BACKGROUND:Controversy exists over the use of adjuvant chemotherapy for locally advanced (stages II-III) rectal cancer (LARC) patients who demonstrate pathologic complete response (pCR) following neoadjuvant chemoradiation. We conducted a retrospective analysis to determine whether adjuvant chemotherapy imparts survival benefit among this population. METHODS:The National Cancer Database (NCDB) was queried to identify LARC patients with pCR following neoadjuvant chemoradiation. The cohort was stratified by receipt of adjuvant chemotherapy. Multiple imputation and a Cox proportional hazards model were employed to estimate the effect of adjuvant chemotherapy on overall survival. RESULTS:There were 24,418 patients identified in the NCDB with clinically staged II or III rectal cancer who received neoadjuvant chemoradiation. Of these, 5606 (23.0%) had pCR. Among patients with pCR, 1401 (25%) received adjuvant chemotherapy and 4205 (75%) did not. Patients who received adjuvant chemotherapy were slightly younger, more likely to have private insurance, and more likely to have clinically staged III disease, but did not differ significantly in comparison to patients who did not receive adjuvant chemotherapy with respect to race, sex, facility type, Charlson comorbidity score, histologic tumor grade, procedure type, length of stay, or rate of 30-day readmission following surgery. On adjusted analysis, receipt of adjuvant chemotherapy was associated with a lower risk of death at a given time compared to patients who did not receive adjuvant chemotherapy (HR 0.808; 95% CI 0.679-0.961; p = 0.016). CONCLUSION:Supporting existing NCCN guidelines, the findings from this study suggest that adjuvant chemotherapy improves survival for LARC with pCR following neoadjuvant chemoradiation.

Authors

Turner, MC; Keenan, JE; Rushing, CN; Gulack, BC; Nussbaum, DP; Benrashid, E; Hyslop, T; Strickler, JH; Mantyh, CR; Migaly, J

MLA Citation

Turner, MC, Keenan, JE, Rushing, CN, Gulack, BC, Nussbaum, DP, Benrashid, E, Hyslop, T, Strickler, JH, Mantyh, CR, and Migaly, J. "Adjuvant Chemotherapy Improves Survival Following Resection of Locally Advanced Rectal Cancer with Pathologic Complete Response." January 11, 2019.

PMID

30635829

Source

epmc

Published In

Journal of Gastrointestinal Surgery : Official Journal of the Society for Surgery of the Alimentary Tract

Publish Date

2019

DOI

10.1007/s11605-018-04079-8

Background:Colorectal cancer (CRC) has been shown to acquire RAS and EGFR ectodomain mutations as mechanisms of resistance to EGFR inhibition (anti-EGFR). After anti-EGFR withdrawal, RAS and EGFR mutant clones lack a growth advantage relative to other clones and decay, however the kinetics of decay remain unclear. We sought to determine the kinetics of acquired RAS/EGFR mutations after discontinuation of anti-EGFR therapy. Patients and Methods:We present the post-progression circulating tumor DNA (ctDNA) profiles of 135 patients with RAS/BRAF wild-type metastatic CRC treated with anti-EGFR who acquired RAS and/or EGFR mutations during therapy. Our validation cohort consisted of an external dataset of 73 patients with a ctDNA profile suggestive of prior anti-EGFR exposure and serial sampling. A separate retrospective cohort of 80 patients was used to evaluate overall response rate and progression free survival during re-challenge therapies. Results:Our analysis showed that RAS and EGFR relative mutant allele frequency (rMAF) decays exponentially (r2=0.93 for RAS; r2=0.94 for EGFR) with a cumulative half-life of 4.4 months. We validated our findings using an external dataset of 73 patients with a ctDNA profile suggestive of prior anti-EGFR exposure and serial sampling, confirming exponential decay with an estimated half-life of 4.3 months. A separate retrospective cohort of 80 patients showed that patients had a higher overall response rate during re-challenge therapies after increasing time intervals, as predicted by our model. Conclusion:These results provide scientific support for anti-EGFR re-challenge and guide the optimal timing of re-challenge initiation.

Authors

Parseghian, CM; Loree, JM; Morris, VK; Liu, X; Clifton, KK; Napolitano, S; Henry, JT; Pereira, AA; Vilar, E; Johnson, B; Kee, B; Raghav, K; Dasari, A; Wu, J; Garg, N; Raymond, VM; Banks, KC; Talasaz, AA; Lanman, RB; Strickler, JH; Hong, DS; Corcoran, RB; Overman, MJ; Kopetz, S

MLA Citation

Parseghian, CM, Loree, JM, Morris, VK, Liu, X, Clifton, KK, Napolitano, S, Henry, JT, Pereira, AA, Vilar, E, Johnson, B, Kee, B, Raghav, K, Dasari, A, Wu, J, Garg, N, Raymond, VM, Banks, KC, Talasaz, AA, Lanman, RB, Strickler, JH, Hong, DS, Corcoran, RB, Overman, MJ, and Kopetz, S. "Anti-EGFR Resistant Clones Decay Exponentially After Progression: Implications for Anti-EGFR Re-challenge." Annals of Oncology : Official Journal of the European Society for Medical Oncology (November 21, 2018).

PMID

30462160

Source

epmc

Published In

Annals of Oncology

Publish Date

2018

DOI

10.1093/annonc/mdy509

An increasing number of patients with metastatic colorectal cancer (mCRC) are able to receive 3 or more lines of therapy. Treatments in this setting can include regorafenib (an oral multikinase inhibitor), trifluridine/tipiracil hydrochloride (TAS-102), antibodies that target epidermal growth factor receptor for patients with RAS wild-type tumors (if no prior exposure), and, where approved, anti-programmed cell death protein 1 inhibitors for patients with microsatellite instability-high mCRC. Although guidelines describe the available treatment options, few insights are provided to guide selection and sequencing. In this article, we share expert opinion from diverse geographic regions, to offer guidance for best practice when selecting and managing third-line treatment for mCRC. Various factors, including performance status, age, and tumor sidedness, can be used to guide treatment selection. Biomarkers, such as RAS, BRAF, and microsatellite instability, can be useful for treatment stratification. Management of adverse events, to maintain quality of life, is a key consideration and is crucial to best practice in this setting. Common toxicities associated with third-line treatments are hand-foot skin reaction, fatigue, diarrhea, and cytopenias. Patients who receive third-line and later-line treatments should be monitored for these events, especially during the first 2 cycles. Dose modifications can also be used to manage toxicities and to minimize the effect on quality of life, while maximizing treatment benefit. Clinical trials of emerging agents, new treatment combinations, and novel therapies continue the efforts to improve outcomes for patients with mCRC. Sharing expert opinions on best practice for treatment selection and management can ultimately improve outcomes for patients with mCRC.

Authors

Bekaii-Saab, T; Kim, R; Kim, TW; O'Connor, JM; Strickler, JH; Malka, D; Sartore-Bianchi, A; Bi, F; Yamaguchi, K; Yoshino, T; Prager, GW

MLA Citation

Bekaii-Saab, T, Kim, R, Kim, TW, O'Connor, JM, Strickler, JH, Malka, D, Sartore-Bianchi, A, Bi, F, Yamaguchi, K, Yoshino, T, and Prager, GW. "Third- or Later-line Therapy for Metastatic Colorectal Cancer: Reviewing Best Practice." Clinical Colorectal Cancer (November 16, 2018). (Review)

PMID

30598357

Source

epmc

Published In

Clinical Colorectal Cancer

Publish Date

2018

DOI

10.1016/j.clcc.2018.11.002

AIMS:This analysis investigated the cost-effectiveness of panitumumab plus mFOLFOX6 (oxaliplatin, 5-fluorouracil, and leucovorin) compared with bevacizumab plus mFOLFOX6 in the first-line treatment of patients with wild-type RAS metastatic colorectal cancer (mCRC). MATERIALS AND METHODS:The cost-effectiveness analysis was developed from a third-party payer perspective in the US and was implemented using a partitioned survival model with health states for first-line treatment (progression-free), disease progression with and without subsequent active treatment, and death. Survival analyses of patients with wild-type RAS mCRC from the PEAK head-to-head clinical trial of panitumumab vs bevacizumab were performed to estimate time in the model health states. Additional data from PEAK informed the amount of each drug consumed, duration of therapy, subsequent therapy use, and toxicities related to mCRC treatment. Literature and US public data sources were used to estimate unit costs associated with treatment and duration of subsequent active therapies. Utility weights were calculated from patient-level data from panitumumab trials in the first-, second-, and third-line settings. A life-time perspective was taken with future costs and outcomes discounted at 3% per annum. Scenario, one-way, and probabilistic sensitivity analyses were performed. RESULTS:Compared with bevacizumab, the use of panitumumab resulted in an incremental cost of US $60,286, and an incremental quality-adjusted life-year (QALY) of 0.445, translating into a cost per QALY gained of US $135,391 in favor of panitumumab. Results were sensitive to wastage and dose rounding assumptions modeled. LIMITATIONS:Progression-free and overall survival were extrapolated beyond the follow-up of the primary analysis using fitted parametric curves. Costs and quality of life were estimated from multiple and different data sources. CONCLUSIONS:The efficacy of panitumumab in extending progression-free and overall survival and improving quality of life makes it a cost-effective option for first-line treatment of patients with wild-type RAS mCRC compared with bevacizumab.

Authors

Graham, CN; Christodoulopoulou, A; Knox, HN; Sabatelli, L; Hechmati, G; Garawin, T; Strickler, JH

MLA Citation

Graham, CN, Christodoulopoulou, A, Knox, HN, Sabatelli, L, Hechmati, G, Garawin, T, and Strickler, JH. "A within-trial cost-effectiveness analysis of panitumumab compared with bevacizumab in the first-line treatment of patients with wild-type RAS metastatic colorectal cancer in the US." Journal of Medical Economics 21.11 (November 2018): 1075-1083.

PMID

30091652

Source

epmc

Published In

Journal of Medical Economics

Volume

21

Issue

11

Publish Date

2018

Start Page

1075

End Page

1083

DOI

10.1080/13696998.2018.1510409

PURPOSE:This first-in-human study evaluated telisotuzumab vedotin (Teliso-V), formerly called ABBV-399, an antibody-drug conjugate of the anti-c-Met monoclonal antibody ABT-700 and monomethyl auristatin E. MATERIALS AND METHODS:For dose escalation, three to six patients with advanced solid tumors were enrolled in eight cohorts (0.15 to 3.3 mg/kg). The dose-expansion phase enrolled patients with non-small-cell lung cancer (NSCLC) with c-Met-overexpressing tumors (c-Met positive; immunohistochemistry membrane H-score ≥ 150). Patients received Teliso-V monotherapy intravenously on day 1 once every 3 weeks. Safety, tolerability, pharmacokinetics, and maximum tolerated dose were determined. RESULTS:Forty-eight patients were enrolled (median age, 65 years; 35.4% NSCLC; median four prior therapies). One patient each in the 3.0-mg/kg (n = 9) and 3.3-mg/kg (n = 3) cohorts experienced dose-limiting toxicities. Although the maximum tolerated dose was not formally identified, the recommended phase II dose was defined as 2.7 mg/kg on the basis of overall safety and tolerability. The most frequent treatment-emergent adverse events (any grade) were fatigue (42%), nausea (27%), constipation (27%), decreased appetite (23%), vomiting (21%), dyspnea (21%), diarrhea (19%), peripheral edema (19%), and neuropathy (17%). The most frequent Teliso-V-related grade ≥ 3 adverse events were fatigue, anemia, neutropenia, and hypoalbuminemia (4% each). Teliso-V and total antibody pharmacokinetics were approximately dose proportional, with a mean harmonic half-life of 2 to 4 days each. Prospective screening identified 35 (60%) of 58 patients with c-Met-positive NSCLC. Of 16 patients with c-Met-positive NSCLC who were treated with Teliso-V 2.4 to 3.0 mg/kg, three (18.8%; 95% CI, 4.1% to 45.7%) achieved a partial response (median response duration, 4.8 months; median progression-free survival, 5.7 months; 95% CI, 1.2 months to 15.4 months). No other patients experienced a response. CONCLUSION:Teliso-V monotherapy demonstrated favorable safety and tolerability profiles, with encouraging evidence of antitumor activity in patients with c-Met-positive NSCLC.

