74 Impact Factor
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Monica M Mita,
Eric K Rowinsky,
Leonardo Forero,
S Gail Eckhart,
Elzbieta Izbicka,
Geoffrey R Weiss,
Muralidhar Beeram, Alain C Mita,
Johann S de Bono,
Anthony W Tolcher,
Lisa A Hammond,
Paul Simmons,
Kristin Berg,
Chris Takimoto,
Amita Patnaik
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ABSTRACT: This phase II study evaluated the combination of semaxanib, a small molecule tyrosine kinase inhibitor of vascular endothelial growth factor (VEGF) receptor-2, and thalidomide in patients with metastatic melanoma to assess the efficacy, tolerability, pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of the combination.
Patients with metastatic melanoma, who had failed at least one prior biologic and/or chemotherapeutic regimen, were treated with escalating doses of thalidomide combined with a fixed dose of semaxanib.
Twelve patients were enrolled and received 44 courses of semaxanib at the fixed dose of 145 mg/m2 intravenously twice-weekly in combination with thalidomide, commencing at 200 mg daily with intrapatient dose escalation as tolerated. Treatment with semaxanib was initiated 1 day before thalidomide in the first course, permitting the assessment of the PKs of semaxanib alone (course 1) and in combination with thalidomide (course 2). The principal toxicities included deep venous thrombosis, headache, and lower extremity edema. Of ten patients evaluable for response, one complete response lasting 20 months and one partial response lasting 12 months were observed. Additionally, four patients had stable disease lasting from 2 to 10 months. The PKs of semaxanib were characterized by drug exposure parameters comparable to those observed in single-agent phase II studies, indicating the absence of major drug-drug interactions. Maximum semaximib plasma concentration values were 1.2-3.8 microg/ml in course 1 and 1.1-3.9 microg/ml in course 2. The mean terminal half-life was 1.3 ( +/- 0.31) h. Biological studies revealed increasing serum VEGF concentrations following treatment in patients remaining on study for more than 4 months.
The combination of semaxanib and thalidomide was feasible and demonstrated anti-tumor activity in patients with metastatic melanoma who had failed prior therapy. Further evaluations of therapeutic strategies that target multiple angiogenesis pathways may be warranted in patients with advanced melanoma and other malignancies.
Cancer Chemotherapy and Pharmacology 03/2007; 59(2):165-74. · 2.83 Impact Factor
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Alain C Mita,
Lisa A Hammond,
Peter L Bonate,
Geoffrey Weiss,
Heather McCreery,
Samira Syed,
Mitchell Garrison,
Quincy S C Chu,
Johann S DeBono,
Christopher B Jones,
Steve Weitman,
Eric K Rowinsky
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ABSTRACT: To determine the safety, tolerability, and pharmacokinetics and to seek preliminary evidence of anticancer activity of tasidotin (ILX651), a novel dolastatin analogue, when administered as a 30-minute i.v. infusion weekly for 3 weeks every 4 weeks.
Thirty patients with advanced solid malignancies were treated with 82 courses at six dose levels ranging from 7.8 to 62.2 mg/m2 weekly, initially according to an accelerated dose-escalation scheme, which evolved into a Fibonacci scheme as a relevant degree of toxicity was observed. Plasma and urine were sampled to characterize the pharmacokinetic behavior of tasidotin.
A high incidence of neutropenia complicated by fever (one patient), or precluding treatment on day 15 (three patients), was the principal toxicity of tasidotin, at doses above 46.8 mg/m2. At all dose levels, nonhematologic toxicities were generally mild to moderate and manageable. Grade 3 toxicities included diarrhea and vomiting (one patient each). Drug-induced neurosensory symptoms were mild and there was no evidence of cardiovascular toxicity, which has been previously associated with other dolastatins. Tasidotin pharmacokinetics were mildly nonlinear, whereas metabolite kinetics were linear. A patient with non-small cell lung carcinoma experienced a minor response, and a patient with hepatocellular carcinoma had stable disease lasting 11 months.
The recommended dose for phase II studies of tasidotin administered on this schedule is 46.8 mg/m2. The mild myelosuppression and manageable nonhematologic toxicities at the recommended dose, the evidence of antitumor activity, and the unique mechanistic aspects of tasidotin warrant further disease-directed evaluations on this and alternative schedules.
Clinical Cancer Research 10/2006; 12(17):5207-15. · 7.74 Impact Factor
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Journal of Clinical Oncology 08/2006; 24(21):3509-10; author reply 3510-1. · 18.37 Impact Factor
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Alain C Mita,
Christopher J Sweeney,
Sharyn D Baker,
Andrew Goetz,
Lisa A Hammond,
Amita Patnaik,
Anthony W Tolcher,
Miguel Villalona-Calero,
Alan Sandler,
Tuhin Chaudhuri,
Kathleen Molpus,
Jane E Latz,
Lorinda Simms,
Ajai K Chaudhary,
Robert D Johnson,
Eric K Rowinsky,
Chris H Takimoto
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ABSTRACT: This phase I study was conducted to determine the toxicities, pharmacokinetics, and recommended doses of pemetrexed in cancer patients with normal and impaired renal function.
Patients received a 10-minute infusion of 150 to 600 mg/m2 of pemetrexed every 3 weeks. Patients were stratified for independent dose escalation by measured glomerular filtration rate (GFR) into four cohorts ranging from > or = 80 to less than 20 mL/min. Pemetrexed plasma and urine pharmacokinetics were evaluated for the first cycle. Patients enrolled after December 1999 were supplemented with oral folic acid and intramuscular vitamin B12.
Forty-seven patients were treated with 167 cycles of pemetrexed. Hematologic dose-limiting toxicities occurred in vitamin-supplemented patients (two; 15%) and non-supplemented patients (six; 18%), and included febrile neutropenia (four patients) and grade 4 thrombocytopenia (two patients). Nonhematologic toxicities included fatigue, diarrhea, and nausea, and did not correlate with renal function. Accrual was discontinued in patients with GFR less than 30 mL/min after one patient with a GFR of 19 mL/min died as a result of treatment-related toxicities. Pemetrexed plasma clearance positively correlated with GFR (r2 = 0.736), resulting in increased drug exposures in patients with impaired renal function. With vitamin supplementation, pemetrexed 600 mg/m2 was tolerated by patients with a GFR > or = 80 mL/min, whereas patients with a GFR of 40 to 79 mL/min tolerated a dose of 500 mg/m2.
Pemetrexed was well tolerated at doses of 500 mg/m2 with vitamin supplementation in patients with GFR > or = 40 mL/min. Additional studies are needed to define appropriate dosing for renally impaired patients receiving higher dose pemetrexed with vitamin supplementation.
Journal of Clinical Oncology 02/2006; 24(4):552-62. · 18.37 Impact Factor
