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Dive into the research topics where Robert G. Maki is active.

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Featured researches published by Robert G. Maki.


Clinical Cancer Research | 2005

Acquired resistance to imatinib in gastrointestinal stromal tumor occurs through secondary gene mutation

Cristina R. Antonescu; Peter Besmer; Tianhua Guo; Knarik Arkun; Glory Hom; Beata Koryotowski; Margaret Leversha; Philip D. Jeffrey; Diann DeSantis; Samuel Singer; Murray F. Brennan; Robert G. Maki; Ronald P. DeMatteo

Most gastrointestinal stromal tumors (GIST) have an activating mutation in either KIT or PDGFRA. Imatinib is a selective tyrosine kinase inhibitor and achieves a partial response or stable disease in about 80% of patients with metastatic GIST. It is now clear that some patients with GIST develop resistance to imatinib during chronic therapy. To identify the mechanism of resistance, we studied 31 patients with GIST who were treated with imatinib and then underwent surgical resection. There were 13 patients who were nonresistant to imatinib, 3 with primary resistance, and 15 with acquired resistance after initial benefit from the drug. There were no secondary mutations in KIT or PDGFRA in the nonresistant or primary resistance groups. In contrast, secondary mutations were found in 7 of 15 (46%) patients with acquired resistance, each of whom had a primary mutation in KIT exon 11. Most secondary mutations were located in KIT exon 17. KIT phosphorylation was heterogeneous and did not correlate with clinical response to imatinib or mutation status. That acquired resistance to imatinib in GIST commonly occurs via secondary gene mutation in the KIT kinase domain has implications for strategies to delay or prevent imatinib resistance and to employ newer targeted therapies.


The Lancet | 2013

Efficacy and safety of regorafenib for advanced gastrointestinal stromal tumours after failure of imatinib and sunitinib (GRID): an international, multicentre, randomised, placebo-controlled, phase 3 trial.

George D. Demetri; Peter Reichardt; Yoon-Koo Kang; Jean-Yves Blay; Piotr Rutkowski; Hans Gelderblom; Peter Hohenberger; Michael Leahy; Margaret von Mehren; Heikki Joensuu; Giuseppe Badalamenti; Martin E. Blackstein; Axel Le Cesne; Patrick Schöffski; Robert G. Maki; Sebastian Bauer; Binh Bui Nguyen; Jianming Xu; Toshirou Nishida; John Chung; Christian Kappeler; Iris Kuss; Dirk Laurent; Paolo G. Casali

BACKGROUND Until now, only imatinib and sunitinib have proven clinical benefit in patients with gastrointestinal stromal tumours (GIST), but almost all metastatic GIST eventually develop resistance to these agents, resulting in fatal disease progression. We aimed to assess efficacy and safety of regorafenib in patients with metastatic or unresectable GIST progressing after failure of at least imatinib and sunitinib. METHODS We did this phase 3 trial at 57 hospitals in 17 countries. Patients with histologically confirmed, metastatic or unresectable GIST, with failure of at least previous imatinib and sunitinib were randomised in a 2:1 ratio (by computer-generated randomisation list and interactive voice response system; preallocated block design (block size 12); stratified by treatment line and geographical region) to receive either oral regorafenib 160 mg daily or placebo, plus best supportive care in both groups, for the first 3 weeks of each 4 week cycle. The study sponsor, participants, and investigators were masked to treatment assignment. The primary endpoint was progression-free survival (PFS). At disease progression, patients assigned placebo could crossover to open-label regorafenib. Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01271712. RESULTS From Jan 4, to Aug 18, 2011, 240 patients were screened and 199 were randomised to receive regorafenib (n=133) or matching placebo (n=66). Data cutoff was Jan 26, 2012. Median PFS per independent blinded central review was 4·8 months (IQR 1·4-9·2) for regorafenib and 0·9 months (0·9-1·8) for placebo (hazard ratio [HR] 0·27, 95% CI 0·19-0·39; p<0·0001). After progression, 56 patients (85%) assigned placebo crossed over to regorafenib. Drug-related adverse events were reported in 130 (98%) patients assigned regorafenib and 45 (68%) patients assigned placebo. The most common regorafenib-related adverse events of grade 3 or higher were hypertension (31 of 132, 23%), hand-foot skin reaction (26 of 132, 20%), and diarrhoea (seven of 132, 5%). INTERPRETATION The results of this study show that oral regorafenib can provide a significant improvement in progression-free survival compared with placebo in patients with metastatic GIST after progression on standard treatments. As far as we are aware, this is the first clinical trial to show benefit from a kinase inhibitor in this highly refractory population of patients. FUNDING Bayer HealthCare Pharmaceuticals.


