Chris H Takimoto

Karmanos Cancer Institute, Detroit, Michigan, United States

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Publications (115)667.8 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: BIIB021 is the first oral, synthetic, non-geldanamycin based HSP90 inhibitor that showed activity in pre-clinical models at low nanomolar concentrations. We performed a Phase 1 trial of BIIB021 administered to subjects with advanced solid tumors. Sixty patients received BIIB021 capsules orally on Days 1, 4, 8, 11, 15, and 18 of each course in Schedule 1, and on Days 1, 4, 8, 11, 15, 18, 22, and 25 of each course in Schedule 2. The treatment schedules were repeated every 28 days. In addition to determining the MTD, we evaluated pharmacokinetics of BIIB021 and pharmacodynamic effects of BIIB021 (Hsp70, HER2 extra-cellular domain [HER2-ECD]). The MTD was 700 mg twice weekly when BIIB021 was dosed for 3 weeks out of each 4-week course. The MTD for continuous dosing regimen was established at 600 mg twice weekly. Gastrointestinal (nausea, vomiting), hot flashes, and neurologic (dizziness) events characterize the safety profile of BIIB021 dosed twice weekly, with events mostly mild or moderate. Plasma exposure to BIIB021 was dose-dependent. Cmax occurred at approximately 90 minutes and t1/2 was approximately 1 hour across dosing cohorts of 25 to 800 mg BIIB021 twice weekly. The biological activity of BIIB021 was demonstrated in serum, PBMCs, and tumor tissue. Hsp70 levels were increased (>150% from baseline) and serum HER2-ECD was significantly decreased (>15% inhibition from baseline). BIIB021 twice weekly, given with or without the 1 of 4-week rest period was tolerated in subjects with advanced solid tumors at doses that are pharmacodynamically active.
    Clinical Cancer Research 10/2013; · 7.84 Impact Factor
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    ABSTRACT: PURPOSE: In this first-in-human study of AEE788, a tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR), HER-2, and vascular endothelial growth factor (VEGFR-2), a comprehensive pharmacodynamic program was implemented in addition to the evaluation of safety, pharmacokinetics, and preliminary efficacy of AEE788 in cancer patients. EXPERIMENTAL DESIGN: Patients with advanced, solid tumors received escalating doses of oral AEE788 once daily. Primary endpoints were to determine dose-limiting toxicities (DLTs) and maximum-tolerated dose (MTD). A nonlinear model (Emax model) was used to describe the relationship between AEE788 exposure and target-pathway modulation in skin and tumor tissues. RESULTS: Overall, 111 patients were treated (25 mg/d-550 mg/d). DLTs included rash and diarrhea; MTD was 450 mg/day. Effects on biomarkers correlated to serum AEE788 concentrations. The concentration at 50% inhibition (IC50) for EGFR in skin (0.033 µM) and tumor (0.0125 µM) were similar to IC50 in vitro suggesting skin may be surrogate tissue for estimating tumor EGFR inhibition. No inhibition of p-MAPK and Ki67 was observed in skin vessels at ≤ MTD. Hence, AEE788 inhibited EGFR, but not VEGFR, at doses ≤ MTD. A total of 16/96 evaluable patients demonstrated a > 10% shrinkage of tumor size; one partial response was observed. CONCLUSION: Our pharmacodynamic-based study showed effective inhibition of EGFR, but not of VEGFR at tolerable AEE788 doses. Emax modeling integrated with biomarker data effectively guided real-time decision making in the early development of AEE788. Despite clinical activity, target inhibition of only EGFR led to discontinuation of further AEE788 development.
