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Featured researches published by Heidi Steinfeldt.


Journal of Clinical Oncology | 2005

Phase I Trial of the Oral Antiangiogenesis Agent AG-013736 in Patients With Advanced Solid Tumors: Pharmacokinetic and Clinical Results

Hope S. Rugo; Roy S. Herbst; Glenn Liu; John W. Park; Merrill S. Kies; Heidi Steinfeldt; Yazdi K. Pithavala; Steven D. Reich; James L. Freddo; George Wilding

PURPOSE We studied the safety, clinical activity, and pharmacokinetics (PK) of AG-013736, an oral receptor tyrosine kinase inhibitor of vascular endothelial cell growth factor, platelet-derived growth factor, and c-Kit, in patients with advanced cancer. PATIENTS AND METHODS Patients received fixed doses of AG-013736 orally in 28-day cycles. In the first cohort, patients initially received two single test doses of AG-013736 (10 and 30 mg); subsequent dosing was determined by individual PK parameters. Doses in subsequent cohorts were assigned by using a traditional dose-escalation/de-escalation rule based on observed toxicities in the current and previous cohorts. PK analysis included evaluation of the effect of food and antacid. RESULTS Thirty-six patients received AG-013736 at doses ranging from 5 to 30 mg by mouth twice daily. The dose-limiting toxicities observed included hypertension, hemoptysis, and stomatitis and were seen primarily at the higher dose levels. The observed hypertension was manageable with medication. Stomatitis was generally tolerable and managed by dose reduction or drug holidays. AG-013736 was absorbed rapidly, with peak plasma concentrations observed within 2 to 6 hours after dosing. The maximum-tolerated dose and recommended phase II dose of AG-013736 is 5 mg, twice daily, administered in the fasted state. No significant drug interaction with antacid was seen. There were three confirmed partial responses and other evidence of clinical activity. CONCLUSION In this study, we have demonstrated clinical activity and safety of AG-013736 in patients with advanced solid tumors and identified the dose for phase II testing. The unique phase I study design allowed early identification of important absorption and metabolic issues critical to phase II testing of this agent.


Clinical Cancer Research | 2008

Phase I Study of the Poly(ADP-Ribose) Polymerase Inhibitor, AG014699, in Combination with Temozolomide in Patients with Advanced Solid Tumors

Ruth Plummer; Chris Jones; Mark R. Middleton; Richard Wilson; Jeff Evans; Anna Olsen; Nicola J. Curtin; Alan V. Boddy; Peter J. McHugh; David R. Newell; Adrian L. Harris; Patrick Johnson; Heidi Steinfeldt; Raz Dewji; D. D. Wang; L. Robson; Hilary Calvert

Purpose: One mechanism of tumor resistance to cytotoxic therapy is repair of damaged DNA. Poly(ADP-ribose) polymerase (PARP)-1 is a nuclear enzyme involved in base excision repair, one of the five major repair pathways. PARP inhibitors are emerging as a new class of agents that can potentiate chemotherapy and radiotherapy. The article reports safety, efficacy, pharmacokinetic, and pharmacodynamic results of the first-in-class trial of a PARP inhibitor, AG014699, combined with temozolomide in adults with advanced malignancy. Experimental Design: Initially, patients with solid tumors received escalating doses of AG014699 with 100 mg/m2/d temozolomide × 5 every 28 days to establish the PARP inhibitory dose (PID). Subsequently, AG014699 dose was fixed at PID and temozolomide escalated to maximum tolerated dose or 200 mg/m2 in metastatic melanoma patients whose tumors were biopsied. AG014699 and temozolomide pharmacokinetics, PARP activity, DNA strand single-strand breaks, response, and toxicity were evaluated. Results: Thirty-three patients were enrolled. PARP inhibition was seen at all doses; PID was 12 mg/m2 based on 74% to 97% inhibition of peripheral blood lymphocyte PARP activity. Recommended doses were 12 mg/m2 AG014699 and 200 mg/m2 temozolomide. Mean tumor PARP inhibition at 5 h was 92% (range, 46-97%). No toxicity attributable to AG014699 alone was observed. AG014699 showed linear pharmacokinetics with no interaction with temozolomide. All patients treated at PID showed increases in DNA single-strand breaks and encouraging evidence of activity was seen. Conclusions: The combination of AG014699 and temozolomide is well tolerated, pharmacodynamic assessments showing proof of principle of the mode of action of this new class of agents.