Journal of Clinical Oncology | 2008

Primary and Secondary Kinase Genotypes Correlate With the Biological and Clinical Activity of Sunitinib in Imatinib-Resistant Gastrointestinal Stromal Tumor

Michael C. Heinrich; Robert G. Maki; Christopher L. Corless; Cristina R. Antonescu; Amy Harlow; Diana J. Griffith; Ajia Town; Arin McKinley; Wen Bin Ou; Jonathan A. Fletcher; Christopher D. M. Fletcher; Xin Huang; Darrel P. Cohen; Charles M. Baum; George D. Demetri

PURPOSE Most gastrointestinal stromal tumors (GISTs) harbor mutant KIT or platelet-derived growth factor receptor alpha (PDGFRA) kinases, which are imatinib targets. Sunitinib, which targets KIT, PDGFRs, and several other kinases, has demonstrated efficacy in patients with GIST after they experience imatinib failure. We evaluated the impact of primary and secondary kinase genotype on sunitinib activity. PATIENTS AND METHODS Tumor responses were assessed radiologically in a phase I/II trial of sunitinib in 97 patients with metastatic, imatinib-resistant/intolerant GIST. KIT/PDGFRA mutational status was determined for 78 patients by using tumor specimens obtained before and after prior imatinib therapy. Kinase mutants were biochemically profiled for sunitinib and imatinib sensitivity. RESULTS Clinical benefit (partial response or stable disease for > or = 6 months) with sunitinib was observed for the three most common primary GIST genotypes: KIT exon 9 (58%), KIT exon 11 (34%), and wild-type KIT/PDGFRA (56%). Progression-free survival (PFS) was significantly longer for patients with primary KIT exon 9 mutations (P = .0005) or with a wild-type genotype (P = .0356) than for those with KIT exon 11 mutations. The same pattern was observed for overall survival (OS). PFS and OS were longer for patients with secondary KIT exon 13 or 14 mutations (which involve the KIT-adenosine triphosphate binding pocket) than for those with exon 17 or 18 mutations (which involve the KIT activation loop). Biochemical profiling studies confirmed the clinical results. CONCLUSION The clinical activity of sunitinib after imatinib failure is significantly influenced by both primary and secondary mutations in the predominant pathogenic kinases, which has implications for optimization of the treatment of patients with GIST.


Journal of Clinical Oncology | 2009

Phase II Study of Sorafenib in Patients With Metastatic or Recurrent Sarcomas

Robert G. Maki; David R. D'Adamo; Mary Louise Keohan; Michael Saulle; Scott M. Schuetze; Samir D. Undevia; Michael B. Livingston; Matthew M. Cooney; Martee L. Hensley; Monica M. Mita; Chris H. Takimoto; Andrew S. Kraft; Anthony Elias; Bruce Brockstein; Nathalie E. Blachère; Mark A. Edgar; Lawrence H. Schwartz; Li Xuan Qin; Cristina R. Antonescu; Gary K. Schwartz

PURPOSE Since activity of sorafenib was observed in sarcoma patients in a phase I study, we performed a multicenter phase II study of daily oral sorafenib in patients with recurrent or metastatic sarcoma. PATIENTS AND METHODS We employed a multiarm study design, each representing a sarcoma subtype with its own Simon optimal two-stage design. In each arm, 12 patients who received 0 to 1 prior lines of therapy were treated (0 to 3 for angiosarcoma and malignant peripheral-nerve sheath tumor). If at least one Response Evaluation Criteria in Solid Tumors (RECIST) was observed, 25 further patients with that sarcoma subtype were accrued. Results Between October 2005 and November 2007, 145 patients were treated; 144 were eligible for toxicity and 122 for response. Median age was 55 years; female-male ratio was 1.8:1. The median number of cycles was 3. Five of 37 patients with angiosarcoma had a partial response (response rate, 14%). This was the only arm to meet the RECIST response rate primary end point. Median progression-free survival was 3.2 months; median overall survival was 14.3 months. Adverse events (typically dermatological) necessitated dose reduction for 61% of patients. Statistical modeling in this limited patient cohort indicated sorafenib toxicity was correlated inversely to patient height. There was no correlation between phosphorylated extracellular signal regulated kinase expression and response in six patients with angiosarcoma with paired pre- and post-therapy biopsies. CONCLUSION As a single agent, sorafenib has activity against angiosarcoma and minimal activity against other sarcomas. Further evaluation of sorafenib in these and possibly other sarcoma subtypes appears warranted, presumably in combination with cytotoxic or kinase-specific agents.


