Utah Cancer Specialists

Salt Lake City, UT, United States

Utah Cancer Specialists

Salt Lake City, UT, United States

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Saltz L.,Sloan Kettering Cancer Center | Badarinath S.,North Florida Hematology and Oncology Associates | Bienvenu B.,Louisiana Hematology Oncology Associates | Harker W.G.,Utah Cancer Specialists | And 19 more authors.
Clinical Colorectal Cancer | Year: 2012

Background: Cetuximab (C), alone or with irinotecan, demonstrates activity in irinotecan-refractory colorectal cancer (CRC). Activity of 5-fluorouracil (5-FU), leucovorin (L), and bevacizumab (B), and preliminary data of cetuximab + bevacizumab, and toxicity profiles suggests that FOLF-CB (5-FU, L, C+B) may have activity with a favorable toxicity profile as first-line therapy. Methods: Eligible patients were randomized at registration to either arm A (mFOLFOX6-B) (modified, 5-FU. L (folinic acid), oxaliplatin (O) + bevacizumab), administered days 1 and 15 of each 28-day cycle as bevacizumab 5 mg/kg, oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, and 5-FU 400 mg/m2 then 1200 mg/m2/day for 48 hours, or arm B (FOLF-CB), which included bevacizumab, leucovorin, and 5-FU as in arm A and cetuximab 400 mg/m 2 day 1 cycle 1; all other weekly cetuximab doses were 250 mg/m 2. Results: Two hundred forty-seven patients (arm A/arm B 124/123) were enrolled, and 239 were treated (118/121). Twelve-month progression-free survival (PFS) was 45%/32%, objective response rates (ORR) (complete response [CR] + partial response [PR]) were 52%/41%, disease control rates (CR+PR+stable disease [SD]) were 87%/83%, and median overall survival (OS) was 21/19.5 months, respectively. Grade 3-4 neutropenia was higher in arm A (28%/7%), as was grade 3 fatigue (12%/3%), and grade 3 neuropathy (11%/< 1%), whereas acneiform rash was confined to arm B. Retrospective analysis of KRAS mutational status did not demonstrate KRAS as a meaningful determinant of activity, except in arm B patients with KRAS-mutated tumors, which resulted in inferior PFS. Patient satisfaction favored the control (mFOLFOX6-B). Conclusion: FOLF-CB was not superior to mFOLFOX6-B in terms of 12-month PFS and ORR, and was not more acceptable to patients. This trial supports the conclusion of other recently reported trials that concurrent cetuximab+bevacizumab should not be routinely used in metastatic CRC. © 2012 Elsevier Inc. All rights reserved.


Wang Y.-F.,Peking University | Yang Y.-L.,Peking University | Gao Z.-F.,Peking University | Zhou C.-J.,Beijing Childrens Hospital | And 5 more authors.
Journal of Hematology and Oncology | Year: 2012

Background: Systemic anaplastic large cell lymphoma (S-ALCL) is a rare disease with a highly variable prognosis and no standard chemotherapy regimen. Anaplastic lymphoma kinase (ALK) has been reported as an important prognostic factor correlated with S-ALCL in many but not all studies. In our study, we retrospectively analyzed 92 patients with S-ALCL from the Peking University Lymphoma Center for clinical and molecular prognostic factors to make clear the role of ALK and other prognostic factors in Han Chinese S-ALCL. Results: The majority of Chinese S-ALCL patients were young male patients (median age 26, male/female ratio 1.7) and the median age was younger than previous reports regardless of ALK expression status. The only statistically significant different clinical characteristic in S-ALCL between ALK positive (ALK +) and ALK negative (ALK-) was age, with a younger median age of 22 for ALK+ compared with 30 for ALK-. However, when pediatric patients (18) were excluded, there was no age difference between ALK+ and ALK-. The groups did not differ in the proportion of males, those with clinical stage III/IV (49 vs 51%) or those with extranodal disease (53 vs 59%). Of 73 evaluable patients, the 3-year and 5-year survival rates were 60% and 47%, respectively. Univariate analysis showed that three factors: advanced stage III/IV, lack of expression of ALK, and high Ki-67 expression, were associated with treatment failure in patients with S-ALCL. However, ALK expression correlated with improved survival only in patients younger than 14years, while not in adult patients. In multivariate analysis, only clinical stage was an independent prognostic factor for survival. Expressions of Wilms tumor 1 (WT1) and B-cell lymphoma 2 protein (BCL-2) correlated with the expression of ALK, but they did not have prognostic significance. High Ki-67 expression was also a poor prognostic factor. Conclusions: Our results show that ALK expression alone is not sufficient to determine the outcome of ALCL and other prognostic factors must be considered. Clinical stage is an independent prognostic factor. Ki-67 expression is a promising prognostic factor. © 2012 Wang et al.; licensee BioMed Central Ltd.


