Continuous Daily Dosing Research Articles

Abstract 4682: Sunitinib (SU) in advanced NSCLC: Correlation of circulating biomarkers with clinical outcome

Abstract Introduction SU is an oral multitargeted inhibitor of VEGFRs, PDGFRs, KIT, FLT3, CSF-1R and RET. Antitumor activity and safety of SU in NSCLC were reported in phase II trials. We investigated potential biomarkers of clinical outcome with SU in NSCLC. Methods Patients (pts) with Stage IIIB/IV NSCLC in two phase II trials received single-agent SU either as maintenance therapy (n=66: 50 mg/day on Schedule 4/2 [6-week cycle: 4 weeks on followed by 2 weeks off treatment]) following first-line paclitaxel/carboplatin, or as refractory treatment (n=63: 50 mg/day on Schedule 4/2 for up to 9 cycles, or n=47: 37.5 mg/day on a continuous daily dose [CDD] schedule of 4-week cycles for up to 13 cycles). Soluble (s) plasma proteins (VEGF-A, VEGF-C, sVEGFR-2, sVEGFR-3, sE-selectin, sKIT) assayed by ELISA pre-dose and at regular intervals in both trials were analyzed for association with efficacy. Results In the trial of SU maintenance therapy, median progression-free survival (PFS) and overall survival (OS) were greater for pts with sVEGFR-3 levels < median ratio to baseline (BL) (n=10) vs. pts with sVEGFR-3 levels ≥ median ratio to BL (n=11) at Cycle 3 Day 1 (PFS: hazard ratio [HR] 3.6, 95% CI 1.19-11.13, p=0.0153; OS: HR 3.8 [1.35-10.88] p=0.0074). Median PFS was also greater for pts with VEGF-C levels ≥ median ratio to BL (n=15) vs. pts with VEGF-C levels < median ratio to BL (n=15) at Cycle 2 Day 28 (HR 0.3 [0.12-0.80] p=0.0109), a similar but non-significant trend was observed for OS. While PFS did not differ based on sE-selectin levels, pts with sE-selectin levels < median ratio to BL had greater median OS vs. pts with sE-selectin levels ≥ median ratio to BL at Cycle 3 Day 1 (n=8 vs. n=8: HR 4.4 [1.09-17.56] p=0.0241) and end of treatment (n=8 vs. n=9: HR 3.4 [1.10-10.41], p=0.0251). sVEGFR-3 median ratios to BL for pts with complete response (CR), partial response (PR) or stable disease (SD) ≥6 weeks (n=15) were lower vs. progressive disease (PD, n=5) at Cycle 3 Day 1 (0.57 vs. 0.92 p=0.029). In the trial of SU in refractory NSCLC, for Schedule 4/2 VEGF-A mean ratios to BL were higher in pts with CR/PR/SD ≥6 weeks (n=24) vs. PD (n=23) at Cycle 1 Day 14 (4.1 vs. 2.5 p=0.046). sVEGFR-2 and sVEGFR-3 mean ratios to BL were lower in pts with CR/PR/SD ≥6 weeks vs. PD at Cycle 2 Day 28 (0.4 [n=22] vs. 0.6 [n=8] p=0.03) and Cycle 1 Day 28 (0.3 [n=23] vs. 0.4 [n=19] p=0.043), respectively. In the CDD cohort, sVEGFR-2 mean ratios to BL were greater in pts with PFS ≥ median vs. PFS < median at Cycle 3 Day1 (0.5 [n=13] vs. 0.4 [n=4] p=0.032). Mean BL sVEGFR-3 levels were lower in pts with PR/SD vs. PD (41,498 [n=10] vs. 56,210 [n=20] pg/mL p=0.02). No significant difference in sKIT BL levels or ratios to BL were observed and no further strong correlations were apparent for other analytes in either cohort. Conclusions Soluble protein levels at some timepoints correlate with clinical outcome in advanced NSCLC pts treated with SU; low sVEGFR-3 levels were associated with favorable outcome in all analyses. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4682.

Abstract 366: Changes in gene expression profiles in human breast & liver cancer cells and xenografts acquiring resistance to sunitinib

Abstract Background: Deciphering acquired mechanisms of resistance to sunitinib, a multitarget receptor tyrosine kinase inhibitors blocking VEGFR, PDGFR, KIT, and RET, remains a major clinical challenge for developing a second generation of compounds, simultaneous and sequential combination strategies. This study aimed characterizing molecular changes associated with acquired cellular resistance to sunitinib in two human cancer models. Materials and Methods: Parental MCF7 breast carcinoma and SK-HEP1 hepatocellular carcinoma cells primarily sensitive to sunitinib were exposed to stepwise increasing doses of sunitinib for >4 months and >7 months, respectively. MCF7-suni and SK-HEP1-suni were shown to grow in the presence of 3-fold IC50 concentrations as compared to parental cells. Mouse xenograft bearing MCF7 were treated with subtoxic doses of sunitinib 2-20mg/kg/day. mRNA levels of a panel of 75 selected genes were evaluated in sensitive and resistant cell lines using q-RT-PCR. Protein phoshorylation (p) was assessed by western-blot analysis. Results: MCF-7 cells expressed PDGFRA and SK-HEP1 cells expressed PDGFRB, both having low/no baseline levels of VEGFR1-3 and RET mRNA expression. Exposure to 48-hour sunitinib led to IC50s of 5.5µM and 4.5µM in MCF-7 and SK-HEP1, respectively. In SK-HEP1 cells, exposure to sunitinib was associated with a decreased p-AKTS473, p-70S6KT389 and p-ERKT202/Y204. IC50s of sunitinib were 10µM in MCF7-suni and 11 µM in SK-HEP1-suni. Sustained exposure to sunitinib led to >3-fold increased mRNA expression of VEGFC, VEGFR1, VEGFR3, Neuropilin-1, CXCL12, CXCR4, HIF1-alpha, PDGFRA, endothelin-1, RET, and in a lesser extend EG-VEGF in MCF7-suni as compared to parental MCF7. Protracted exposure to sunitinib in SK-HEP1-suni led to a >3-fold increase mRNA expression of VEGFA-D, VEGFR3, CXCL12, CXCR4, PDGFRA, and RET as compared to parental SK-HEP1 cells. At IC50 concentration, p-ERKT202/Y204 was decreased in SK-HEP1-suni cells. To mimic acquired resistance to sunitinib in human, mice bearing MCF7 xenografts were treated using continuous daily dosing of sunitinib until occurrence of tumor progression under therapy occurring around day 20. mRNA expressions were compared in tumors at baseline and at the time of progression. Increased >3-fold mRNA expressions of CXCR4, CXCL12, PDGFRA were observed in progressive xenograft as compared to untreated control tumors. Conclusions: Our results suggest that acquired in vitro & in vivo resistance of human cancer cells to sunitinib may involve the increased expression of several known targets of sunitinib as well as the expression of other family of receptor involved in tumor angiogenesis, invasion, and metastasis. Further works shall focus in understanding the intriguing role of CXCR4/CXCL12 (SDF-1) in the development of resistance to sunitinib. Partially granted by FNAB. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 366.

