Search

3102 Background: Preclinical studies show that evasion of death receptor (DR)-mediated apoptosis may depend on intact growth factor signaling. DR agonists have not previously been combined with IGF-1R inhibitors in published clinical studies. The combination may yield synergistic targeted antitumor activity without added toxicity. This study combined 2 investigational, fully human monoclonal antibodies: conatumumab, a human DR5 agonist; and AMG 479, an IGF-1R antagonist. Methods: Eligible pts had locally advanced or metastatic chemotherapy refractory solid tumors, ECOG PS of 0 or 1, and adequate glycemic control if diabetic. Pts enrolled into 3 sequential dose cohorts and received conatumumab 1, 3, or 15 mg/kg IV and AMG 479 18 mg/kg IV on day 1 of each Q3W cycle. Dose escalation was based on

Ninety-seven patients with primary osteosarcoma of the extremities, all age 16 or older, were treated with adriamycin, 90 mg/m2, continuous i.v. infusion over 96 h, followed by cis-platinum, 120-160 mg/m2 by intra-arterial infusion. The first 37 patients, treated from 1979-1982, had a 59% complete response rate and a 54% 5-year continuous disease free survival (CDFS). Patients with complete response had an 85% 5-year CDFS compared with 13% for patients with partial and poor response. Patients treated between 1983-1988 with an intensified regimen have a 68% complete response rate and a 69% 3-year CDFS. Those who did not achieve complete remission were switched to an alternating chemotherapy program emphasizing the use of high-dose methotrexate. Limb salvage has been accomplished in 59% of patients in the first group and 80% in patients of the second group. Preoperative chemotherapy allows informed decisions to be made in postoperative management which can influence overall cure rates. Long-term follow-up is essential before final interpretation of the data.

9028 Background: AP23573 (AP) is a non-prodrug rapamycin analog, which potently inhibits mTOR, a downstream effector of the PI3K/Akt pathway. AP has demonstrated some anti-tumor efficacy in sarcoma...

9000 Background: Trabectedin (Yondelis), a marine-derived alkaloid, has shown antitumor activity as therapy for advanced STS in pts refractory to conventional chemotherapy. LMS and LPS pts were selected for further study since these subtypes appeared to have somewhat higher rates of clinical benefit than other STS subtypes. Methods: To evaluate the efficacy and tolerability of ET-743 administered either as a 3-hr IV infusion given weekly for 3 consecutive weeks in a 4 week cycle (Arm A) or as a 24-hr IV infusion q 3 weeks (Arm B) to pts following progression despite prior doxorubicin plus ifosfamide chemotherapy. Pts with PS 0–1, normal bilirubin and alkaline phosphatase (AP) levels, and measurable LMS or LPS were eligible for study. Patients were pretreated with dexamethasone.The ET-743 dose was reduced if any abnormal elevation of bilirubin or AP was noted between cycles, or if any other unacceptable toxicity occurred. Histology will be centrally reviewed and patients whose diagnosis cannot be confirmed...

During a 37-year period, 26 patients were seen who had chondrosarcoma with additional mesenchymal components ("dedifferentiated low-grade chondrosarcoma"). Sixteen were men and 10 were women aged 30 to 85 years (median, 61 years). The tumors' chondroid areas were of borderline or low-grade malignancy. The additional mesenchymal component was histologically classified as malignant fibrous histiocytoma (16), rhabdomyosarcoma (4), low-grade fibrosarcoma (3), osteosarcoma (2), and undifferentiated sarcoma (1). Preferred locations were pelvis (10) and femur (8). Symptoms had been present for 1 year or less in most cases. Pain was the most common symptom. In 15 of 26, major amputation was the primary treatment. Twelve patients received chemotherapy, usually after developing metastatic disease, but only one achieved a partial response. Median disease-free interval after diagnosis was 4 months, median survival was 6 months, and 19 patients died within 1 year. Of 4 who survived longer than 18 months, 3 presented with a low-grade fibrosarcoma. Survival and development of metastasis appeared unrelated to cell type, initial treatment, or chemotherapy, except when the tumor's initial nonchondroid component was low-grade fibrosarcoma.