Authors

Strickler, JH; Weekes, CD; Nemunaitis, J; Ramanathan, RK; Heist, RS; Morgensztern, D; Angevin, E; Bauer, TM; Yue, H; Motwani, M; Parikh, A; Reilly, EB; Afar, D; Naumovski, L; Kelly, K

MLA Citation

Strickler, JH, Weekes, CD, Nemunaitis, J, Ramanathan, RK, Heist, RS, Morgensztern, D, Angevin, E, Bauer, TM, Yue, H, Motwani, M, Parikh, A, Reilly, EB, Afar, D, Naumovski, L, and Kelly, K. "First-in-Human Phase I, Dose-Escalation and -Expansion Study of Telisotuzumab Vedotin, an Antibody-Drug Conjugate Targeting c-Met, in Patients With Advanced Solid Tumors." Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology 36.33 (November 2018): 3298-3306.

PMID

30285518

Source

epmc

Published In

Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology

Volume

36

Issue

33

Publish Date

2018

Start Page

3298

End Page

3306

DOI

10.1200/jco.2018.78.7697

Authors

Wainberg, Z; Strickler, J; Gordon, M; Barve, M; Wang, L; Yue, H; Motwani, M; Kasichayanula, S; Naumovski, L; Hamilton, E

MLA Citation

Wainberg, Z, Strickler, J, Gordon, M, Barve, M, Wang, L, Yue, H, Motwani, M, Kasichayanula, S, Naumovski, L, and Hamilton, E. "Phase 1b open-label study evaluating the safety, pharmacokinetics, and preliminary efficacy of ABT-165 plus FOLFIRI in patients with second-line (2L) colorectal cancer (CRC)." ESMO 20th World Congress on Gastrointestinal Cancer. June 20, 2018 - June 23, 2018. Barcelona, SPAIN.: OXFORD UNIV PRESS, June 1, 2018.

Source

wos

Published In

Annals of Oncology

Volume

29

Publish Date

2018

Start Page

66

End Page

66

Authors

Wainberg, Z; Wang, L; Yue, H; Motwani, M; Kasichayanula, S; Blaney, M; Naumovski, L; Strickler, J

MLA Citation

Wainberg, Z, Wang, L, Yue, H, Motwani, M, Kasichayanula, S, Blaney, M, Naumovski, L, and Strickler, J. "ABT-165 plus FOLFIRI vs bevacizumab plus FOLFIRI in patients with metastatic colorectal cancer (mCRC) previously treated with fluoropyrimidine/oxaliplatin and bevacizumab - Trial in progress." ESMO 20th World Congress on Gastrointestinal Cancer. June 20, 2018 - June 23, 2018. Barcelona, SPAIN.: OXFORD UNIV PRESS, June 1, 2018.

Source

wos

Published In

Annals of Oncology

Volume

29

Publish Date

2018

Authors

Bekaii-Saab, T; Marcello, K; Fisher, G; Kopetz, S; Strickler, J; Venook, A; Obholz, K

MLA Citation

Bekaii-Saab, T, Marcello, K, Fisher, G, Kopetz, S, Strickler, J, Venook, A, and Obholz, K. "Variability of current global practice patterns in the management of metastatic colorectal cancer." ESMO 20th World Congress on Gastrointestinal Cancer. June 20, 2018 - June 23, 2018. Barcelona, SPAIN.: OXFORD UNIV PRESS, June 1, 2018.

Source

wos

Published In

Annals of Oncology

Volume

29

Publish Date

2018

Start Page

73

End Page

73

Anti-EGFR therapies have failed to improve survival for unselected patients with metastatic gastroesophageal cancer, but in a subset of patients, EGFR amplification may predict treatment benefit. Maron and colleagues report the clinical activity of anti-EGFR therapies in a cohort of patients with EGFR-amplified metastatic gastroesophageal cancer and utilize serial blood and tumor tissue collection to identify molecular drivers of treatment sensitivity and resistance. Their insights offer a path to overcome technical limitations associated with EGFR amplification and facilitate molecularly targeted therapeutic strategies. Cancer Discov; 8(6); 679-81. ©2018 AACRSee related article by Maron et al., p. 696.

Authors

Strickler, JH

MLA Citation

Strickler, JH. "EGFR Amplification as a Target in Gastroesophageal Adenocarcinoma: Do Anti-EGFR Therapies Deserve a Second Chance?." Cancer Discovery 8.6 (June 2018): 679-681.

PMID

29858225

Source

epmc

Published In

Cancer Discovery

Volume

8

Issue

6

Publish Date

2018

Start Page

679

End Page

681

DOI

10.1158/2159-8290.cd-18-0191

Authors

Jia, J; Niedzwiecki, D; Uronis, HE; Morse, M; Zafar, Y; Hsu, SD; Bolch, E; Nagy, RJ; Lanman, RB; Talasaz, A; Haley, S; Nixon, AB; Strickler, JH

MLA Citation

Jia, J, Niedzwiecki, D, Uronis, HE, Morse, M, Zafar, Y, Hsu, SD, Bolch, E, Nagy, RJ, Lanman, RB, Talasaz, A, Haley, S, Nixon, AB, and Strickler, JH. "A phase I/II trial of cabozantinib (C) with or without panitumumab (P) in patients (pts) with RAS wild-type (WT) metastatic colorectal cancer (mCRC): Clinical outcomes in pts with MET amplification (amp) detected in blood.": American Society of Clinical Oncology (ASCO), May 20, 2018.

Source

crossref

Published In

Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology

Volume

36

Issue

15_suppl

Publish Date

2018

Start Page

3555

End Page

3555

DOI

10.1200/jco.2018.36.15_suppl.3555

BACKGROUND:Veliparib is a potent poly(ADP-ribose) polymerase inhibitor. This phase 1 study aimed to establish the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of veliparib combined with various FOLFIRI regimens in patients with solid tumours. METHODS:Patients received veliparib (10-270 mg BID, days 1-5, 15-19) and FOLFIRI (days 1-3, 15-17) in three regimens containing 5-fluorouracil 2,400 mg/m2: irinotecan 150 mg/m2 and folinic acid 400 mg/m2 (part 1); irinotecan 180 mg/m2, folinic acid 400 mg/m2, and 5-fluorouracil 400 mg/m2 bolus (part 2), or irinotecan 180 mg/m2 (part 3). The RP2D was further evaluated in safety expansion cohorts. Preliminary antitumour activity was also assessed. RESULTS:Ninety-two patients received ≥1 veliparib dose. MTD was not reached; RP2D was set at 200 mg BID veliparib plus FOLFIRI (without 5-fluorouracil bolus). Most common treatment-emergent adverse events were neutropenia (66.3%), diarrhoea, and nausea (60.9% each). Dose-limiting toxicities (n = 4) were grade 3 gastritis and grade 4 neutropenia and febrile neutropenia. Veliparib exposure was dose-proportional, with no effects on the pharmacokinetics of FOLFIRI components. Fifteen patients had a partial response (objective response rate, 17.6%). CONCLUSIONS:The acceptable safety profile and preliminary antitumour activity of veliparib plus FOLFIRI support further evaluation of this combination.

Authors

Berlin, J; Ramanathan, RK; Strickler, JH; Subramaniam, DS; Marshall, J; Kang, Y-K; Hetman, R; Dudley, MW; Zeng, J; Nickner, C; Xiong, H; Komarnitsky, P; Shepherd, SP; Hurwitz, H; Lenz, H-J

MLA Citation

Berlin, J, Ramanathan, RK, Strickler, JH, Subramaniam, DS, Marshall, J, Kang, Y-K, Hetman, R, Dudley, MW, Zeng, J, Nickner, C, Xiong, H, Komarnitsky, P, Shepherd, SP, Hurwitz, H, and Lenz, H-J. "A phase 1 dose-escalation study of veliparib with bimonthly FOLFIRI in patients with advanced solid tumours." April 2018.

PMID

29527010

Source

epmc

Published In

British Journal of Cancer

Volume

118

Issue

7

Publish Date

2018

Start Page

938

End Page

946

DOI

10.1038/s41416-018-0003-3

"Liquid biopsy" approaches analyzing cell-free DNA (cfDNA) from the blood of patients with cancer are increasingly utilized in clinical practice. However, it is not yet known whether cfDNA sequencing from large cohorts of patients with cancer can detect genomic alterations at frequencies similar to those observed by direct tumor sequencing, and whether this approach can generate novel insights. Here, we report next-generation sequencing data from cfDNA of 1,397 patients with colorectal cancer. Overall, frequencies of genomic alterations detected in cfDNA were comparable to those observed in three independent tissue-based colorectal cancer sequencing compendia. Our analysis also identified a novel cluster of extracellular domain (ECD) mutations in EGFR, mediating resistance by blocking binding of anti-EGFR antibodies. Patients with EGFR ECD mutations displayed striking tumor heterogeneity, with 91% harboring multiple distinct resistance alterations (range, 1-13; median, 4). These results suggest that cfDNA profiling can effectively define the genomic landscape of cancer and yield important biological insights.Significance: This study provides one of the first examples of how large-scale genomic profiling of cfDNA from patients with colorectal cancer can detect genomic alterations at frequencies comparable to those observed by direct tumor sequencing. Sequencing of cfDNA also generated insights into tumor heterogeneity and therapeutic resistance and identified novel EGFR ectodomain mutations. Cancer Discov; 8(2); 164-73. ©2017 AACR.This article is highlighted in the In This Issue feature, p. 127.

Authors

Strickler, JH; Loree, JM; Ahronian, LG; Parikh, AR; Niedzwiecki, D; Pereira, AAL; McKinney, M; Korn, WM; Atreya, CE; Banks, KC; Nagy, RJ; Meric-Bernstam, F; Lanman, RB; Talasaz, A; Tsigelny, IF; Corcoran, RB; Kopetz, S

MLA Citation

Strickler, JH, Loree, JM, Ahronian, LG, Parikh, AR, Niedzwiecki, D, Pereira, AAL, McKinney, M, Korn, WM, Atreya, CE, Banks, KC, Nagy, RJ, Meric-Bernstam, F, Lanman, RB, Talasaz, A, Tsigelny, IF, Corcoran, RB, and Kopetz, S. "Genomic Landscape of Cell-Free DNA in Patients with Colorectal Cancer." Cancer Discovery 8.2 (February 2018): 164-173.