    Clinical Cancer Research 09/2012; · 7.84 Impact Factor
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    ABSTRACT: The proteasome inhibitor bortezomib undergoes oxidative hepatic metabolism. This study (NCI-6432; NCT00091117) was conducted to evaluate bortezomib pharmacokinetics and safety in patients with varying degrees of hepatic impairment, to inform dosing recommendations in these special populations. Patients received bortezomib on days 1, 4, 8, and 11 of 21-day cycles. Patients were assigned to four hepatic function groups based on the National Cancer Institute Organ Dysfunction Working Group classification. Those with normal function received bortezomib at the 1.3 mg/m(2) standard dose. Patients with severe, moderate, and mild impairment received escalating doses from 0.5, 0.7, and 1.0 mg/m(2), respectively, up to a 1.3 mg/m(2) maximum. Serial blood samples were collected for 24 hours postdose on days 1 and 8, cycle 1, for bortezomib plasma concentration measurements. Sixty-one patients were treated, including 14 with normal hepatic function and 17, 12, and 18 with mild, moderate, and severe impairment, respectively. Mild hepatic impairment did not alter dose-normalized bortezomib exposure (AUC(0-tlast)) or C(max) compared with patients with normal function. Mean dose-normalized AUC(0-tlast) was increased by approximately 60% on day 8 in patients with moderate or severe impairment. Patients with mild hepatic impairment do not require a starting dose adjustment of bortezomib. Patients with moderate or severe hepatic impairment should be started at a reduced dose of 0.7 mg/m(2).
    Clinical Cancer Research 03/2012; 18(10):2954-63. · 7.84 Impact Factor
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    ABSTRACT: Bexarotene (Targretin(®) capsules) is a retinoid-X-receptor agonist and an inducer of CYP3A4-mediated metabolism. This phase I trial evaluated the pharmacokinetic (PK) and drug-drug interactions of bexarotene with chemotherapy and a lipid-lowering agent (atorvastatin or fenofibrate). This trial was run in parallel with phase III trials of the combinations to determine whether repeated doses of bexarotene capsules affect the pharmacokinetics (PK) of the chemotherapeutic or the lipid-lowering agents. Patients (n = 48) with advanced non-small cell lung cancer were treated with repetitive cycles of either paclitaxel/carboplatin or cisplatin/vinorelbine chemotherapy, bexarotene (400 mg/m(2)/day) administered continuously starting on day 4 of chemotherapy, and a lipid-lowering drug, either atorvastatin or fenofibrate, starting at least 5 days before chemotherapy due to hypertriglyceridemia induced by bexarotene. Extensive plasma sampling to characterize the PK profiles of the lipid-lowering drugs, relevant chemotherapy agents was performed on day 1 (without bexarotene) and during chemotherapy cycles 2 or 3 (with bexarotene). Here, we report the drug-drug interactions between the lipid-lowering agents and bexarotene. Mean atorvastatin clearance and dose-corrected AUC values were reduced by nearly 50% with the addition of concomitant bexarotene. As fenofibrate was less effective at controlling hypertriglyceridemia, too few patients received this agent to make any meaningful conclusions about drug-drug interactions. A drug-drug interaction was seen in this trial with bexarotene co-administration leading to a significant reduction in the AUC of atorvastatin. The likely mechanism for this interaction is through induction of CYP3A4 by bexarotene given the role of this enzyme in the metabolism of atorvastatin. Knowledge of this interaction is important for optimizing lipid management with atorvastatin for patients receiving bexarotene.