Based on the independent activity of cisplatin, vinblastine, and dimethyl-triazeno-imidazole-carboxamide (DTIC) (CVD), a combination of these agents was used in the treatment of patients with advanced melanoma. Vinblastine was used in a dose of 1.6 mg/m2/d for 5 days, DTIC was used in a dose of 800 mg/m2 intravenously (IV) on day 1, and cisplatin was used in a dose of 20 mg/m2/d for 4 days starting on day 2 of chemotherapy. The courses of chemotherapy were repeated at 3-week intervals. All patients were premedicated with antiemetics, and IV hydration was used before cisplatin. Fifty-two consecutive patients were registered and 50 were evaluable for response. Two patients achieved a complete response (CR) and 18 patients had a partial response (PR) for an overall response rate of 40% (95% confidence interval, 27% to 55%). The median duration of response was 9 months and the median survival time of the responders was 12 months. The overall median survival time of patients treated on this protocol was 9 months. The treatment was associated with significant toxicity consisting of nausea, vomiting, diarrhea, and partial hair loss. Additionally, neutropenia with a median nadir granulocyte count of 500/microliters was observed, and significant anemia required blood transfusions in a majority of the patients after three to four courses of chemotherapy. The dose-limiting toxicity was peripheral neuropathy which required discontinuation of cisplatin after six to eight courses of chemotherapy. We believe that this triple-drug regimen has significant activity that appears to be superior to the single-agent activity of these drugs, both in terms of increased response rate and duration of response.

Malignant fibrous histiocytoma (MFH) of the jaws is a highly malignant tumor that recurs, metastasizes, and usually causes death despite aggressive surgical therapy. This clinicopathologic review looks at five patients with MFH of the maxilla and six with MFH of the mandible. Five male and six female patients ranged in age from 12 to 75 years (mean, 35.4 years). All patients had large lytic areas of bone destruction, often with soft tissue extension. Two cases were postirradiation sarcomas, one of the maxilla and the other of the mandible. All patients underwent surgery and eight patients received chemotherapy when disease recurred locally or metastasized. Seven patients had local recurrences 3 to 13 months following surgery, and six patients had distant metastases. Of the 11 patients, 7 died of their disease, 1 died of unknown causes, and another with extensive local disease was lost to follow-up after 1.7 years. Two patients with recurrent disease are alive at 18 and 27 months postoperatively. Cancer 56: 1590-1596, 1985.

Thirty-seven cases of uterine leiomyosarcoma are presented, along with nine cases of leiomyoma variants from which they were distinguished. All patients were followed for a minimum of 10 years. In cases with nuclear pleomorphism, leiomyosarcoma was diagnosed when there were five or more mitotic figures in ten consecutive high-power (±400) fields in the most active area of the tumor, and also when there were fewer mitotic figures but extensive tumor necrosis (there was only one leiomyosarcoma without nuclear pleomorphism, and it had more than 20 mitotic figures in ten high-power fields). Tumor size was the major prognostic factor in the leiomyosarcoma group; five of eight patients with neoplasms measuring less than 5 cm in maximum dimension survived, whereas no patient with a larger tumor did so. Other pathologic and clinical variables, including mitotic rate, tumor necrosis, degree of nuclear pleomorphism, vascular invasion, and patient age, had no significant relationship to survival or tumor behavior in leiomyosarcoma when tumor size was taken into account. The nine cases of leiomyoma variants consisted of three atypical leiomyomas (which had nuclear pleomorphism, one or no mitotic figures per ten high-power fields, and no necrosis), two plexiform leiomyomas, two cases of peritoneal leiomyomatosis, one palisaded leiomyoma, and one case of intravenous leiomyomatosis; all of these patients were tumor-free on follow-up.