Sunitinib in combination with gemcitabine plus cisplatin for advanced non-small cell lung cancer: A phase I dose-escalation study

Purpose To determine the maximum tolerated dose (MTD) of sunitinib plus gemcitabine/cisplatin for first-line treatment of patients with advanced non-small cell lung cancer (NSCLC). Safety, pharmacokinetics, and antitumor activities were evaluated. Methods Patients ≥18 years with Eastern Cooperative Oncology Group performance status 0/1 and stage IIIB/IV NSCLC were included in this open-label, multicenter, dose-escalation phase I study. Treatment was administered in 3-week cycles: oral sunitinib 37.5 or 50 mg/day intermittently (Schedule 2/1: 2 weeks on treatment, 1 week off treatment) or 25 mg continuous daily dosing (CDD) schedule with intravenous infusions of gemcitabine (1000 or 1250 mg/m 2 days 1, 8) and cisplatin (80 mg/m 2 day 1). Results A total of 28 evaluable patients were assigned to four dose levels. Most adverse events (AEs) on the Schedule 2/1 MTD were mild to moderate. Dose delays due to myelosuppression occurred on both schedules, limiting treatment to a median of four cycles. Four of 18 evaluable patients (22%) on Schedule 2/1 and 1 of 6 patients (17%) on the CDD schedule had confirmed partial responses. Conclusions The MTD was identified as sunitinib 37.5 mg (Schedule 2/1), gemcitabine 1250 mg/m 2, and cisplatin 80 mg/m 2, with most AEs being mild to moderate. However, frequent dose delays due to myelosuppression occurred. There was evidence of antitumor activity with this combination.

Phase I Clinical Trial of the CYP17 Inhibitor Abiraterone Acetate Demonstrating Clinical Activity in Patients With Castration-Resistant Prostate Cancer Who Received Prior Ketoconazole Therapy

Abiraterone acetate is a prodrug of abiraterone, a selective inhibitor of CYP17, the enzyme catalyst for two essential steps in androgen biosynthesis. In castration-resistant prostate cancers (CRPCs), extragonadal androgen sources may sustain tumor growth despite a castrate environment. This phase I dose-escalation study of abiraterone acetate evaluated safety, pharmacokinetics, and effects on steroidogenesis and prostate-specific antigen (PSA) levels in men with CPRC with or without prior ketoconazole therapy. Thirty-three men with chemotherapy-naïve progressive CRPC were enrolled. Nineteen patients (58%) had previously received ketoconazole for CRPC. Bone metastases were present in 70% of patients, and visceral involvement was present in 18%. Three patients (9%) had locally advanced disease without distant metastases. Fasted or fed cohorts received abiraterone acetate doses of 250, 500, 750, or 1,000 mg daily. Single-dose pharmacokinetic analyses were performed before continuous daily dosing. Adverse events were predominantly grade 1 or 2. No dose-limiting toxicities were observed. Hypertension (grade 3, 12%) and hypokalemia (grade 3, 6%; grade 4, 3%) were the most frequent serious toxicities and responded to medical management. Confirmed > or = 50% PSA declines at week 12 were seen in 18 (55%) of 33 patients, including nine (47%) of 19 patients with prior ketoconazole therapy and nine (64%) of 14 patients without prior ketoconazole therapy. Substantial declines in circulating androgens and increases in mineralocorticoids were seen with all doses. Abiraterone acetate was well tolerated and demonstrated activity in CRPC, including in patients previously treated with ketoconazole. Continued clinical study is warranted.

A Phase II Study of the Histone Deacetylase Inhibitor, Vorinostat, in Combination with Trastuzumab in Patients with Advanced Metastatic and/or Local Chest Wall Recurrent HER-2 Amplified Breast Cancer Resistant to Transtuzumab-Containing Therapy: (E1104) a Trial of the Eastern Cooperative Oncology Group.

Abstract BackgroundVorinostat, also known as suberoylanilide hydroxamic acid or SAHA, is a potent, small molecule, pan-inhibitor of histone deacetylase (HDAC) with excellent oral bioavailability, and is commercially approved for cutaneous T cell lymphoma. Pan HDAC inhibitors induce acetylation of histone tails, relaxing condensed chromatin for transcriptional regulation of specific genes and can also target non histone nuclear proteins. In pre-clinical studies of HER-2 overexpressing breast cancer cells, vorinostat(V) synergistically augmented the effects of trastuzumab(T) by downregulating Her-2, pAKT, pERK 1/2, reduced apoptosis by decreasing Bcl-2, Bcl-XL, XIAP and survivin levels, while inducing pro-apoptotic Bim and Bak. Therefore, we hypothesized that adding vorinostat to trastuzumab would reverse trastuzumab resistance in patients with HER-2 positive metastatic breast cancer.MethodsAn open label dose de-escalation schema for the initial portion of the trial was planned. V 200 mg bid continuous daily dosing with 6 mg/kg T every 21 days was administered. Eligible patients: HER-2 positive by IHC (3+) or FISH, subsequently centrally confirmed; measurable metastatic or chest wall disease; any number of prior therapies including endocrine, chemotherapy, prior treatment with T and/or lapatinib were allowed; evidence of progressive disease on prior T was required. The Phase II primary objective was response rate by RECIST criteria.ResultsMedian age - 54 (range 40-69); PS was 0 or 1; 6 patients - ER+; median number of prior therapies - 3 (range 2-6). Six patients were treated at the starting dose of 200 mg bid daily V combined with 6 mg/kg T every 21 days. There were no dose limiting adverse events at this dosing level, eliminating the need to de-escalate and this was determined to be the optimal Phase II dose. A total of 16 patients were enrolled. The most common AEs (all grades) were 62%-diarrhea, 37%-nausea, fatigue; 31%-anemia, anorexia, vomiting, elevated creatinine, hyperglycemia, hypokalemia; 25%-thrombocytopenia. Grade 3,4 toxicities were dyspnea(n=2) and thrombocytopenia(n=2). Of the 16 total enrolled, 10 were centrally confirmed to have HER-2 positive disease by the ECOG Pathology Coordinating Office, 5 were HER-2 negative and 1 had insufficient tissue. None of 11 patients with centrally confirmed HER-2 positive disease (or unknown) had an objective response. One of 5 patients with centrally confirmed HER-2 negative disease had an objective response.ConclusionsIn this heavily pre-treated population who had either relapsed or progressed during trastuzumab containing therapy (either alone or in combination with chemotherapy), we failed to confirm our hypothesis that adding the histone deacetylase inhibitor, vorinostat, could reverse trastuzumab resistance. Correlative studies including hyperacetylation status of PBMC, CTC enumeration and peripheral as well as tumor methylation are ongoing. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5084.

