Howard A. Burris III

Sarah Cannon Research Institute, Nashville, Tennessee, United States

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Publications (16)77.91 Total impact

  • Cancer Research 05/2015; 75(9 Supplement):OT2-1-08-OT2-1-08. DOI:10.1158/1538-7445.SABCS14-OT2-1-08 · 9.33 Impact Factor
  • Cancer Research 05/2015; 75(9 Supplement):OT2-3-01-OT2-3-01. DOI:10.1158/1538-7445.SABCS14-OT2-3-01 · 9.33 Impact Factor
  • Cancer Research 05/2015; 75(9 Supplement):OT2-1-07-OT2-1-07. DOI:10.1158/1538-7445.SABCS14-OT2-1-07 · 9.33 Impact Factor
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    ABSTRACT: Trametinib (Mekinist®) is a selective inhibitor of mitogen-activated protein kinase kinase (MEK) approved in the United States as a single agent and in combination with dabrafenib (Tafinlar®) for treatment of patients with unresectable or metastatic melanoma with a positive BRAF V600E/V600K mutation for which a pediatric oral solution formulation is being developed. This open-label, two-period, two-treatment, randomized, crossover study assessed the relative bioavailability of the trametinib pediatric oral solution compared to the tablet formulation after a single-dose administration to adult patients with solid tumors. Primary pharmacokinetic endpoints derived from standard non-compartmental methods were AUC0-inf, AUC0-t, and Cmax. As expected, Cmax was higher and Tmax earlier for the pediatric oral solution compared to the tablet formulation. Administration of the trametinib pediatric oral solution resulted in a 12%, 10%, 18% and 71% higher AUC0-inf, AUClast, AUC0-24 and Cmax, respectively, as compared to the tablet formulation. Safety results were aligned with the known safety profile of trametinib. No serious or non-serious adverse events resulted in study drug withdrawal. Palatability of the pediatric oral solution was evaluated and found to be acceptable to most adult patients, but may differ in the pediatric population.
    Clinical Pharmacology in Drug Development 10/2014; 4(4). DOI:10.1002/cpdd.152
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    ABSTRACT: Background: We assessed the maximum tolerated regimen (MTR) and dose-limiting toxicities of pazopanib and lapatinib in combination with weekly paclitaxel, and the effect of pazopanib and lapatinib on paclitaxel pharmacokinetics. Methods: Patients received intravenous paclitaxel on days 1, 8, and 15 of a 28-day cycle concurrently with daily pazopanib and lapatinib. Dose levels of paclitaxel (mg m−2)/pazopanib(mg)/lapatinib(mg) were 50/400/1000, 50/800/1000, 80/800/1000, and 80/400/1000. At the MTR, additional patients were enrolled to further evaluate tolerability, and the potential effects of pazopanib and lapatinib, inhibitors of cytochrome P450 (CYP)3A4, on the pharmacokinetics of paclitaxel, a CYP2C8 and CYP3A4 substrate. Results: Twenty-six patients were enrolled. Dose-limiting toxicities at the MTR (80/400/1000) included grade 4 thrombosis and grade 3 aspartate aminotransferase elevation. Other toxicities included diarrhoea, neutropenia, fatigue, and liver enzyme elevations. Coadministration of pazopanib 400 mg and lapatinib 1000 mg increased paclitaxel maximum plasma concentration (38%) and area under the curve (37%) relative to paclitaxel alone. One patient with a salivary gland tumour had a partial response; three patients had stable disease (⩾6 months). Conclusions: Pazopanib 400 mg per day and lapatinib 1000 mg per day can be combined with paclitaxel 80 mg m−2 in 28-day cycles. Coadministration of pazopanib and lapatinib, weak inhibitors of CYP2C8 and CYP3A4, had an inhibitory effect on paclitaxel clearance.