Based on the reports of activity of interferons against metastatic melanomas, we conducted a phase II study of recombinant interferon alfa-2a (Roferon-A, Hoffmann-La Roche, Nutley, NJ) in 66 patients with disseminated melanoma. All patients had excellent Eastern Cooperative Oncology Group (ECOG) performance status (0 to 1), and no evidence of brain metastases. Thirty patients had previously received chemotherapy and the remainder were untreated. The first 35 patients were treated on a daily schedule starting with a Roferon-A dose of 3 X 10(6) U/d and escalating to a maximum of 36 X 10(6) U/d over a period of 12 days. Because of excessive toxicity, the second group of 31 patients were treated on a fixed dose of 18 X 10(6) U/d [corrected] three times weekly (TIW). Among the 62 evaluable patients, five achieved an objective response for a response rate of 8% (95% confidence limits, 3% to 18%). Four patients had minor regressions and eight patients had stability of disease. The responses were evenly distributed between the two dose schedules. The major toxicity of interferon consisted of a constitutional syndrome of anorexia, fever, weight loss, and fatigue, which required a dose reduction in 75% of the patients on the daily schedule. Our data revealed a modest level of activity, which was not influenced by prior treatment or by the dose or schedule of interferon. Because of substantial toxicity with the daily schedule, we recommend a dose of 18 X 10(6) U/d [corrected] if interferon is used in the treatment of patients with melanoma.

Adjuvant chemotherapy prolongs the survival of patients with high-grade osteosarcoma. Preoperative chemotherapy allows identification of effective agents for adjuvant chemotherapy based on response of the primary tumor. Preoperative determination of tumor response has therapeutic implications, and angiography offers a less subjective means of assessing it than do conventional radiography or computed tomography. Changes in tumor vascularity, as seen angiographically, after two courses and at the time of the last of several courses of preoperative chemotherapy were correlated with histologic tumor necrosis of resected specimens in 81 patients. Angiographically, 40% of the histologic responders and 91% of the nonresponders were identified after two courses of preoperative chemotherapy. After a median of four courses of chemotherapy, 91% of the responders but only 50% of the nonresponders were identified angiographically. Angiographic assessment of tumor vascularity, although not of absolute value, offers a useful guideline for determining the preoperative chemotherapy strategy.

Seventeen breast cancer patients with tumor-associated fever are described. All other potential causes of fever were excluded in each patient, and it was diagnosis of exclusion. Fever was the first manifestation of recurrence in seven patients. In ten patients fever developed in association with new sites of metastases or progression of disease. New sites of metastasis in most of the patients were liver, bone marrow, or lungs. Seven patients had metastatic disease that responded to chemotherapy or hormonal therapy; fever subsided in only these patients (responding group). In nine patients neither tumor nor fever showed response to systemic treatment (nonresponding group). Overall survival after onset of fever was better in the responding group than nonresponding group.

The patient presented in this report has a large basal cell carcinoma on the wrist and thigh. The lesion on the wrist was nonresectable without amputation. The patient showed an impressive response to chemotherapy with systemic cyclophosphamide, adriamycin, and intra-arterial cisplatin. The tumor could be excised by a simple excision on both sites and showed no residual tumor on the hand and only a microscopic focus on the thigh. The patient continues to be free of disease 3 years after the initiation of the therapy.

Because treatment with surgery and combination chemotherapy produces a high cure rate in young men with osteosarcoma, their subsequent reproductive function is an important concern. Semen analyses of osteosarcoma patients, therefore, were performed before, during, and after treatment with the PADIC regimen consisting of cisplatin, Adriamycin (doxorubicin), and dacarbazine or, in some cases, the PADIC regimen plus additional drugs. Results showed that semen volume was not affected and that sperm motility was reduced only during treatment. Although nearly all patients were rendered azoospermic during treatment, sperm production resumed in 30 of 32 patients examined at least 2 years after treatment. Analysis with correction for censored data indicates that, in 78% of treated men, sperm counts will return to more than 10 million/ml. The percentage of men whose sperm counts recovered to normal was lower for those receiving cisplatin dosages greater than or equal to 600 mg/m2; no trends were observed with Adriamycin and dacarbazine dosages. The inclusion of additional drugs such as methotrexate, bleomycin, dactinomycin, or cyclophosphamide (less than 4 g/m2) did not significantly affect the recovery of spermatogenesis. We conclude that the risk of long-term infertility from treatment with the PADIC regimen is low.