Phase III Randomized Trial of Sunitinib (SU) vs. Capecitabine (C) in Patients (Pts) with Previously Treated HER2-Negative Advanced Breast Cancer (ABC).

Abstract BackgroundC monotherapy is approved for pts with ABC who progress after anthracycline (A) and taxane (T) therapies. SU is an oral, multitargeted tyrosine kinase inhibitor that has demonstrated a single-agent response rate of 11% in heavily pretreated ABC.MethodsTo test the hypothesis that SU is superior to C, we compared the 2 agents in a multicenter, randomized, open-label, phase III trial of 700 pts. Eligible pts (≥18 yrs, ECOG PS ≤2) had HER2-negative ABC that recurred after A and T therapy in the (neo)adjuvant, metastatic, or locally advanced disease settings. Pts were randomized (1:1) to continuous daily dosing of SU 37.5 mg or to C 1,250 mg/m2 (1,000 mg/m2 in pts >65 yrs) twice daily on days 1–14 q3wk. The primary endpoint was progression-free survival (PFS). Secondary endpoints included objective response rate (ORR), overall survival (OS), clinical benefit rate (CBR), patient-reported outcomes, and safety.ResultsAfter a pre-planned interim analysis showed that the primary endpoint would not be reached, the Independent Data Monitoring Committee recommended stopping trial enrollment for futility. Pts randomized to SU were offered alternative treatment (tx). As of March 2009, 464 pts were randomized to SU (n=231; mean age 52.7 yrs; 29 pts ≥65 yrs) or C (n=233; mean age 52.4 yrs; 44 pts ≥65 yrs). 22.9% vs. 35.6% of pts continued to receive SU and C, respectively. Tx was discontinued due to adverse events (AEs) in 10.8% of pts in the SU arm vs. 7.7% of pts in the C arm. Most common AEs leading to discontinuation of SU were neutropenia (3 pts) and hand–foot syndrome, congestive cardiac failure, epistaxis, and thrombocytopenia (2 pts each). C was discontinued due to neutropenia in 3 pts. Median PFS was 2.8 mos (95% CI: 2.4–3.9; 162 PFS events) vs. 4.2 mos (95% CI: 3.4–5.0; 135 PFS events) for SU vs. C, respectively (HR 1.473; 95% CI: 1.167–1.858; P<0.001). ORR for SU was 9.1% (95% CI: 5.7–13.6) vs. 12.9% (95% CI: 8.9–17.9) for C. CBR was 14.3% (95% CI: 10.0–19.5) for SU vs. 21.9% (95% CI: 16.8–27.8) for C. Other secondary endpoint analyses are ongoing.ConclusionsAlthough some pts continue to benefit from SU, these data suggest that SU is not superior to C given as monotherapy. The observed AE profiles were similar to those previously reported for SU and C. C was better tolerated than SU. SU cannot be recommended as monotherapy on this dosing schedule. Phase III studies with SU in combination with chemotherapy and other agents are ongoing in ABC. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 46.

Abstract B210: Shed MET (sMET), VEGFA, and sVEGFR2 are markers of foretinib treatment in metastatic gastric cancer patients

Abstract Foretinib (formerly GSK1363089) is a small molecule multikinase inhibitor which includes inhibition of MET and VEGFR2. The ongoing phase II study, MET111643, is evaluating the safety and efficacy of 2 dosing schedules (continuous daily dosing and intermittent 5 days on/9 days off dosing) of foretinib as a single agent in pts with metastatic GC. An additional component of the study is to collect patient plasma samples before and during treatment with foretinib, to explore the potential pharmacodynamic effect and/or the modulation by foretinib of MET and VEGFR2. Plasma samples were collected from 42 pts on the intermittent 5 days on/9 off foretinib schedule at baseline and prior to dosing on days 5, 15, 29, and 47. The plasma levels of sMET, HGF, sVEGFR2, and VEGFA were measured using the Meso Scale Discovery platform (MSD). These marker changes from baseline were analyzed at each time point using analysis of variance and their relationships with plasma concentrations of foretinib (PK) and clinical outcome (progression free survival [PFS] and RECIST response) were also examined. Statistically significant increases from baseline of sMET at days 5, 15, 29, and 47 (p<.0001, p =.0344, p=.0353, p<.0001 respectively), VEGFA at days 5 (p<.0001) and 47 (p<.0001), and HGF at day 47 (p<.0001) were observed. Statistically significant decreases of sVEGFR2 at days 5, 15, 29, and 47 (all p<.0001) were also observed. Plasma VEGFA levels at day 5, 15, 29 are weakly correlated with PK (p=.033, p=.0138, p=.0165, respectively). Plasma sMET levels and changes from baseline at day 47 showed significant correlation with baseline tumor SLD (sum of longest diameter, R=0.54, p=0.0042; R=0.40, p=0.0443 respectively). Plasma VEGFA levels and changes from baseline at day 47 showed significant correlation with baseline tumor SLD (R=0.55, 0.44, respectively, p<0.01) and SLD at 8 weeks (R=0.64, 0.61, respectively, p<0.01). No correlation was observed between these four markers and PFS/RECIST response. Changes in sMET, VEGFA, and sVEGFR2 levels were observed for both intermittent and daily dosing schedules in the gastric cancer study. Although SLD at 8 weeks did not change significantly from baseline in the GC study, plasma levels of sMET and VEGFA correlated positively with the week 8 magnitude of SLD. Hence plasma levels of sMET and VEGFA may reflect biological changes following foretinib treatment. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B210.

