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Dive into the research topics where Alison L. Hannah is active.

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Featured researches published by Alison L. Hannah.


Clinical Cancer Research | 2004

Phase II study of SU5416, a small molecule vascular endothelial growth factor tyrosine kinase receptor inhibitor, in patients with refractory multiple myeloma

Maurizio Zangari; Elias Anaissie; Alison Stopeck; Alyssa Morimoto; Nguyen Tan; Jeffrey E. Lancet; Maureen Cooper; Alison L. Hannah; Guillermo Garcia-Manero; S. Faderl; Hagop M. Kantarjian; Julie M. Cherrington; Maher Albitar; Francis J. Giles

Purpose: Increased bone marrow angiogenesis and vascular endothelial growth factor (VEGF) levels are of adverse prognostic significance in patients with multiple myeloma (MM). VEGF, a soluble circulating angiogenic molecule, acts via receptor tyrosine kinases, including VEGF receptor 2. SU5416 is a small molecule VEGF receptor 2 inhibitor. Experimental Design: Adult patients with advanced MM were entered on a multicenter phase II study. Results: Twenty-seven patients (median age 69, range 39–79), median 4 (0–10) lines of prior therapy, 14 with prior thalidomide therapy, received SU5416 at 145 mg/m2 twice weekly i.v. for a median of two 4-week cycles (range 0.2–9). Grade 3/4 toxicities were rarely observed; the most frequent was thrombocytopenia (12%). Mild-to-moderate toxicities included nausea (63%), headache (56%), diarrhea, vomiting (both 37%), and fatigue (33%). There were three thromboembolic episodes and five cases of new onset hypertension. Two (7%) patients did not complete the first 4-week cycle of therapy because of adverse events (pneumonia and headache). There were no objective responses. Four patients had disease stabilization for ≥4 months. A decrease in median VEGF plasma levels was observed in patients with stable disease (n = 7) compared with patients with progressive disease (n = 5). Overall median survival was 42 weeks (range 3–92+). Conclusions: Although SU5416 had minimal clinical activity, signs of biological activity (decrease in plasma VEGF levels) suggest that angiogenic modulation may be of value in patients with MM.


Blood | 2016

Phase 3 trial of defibrotide for the treatment of severe veno-occlusive disease and multi-organ failure.

Paul G. Richardson; Marcie L. Riches; Nancy A. Kernan; Joel A. Brochstein; Shin Mineishi; Amanda M. Termuhlen; Sally Arai; Stephan A. Grupp; Eva C. Guinan; Paul L. Martin; Gideon Steinbach; Amrita Krishnan; Eneida R. Nemecek; Sergio Giralt; Tulio E. Rodriguez; Reggie Duerst; John Doyle; Joseph H. Antin; Angela Smith; Leslie Lehmann; Richard E. Champlin; Alfred P. Gillio; Rajinder Bajwa; Ralph B. D'Agostino; Joseph M. Massaro; Diane Warren; Maja Miloslavsky; Robin Hume; Massimo Iacobelli; Bijan Nejadnik

Hepatic veno-occlusive disease (VOD), also called sinusoidal obstruction syndrome (SOS), is a potentially life-threatening complication of hematopoietic stem cell transplantation (HSCT). Untreated hepatic VOD/SOS with multi-organ failure (MOF) is associated with >80% mortality. Defibrotide has shown promising efficacy treating hepatic VOD/SOS with MOF in phase 2 studies. This phase 3 study investigated safety and efficacy of defibrotide in patients with established hepatic VOD/SOS and advanced MOF. Patients (n = 102) given defibrotide 25 mg/kg per day were compared with 32 historical controls identified out of 6867 medical charts of HSCT patients by blinded independent reviewers. Baseline characteristics between groups were well balanced. The primary endpoint was survival at day +100 post-HSCT; observed rates equaled 38.2% in the defibrotide group and 25% in the controls (23% estimated difference; 95.1% confidence interval [CI], 5.2-40.8;P= .0109, using a propensity-adjusted analysis). Observed day +100 complete response (CR) rates equaled 25.5% for defibrotide and 12.5% for controls (19% difference using similar methodology; 95.1% CI, 3.5-34.6;P= .0160). Defibrotide was generally well tolerated with manageable toxicity. Related adverse events (AEs) included hemorrhage or hypotension; incidence of common hemorrhagic AEs (including pulmonary alveolar [11.8% and 15.6%] and gastrointestinal bleeding [7.8% and 9.4%]) was similar between the defibrotide and control groups, respectively. Defibrotide was associated with significant improvement in day +100 survival and CR rate. The historical-control methodology offers a novel, meaningful approach for phase 3 evaluation of orphan diseases associated with high mortality. This trial was registered at www.clinicaltrials.gov as #.