    Cancer Chemotherapy and Pharmacology 11/2011; 69(2):563-71. · 2.80 Impact Factor
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    ABSTRACT: Preclinical data suggest that the synthetic retinoid bexarotene may be an effective chemopreventive agent and that it may act synergistically in combination with platinum-based chemotherapy. The primary objective of this study was to determine whether repeated doses of bexarotene capsules affect pharmacokinetic parameters of paclitaxel or carboplatin in patients with advanced non-small cell lung cancer. Patients received treatment with paclitaxel (200 mg/m(2)) and carboplatin to provide a target AUC of 6 mg min/mL (day 1) every 3 weeks. Continuous oral bexarotene therapy (400 mg/m(2)/day) was initiated on Day 4, and patients started lipid-lowering therapy prior to beginning chemotherapy. Blood sampling to characterize the pharmacokinetic profiles of the chemotherapeutic agents with or without bexarotene was performed during cycle 1 (without concomitant bexarotene) and during cycle 2 (with concomitant bexarotene). An analysis of drug concentration data from 16 patients indicated that bexarotene did not affect the pharmacokinetics of paclitaxel, free carboplatin, or total carboplatin concentrations. However, both maximal plasma concentrations and total exposure of bexarotene increased by 80% in the presence of paclitaxel-carboplatin by an, as of yet, unexplained mechanism. The toxicities observed resembled those of either the chemotherapy regimen or bexarotene alone, and there was no evidence for an enhancement of any drug-related toxicity with the combined treatment. The administration of bexarotene, paclitaxel, and carboplatin is feasible and safe; however, the increased bexarotene plasma concentrations and exposure warrant further investigation if this combination is to be utilized clinically.
    Cancer Chemotherapy and Pharmacology 11/2011; 69(3):825-34. · 2.80 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
  • Chee M Ng, A Patnaik, M Beeram, C C Lin, C H Takimoto
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    ABSTRACT: The objective of this study was to develop a mechanism-based population pharmacokinetic/pharmacodynamic (PK/PD) model in describing troxacitabine-induced neutropenia in patients with cancer. A total of 727 PK/PD samples from 31 patients with cancer were included in the analysis. A mechanism-based population PD model was developed to describe neutropenia and the final model consisted of (1) a drug-sensitive uncommitted progenitor cell compartment (2) three transit compartments, and (3) a circulating neutrophil compartment with feedback mechanism. The troxacitabine affected the proliferation of sensitive progenitor cells through an inhibitory E (max) model. The model parameters were estimated using the MCPEM algorithm that was implemented in a parallel computing platform consisting of a single computer equipped with a quad-core INTEL central processor unit. The mechanism-based PK/PD model developed using parallelized MCPEM method adequately describes the complex relationship between the exposure and absolute neutrophil counts in troxacitabine-treated patients with cancer. The simulation results suggested that the less frequent dosing schedule of troxacitabine used currently in clinical studies was associated with less incidence of neutropenia compared to more frequent dosing schedule.
    Cancer Chemotherapy and Pharmacology 05/2011; 67(5):985-94. · 2.80 Impact Factor
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    ABSTRACT: To determine the toxicities, pharmacokinetics, pharmacodynamics, and maximum tolerated dose of bortezomib in patients with renal impairment and to develop dosing guidelines for such a patient population. Sixty-two adult cancer patients received intravenous bortezomib at 0.7-1.5 mg/m(2) on days 1, 4, 8, and 11 every 3 weeks. Patients were stratified by 24-h creatinine clearance (CrCl) normalized to body surface area (BSA) 1.73 m(2) into five cohorts: normal renal function (≥ 60 ml/min/1.73 m(2)); mild dysfunction (40-59 ml/min/1.73 m(2)); moderate dysfunction (20-39 ml/min/1.73 m(2)); severe dysfunction (<20 ml/min/1.73 m(2)); and dialysis. Dose escalation was planned for the four cohorts with renal dysfunction. Plasma bortezomib concentrations and blood 20S proteasome inhibition were assayed. Bortezomib escalation to the standard 1.3 mg/m(2) dose was well tolerated in all patients with CrCl ≥ 20 ml/min/1.73 m(2); 0.7 mg/m(2) was tolerated in three patients with severe renal dysfunction (<20 ml/min/1.73 m(2)). Bortezomib dose escalation was well tolerated in nine dialysis patients, including to 1.3 mg/m(2) in four patients. Decreased CrCl did not affect bortezomib pharmacokinetics or pharmacodynamics. Bortezomib-related side-effects were neither more common nor severe in patients with renal dysfunction versus those with normal renal function. Bortezomib 1.3 mg/m(2) is well tolerated, and dose reductions are not necessary in patients with renal dysfunction. Extrapolation from clinical and pharmacologic data suggests patients with severe renal dysfunction, including dialysis patients, can receive bortezomib at the full dose established to be clinically effective in the general patient population.