Abstract A55: A first-in-human, phase I study of an oral hedgehog pathway antagonist, BMS-833923 (XL139), in subjects with advanced or metastatic solid tumors

Abstract Background: The hedgehog pathway is dysregulated in basal cell carcinoma, medulloblastoma, pancreatic, lung, gastric, and a variety of other cancers. BMS-833923 is a potent, oral, small molecule antagonist of hedgehog signaling. Methods: Subjects with advanced or metastatic solid tumors were enrolled into a multiple ascending dose study to identify a maximum tolerated dose and evaluate safety, tolerability, pharmacokinetics (PK), and pharmacodynamics of BMS-833923. All subjects receive a single dose one week prior to continuous daily dosing. The single dose window allows for single dose PK collection for one week. To identify the pharmacologically active dose range surrogate tissue was collected prior to Day 1 and again on Day 22 of the first cycle. Results: As of August 14, 2009 sixteen subjects have been treated at four dose levels: 30 mg (n=5), 60 mg (n=3), 120 mg (n=3), and 240 mg (n=5); with mean patient age of 56 (range 21–78) and ECOG performance 0–1. No subjects in the first three dose cohorts experienced drug-related CTCAE AEs greater than Grade 2. One subject with medulloblastoma in the 30 mg dose cohort continues on study for more than 10 months with stable disease. Treatment of patients in the fourth cohort at 240 mg continuous daily dosing is still on-going. In this cohort one subject experienced drug-related CTCAE Grade 2 lipase elevation and pancreatitis that quickly resolved when drug was withheld. This subject has a diagnosis of Gorlin Syndrome, which is caused by germline mutations in the hedgehog pathway genes Patched or Smoothened. This subject experienced a partial response (PR) that is still ongoing. BMS-833923 PK properties showed dose proportionality between the 30, 60, and 120 mg dose cohorts with a Cmax of 30 ng/ml, 56 ng/ml and 102 ng/ml respectively. The terminal half-life was greater than 7 days and drug accumulations were observed. Conclusion: BMS-833923 is generally well tolerated at daily doses of 30, 60, 120 mg. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A55.

Abstract B138: SB2312, a novel and potent dual inhibitor of mTOR and PI3K with high target inhibition and antitumor efficacy

Abstract Background: Dysregulation of the PI3K signaling pathway, either through activating mutations, amplification of PI3K or deletion of PTEN has been linked to a wide range of hyperproliferative diseases. The development of small molecule modulators of key proteins in this signaling cascade has focused mainly on mTOR or PI3K. Recent investigations have shown a significant overlap in the activity of small molecule inhibitors against these two proteins. Inhibitors that are currently progressing through preclinical and early clinical development have been shown to affect both mTOR and PI3K to some extent. However, most reported inhibitors do not inhibit both of these kinases in a close dose range. Our drug discovery program has focused on equipotent inhibition of both targets. SB2312 is a novel compound with very favorable drug-like properties, giving rise to equivalent targeting of both mTOR and PI3K in cells and tumor tissue and resulting in a more efficient inhibition of this pathway compared to reference compounds currently under evaluation in clinical trials. Methods: In vitro-IC50 for mTOR and PI3K were determined using recombinant enzymes. Inhibitory activity of SB2312 on the mTOR/PI3K signaling pathway was determined by Western-blot analysis, Surefire assays, and proliferation assays in various cancer cell lines. Efficacious doses of SB2312 or reference compounds were selected after pharmacokinetic and biomarker analysis of PC3 tumor-bearing mice, treated with single oral doses. Anti-tumor efficacy of SB2312 and reference compounds was evaluated in mouse xenograft models after continuous daily oral dosing. Results: SB2312 is a potent and selective dual mTOR and PI3K inhibitor (IC50: 55 nM and 18 nM, respectively) and has no significant activity on a large panel of protein kinases or enzymes and receptors. Efficient and equivalent inhibition of mTOR and PI3K in human cell lines was demonstrated by blockade of the phosphorylation of S6KT389 (IC50= 70 nM) and AKTS473 (IC50= 21 nM). SB2312 inhibits the proliferation of a broad range of human tumor cell lines independently of their PI3K pathway mutation status (IC50= 112–882 nM) and is also effective against rapamycin-resistant cell lines. SB2312 has very favorable physicochemical and pharmacokinetic properties, with high oral bioavailability and tumor exposure. Efficient and sustained inhibition of PI3K and mTOR was demonstrated in tumor tissues from a PC3 tumor xenograft model, along with dose-dependent anti-tumor activity at very well tolerated doses. Tumor growth inhibition was 53%, 105%, and 117% at 11, 33, and 80 mg/kg SB2312, respectively, without any body weight loss at any of these doses. Summary: Herein, we report SB2312, a novel, potent and selective dual mTOR/PI3K inhibitor with excellent drug-like properties. Our studies show superior and sustained blockade of the mTOR/PI3K pathway and high antitumor efficacy at well tolerated doses. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B138.

