A Phase II Study of Flavopiridol in Patients With Previously Untreated Advanced Soft Tissue Sarcoma

Purpose. Flavopiridol is a potent cyclin-dependent kinase (CDK) inhibitor that has preclinical activity in many tumours. This synthetic flavonoid was tested in a phase II nonrandomized, nonblinded multicentre clinical trial to determine its activity and toxicity in patients with previously untreated metastatic or locally advanced soft tissue sarcoma.Methods. A total of 18 patients with histologically confirmed nonoperable soft tissue was treated with flavopiridol administered at a dose of 50 mg/m2IV over 1 hour daily×3days every 3 weeks.Results. Eighteen patients were accrued to the study over a period of 6 months. No objective responses were noted in the seventeen evaluable patients. Eight patients (47%) exhibited stable disease after 2 cycles (median duration of 4.3 months (range 1.4–6.9 months). Kaplan-Meier estimates for 3- and 6-month progression-free survivial rates were 44 percent and 22 percent, respectively. The only grade 3 toxicities were diarrhea (N=2), nausea (N=2), gastritis (N=1), and fatigue (N=1). Ninety-four percent of patients received≥90% of the planned dose intensity, during 55 treatment cycles.Conclusions. Flavopiridol was well tolerated at the dose and schedule used in this study, however, no objective treatment responses were seen and thus our results do not support further exploration of flavopiridol as a monotherapy at this dose and schedule in soft tissue sarcomas.

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Phase II Study of ET-743 in Advanced Soft Tissue Sarcomas: A European Organisation for the Research and Treatment of Cancer (EORTC) Soft Tissue and Bone Sarcoma Group Trial

Journal of Clinical Oncology ◽

10.1200/jco.2005.01.180 ◽

2005 ◽

Vol 23 (3) ◽

pp. 576-584 ◽

Cited By ~ 301

Author(s):

A. Le Cesne ◽

J.Y. Blay ◽

I. Judson ◽

A. Van Oosterom ◽

J. Verweij ◽

...

Keyword(s):

Soft Tissue ◽

Soft Tissue Sarcoma ◽

Phase Ii ◽

Median Duration ◽

Phase Ii Study ◽

Progression Free Survival ◽

Advanced Soft Tissue Sarcoma ◽

Free Survival ◽

Grade 3 ◽

Line Chemotherapy

Purpose This nonrandomized multicenter phase II study was performed to evaluate the activity and safety of Ecteinascidin (ET-743) administered at a dose of 1.5 mg/m2 as a 24-hour continuous infusion every 3 weeks in patients with pretreated advanced soft tissue sarcoma. Patients and Methods Patients with documented progressive advanced soft tissue sarcoma received ET-743 as second- or third-line chemotherapy. Antitumor activity was evaluated every 6 weeks until progression, excessive toxicity, or patient refusal. Results One hundred four patients from eight European institutions were included in the study (March 1999 to November 2000). A total of 410 cycles were administered in 99 assessable patients. Toxicity mainly involved reversible grade 3 to 4 asymptomatic elevation of transaminases in 40% of patients, and grade 3 to 4 neutropenia was observed in 52% of patients. There were eight partial responses (PR; objective regression rate, 8%), 45 no change (NC; > 6 months in 26% of patients), and 39 progressive disease. A progression arrest rate (PR + NC) of 56% was observed in leiomyosarcoma and 61% in synovialosarcoma. The median duration of the time to progression was 105 days, and the 6-month progression-free survival was 29%. The median duration of survival was 9.2 months. Conclusion ET-743 seems to be a promising active agent in advanced soft tissue sarcoma, with no cumulative toxicities. The 6-months progression-free survival observed in advanced soft tissue sarcoma compares favorably with those obtained with other active drugs tested in second-line chemotherapy in previous European Organisation for the Research and Treatment of Cancer trials. The median overall survival was unusually long in these heavily pretreated patients mainly due to the high number of patients who benefit from the drug in terms of tumor control.