    British Journal of Cancer 05/2014; 110(11). DOI:10.1038/bjc.2014.233 · 4.84 Impact Factor
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    ABSTRACT: Background: Rucaparib, a potent, oral small molecule inhibitor of poly (ADP-ribose) polymerase (PARP) 1 and −2, is being developed for treatment of homologous recombination repair deficient (HRD) ovarian cancer. This study evaluated rucaparib as monotherapy. Primary objectives were to define the maximum tolerated dose (MTD), recommended Phase 2 dose (RP2D), and PK of continuous oral rucaparib. Materials and Methods: A standard 3+3 dose escalation design was used. Intra-patient dose escalation was allowed. Patients (pts) aged ≥18 with advanced solid tumor that progressed on standard treatments were recruited. Measurable disease was not required. Rucaparib was taken orally qd or bid continuously until disease progression. Plasma PK assessments included full profile, trough levels, and food effect. Results: 33 pts (median age 49yrs [range 21–71]; 30 female; 17 ECOG PS=0; 18 breast cancer (BC), 10 ovarian/peritoneal cancer (OC), 5 other tumor) were enrolled in 7 dose cohorts (40, 80, 160, 300 and 500mg qd, and 240, 360mg bid). One pt at 360mg bid experienced DLT of CTCAE grade 3 nausea. No pts discontinued treatment due to toxicity. Treatment-related adverse events (primarily grade 1–2) reported in ≥10% of pts include fatigue (n=8), nausea (n=5), anorexia (n=4), vomiting (n=4), and diarrhea (n=3). Grade 3/4 toxicities have been minimal and no myelosuppression has been observed. To date, two pts (1 BC, 1 OC; both BRCA1mut; 300mg qd) achieved a PR (duration 14 and 21+ wks, respectively). An additional 10 pts (5 OC, 4 BC, 1 CRC; 7 BRCAmut, 2 BRCAunk, 1 BRCAwt) achieved a best response of stable disease (SD) >12 wks thus far. Three pts (all BRCAmut OC) are ongoing in wks 26, 27, and 40. Five recently enrolled pts are also ongoing. Overall disease control rate (CR+PR+SD>12 wks) to date in all evaluable OC pts across all dose levels is 86% (6/7). Dose proportional PK was observed up to 500mg qd with mean t1/2 of 15h (range 4.3–29h). Following qd dosing, steady state was achieved by Day 8. As expected, bid dosing increased trough levels above 2µM target with low interpatient variability. Conclusion: Continuous oral rucaparib is well tolerated, with encouraging clinical activity, including objective responses and durable SD, observed during dose-escalation. Once confirmed, the RP2D will be evaluated in platinum-sensitive OC pts with a gBRCA mutation.
    European Society of Medical Oncology 2013, European Journal of Cancer, September 2013; 09/2013
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    ABSTRACT: Background Postmenopausal women with hormone receptor–positive (HR+) breast cancer in whom disease progresses or there is recurrence while taking a nonsteroidal aromatase inhibitor (NSAI) are usually treated with exemestane (EXE), but no single standard of care exists in this setting. The BOLERO-2 trial demonstrated that adding everolimus (EVE) to EXE improved progression-free survival (PFS) while maintaining quality of life when compared with EXE alone. Because many women with HR+ advanced breast cancer are elderly, the tolerability profile of EVE plus EXE in this population is of interest. Patients and Methods BOLERO-2, a phase III randomized trial, compared EVE (10 mg/d) and placebo (PBO), both plus EXE (25 mg/d), in 724 postmenopausal women with HR+ advanced breast cancer recurring/progressing after treatment with NSAIs. Safety and efficacy data in elderly patients are reported at 18-month median follow-up. Results Baseline disease characteristics and treatment histories among the elderly subsets (≥ 65 years, n = 275; ≥ 70 years, n = 164) were generally comparable with younger patients. The addition of EVE to EXE improved PFS regardless of age (hazard ratio, 0.59 [≥ 65 years] and 0.45 [≥ 70 years]). Adverse events (AEs) of special interest (all grades) that occurred more frequently with EVE than with PBO included stomatitis, infections, rash, pneumonitis, and hyperglycemia. Elderly EVE-treated patients had similar incidences of these AEs as did younger patients but had more on-treatment deaths. Conclusion Adding EVE to EXE offers substantially improved PFS over EXE and was generally well tolerated in elderly patients with HR+ advanced breast cancer. Careful monitoring and appropriate dose reductions or interruptions for AE management are recommended during treatment with EVE in this patient population.
