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Ezra E W Cohen,
Kehua Wu,
Christine Hartford,
Masha Kocherginsky,
Kimberly Napoli Eaton,
Yuanyuan Zha,
Anitha Nallari,
Michael L Maitland,
Kammi Fox-Kay,
Kristin Moshier,
Larry House,
Jacqueline Ramirez, Samir D Undevia,
Gini F Fleming,
Thomas F Gajewski,
Mark J Ratain
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ABSTRACT: Sirolimus is the eponymous inhibitor of the mTOR; however, only its analogs have been approved as cancer therapies. Nevertheless, sirolimus is readily available, has been well studied in organ transplant patients, and shows efficacy in several preclinical cancer models.
Three simultaneously conducted phase I studies in advanced cancer patients used an adaptive escalation design to find the dose of oral, weekly sirolimus alone or in combination with either ketoconazole or grapefruit juice that achieves similar blood concentrations as its intravenously administered and approved prodrug, temsirolimus. In addition, the effect of sirolimus on inhibition of p70S6 kinase phosphorylation in peripheral T cells was determined.
Collectively, the three studies enrolled 138 subjects. The most commonly observed toxicities were hyperglycemia, hyperlipidemia, and lymphopenia in 52%, 43%, and 41% of subjects, respectively. The target sirolimus area under the concentration curve (AUC) of 3,810 ng-h/mL was achieved at sirolimus doses of 90, 16, and 25 mg in the sirolimus alone, sirolimus plus ketoconazole, and sirolimus plus grapefruit juice studies, respectively. Ketoconazole and grapefruit juice increased sirolimus AUC approximately 500% and 350%, respectively. Inhibition of p70 S6 kinase phosphorylation was observed at all doses of sirolimus and correlated with blood concentrations. One partial response was observed in a patient with epithelioid hemangioendothelioma.
Sirolimus can be feasibly administered orally, once weekly with a similar toxicity and pharmacokinetic profile compared with other mTOR inhibitors and warrants further evaluation in studies of its comparative effectiveness relative to recently approved sirolimus analogs.
Clinical Cancer Research 08/2012; 18(17):4785-93. · 7.74 Impact Factor
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ABSTRACT: Background: Cilengitide (EMD121974) is a cyclized pentapeptide that is a potent and selective integrin antagonist which has shown activity
in malignant gliomas. In all previous studies, cilengitide has been administered in an intermittent fashion. However, cilengitide
has a short half-life of 3–5h with no evidence of drug accumulation. These data prompted the initiation of this phase I study
of continuous infusion cilengitide. Methods: Cilengitide was administered as a continuous infusion without break in 4-week cycles. Plasma samples for pharmacokinetic
studies were obtained weekly in cycle 1 immediately prior to and 2h after infusion bag change. Results: Thirty-five patients were treated (median age 56; 23 males) at dose levels of 1, 2, 4, 8, 12, 18, 27, and 40mg/h. Toxicities
were limited to grade ≤2 and showed no relation to dose. Fatigue was most common (17%), while all other toxicities were reported
in <10% of patients. No dose-limiting toxicities were observed, and therefore the maximum tolerated dose was not reached.
Pharmacokinetic analysis showed that values for clearance and volume of distribution were comparable across dose levels, and
the steady-state concentration increased proportionally with dose. Conclusions: Cilengitide can be safely administered as a continuous infusion at doses up to at least 40mg/h, which represents the maximum
feasible dose due to drug solubility and delivery limitations. The pharmacokinetics of continuous infusion cilengitide are
linear and consistent with the results obtained using a twice weekly infusion.
KeywordsCilengitide–EMD121974–Continuous infusion
Investigational New Drugs 04/2012; 30(2):604-610. · 3.36 Impact Factor
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[show abstract]
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ABSTRACT: Cilengitide (EMD121974) is a cyclized pentapeptide that is a potent and selective integrin antagonist which has shown activity in malignant gliomas. In all previous studies, cilengitide has been administered in an intermittent fashion. However, cilengitide has a short half-life of 3-5 h with no evidence of drug accumulation. These data prompted the initiation of this phase I study of continuous infusion cilengitide.
Cilengitide was administered as a continuous infusion without break in 4-week cycles. Plasma samples for pharmacokinetic studies were obtained weekly in cycle 1 immediately prior to and 2 h after infusion bag change.