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Liposomal anthracyclines and ifosfamide in the first line treatment of advanced soft tissue sarcomas: A two cohort phase II study

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.9563 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 9563-9563

Author(s):

J. M. Siehl ◽

E. Thiel ◽

A. Schmittel ◽

G. Hütter ◽

U. Keilholz

Keyword(s):

Soft Tissue ◽

Soft Tissue Sarcoma ◽

Phase Ii ◽

Response Rate ◽

Phase Ii Study ◽

Soft Tissue Sarcomas ◽

Study Endpoint ◽

Primary Study ◽

First Line ◽

Advanced Soft Tissue Sarcoma

9563 Objectives: The current first line standard chemotherapy for advanced soft-tissue sarcomas is the combination of doxorubicine and ifosfamide. Liposomal encapsulation is a strategy pursued to reduce toxicity and improve tumor uptake. There are so far only limited systematic data regarding the efficacy of liposomal anthracyclines in advanced soft-tissue sarcomas. We have previously reported on a phase II study with liposomal daunorubicine (L-Dauno) with ifosfamide, named IDx1. Here we report on an additional cohort of the phase II study using liposomal doxorubicine (L-Doxo). Methods: In a single-arm two cohort phase II study 55 patients with advanced soft-tissue sarcoma had received first line a maximum of 6 cycles (median 2 cycles) of ifosphamide (5 g/m2) and in cohort 1 L-Dauno (100 mg/m2, 40 patients) or in cohort 2 the approximate equivalent of L-Doxo (75 mg/m2, 15 patients). Cycles were repeated every 4 weeks in absence of disease progression. Primary study endpoint was response rate. Results: The overall response rate was 25% (n = 14). In the L-Dauno group the results were as follows: CR 3% (n = 1), PR 29% (n = 10), SD 17% (n = 6), PD 37% (n = 13), NED or intermittent death 14% (n = 5), and in the L-Doxo group: PR 20% (n =3), SD 26% (n =4) and PD 53% (n = 8). Interestingly, all three liposarcoma patients (two in the L-Dauno group, one in the L-Doxo group) responded, whereas liposarcoma usually carries a poor response rate. For both combinations toxicity was similarly tolerable with short episodes of hematotoxicity (leucocyte nadir on day 9, platelet nadir on day 11), 11 febrile episodes, no grade 3 or 4 mucositis, no cardiac toxicity and 5 episodes of grade 2 acute ifosfamide-related CNS-toxicity. Based on the hematotoxicity kinetics, three weekly regimens appear feasible. Conclusion: The combination of liposomal anthracyclines and ifosfamide is a safe and effective first line regimen in the treatment for advanced soft tissue sarcoma. Further evaluation in a randomized trial will be pursued. The unexpected high responsiveness of liposarcoma warrants further phase II investigation. 1Siehl JM et al. Cancer 2005. No significant financial relationships to disclose.

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Sequential Dose-Dense Doxorubicin and Ifosfamide in Advanced Soft-Tissue Sarcoma Patients in an Out-Patient-Basis Schedule

Sarcoma ◽

10.1155/2011/984340 ◽

2011 ◽

Vol 2011 ◽

pp. 1-7

Author(s):

G. F. G. Almeida ◽

G. Castro ◽

I. M. L. Snitcovsky ◽

S. A. Siqueira ◽

E. H. Akaishi ◽

...

Keyword(s):

Soft Tissue ◽

Soft Tissue Sarcoma ◽

High Frequency ◽

Locally Advanced ◽

Front Line ◽

Advanced Soft Tissue Sarcoma ◽

Grade 3 ◽

Dose Dense ◽

Sequential Strategy

Aims. This phase II study explored activity/safety of front-line dose-dense chemotherapy in high-grade STS (soft tissue sarcoma) patients and tested ezrin as prognostic factor.Patients and Methods. The protocol consisted of three cycles of doxorubicin (DOXO) 30 mg/m2on days 1–3 every 2 weeks, followed by three cycles of ifosfamide (IFO) 2.5 g/m2two hours a day on days 1–5 every 3 weeks, with GCSF support. Ezrin was assessed immunohistochemically.Results. Twenty patients, 13 metastatic and 7 locally advanced, were enrolled. Median age was 39 years (25–60). Median dose intensities were 42 mg/m2/week and 3.6 g/m2/week for DOXO and IFO, respectively. Grade 3/4 toxicities occurred in 18 patients. Response rate was 15% (3 of 20) by RECIST. Patients younger than 45 years with locally advanced disease and synovial histology presented longer survival. A trend towards longer survival was observed among ezrin-positive patients.Conclusions. This dose-dense schedule should not be routinely used due to its high frequency of toxic events; however, a sequential strategy with DOXO and IFO may benefit selected patients and should be further explored with lower doses. The role of ezrin as a prognostic marker should be confirmed in a larger group of patients.

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Efficacy of lenograstim on hematologic tolerance to MAID chemotherapy in patients with advanced soft tissue sarcoma and consequences on treatment dose-intensity.

Journal of Clinical Oncology ◽

10.1200/jco.1995.13.10.2629 ◽

1995 ◽

Vol 13 (10) ◽

pp. 2629-2636 ◽

Cited By ~ 47

Author(s):

B N Bui ◽

B Chevallier ◽

C Chevreau ◽

I Krakowski ◽

A M Peny ◽

...