Abstract C124: Pharmacokinetics and safety of sorafenib in combination with capecitabine in advanced solid tumors

Abstract Background: This study had two primary objectives: first to address a possible increase in capecitabine (C) exposure when co-administered with sorafenib, and second, to further characterize the overall toxicity of this combination in both a 21 and a 14 day schedule. Methods: Eligibility included patients (pts) with advanced solid tumors, ECOG 0–1, and adequate organ function. The study enrolled two simultaneous 21 day schedules of the combination: Cohort A received C 750 mg/m2 BID for 14 days of a 21-day cycle and Cohort B received C 1000 mg/m2 BID for 14 days of a 21-day cycle. In both Cohorts A and B, following a 7day lead in of C alone, sorafenib was dosed 400 mg BID daily for 21 days. Steady-state PK (pre, 30 min, 1, 2, 4, 6, 8, and 12 hr) was obtained following 7 days of exposure to C alone (both C and 5FU levels measured), sorafenib alone (both sorafenib levels and its metabolites), and both C and sorafenib in combination. Cohort C explored an alternate schedule without PK of 7 day on/7 day off flat dose C1000 mg BID in combination with continuous daily dosing of sorafenib 400 mg BID. Results: 32 pts were enrolled between 2/08 and 4/09: median age 63 yrs (range 35–87); ECOG 0 75%; male 56%; and Caucasian 81%. HFSR was the primary toxicity with 16 (50%) of the 32 pts experiencing grade 3 events. Grade 3 HFSR by dose-level: C 750 mg/m2 was 33% and 1000 mg/m2 was 75%. Of the 16 pts that developed grade 3 HFSR, 75% of the time it occurred within the first 2 cycles. Grade 3 HFSR was also the DLT of Cohort C and defined the MTD at 1000 mg BID flat dose of C. Other grade 3 non-hematologic toxicities were rare: diarrhea 6%, mucositis 3%, and fatigue 3%. There were no grade 4 hematologic or non-hematologic toxicities. Upon co-administration with C (either 750 or 1000 mg/m2) there was no significant change in the Cmax or AUC(0–12) of sorafenib or its metabolites. Conversely, upon co-administration of sorafenib, at the C 750 mg/m2 dose-level (n=6 pts) there was a 15% increase C AUC(0–12) and no change in the 5FU AUC(0–12). At the C 1000 mg/m2 dose-level (n=12 pts), there was a 16% increase in C AUC(0–12) and an 8% increase in 5FU AUC(0–12). However these trends did not meet statistical significance, LS geometric means ratio for AUC(0–12) for C 750 mg/m2 1.15 (90%CI 0.90–1.46) and C 1000 mg/m2 1.16 (90%CI 0.94–1.43). G3 HFSR did not directly correlate with exposures of capecitabine, 5FU, or sorafenib. One pancreatic cancer patient had a PR and remains on study > 9 months. 34% of pts had stable disease lasting ≥ 4 cycles. Conclusions: Co-administration of sorafenib resulted in a mild increase in capecitabine AUC, though this increase did not reach statistical significance. Capecitabine did not affect the AUC of sorafenib or its metabolites. The rate of grade 3 HFSR is concerning and limits the feasibility of prolonged dosing with capecitabine 1000 mg/m2 on the 21 day schedule. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C124.

A Phase II Multicenter Study of Lenalidomide in Relapsed or Refractory Classical Hodgkin Lymphoma.

Abstract 3693Poster Board III-629 BackgroundRelapsed or refractory (rel/ref) classical Hodgkin lymphoma (cHL) remains a clinical challenge with limited effective treatments after high dose therapy with autologous stem cell transplantation (ASCT). Lenalidomide (Revlimid®) is an approved anti-neoplastic therapy for multiple myeloma and myelodysplastic syndrome with del(5q). In ongoing investigations it has a manageable toxicity profile and promising clinical activity in a number of B cell malignancies. Multiple potential mechanisms of action for lenalidomide have been identified including direct effects on tumor cells, alteration of the tumor microenvironment, anti-angiogenic properties, modification of cytokine profiles, and immune (T and NK) cell modulation. Since these effects have the potential to alter factors involved in cHL pathogenesis, we hypothesized that lenalidomide may have clinical activity in cHL. MethodsN=38 rel/ref cHL patients (pts) who previously underwent (or were not candidates for) ASCT were enrolled from October 2007 to May 2009 in a prospective, multi-center, Phase II study of single agent lenalidomide. The treatment regimen was 25 mg/day of lenalidomide on days 1-21 of a 28 day cycle. Treatment continued until progressive disease or an unacceptable adverse event at the lowest allowed dose (5 mg) of lenalidomide. The primary endpoint was overall response rate [complete remission (CR) + partial remission (PR)] as defined by the 2007 revised IWG criteria, and cytostatic response defined as CR + PR + stable disease (SD) > 6 months. ResultsMedian age at treatment was 34 (range 25-63) years with 23 females. Median number of prior therapies was 4 (range 2-9). 33 pts had received a prior stem cell transplant (29 ASCT, 1 syngeneic, 3 both ASCT and allogeneic). 22 pts (58%) had not responded to their last prior therapy, and the median time from last prior therapy to enrollment on this study was 3 (range 1-66) months. Median time of follow-up from enrollment on this study was 12 (range 3-22) months. Of the 38 enrolled pts, 3 were removed from the study prior to receiving 2 cycles of lenalidomide due to: elevated bilirubin and transaminases (n=1), desquamating rash (n=1), and rapid disease progression during cycle 1 (n=1). Median number of lenalidomide cycles administered per patient was 4 (range 2-22). For the 35 evaluable pts, we observed 1 CR, 5 PR, and 6 SD > 6 months for an overall response rate of 17% (6/35) and an overall cytostatic response rate of 34% (12/35). Median duration of CR/PR was 4.5 (range 2-10) months. The CR was observed after 2 cycles, and PRs were observed after 2 (n=2), 4 (n=1), 6 (n=1), and 18 (n=1) cycles of lenalidomide. Currently, lenalidomide treatment continues in 5 pts with SD (n=4, at ≥3, ≥7, ≥9, ≥15 cycles) or PR (n=1, ≥22 cycles). Of note, 8/12 (67%) lenalidomide responders had failed to respond to their last prior therapy before enrollment. In general, the treatment was well tolerated, and the most common grade 3-4 adverse events were neutropenia (40%), anemia (24%), leukopenia (21%), and thrombocytopenia (16%). The lenalidomide dose was reduced in 6 pts for cytopenias (n=2), fatigue (n=2), ALT/AST (n=1), and neuropathy (n=1), and discontinued in 4 pts for rash (n=2), elevated bilirubin/transaminases (n=1), and cytopenias (n=1). For pts with dose reduction, the lenalidomide doses ranged from 20 mg to 5 mg. No tumor lysis syndrome or documented tumor flare reactions were observed. ConclusionsSingle agent lenalidomide therapy has preliminary evidence of activity in pts with rel/ref cHL, including pts progressing after ASCT. Continuous daily dosing of lenalidomide is currently being evaluated in an effort to maximize single agent efficacy, and exploration of lenalidomide combinations with other active agents in rel/ref cHL is warranted. Disclosures:Fehniger:Celgene: research funding solely to support this clinical trial. Off Label Use: The use of Lenalidomide in relapsed or refractory Hodgkin lymphoma. Bartlett:Celgene: research funding solely to support this clinical trial.