Thirty-five patients were treated (median age 56; 23 males) at dose levels of 1, 2, 4, 8, 12, 18, 27, and 40 mg/h. Toxicities were limited to grade ≤ 2 and showed no relation to dose. Fatigue was most common (17%), while all other toxicities were reported in <10% of patients. No dose-limiting toxicities were observed, and therefore the maximum tolerated dose was not reached. Pharmacokinetic analysis showed that values for clearance and volume of distribution were comparable across dose levels, and the steady-state concentration increased proportionally with dose.
Cilengitide can be safely administered as a continuous infusion at doses up to at least 40 mg/h, which represents the maximum feasible dose due to drug solubility and delivery limitations. The pharmacokinetics of continuous infusion cilengitide are linear and consistent with the results obtained using a twice weekly infusion.
Investigational New Drugs 04/2012; 30(2):604-10. · 3.36 Impact Factor
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Tara C Gangadhar,
Ezra E W Cohen,
Kehua Wu,
Linda Janisch,
David Geary,
Masha Kocherginsky,
Larry K House,
Jackie Ramirez, Samir D Undevia,
Michael L Maitland,
Gini F Fleming,
Mark J Ratain
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ABSTRACT: Sirolimus is the prototypical mTOR inhibitor. Sorafenib and sunitinib are small molecule inhibitors of multiple kinases including VEGF receptor (VEGFR) kinases. These agents have different mechanisms of action, providing a strong rationale for combination.
Patients with advanced cancer were assigned to receive either sirolimus or the VEGFR inhibitor alone for a 2-week lead-in period, followed by combination therapy. The primary end point of each trial was to determine whether a drug interaction exists between sirolimus and either sorafenib or sunitinib, as defined by a difference in C(max) for each drug alone compared with its C(max) during combination therapy.
The sorafenib and sunitinib trials enrolled 34 and 23 patients, respectively. There were no clinically significant differences in C(max) for any of the drugs alone compared with the C(max) during combination therapy. Toxicity profiles were similar to those expected for each drug alone. One patient with adrenal cortical cancer had a partial response to sirolimus and sunitnib.
Sirolimus can be safely combined with sorafenib or sunitinib. Our trial design is feasible and informative in screening for potential drug-drug interactions, using a relatively small number of patients and limited pharmacokinetic sampling.
Clinical Cancer Research 03/2011; 17(7):1956-63. · 7.74 Impact Factor
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Nisha C Kakodkar,
Radhika Peddinti,
Morris Kletzel,
Yufeng Tian,
Lisa J Guerrero, Samir D Undevia,
David Geary,
Alexandre Chlenski,
Qiwei Yang,
Helen R Salwen,
Susan L Cohn
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ABSTRACT: The quinoxaline anti-tumor agent (R+)XK469 mediates its effects by topoisomerase IIB inhibition. This report describes a 14-year old with relapsed neuroblastoma who experienced disease stabilization for 14 months while receiving (R+)XK469 monotherapy. Due to this favorable response, laboratory studies were undertaken to determine efficacy in the preclinical setting. (R+)XK469 inhibited proliferation, caused G(2) cell cycle arrest of neuroblastoma cells in vitro, and inhibited growth of neuroblastoma xenograft tumors. These preclinical results, coupled with the favorable clinical response, demonstrate that (R+)XK469 and similar anti-tumor agents may be effective in the treatment of high-risk neuroblastoma and warrant further testing.
Pediatric Blood & Cancer 01/2011; 56(1):164-7. · 1.89 Impact Factor
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Peter H O'Donnell,
Andrew S Artz, Samir D Undevia,
Rish K Pai,
Paula Del Cerro,
Sarah Horowitz,
Lucy A Godley,
John Hart,
Federico Innocenti,
Richard A Larson,
Olatoyosi M Odenike,
Wendy Stock,
Koen Van Besien
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ABSTRACT: Disease recurrence after allogeneic hematopoietic cell transplant (alloHCT) remains common, making improvements in conditioning regimens desirable. A dose-response relationship between busulfan exposure and outcome is known. Using individual real-time monitoring of the busulfan area under the curve (AUC), we aimed to determine the maximum-tolerated busulfan AUC in a conditioning regimen with fludarabine/alemtuzumab. Thirty-six patients with advanced hematologic malignancies were treated. Busulfan levels after a test dose and conditioning dose 1 allowed targeting of subsequent AUCs and dose-escalation above the starting AUC of 4800 µmol-min/L. Clearance of busulfan test doses was not always sufficiently predictive of treatment dose AUC and, on average, test dose clearance was faster than treatment dose clearance. When the study was modified to use conditioning dose 1 pharmacokinetics instead, accurately targeted treatment AUCs were achieved, and dose-escalation was possible. Severe, late-occurring sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD) was the dose-limiting toxicity seen in 5/8 patients at an AUC level of 6800 µmol-min/L. The risk for SOS/VOD correlated with the highest observed AUC (AUC(max)) rather than with the average cumulative AUC (AUC(avg)). Busulfan dose-escalation to a maximum-tolerated AUC of 5800 µmol-min/L-higher than that achieved by current standard busulfan regimens-was accurate and achievable using real-time pharmacokinetics monitoring of the first conditioning dose. This AUC is now being studied in phase II for patients receiving busulfan/fludarabine/alemtuzumab as alloHCT conditioning.