Journal of Clinical Oncology | 1999

Phase I and Pharmacologic Study of the Tyrosine Kinase Inhibitor SU101 in Patients With Advanced Solid Tumors

S. Gail Eckhardt; Jinee Rizzo; Kevin R. Sweeney; Gillian F. Cropp; Sharyn D. Baker; Maura Kraynak; John G. Kuhn; Miguel A. Villalona-Calero; Lisa A. Hammond; Geoffrey R. Weiss; Allison Thurman; Lon Smith; Ronald L. Drengler; John R. Eckardt; Judy Moczygemba; Alison L. Hannah; Daniel D. Von Hoff; Eric K. Rowinsky

PURPOSE To evaluate the clinical feasibility and pharmacologic behavior of the platelet-derived growth factor (PDGF) tyrosine kinase inhibitor SU101, administered on a prolonged, intermittent dosing schedule to patients with advanced solid malignancies. PATIENTS AND METHODS Twenty-six patients were treated with SU101 doses ranging from 15 to 443 mg/m(2) as a 24-hour continuous intravenous (IV) infusion weekly for 4 weeks, repeated every 6 weeks. Pharmacokinetic studies were performed to characterize the disposition of SU101 and its major active metabolite, SU0020. Immunohistochemical staining of PDGF-alpha and -beta receptors was performed on malignant tumor specimens obtained at diagnosis. RESULTS Twenty-six patients were treated with 52 courses (187 infusions) of SU101. The most common toxicities were mild to moderate nausea, vomiting, and fever. Two patients experienced one episode each of grade 3 neutropenia at the 333 and 443 mg/m(2) dose levels. Dose escalation of SU101 above 443 mg/m(2)/wk was precluded by the total volume of infusate required, 2.5 to 3.0 L. Individual plasma SU101 and SU0020 concentrations were described by a one-compartment model that incorporates both first-order formation and elimination of SU0020. SU101 was rapidly converted to SU0020, which exhibited a long elimination half-life averaging 19 +/- 12 days. At the 443 mg/m(2)/wk dose level, trough plasma SU0020 concentrations during weeks 2 and 4 ranged from 54 to 522 micromol/L. Immunohistochemical studies revealed PDGF-alpha and -beta receptor staining in the majority (15 of 19) of malignant neoplasms. CONCLUSION SU101 was well tolerated as a 24-hour continuous IV infusion at doses of up to 443 mg/m(2)/wk for 4 consecutive weeks every 6 weeks. Although further dose escalation was precluded by infusate volume constraints, this SU101 dose schedule resulted in the achievement and maintenance of substantial plasma concentrations of the major metabolite, SU0020, for the entire treatment period.


Journal of Pharmacy and Pharmacology | 2001

Pharmacokinetics and interspecies scaling of a novel VEGF receptor inhibitor, SU5416.

Juthamas Sukbuntherng; Gillian F. Cropp; Alison L. Hannah; Gregory S. Wagner; Laura Kay Shawver; Lida Antonian