Brufsky A.M.,University of Pittsburgh | Harker W.G.,Utah Cancer Specialists | Beck J.T.,Highlands Oncology Group | Bosserman L.,Wilshire Oncology Medical Group Inc. | And 8 more authors.
Cancer | Year: 2012

Background: Postmenopausal breast cancer (BC) patients receiving adjuvant aromatase inhibitor therapy are at risk of progressive bone loss and fractures. Zoledronic acid inhibits osteoclastic bone resorption, is effective in maintaining bone health, and may therefore be beneficial in this setting. Methods: Overall, 602 postmenopausal women with early, hormone receptor-positive BC receiving adjuvant letrozole were randomized (301 each group) to receive upfront or delayed-start zoledronic acid (4 mg intravenously every 6 months) for 5 years. The primary endpoint was the change in lumbar spine (LS) bone mineral density (BMD) at month 12. Secondary endpoints included changes in LS BMD, total hip BMD, and bone turnover markers at 2, 3, and 5 years; fracture incidence at 3 years; and time to disease recurrence. Results: At month 61, the adjusted mean difference in LS and total hip BMDs between the upfront and delayed groups was 8.9% and 6.7%, respectively (P <.0001, for both). Approximately 25% of delayed patients received zoledronic acid by month 61. Only 1 patient experienced grade 4 renal dysfunction; no confirmed cases of osteonecrosis of the jaw were reported. Fracture rates (upfront, 28 [9.3%]; delayed, 33 [11%]; P =.3803) and Kaplan-Meier disease recurrence rates (upfront, 9.8 [95% confidence interval (CI), 6.0-10.3]; delayed, 10.5 [95% CI, 6.6-14.4]; P =.6283) were similar at month 61. Conclusions: Upfront zoledronic acid seems to be the preferred treatment strategy versus delayed administration, as it significantly and progressively increases BMD in postmenopausal women with early BC receiving letrozole for 5 years, and long-term coadministration of letrozole and zoledronic acid is well tolerated. © 2011 American Cancer Society.


Chan A.,Curtin University Australia | Delaloge S.,Institute Gustave Roussy | Holmes F.A.,Texas Oncology | Moy B.,Massachusetts General Hospital | And 26 more authors.
The Lancet Oncology | Year: 2016