    Clinical Breast Cancer 01/2013; 13(6):421–432.e8. · 2.11 Impact Factor
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    ABSTRACT: Purpose: IHL-305 is a novel PEGylated liposome containing irinotecan. This study examined the safety profile and pharmacokinetics of IHL-305 and established the maximum tolerated dose and recommended phase II dose (RP2D). Patients and methods: In a standard 3 + 3 design, IHL-305 was administered IV on day 1 of a 28-day treatment schedule. Subsequently, a 14-day treatment schedule was also explored. Two patient populations were evaluated separately: Patients with at least one wild-type (wt) allele of UGT1A1 (UDP glucoronosyltransferase 1A1) wt/wt or wt/*28 as one group (referred to as UGT1A1 wt group) and patients with UGT1A1*28 homozygous variant (*28/*28) as another group. Results: Sixty patients were treated: 42 on the 28-day schedule and 18 on the 14-day schedule. Seven patients were homozygous variant (*28/*28). In the UGT1A1 wt group, the MTD and RP2D of IHL-305 was 160 mg/m(2) every 28 days and 80 mg/m(2) every 14 days. DLTs included nausea, vomiting, diarrhea, and neutropenia. The most common adverse events were nausea (75 %), vomiting (52 %), diarrhea (62 %), anorexia (57 %), and fatigue (57 %). At the MTD for both schedules, IHL-305 administration resulted in a high and prolonged exposure of sum total irinotecan, released irinotecan, and SN-38 in plasma. One partial response was observed in a patient with breast cancer and eight patients had stable disease for >6 months. Conclusions: IHL-305, a novel preparation of irinotecan encapsulated in liposomes, can be safely given to patients in a repeated fashion on a 4- or 2-week dosing schedule.
    Cancer Chemotherapy and Pharmacology 09/2012; 70(5). DOI:10.1007/s00280-012-1960-5 · 2.77 Impact Factor
  • Howard A. Burris III
    Community Oncology 09/2012; 9(9):S23–S25. DOI:10.1016/j.cmonc.2012.09.001
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    ABSTRACT: Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate comprising trastuzumab and DM1, a microtubule polymerization inhibitor, covalently bound via a stable thioether linker. To characterize the pharmacokinetics (PK) of T-DM1 in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer, data from four studies (TDM3569g, TDM4258g, TDM4374g, and TDM4688g) of single-agent T-DM1 administered at 3.6 mg/kg every 3 weeks (q3w) were assessed in aggregate. Multiple analytes-T-DM1, total trastuzumab (TT), DM1, and key metabolites-were quantified using enzyme-linked immunosorbent assays or liquid chromatography tandem mass spectrometry. PK parameters of T-DM1, TT, and DM1 exposure were calculated using standard noncompartmental approaches and correlated to efficacy (objective response rate) and safety (platelet counts, hepatic transaminase concentrations). Immunogenicity was evaluated by measuring anti-therapeutic antibodies (ATA) to T-DM1 after repeated dosing using validated bridging antibody electrochemiluminescence or enzyme-linked immunosorbent assays. PK parameters for T-DM1, TT, and DM1 were consistent across studies at cycle 1 and steady state. T-DM1 PK was not affected by residual trastuzumab from prior therapy or circulating extracellular domain of HER2. No significant correlations were observed between T-DM1 exposure and efficacy, thrombocytopenia, or increased concentrations of transaminases. Across the studies, ATA formation was detected in 4.5% (13/286) of evaluable patients receiving T-DM1 q3w. The PK profile of single-agent T-DM1 (3.6 mg/kg q3w) is predictable, well characterized, and unaffected by circulating levels of HER2 extracellular domain or residual trastuzumab. T-DM1 exposure does not correlate with clinical responses or key adverse events.