We report a study of 27 patients with small cell osteosarcoma (SCO), 17 from the M. D. Anderson Cancer Center (MDAH) and ten from the Pediatric Oncology Group (POG). There were 12 male patients and 15 female patients; 19 were white, five were black, and three were Hispanic. They ranged from 6 to 28 years of age with a median of 14 years. Histologically there were three patterns: Ewing's-like, lymphoma-like, and spindle cell. All cases showed osteoid formation and a few had chondroid areas. There was cytoplasmic glycogen in ten cases. Initial treatment for MDAH patients included intraarterial infusion of cisplatin in ten, amputation in four, partial mandibulectomies in two, and biopsy with local radiotherapy and systemic chemotherapy in one. All POG patients had resection or amputation followed by adjuvant chemotherapy. Twelve patients are alive, of whom nine have had significant follow-ups for 25 to 90 months. Fourteen patients are dead of lung, spine, and brain metastases from 1 to 23 months after initial diagnosis. One patient is alive with lung relapse at 4 months. In summary, SCO is a high-grade variant of osteosarcoma, with an incidence of up to 4% of all osteosarcomas, that affects patients of the same age group and has the same anatomic location as conventional osteosarcoma. Currently, SCO appears to have a prognosis that is the same as or slightly worse than that of conventional osteosarcoma. Furthermore, although intraarterial infusion is effective for the primary tumors in the bone, distant metastases are difficult to control.

Aim This randomised phase III trial evaluated first-line trabectedin versus doxorubicin-based chemotherapy (DXCT) in patients with advanced/metastatic translocation-related sarcomas (TRS). Methods Patients were randomly assigned (1:1) to receive trabectedin 1.5mg/m 2 24-h intravenous (i.v.) infusion every 3weeks (q3wk) ( Arm A ), or doxorubicin 75mg/m 2 i.v. q3wk, or doxorubicin 60mg/m 2 i.v. plus ifosfamide (range, 6–9g/m 2 ) i.v. q3wk ( Arm B ). Progression-free survival (PFS) by independent review was the primary efficacy end-point. Results One hundred and twenty-one patients were randomised; 88 of them had TRS confirmed by central pathology review (efficacy population). Twenty-nine PFS events were assessed by independent review (16 with trabectedin; 13 with DXCT). PFS showed non-significant difference between arms (stratified log rank test, p =0.9573; hazard ratio=0.86, p =0.6992). At the time of this analysis, 63.9% and 58.3% of patients were alive in trabectedin and DXCT arms, respectively. There was no statistically significant difference in survival curves. Response rate according to Response Evaluation Criteria in Solid Tumours (RECIST) v.1.0 was significantly higher in DXCT arm (27.0% versus 5.9%), but response according to Choi criteria showed fewer differences between treatment arms (45.9% versus 37.3%). Safety profile was as expected for both arms, with higher incidence of severe neutropenia, alopecia and mucositis in the DXCT arm. Conclusion Neither trabectedin nor doxorubicin-based chemotherapy showed significant superiority in the first-line treatment of patients with advanced translocation-related sarcoma.

A phase II study of detorubicin, the semisynthetic 14-diethoxyacetoxy ester of daunorubicin, was conducted in 42 patients with metastatic melanoma. The drug was administered in a dose range of 120 to 180 mg/m2 and repeated at 3-week intervals. One clinical complete remission (soft tissue) and seven partial responses (three visceral and four soft tissue) were observed among the 22 patients who had undergone no prior chemotherapy, a complete and partial response rate of 36%. The duration of response varied from 2 to 27 months with a median of 10 months. There were also four (19%) minor responses (one visceral and three soft tissue). In contrast, among the 20 patients who had undergone prior chemotherapy treatment, only three patients showed a minor response. General toxicities were acceptable and were similar to those of Adriamycin (Adria Laboratories, Columbus, Ohio). Cardiac toxicity was evaluated by cardiac biopsy and radionuclide scan. Cardiac biopsy changes were identical to those observed with Adriamycin and were progressive with cumulative dose. One patient had a high-grade biopsy at a cumulative detorubicin dose of 1,420 mg/m2. Similarly, a trend of decreasing ejection fraction with cumulative dose was noted. Only one patient developed congestive heart failure at a cumulative dose of 1,290 mg/m2, that was well compensated with digoxin and diuretics. In contrast to Adriamycin, detorubicin has shown activity in previously untreated patients with metastatic melanoma.