Background: Neratinib, an irreversible tyrosine-kinase inhibitor of HER1, HER2, and HER4, has clinical activity in patients with HER2-positive metastatic breast cancer. We aimed to investigate the efficacy and safety of 12 months of neratinib after trastuzumab-based adjuvant therapy in patients with early-stage HER2-positive breast cancer. Methods: We did this multicentre, randomised, double-blind, placebo-controlled, phase 3 trial at 495 centres in Europe, Asia, Australia, New Zealand, and North and South America. Eligible women (aged ≥18 years, or ≥20 years in Japan) had stage 1-3 HER2-positive breast cancer and had completed neoadjuvant and adjuvant trastuzumab therapy up to 2 years before randomisation. Inclusion criteria were amended on Feb 25, 2010, to include patients with stage 2-3 HER2-positive breast cancer who had completed trastuzumab therapy up to 1 year previously. Patients were randomly assigned (1:1) to receive oral neratinib 240 mg per day or matching placebo. The randomisation sequence was generated with permuted blocks stratified by hormone receptor status (hormone receptor-positive [oestrogen or progesterone receptor-positive or both] vs hormone receptor-negative [oestrogen and progesterone receptor-negative]), nodal status (0, 1-3, or ≥4), and trastuzumab adjuvant regimen (sequentially vs concurrently with chemotherapy), then implemented centrally via an interactive voice and web-response system. Patients, investigators, and trial sponsors were masked to treatment allocation. The primary outcome was invasive disease-free survival, as defined in the original protocol, at 2 years after randomisation. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00878709. Findings: Between July 9, 2009, and Oct 24, 2011, we randomly assigned 2840 women to receive neratinib (n=1420) or placebo (n=1420). Median follow-up time was 24 months (IQR 20-25) in the neratinib group and 24 months (22-25) in the placebo group. At 2 year follow-up, 70 invasive disease-free survival events had occurred in patients in the neratinib group versus 109 events in those in the placebo group (stratified hazard ratio 0·67, 95% CI 0·50-0·91; p=0·0091). The 2-year invasive disease-free survival rate was 93·9% (95% CI 92·4-95·2) in the neratinib group and 91·6% (90·0-93·0) in the placebo group. The most common grade 3-4 adverse events in patients in the neratinib group were diarrhoea (grade 3, n=561 [40%] and grade 4, n=1 [<1%] vs grade 3, n=23 [2%] in the placebo group), vomiting (grade 3, n=47 [3%] vs n=5 [<1%]), and nausea (grade 3, n=26 [2%] vs n=2 [<1%]). QT prolongation occurred in 49 (3%) patients given neratinib and 93 (7%) patients given placebo, and decreases in left ventricular ejection fraction (≥grade 2) in 19 (1%) and 15 (1%) patients, respectively. We recorded serious adverse events in 103 (7%) patients in the neratinib group and 85 (6%) patients in the placebo group. Seven (<1%) deaths (four patients in the neratinib group and three patients in the placebo group) unrelated to disease progression occurred after study drug discontinuation. The causes of death in the neratinib group were unknown (n=2), a second primary brain tumour (n=1), and acute myeloid leukaemia (n=1), and in the placebo group were a brain haemorrhage (n=1), myocardial infarction (n=1), and gastric cancer (n=1). None of the deaths were attributed to study treatment in either group. Interpretation: Neratinib for 12 months significantly improved 2-year invasive disease-free survival when given after chemotherapy and trastuzumab-based adjuvant therapy to women with HER2-positive breast cancer. Longer follow-up is needed to ensure that the improvement in breast cancer outcome is maintained. Funding: Wyeth, Pfizer, Puma Biotechnology. © 2016 Elsevier Ltd.


PubMed | South Texas Oncology and Hematology, Texas Oncology, Instituto Valenciano Of Oncologia, Complutense University of Madrid and 23 more.
Type: Clinical Trial, Phase III | Journal: The Lancet. Oncology | Year: 2016