PMID

29196463

Source

epmc

Published In

Cancer Discovery

Volume

8

Issue

2

Publish Date

2018

Start Page

164

End Page

173

DOI

10.1158/2159-8290.CD-17-1009

Authors

Loree, JM; Strickler, JH; Pereira, AAL; Lam, M; Raghav, KPS; Morris, VK; Menter, D; Banks, K; Nagy, RJ; Raymond, V; Overman, MJ; Talasaz, A; Lanman, RB; Kopetz, S

MLA Citation

Loree, JM, Strickler, JH, Pereira, AAL, Lam, M, Raghav, KPS, Morris, VK, Menter, D, Banks, K, Nagy, RJ, Raymond, V, Overman, MJ, Talasaz, A, Lanman, RB, and Kopetz, S. "Serial monitoring of ctDNA to highlight mutation profiles in colorectal cancer.": American Society of Clinical Oncology (ASCO), February 2018.

Source

crossref

Published In

Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology

Volume

36

Issue

4_suppl

Publish Date

2018

Start Page

641

End Page

641

DOI

10.1200/jco.2018.36.4_suppl.641

AIMS:This phase 1, open-label, crossover study sought to evaluate drug-drug interactions between tivantinib and cytochrome P450 (CYP) substrates and tivantinib and P-glycoprotein. METHODS:The effect of tivantinib doses on the pharmacokinetics of the probe drugs for CYP1A2 (caffeine), CYP2C9 (S-warfarin), CYP2C19 (omeprazole), and CYP3A4 (midazolam), and for P-glycoprotein (digoxin) was investigated in 28 patients with advanced cancer using a cocktail probe approach. Patients received single doses of probe drugs alone and, after 5 days of treatment, with tivantinib 360 mg twice daily. RESULTS:The ratios of geometric least squares mean (90% confidence interval) for the area under the concentration-time curve from time zero to the last quantifiable concentration in the presence/absence of tivantinib were 0.97 (0.89-1.05) for caffeine, 0.88 (0.76-1.02) for S-warfarin, 0.89 (0.60-1.31) for omeprazole, 0.83 (0.67-1.02) for midazolam, and 0.69 (0.51-0.94) for digoxin. Similar effects were observed for maximum plasma concentrations; the ratio for digoxin in the presence/absence of tivantinib was 0.75 (0.60-0.95). CONCLUSIONS:The data suggest that tivantinib 360 mg twice daily has either a minimal or no effect on the pharmacokinetics of probe drugs for CYP1A2, CYP2C9, CYP2C19 and CYP3A4 substrates, and decreases the systemic exposure of P-glycoprotein substrates when administered with tivantinib.

Authors

Tachibana, M; Papadopoulos, KP; Strickler, JH; Puzanov, I; Gajee, R; Wang, Y; Zahir, H

MLA Citation

Tachibana, M, Papadopoulos, KP, Strickler, JH, Puzanov, I, Gajee, R, Wang, Y, and Zahir, H. "Evaluation of the pharmacokinetic drug interaction potential of tivantinib (ARQ 197) using cocktail probes in patients with advanced solid tumours." British Journal of Clinical Pharmacology 84.1 (January 2018): 112-121.

PMID

28865153

Source

epmc

Published In

British Journal of Clinical Pharmacology

Volume

84

Issue

1

Publish Date

2018

Start Page

112

End Page

121

DOI

10.1111/bcp.13424

MET amplification is rare in treatment-naïve metastatic colorectal cancer (CRC) tumors, but can emerge as a mechanism of resistance to anti-EGFR therapies. Preclinical and clinical data suggest that patients with MET amplified tumors benefit from MET-targeted therapy. Cabozantinib is an inhibitor of multiple tyrosine kinases, included c-MET. Panitumumab is an inhibitor of EGFR. This report describes a patient with KRAS, NRAS, and BRAF wild-type metastatic CRC who experienced disease progression on all standard chemotherapy and anti-EGFR antibody therapy. The patient was enrolled in a clinical trial evaluating the combination of cabozantinib plus panitumumab. After only 6 weeks of treatment, the patient experienced a significant anti-tumor response. Although tumor tissue was negative for MET amplification, molecular profiling of cell-free DNA (cfDNA) revealed MET amplification. This case represents the first report showing the activity of cabozantinib in combination with panitumumab in a patient with metastatic CRC, and suggests that MET amplification in cfDNA may be a biomarker of response. A clinical trial targeting MET amplified metastatic CRC is currently underway.

Authors

Jia, J; Morse, MA; Nagy, RJ; Lanman, RB; Strickler, JH

MLA Citation

Jia, J, Morse, MA, Nagy, RJ, Lanman, RB, and Strickler, JH. "Cell-Free DNA Profiling to Discover Mechanisms of Exceptional Response to Cabozantinib Plus Panitumumab in a Patient With Treatment Refractory Metastatic Colorectal Cancer." Frontiers in Oncology 8 (January 2018): 305-null.

PMID

30211110

Source

epmc

Published In

Frontiers in Oncology

Volume

8

Publish Date

2018

Start Page

305

DOI

10.3389/fonc.2018.00305

Oncogenic mutations in B-type Raf kinase (BRAF) occur in 7-10% of metastatic colorectal cancers (mCRC). Despite recent improvements in survival in the general population of patients with mCRC, patients with BRAF-mutant mCRC continue to have poor response to most systemic therapies, and prognosis remains poor. There is a substantial unmet need for novel therapeutic strategies to treat patients with BRAF-mutant mCRC. This review outlines the epidemiology, molecular pathogenesis, prognosis, and mechanisms of treatment resistance of BRAF-mutated CRC. Additionally, this review highlights novel therapeutic strategies aimed at enhancing response and improving outcomes.

Authors

Strickler, JH; Wu, C; Bekaii-Saab, T

MLA Citation

Strickler, JH, Wu, C, and Bekaii-Saab, T. "Targeting BRAF in metastatic colorectal cancer: Maximizing molecular approaches." Cancer Treatment Reviews 60 (November 2017): 109-119. (Review)

PMID

28946014

Source

epmc

Published In

Cancer Treatment Reviews

Volume

60

Publish Date

2017

Start Page

109

End Page

119

DOI

10.1016/j.ctrv.2017.08.006

Authors

Angevin, E; Strickler, J; Weekes, C; Heist, R; Morgensztern, D; Fan, X; Olyaie, O; Motwani, M; Afar, D; Naumovski, L; Kelly, K

MLA Citation

Angevin, E, Strickler, J, Weekes, C, Heist, R, Morgensztern, D, Fan, X, Olyaie, O, Motwani, M, Afar, D, Naumovski, L, and Kelly, K. "First-In-Human Phase 1 Study of ABBV-399, an Antibody-Drug Conjugate (ADC) Targeting C-Met, in Patients with Non-Small Cell Lung Cancer (NSCLC)." January 2017.

Source

wos-lite

Published In

Journal of Thoracic Oncology

Volume

12

Issue

1

Publish Date

2017

Start Page

S395

End Page

S396

Authors

Bendell, J; Eckhardt, GS; Hochster, HS; Morris, VK; Strickler, J; Kapoun, AM; Wang, M; Xu, L; McGuire, K; Dupont, J; Faoro, L; Munster, P

MLA Citation

Bendell, J, Eckhardt, GS, Hochster, HS, Morris, VK, Strickler, J, Kapoun, AM, Wang, M, Xu, L, McGuire, K, Dupont, J, Faoro, L, and Munster, P. "Initial results from a phase 1a/b study of OMP-131R10, a first-in-class anti-RSPO3 antibody, in advanced solid tumors and previously treated metastatic colorectal cancer (CRC)." December 2016.

Source

crossref

Published In

European Journal of Cancer

Volume

69

Publish Date

2016

Start Page

S29

End Page

S30

DOI

10.1016/S0959-8049(16)32668-5

"Liquid biopsies" are blood based assays used to detect and analyze circulating tumor products, including circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), circulating messenger RNA (mRNA), circulating microRNA (miRNA), circulating exosomes, and tumor educated platelets (TEP). For patients with gastrointestinal (GI) malignancies, blood based biopsies may offer several advantages. First, tumor tissue samples are often challenging to procure, and when obtainable, are often insufficient for genomic profiling. Second, blood based assays offer a real-time overview of the entire tumor burden, and allow anatomically unbiased genomic profiling. Third, given the convenience and relative safety of liquid biopsies, this technology may facilitate identification of genomic alterations that confer sensitivity and resistance to targeted therapeutics. This review will assess the clinical applications of circulating tumor products for patients with GI tumors.

Authors

Zhu, J; Strickler, JH

MLA Citation

Zhu, J, and Strickler, JH. "Clinical applications of liquid biopsies in gastrointestinal oncology." Journal of gastrointestinal oncology 7.5 (October 2016): 675-686. (Review)

Website

https://hdl.handle.net/10161/17205

PMID

27747082

Source

epmc

Published In

Journal of Gastrointestinal Oncology

Volume

7

Issue

5

Publish Date

2016

Start Page

675

End Page

686

DOI

10.21037/jgo.2016.08.08

Authors

Angevin, E; Kelly, K; Heist, R; Morgensztern, D; Weekes, C; Bauer, TM; Ramanathan, RK; Nemunaitis, J; Fan, X; Olyaie, O; Parikh, A; Reilly, E; Afar, D; Naumovski, L; Strickler, J

MLA Citation

Angevin, E, Kelly, K, Heist, R, Morgensztern, D, Weekes, C, Bauer, TM, Ramanathan, RK, Nemunaitis, J, Fan, X, Olyaie, O, Parikh, A, Reilly, E, Afar, D, Naumovski, L, and Strickler, J. "First-in-human phase 1, dose-escalation and -expansion study of ABBV-399, an antibody-drug conjugate (ADC) targeting c-Met, in patients (pts) with advanced solid tumors.": Oxford University Press (OUP), October 2016.