Keyword(s):

Soft Tissue ◽

Soft Tissue Sarcoma ◽

Locally Advanced ◽

Dose Intensity ◽

Progressive Increase ◽

Daily Injection ◽

Advanced Soft Tissue Sarcoma ◽

Double Blind ◽

Significant Treatment ◽

Treatment Dose

PURPOSE This two-arm, double-blind, randomized trial was conducted to determine the effects of lenograstim, a glycosylated recombinant human granulocyte colony-stimulating factor (rHu-G-CSF), on the hematologic tolerance of patients with sarcoma treated with mesna, doxorubicin, ifosfamide, and doxorubicin (MAID) chemotherapy. PATIENTS AND METHODS Forty-eight patients with metastatic or locally advanced soft tissue sarcoma were, following the first cycle of a combination with doxorubicin 60 mg/m2, ifosfamide 7.5 g/m2, and dacarbazine 900 mg/m2, ifosfamide 7.5 g/m2, and dacarbazine 900 mg/m2 given on days 1 to 3, randomized to receive either lenograstim 5 micrograms/kg/d by once-daily injection from day 4 to day 13, or its vehicle. For subsequent cycles, 28 patients continued on the same chemotherapy and lenograstim was systematically given as prophylactic treatment in an open manner. RESULTS Following the first cycle of MAID, the duration of neutropenia was reduced in patients who received lenograstim as compared with those who received placebo, with a median duration of neutropenia ( < 0.5 x 10(9)/L neutrophils) of 0 days (range, 0 to 3) and 5 days (range, 0 to 10), respectively (P < .001). All patients who received lenograstim had recovered at least 1 x 10(9)/L neutrophils (polymorphonuclear lymphocytes [PMN]) on day 14, compared with only one of 26 in the placebo group (P < .001). The median time to recover this neutrophil level was 12 days (range, 10 to 13) and 17 days (range, 14 to 21), respectively (P < .001). Neutropenic fever occurred in five (23%) and 15 (58%) patients respectively (P = .02). Twenty-eight patients received at least two cycles (median, four) of MAID at the same dose. Toxicity remained constant across all treatment cycles. A progressive increase in thrombocytopenia was noted, with median platelet nadirs of 102 x 10(9)/L at cycle 2 and 19.5 x 10(9)/L at cycle 6, but did not result in significant treatment modifications. Consequently, median relative dose-intensities remained greater than 0.95 for up to six consecutive MAID cycles. CONCLUSION Lenograstim significantly improved hematologic tolerance in patients treated with the MAID chemotherapy regimen and, therefore, allowed optimal adhesion to the theoretic doses planned for up to six cycles. Whether such an optimization in relative dose-intensity will result in an improvement of treatment efficacy remains to be determined.

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A Retrospective Analysis of Vinorelbine Chemotherapy for Patients With Previously Treated Soft-Tissue Sarcomas

Sarcoma ◽

10.1155/srcm/2006/15947 ◽

2006 ◽

Vol 2006 ◽

pp. 1-4 ◽

Cited By ~ 23

Author(s):

Sibyl E. Anderson ◽

Mary L. Keohan ◽

David R. D'Adamo ◽

Robert G. Maki

Keyword(s):

Soft Tissue ◽

Soft Tissue Sarcoma ◽

Epithelioid Sarcoma ◽

Single Agent ◽

Soft Tissue Sarcomas ◽

Median Number ◽

Kaplan Meier ◽

Pretreated Group ◽

Heavily Pretreated ◽

Grade 3

Introduction. The role of vinorelbine in specific soft tissue sarcoma subtypes is unclear. We present retrospective single institution experience with single-agent vinorelbine in subjects with metastatic soft tissue malignancies.Methods. Fifty-eight patients were treated with single agent intravenous vinorelbine between April 1997 and December 2004. Doxorubicin had been administered previously to 53 subjects (91%), and the median number of lines of previous chemotherapy was 3 (range 0–7).Results. Patients received a median 6 doses of vinorelbine (range 1–65). The overall response rate was 6%(3 patients: 1 angiosarcoma, 1 epithelioid sarcoma, and 1 embryonal rhabdomyosarcoma). Fourteen patients (26%) experienced a best result of stable disease. Median time to progression was 1.8 months (95%confidence intervals 1.5–2.1 months, Kaplan-Meier estimate). Eight patients experienced grade 3 or 4 toxicity, most commonly febrile neutropenia.Conclusion. Vinorelbine demonstrates limited activity in a heavily pretreated group of soft-tissue sarcoma patients. Prospective investigation may be considered for selected sarcoma subtypes.

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