Transcatheter intra-arterial infusion of chemotherapeutic agents for osteosarcomas and embolization of inoperable giant cell tumors of the axial skeleton have become essential components in patient management [1–13].

Sixty-six patients who underwent endomyocardial biopsy for detection of mitoxantrone (Novantrone; dihydroxyanthracenedione) cardiac toxicity were evaluated. All but one had breast cancer, 29 had received prior doxorubicin and 29 of the 37 patients who had not had prior doxorubicin received it or another anthracycline subsequently. Endomyocardial biopsy was carried out initially after four courses of chemotherapy with increasing intervals thereafter. Although cardiac ejection fraction was determined before each course of chemotherapy, our data are limited to cardiac ejection fractions from our own institution which were repeated approximately every four courses. Endomyocardial biopsy changes consisting of dilatation of the sarcoplasmic reticulum with vacuole formation, and myofibrillar dropout are similar to the early changes of anthracycline cardiomyopathy. While there was a slight suggestion of increasing biopsy grade with increasing mitoxantrone dose, no significant changes in cardiac ejection fraction could be associated, regardless of prior doxorubicin therapy. We concluded that mitoxantrone does show morphologic evidence of cardiac toxicity; however, the structural changes are minor and are haemodynamically insignificant. Determination of how much mitoxantrone treatment may contribute to the deterioration of pre-existing doxorubicin damage must await the outcome of longer follow-up.

The use of adriamycin is frequently limited by the development of a cumulative-dose-dependent cardiomyopathy, which increases substantially in incidence at doses ≥550 mg/m2. To avoid the potential development of fatal refractory congestive heart failure (CHF), dose limitation to 450–550 mg/m2has been recommended by a variety of authors.1–3Since an oncologist may not wish to stop treatment of an individual patient at an arbitrary level, a considerable investment of time and resources has been made in an effort to extend the use of adriamycin or develop analogs with diminished cardiotoxicity to accomplish the same aim.

Intra-arterial cis-platinum was introduced into the treatment of human cancer in 1977 in a patient with intransit metastases of malignant melanoma.(1) After an impressive response in that patient, a broad Phase II study was initiated. (2) One of the earliest patients on that study had an extensive malignant fibrous histiocytoma of the pubis with a soft-tissue mass which filled more than half the pelvis. The tumor had progressed in size despite therapy with radiation, 70 Gray, plus weekly systemic adriamycin. When she presented to us, she had extensive peripheral edema and was considered inoperable for a hemipelvectomy. We reasoned that since cis-platinum had some reported activity against osteosarcoma, malignant fibrous histiocytoma of bone might respond in a similar way, and that since the tumor was localized to the pelvis, the intra-arterial route would be optimal. The patient was treated, returned home to California, and called two weeks later to report the development of a new mass.