Neratinib, an irreversible tyrosine-kinase inhibitor of HER1, HER2, and HER4, has clinical activity in patients with HER2-positive metastatic breast cancer. We aimed to investigate the efficacy and safety of 12 months of neratinib after trastuzumab-based adjuvant therapy in patients with early-stage HER2-positive breast cancer.We did this multicentre, randomised, double-blind, placebo-controlled, phase 3 trial at 495 centres in Europe, Asia, Australia, New Zealand, and North and South America. Eligible women (aged 18 years, or 20 years in Japan) had stage 1-3 HER2-positive breast cancer and had completed neoadjuvant and adjuvant trastuzumab therapy up to 2 years before randomisation. Inclusion criteria were amended on Feb 25, 2010, to include patients with stage 2-3 HER2-positive breast cancer who had completed trastuzumab therapy up to 1 year previously. Patients were randomly assigned (1:1) to receive oral neratinib 240 mg per day or matching placebo. The randomisation sequence was generated with permuted blocks stratified by hormone receptor status (hormone receptor-positive [oestrogen or progesterone receptor-positive or both] vs hormone receptor-negative [oestrogen and progesterone receptor-negative]), nodal status (0, 1-3, or 4), and trastuzumab adjuvant regimen (sequentially vs concurrently with chemotherapy), then implemented centrally via an interactive voice and web-response system. Patients, investigators, and trial sponsors were masked to treatment allocation. The primary outcome was invasive disease-free survival, as defined in the original protocol, at 2 years after randomisation. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00878709.Between July 9, 2009, and Oct 24, 2011, we randomly assigned 2840 women to receive neratinib (n=1420) or placebo (n=1420). Median follow-up time was 24 months (IQR 20-25) in the neratinib group and 24 months (22-25) in the placebo group. At 2 year follow-up, 70 invasive disease-free survival events had occurred in patients in the neratinib group versus 109 events in those in the placebo group (stratified hazard ratio 067, 95% CI 050-091; p=00091). The 2-year invasive disease-free survival rate was 939% (95% CI 924-952) in the neratinib group and 916% (900-930) in the placebo group. The most common grade 3-4 adverse events in patients in the neratinib group were diarrhoea (grade 3, n=561 [40%] and grade 4, n=1 [<1%] vs grade 3, n=23 [2%] in the placebo group), vomiting (grade 3, n=47 [3%] vs n=5 [<1%]), and nausea (grade 3, n=26 [2%] vs n=2 [<1%]). QT prolongation occurred in 49 (3%) patients given neratinib and 93 (7%) patients given placebo, and decreases in left ventricular ejection fraction (grade 2) in 19 (1%) and 15 (1%) patients, respectively. We recorded serious adverse events in 103 (7%) patients in the neratinib group and 85 (6%) patients in the placebo group. Seven (<1%) deaths (four patients in the neratinib group and three patients in the placebo group) unrelated to disease progression occurred after study drug discontinuation. The causes of death in the neratinib group were unknown (n=2), a second primary brain tumour (n=1), and acute myeloid leukaemia (n=1), and in the placebo group were a brain haemorrhage (n=1), myocardial infarction (n=1), and gastric cancer (n=1). None of the deaths were attributed to study treatment in either group.Neratinib for 12 months significantly improved 2-year invasive disease-free survival when given after chemotherapy and trastuzumab-based adjuvant therapy to women with HER2-positive breast cancer. Longer follow-up is needed to ensure that the improvement in breast cancer outcome is maintained.Wyeth, Pfizer, Puma Biotechnology.


Swierczek S.,University of Utah | Agarwal A.M.,University of Utah | Agarwal A.M.,Arup | Naidoo K.,University of Witwatersrand | And 7 more authors.
Haematologica | Year: 2013

Hereditary pyropoikilocytosis is a severe hemolytic anemia caused by spectrin deficiency and defective spectrin dimer self-association, typically found in African populations. We describe two Utah families of northern European ancestry including 2 propositi with atypical non-microcytic hereditary pyropoikilocytosis, 7 hereditary elliptocytosis members and one asymptomatic carrier. The underlying molecular defect is a novel mutation in the alpha(α) spectrin gene, SPTAR34P that impairs spectrin tetramer formation. It is inherited in trans to the hypomorphic SPTAαLELY in the 2 propositi and 5 of 7 hereditary elliptocytosis individuals indicating that SPTAαLELY is not the sole determinant of the variable clinical expression. α Spectrin mRNA was mildly decreased in all hereditary elliptocytosis subjects, whereas both hereditary pyropoikilocytosis propositi had a severe decrease to ~10% of normal. Genotyping identified a unique SPTA intragenic crossover and uniparental disomy in one hereditary elliptocytosis individual. Two additional crossover events demonstrated the susceptibility of SPTA gene to rearrangement and revealed a novel segregation of the two SPTAαLELY mutations. We conclude that the profound phenotypic heterogeneity in these families can be attributed to the SPTAR34P mutation in combination with: 1) inheritance in trans of either SPTAαLELY; or 2) the wild-type SPTA; 3) a decrease of α spectrin mRNA; and 4) SPTA intragenic crossover. © 2013 Ferrata Storti Foundation.