The pharmacokinetics and allometric relationships of SU5416, a novel small anti‐angiogenesis agent, were studied. The pharmacokinetics of SU5416 were examined in mice, rats, dogs, and cancer patients. The in‐vitro intrinsic clearance (CLint) was estimated from the in‐vitro metabolism study in mouse, rat, dog, monkey and human liver microsomes. The parameters of interest were correlated across species as a function of bodyweight using an allometric approach. The steady‐state volume of distribution (Vdss), plasma clearance (CLs), and CLint of SU5416 were well correlated across species. The exponent of the allometric relationship (b) of the corresponding parameters was 0.92, 0.80 and 0.66, respectively. The elimination half‐life (t½) was consistent across species and independent of bodyweight. The prediction of CLs, Vdss, CLint, and t½ in humans using the data from mouse, rat, and dog, and monkey (for CLint) was reasonably good (within 4‐fold of the observed values). However, an improved prediction (within 2‐fold of the observed values) of the corresponding parameters in humans was obtained when extrapolation from only the rodent data was performed, suggesting that the rodent data are sufficient for the scale‐up of SU5416 pharmacokinetic parameters in humans. Using allometry, it was possible to achieve reasonable predictions of the pharmacokinetic parameters of SU5416 in cancer patients with various solid tumours.


Lancet Oncology | 2013

Two schedules of etirinotecan pegol (NKTR-102) in patients with previously treated metastatic breast cancer: a randomised phase 2 study

Ahmad Awada; Agustin A. Garcia; Stephen Chan; Guy Jerusalem; Robert E. Coleman; Manon T Huizing; Aminder Mehdi; Sue M O'Reilly; John T. Hamm; Peter Barrett-Lee; Veronique Cocquyt; Kostandinos Sideras; David Young; Carol Zhao; Yen Lin Chia; Ute Hoch; Alison L. Hannah; Edith A. Perez

BACKGROUND New therapeutic options are needed for patients with heavily pretreated breast cancer. Etirinotecan pegol is a long-acting topoisomerase-I inhibitor designed to provide prolonged tumour-cell exposure to SN38, the active metabolite. We aimed to assess the efficacy and safety of two etirinotecan pegol dosing schedules in patients with previously treated metastatic breast cancer to determine an optimum dosing schedule for phase 3 trials. METHODS In this randomised, two-stage, open-label phase 2 trial, we recruited patients aged 18 years or older who had received taxane therapy and undergone two or fewer previous chemotherapy regimens for metastatic breast cancer, with an Eastern Cooperative Oncology Group performance status of 0 or 1, from 18 sites in three countries. Eligible patients were randomly assigned (1:1) to etirinotecan pegol 145 mg/m(2) every 14 days or every 21 days. The primary endpoint was the proportion of patients with a confirmed objective response as defined by Response Evaluation Criteria in Solid Tumors version 1.0, analysed by intention to treat. Safety was assessed in all patients who received at least one dose of study drug. FINDINGS 70 patients (35 in each group) were randomly assigned to treatment between Feb 17, 2009 and April 13, 2010. Of the 70 patients, 20 (29%; 95% CI 18·4-40·6) achieved an objective response (two [3%] had a complete response and 18 [26%] had a partial response). Ten patients on the 14-day schedule achieved an objective response (29%; 95% CI 14·6-46·3; eight partial responses, two complete responses) as did ten on the 21-day schedule (29%; 95% CI 14·6-46·3; all partial responses). The most common grade 3 or worse adverse events were delayed diarrhoea (seven [20%] of 35 patients on the 14-day schedule vs eight [23%] of 35 patients on the 21-day schedule), fatigue (five [14%] vs three [9%]), neutropenia (four [11%] vs four [11%]), and dehydration (three [9%] vs four [11%]); 14 [20%] patients discontinued treatment because of drug-related toxicity. There were two possible drug-related deaths (acute renal failure and septic shock) in the 14-day group; other drug-related serious adverse events reported by more than one patient included ten [14%] patients with diarrhoea (six [17%] patients on the 14-day schedule vs four [11%] on the 21-day schedule), six [9%] with dehydration (two [6%] vs four [11%]), two [3%] with nausea (two [6%] vs none), and two [3%] with vomiting (two [6%] vs none). INTERPRETATION On the basis of the overall clinical data, pharmacokinetics, and tolerability profile, etirinotecan pegol 145 mg/m(2) every 21 days has been selected for a phase 3 trial against treatment of physicians choice in patients with advanced breast cancer.