Source

crossref

Published In

Annals of Oncology

Volume

27

Issue

suppl_6

Publish Date

2016

DOI

10.1093/annonc/mdw368.14

To provide evidence-based recommendations to oncologists and others for treatment of patients with locally advanced, unresectable pancreatic cancer.American Society of Clinical Oncology convened an Expert Panel of medical oncology, radiation oncology, surgical oncology, gastroenterology, palliative care, and advocacy experts and conducted a systematic review of the literature from January 2002 to June 2015. Outcomes included overall survival, disease-free survival, progression-free survival, and adverse events.Twenty-six randomized controlled trials met the systematic review criteria.A multiphase computed tomography scan of the chest, abdomen, and pelvis should be performed. Baseline performance status and comorbidity profile should be evaluated. The goals of care, patient preferences, psychological status, support systems, and symptoms should guide decisions for treatments. A palliative care referral should occur at first visit. Initial systemic chemotherapy (6 months) with a combination regimen is recommended for most patients (for some patients radiation therapy may be offered up front) with Eastern Cooperative Oncology Group performance status 0 or 1 and a favorable comorbidity profile. There is no clear evidence to support one regimen over another. The gemcitabine-based combinations and treatments recommended in the metastatic setting (eg, fluorouracil, leucovorin, irinotecan, and oxaliplatin and gemcitabine plus nanoparticle albumin-bound paclitaxel) have not been evaluated in randomized controlled trials involving locally advanced, unresectable pancreatic cancer. If there is local disease progression after induction chemotherapy, without metastasis, then radiation therapy or stereotactic body radiotherapy may be offered also with an Eastern Cooperative Oncology Group performance status ≤ 2 and an adequate comorbidity profile. If there is stable disease after 6 months of induction chemotherapy but unacceptable toxicities, radiation therapy may be offered as an alternative. Patients with disease progression should be offered treatment per the ASCO Metastatic Pancreatic Cancer Treatment Guideline. Follow-up visits every 3 to 4 months are recommended. Additional information is available at www.asco.org/guidelines/LAPC and www.asco.org/guidelines/MetPC and www.asco.org/guidelineswiki.

Authors

Balaban, EP; Mangu, PB; Khorana, AA; Shah, MA; Mukherjee, S; Crane, CH; Javle, MM; Eads, JR; Allen, P; Ko, AH; Engebretson, A; Herman, JM; Strickler, JH; Benson, AB; Urba, S; Yee, NS

MLA Citation

Balaban, EP, Mangu, PB, Khorana, AA, Shah, MA, Mukherjee, S, Crane, CH, Javle, MM, Eads, JR, Allen, P, Ko, AH, Engebretson, A, Herman, JM, Strickler, JH, Benson, AB, Urba, S, and Yee, NS. "Locally Advanced, Unresectable Pancreatic Cancer: American Society of Clinical Oncology Clinical Practice Guideline." Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology 34.22 (August 2016): 2654-2668.

PMID

27247216

Source

epmc

Published In

Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology

Volume

34

Issue

22

Publish Date

2016

Start Page

2654

End Page

2668

DOI

10.1200/jco.2016.67.5561

UNLABELLED: Amplification of the MET oncogene is associated with poor prognosis, metastatic dissemination, and drug resistance in many malignancies. We developed a method to capture and characterize circulating tumor cells (CTC) expressing c-MET using a ferromagnetic antibody. Immunofluorescence was used to characterize cells for c-MET, DAPI, and pan-CK, excluding CD45(+) leukocytes. The assay was validated using appropriate cell line controls spiked into peripheral blood collected from healthy volunteers (HV). In addition, peripheral blood was analyzed from patients with metastatic gastric, pancreatic, colorectal, bladder, renal, or prostate cancers. CTCs captured by c-MET were enumerated, and DNA FISH for MET amplification was performed. The approach was highly sensitive (80%) for MET-amplified cells, sensitive (40%-80%) for c-MET-overexpressed cells, and specific (100%) for both c-MET-negative cells and in 20 HVs. Of 52 patients with metastatic carcinomas tested, c-MET CTCs were captured in replicate samples from 3 patients [gastric, colorectal, and renal cell carcinoma (RCC)] with 6% prevalence. CTC FISH demonstrated that MET amplification in both gastric and colorectal cancer patients and trisomy 7 with gain of MET gene copies in the RCC patient. The c-MET CTC assay is a rapid, noninvasive, sensitive, and specific method for detecting MET-amplified tumor cells. CTCs with MET amplification can be detected in patients with gastric, colorectal, and renal cancers. IMPLICATIONS: This study developed a novel c-MET CTC assay for detecting c-MET CTCs in patients with MET amplification and warrants further investigation to determine its clinical applicability. Mol Cancer Res; 14(6); 539-47. ©2016 AACR.

Authors

Zhang, T; Boominathan, R; Foulk, B; Rao, C; Kemeny, G; Strickler, JH; Abbruzzese, JL; Harrison, MR; Hsu, DS; Healy, P; Li, J; Pi, C; Prendergast, KM; Hobbs, C; Gemberling, S; George, DJ; Hurwitz, HI; Connelly, M; Garcia-Blanco, MA; Armstrong, AJ

MLA Citation

Zhang, T, Boominathan, R, Foulk, B, Rao, C, Kemeny, G, Strickler, JH, Abbruzzese, JL, Harrison, MR, Hsu, DS, Healy, P, Li, J, Pi, C, Prendergast, KM, Hobbs, C, Gemberling, S, George, DJ, Hurwitz, HI, Connelly, M, Garcia-Blanco, MA, and Armstrong, AJ. "Development of a Novel c-MET-Based CTC Detection Platform." Mol Cancer Res 14.6 (June 2016): 539-547.

Website

http://hdl.handle.net/10161/11944

PMID

26951228

Source

pubmed

Published In

Mol Cancer Res

Volume

14

Issue

6

Publish Date

2016

Start Page

539

End Page

547

DOI

10.1158/1541-7786.MCR-16-0011

Authors

Ryan, DP; Murphy, J; Mahalingam, D; Strickler, J; Stein, S; Sirard, C; Landau, S; Bendell, J

MLA Citation

Ryan, DP, Murphy, J, Mahalingam, D, Strickler, J, Stein, S, Sirard, C, Landau, S, and Bendell, J. "Current results of a phase I study of DKN-01 in combination with paclitaxel (P) in patients (pts) with advanced DKK1+esophageal cancer (EC) or gastro-esophageal junction tumors (GEJ)." June 2016.

Source

wos-lite

Published In

Annals of Oncology

Volume

27

Publish Date

2016

Start Page

108

End Page

108

Authors

Clarke, JM; Blobe, GC; Strickler, JH; Uronis, HE; Zafar, Y; Morse, M; Dropkin, E; Howard, L; O'Neill, M; Rushing, CN; Niedzwiecki, D; Watson, H; Arrowood, C; Hurwitz, H

MLA Citation

Clarke, JM, Blobe, GC, Strickler, JH, Uronis, HE, Zafar, Y, Morse, M, Dropkin, E, Howard, L, O'Neill, M, Rushing, CN, Niedzwiecki, D, Watson, H, Arrowood, C, and Hurwitz, H. "Phase Ib study of regorafenib (rego) and PF-03446962 (PF) in patients with refractory metastatic colorectal cancer (mCRC) (REGAL)." May 20, 2016.

Source

wos-lite

Published In

Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology

Volume

34

Issue

15

Publish Date

2016

DOI

10.1200/JCO.2016.34.15_suppl.e15013

Authors

Strickler, JH; Rushing, CN; Uronis, HE; Morse, M; Blobe, GC; Zafar, Y; Hsu, SD; Arrowood, C; Ley, SH; Dropkin, E; Niedzwiecki, D; Hurwitz, H

MLA Citation

Strickler, JH, Rushing, CN, Uronis, HE, Morse, M, Blobe, GC, Zafar, Y, Hsu, SD, Arrowood, C, Ley, SH, Dropkin, E, Niedzwiecki, D, and Hurwitz, H. "Phase Ib study of cabozantinib plus panitumumab in KRAS wild-type (WT) metastatic colorectal cancer (mCRC)." May 20, 2016.

Source

wos-lite

Published In

Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology

Volume

34

Issue

15

Publish Date

2016

DOI

10.1200/JCO.2016.34.15_suppl.3548

Authors

Strickler, JH; Rangwala, FA; Rushing, C; Niedzwiecki, D; Altomare, I; Uronis, HE; Hsu, SD; Zafar, Y; Morse, M; Chang, DZ; Wells, JL; Blackwell, KL; Marcom, PK; Webb, AR; Dropkin, E; Arrowood, C; Hurwitz, H

MLA Citation

Strickler, JH, Rangwala, FA, Rushing, C, Niedzwiecki, D, Altomare, I, Uronis, HE, Hsu, SD, Zafar, Y, Morse, M, Chang, DZ, Wells, JL, Blackwell, KL, Marcom, PK, Webb, AR, Dropkin, E, Arrowood, C, and Hurwitz, H. "X-TRAP: Phase I/II study of capecitabine (X) plus ziv-aflibercept (TRAP) in metastatic colorectal cancer (mCRC)." February 2016.

Source

crossref

Published In

Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology

Volume

34

Issue

4_suppl

Publish Date

2016

Start Page

687

End Page

687

DOI

10.1200/jco.2016.34.4_suppl.687

Studies have suggested increased cancer incidence associated with long-term dual antiplatelet therapy (DAPT) for acute coronary syndrome (ACS). We evaluated cancer incidence and treatment-related differences in an analysis of DAPT for ACS.The Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes trial enrolled 9326 participants with ACS, who received aspirin plus clopidogrel or prasugrel. Median treatment exposure was 15 months. Cancer history and screening procedures were collected. Suspected non-benign neoplasm events were reported and adjudicated. The primary outcome was detection of new, non-benign neoplasm. Factors associated with neoplasm events, the relationship of these events to cardiovascular and bleeding endpoints, and treatment-related differences in neoplasm detection were studied. Among 9240 participants who received ≥1 dose of study drug, 1.8% had a confirmed neoplasm event. The efficacy composite of cardiovascular death, myocardial infarction, or stroke occurred more frequently among those with a neoplasm event vs. those without (18.2 vs. 13.5%) as did Global Use of Strategies to Open Occluded Coronary Arteries severe/moderate bleeding (11.2 vs. 1.5%). Screening rates were substantially higher in North America and Western Europe/Scandinavia vs. other regions. Factors most strongly associated with detection of neoplasm events were older age, region, male sex, and current/recent smoking. Among the pre-specified population without a history of neoplasm or previous curative treatment for neoplasm (n = 9105), the incidence of neoplasm events was similar with prasugrel vs. clopidogrel (1.8 vs. 1.7%; HR = 1.04; 95% CI 0.77-1.42; P = 0.79).Neoplasm events were infrequent during long-term DAPT after ACS, were associated with differential cancer-screening practices across regions, and the frequency of neoplasm detection was similar with prasugrel vs. clopidogrel.ClinicalTrials.gov identifier: NCT00699998.

Authors

Roe, MT; Cyr, DD; Eckart, D; Schulte, PJ; Morse, MA; Blackwell, KL; Ready, NE; Zafar, SY; Beaven, AW; Strickler, JH; Onken, JE; Winters, KJ; Houterloot, L; Zamoryakhin, D; Wiviott, SD; White, HD; Prabhakaran, D; Fox, KAA; Armstrong, PW; Ohman, EM; TRILOGY ACS Investigators,

MLA Citation

Roe, MT, Cyr, DD, Eckart, D, Schulte, PJ, Morse, MA, Blackwell, KL, Ready, NE, Zafar, SY, Beaven, AW, Strickler, JH, Onken, JE, Winters, KJ, Houterloot, L, Zamoryakhin, D, Wiviott, SD, White, HD, Prabhakaran, D, Fox, KAA, Armstrong, PW, Ohman, EM, and TRILOGY ACS Investigators, . "Ascertainment, classification, and impact of neoplasm detection during prolonged treatment with dual antiplatelet therapy with prasugrel vs. clopidogrel following acute coronary syndrome." European Heart Journal 37.4 (January 2016): 412-422.