PubMed | Utah Cancer Specialists., Foundation Medicine, University of Utah and Albany Medical College
Type: Journal Article | Journal: Oncoscience | Year: 2015

To identify exceptional responders among patients with advanced pancreatic cancer enrolled in first-in-man (FIM) studies.A Scopus search identified 66 FIM studies that enrolled at least one patient with advanced pancreatic cancer between 2002-2012. Descriptive statistics were used to summarize categorical variables. We also screened CRKL amplifications in the FoundationOne pancreatic cancer database.Most FIM studies included targeted therapies (76 vs. 24%). The most common targeted therapy involved cell cycle inhibitors (24%). Pharmacodynamic analyses were more frequently done in trials with targeted therapies (70 vs. 31%, p=0.006). Response rates were similar. Treatment-related death was 0.5%. Skin, cardiovascular and metabolic grade 3-4 toxicities were more frequent with targeted therapies. Four exceptional responses were identified including a complete response to bosutinib (Src Inhibitor) and partial responses to trametinib (MEK inhibitor) (2 patients) and CHR-3996 (histone deacetylase inhibitor). We found that CRKL amplifications, a potential biomarker for Src inhibitors, are present in 1% of PDA.We retrospectively identified extraordinary responses among patients with advanced PDA enrolled in FIM studies with Src, HDAC and MEK inhibitors. We identified CRKL amplifications are present in 1% of PDA and need to be evaluated as predictive biomarker for Src inhibitors.


Borson R.,St Louis Cancer And Breast Institute | Harker G.,Utah Cancer Specialists | Reeves J.,Mercy Hospital | Beck T.,Highlands Oncology Group | And 16 more authors.
Clinical Breast Cancer | Year: 2012

Background: In first-line treatment of metastatic breast cancer, the best use of the available therapeutic agents is unclear. This study evaluated the efficacy and safety of combined therapy with bevacizumab and gemcitabine. Patients: Women who were to undergo first-line treatment for locoregionally recurrent or metastatic breast cancer were eligible. Patients must have received a taxane-containing regimen in the neoadjuvant and/or adjuvant setting with a < 12-month disease-free interval. Methods: This was a single-arm, phase II trial. On day 1 of each 14-day cycle, patients received gemcitabine (2500 mg/m2) followed by bevacizumab (10 mg/kg). Patients were treated until complete response, progressive disease (PD), or intolerable toxicity. The primary endpoint was progression-free survival (PFS). Results: Fifty-two women were enrolled and treated. The median PFS was 4.8 months (95% confidence interval [CI], 3.4-7.6), the 1-year overall survival rate was 68.7% (95% CI, 54.1%-79.5%), and the response rate was 21.4% (95% CI, 10.3%-36.8%). The clinical benefit rate was 35.7%. The median PFS in the triple-negative (n = 19) and non-triple-negative (n = 33) subsets was 3.9 months (95% CI, 2.7-11.7) and 4.9 months (95% CI, 3.4-8.1), respectively. The most common (all grades) drug-related adverse events (AEs) were nausea (51.9%), fatigue (46.2%), decreased appetite (25.0%), and anemia (25.0%). The most common grade 3 or grade 4 drug-related AEs were neutropenia (13.5%), leukopenia (11.5%), and hypertension (7.7%). Conclusion: Although the gemcitabine-bevacizumab doublet appears active, the median PFS was lower than expected. There were no unexpected safety signals at this dose and schedule of this combination. © 2012 Elsevier Inc.