Journal of Clinical Oncology | 2005

Dynamic Contrast-Enhanced Magnetic Resonance Imaging As a Pharmacodynamic Measure of Response After Acute Dosing of AG-013736, an Oral Angiogenesis Inhibitor, in Patients With Advanced Solid Tumors: Results From a Phase I Study

Glenn Liu; Hope S. Rugo; George Wilding; Teresa M. McShane; Jeffrey L. Evelhoch; Chaan Ng; Edward F. Jackson; Frederick Kelcz; Benjamin M. Yeh; Fred Lee; Chusilp Charnsangavej; John W. Park; Edward Ashton; Heidi Steinfeldt; Yazdi K. Pithavala; Steven D. Reich; Roy S. Herbst

PURPOSE Identifying suitable markers of biologic activity is important when assessing novel compounds such as angiogenesis inhibitors to optimize the dose and schedule of therapy. Here we present the pharmacodynamic response to acute dosing of AG-013736 measured by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). PATIENTS AND METHODS Thirty-six patients with advanced solid tumors were treated with various doses of AG-013736. In addition to standard measures of objective disease response and pharmacokinetic analysis, DCE-MRI scans were acquired at baseline and repeated at cycle 1--day 2 after the scheduled morning dose of the AG-013736 in 26 patients. Indicators of a vascular response, such as the volume transfer constant (K(trans)) and initial area under the curve (IAUC), were calculated to assess the effect of treatment on tumor vascular function. RESULTS Evaluable vascular response data were obtained in 17 (65%) of 26 patients. A linear correlation was found in which the percentage change from baseline to day 2 in K(trans) and IAUC was inversely proportional to AG-013736 exposure. Using a conservative a priori assumption that a > or = 50% decrease in K(trans) was indicative of an objective vascular response, a 50% decrease in K(trans) was achieved and corresponded to a plasma AUC(0-24) of > 200 ng . h/mL. CONCLUSION A sufficient decrease in tumor vascular parameters was observed at a dose chosen for additional phase II testing by conventional toxicity criteria. In addition, the day 2 vascular response measured using DCE-MRI seems to be a useful indicator of drug pharmacology, and additional research is needed to determine if it is a suitable marker for predicting clinical activity.


Journal of Clinical Oncology | 2004

Clinical and dynamic imaging results of the first phase I study of AG–013736, an oral anti-angiogenesis agent, in patients (pts) with advanced solid tumors

Hope S. Rugo; Roy S. Herbst; Glenn Liu; John W. Park; Merrill S. Kies; Yazdi K. Pithavala; Teresa M. McShane; Heidi Steinfeldt; Steven D. Reich; George Wilding