Phase I Study of Oral Lenalidomide in Patients With Refractory Metastatic Cancer

Objectives of this study were to determine the maximum tolerated dose and to characterize the side effect profile and pharmacokinetics of lenalidomide in patients with advanced refractory solid tumors. Patients were treated on a modified Fibronacci dose escalation scheme with an oral daily dose of lenalidomide. A total of 45 patients with 8 different tumor types were accrued. Doses administered included 5, 10, and 20 mg continuous daily doses, every 28 days (n = 15), later modified to intermittent doses of 15, 20, 25, 30, 35, and 40 mg, with a 21 days-on and 7 days-off schedule, due to observed side effects. Lenalidomide exhibited a linear pharmacokinetics over a wide range of doses with the mean half-life of 3.9 hours. The renal function affected lenalidomide clearance, resulting in 50% reduction in patients with mild renal impairment compared with patients with normal function (CL/F = 243 mL/min). Stable disease was documented in 12 of 44 evaluable patients, of whom 9 patients had prostate cancer. Most frequent grade 1 and 2 toxicities included fatigue, nausea, pruritus/rash, neutropenia, and neuropathy. Grade 3/4 events were predominantly hematologic. Lenalidomide was well tolerated up to a 35-mg/d intermittent dosing schedule at doses higher than previously indicated for hematologic malignancies.

Phase I study of sunitinib (SU) in combination with pemetrexed (Pem) in patients (pts) with advanced solid tumors (ST)

e14630 Background: SU is an oral, multitargeted tyrosine kinase inhibitor of VEGFRs, PDGFRs, KIT, RET, FLT3, and CSR-1, and shows antitumor activities in several types of solid malignancies. Non-small-cell lung cancer (NSCLC) xenograft data indicate SU enhanced the antitumor activity of Pem. This phase I study was designed to evaluate the safety, tolerability, and pharmacokinetics (PK) of combination therapy with the oral SU and Pem for Japanese patients with advanced ST. Methods: Pts with ST refractory to standard therapy were randomly assigned to receive either oral SU 50 mg/day for 2 weeks followed by 1 week rest (Schedule 2/1, S-2/1) or SU 37.5 mg continuous daily dose (CDD). Fixed-dose Pem (500mg/m2 IV) was administered on day1 every 21 days. A standard “3+3” design was employed in both treatment schedules and treatment continued until tumor progression or dose-limiting toxicity (DLT) was observed. Results: A total of 12 pts (med. age 63 years, range 49–69; 10 Male/ 2 Female) have been enrolled (6 pts in the S-2/1 arm and 6 pts in the CDD arm). The most common cancer is NSCLC (9 pts, 75%). All patients completed their first cycle for DLT evaluation, and no DLTs were observed in either treatment arm. The most common toxicities were fatigue (n=8), anorexia (n=6), and thrombocytopenia (n=12). Treatment-related ≥ grade 3 adverse events (AEs) included fatigue (n=1), hypertension (n=1), neutropenia (n=4), leucopenia (n=3), thrombocytopenia (n=2), lymphopenia (n=2), and increased ALT (n=1). Three pts (S-2/1: 2, CDD: 1) required dose reduction of SU due to G3 toxicities. All toxicities were clinically manageable and reversible. One pt with NSCLC had a documented PR with cavity formation inside the tumor. Conclusions: SU 37.5 mg/day (CDD schedule) plus Pem 500mg/m2 every 21 days, and SU 50 mg/day (S-2/1 schedule) plus Pem 500mg/m2 every 21 days were well tolerated and associated with encouraging antitumor activity. [Table: see text]

Phase I dose-escalation study of XL147, a PI3K inhibitor administered orally to patients with solid tumors

3500 Background: XL147 is a selective inhibitor of Class I PI3K isoforms. In preclinical cancer models XL147 is cytostatic or cytoreductive as monotherapy and enhances the efficacy of targeted agents and chemotherapeutics. This open label, Phase 1 dose escalation study assesses the safety, pharmacokinetics, pharmacodynamics, and efficacy of XL147 in advanced solid tumors. Methods: For each 28 day cycle, patients (pts) receive XL147 on Days 1–21 (21/7) or as a continuous daily dose (CDD). Cycle 1 safety data determine dose-limiting toxicities (DLTs). Tumor response is assessed every 8 weeks. Results: As of December 2008, 39 pts have been treated: 36 on 21/7 across 7 dose levels (30–900 mg) and 3 on CDD at 100 mg. At 900 mg, 2 of 3 pts experienced a DLT of reversible grade 3 rash, and the MTD was established as 600 mg based on 15 pts. Drug-related toxicities included grade 3 skin rash (3 pts), grade 3 arterial thrombosis (1 pt), grade 2 transaminase elevation (1 pt), and grade 1 hyperglycemia (4 pts). XL147 exposure increased with dose from 30–400 mg and was similar from 400–900 mg. XL147 reached steady-state plasma concentrations by Day 15–20. Mean t1/2, z at steady-state ranged from 3.7–6.3 days. Doses ≥400 mg yielded exposures that exceeded the EC90 in xenograft models. A trend suggesting augmented food-induced changes in insulin was evident; however, glucose was minimally affected. XL147 reduced levels of phosphorylated PI3K pathway components in PBMCs, hair, skin, and tumor tissues in an exposure-dependent manner. In 2 pts dosed at the MTD, reductions of ≥70% in PI3K pathway signaling were observed in tumor tissue without compensatory upregulation of MEK/ERK phosphorylation. As of December 2008, 6 pts (3 NSCLC, 1 BCC, 1 NHL, 1 PC) continued on study >6 months including 3 >10 months (NHL, NSCLC, BCC). One pt with hormone refractory PC has sustained a normalization of PSA levels through 5 months. Conclusions: XL147 was generally well tolerated with the MTD for the 21/7 schedule defined as 600 mg. The most common drug-related toxicity was skin rash. Inhibition of PI3K pathway signaling has been demonstrated in tumor and surrogate tissues. Prolonged stable disease has been observed. [Table: see text]