Motzer R.J.,Sloan Kettering Cancer Center | Barrios C.H.,Pontifical Catholic University of Rio Grande do Sul | Kim T.M.,Seoul National University | Falcon S.,Hospital Nacional Edgardo Rebagliati Martins | And 19 more authors.
Journal of Clinical Oncology | Year: 2014

Purpose A multicenter, randomized phase II trial, RECORD-3, was conducted to compare first-line everolimus followed by sunitinib at progression with the standard sequence of first-line sunitinib followed by everolimus in patients with metastatic renal cell carcinoma. Patients and Methods RECORD-3 used a crossover treatment design. The primary objective was to assess progression-free survival (PFS) noninferiority of first-line everolimus compared with first-line sunitinib. Secondary end points included combined PFS for each sequence, overall survival (OS), and safety. Results Of 471 enrolled patients, 238 were randomly assigned to first-line everolimus followed by sunitinib, and 233 were randomly assigned to first-line sunitinib followed by everolimus. The primary end point was not met; the median PFS was 7.9 months for first-line everolimus and 10.7 months for first-line sunitinib (hazard ratio [HR], 1.4; 95% CI, 1.2 to 1.8). Among patients who discontinued first-line, 108 (45%) crossed over from everolimus to second-line sunitinib, and 99 (43%) crossed over from sunitinib to second-line everolimus. The median combined PFS was 21.1 months for sequential everolimus then sunitinib and was 25.8 months for sequential sunitinib then everolimus (HR, 1.3; 95% CI, 0.9 to 1.7). The median OS was 22.4 months for sequential everolimus and then sunitinib and 32.0 months for sequential sunitinib and then everolimus (HR, 1.2; 95% CI, 0.9 to 1.6). Common treatment-emergent adverse events during first-line everolimus or sunitinib were stomatitis (53% and 57%, respectively), fatigue (45% and 51%, respectively), and diarrhea (38% and 57%, respectively). Conclusion Everolimus did not demonstrate noninferiority compared with sunitinib as a first-line therapy. The trial results support the standard treatment paradigm of first-line sunitinib followed by everolimus at progression. Copyright © 2014 American Society of Clinical Oncology. All rights reserved.


Mirtsching B.,Center for Oncology Research and Treatment | Cosgriff T.,Hematology and Oncology Specialists | Harker G.,Utah Cancer Specialists | Keaton M.,Augusta Oncology Associates | And 2 more authors.
Clinical Breast Cancer | Year: 2011

Introduction: Weekly administration of nanoparticle albumin-bound (nab) paclitaxel as a first-line treatment for metastatic breast cancer (MBC) has not been fully investigated. The addition of trastuzumab, a monoclonal antibody against human epidermal growth factor receptor 2 (HER2), is less understood. This phase II study evaluated the efficacy and safety of weekly nab paclitaxel in the first-line MBC setting. Patients whose tumors overexpressed HER2 also received trastuzumab. Patients and Methods: Patients with locally advanced or metastatic breast cancer received nab paclitaxel (125 mg/m2) by 30-minute intravenous infusion weekly for 3 of 4 weeks. Patients who were HER2-positive received concurrent trastuzumab. Results: Seventy-two patients were enrolled; HER2 expression was detected in 22 patients. The overall response rate (ORR) was 42.2% (95% CI, 30%-55%); 5 patients had a complete response (CR) and 22 patients had a partial response (PR). Additionally, 17 patients experienced stable disease (SD), providing an overall benefit (CR + PR + SD) of 68.8%. Patients with HER2-positive tumors had an ORR of 52.4%; the ORR was 38.1% in the HER2-negative population (P =.3). Median progression-free survival was 14.5 months (range, 1-49.3 months) and survival rates at 1 year and 2 years were 69% and 62%, respectively. The most commonly observed toxicities were pain (64%), fatigue (58%), sensory neuropathy (54%), infection (46%), nausea (38%), alopecia (33%), and anemia (33%). Conclusion: Our findings demonstrate that weekly nab paclitaxel has a favorable safety profile and is well tolerated as a first-line treatment for MBC. An ORR of 42% and an overall benefit of 69% is extremely encouraging, particularly in the HER2-positive population where 52% of patients responded. © 2011 Published by Elsevier Inc.

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