    Cancer Chemotherapy and Pharmacology 04/2011; 68(6):1439-47. · 2.80 Impact Factor
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    ABSTRACT: Patupilone is a novel microtubule-targeting cytotoxic agent, which exerts its antitumor effect through microtubule stabilization. Pharmacokinetics, pharmacodynamics, and safety of warfarin when administered concomitantly with patupilone were investigated, and antitumor activity was assessed. This was a phase I, two-center, drug-drug interaction study. In the core phase of the study, treatment consisted of warfarin 20 mg orally (days 1 and 29) and patupilone 10 mg/m(2) i.v. (days 8 and 29). Patients benefiting from patupilone treatment continued treatment every 3 weeks (extension phase) until progression of disease, death, or unacceptable toxicity. Seventeen patients were treated (core phase, 17; extension, 9). The geometric mean ratios (comedication/monotherapy) for C(max) and area under the curve(0-168) of warfarin were near unity and their 90% confidence intervals were within the equivalence limits of 0.80 and 1.25. The half-life, plasma clearance, and International Normalized Ratio (INR) of warfarin were not affected by patupilone coadministration. The most common adverse events were diarrhea, nausea, vomiting, abdominal pain, anorexia, dehydration, asthenia, and peripheral neuropathy. Five (29.4%) patients experienced grade 3 study drug-related adverse events (diarrhea, 17.6%; increased INR, 11.8%; dehydration, 5.9%; and neutropenia, 5.9%). One patient with triple-negative breast cancer (estrogen receptor, progesterone receptor, and HER2/neu negative) had a partial response (35% decrease in tumor measurements by Response Evaluation Criteria in Solid Tumors), and 11 had stable disease for 6 weeks or more (≥12 weeks, 6 patients). The pharmacokinetics and pharmacodynamics of warfarin were not affected by patupilone coadministration, suggesting that patupilone has no clinically relevant effect on CYP2C9 metabolism. Patupilone showed antitumor activity in triple-negative breast cancer.
    Molecular Cancer Therapeutics 01/2011; 10(1):209-17. · 5.60 Impact Factor
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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. · 7.84 Impact Factor
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    ABSTRACT: This study evaluated the pharmacokinetic and safety profiles of arsenic trioxide given twice per week in adult cancer patients with advanced malignancies and varying degrees of renal function. Patients received intravenous arsenic trioxide 0.15 mg/kg twice weekly for 4 weeks, followed by a 2-week rest period. The pharmacokinetic profiles of the pharmacologically active arsenical species, arsenious acid (As(III)), and its metabolites, monomethylarsonic acid (MMA(V)) and dimethylarsinic acid (DMA(V)), were evaluated during the first cycle for 72 h following doses on days 1 and 22. Safety assessments were made at each treatment visit. Twenty patients received an average of 11 doses. Compared with normal renal function, mild to severe renal impairment decreased urinary excretion of As(III) and increased exposure to MMA(V) and DMA(V) 1.4- to 8-fold after multiple dose administration. Only severe renal impairment substantially increased exposure to As(III) (AUC(0-t ) increased by 18% after a single dose and 40% after multiple doses). The safety profile of arsenic trioxide after limited treatment on a twice-per-week schedule was comparable across all renal function groups. Renal impairment did increase the systemic exposure to arsenic and its methylated metabolites following standard daily dosing of arsenic trioxide. The data from the limited number of patients with severe renal dysfunction did not suggest that severe renal impairment affected the safety profile of arsenic trioxide in cancer patients who received limited treatment with arsenic trioxide.