Lancet Oncology | 2015

Etirinotecan pegol (NKTR-102) versus treatment of physician's choice in women with advanced breast cancer previously treated with an anthracycline, a taxane, and capecitabine (BEACON): a randomised, open-label, multicentre, phase 3 trial

Edith A. Perez; Ahmad Awada; Joyce O'Shaughnessy; Hope S. Rugo; Chris Twelves; Seock-Ah Im; Patricia Gómez-Pardo; Lee S. Schwartzberg; V. Dieras; Denise A. Yardley; David A. Potter; Audrey Mailliez; Alvaro Moreno-Aspitia; Jin Seok Ahn; Carol Zhao; Ute Hoch; Mary Tagliaferri; Alison L. Hannah; Javier Cortes

BACKGROUND New options are needed for patients with heavily pretreated breast cancer. Etirinotecan pegol is a long-acting topoisomerase-I inhibitor that prolongs exposure to, but reduces the toxicity of, SN38 (the active metabolite of irinotecan). We assessed whether etirinotecan pegol is superior to currently available treatments for patients with previously treated, locally recurrent or metastatic breast cancer. METHODS In this open-label, multicentre, randomised phase 3 study (BEACON; BrEAst Cancer Outcomes with NKTR-102), conducted at 135 sites in 11 countries, patients with locally recurrent or metastatic breast cancer previously treated with an anthracycline, a taxane, and capecitabine (and two to five previous regimens for advanced disease) were randomly assigned (1:1) centrally via an interactive response system to etirinotecan pegol (145 mg/m(2) as a 90-min intravenous infusion every 3 weeks) or single-drug treatment of physicians choice. Patients with stable brain metastases and an Eastern Cooperative Oncology Group performance status of 0-1 were eligible. Randomisation was stratified with a permuted block scheme by region, previous eribulin, and receptor status. After randomisation, patients and investigators were aware of treatment assignments. The primary endpoint was overall survival in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01492101. FINDINGS Between Dec 19, 2011, and Aug 20, 2013, 852 patients were randomly assigned; 429 to etirinotecan pegol and 423 to treatment of physicians choice. There was no significant difference in overall survival between groups (median 12·4 months [95% CI 11·0-13·6] for the etirinotecan pegol group vs 10·3 months [9·0-11·3] for the treatment of physicians choice group; hazard ratio 0·87 [95% CI 0·75-1·02]; p=0·084). The safety population includes the 831 patients who received at least one dose of assigned treatment (425 assigned to etirinotecan pegol and 406 to treatment of physicians choice). Serious adverse events were recorded for 128 (30%) patients treated with etirinotecan pegol and 129 (32%) treated with treatment of physicians choice. Fewer patients in the etirinotecan pegol group had grade 3 or worse toxicity than those in the treatment of physicians choice group (204 [48%] vs 256 [63%]; p<0·0001). The most common grade 3 or worse adverse events were diarrhoea (41 [10%] in the experimental group vs five [1%] in the control group), neutropenia (41 [10%] vs 125 [31%]), and peripheral neuropathy (two [<1%] vs 15 [4%]). Three patients in the etirinotecan pegol group died of treatment-related adverse events (pneumonia, myelodysplastic syndrome, and acute renal failure) and two in the treatment of physicians choice group (neutropenic sepsis and septic shock). INTERPRETATION This trial did not demonstrate an improvement in overall survival for etirinotecan pegol compared to treatment of physicians choice in patients with heavily pre-treated advanced breast cancer. The toxicity profile noted in the etirinotecan pegol group differed from that in the control group. In view of the frequency of cross-resistance and overlapping toxicities noted with many available drugs and the need for effective drugs in highly refractory disease, etirinotecan pegol may warrant further research in some subgroups of patients. FUNDING Nektar Therapeutics.