Leukemia & lymphoma 10/2010; 51(12):2240-9. · 2.40 Impact Factor
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ABSTRACT: Hypertension is a mechanism-based toxicity of sorafenib and other cancer therapeutics that inhibit the vascular endothelial growth factor (VEGF) signaling pathway. This prospective, single-center, cohort study characterized ambulatory blood pressure monitoring as an early pharmacodynamic biomarker of VEGF signaling pathway inhibition by sorafenib.
Fifty-four normotensive advanced cancer patients underwent 24-hour ambulatory blood pressure monitoring before and between days 6 and 10 of sorafenib therapy. After blood pressure changes were detected among the first cohort within 10 days, ambulatory blood pressure monitoring was done during the first 24 hours of treatment for the second cohort.
For the entire patient population, the blood pressure increase [mean systolic, +10.8 mm Hg; 95% confidence interval (95% CI), 8.6-13.0; range, -5.2 to +28.7 mm Hg; mean diastolic, +8.0 mm Hg; 95% CI, 6.3-9.7; range, -4.4 to +27.1 mm Hg] was detected between days 6 and 10 (P < 0.0001 for both) and plateaued thereafter. Variability in blood pressure change did not associate with: age, body size, sex, self-reported race, baseline blood pressure, or steady-state sorafenib plasma concentrations. In the second cohort, the blood pressure elevation was detected during the first 24 hours (mean systolic, +8.2 mm Hg; 95% CI, 5.0-11.3; mean diastolic, +6.5 mm Hg; 95% CI, 4.7-8.3; P < 0.0001 for both).
Ambulatory blood pressure monitoring detects the blood pressure response to VEGF signaling pathway inhibition by sorafenib during the first 24 hours of treatment. The magnitude of blood pressure elevation is highly variable and unpredictable but could be important in optimizing the therapeutic index of VEGF signaling pathway inhibitor therapy.
Clinical Cancer Research 09/2009; 15(19):6250-7. · 7.74 Impact Factor
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ABSTRACT: Various neoadjuvant approaches have been evaluated for the treatment of locally advanced soft-tissue sarcomas. This retrospective study describes a uniquely modified version of the Eilber regimen developed at the University of Chicago.
We treated 34 patients (28 Stage III and 6 Stage IV) with locally advanced soft-tissue sarcomas of an extremity between 1995 and 2008. All patients received preoperative therapy including ifosfamide (2.5 g/m2 per day for 5 days) with concurrent radiation (28 Gy in 3.5-Gy daily fractions), sandwiched between various chemotherapy regimens. Postoperatively, 47% received further adjuvant chemotherapy.
Most tumors (94%) were Grade 3, and all were T2b, with a median size of 10.3 cm. Wide excision was performed in 29 patients (85%), and 5 required amputation. Of the resected tumor specimens, 50% exhibited high (> or =90%) treatment-induced necrosis and 11.8% had a complete pathologic response. Surgical margins were negative in all patients. The 5-year survival rate was 42.3% for all patients and 45.2% for Stage III patients. For limb-preservation patients, the 5-year local control rate was 89.0% and reoperation was required for wound complications in 17.2%. The 5-year freedom-from-distant metastasis rate was 53.4% (Stage IV patients excluded), and freedom from distant metastasis was superior if treatment-induced tumor necrosis was 90% or greater (84.6% vs. 19.9%, p = 0.02).
This well-tolerated concurrent chemoradiotherapy approach yields excellent rates of limb preservation and local control. The resulting treatment-induced necrosis rates are predictive of subsequent metastatic risk, and this information may provide an opportunity to guide postoperative systemic therapies.