    Cancer Chemotherapy and Pharmacology 11/2009; 66(2):345-56. · 2.80 Impact Factor
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    Chris H Takimoto
    European journal of cancer (Oxford, England: 1990) 09/2009; 45 Suppl 1:436-8. · 4.12 Impact Factor
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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. · 7.84 Impact Factor
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    ABSTRACT: To assess the feasibility of administering troxacitabine, an L-nucleoside analog that is not a substrate for deoxycytidine deaminase, in combination with cisplatin, to identify pharmacokinetic interactions, and to seek preliminary evidence of antitumor activity. Patients with advanced solid malignancies were treated with cisplatin intravenously over an hour followed by troxacitabine intravenously over 30 min on day 1 every 28 days at the following cisplatin/troxacitabine (mg/m(2)) dose levels 50/4.8, 75/4.8, 50/6.4, 75/6.4, and 75/8.0. Plasma and urine sampling were performed to characterize the pharmacokinetic parameters of troxacitabine in combination with cisplatin. Thirty-one patients received 77 courses of cisplatin/troxacitabine at five dose levels. Grade 4 neutropenia lasting more than 5 days and/or grade 4 thrombocytopenia were consistently experienced by minimally pretreated (MP) and heavily pretreated (HP) patients at doses exceeding 75/6.4 and 50/4.8 mg/m(2), respectively. Mean values for the volume of distribution at steady state and clearance of troxacitabine were 196-396 L and 7.2-9.8 L/h, respectively. A patient with metastatic non-small cell lung cancer experienced a 42% reduction in extent of disease for 6 months. The combination of cisplatin and troxacitabine produces dose-limiting myelosuppression at lower doses of troxacitabine than single agent doses. The recommended phase II doses of cisplatin/troxacitabine are 75/6.4 and 50/4.8 mg/m(2), every 4 weeks, for MP and HP patients, respectively. The addition of cisplatin did not substantially alter the pharmacokinetic behavior of troxacitabine.
    Cancer Chemotherapy and Pharmacology 06/2009; 65(1):167-75. · 2.80 Impact Factor
  • Ricardo M Attar, Chris H Takimoto, Marco M Gottardis
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    ABSTRACT: The understanding of the key role that androgens play on the normal and pathological physiology of the prostate guided the development of different therapies for the treatment of locally advanced or metastatic prostate cancer (PCa). These so-called androgen deprivation therapies include surgical or chemical castration, achieved by the administration of gonadotropin-releasing hormone analogs; inhibition of steroidogenic enzymes; and finally, blocking of the binding of androgens to their receptor (AR) by the use of antiandrogens. Despite an excellent initial response, in approximately 2 to 3 years, most of these patients will succumb to the castration resistant form of the disease. Remarkably, even in the presence of castration levels of circulating androgens, these tumors are still dependent on a functional AR, and several molecular mechanisms have been proposed to explain this phenomenon. These include: (1) gene amplification and increased expression of the AR mRNA and protein, (2) selection of mutations in the AR that confer broader ligand specificity, (3) changes in the ratios or expression between the AR and its coregulators, (4) increased expression of steroidogenic enzymes, and (5) up-regulation of cross-talk signal transduction pathways that can activate the AR in a ligand-independent manner. We will summarize how these molecular hypotheses are being tested in the clinic by the latest therapeutic modalities.