Leukemia Research | 2010

Clinical correlation of circulating heat shock protein 70 in acute leukemia

Chen Hsiung Yeh; Richard Tseng; Alison L. Hannah; Zeev Estrov; Elihu H. Estey; Hagop M. Kantarjian; Maher Albitar

The heat shock protein 70 (HSP70) is one of the molecular chaperone family involved in the protection of cells upon exposure to various types of stresses. Plasma circulating HSP70 (cHSP70) is believed to play a role in the anti-tumor immune responses and its levels may reflect the levels of severity or the disease condition. Using electrochemiluminescence protein detection immunoassay, we measured the cHSP70 levels in the plasma of patients with acute myeloid leukemia (AML) (n=96), myelodysplastic syndrome (MDS) (n=28), and acute lymphoblastic leukemia (ALL) (n=40) and compared with those in normal individuals (n=99). cHSP70 levels were significantly higher in AML (median: 10.71 ng/mL, range: 1.93-79.0 ng/mL) and ALL (median: 27.59 ng/mL, range: 5.09-129.6 ng/mL) as compared to those in MDS (median: 4.54 ng/mL, range: 1.35-58.3 ng/mL) or healthy controls (median: 4.13 ng/mL, range: 1.75-13.6 ng/mL). Levels of cHSP70 showed significant positive correlation with lactate dehydrogenase (LDH) and white blood cells (WBC) in AML and ALL patients, which may reflect overall tumor load. Furthermore, patients with higher levels of cHSP70 had significantly shorter survival in AML (P=0.04) and ALL (P=0.05), suggesting that in these two acute diseases, cHSP70 is an indicator for poor prognosis. Our data support the potential of using free cHSP70 as a biomarker in leukemias and potentially other types of cancers.


American Journal of Clinical Oncology | 2006

Phase I/pilot study of SU5416 (semaxinib) in combination with irinotecan/bolus 5-FU/LV (IFL) in patients with metastatic colorectal cancer.

Albert C. Lockhart; Gillian F. Cropp; Jordan Berlin; Edwin F. Donnelly; Robert D. Schumaker; Larry J. Schaaf; Kenneth R. Hande; Arthur C. Fleischer; Alison L. Hannah; Mace L. Rothenberg

Objectives:Determine the toxicity, tolerability, and pharmacokinetics of SU5416, a vascular endothelial growth factor receptor-2 (VEGFR-2) tyrosine kinase inhibitor, coadministered with bolus 5-fluorouracil (5-FU), leucovorin, and irinotecan (IFL) in untreated patients with metastatic colorectal cancer. Methods:SU5416 (85 or 145 mg/m2) was administered twice weekly throughout a 6-week period along with standard IFL (4 weeks on/2 weeks off). Plasma samples were assayed for SU5416, irinotecan, and SN-38 by reverse-phase HPLC. Contrast enhanced, color Doppler sonography was performed on patients at the MTD to identify changes in tumor perfusion. Results:Eleven patients received treatment with SU5416 85 mg/m2 (n = 5) or 145 mg/m2 (n = 6). At 85 mg/m2, no DLTs were observed. At 145 mg/m2, grade 3 diarrhea and vomiting were observed during cycle 1; other grade 3 toxicities included fatigue, nausea, anorexia, anemia, pain, urinary retention, and hypertension. The pharmacokinetics of irinotecan and SN-38 were not altered by coadministration of SU5416. SU5416 pharmacokinetics were not altered by IFL. Contrast-enhanced, color Doppler sonography was performed on 2 patients and demonstrated reduced tumor perfusion after treatment in a patient who responded to treatment and increased perfusion in a patient who developed progressive disease. Three patients (27%) had confirmed partial responses, 2 patients (18%) had unconfirmed partial responses, and 4 patients (36%) had stable disease. Conclusions:Twice weekly SU5416 can be administered with bolus IFL without unexpected toxicities or altering the pharmacokinetic behavior of the administered drugs. Changes in tumor blood perfusion can be detected by contrast-enhanced, color Doppler sonography. The further development of SU5416 was halted before this study was completed.