    Cancer Chemotherapy and Pharmacology 01/2012; 69(5):1229-40. DOI:10.1007/s00280-011-1817-3 · 2.77 Impact Factor
  • EJC Supplements 11/2010; 8(7):119-119. DOI:10.1016/S1359-6349(10)72082-6 · 9.39 Impact Factor
  • EJC Supplements 09/2009; 7(2):546-546. DOI:10.1016/S1359-6349(09)71850-6 · 9.39 Impact Factor
  • EJC Supplements 09/2009; 7(2):266-267. DOI:10.1016/S1359-6349(09)70912-7 · 9.39 Impact Factor
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    ABSTRACT: Background We previously reported the development of tracheoesophageal (TE) fistulae in patients with small-cell lung cancer (SCLC) treated with chemoradiation and concurrent and sequential bevacizumab (J Clin Oncol 2008; 26(15 suppl):410s [Abstract 7554]). In this phase II trial, we evaluated concurrent chemoradiation and bevacizumab in patients with unresectable stage III non—small-cell lung cancer (NSCLC) and observed similar fistula development.Patients and Methods This was a phase II trial designed to enroll 50 patients, with a primary aim of achieving a 40% improvement in historical 10-month median time to progression (α, .05; β, .20). Patients with newly diagnosed unresectable nonsquamous stage III NSCLC, measurable disease, Eastern Cooperative Oncology Group performance status 0/1, signed informed consent, and no pleural or pericardial effusions were eligible. Hemoptysis or need for anticoagulation were exclusion factors. Treatment was composed of induction, consolidation, and maintenance phases. Induction treatment included carboplatin area under the curve (AUC) = 5 intravenous (I.V.), pemetrexed 500 mg/m2 I.V., and bevacizumab 15 mg/kg I.V. weeks 1 and 4. Radiation was administered concurrently 1.8 Gy per day to 61.2 Gy. After a break in therapy from weeks 8 to 16, consolidative therapy commenced and included carboplatin AUC = 6 I.V., pemetrexed 500 mg/m2 I.V., and bevacizumab 15 mg/kg I.V. weeks 16, 19, and 22. Maintenance therapy was composed of bevacizumab 15 mg/kg every 3 weeks for 9 cycles. Patients were restaged after induction and consolidation phases (per Response Evaluation Criteria in Solid Tumors).ResultsEnrollment was staggered in groups of 5 for safety monitoring beginning in February 2007. Among the first 5 patients, 2 patients developed TE fistulae. Patient 1 developed a TE fistula 34 weeks into therapy (during the fourth maintenance bevacizumab and 26 weeks after chemoradiation). Patient 2 developed a TE fistula 40 weeks into therapy (during the sixth maintenance bevacizumab and 32 weeks after chemoradiation). Both patients experienced antecedent severe esophagitis. Both patients were managed with stents and are alive. The other 3 patients have not developed TE fistulae to date and are alive. The trial was subsequently closed for safety in December 2007.ConclusionTE fistula development has occurred in both SCLC and NSCLC trials where chemotherapy, bevacizumab, and radiation were administered. Strategies to safely incorporate novel therapies into standard chemoradiation lung cancer regimens are needed.
    Clinical Lung Cancer 09/2008; 9(5):303. DOI:10.1016/S1525-7304(11)70869-5 · 3.10 Impact Factor
  • Lung Cancer 08/2003; 41. DOI:10.1016/S0169-5002(03)92543-8 · 3.96 Impact Factor
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    ABSTRACT: The purpose of the study was to evaluate the combination of gemcitabine and vinorelbine in the treatment of patients with relapsed or refractory small cell lung cancer. Between March 1998 and February 1999, 30 patients with relapsed or refractory small cell lung cancer who had received treatment with one previous combination chemotherapy regimen entered this multicenter, community-based clinical trial. All patients had received previous platinum/etoposide combination chemotherapy; in addition, 12 patients had received paclitaxel as part of their first-line therapy. All patients received gemcitabine 1000 mg/m(2) and vinorelbine 20 mg/m(2) on days 1, 8, and 15 of each 28-day cycle. Patients were reevaluated for response after two cycles of therapy; those with objective response or stable disease continued treatment for six courses or until disease progression. Three of 28 evaluable patients (10%) had partial responses to treatment. None of the 17 patients with refractory disease responded, while 3 of 12 patients (25%) with relapsed disease had partial responses. Median survival was 5 months. Treatment was generally well tolerated; myelosuppression was the major toxicity, but only two patients developed febrile neutropenia, and there were no treatment-related deaths. Non-hematologic toxicity was uncommon; alopecia did not occur with this regimen. The activity of gemcitabine and vinorelbine in patients with previously treated small cell lung cancer is modest and is limited to patients with relapsed (versus refractory) disease. In patients with relapsed small cell lung cancer, this regimen provides an additional treatment option, with decreased toxicity when compared to other second-line options. However, novel treatment approaches are necessary before substantial improvements in treating this patient population will be realized.
    Cancer Investigation 01/2003; 21(2):193-199. DOI:10.1081/CNV-120016415 · 2.22 Impact Factor