Iproplatin [cis-dichlor-trans-dihydroxy-bis-isopropylamine platinum (CHIP, JM9)] is a new antineoplastic platinum analogue with an octahedral conformation. It has more water solubility than does cisplatin and was found to have less neurotoxicity and nephrotoxicity in experimental animals than cisplatin. Like cisplatin, it has been demonstrated to have a broad spectrum of activity in experimental tumor systems. A phase I study of iproplatin was conducted in 28 patients (12 with melanoma, 8 with sarcoma, 6 with breast cancer, and 2 with colon cancer). All patients had failed prior chemotherapy. Four consecutive doses of iproplatin were administered at weekly intervals followed by a rest period of two weeks for hematologic recovery (one course). One hundred forty-two weekly doses were administered with all patients except three receiving at least one full course. The weekly starting dose of 40 mg/m2 was increased to 120 mg/m2 given over 30 minutes without hydration. Myelosuppression predominantly thrombocytopenia, was the dose-limiting toxicity at weekly doses of ≥ 95 mg/m2 per course. With iproplatin doses 75 mg/m2, 95 mg/m2, and 120 mg/m2, the lowest median granulocyte counts were 2.6 × 103/mm3, 2.2 × l03/mm3, and 1.8 × 103/mm3, respectively. Similarly, at iproplatin doses of 75 mg/m2, 95 mg/m2, and 120 mg/m2, the lowest median platelet counts were 144 × 103/mm3, 99 × 103/mm3, and 31 × 103/mm3, respectively. Mild to moderate nausea and vomiting were observed in the majority of patients. No significant neurotoxicity, nephrotoxicity, or ototoxicity was observed. Objective tumor regression was not observed in this study. The toxicity pattern of this schedule was not found to be significantly different from other schedules reported. If this schedule is pursued for phase II studies, a dose of 95 mg/m2/week x 4 repeated at 6-week intervals will be the recommended doses in patients who have been previously treated.

TPS10101 Background: One third of sarcoma histotypes have specific chromosomal translocations which result in abnormal transcription factors, integral to the change to a malignant phenotype. T is the first of a new class of anti-tumor agents with a transcription-targeted mechanism of action. In vitro evidence exists of the ability of T to interfere with the aberrant transcription factor’s binding to DNA promoters in TRS. Patients with TRS, such as myxoid/round cell liposarcomas (MRCL) have benefited from long-lasting tumor control in response to T. Methods: A randomized, phase III study of T (1.5 mg/m2 in 24-h intravenous infusion every 3 weeks [q3wk]) vs doxorubicin 75 mg/m2 q3wk, or doxorubicin 60 mg/m2 with ifosfamide 6-9 g/m2 q3wk) as first line treatment in patients with advanced TRS. Primary aim: to determine the efficacy of T vs doxorubicin-based therapy by comparing progression-free survival (PFS) in each arm. Secondary aims: comparison of PFS rates at six months, response rate (RR), PFS and RR by histological type (MRCL vs other subtypes), overall survival, safety, exploratory response evaluation by Choi criteria and pharmacogenomic analyses. Patients with confirmed TRS of the following subtypes: MRCL, alveolar soft part sarcoma,angiomatoid fibrous histiocytoma, clear cell sarcoma, desmoplastic small round cell tumor, low grade endometrial stromal sarcoma, low grade fibromyxoid sarcoma,myxoid chondrosarcoma and synovial sarcoma, are stratified by performance status (PS 0 vs 1-2) and sarcoma subtype (MRCL vs other subtypes) and randomized (1:1 ratio) to T or doxorubicin ± ifosfamide. Confirmation of the translocation by fluorescence in situ hybridization is compulsory for inclusion in the primary efficacy analysis. An adaptive design was chosen to test the reduction in relative risk of progression or death with T, an interim analysis will be conducted with 45 PFS events from 80 evaluable patients. To date 117 patients have been enrolled from six countries and 29 centers. An independent data monitoring committee met on 15 November 2011 and concluded that the trial should continue as planned.

10579 Background: Pazopanib has been introduced recently in the treatment for patients with advanced STS. Multiple chemotherapies have been investigated for the treatment of advanced and recurrent ...