Annals of Surgery | 2007

Results of tyrosine kinase inhibitor therapy followed by surgical resection for metastatic gastrointestinal stromal tumor.

Ronald P. DeMatteo; Robert G. Maki; Samuel Singer; Mithat Gonen; Murray F. Brennan; Cristina R. Antonescu

Introduction:Gastrointestinal stromal tumor (GIST) is the most common sarcoma of the intestinal tract. Nearly all tumors have an activating mutation in the KIT or, less often, PDGFR&agr;, gene. Therapy with tyrosine kinase inhibitors benefits over 80% of patients with advanced GIST, but most patients eventually develop drug resistance. Methods:Forty patients with metastatic GIST were treated with tyrosine kinase inhibitors and then underwent surgical resection. Based on the growth of their tumors by serial radiologic imaging, patients were categorized at the time of operation as having responsive disease, focal resistance (1 tumor growing), or multifocal resistance (more than 1 tumor growing). Patients were followed for a median of 15 months (range, 6–46 months) after surgery. Results:Initially, molecular therapy achieved stable disease or a partial response in all but 1 patient. Surgery was performed after a median of 15 months, and there were no perioperative deaths. After operation, the 20 patients with responsive disease had a 2-year progression-free survival of 61% and 2-year overall survival of 100%. In contrast, the 13 patients with focal resistance progressed after surgery at a median of 12 months and the 2-year overall survival was 36%. There were 7 patients with multifocal resistance and they progressed postoperatively at a median of 3 months and had a 1-year overall survival of 36%. Conclusion:Selected patients with metastatic GIST who have responsive disease or focal resistance to tyrosine kinase inhibitor therapy may benefit from elective surgical resection. Surgery for patients with metastatic GIST who have multifocal resistance is generally not indicated, and these patients should be considered for clinical trials of new systemic agents.


Cancer Journal | 2005

A 14-year Retrospective Review of Angiosarcoma: Clinical Characteristics, Prognostic Factors, and Treatment Outcomes with Surgery and Chemotherapy

Matthew G. Fury; Cristina R. Antonescu; Kimberly J. Van Zee; Murray E Brennan; Robert G. Maki

PURPOSEAngiosarcoma is a rare vascular malignancy, and there are few published data to guide chemotherapy treatment decisions. We present a retrospective analysis of angiosarcoma encompassing all anatomic sites of disease presenting to a single institution over a 14-year period. Characteristics at presentation and prognostic factors are reviewed. For patients with unresectable disease, progression-free survival with various chemotherapy regimens is described. PATIENTS AND METHODSPathological confirmation of all cases was performed before they were included in this analysis. One hundred twenty-five patients with angiosarcoma were seen and treated between January 1, 1990 and December 31, 2003. RESULTSAngiosarcoma showed marked variation by anatomic site regarding gender ratio, median age at diagnosis, overall survival, and response to chemotherapy. Overall 5-year survival was 31% for angiosarcoma. Superficial depth and negative microscopic surgical margins correlated with longer overall survival, but tumor size did not reach significance as a prognostic factor. For unresectable angiosarcoma, doxorubicin-based regimens yielded progression-free survival of 3.7–5.4 months. Paclitaxel achieved a progression-free survival of 6.8 months for scalp angiosarcoma and 2.8 months for sites below the clavicle. DISCUSSIONAngiosarcoma is an aggressive malignancy characterized by biologic heterogeneity at different anatomic sites and relative sensitivity to paclitaxel and doxorubicin.