International journal of radiation oncology, biology, physics 08/2009; 76(4):1147-53. · 4.59 Impact Factor
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ABSTRACT: XK469 is a novel topoisomerase II inhibitor structurally akin to several propionic acid derivatives, such as ibuprofen and diclofenac, which are metabolised by CYP2C9. We report eight subjects who experienced significant elevation of INR while receiving concomitant R(+)XK469 and warfarin. The aim of the study is to investigate whether R(+)XK469 interacts with S-warfarin by inhibition of CYP2C9.
The effect of R(+)XK469 on S-warfarin hydroxylation was determined by the measurement of S-7-hydroxywarfarin formation in pooled human liver microsomes and cDNA-expressed CYP2C9.
R(+)XK469 competitively inhibited S-warfarin hydroxylation. The K(i) values of R(+)XK469 were estimated to be 959+/-426 microM for human liver microsomes and to be 377+/-92 microM for CYP2C9.
At the recommended phase II dose of R(+)XK469, the ratio of C(max)/K(i) is >1. This suggests that coadministration of R(+)XK469 and warfarin results in a clinically significant pharmacokinetic interaction due to CYP2C9 inhibition by R(+)XK469.
European journal of cancer (Oxford, England: 1990) 05/2009; 45(11):1904-8. · 4.12 Impact Factor
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Wendy Stock, Samir D Undevia,
Carol Bivins,
Farhad Ravandi,
Olatoyosi Odenike,
Stefan Faderl,
Elizabeth Rich,
Gautam Borthakur,
Lucy Godley,
Srdan Verstovsek,
Andrew Artz,
William Wierda,
Richard A Larson,
Yanming Zhang,
Jorge Cortes,
Mark J Ratain,
Francis J Giles
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ABSTRACT: A phase I study was performed to determine the safety and pharmacokinetics of XK469R in patients with refractory acute leukemia. The study aimed to determine the maximum tolerated dose (MTD) and dose limiting toxicity (DLT) of XK469R given intravenously over 30 to 60 min on days 1, 3, and 5 of a 21 day cycle. Patients were treated in successive cohorts of six until DLT was observed. Once the MTD was determined, an additional cohort of six patients was enrolled at the previous dose level and that dose was considered the recommended phase 2 dose (RPTD). Forty-six patients were treated at dose levels of 1,400, 1,750, 2,200, and 2,750 mg. The DLTs were: mucositis, colitis and hyperbilirubinemia. Reversible myelosuppression was noted at all dose levels. One (2%) of 42 patients achieved a complete remission and five patients (11%) had hematologic improvement. The half-life of the drug was long with a mean value of 48 h. The mean clearance was 206 mL/h with a coefficient of variation of 32%. No correlation was observed between the development of DLT and pharmacokinetics. The RTPD is 1,750 mg. XK469R induced hematological responses in patients with refractory leukemia at tolerable doses.
Investigational New Drugs 09/2008; 26(4):331-8. · 3.36 Impact Factor
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ABSTRACT: To investigate the safety and pharmacokinetics of R(+)XK469, a quinoxaline analogue, in patients with advanced refractory solid tumours. Preclinical studies suggested that efficacy was independent of schedule but that toxicity was decreased by dividing the dose.
R(+)XK469 was initially administered as a 30 min intravenous infusion on days 1-5 of a 21-d cycle. Based on the demonstration of a long half-life, the dosing schedule was subsequently amended to infusion on days 1, 3 and 5 of a 21-d cycle. An alternate single-dose schedule of once every 21 d was also explored. Blood samples were collected for pharmacokinetic studies.
Dose-limiting toxicity (DLT) was neutropaenia. There was significant interindividual variability in clearance as evidenced by a coefficient of variation of 46%. A flat-dosing scheme (not based on body surface area) was justified by the absence of correlation between clearance and body surface area. A partial response was observed in a patient with nasopharyngeal carcinoma.
The recommended phase II doses are 850-1100 mg/d on days 1, 3 and 5 of a 21-d cycle and 2500 mg on day 1 of a 21-d cycle. The observed interpatient pharmacokinetic variability should prompt investigation into the presence of genetic polymorphism in relevant metabolizing enzymes.