PMID

26637834

Source

epmc

Published In

European Heart Journal

Volume

37

Issue

4

Publish Date

2016

Start Page

412

End Page

422

DOI

10.1093/eurheartj/ehv611

Authors

Zhu, J; Strosberg, JR; Dropkin, E; Strickler, JH

MLA Citation

Zhu, J, Strosberg, JR, Dropkin, E, and Strickler, JH. "Treatment of High-Grade Metastatic Pancreatic Neuroendocrine Carcinoma with FOLFIRINOX." Journal of Gastrointestinal Cancer 46.2 (June 2015): 166-169.

PMID

25662891

Source

epmc

Published In

Journal of Gastrointestinal Cancer

Volume

46

Issue

2

Publish Date

2015

Start Page

166

End Page

169

DOI

10.1007/s12029-015-9689-0

Authors

Zhang, T; Boominathan, R; Foulk, B; Connelly, MC; Rao, C; Kemeny, G; Strickler, JH; Abbruzzese, JL; Harrison, MR; George, DJ; Hurwitz, H; Garcia-Blanco, MA; Armstrong, AJ

MLA Citation

Zhang, T, Boominathan, R, Foulk, B, Connelly, MC, Rao, C, Kemeny, G, Strickler, JH, Abbruzzese, JL, Harrison, MR, George, DJ, Hurwitz, H, Garcia-Blanco, MA, and Armstrong, AJ. "Evaluation of a novel c-MET based circulating tumor cell (CTC) biomarker in patients with gastrointestinal (GI) and genitourinary (GU) malignancies." May 20, 2015.

Source

wos-lite

Published In

Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology

Volume

33

Issue

15

Publish Date

2015

To assess safety/tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity of DEBIO1143, an antagonist of inhibitor apoptosis proteins.This first-in-man study in patients with advanced cancer used an accelerated dose titration design. DEBIO1143 was given orally once daily on days 1-5 every 2 or 3 weeks until disease progressed or patients dropped out. The starting dose of 5 mg was escalated by 100% in single patients until related grade 2 toxicity occurred. This triggered expansion to cohorts of three and subsequently six patients and reduction in dose increments to 50%. Maximum tolerated dose (MTD) was exceeded when any two patients within the same cohort experienced dose-limiting toxicity (DLT). On days 1 and 5, PK and PD samples were taken.Thirty-one patients received doses from 5 to 900 mg. Only one DLT was reported at 180 mg. No MTD was found. Most common adverse drug reactions were fatigue (26%), nausea (23%), and vomiting (13%). Average t max and T 1/2 was about 1 and 6 h, respectively. Exposure increased proportionally with doses from 80 to 900 mg, without accumulation over 5 days. Plasma CCL2 increased at 3-6 h postdose and epithelial apoptosis marker M30 on day 5; cIAP-1 levels in PBMCs decreased at all doses >80 mg. Five patients (17%) had stable disease as the best treatment response.DEBIO1143 was well tolerated at doses up to 900 mg and elicited PD effects at doses greater 80 mg. Limited antitumor activity may suggest development rather as adjunct treatment.

Authors

Hurwitz, HI; Smith, DC; Pitot, HC; Brill, JM; Chugh, R; Rouits, E; Rubin, J; Strickler, J; Vuagniaux, G; Sorensen, JM; Zanna, C

MLA Citation

Hurwitz, HI, Smith, DC, Pitot, HC, Brill, JM, Chugh, R, Rouits, E, Rubin, J, Strickler, J, Vuagniaux, G, Sorensen, JM, and Zanna, C. "Safety, pharmacokinetics, and pharmacodynamic properties of oral DEBIO1143 (AT-406) in patients with advanced cancer: results of a first-in-man study." Cancer chemotherapy and pharmacology 75.4 (April 2015): 851-859.

PMID

25716544

Source

epmc

Published In

Cancer Chemotherapy and Pharmacology

Volume

75

Issue

4

Publish Date

2015

Start Page

851

End Page

859

DOI

10.1007/s00280-015-2709-8

Authors

O'Reilly, EM; Smith, LS; Bendell, JC; Strickler, JH; Zalupski, M; Gluck, W; Kapoun, A; Yen, W-C; Xu, L; Hill, D; Zhou, L; Dupont, J; Cohn, AL

MLA Citation

O'Reilly, EM, Smith, LS, Bendell, JC, Strickler, JH, Zalupski, M, Gluck, W, Kapoun, A, Yen, W-C, Xu, L, Hill, D, Zhou, L, Dupont, J, and Cohn, AL. "Final results of phase Ib of anticancer stem cell antibody tarextumab (OMP-59R5, TRXT, anti-Notch 2/3) in combination with nab-paclitaxel and gemcitabine (Nab-P+Gem) in patients (pts) with untreated metastatic pancreatic cancer (mPC).": American Society of Clinical Oncology (ASCO), January 20, 2015.

Source

crossref

Published In

Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology

Volume

33

Issue

3_suppl

Publish Date

2015

Start Page

278

End Page

278

DOI

10.1200/jco.2015.33.3_suppl.278

Authors

Kang, Y-K; LoRusso, P; Salgia, R; Yen, C-J; Lin, C-C; Ramanathan, RK; Kaminker, P; Sokolova, I; Bhathena, A; Wang, L; Naumovski, L; Strickler, JH

MLA Citation

Kang, Y-K, LoRusso, P, Salgia, R, Yen, C-J, Lin, C-C, Ramanathan, RK, Kaminker, P, Sokolova, I, Bhathena, A, Wang, L, Naumovski, L, and Strickler, JH. "Phase I study of ABT-700, an anti-c-Met antibody, in patients (pts) with advanced gastric or esophageal cancer (GEC)." January 20, 2015.

Source

crossref

Published In

Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology

Volume

33

Issue

3_suppl

Publish Date

2015

Start Page

167

End Page

167

DOI

10.1200/jco.2015.33.3_suppl.167

© 2015 The Author(s). Purpose: To assess safety/tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity of DEBIO1143, an antagonist of inhibitor apoptosis proteins. Methods: This first-in-man study in patients with advanced cancer used an accelerated dose titration design. DEBIO1143 was given orally once daily on days 1-5 every 2 or 3 weeks until disease progressed or patients dropped out. The starting dose of 5 mg was escalated by 100 % in single patients until related grade 2 toxicity occurred. This triggered expansion to cohorts of three and subsequently six patients and reduction in dose increments to 50 %. Maximum tolerated dose (MTD) was exceeded when any two patients within the same cohort experienced dose-limiting toxicity (DLT). On days 1 and 5, PK and PD samples were taken. Results: Thirty-one patients received doses from 5 to 900 mg. Only one DLT was reported at 180 mg. No MTD was found. Most common adverse drug reactions were fatigue (26 %), nausea (23 %), and vomiting (13 %). Average t max and T 1/2 was about 1 and 6 h, respectively. Exposure increased proportionally with doses from 80 to 900 mg, without accumulation over 5 days. Plasma CCL2 increased at 3-6 h postdose and epithelial apoptosis marker M30 on day 5; cIAP-1 levels in PBMCs decreased at all doses >80 mg. Five patients (17 %) had stable disease as the best treatment response. Conclusion: DEBIO1143 was well tolerated at doses up to 900 mg and elicited PD effects at doses greater 80 mg. Limited antitumor activity may suggest development rather as adjunct treatment.

Authors

Hurwitz, HI; Smith, DC; Pitot, HC; Brill, JM; Chugh, R; Rouits, E; Rubin, J; Strickler, J; Vuagniaux, G; Sorensen, JM; Zanna, C

MLA Citation

Hurwitz, HI, Smith, DC, Pitot, HC, Brill, JM, Chugh, R, Rouits, E, Rubin, J, Strickler, J, Vuagniaux, G, Sorensen, JM, and Zanna, C. "Safety, pharmacokinetics, and pharmacodynamic properties of oral DEBIO1143 (AT-406) in patients with advanced cancer: Results of a first-in-man study." Cancer Chemotherapy and Pharmacology 75.4 (January 1, 2015): 851-859.

Source

scopus

Published In

Cancer Chemotherapy and Pharmacology

Volume

75

Issue

4

Publish Date

2015

Start Page

851

End Page

859

DOI

10.1007/s00280-015-2709-8

Authors

Kapoun, A; O'Reilly, E; Cohn, A; Bendell, JC; Smith, L; Strickler, JH; Gluck, W; Liu, YW; Wallace, B; Tam, R; Cancilla, B; Brunner, A; Hill, D; Zhou, L; Dupont, J; Zhang, C; Wang, M

MLA Citation

Kapoun, A, O'Reilly, E, Cohn, A, Bendell, JC, Smith, L, Strickler, JH, Gluck, W, Liu, YW, Wallace, B, Tam, R, Cancilla, B, Brunner, A, Hill, D, Zhou, L, Dupont, J, Zhang, C, and Wang, M. "465 Biomarker analysis in Phase 1b study of anti-cancer stem cell antibody Tarextumab (TAR) in combination with nab-paclitaxel and gemcitabine (Nab-P+Gem) demonstrates pharmacodynamic (PD) modulation of the Notch pathway in patients (pts) with untreated metastatic pancreatic cancer (mPC).": Elsevier BV, November 2014.

Source

crossref

Published In

European Journal of Cancer

Volume

50

Publish Date

2014

Start Page

152

End Page

152

DOI

10.1016/s0959-8049(14)70591-x

To define maximum tolerated dose (MTD), toxicities, and pharmacodynamics of capecitabine, oxaliplatin, bevacizumab, and everolimus in advanced solid tumor patients.This was a standard "3 + 3" dose-escalation trial. All subjects received bevacizumab 7.5 mg/kg on day 1 of each cycle. Doses for capecitabine, oxaliplatin and everolimus were modified per dose limiting toxicity (DLT). Baseline and on-treatment plasma biomarkers were analyzed. Archived tumor mRNA levels were evaluated for NRP1, NRP2 and VEGF-A isoforms.Twenty-nine patients were evaluable for toxicity and 30 for efficacy. Two DLTs were observed in cohort 1 and one DLT each was observed in cohort -1 and -1b. Grade ≥3 toxicities included neutropenia, hypertension, perforation/fistula/hemorrhage, hypertriglyceridemia, diarrhea, and thromboembolism. Twelve subjects experienced partial response (PR); 12 had stable disease as best response. Three of seven chemorefractory metastatic colorectal cancer (mCRC) subjects experienced PR; 8 of 15 chemonaive mCRC subjects experienced PR. Plasma TβRIII and IL-6 increased on treatment but without correlation to outcome. Increased VEGF165 levels significantly correlated with longer progression free survival.Everolimus with full dose capecitabine, oxaliplatin, and bevacizumab had unacceptable toxicity. MTD was: everolimus 5 mg daily; capecitabine 680 mg/m(2) BID days 1-14; oxaliplatin 100 mg/m(2) and bevacizumab 7.5 mg/kg, day 1. Activity was noted in mCRC.