    Clinical Cancer Research 06/2009; 15(10):3251-5. · 7.84 Impact Factor
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    ABSTRACT: PURPOSE Since activity of sorafenib was observed in sarcoma patients in a phase I study, we performed a multicenter phase II study of daily oral sorafenib in patients with recurrent or metastatic sarcoma. PATIENTS AND METHODS We employed a multiarm study design, each representing a sarcoma subtype with its own Simon optimal two-stage design. In each arm, 12 patients who received 0 to 1 prior lines of therapy were treated (0 to 3 for angiosarcoma and malignant peripheral-nerve sheath tumor). If at least one Response Evaluation Criteria in Solid Tumors (RECIST) was observed, 25 further patients with that sarcoma subtype were accrued. Results Between October 2005 and November 2007, 145 patients were treated; 144 were eligible for toxicity and 122 for response. Median age was 55 years; female-male ratio was 1.8:1. The median number of cycles was 3. Five of 37 patients with angiosarcoma had a partial response (response rate, 14%). This was the only arm to meet the RECIST response rate primary end point. Median progression-free survival was 3.2 months; median overall survival was 14.3 months. Adverse events (typically dermatological) necessitated dose reduction for 61% of patients. Statistical modeling in this limited patient cohort indicated sorafenib toxicity was correlated inversely to patient height. There was no correlation between phosphorylated extracellular signal regulated kinase expression and response in six patients with angiosarcoma with paired pre- and post-therapy biopsies. CONCLUSION As a single agent, sorafenib has activity against angiosarcoma and minimal activity against other sarcomas. Further evaluation of sorafenib in these and possibly other sarcoma subtypes appears warranted, presumably in combination with cytotoxic or kinase-specific agents.
    Journal of Clinical Oncology 06/2009; 27(19):3133-40. · 18.04 Impact Factor
  • Chris H Takimoto
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    ABSTRACT: The maximum tolerated dose (MTD) has been the classically recommended phase II dose for cytotoxic chemotherapy anticancer agents. However, the development of molecular targeted therapies with highly specific mechanisms of action has raised questions about the paradigm of dosing at the MTD. Inhibition of the molecular target may occur at dose levels substantially below those producing dose limiting toxicities. The impact of targeted therapies on our dose selection strategies has been immense; however, defining the MTD in phase I oncology trials still provides valuable information for future drug development. But, the MTD should not be selected blindly as the recommended phase II dose for efficacy testing. Optimal dose selection for targeted cancer agents needs to be evaluated using all available information collected during the early stages of drug development. Definition of the optimal dose may need to be deferred until randomized phase II trials can be conducted. Future clinical trail designs in oncology drug development need to reflect this paradigm shift.
    Targeted Oncology 05/2009; 4(2):143-7. · 3.46 Impact Factor
  • Chee M Ng, S Bai, C H Takimoto, M T Tang, A W Tolcher
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    ABSTRACT: Volociximab is a chimeric IgG(4) that is being developed as a novel first-in-class anti-angiogenic, α(5)β(1) integrin inhibitor for the treatment of solid tumors. A mechanism-based pharmacokinetic (PK)/pharmacodynamic (PD) model was developed to investigate the dynamic interaction between volociximab concentrations and free monocyte α(5)β(1) integrin levels in cancer patients. Twenty-one cancer patients from six dose cohorts (0.5, 1.0, 2.5, 5.0, 10, and 15 mg/kg) were included in the analysis. The fully integrated receptor-binding PK/PD model was developed and fit simultaneously to the PK/PD data. A Monte-Carlo parametric expectation-maximization method implement in S-ADAPT program was used to obtain estimates of population parameters and inter- and intra-subject variability. The PK/PD time profiles were well described by the model and the parameters were estimated with good precision. The model was used to simulate PK/PD time profiles for multiple dose regimens at various dose levels, and the results suggested that the monocyte α(5)β(1) integrin binding was saturated (≤5% free) at week 16 in the majority of patients treated with volociximab doses ≥10 mg/kg IV every 2 weeks. The developed model is useful for anticipating the drug exposures and extent of volociximab binding to peripheral monocyte α(5)β(1) integrin in untested regimens and for optimizing the design of future clinical trials.