British Journal of Haematology | 2017

Earlier defibrotide initiation post-diagnosis of veno-occlusive disease/sinusoidal obstruction syndrome improves Day +100 survival following haematopoietic stem cell transplantation

Paul G. Richardson; Angela Smith; Brandon M. Triplett; Nancy A. Kernan; Stephan A. Grupp; Joseph H. Antin; Leslie Lehmann; Maja Miloslavsky; Robin Hume; Alison L. Hannah; Bijan Nejadnik; Robert J. Soiffer

Hepatic veno‐occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a progressive, potentially fatal complication of conditioning for haematopoietic stem cell transplant (HSCT). The VOD/SOS pathophysiological cascade involves endothelial‐cell activation and damage, and a prothrombotic‐hypofibrinolytic state. Severe VOD/SOS (typically characterized by multi‐organ dysfunction) may be associated with >80% mortality. Defibrotide is approved for treating severe hepatic VOD/SOS post‐HSCT in the European Union, and for hepatic VOD/SOS with renal or pulmonary dysfunction post‐HSCT in the United States. Previously, defibrotide (25 mg/kg/day in 4 divided doses for a recommended ≥21 days) was available through an expanded‐access treatment protocol for patients with VOD/SOS. Data from this study were examined post‐hoc to determine if the timing of defibrotide initiation post‐VOD/SOS diagnosis affected Day +100 survival post‐HSCT. Among 573 patients, defibrotide was started on the day of VOD/SOS diagnosis in approximately 30%, and within 7 days in >90%. The relationship between Day +100 survival and treatment initiation before/after specific days post‐diagnosis showed superior survival when treatment was initiated closer to VOD/SOS diagnosis with a statistically significant trend over time for better outcomes with earlier treatment initiation (P < 0·001). These results suggest that initiation of defibrotide should not be delayed after diagnosis of VOD/SOS.


Biology of Blood and Marrow Transplantation | 2017

Defibrotide for Patients with Hepatic Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome: Interim Results from a Treatment IND Study

Paul G. Richardson; Angela Smith; Brandon M. Triplett; Nancy A. Kernan; Stephan A. Grupp; Joseph H. Antin; Leslie Lehmann; Tsiporah Shore; Massimo Iacobelli; Maja Miloslavsky; Robin Hume; Alison L. Hannah; Bijan Nejadnik; Robert J. Soiffer

Hepatic veno-occlusive disease, or sinusoidal obstruction syndrome (VOD/SOS), is a serious and potentially fatal complication of conditioning for hematopoietic stem cell transplantation (HSCT) or of chemotherapy regimens alone. Defibrotide is a complex mixture of single-stranded polydeoxyribonucleotides that is approved in the United States for treating hepatic VOD/SOS with renal or pulmonary dysfunction post-HSCT and in the European Union, Israel, and South Korea for treating severe hepatic VOD/SOS post-HSCT. Defibrotide was previously available in the United States as an investigational drug through a treatment protocol (treatment IND) study. Interim results of that large, treatment IND study of patients with VOD/SOS and with or without multiorgan dysfunction (MOD; also known as multiorgan failure) are presented here. Defibrotide was administered i.v. at 6.25 mg/kg every 6 hours (25 mg/kg/day), with a recommended treatment duration of at least 21 days. Enrolled patients (n = 681) were diagnosed with VOD/SOS based on Baltimore or modified Seattle criteria or liver biopsy analysis. Among the 573 HSCT recipients, 288 (50.3%; 95% confidence interval [CI], 46.2% to 54.4%) were alive at day +100 post-HSCT. Day +100 survival for the pediatric (≤16 years) and adult (>16 years) subgroups was 54.5% (95% CI, 49.1% to 60.0%; n = 174 of 319) and 44.9% (95% CI, 38.8% to 51.0%; n = 114 of 254), respectively. In the MOD subgroup, 159 of 351 patients (45.3%; 95% CI, 40.1% to 50.5%) of patients were alive at day +100 post-HSCT. Treatment with defibrotide was generally well tolerated, and drug-related toxicities were consistent with previous studies. Adverse events were reported in 69.6% of safety-evaluable patients (399 of 573). Other than VOD/SOS and associated MOD symptoms, the most commonly reported treatment-emergent adverse event was hypotension (13.8%). Day +100 survival results observed in this trial were consistent with results seen in previous trials of defibrotide for VOD/SOS in adult and pediatric patients. These data support the potential benefit of defibrotide in treating a VOD/SOS patient population that includes those with and without MOD.

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Hope S. Rugo

University of California

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Nancy A. Kernan

Memorial Sloan Kettering Cancer Center

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Stephan A. Grupp

Children's Hospital of Philadelphia

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Ahmad Awada

Université libre de Bruxelles

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