Extended phase I trial of the oral pan-Bcl-2 inhibitor AT-101 by multiple dosing schedules in patients with advanced cancers

e14537 Background: Over-expression of Bcl-2 family proteins is common in human cancers. Initial trials of the oral, pan-Bcl-2 inhibitor AT-101 showed acute dose limiting toxicity of Gr 3–4 AST/ALT (MTD 40 mg/d) and ileus with prolonged dosing daily (QD) for 21/28 days per cycle (Saleh, NCI/EORTC, 2005; James, ASCO, 2006 and Saleh, ASCO, 2007). MTD in the QD schedule has been previously reported. In this study different dosing schedules of AT-101 were tested in adults with advanced cancers and final results for the pulse dosing schedule of twice a day for three days every other week (b.i.d. x 3d EOW) are being reported. Methods: Serial patient (pt) cohorts received AT-101 at escalating doses of 30–80 mg b.i.d. x 3d EOW. Adverse events (AEs) were graded by the NCI CTCAE v3.0. Efficacy was determined by RECIST. Results: 37 pts have been enrolled. Safety data is available on 34/37 pts. In this b.i.d. x 3d EOW dosing schedule, ileus/small bowel obstruction (SBO) occurred in 3 pts (one at each dose level of 30, 40 and 50 mg) and was the dose limiting toxicity for this schedule. Of note, the SBO that occurred at 30 mg was felt to be unrelated to study agent therefore, 30 mg b.i.d. x 3d EOW was the MTD determined for this schedule. The most common (>50%) grade 1–2 AEs included: nausea, vomiting, diarrhea, fatigue and anorexia. Grade 3–4 AEs occurring in > 2 pts include: nausea, abdominal pain, elevated AST (3 pts each), vomiting, fatigue, dehydration (4 pts each), hypokalemia (5 pts). Stable disease was reported in 13/37 (35%) pts. One pt with NSCLC continues on study with stable disease for 33 cycles and 2 additional pts were on study with stable disease for 18 and 9 cycles. The mean Plasma Cmax was 301 ng/ml (+ 477 ng/ml SD) and mean AUC for 30 mg b.i.d.x3d EOW was 1080 ng*hr/ml (+ 1990 ng/ml SD) with a median peak concentration at 4 hours post dose. Conclusions: Pulse dosing of AT-101 achieved an MTD of 30mg b.i.d. x 3d EOW and is associated with reduced toxicity than continuous daily dosing, and may be preferable in combination regimens. [Table: see text]

Effect of TKI258 on plasma biomarkers and pharmcokinetics in patients with advanced melanoma

9020 Background: TKI258 (dovitinib lactate), is a multi-tyrosine kinase inhibitor of VEGF receptors-1,2,3, FGF receptors-1, 2, 3, PDGFR-β, and c-KIT. A phase I study was conducted to determine the maximum tolerated dose (MTD), the biological activity and the preliminary efficacy of TKI258 in patients with advanced melanoma. A panel of plasma biomarkers of angiogenesis and soluble receptors were evaluated to determine the pharmacodynamic effect of TKI258. Methods: Patients were treated orally with 200, 300, 400 or 500 mg/day on a once daily continuous dose schedule. The MTD was defined at 400 mg/day. Plasma samples from 43 patients were collected. Plasma concentration of TKI258 was measured by LC/MS/MS. Plasma VEGF, placental growth factor (PLGF), basic FGF (bFGF), and soluble VEGFR1 and VEGFR2 (sVEGFR1 and 2), and c-Kit were measured by multiplex assays using the Meso-Scale Discovery platform. Plasma FGF23 was evaluated by ELISA as a pharmcodynamic marker of FGFR1 inhibition. Results: Following 400 mg or 500 mg continuous daily dosing, the mean plasma exposure (AUC24hr) was approximately 3000 ng/mL*h and 4100 ng/mL*h, respectively. No accumulation in TKI258 plasma exposure was observed at doses of 400mg or below, while accumulation up to 2.5-fold was observed on day 15 following the 500 mg daily dose. At the end of the first treatment cycle, mean plasma VEGF, PLGF and FGF23 levels increased over baseline by 100%, 198% and 68%, respectively, while mean plasma sVEGFR2 levels decreased by 15% in patients treated with 400 and 500 mg/day TKI258. Further analysis of correlations with pharmacokinetic and clinical parameters is ongoing. Conclusions: TKI258 therapy is associated with increases of plasma VEGF and PLGF as well as decreases of sVEGFR2 suggesting VEGFR inhibition. Induction of plasma FGF23 suggest that FGFR may be inhibited at doses of 400 mg/day and above. This panel of circulating proteins may have utility as pharmacodynamic biomarkers of TKI258 activity in patients with advanced melanoma. [Table: see text]

Administration of sunitinib to patients with non-small cell lung cancer and irradiated brain metastases: A phase II trial

