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1.  Phase II SWOG-directed Intergroup Trial (S0505) of Sorafenib in Advanced Soft Tissue Sarcomas 
Cancer  2011;118(3):770-776.
Advanced soft tissues sarcomas (STS) have limited therapeutic options. Sorafenib (BAY 43–9006) is a multi-targeted tyrosine kinase inhibitor of raf, VEGFR1-3, PDGFRB, flt-3, and c-kit.
We tested sorafenib at a dose of 400 mg BID in patients with advanced sarcomas of vascular derivation (VS), high grade liposarcomas and leiomyosarcomas who had received 0–1 prior regimens for advanced disease.
Fifty one patients were accrued, with thirty-seven evaluable for toxicity and response. There were no unexpected side effects and no confirmed responses. Median progression free survival and overall survival were 3 months and 17 months, respectively. Six of 8 patients in the VS cohort had prolonged clinical benefit (stable disease or better), resulting in a median progression free survival of 5 months, compared with 2–3 months for liposarcoma and leiomyosarcomas respectively.
Sorafenib, at this dose and schedule, did not result in RECIST responses in VS, liposarcoma or leiomyosarcoma.
PMCID: PMC3576704  PMID: 21751200
Tyrosine kinase inhibitor; liposarcoma; leiomyosarcoma; angiosarcoma; solitary fibrous tumor
2.  Growth modulation index as metric of clinical benefit assessment among advanced soft tissue sarcoma patients receiving trabectedin as a salvage therapy 
Annals of Oncology  2012;24(2):537-542.
The growth modulation index (GMI) is the ratio of time to progression with the nth line (TTPn) of therapy to the TTPn−1 with the n-1th line. GMI >1.33 is considered as a sign of activity in phase II trials.
Patients and Methods
This retrospective analysis evaluated the concordance between the GMI and the efficacy outcomes in 279 patients with advanced soft tissue sarcoma (ASTS) treated with trabectedin 1.5 mg/m² (24-h infusion every 3 weeks) in four phase II trials.
One hundred and forty-two (51%) patients received one prior line and 137 ≥2 lines. The median TTPn was 2.8 months (range 0.2–26.8), whereas the median TTPn−1 was 4.0 months (0.3–79.5). The median GMI was 0.6 (0.0–14.4). Overall, 177 patients (63%) had a GMI <1; 21 (8%) a GMI equal to 1–1.33 and 81 (29%) a GMI >1.33, which correlated with the median overall survival in those patients (9.1, 13.9 and 23.8 months, respectively, P = 0.0005). A high concordance rate between the GMI and response rate (P < 0.0001) and progression-free survival (PFS, P < 0.0001) was observed. Good performance status (PS) was the only factor associated with GMI >1.33 (PS = 0; P < 0.04).
A high GMI was associated with favorable efficacy outcomes in patients treated with trabectedin. Further research is needed to assess GMI as an indicator in this setting.
PMCID: PMC4271084  PMID: 23117071
growth modulation index; sarcoma; time-to-progression ratio; trabectedin
3.  A nonrandom association of gastrointestinal stromal tumor (GIST) and desmoid tumor (deep fibromatosis): case series of 28 patients 
Annals of Oncology  2011;23(5):1335-1340.
Gastrointestinal stromal tumors (GISTs) and desmoid tumors (DTs) are two rare mesenchymal tumor. Anecdotal reports of individuals with both diseases led us to make the hypothesis that the association is a nonrandom event as the probability would be extremely low to observe such cases if they were independent events.
Patients and methods:
We evaluated the existence of patients with GIST and DT in a large multicenter cohort at 10 institutions in the United States, Australia and Europe. Data on gender, age at diagnosis, KIT, PDGFRA, CTNNB1 mutation status and follow-up time after diagnosis were collected.
We identified 28 patients diagnosed with both tumors. DT was diagnosed after GIST in 75% of patients and concomitantly in 21%. In only one case (4%), GIST was diagnosed after DT. KIT or PDGFRA mutations were detected in 12 of 14 GIST, 9 in KIT exon 11, 2 in KIT exon 9 and 1 in PDGFRA.
A statistical analysis of these 28 cases suggests a nonrandom association between GIST and DT. Further studies may be able to elucidate the underlying biology responsible for this association.
PMCID: PMC3493136  PMID: 21994214
beta-catenin; deep fibromatosis; desmoid tumor; GIST; imatinib; KIT
4.  Evaluation of nilotinib in advanced GIST previously treated with imatinib and sunitinib 
Patients with advanced GIST following standard imatinib and sunitinib often have good performance status and need additional therapy. This study tested nilotinib, a second-generation tyrosine kinase inhibitor, in patients with advanced GIST refractory to standard therapies.
This single-center open-label phase II study has a primary objective to determine progression-free survival at 6 months. Using a novel statistical design, 17 patients were to be enrolled; if ≥10 were progression free (PF) at 2 months, 19 additional patients would be enrolled. The therapy was considered of benefit if ≥13 of 36 patients were PF at 6 months. All patients signed informed consent and entry criteria included normal cardiac function. Exploratory analyses correlating genotype with response were also performed.
Thirteen patients were treated; 2 had received agents after imatinib and sunitinib. Treatment was well tolerated with one grade 4 anemia attributed to nilotinib. No measurable responses were observed; median time to progression was 2 months. One patient remained on study with stable disease for 12 months. Mutation testing is available from 10 primary tumors with 7 exon 11 mutations, 1 exon 9 mutation, and 2 without KIT/PDGFR mutations. Two samples from recurrent disease had 2 mutations, both primary exon 11 mutations with an additional exon 17 mutation, including the patient with prolonged stable disease.
