S2922 A Imatinib-Resistant Metastatic GIST Tumor Manifests as Diffuse Pruritus

9545 Background: Although imatinib induces durable clinical benefit in pts with metastatic GIST, resistance may emerge. AMN107 is a novel agent rationally designed to inhibit the PDGFR, KIT and Bcr-Abl tyrosine kinases. It has been shown to inhibit the proliferation of both imatinib-sensitive and imatinib-resistant GIST cells in vitro. Methods: Cohorts of imatinib-resistant GIST pts with radiological progressive disease (PD) were treated with AMN107 alone (400 mg p.o. bid) or with escalating doses of AMN107 (200 mg qd, 400 mg qd, or 400 mg bid) in combination with imatinib (400 mg p.o. bid). Pharmacokinetic (PK) analyses were performed for both AMN107 and imatinib. Serial tumor assessments included CT and 18FDG-PET scans. Results: As of 30 November 2005, 30 pts (13 women and 17 men), median age 51 yr (range 24–83) received AMN107 alone (n=18) or in combination up to 400 mg qd with imatinib (n=12) for 7 to 98 days (median 49 days). This study continues to accrue. Serious adverse events (SAE’s) reported in four patients deemed related to disease included abdominal pain, peritonitis and anemia. Grade 1/2 drug-related adverse events included hyperbilirubinemia, myalgias, peripheral edema and skin rash. Dose-limiting toxicity (Grade 3 elevated bilirubin) was reported in one pt on AMN107 alone. Efficacy data available for 18 patients show that three patients experienced progressive disease and 15 patients had stable disease, although the duration of follow-up was short. PK results in a limited number of patients showed that the effect of imatinib co-administration on AMN107 PK appears to be minimal, while AMN107 increases imatinib exposure on the average by 50%. Conclusions: AMN107 alone or in combination with imatinib has acceptable tolerability in patients with imatinib-resistant GIST. These initial data suggest there may be relevant activity of AMN107 alone and in combination with imatinib in imatinib-resistant metastatic GIST patients. [Table: see text]

Download Full-text

Assessment of response using FDG-PET and CT in a phase I study of AMN107 alone or in combination with imatinib (IM) in patients with imatinib-resistant (IM-R) gastrointestinal stromal tumors (GIST)

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.3087 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 3087-3087 ◽

Cited By ~ 1

Author(s):

A. D. Van Den Abbeele ◽

A. S. Barnes ◽

D. J. De Vries ◽

J. T. Yap ◽

P. Reichardt ◽

...

Keyword(s):

Fdg Pet ◽

Metabolic Response ◽

Rapid Assessment ◽

Single Agent ◽

Metastatic Gist ◽

Standardized Uptake Values ◽

Imatinib Resistant ◽

Imaging Results ◽

Time Point

3087 Background: Although IM induces durable clinical benefit in pts with metastatic GIST, resistance to this single agent may emerge over time and new approaches are needed. AMN107 is a new agent rationally designed to inhibit in a structurally different manner the tyrosine kinase activities of KIT, PDGFR, and Bcr-Abl. Since AMN107 has demonstrated the ability to inhibit the proliferation of both IM-sensitive and IM-R GIST cells in vitro, a clinical trial was begun to test this agent with rapid assessment of impact using FDG-PET. Methods: Pts with IM-R GIST were treated with AMN107 alone (400 mg p.o. bid), or a combination of IM (400 mg p.o. bid) and inter-cohort dose escalations of AMN107 (200 mg qd, 400 mg qd, and 400 mg p.o. bid). FDG-PET and CT were performed at baseline and after 1 and 4 wks on therapy. Maximum standardized uptake values (SUVmax) were measured in 11 pts in up to 5 lesions with the greatest FDG uptake/pt (n=46 lesions). For each patient, the summation SUVmax (sSUVmax) of all lesions was calculated at each time point. Percentage change in SUVmax and sSUVmax was calculated at wks 1 and 4 compared to baseline. Metabolic response was assessed using EORTC thresholds for % SUVmax change (PR≤ -25% <SD< +25%≤ PD). The longest diameters of all lesions analyzed by PET were measured on corresponding CT images, summed at each time point, and the % change was calculated at wks 1 and 4 compared to baseline. CT response was assessed using conventional RECIST thresholds. Results: At 1 wk, PET imaging of 11 evaluable pts documented metabolic PR in 3/11, SD in 7/11, and PD in 1/11. After 4 wks on therapy, 2 pts whose PET was stable after 1 wk had converted to metabolic PR, and all other imaging results were unchanged. The CT response for all 11 pts was SD after 1 and 4 wks on therapy. Conclusions: These findings suggest that a metabolic response to AMN107, or the combination of AMN107 plus IM, is seen with FDG-PET while CT anatomic response remains SD at 1 and 4 wks. [Table: see text] [Table: see text]