European journal of cancer (Oxford, England: 1990) 08/2008; 44(12):1684-92. · 4.12 Impact Factor
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ABSTRACT: Malignant peripheral nerve sheath tumors are rare spindle-cell sarcomas derived from Schwann cells or pluripotent cells of the neural crest. They arise from the spinal roots, peripheral nerves, brachial and lumbosacral plexi, cranial nerves and terminal nerve fibers within soft tissue, intestine, lung and bone. These tumors recur either locally, or metastasize distally. Most of these tumors occur in association with neurofibromatosis type 1. Spinal cord metastasis from malignant nerve sheath tumors associated with neurofibromatosis type 1 is very rare. We describe a rare case of near-total spinal cord metastasis in a patient with malignant nerve sheath tumor in the absence of neurofibromatosis, and highlight the microscopic findings and natural history of this disease process.
Journal of Neuro-Oncology 10/2005; 74(2):183-5. · 3.21 Impact Factor
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ABSTRACT: The translation of advances in cancer biology to drug discovery can be complicated by pharmacokinetic variation between individuals and within individuals, and this can result in unpredictable toxicity and variable antineoplastic effects. Previously unrecognized variables (such as genetic polymorphisms) are now known to have a significant impact on drug disposition. How can the pharmacokinetic variability of anticancer agents be reduced? This will require the understanding of correlations between pharmacokinetics and treatment outcomes, the identification of relevant patient parameters, mathematical modelling of individual and population pharmacokinetics, and the development of algorithms that will tailor doses to the individual patient.
Nature reviews. Cancer 07/2005; 5(6):447-58. · 37.54 Impact Factor
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ABSTRACT: CEP-2563 dihydrochloride (CEP-2563) is a soluble lysinyl-beta-alanyl ester of CEP-751, a potent inhibitor of the trk family of receptor tyrosine kinases and the platelet-derived growth factor (PDGF) receptor tyrosine kinase. CEP-2563 was developed because of the limited aqueous solubility of CEP-751. Preclinical models have demonstrated that both CEP-751 and CEP-2563 have antitumor activity in a variety of tumors. A Phase I clinical trial involving 18 patients was conducted to determine the toxicity profile, maximum tolerated dose (MTD), toxicity profile, and pharmacokinetics of CEP-2563 in patients with advanced solid tumors refractory to standard therapy. CEP-2563 was administered over 1 hour via a central venous catheter once daily for five consecutive days every three weeks. A rapid dose titration strategy with initial single patient cohorts and 100% dose escalations was used. With the appearance of drug-related toxicity, escalations were decreased to 50% or 25% and cohorts were expanded to 3 or 6 patients until establishment of the MTD. Dose escalation rapidly proceeded to 320 mg/m(2)/d. The dose limiting toxicities (DLTs) observed were grade 3 hypotension and grade 2 allergic reaction. Other toxicities included anemia, thrombocytopenia, anorexia, asthenia, diarrhea, fatigue, headache, nausea, vomiting, and rash. Pharmacokinetic analysis showed that CEP-2563 is reliably converted to CEP-751. This study demonstrated that single agent CEP-2563 therapy is feasible with acceptable toxicities. The recommended phase II dose is 256 mg/m(2)/d. Rapid dose escalation with single patient cohorts was a safe and efficient method of conducting this phase I trial.
Investigational New Drugs 12/2004; 22(4):449-58. · 3.36 Impact Factor
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ABSTRACT: The anticancer agent irinotecan has been demonstrated to improve the survival rate in patients with metastatic colorectal cancer. Its usage has been limited by severe toxicity. To modulate irinotecan pharmacokinetics and reduce the prevalence of severe toxicity, patients were treated with cyclosporine (INN, ciclosporin) and the irinotecan dose was increased from 25 to 72 mg/m2 weekly. Phenobarbital was then added, allowing dose escalation to 144 mg/m2. Dose-limiting toxicities were neutropenia and diarrhea. Irinotecan was well tolerated at the recommended phase II dose of 120 mg/m2, with a 6% prevalence of grade 4 neutropenia and an 18% prevalence of grade 3 diarrhea. Cyclosporine increased 7-ethyl-10-hydroxycamptothecin (SN-38) area under the concentration-time curve (AUC) by 23% to 630% and reduced irinotecan clearance by 39% to 64% when compared with historical controls. Phenobarbital increased irinotecan clearance by 27% (P < or =.001) and reduced SN-38 AUC by 75% (P < or =.001) when compared with patients treated with cyclosporine alone. Five partial responses were observed. Pharmacokinetic modulation of irinotecan with cyclosporine and phenobarbital has been demonstrated; further studies are necessary to evaluate whether this strategy improves the therapeutic index.