Authors

Rangwala, F; Bendell, JC; Kozloff, MF; Arrowood, CC; Dellinger, A; Meadows, J; Tourt-Uhlig, S; Murphy, J; Meadows, KL; Starr, A; Broderick, S; Brady, JC; Cushman, SM; Morse, MA; Uronis, HE; Hsu, SD; Zafar, SY; Wallace, J; Starodub, AN; Strickler, JH; Pang, H; Nixon, AB; Hurwitz, HI

MLA Citation

Rangwala, F, Bendell, JC, Kozloff, MF, Arrowood, CC, Dellinger, A, Meadows, J, Tourt-Uhlig, S, Murphy, J, Meadows, KL, Starr, A, Broderick, S, Brady, JC, Cushman, SM, Morse, MA, Uronis, HE, Hsu, SD, Zafar, SY, Wallace, J, Starodub, AN, Strickler, JH, Pang, H, Nixon, AB, and Hurwitz, HI. "Phase I study of capecitabine, oxaliplatin, bevacizumab, and everolimus in advanced solid tumors." Investigational New Drugs 32.4 (August 2014): 700-709.

PMID

24711126

Source

epmc

Published In

Investigational New Drugs

Volume

32

Issue

4

Publish Date

2014

Start Page

700

End Page

709

DOI

10.1007/s10637-014-0089-2

Authors

Strickler, JH; LoRusso, P; Yen, C-J; Lin, C-C; Kang, Y-K; Kaminker, P; Ansell, P; Bhathena, A; Wong, S; Dudley, MW; Naumovski, L; Ramanathan, RK

MLA Citation

Strickler, JH, LoRusso, P, Yen, C-J, Lin, C-C, Kang, Y-K, Kaminker, P, Ansell, P, Bhathena, A, Wong, S, Dudley, MW, Naumovski, L, and Ramanathan, RK. "Phase 1, open-label, dose-escalation, and expansion study of ABT-700, an anti-C-met antibody, in patients (pts) with advanced solid tumors.": American Society of Clinical Oncology (ASCO), May 20, 2014.

Source

crossref

Published In

Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology

Volume

32

Issue

15_suppl

Publish Date

2014

Start Page

2507

End Page

2507

DOI

10.1200/jco.2014.32.15_suppl.2507

Dasatinib inhibits src family kinases and has anti-angiogenic properties. We conducted a phase I study of dasatinib, capecitabine, oxaliplatin, and bevacizumab (CapeOx/bevacizumab), with an expansion cohort in metastatic colorectal cancer (CRC).Patients were enrolled in a dose escalation cohort to establish the maximum tolerated dose (MTD) and the recommended phase II dose (RP2D). Using a "3 + 3" design, twelve patients with advanced solid tumors received dasatinib (50 mg twice daily or 70 mg daily), capecitabine (850 mg/m(2) twice daily, days 1-14), oxaliplatin (130 mg/m(2) on day 1) and bevacizumab (7.5 mg/kg on day1), every 3 weeks. Ten patients with previously untreated metastatic CRC were then enrolled in an expansion cohort. Activated src (src(act)) expression was measured by immunohistochemistry, using an antibody that selectively recognizes the active conformation of src (clone 28).Twenty-two patients were enrolled between June 2009 and May 2011. Two DLTs were observed in the 50 mg bid dasatinib cohort, and one DLT was observed in the 70 mg daily dasatinib cohort. The MTD and RP2D for dasatinib was 70 mg daily. The most common treatment-related adverse events were fatigue (20; 91 %) and diarrhea (18; 82 %). Biomarker analysis of src(act) expression demonstrated that the overall response rate (ORR) was 75 % (6/8) for patients with high src(act) expression (IHC ≥ 2), compared to 0 % (0/8) for patients with low srcact expression (IHC 0 or 1); (p = 0.007).The RP2D of dasatinib is 70 mg daily in combination with CapeOx/bevacizumab. High levels of srcact expression may predict those patients most likely to benefit from dasatinib.

Authors

Strickler, JH; McCall, S; Nixon, AB; Brady, JC; Pang, H; Rushing, C; Cohn, A; Starodub, A; Arrowood, C; Haley, S; Meadows, KL; Morse, MA; Uronis, HE; Blobe, GC; Hsu, SD; Zafar, SY; Hurwitz, HI

MLA Citation

Strickler, JH, McCall, S, Nixon, AB, Brady, JC, Pang, H, Rushing, C, Cohn, A, Starodub, A, Arrowood, C, Haley, S, Meadows, KL, Morse, MA, Uronis, HE, Blobe, GC, Hsu, SD, Zafar, SY, and Hurwitz, HI. "Phase I study of dasatinib in combination with capecitabine, oxaliplatin and bevacizumab followed by an expanded cohort in previously untreated metastatic colorectal cancer." Investigational New Drugs 32.2 (April 2014): 330-339.

PMID

24173967

Source

epmc

Published In

Investigational New Drugs

Volume

32

Issue

2

Publish Date

2014

Start Page

330

End Page

339

DOI

10.1007/s10637-013-0042-9

Small bowel duplications are congenital structures commonly lined by heterotopic gastric or pancreatic mucosa. Though benign in children, small bowel duplications have the potential for malignant degeneration in adulthood. Here, we present the first reported case of metastatic adenocarcinoma arising from a small bowel duplication lined by gastroesophageal mucosa. The cancer demonstrated overexpression of the HER2/neu oncoprotein and amplification of the HER2/neu gene. This represents the only report of HER2 overexpression in this type of lesion. The patient is being treated with traditional chemotherapeutic agents in addition to monoclonal antibody therapy directed at the HER2 protein, and has demonstrated a clinical benefit from treatment. This case demonstrates that the anatomic location of a mass may be distinct from its biological origin, and this difference may have important practical implications for diagnostic testing and treatment.

Authors

Nussbaum, DP; Bhattacharya, SD; Jiang, X; Cardona, DM; Strickler, JH; Blazer, DG

MLA Citation

Nussbaum, DP, Bhattacharya, SD, Jiang, X, Cardona, DM, Strickler, JH, and Blazer, DG. "Gastroesophageal heterotopia and HER2/neu overexpression in an adenocarcinoma arising from a small bowel duplication." Archives of pathology & laboratory medicine 138.3 (March 2014): 428-431.

PMID

24576036

Source

epmc

Published In

Archives of Pathology & Laboratory Medicine

Volume

138

Issue

3

Publish Date

2014

Start Page

428

End Page

431

DOI

10.5858/arpa.2012-0523-cr

Worldwide, colorectal cancer (CRC) is responsible for over 600,000 deaths annually and remains a significant public health concern. Because of therapeutic advancements over the past two decades, patients with metastatic CRC are living longer with an improved quality of life. This review will highlight recent trial evidence that improves outcomes for patients with metastatic disease. Topics will include the optimal use of first-line combination chemotherapy, bevacizumab in patients with advanced age or comorbidities, maintenance chemotherapy, first-line use of anti-EGFR therapies, first-line cetuximab versus bevacizumab, anti-angiogenic therapies past progression, and management of treatment-refractory disease. Clinical trial evidence will be presented, along with guidance on how to integrate recent evidence into clinical practice. Finally, this review will examine innovative drug development strategies, and will discuss potentially actionable targets identified by molecular testing. © 2013 Springer Science+Business Media New York.

Authors

Strickler, JH; Hurwitz, HI

MLA Citation

Strickler, JH, and Hurwitz, HI. "Palliative treatment of metastatic colorectal cancer: What is the optimal approach? Topical collection on gastrointestinal cancers." Current Oncology Reports 16.1 (January 1, 2014).

Source

scopus

Published In

Current Oncology Reports

Volume

16

Issue

1

Publish Date

2014

DOI

10.1007/s11912-013-0363-z

Purpose Dasatinib inhibits src family kinases and has anti-angiogenic properties. We conducted a phase I study of dasatinib, capecitabine, oxaliplatin, and bevacizumab (CapeOx/bevacizumab), with an expansion cohort in metastatic colorectal cancer (CRC). Methods Patients were enrolled in a dose escalation cohort to establish the maximum tolerated dose (MTD) and the recommended phase II dose (RP2D). Using a "3 + 3" design, twelve patients with advanced solid tumors received dasatinib (50 mg twice daily or 70 mg daily), capecitabine (850 mg/m2 twice daily, days 1-14), oxaliplatin (130 mg/m2 on day 1) and bevacizumab (7.5 mg/kg on day1), every 3 weeks. Ten patients with previously untreated metastatic CRC were then enrolled in an expansion cohort. Activated src (srcact) expression was measured by immunohistochemistry, using an antibody that selectively recognizes the active conformation of src (clone 28). Results Twenty-two patients were enrolled between June 2009 and May 2011. Two DLTs were observed in the 50 mg bid dasatinib cohort, and one DLT was observed in the 70 mg daily dasatinib cohort. The MTD and RP2D for dasatinib was 70 mg daily. The most common treatment-related adverse events were fatigue (20; 91 %) and diarrhea (18; 82 %). Biomarker analysis of srcact expression demonstrated that the overall response rate (ORR) was 75 % (6/8) for patients with high src act expression (IHC ≥ 2), compared to 0 % (0/8) for patients with low srcact expression (IHC 0 or 1); (p = 0.007). Conclusions The RP2D of dasatinib is 70 mg daily in combination with CapeOx/bevacizumab. High levels of srcact expression may predict those patients most likely to benefit from dasatinib. © 2013 Springer Science+Business Media New York.

Authors

Strickler, JH; McCall, S; Nixon, AB; Brady, JC; Pang, H; Rushing, C; Cohn, A; Starodub, A; Arrowood, C; Haley, S; Meadows, KL; Morse, MA; Uronis, HE; Blobe, GC; Hsu, SD; Zafar, SY; Hurwitz, HI

MLA Citation

Strickler, JH, McCall, S, Nixon, AB, Brady, JC, Pang, H, Rushing, C, Cohn, A, Starodub, A, Arrowood, C, Haley, S, Meadows, KL, Morse, MA, Uronis, HE, Blobe, GC, Hsu, SD, Zafar, SY, and Hurwitz, HI. "Phase i study of dasatinib in combination with capecitabine, oxaliplatin and bevacizumab followed by an expanded cohort in previously untreated metastatic colorectal cancer." Investigational New Drugs 32.2 (January 1, 2014): 330-339.