10514 Background: Preclinical data demonstrate p53-dependent MIC-1 activation by both D and the MDM2 inhibitor RG7112. This study evaluated the tolerability of combining D with RG7112 in ASTS patients (pts) and pharmacokinetic (PK) and pharmacodynamic (PD) parameters of the combination. Methods: A phase 1b 3+3 dose escalation study was designed. Pts with ASTS in whom D was considered appropriate were eligible. D was administered IV at either 50 mg/m2 or 60 mg/m2on day 1 with RG7112 administered orally 500 or 1000 mg QD for 3 or 5 days (d1-3 or d1-5) in 28-d treatment cycles. Safety, PK and PD, including serum MIC-1 (an indicator of p53 activation), were assessed. Results: As of January 15, 2013, enrollment was complete with 23 pts with ASTS accrued; safety data for cycle 1 was available for preliminary review in 20 pts. Growth factor support was mandated following the first dosing group (D 60 mg/m2and RG7112 500 mg x 5d) due to febrile neutropenia or grade 4 neutropenia. Of the 20 pts for which cycle 1 safety data is available, 13 pts reported neutropenia (12 grade 3/4); 5 reported grade 3/4 febrile neutropenia (3 following mandatory GCSF prophylaxis); 12 pts developed thrombocytopenia (9 grade 3/4). PK parameters of the combination therapy are similar to single agent values and did not demonstrate evidence of drug-drug interactions. Serum MIC-1 rapidly increased to levels greater than for either agent alone. Best response to date is stable disease in 8/16 pts who have had interim evaluations. Conclusions: Combination therapy with D and RG7112 resulted in a high rate of grade 3/4 neutropenia (60%) or thrombocytopenia (45%). PK analysis does not suggest this is due to changes in the metabolism of either drug. This combination demonstrates apparent potentiation of p53 activation demonstrated by increased MIC-1 levels greater than additive effects of the single agents. Biomarker analyses, safety, PK, and MIC-1 data will be presented. Clinical trial information: NCT01605526. [Table: see text]

10013 Background: Von Hoff has proposed GMI >1.33 in cancer clinical trials as a sign of drug activity. GMI is the ratio between time to progression (TTP) with the nth line (TTPn) of therapy divided by the TTPn-1 with the n-1th line of therapy. With this endpoint, each patient is his/her own control. Methods: We have carried out a retrospective analysis of 279 pretreated ASTS patients treated in four consecutive phase II trials with trabectedin 1.5 mg/m², given as a 24-hour infusion every 3 weeks. Results: The study population consisted of 170 women and 109 men with a median age of 52. The two most common histologies were leiomyosarcoma (145 patients, 52%) and liposarcoma (59, 21%). 142 (51%) patients received one prior line and 137 (49%) ≥2 lines. The median TTPn was 2.8 months (range: 0.2-26.8), whereas the median TTPn-1 was 4.0 months (range: 0.3-79.5). The Spearman correlation coefficient between TTPn-1 and TTPn was 0.07 (p=0.23). The median GMI was 0.6 (range: 0.0-14.4). 177 patients (63%) had a GMI 1.33. The median overall survival (OS) strongly correlated with GMI groups: OS was 9.1, 13.9 and 23.8 months, respectively (p=0.0005, log-rank test). There were also a strong correlations between response rate and GMI (p1.33. Sarcoma grade (p=0.21), histological subtype (p=0.16), and number of prior chemotherapy lines (p=0.95) were not associated with GMI>1.33. Conclusions: Overall,≈30% of patients experienced GMI>1.33 regardless of histological subtype or grade, and number of prior lines of chemotherapy. Patients with PS=0 benefit more from trabectedin. GMI>1.33 is associated with longer OS (median ≈24 months). GMI is better defined than previously described parameter such as "Tumor Growth Rate" (Lopez-Martin, Abstract 3293, ASCO 2003). GMI as an indicator of drug activity merits further exploration in this setting.