    Cancer Chemotherapy and Pharmacology 05/2009; 65(2):207-17. · 2.80 Impact Factor
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    ABSTRACT: The objectives of the analysis were to characterize the time course of neutropenia after pemetrexed administration using an established semimechanistic-physiologic model, characterize the relationship between pemetrexed exposure and neutropenia, and describe differences in neutropenic response by vitamin supplementation status and between Japanese and Western patients. An eight-compartment population pharmacokinetic/pharmacodynamic model was used to describe the absolute neutrophil count (ANC)-time profile (neutropenic response) following pemetrexed doses of 300 to 1,400 mg/m(2) administered every 21 days. The analyses pooled data from 13 studies including 279 patients (161 supplemented with oral folic acid and intramuscular vitamin B(12), and 118 unsupplemented; 248 Western and 31 Japanese) who received 857 treatment cycles. Vitamin supplementation status, ethnic origin, and drug exposure were the dominant predictors of neutropenic response. Vitamin supplementation diminishes neutropenic response to pemetrexed. Model-predicted ANC nadirs for the "typical" Western patient receiving 500 mg/m(2) pemetrexed +/- vitamin supplementation were 2.74 x 10(9)/L and 1.70 x 10(9)/L, respectively. Japanese patients had a less pronounced neutropenic response to pemetrexed relative to Western patients. The model-predicted ANC nadir for Japanese patients receiving 500 mg/m(2) pemetrexed with vitamin supplementation was 2.66 x 10(9)/L. Values for the 1,000 mg/m(2) dose with vitamin supplementation were 1.91 x 10(9)/L and 1.34 x 10(9)/L for Japanese and Western patients, respectively. Increased albumin, decreased cystathionine, and decreased body surface area were also associated with increased neutropenic response. The neutropenic response to higher pemetrexed doses administered with vitamin supplementation is tolerable. All other factors equal, Japanese patients have a lesser neutropenic response to pemetrexed relative to Western patients.
    Clinical Cancer Research 02/2009; 15(1):346-54. · 7.84 Impact Factor
  • Chris H. Takimoto, Muralidhar Beeram
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    ABSTRACT: The taxanes are a versatile and important class of drugs that target microtubules. Paclitaxel and docetaxel are some of the most widely used cancer chemofherapeutic agents in clinical oncology. In this chapter, we discuss the most common dose and treatment schedules, clinical efficacy, and the toxicity profiles of these agents in detail.
    01/2009: pages 395-419;

Publication Stats

2k Citations
667.80 Total Impact Points

Institutions

  • 2012
    • Karmanos Cancer Institute
      Detroit, Michigan, United States
    • Massachusetts General Hospital
      Boston, Massachusetts, United States
  • 2011
    • The Children's Hospital of Philadelphia
      Philadelphia, Pennsylvania, United States
  • 2008–2011
    • South Texas Accelerated Research Therapeutics
      San Antonio, Texas, United States
  • 2001–2011
    • University of Texas Health Science Center at San Antonio
      • • Institute for Drug Development
      • • Cancer Therapy & Research Center
      • • Division of Hospital Medicine
      San Antonio, TX, United States
  • 2009
    • Albert Einstein College of Medicine
      New York City, New York, United States
    • Eli Lilly
      Indianapolis, Indiana, United States
  • 2008–2009
    • Johnson & Johnson
      New Brunswick, New Jersey, United States
  • 2006
    • Indiana University-Purdue University Indianapolis
      Indianapolis, Indiana, United States
  • 2005
    • University of Alabama at Birmingham
      Birmingham, Alabama, United States
  • 2003
    • Brooke Army Medical Center
      Houston, Texas, United States
    • Ann & Robert H. Lurie Children's Hospital of Chicago
      Chicago, Illinois, United States
  • 1994–2003
    • National Cancer Institute (USA)
      • • Cancer Therapy Evaluation Program
      • • Developmental Therapeutics Program
      • • Division of Cancer Treatment and Diagnosis
      • • Community Clinical Oncology Program (CCOP)
      Maryland, United States
  • 1993–1999
    • National Institutes of Health
      • Branch of Medical Oncology Branch and Affiliates
      Maryland, United States