8077 Background: Sunitinib (SU), an oral, multitargeted inhibitor of VEGFRs, PDGFRs, KIT, FLT3, CSF-1R, and RET has promising single-agent antitumor activity in refractory non-small cell lung cancer (NSCLC) (Socinski JCO 2008). Brain metastases (BrMs) occur in ≥25% of NSCLC patients (pts); preclinical data suggest that VEGF signaling is required for the growth of BrMs, and that SU can cross the blood-brain barrier. This study assessed the safety and preliminary efficacy of SU in NSCLC pts with BrMs. Methods: NSCLC pts who had received ≤2 prior systemic therapies and prior whole brain radiation therapy (WBRT) were eligible to receive SU at a starting dose of 37.5 mg with continuous daily dosing (CDD) in 4-wk cycles. Antitumor efficacy was based on overall (RECIST) and intracranial (WHO) tumor assessments. Intracranial disease was assessed by MRI. Safety was assessed by monitoring adverse events (AEs) and health-related quality of life was assessed using FACT/NCCN Lung Symptom Index (FLSI) and Brain Symptom Index (FBrSI). Study termination was to occur when 3 cases of intracranial hemorrhage (ICH) associated with neurologic deficit were noted. Results: To date, 47 pts, including 28 with adenocarcinoma and 10 with squamous cell carcinoma, received SU for a median of 2 cycles (range: 1, 9). The median age of pts was 61 yrs (range: 35, 75), most were male (n=26, 55%), were ever smokers (n=36, 77%) and all had good performance status (ECOG 0/1). In total, 25 pts (53%) experienced non-neurologic grade (G) 3/4 AEs; the most frequent were fatigue/asthenia and dyspnea. Neurologic AEs occurred in 4 pts (9%), including intracranial pressure increased, mental impairment, and gait disturbance (each n=1 and G1) and 1 pt with G3 convulsion and peripheral motor neuropathy. Importantly, no cases of ICH were noted. Stable disease occurred in 7 (19%) of 36 measurable pts. Median PFS was 10.9 wks (95% CI: 6.4,15.4). Median OS was 19.6 wks (95% CI:13.1, NR). Mean change from baseline in FLSI and FBrSI scores did not differ significantly at any time point. Conclusions: Oral SU 37.5 mg on a CDD schedule had a manageable safety profile in NSCLC pts with BrMs. These data support the investigation of SU in combination with agents with known antitumor activity in pts with BrMs. [Table: see text]

Phase II trial of sunitinib malate in patients with temozolomide refractory recurrent high-grade glioma

2038 Background: High-grade gliomas (HGG) are characterized by neo-angiogenesis. Sunitinib is a small molecule tyrosine kinase inhibitor that inhibits multiple receptors (including VEGFR, PDGFR, and c-Kit). We investigated sunitinib for the treatment of patients (pts) with temozolomide (TMZ) refractory recurrent HGG. Methods: Pts were recruited according to a 2-stage phase II design and received a daily dose of 37.5 mg sunitinib. T1 ± Gd and T2 weighted MRI images were obtained after 4 and 8 weeks of sunitinib and q8 weeks thereafter. We assessed the antiangiogenic effect by calculating the cerebral blood volume (CBV) and cerebral blood flow (CBF) from dynamic susceptibility (DSC) based perfusion MRI and determined the lesion-to-normal-white matter CBV (CBVLTN) and CBF (CBFLTN) ratios. Uptake of fluorinated fenyl-methyl-alanine within the CNS was assessed by PET at baseline and reassessed in responding pts. Results: 21 pts were enrolled (median age 43 [range 34–71]; M/F 15/6; KPS 90–80: 11 pts, KPS 70–60: 10 pts). All pts had PD following surgery, RT and TMZ. A total of 142 treatment weeks (range 2–84) were evaluated; 81% of the administrations were at the 37,5 mg-, 19% at the 25 mg dose level. Most frequent AEs were: skin toxicity (gr2, n = 1; gr 3, n = 1), fatigue (gr 2, n = 4), hypertension (gr 2, n = 3), diarrhea (gr 2, n = 2), mucositis (gr 3; n = 1), afebrile- (gr 2, n = 3) and febrile neutropenia (gr 3, n = 1; gr 4, n = 1), thrombocytopenia (gr 2, n = 4; gr 3, n = 1; gr 4, n = 1), and lymphocytopenia (gr 2, n = 2; gr 3, n = 4). Decrease in CBVLTN and CBFLTN was observed in 6/14 evaluable pts after 4 weeks of sunitinib, 5/19 evaluable pts had SD on T1±Gd after 8 weeks; one pt experienced a marked clinical improvement with a reduction in the tumor metabolism on PET. After a median follow-up of 11 months, median TTP and -OS are1,6 and 3,8 months respectively. Three pts with a secondary glioblastoma (age <40 year) had an objective PR when administered CCNU at PD under sunitinib (with a TTP of 2, 8 and +9 mths respectively). Characterization of the VEGFR, PDGFR, and Kit gene copy numbers and protein expression in the tumors is ongoing. Conclusions: Sunitinib at a continuous daily dose of 37.5 mg has a transient antiangiogenic effect in pts with recurrent HGG but is of insufficient clinical benefit to warrant further investigation as a single agent. [Table: see text]

An open-label study of sunitinib (SU) plus exemestane (E) in the first-line treatment of hormone receptor (HR)-positive metastatic breast cancer (MBC)

e12019 Background: SU, an oral multitargeted tyrosine kinase inhibitor of VEGFRs, PDGFRs, KIT, FLT3, CSF-1R and RET has activity in heavily pretreated pts with MBC. The aromatase inhibitor (AI), E, has proven 1st-line activity that compares favorably with tamoxifen in pts with HR+ BC in the adjuvant setting (Jones et al. 2008). Combining agents that target different signaling pathways may have additive/synergistic activity; combining the AI letrozole with the anti-VEGF agent bevacizumab prolonged progression-free survival to >14 mos as 1st-line therapy for HR+ MBC (Dickler et al. 2008). An open-label, phase I, dose-finding study of first-line SU + E was conducted in HR+ MBC pts. Methods: Eligible pts (postmenopausal; female; ≥18 yrs) had an ECOG PS ≤1, LVEF ≥50% and locally recurrent (unresectable) or MBC. Exclusion criteria included HER2+ BC (unless pt had progressed after trastuzumab) and prior treatment in the metastatic setting. Pts received SU 37.5 mg/d + E 25 mg/d on a continuous daily dosing regimen; if dose-limiting toxicities (DLTs) were experienced by >1/6 pts in the first 8 wks then further pts would be enrolled at SU 25 mg/d + E 25 mg/d. Pharmacokinetic (PK) analyses were performed for each drug and the active SU metabolite SU12662. Results: As of December 2008, enrollment was completed (N=6; mean age 59 ± 11 yrs; 50% of pts had ≥3 metastatic sites). No DLTs were observed and no dose reductions were required throughout the treatment period. An overview of key data is shown below. One death occurred on study (non treatment-related Enterobacter sepsis). No treatment-related G4/5 AEs occurred. PK parameter values determined for SU and E suggested increases in the systemic exposure of both drugs when administered concurrently. Conclusions: These data indicate that SU + E was tolerable with manageable toxicities, with increases in PK parameters and a similar AE profile to that of either single agent alone. This combination should be considered in future clinical trials. [Table: see text] [Table: see text]

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

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.