2503 Background: AG-013736 is a potent and selective inhibitor of VEGF and PDGF receptor tyrosine kinases with broad preclinical activity in xenograft models of solid tumors. METHODS The primary objective was to determine maximum tolerated dose (MTD) and safety. Efficacy, pharmacokinetics (PK), and tumor vascular response were also evaluated. AG-013736 was administered orally once or twice daily in 28-day cycles in escalating doses to pts with solid tumors. RESULTS 36 pts in 6 cohorts were treated. At least 2 cycles of data are available on the first 30. Tumor diagnoses: breast (11), thyroid (5), renal cell (5), lung (4), and other (5). The MTD was 5 mg twice daily (BID) fasted (no food or beverage within 2 hours of dose). TOXICITY Dose-limiting toxicities (DLTs) at doses >MTD (16 pts) were hypertension (HTN) (6 pts); seizures associated with HTN (2); elevated liver function tests (2); mesenteric vein thrombosis and pancreatitis (1); and stomatitis (2). One pt with a cavitating lung lesion died of hemoptysis while on drug. At doses ≤MTD (14 pts), DLT was limited to grade 2 stomatitis in 1 pt; non-dose limiting HTN, managed by conventional antihypertensive meds, was observed in 6 pts. RESPONSE Two durable partial responses (10+, 5 mo) by RECIST criteria were observed (in renal cell and adenoid cystic carcinomas); 7 pts had stable disease lasting ≥4 mo. PK: AG-013736 plasma concentrations were variable (39%-96% CV), linear within the dose range, with peaks at 2-4 h, and terminal half-life of 3-5 h. Plasma exposures were higher (∼ 49%) and intra-pt variability was reduced in the fasted vs fed state. Vascular response: Dynamic contrast enhanced MRI was performed at baseline, and after 2, 28, and 56 days of therapy. The % change in mean Ktrans and initial area under the contrast intensity X time curve (IAUC) was computed. 6 of 18 pts with evaluable serial scans had a tumor vascular response, defined as ≥50% decrease from baseline parameter values to day 2; correlation with PK and response will be reported. CONCLUSIONS There is sufficient safety and activity of AG-013736 to warrant Phase II trials at a recommended dose of 5 mg BID fasted. [Table: see text].


Leukemia Research | 2006

The anti-angiogenesis agent, AG-013736, has minimal activity in elderly patients with poor prognosis acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS).

Francis J. Giles; William T. Bellamy; Zeev Estrov; Susan O'Brien; Srdan Verstovsek; Farhad Ravandi; Miloslav Beran; Paul Bycott; Yazdi K. Pithavala; Heidi Steinfeldt; Steven D. Reich; Alan F. List; Karen W.L. Yee


Journal of Clinical Oncology | 2005

First in human phase I trial of the PARP inhibitor AG-014699 with temozolomide (TMZ) in patients (pts) with advanced solid tumors

Ruth Plummer; Mark R. Middleton; Richard Wilson; Chris Jones; Jeff Evans; L. Robson; Heidi Steinfeldt; R. Kaufman; Steven D. Reich; Ah Calvert


Archive | 2005

THERAPEUTIC COMBINATIONS COMPRISING POLY(ADP-RIBOSE) POLYMERASES INHIBITOR

Heidi Steinfeldt; Theodore James Boritzki; Ah Calvert; Nicola J. Curtin; Mohamed Raza Dewji; Zdenek Hostomsky; Chris Jones; Rhonda Kaufman; Karen J. Klamerus; David R. Newell; Elizabeth R. Plummer; Steven D. Reich; Ian J. Stratford; Huw D. Thomas; Kaye J. Williams


Archive | 2004

Dosage forms and methods of treatment using VEGFR inhibitors

James L. Freddo; Dana Hu-Lowe; Yazdi K. Pithavala; Heidi Steinfeldt


Archive | 2004

Dosage forms comprising ag013736

James L. Freddo; Dana Hu-Lowe; Yazdi K. Pithavala; Heidi Steinfeldt


Blood | 2004

Phase 2 Study of the Anti-Angiogenesis Agent AG-013736 in Patients with Poor Prognosis Acute Myeloid Leukemia (AML) or Myelodysplastic Syndrome (MDS).

Francis J. Giles; Heidi Steinfeldt; William T. Bellamy; Paul Bycott; Yazdi K. Pithavala; Steven D. Reich; Alan F. List

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George Wilding

University of Wisconsin-Madison

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Glenn Liu

University of Wisconsin-Madison

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Hope S. Rugo

University of California

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John W. Park

University of California

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Chris Jones

Institute of Cancer Research

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