Nilotinib was well tolerated in these patients with advanced GIST. Accrual was halted due to insufficient clinical benefit. However, nilotinib may provide benefit to specific subsets of advanced GIST with exon 17 mutations.
PMCID: PMC3313017  PMID: 22119758
GIST; Tyrosine kinase inhibitor; Nilotinib; Kit mutations; Secondary mutations
5.  Targeting ErbB2 and ErbB3 with a bispecific single-chain Fv enhances targeting selectivity and induces a therapeutic effect in vitro 
British Journal of Cancer  2008;99(9):1415-1425.
Inappropriate signalling through the EGFR and ErbB2/HER2 members of the epidermal growth factor family of receptor tyrosine kinases is well recognised as being causally linked to a variety of cancers. Consequently, monoclonal antibodies specific for these receptors have become increasingly important components of effective treatment strategies for cancer. Increasing evidence suggests that ErbB3 plays a critical role in cancer progression and resistance to therapy. We hypothesised that co-targeting the preferred ErbB2/ErbB3 heterodimer with a bispecific single-chain Fv (bs-scFv) antibody would promote increased targeting selectivity over antibodies specific for a single tumour-associated antigen (TAA). In addition, we hypothesised that targeting this important heterodimer could induce a therapeutic effect. Here, we describe the construction and evaluation of the A5-linker-ML3.9 bs-scFv (ALM), an anti-ErbB3/ErbB2 bs-scFv. The A5-linker-ML3.9 bs-scFv exhibits selective targeting of tumour cells in vitro and in vivo that co-express the two target antigens over tumour cells that express only one target antigen or normal cells that express low levels of both antigens. The A5-linker-ML3.9 bs-scFv also exhibits significantly greater in vivo targeting of ErbB2‘+'/ErbB3‘+' tumours than derivative molecules that contain only one functional arm targeting ErbB2 or ErbB3. Binding of ALM to ErbB2‘+'/ErbB3‘+' cells mediates inhibition of tumour cell growth in vitro by effectively targeting the therapeutic anti-ErbB3 A5 scFv. This suggests both that ALM could provide the basis for an effective therapeutic agent and that engineered antibodies selected to co-target critical functional pairs of TAAs can enhance the targeting specificity and efficacy of antibody-based cancer therapeutics.
PMCID: PMC2576487  PMID: 18841159
engineered antibody; bispecific; ErbB
6.  A phase I study of the safety and pharmacokinetics of trabectedin in combination with pegylated liposomal doxorubicin in patients with advanced malignancies 
Annals of Oncology  2008;19(10):1802-1809.
Background: To determine the maximum tolerated dose (MTD), safety, potential pharmacokinetic (PK) interactions, and effect on liver histology of trabectedin in combination with pegylated liposomal doxorubicin (PLD) for advanced malignancies.
Patients and methods: Entry criteria for the 36 patients included normal liver function, prior doxorubicin exposure <250 mg/m2, and normal cardiac function. A 1-h PLD (30 mg/m2) infusion was followed immediately by one of six trabectedin doses (0.4, 0.6, 0.75, 0.9, 1.1, and 1.3 mg/m2) infused over 3 h, repeated every 21 days until evidence of complete response (CR), disease progression, or unacceptable toxicity. Plasma samples were obtained to assess PK profiles.
Results: The MTD of trabectedin was 1.1 mg/m2. Drug-related grade 3 and 4 toxic effects were neutropenia (31%) and elevated transaminases (31%). Six patients responded (one CR, five partial responses), with an overall response rate of 16.7%, and 14 had stable disease (less than a 50% reduction and less than a 25% increase in the sum of the products of two perpendicular diameters of all measured lesions and the appearance of no new lesions) >4 months (39%). Neither drug had its PK affected significantly by concomitant administration compared with trabectedin and PLD each given as a single agent.
Conclusion: Trabectedin combined with PLD is generally well tolerated at therapeutic doses of both drugs in pretreated patients with diverse tumor types and appears to provide clinical benefit. These results support the need for additional studies of this combination in appropriate cancer types.
PMCID: PMC2598415  PMID: 18497430
ET-743; ovarian cancer; pegylated liposomal doxorubicin (PLD); sarcomas; trabectedin
7.  Phase II Trial of Dolastatin-10, a Novel Anti-Tubulin Agent, in Metastatic Soft Tissue Sarcomas 
Sarcoma  2004;8(4):107-111.
Patients:Soft tissue sarcomas are uncommon malignancies with few therapeutic options for recurrent or metastatic disease. Dolastatin-10 (Dol-10) is a pentapeptide anti-microtubule agent that binds to tubulin sites distinct from vinca alkaloids. Based on the novel mechanism of action, limited activity of other anti-microtubular agents, and anti-neoplastic activity in pre-clinical screening of Dol-10, this multi-institutional phase II study was conducted to determine the objective response rate of Dol-10 in recurrent or metastatic soft tissue sarcomas that had not been treated with chemotherapy outside of the adjuvant setting.
Methods: Dol-10 was given intravenously at a dose of 400 μg/m2 and repeated every 21 days. Toxicities were assessed using the Common Toxicity Criteria (version 2.0). Radiographic studies and tumor measurements were repeated every two cycles to assess response [Miller AB, et al. Cancer 1981; 47(1): 207].
Results: Dol-10 was associated with hematological toxicity and with some vascular toxicities. There was no significant gastrointestinal, hepatic or renal toxicity. There was one death on study due to respiratory failure. There were no objective responses in 12 patients treated with Dol-10.
Discussion: Based on this phase II trial, further study of Dol-10 on this schedule is not recommended in advanced or metastatic soft tissue sarcomas.
PMCID: PMC2395616  PMID: 18521404

Results 1-8 (8)