Source

scopus

Published In

Investigational New Drugs

Volume

32

Issue

2

Publish Date

2014

Start Page

330

End Page

339

DOI

10.1007/s10637-013-0042-9

Purpose: To define maximum tolerated dose (MTD), toxicities, and pharmacodynamics of capecitabine, oxaliplatin, bevacizumab, and everolimus in advanced solid tumor patients. Design: This was a standard "3 + 3" dose-escalation trial. All subjects received bevacizumab 7.5 mg/kg on day 1 of each cycle. Doses for capecitabine, oxaliplatin and everolimus were modified per dose limiting toxicity (DLT). Baseline and on-treatment plasma biomarkers were analyzed. Archived tumor mRNA levels were evaluated for NRP1, NRP2 and VEGF-A isoforms. Results: Twenty-nine patients were evaluable for toxicity and 30 for efficacy. Two DLTs were observed in cohort 1 and one DLT each was observed in cohort -1 and -1b. Grade ≥3 toxicities included neutropenia, hypertension, perforation/fistula/hemorrhage, hypertriglyceridemia, diarrhea, and thromboembolism. Twelve subjects experienced partial response (PR); 12 had stable disease as best response. Three of seven chemorefractory metastatic colorectal cancer (mCRC) subjects experienced PR; 8 of 15 chemonaive mCRC subjects experienced PR. Plasma TβRIII and IL-6 increased on treatment but without correlation to outcome. Increased VEGF165 levels significantly correlated with longer progression free survival. Conclusions: Everolimus with full dose capecitabine, oxaliplatin, and bevacizumab had unacceptable toxicity. MTD was: everolimus 5 mg daily; capecitabine 680 mg/m2 BID days 1-14; oxaliplatin 100 mg/m2 and bevacizumab 7.5 mg/kg, day 1. Activity was noted in mCRC. © 2014 Springer Science+Business Media.

Authors

Rangwala, F; Bendell, JC; Kozloff, MF; Arrowood, CC; Dellinger, A; Meadows, J; Tourt-Uhlig, S; Murphy, J; Meadows, KL; Starr, A; Broderick, S; Brady, JC; Cushman, SM; Morse, MA; Uronis, HE; Hsu, SD; Zafar, SY; Wallace, J; Starodub, AN; Strickler, JH; Pang, H; Nixon, AB; Hurwitz, HI

MLA Citation

Rangwala, F, Bendell, JC, Kozloff, MF, Arrowood, CC, Dellinger, A, Meadows, J, Tourt-Uhlig, S, Murphy, J, Meadows, KL, Starr, A, Broderick, S, Brady, JC, Cushman, SM, Morse, MA, Uronis, HE, Hsu, SD, Zafar, SY, Wallace, J, Starodub, AN, Strickler, JH, Pang, H, Nixon, AB, and Hurwitz, HI. "Phase I study of capecitabine, oxaliplatin, bevacizumab, and everolimus in advanced solid tumors." Investigational New Drugs 32.4 (January 1, 2014): 700-709.

Source

scopus

Published In

Investigational New Drugs

Volume

32

Issue

4

Publish Date

2014

Start Page

700

End Page

709

DOI

10.1007/s10637-014-0089-2

Worldwide, colorectal cancer (CRC) is responsible for over 600,000 deaths annually and remains a significant public health concern. Because of therapeutic advancements over the past two decades, patients with metastatic CRC are living longer with an improved quality of life. This review will highlight recent trial evidence that improves outcomes for patients with metastatic disease. Topics will include the optimal use of first-line combination chemotherapy, bevacizumab in patients with advanced age or comorbidities, maintenance chemotherapy, first-line use of anti-EGFR therapies, first-line cetuximab versus bevacizumab, anti-angiogenic therapies past progression, and management of treatment-refractory disease. Clinical trial evidence will be presented, along with guidance on how to integrate recent evidence into clinical practice. Finally, this review will examine innovative drug development strategies, and will discuss potentially actionable targets identified by molecular testing.

Authors

Strickler, JH; Hurwitz, HI

MLA Citation

Strickler, JH, and Hurwitz, HI. "Palliative treatment of metastatic colorectal cancer: what is the optimal approach?." Current Oncology Reports 16.1 (January 2014): 363-null. (Review)

PMID

24293074

Source

epmc

Published In

Current Oncology Reports

Volume

16

Issue

1

Publish Date

2014

Start Page

363

DOI

10.1007/s11912-013-0363-z

Authors

Strickler, JH; Hurwitz, HI

MLA Citation

Strickler, JH, and Hurwitz, HI. "Palliative Treatment of Metastatic Colorectal Cancer: What is the Optimal Approach?." Current Oncology Reports 16.1 (2014): 1-8.

Source

scopus

Published In

Current Oncology Reports

Volume

16

Issue

1

Publish Date

2014

Start Page

1

End Page

8

Worldwide, colorectal cancer (CRC) is responsible for over 600,000 deaths annually and remains a significant public health concern. Because of therapeutic advancements over the past two decades, patients with metastatic CRC are living longer with an improved quality of life. This review will highlight recent trial evidence that improves outcomes for patients with metastatic disease. Topics will include the optimal use of first-line combination chemotherapy, bevacizumab in patients with advanced age or comorbidities, maintenance chemotherapy, first-line use of anti-EGFR therapies, first-line cetuximab versus bevacizumab, anti-angiogenic therapies past progression, and management of treatment-refractory disease. Clinical trial evidence will be presented, along with guidance on how to integrate recent evidence into clinical practice. Finally, this review will examine innovative drug development strategies, and will discuss potentially actionable targets identified by molecular testing.

Authors

Strickler, JH; Hurwitz, HI

MLA Citation

Strickler, JH, and Hurwitz, HI. "Palliative treatment of metastatic colorectal cancer: what is the optimal approach?." Current oncology reports 16.1 (2014): 363--.

Source

scival

Published In

Current Oncology Reports

Volume

16

Issue

1

Publish Date

2014

Start Page

363-

DOI

10.1007/s11912-013-0363-z

Authors

Tachibana, M; Papadopoulos, KP; Strickler, J; Puzanov, I; Gajee, R; Wang, Y; Zahir, H

MLA Citation

Tachibana, M, Papadopoulos, KP, Strickler, J, Puzanov, I, Gajee, R, Wang, Y, and Zahir, H. "Abstract C85: Drug interaction study of tivantinib in cancer subjects using a cocktail approach." Molecular Cancer Therapeutics 12.11_Supplement (November 1, 2013): C85-C85.

Source

crossref

Published In

Molecular Cancer Therapeutics

Volume

12

Issue

11_Supplement

Publish Date

2013

Start Page

C85

End Page

C85

DOI

10.1158/1535-7163.targ-13-c85

Authors

Strickler, JH; McCall, S; Nixon, AB; Pang, H; Rushing, C; Arrowood, C; Haley, S; Meadows, K; Hurwitz, H

MLA Citation

Strickler, JH, McCall, S, Nixon, AB, Pang, H, Rushing, C, Arrowood, C, Haley, S, Meadows, K, and Hurwitz, H. "Correlation of Src activation with response to dasatinib, capecitabine, oxaliplatin, and bevacizumab in advanced solid tumors." May 20, 2013.

Source

wos-lite

Published In

Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology

Volume

31

Issue

15

Publish Date

2013

Authors

Hurwitz, H; Pitot, H; Strickler, J; Sorensen, JM; Leopold, L; Brill, J; Smith, DC

MLA Citation

Hurwitz, H, Pitot, H, Strickler, J, Sorensen, JM, Leopold, L, Brill, J, and Smith, DC. "Preliminary Report of a First-in-human, Open-label, Multicenter, Phase I Study of AT-406 (Debio 1143), an Oral Small Molecule Multi-IAP Inhibitor, in Solid Tumors and Lymphomas." November 2012.

Source

wos-lite

Published In

European Journal of Cancer

Volume

48

Publish Date

2012

Start Page

25

End Page

25

DOI

10.1016/S0959-8049(12)71874-9

BACKGROUND: The effect of intensified platelet inhibition for patients with unstable angina or myocardial infarction without ST-segment elevation who do not undergo revascularization has not been delineated. METHODS: In this double-blind, randomized trial, in a primary analysis involving 7243 patients under the age of 75 years receiving aspirin, we evaluated up to 30 months of treatment with prasugrel (10 mg daily) versus clopidogrel (75 mg daily). In a secondary analysis involving 2083 patients 75 years of age or older, we evaluated 5 mg of prasugrel versus 75 mg of clopidogrel. RESULTS: At a median follow-up of 17 months, the primary end point of death from cardiovascular causes, myocardial infarction, or stroke among patients under the age of 75 years occurred in 13.9% of the prasugrel group and 16.0% of the clopidogrel group (hazard ratio in the prasugrel group, 0.91; 95% confidence interval [CI], 0.79 to 1.05; P=0.21). Similar results were observed in the overall population. The prespecified analysis of multiple recurrent ischemic events (all components of the primary end point) suggested a lower risk for prasugrel among patients under the age of 75 years (hazard ratio, 0.85; 95% CI, 0.72 to 1.00; P=0.04). Rates of severe and intracranial bleeding were similar in the two groups in all age groups. There was no significant between-group difference in the frequency of nonhemorrhagic serious adverse events, except for a higher frequency of heart failure in the clopidogrel group. CONCLUSIONS: Among patients with unstable angina or myocardial infarction without ST-segment elevation, prasugrel did not significantly reduce the frequency of the primary end point, as compared with clopidogrel, and similar risks of bleeding were observed. (Funded by Eli Lilly and Daiichi Sankyo; TRILOGY ACS ClinicalTrials.gov number, NCT00699998.).

Authors

Roe, MT; Armstrong, PW; Fox, KAA; White, HD; Prabhakaran, D; Goodman, SG; Cornel, JH; Bhatt, DL; Clemmensen, P; Martinez, F; Ardissino, D; Nicolau, JC; Boden, WE; Gurbel, PA; Ruzyllo, W; Dalby, AJ; McGuire, DK; Leiva-Pons, JL; Parkhomenko, A; Gottlieb, S; Topacio, GO; Hamm, C; Pavlides, G; Goudev, AR; Oto, A; Tseng, C-D; Merkely, B; Gasparovic, V; Corbalan, R; Cinteză, M; McLendon, RC; Winters, KJ; Brown, EB; Lokhnygina, Y; Aylward, PE; Huber, K; Hochman, JS; Ohman, EM; TRILOGY ACS Investigators,

MLA Citation

Roe, MT, Armstrong, PW, Fox, KAA, White, HD, Prabhakaran, D, Goodman, SG, Cornel, JH, Bhatt, DL, Clemmensen, P, Martinez, F, Ardissino, D, Nicolau, JC, Boden, WE, Gurbel, PA, Ruzyllo, W, Dalby, AJ, McGuire, DK, Leiva-Pons, JL, Parkhomenko, A, Gottlieb, S, Topacio, GO, Hamm, C, Pavlides, G, Goudev, AR, Oto, A, Tseng, C-D, Merkely, B, Gasparovic, V, Corbalan, R, Cinteză, M, McLendon, RC, Winters, KJ, Brown, EB, Lokhnygina, Y, Aylward, PE, Huber, K, Hochman, JS, Ohman, EM, and TRILOGY ACS Investigators, . "Prasugrel versus clopidogrel for acute coronary syndromes without revascularization." The New England Journal of Medicine 367.14 (October 2012): 1297-1309.