Clinical Pharmacology & Therapeutics 11/2004; 76(5):490-502. · 6.04 Impact Factor
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ABSTRACT: Atrasentan is an orally bioavailable selective antagonist of the endothelin receptor ET(A). Due to the potential activity of this agent against prostate cancer, the majority of subjects enrolled in prior studies had been male. This Phase I study sought to determine the toxicity and pharmacokinetics of daily atrasentan in a population of both female and male subjects with advanced malignancies.
Patients with refractory malignancies received atrasentan once daily at doses ranging from 5 mg to 75 mg. At least 3 subjects were treated at each dose level before enrollment began at the next higher dose level. Enrollment for specific dose levels was expanded if any subject experienced serious drug-related toxicity. Plasma concentration profiles for atrasentan were determined after dosing on days 1 and 28.
Thirty-five patients received atrasentan at doses from 5 mg to 75 mg. The most frequent drug-related adverse events were headache (60%), rhinitis (49%), and peripheral edema (31%). These toxicities were mild to moderate in severity and reversible on cessation of treatment. Dose escalation was stopped at the 75-mg dose level due to the occurrence of three severe adverse events (2 hyponatremia and 1 hypotension). Atrasentan was rapidly absorbed after oral administration; mean time to maximum observed concentration ranged from 0.3 to 1.7 h. Terminal elimination half-life averaged 26 h. No significant difference between sexes was found in any atrasentan pharmacokinetic parameter tested, including maximum observed plasma concentration, time to maximum observed concentration, minimum observed plasma concentration, area under the plasma concentration-time curve, and elimination rate constant.
Atrasentan is well tolerated in both female and male cancer patients at doses of up to 60 mg/day with dose-limiting toxicity observed at 75 mg/day. The most frequently observed toxicities were headache, rhinitis, and edema. There was no statistically significant difference in atrasentan pharmacokinetics between sexes.
Clinical Cancer Research 08/2004; 10(13):4406-11. · 7.74 Impact Factor
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Federico Innocenti, Samir D Undevia,
Lalitha Iyer,
Pei Xian Chen,
Soma Das,
Masha Kocherginsky,
Theodore Karrison,
Linda Janisch,
Jacqueline Ramírez,
Charles M Rudin,
Everett E Vokes,
Mark J Ratain
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ABSTRACT: Severe toxicity is commonly observed in cancer patients receiving irinotecan. UDP-glucuronosyltransferase 1A1 (UGT1A1) catalyzes the glucuronidation of the active metabolite SN-38. This study prospectively evaluated the association between the prevalence of severe toxicity and UGT1A1 genetic variation.
Sixty-six cancer patients with advanced disease refractory to other treatments received irinotecan 350 mg/m(2) every 3 weeks. Toxicity and pharmacokinetic data were measured during cycle 1. UGT1A1 variants (-3279G>T, -3156G>A, promoter TA indel, 211G>A, 686C>A) were genotyped.
The prevalence of grade 4 neutropenia was 9.5%. Grade 4 neutropenia was much more common in patients with the TA indel 7/7 genotype (3 of 6 patients; 50%) compared with 6/7 (3 of 24 patients; 12.5%) and 6/6 (0 of 29 patients; 0%) (P =.001). The TA indel genotype was significantly associated with the absolute neutrophil count nadir (7/7 < 6/7 < 6/6, P =.02). The relative risk of grade 4 neutropenia was 9.3 (95% CI, 2.4 to 36.4) for the 7/7 patients versus the rest of the patients. Pretreatment total bilirubin levels (mean +/- standard deviation) were significantly higher in patients with grade 4 neutropenia (0.83 +/- 0.08 mg/dL) compared to those without grade 4 neutropenia (0.47 +/- 0.03 mg/dL; P <.001). The -3156G>A variant seemed to distinguish different phenotypes of total bilirubin within the TA indel genotypes. The -3156 genotype and the SN-38 area under the concentration versus time curve were significant predictors of ln(absolute neutrophil count nadir; r(2) = 0.51).
UGT1A1 genotype and total bilirubin levels are strongly associated with severe neutropenia, and could be used to identify cancer patients predisposed to the severe toxicity of irinotecan. The hypothesis that the -3156G>A variant is a better predictor of UGT1A1 status than the previously reported TA indel requires further testing.
Journal of Clinical Oncology 04/2004; 22(8):1382-8. · 18.37 Impact Factor