10009 Background: At ASCO 2011 we presented an increase in median progression-free survival (PFS) of pazopanib of 13 weeks (median 7 to 20 weeks; HR 0.31) in a randomized double-blind, placebo-controlled phase III trial in advanced non-adipocytic STS patients pretreated with chemotherapy. Now we present final OS data and predictive factors for OS, such as ethnicity, ancestry and well-known prognostic and predictive factors in STS patients treated with chemotherapy. Methods: At clinical cut-off median follow-up was 25 months. Comparison of both treatments for OS was performed using a two-sided log rank test stratified for number of prior lines of systemic therapy for advanced disease and WHO performance status (PS). HR was calculated with a 2-sided CI. A Kaplan-Meier OS curve was used. Baseline characteristics as potential predictive factors for OS were: PS (0 vs 1), number of lines of prior therapy for advanced disease (0-1 vs 2+), age (≤55 yrs vs > 55 yrs), gender, ethnicity (Hispano or Latino vs other), geographic ancestry (White Caucasian, Asian, other), tumour grade (1-2 vs 3), histology (leiomyosarcoma vs synovial sarcoma vs other). A Cox model was fitted with the investigated factor, treatment arm and associated interaction factor. Data of all 369 randomized patients (123 placebo, 246 pazopanib) were used for the analyses. Results: Median OS (95% CI) was 10.7 (8.7-12.8) in the placebo versus 12.5 (10.6-14.8) months in the pazopanib group, HR: 0.86 (0.67-1.1). Post study protocol systemic treatment was administered in 63% of placebo, and in 49% of pazopanib treated patients. None of the investigated factors showed any statistical significant predictive value for OS. Conclusions: Although pazopanib demonstrated a statically significant increase in PFS compared to placebo, final OS analysis, which showed a trend in favor of pazopanib in patients with metastatic non-adipocytic STS, did not reach statistical significance. The factors studied were not predictive for OS.

TPS10577 Background: Ontuxizumab is a humanized immunoglobulin G-1-kappa monoclonal antibody (mAb) that is the first clinical stage agent to target endosialin. Endosialin (TEM-1/CD248) is a cell su...

10506 Background: Ombrabulin (AVE8062) is a vascular disrupting agent that damages established tumor vasculature and has demonstrated synergistic antitumor activity with cisplatin in vivo. In a phase I study, ombrabulin 25 mg/m² plus cisplatin 75 mg/m² was identified as the recommended dose in pts with solid tumors (AACR 2008; Abs 08-AB-4925). This phase III study evaluated the efficacy and safety of ombrabulin plus cisplatin in pts with advanced soft-tissue sarcoma (NCT00699517). Methods: Pts (aged ≥18 yrs, ECOG PS ≤2) with metastatic soft-tissue sarcoma who had received prior anthracycline and ifosfamide, with ≤2 prior chemotherapies for advanced disease, were randomized (1:1) to receive either ombrabulin 25 mg/m² or Pbo plus cisplatin 75 mg/m² every 3 weeks. The primary objective was to compare progression-free survival (PFS) between arms; secondary objectives included overall survival (OS) and safety. Results: Overall, 355 pts (median age 52 yrs; 51.5% male) were randomized (176 ombrabulin, 179 Pbo) in 44 centers worldwide. Median duration of follow-up was 27.9 and 30.5 months in Pbo and ombrabulin arms, respectively. PFS analysis showed a statistically significant improvement with ombrabulin (median 1.54 vs 1.41 months Pbo; HR=0.76, 95% CI 0.59–0.98; p=0.0302), with 3- and 6-month rates in favor of ombrabulin vs Pbo: 35.4% vs 24.9% and 19.3% vs 10.6%, respectively. A trend for an improvement with ombrabulin was observed in 3 of the 4 prespecified histology strata: liposarcoma, leiomyosarcoma, and “other”, but not for pleomorphic. Analysis of OS did not show statistically significant improvement with ombrabulin (median 11.43 vs 9.33 months Pbo, HR=0.85, 95% CI 0.67–1.09). OS rates at 1 year were in favor of ombrabulin (48.6% vs 42.4% Pbo). Grade 3/4 TEAEs more frequently seen with ombrabulin included neutropenia (19.2% vs 7.9% Pbo) and thrombocytopenia (8.5% vs 3.4% Pbo). Conclusions: Although this trial met its primary efficacy endpoint, the combination of ombrabulin and cisplatin did not demonstrate sufficient clinical benefit in pts with advanced soft-tissue sarcoma to warrant further study. Clinical trial information: NCT00699517.