PMID

22920930

Source

epmc

Published In

The New England Journal of Medicine

Volume

367

Issue

14

Publish Date

2012

Start Page

1297

End Page

1309

DOI

10.1056/nejmoa1205512

To define the maximum tolerated dose, clinical toxicities, and pharmacodynamics of bevacizumab, everolimus, and panobinostat (LBH-589) when administered in combination to patients with advanced solid tumor malignancies.Subjects received 10 mg of panobinostat three times weekly, 5 or 10 mg everolimus daily, and bevacizumab at 10 mg/kg every 2 weeks. Dose-limiting toxicities (DLTs) were assessed in cycle 1; toxicity evaluation was closely monitored throughout treatment. Treatment continued until disease progression or undesirable toxicity. Protein acetylation was assessed in peripheral blood mononuclear cells (PBMC) both at baseline and on treatment.Twelve subjects were evaluable for toxicity and nine subjects for response. DLTs in cohort 1 included grade 2 esophagitis and grade 3 oral mucositis; DLTs in cohort -1 were grade 2 ventricular arrhythmia and grade 2 intolerable skin rash. Common adverse events were diarrhea (50 %), headache (33 %), mucositis/stomatitis (25 %), hyperlipidemia (25 %), and thrombocytopenia (25 %). There was 1 partial response; an additional 2 subjects had stable disease as best response. No consistent changes in protein acetylation in PBMC were observed in samples available from eight patients on treatment compared with baseline.Bevacizumab, everolimus, and panobinostat in combination at the lowest proposed doses did not have an acceptable safety and tolerability profile and did not consistently inhibit HDAC activity; therefore, we do not recommend further evaluation.

Authors

Strickler, JH; Starodub, AN; Jia, J; Meadows, KL; Nixon, AB; Dellinger, A; Morse, MA; Uronis, HE; Marcom, PK; Zafar, SY; Haley, ST; Hurwitz, HI

MLA Citation

Strickler, JH, Starodub, AN, Jia, J, Meadows, KL, Nixon, AB, Dellinger, A, Morse, MA, Uronis, HE, Marcom, PK, Zafar, SY, Haley, ST, and Hurwitz, HI. "Phase I study of bevacizumab, everolimus, and panobinostat (LBH-589) in advanced solid tumors." Cancer Chemotherapy and Pharmacology 70.2 (August 2012): 251-258.

PMID

22744359

Source

epmc

Published In

Cancer Chemotherapy and Pharmacology

Volume

70

Issue

2

Publish Date

2012

Start Page

251

End Page

258

DOI

10.1007/s00280-012-1911-1

Authors

Kollmannsberger, CK; Hurwitz, H; Cleary, JM; Strickler, JH; Drouin, MA; Juretic, M; Hunt, W; Reid, GK; Maroun, CR; Bonfils, C; Wang, J; Karam, A; Besterman, JM; Mehran, M; Shapiro, G

MLA Citation

Kollmannsberger, CK, Hurwitz, H, Cleary, JM, Strickler, JH, Drouin, MA, Juretic, M, Hunt, W, Reid, GK, Maroun, CR, Bonfils, C, Wang, J, Karam, A, Besterman, JM, Mehran, M, and Shapiro, G. "MGCD265, a multitargeted oral tyrosine kinase receptor inhibitor of Met and VEGFR: Dose-escalation phase I study." May 20, 2012.

Source

wos-lite

Published In

Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology

Volume

30

Issue

15

Publish Date

2012

Authors

Strickler, JH; Hurwitz, HI

MLA Citation

Strickler, JH, and Hurwitz, HI. "Maintenance therapy for first-line metastatic colorectal cancer: activity and sustainability." The Oncologist 17.1 (January 10, 2012): 9-10.

PMID

22234629

Source

epmc

Published In

The Oncologist

Volume

17

Issue

1

Publish Date

2012

Start Page

9

End Page

10

DOI

10.1634/theoncologist.2011-0358

Since its approval for the first-line treatment of metastatic colorectal cancer (mCRC), bevacizumab has become a standard treatment option in combination with chemotherapy for patients with mCRC. Bevacizumab has demonstrated efficacy in combination with a number of different backbone chemotherapy regimens, and its widespread use has introduced several important questions regarding the selection and optimization of bevacizumab-based treatment regimens, its use in various patient populations, and the identification of associated adverse events. This review discusses the results of several phase II and phase III clinical trials, as well as large observational studies, to address the use of bevacizumab in the treatment of patients with mCRC in the first-line setting.

Authors

Strickler, JH; Hurwitz, HI

MLA Citation

Strickler, JH, and Hurwitz, HI. "Bevacizumab-based therapies in the first-line treatment of metastatic colorectal cancer." The Oncologist 17.4 (January 2012): 513-524. (Review)

PMID

22477726

Source

epmc

Published In

The Oncologist

Volume

17

Issue

4

Publish Date

2012

Start Page

513

End Page

524

DOI

10.1634/theoncologist.2012-0003

Authors

Strickler, JH; Cohn, AL; Arrowood, C; Haley, S; Morse, M; Uronis, H; Blobe, GC; Hsu, SD; Zafar, Y; Hurwitz, H

MLA Citation

Strickler, JH, Cohn, AL, Arrowood, C, Haley, S, Morse, M, Uronis, H, Blobe, GC, Hsu, SD, Zafar, Y, and Hurwitz, H. "Phase I study of dasatinib in combination with capecitabine, oxaliplatin, and bevacizumab followed by an expanded cohort in previously untreated metastatic colorectal cancer." Journal of Clinical Oncology 29.15_suppl (May 20, 2011): 3586-3586.

Source

crossref

Published In

Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology

Volume

29

Issue

15_suppl

Publish Date

2011

Start Page

3586

End Page

3586

DOI

10.1200/jco.2011.29.15_suppl.3586

3586 Background: SRC is a non-receptor tyrosine kinase involved in normal and tumor cell signaling functions including cell proliferation, angiogenesis and survival. Dasatinib (D) is a potent inhibitor of SRC kinase activity. Preclinical data suggests the addition of D to standard chemotherapy agents for colon cancer may increase anti-tumor activity. We evaluated D in combination with capecitabine (C), oxaliplatin (O) and bevacizumab (B) in a phase I dose escalation study followed by an expanded cohort in first-line colorectal.For dose escalation, eligible patients had advanced solid tumors with adequate organ function and no increased risk for class-related toxicities. B and O were given intravenously, and C and D were orally administered; cycle length was 21 days. C was dosed at 850 mg/m2 on days 1-14; O was dosed at 130 mg/m2 and B was dosed at 7.5 mg/kg on day one of each cycle. D was dosed at 50 mg twice daily in cohort one and 70 mg once daily in cohort -1. Dose limiting toxicity (DLT) was assessed in cycle 1.Dose escalation is complete with 10 subjects evaluable for DLT toxicity and 11 subjects evaluable for efficacy. Two DLTs were observed out of 4 evaluable subjects in cohort one. Six evaluable subjects were enrolled in the -1 cohort with 1 DLT. Two subjects have been enrolled in the expanded cohort. Possible grade ≥3 treatment-related adverse events (AEs) included neutropenia, febrile neutropenia, anorexia, diarrhea, fatigue, anemia, dehydration and grade 5 GI-perforation. One non-treatment related death was due to disease progression. D-related nausea, anorexia and fatigue were responsive to low dose oral steroids; fluid retention was responsive to diuretics. Of 13 subjects evaluable for efficacy, 3 subjects had a partial response (PR), 6 had stable disease (SD) as best response.D in combination with C, O and B is well-tolerated with a toxicity profile similar to standard C, O and B.The recommended phase II dose is C at 850 mg/m2 on days 1-14, O at 130 mg/m2 and B at 7.5 mg/kg on day one of each cycle, and D at 70 mg once daily. Enrollment in the expanded cohort of first-line colorectal is nearing completion.

Authors

Strickler, JH; Cohn, AL; Arrowood, C; Haley, S; Morse, M; Uronis, H; Blobe, GC; Hsu, SD; Zafar, Y; Hurwitz, H

MLA Citation

Strickler, JH, Cohn, AL, Arrowood, C, Haley, S, Morse, M, Uronis, H, Blobe, GC, Hsu, SD, Zafar, Y, and Hurwitz, H. "Phase I study of dasatinib in combination with capecitabine, oxaliplatin, and bevacizumab followed by an expanded cohort in previously untreated metastatic colorectal cancer." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 29.15_suppl (May 2011): 3586-.

PMID

28020244

Source

epmc

Published In

Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology

Volume

29

Issue

15_suppl

Publish Date

2011

Start Page

3586

Purpose: To investigate the antitumor efficacy of T-cell anergy reversal through homeostatic proliferation and regulatory T-cell (Treg) depletion in a clinically relevant murine adoptive immunotherapy model. Experimental Design: B16 melanoma cells were engineered to express the model SIYRYYGL (SIY) antigen to enable immune monitoring. Tumor-specificTcells expanded in tumor-challenged wild-type hosts but became hyporesponsive.To examine whether lymphopenia-induced homeostatic proliferation could reverse tumor-induced T-cell anergy, total splenicTcells were transferred into lymphopenic RAG2-/- mice or control P14/RAG2-/- mice. Tumor growth was measured, and SlY-specific immune responses were monitored using ELISPOT and SIY/Kb tetramers. To determine whether Treg depletion could synergize with homeostatic proliferation, RAG2-/- mice received total or CD25-depleted T cells, followed or preceded by B16.SIY challenge. This approach was further investigated in wild-type mice lymphodepleted with sublethal total body irradiation. Results: Adoptive transfer of total splenic T cells into RAG2 -/- mice moderately affected the growth rate of B16.SIY. As Treg expansion occurred in tumor-bearing mice, CD25+ T cells were depleted from total Tcells before adoptive transfer. Interestingly, transfer of CD25-depleted T cells into RAG 2-/- mice resulted in potent rejection of B16 melanoma in both prophylactic and short-term preimplanted tumor settings and was associated with maintained T-cell effector function. Using a clinically applicable approach, wild-type mice were lymphodepleted using sublethal total body irradiation, which similarly supported tumor rejection upon transfer of CD25-depleted Tcells. Conclusions: Our results indicate that combined CD25 depletion and homeostatic proliferation support a potent antitumor immune response - an approach with potential for clinical translation. © 2008 American Associalion for Cancer Research.

Authors

Kline, J; Brown, IE; Zha, Y-Y; Blank, C; Strickler, J; Wouters, H; Zhang, L; Gajewski, TF

MLA Citation

Kline, J, Brown, IE, Zha, Y-Y, Blank, C, Strickler, J, Wouters, H, Zhang, L, and Gajewski, TF. "Homeostatic proliferation plus regulatory T-cell depletion promotes potent rejection of B16 melanoma." Clinical Cancer Research 14.10 (2008): 3156-3167.

PMID

18483384

Source

scival

Published In

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research

Volume

14

Issue

10

Publish Date

2008

Start Page

3156

End Page

3167

DOI

10.1158/1078-0432.CCR-07-4696

Authors

Coil, DA; Strickler, JH; Rai, SK; Miller, AD

MLA Citation

Coil, DA, Strickler, JH, Rai, SK, and Miller, AD. "Jaagsiekte Sheep Retrovirus Env Protein Stabilizes Retrovirus Vectors against Inactivation by Lung Surfactant, Centrifugation, and Freeze-Thaw Cycling." Journal of Virology 75.18 (September 15, 2001): 8864-8867.

Source

crossref

Published In

Journal of Virology

Volume

75

Issue

18

Publish Date

2001

Start Page

8864

End Page

8867

DOI

10.1128/jvi.75.18.8864-8867.2001