Download Full-text

Sunitinib-Induced Hyperammonemic Encephalopathy in Gastrointestinal Stromal Tumors

Annals of Pharmacotherapy ◽

10.1345/aph.1q038 ◽

2011 ◽

Vol 45 (10) ◽

pp. 1309-1309 ◽

Cited By ~ 15

Author(s):

Na-Ri Lee ◽

Ho-Young Yhim ◽

Chang-Yeol Yim ◽

Jae-Yong Kwak ◽

Eun-Kee Song

Keyword(s):

Emergency Department ◽

Growth Factor ◽

Tyrosine Kinases ◽

Ammonia Level ◽

Hyperammonemic Encephalopathy ◽

Metastatic Gist ◽

Imatinib Resistant ◽

Serum Ammonia Level ◽

Serum Ammonia ◽

Endothelial Growth Factor

Objective: To report 2 cases of hyperammonemic encephalopathy induced by sunitinib in patients with metastatic gastrointestinal stromal tumor (GIST). Case Summary: A 58-year-old man with imatinib-resistant metastatic GIST presented to the emergency department with confusion that developed 17 days after the initiation of sunitinib 50 mg/day. His serum ammonia level was markedly elevated (210 μg/dL). Sunitinib was discontinued, and an enema with lactulose was administered every hour. His neurologic status normalized within 24 hours and his serum ammonia level decreased to 64 μg/dL A 68-year-old woman with imatinib-resistant metastatic GIST was admitted into the emergency department with confusion and irritability that developed 10 days after the start of sunitinib therapy. Her serum ammonia level was markedly elevated (389 μg/dL). Sunitinib was discontinued, and an enema with lactulose was administered every hour. Within 24 hours, her mental status was improved and her serum ammonia level was decreased to 116 μg/dL. Sunitinib was reintroduced, and the same symptoms occurred after day 7 of administration. Sunitinib was not prescribed afterward and the woman did not experience any further encephalopathy symptoms. Discussion: Sunitinib is a small molecule that inhibits multiple receptor tyrosine kinases such as stem cell factor receptor, vascular endothelial growth factor, and platelet-derived growth factor. It is used as second-line therapy for patients with imatinib-resistant GIST. Hyperammonemic encephalopathy is an uncommon fatal complication of chemotherapy. According to the Naranjo probability scale, sunitinib was a probable cause of hyperammonemic encephalopathy in the patients described here. Although the mechanism of hyperammonemia is unclear, hyperammonemic encephalopathy might be caused by a vascular disorder related to the antiangiogenic properties of sunitinib, and it has ethnic differences associated with genetic polymorphisms. Conclusions: Sunitinib may Induce hyperammonemic encephalopathy in some patients. Although further studies are warranted, clinicians should be aware of this severe adverse event when using sunitinib for treatment of GIST.

Download Full-text

Disseminated Peritoneal Leiomyomatosis and metastatic GIST : A management dilemma regarding multiple nodular serosal lesions

10.26226/morressier.59ba7298d462b80296ca1fea ◽

2017 ◽

Author(s):

El-Agwany Ahmed

Keyword(s):

Metastatic Gist ◽

Disseminated Peritoneal Leiomyomatosis

Download Full-text

ON012380: A Non-ATP Competitive Inhibitor of BCR-ABL for the Therapy of Imatinib-Resistant CMLs

10.21236/ada532978 ◽

2010 ◽

Author(s):

E. P. Reddy

Keyword(s):

Competitive Inhibitor ◽

Imatinib Resistant

Download Full-text

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

Journal of Clinical Oncology ◽

10.1200/jco.2007.15.7461 ◽

2008 ◽

Vol 26 (33) ◽

pp. 5352-5359 ◽

Cited By ~ 463

Author(s):

Michael C. Heinrich ◽

Robert G. Maki ◽

Christopher L. Corless ◽

Cristina R. Antonescu ◽

Amy Harlow ◽

...

Keyword(s):

Growth Factor Receptor ◽

Progression Free Survival ◽

Clinical Results ◽

Clinical Activity ◽

Wild Type ◽

Mutational Status ◽

Imatinib Resistant ◽

Exon 9 ◽

Exon 11 ◽

The Impact

PurposeMost gastrointestinal stromal tumors (GISTs) harbor mutant KIT or platelet-derived growth factor receptor α (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 MethodsTumor 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.ResultsClinical benefit (partial response or stable disease for ≥ 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.ConclusionThe 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.

Download Full-text