Journal of Pediatric Hematology Oncology | 2005

Gastrointestinal stromal tumors in children and young adults: a clinicopathologic, molecular, and genomic study of 15 cases and review of the literature.

Sonam Prakash; Lisa Sarran; Nicholas D. Socci; Ronald P. DeMatteo; Jonathan Eisenstat; Alba M Greco; Robert G. Maki; Leonard H. Wexler; Michael P. LaQuaglia; Peter Besmer; Cristina R. Antonescu

Gastrointestinal stromal tumors (GISTs) are mesenchymal tumors of the intestinal tract that typically occur in adults over the age of 40 years. GISTs in younger patients are rare and not well characterized. The objective was to define the characteristics of GISTs in children and young adults (<30 years old). Clinicopathologic and molecular features, including KIT/PDGFRA genotype, in GISTs from 5 children and 10 young adults were analyzed. Gene expression analysis was performed on 5 gastric tumor samples from 2 children, 2 gastric tumors from young adults, and 10 gastric GISTs from older adults using an U133A Affymetrix platform (22,000 genes). All five pediatric GISTs occurred in girls, involved the stomach as multiple nodules, showed predominantly an epithelioid morphology, often involved lymph nodes, and lacked KIT or PDGFRA mutations. Although all five patients developed recurrence (four in the liver, three in the peritoneum, and two in both sites), four are still alive with disease. Of the 10 GISTs in young adults, half occurred in the small bowel and had spindle cell morphology, and one case had lymph node metastasis. KIT mutations were identified in seven cases, four in exon 11 and three in exon 9. Seven patients developed recurrence, and at last follow-up two patients had died of disease. Gene expression analysis showed high expression of PHKA1, FZD2, NLGN4, IGF1R, and ANK3 in the pediatric and young adult versus older adult cases. GISTs that occur in children are a separate clinicopathologic and molecular subset with predilection for girls, multifocal gastric tumors, and wild-type KIT/PDGFRA genotype. In contrast, GISTs in young adults are a more heterogeneous group, including cases that resemble either the pediatric or the older adult-type tumors. The distinct gene expression profile suggests avenues for investigation of pathogenesis and potential therapeutic strategies.


Journal of Clinical Oncology | 2005

Phase II Study of Doxorubicin and Bevacizumab for Patients With Metastatic Soft-Tissue Sarcomas

David R. D'Adamo; Sibyl Anderson; Karen H. Albritton; Jennifer Yamada; Elyn Riedel; Kelly Scheu; Gary K. Schwartz; Helen Chen; Robert G. Maki

PURPOSE To evaluate the antitumor activity and tolerability of bevacizumab and doxorubicin in patients with metastatic soft-tissue sarcoma (STS). PATIENTS AND METHODS Patients may have had up to one nonanthracycline line of therapy. Seventeen patients with metastatic STS were treated with doxorubicin at 75 mg/m2 intravenous (IV) push followed by bevacizumab 15 mg/kg IV every 3 weeks. Dexrazoxane was started for total doxorubicin dose exceeding 300 mg/m2. RESULTS A total of 85 cycles of doxorubicin/bevacizumab were administered, median four cycles (range, one to 11), with three patients receiving one to four cycles of bevacizumab maintenance after reaching 600 mg/m2 doxorubicin. All 17 patients were assessable for response. Two partial responses (12%, 95% CI = 1% to 36%) were observed, lasting seven and 12 cycles of therapy. Eleven patients (65%) had stable disease for four cycles or more. Six patients developed cardiac toxicity grade 2 or greater, with four patients grade 2 (cumulative doxorubicin 75, 150, 300, 300 mg/m2, respectively), one grade 3 (total doxorubicin 591 mg/m2), and one grade 4 (total doxorubicin 420 mg/m2). One patient with extensive lung disease died of recurrent bilateral pneumothoraces, possibly treatment-related. CONCLUSION The 12% response rate for these patients was no greater than that observed for single-agent doxorubicin. However, the 65% of patients with stable disease lasting four cycles or longer suggests further study is warranted in STSs. The observed cardiac toxicity, despite close monitoring and standard use of dexrazoxane, obliges a change in the dose and/or schedule in future studies of this combination.


Journal of Clinical Oncology | 2009

Multicenter Phase II Trial of Sunitinib in the Treatment of Nongastrointestinal Stromal Tumor Sarcomas

Suzanne George; Priscilla Merriam; Robert G. Maki; Annick D. Van den Abbeele; Jeffrey T. Yap; Timothy Akhurst; David C. Harmon; Gauri Bhuchar; Margaret M. O'Mara; David R. D'Adamo; Jeffrey A. Morgan; Gary K. Schwartz; Andrew J. Wagner; James E. Butrynski; George D. Demetri; Mary L. Keohan

PURPOSE To evaluate the potential benefit of continuous daily dosing sunitinib in patients with advanced nongastrointestinal stromal tumor (GIST) sarcomas. PATIENTS AND METHODS A total of 53 patients with advanced non-GIST soft tissue sarcomas received sunitinib 37.5 mg daily. Primary end point was Response Evaluation Criteria in Solid Tumors defined response. Secondary end points were stable disease at 16 and 24 weeks. [(18)F]-fluorodeoxyglucose positron emission tomography was performed on a subset of 24 patients at baseline and after 10 to 14 days of therapy. Results Forty-eight patients were eligible for response. One patient (desmoplastic round cell tumor [DSRCT]) achieved a confirmed partial response (PR) and remained on study for 56 weeks. Ten patients (20%) achieved stable disease for at least 16 weeks. Metabolic PR was seen in 10 (47%) of 21 of patients. Metabolic stable disease was seen in 11 (52%) of 21. There were no unexpected toxicities observed. CONCLUSION Sunitinib demonstrated notable evidence of metabolic response in several patients with non-GIST sarcoma. The relevance of disease control observed in subtypes with an indolent natural history is unknown, however, the durable disease control observed in DSRCT, solitary fibrous tumor, and giant cell tumor of bone suggests that future evaluation of sunitinib in these subtypes may be warranted.


Genes, Chromosomes and Cancer | 2011

A novel WWTR1‐CAMTA1 gene fusion is a consistent abnormality in epithelioid hemangioendothelioma of different anatomic sites

Costantino Errani; Lei Zhang; Yun Shao Sung; Mihai Hajdu; Samuel Singer; Robert G. Maki; John H. Healey; Cristina R. Antonescu

The classification of epithelioid vascular tumors remains challenging, as there is considerable morphological overlap between tumor subtypes, across the spectrum from benign to malignant categories. A t(1;3)(p36.3;q25) translocation was reported in two cases of epithelioid hemangioendothelioma (EHE), however, no follow‐up studies have been performed to identify the gene fusion or to assess its prevalence in a larger cohort of patients. We undertook a systematic molecular analysis of 17 EHE, characterized by classic morphological and immunophenotypic features, from various anatomical locations and with different malignant potential. For comparison, we analyzed 13 epithelioid hemangiomas, five epithelioid angiosarcomas, and four epithelioid sarcoma‐like EHE. A fluorescence in situ hybridization (FISH) positional cloning strategy, spanning the cytogenetically defined regions on chromosomes 1p36.3 and 3q25, confirmed rearrangements in two candidate genes from these loci in all EHE cases tested. None of the other benign or malignant epithelioid vascular tumors examined demonstrated these abnormalities. Subsequent reverse transcription‐polymerase chain reaction (RT‐PCR) confirmed in three EHE the WWTR1‐CAMTA1 fusion product. CAMTA1 and WWTR1 have been previously shown to play important roles in oncogenesis. Our results demonstrate the presence of a WWTR1‐CAMTA1 fusion in all EHE tested from bone, soft tissue, and visceral location (liver, lung) in keeping with a unique and specific pathological entity. Thus, FISH or RT‐PCR analysis for the presence of WWTR1‐CAMTA1 fusion may serve as a useful molecular diagnostic tool in challenging diagnoses.

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Cristina R. Antonescu

Memorial Sloan Kettering Cancer Center

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Murray F. Brennan

Memorial Sloan Kettering Cancer Center

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Gary K. Schwartz

Memorial Sloan Kettering Cancer Center

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Patrick Schöffski

Katholieke Universiteit Leuven

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Ronald P. DeMatteo

Memorial Sloan Kettering Cancer Center

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Samuel Singer

Memorial Sloan Kettering Cancer Center

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Shreyaskumar Patel

University of Texas MD Anderson Cancer Center

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