A Pilot Study of Anti-CTLA4 Antibody Ipilimumab in Patients with Synovial Sarcoma.

Background. Patients with recurrent synovial sarcomas have few options for systemic therapy. Since they express large amounts of endogenous CT (cancer testis) antigens such as NY-ESO-1, we investigated the clinical activity of single agent anti-CTLA4 antibody ipilimumab in patients with advanced or metastatic synovial sarcoma. Methods. A Simon two-stage phase II design was used to determine if there was sufficient activity to pursue further. The primary endpoint was tumor response rate by RECIST 1.0. Patients were treated with ipilimumab 3 mg/kg intravenously every 3 weeks for three cycles and then restaged. Retreatment was possible for patients receiving an extra three-week break from therapy. Sera and peripheral blood mononuclear cells were collected before and during therapy to assess NY-ESO-1-specific immunity. Results. Six patients were enrolled and received 1-3 cycles of ipilimumab. All patients showed clinical or radiological evidence of disease progression after no more than three cycles of therapy, for a RECIST response rate of 0%. The study was stopped for slow accrual, lack of activity, and lack of immune response. There was no evidence of clinically significant either serologic or delayed type hypersensitivity responses to NY-ESO-1 before or after therapy. Conclusion. Despite high expression of CT antigens by synovial sarcomas of patients treated in this study, there was neither clinical benefit nor evidence of anti-CT antigen serological responses. Assessment of the ability of synovial sarcoma cell lines to present cancer-germ cell antigens may be useful in determining the reason for the observed lack of immunological or clinical activity.

Altered bone and mineral metabolism in patients receiving imatinib mesylate.

BACKGROUND: Imatinib mesylate inhibits several tyrosine kinases, including BCR-ABL, the C-KIT receptor, and the platelet-derived growth factor receptors alpha and beta, all of which are associated with disease. We observed that hypophosphatemia developed in some patients with either chronic myelogenous leukemia or gastrointestinal stromal tumors who were receiving imatinib. METHODS: We identified 16 patients who had low serum phosphate levels and 8 patients who had normal serum phosphate levels, all of whom were receiving imatinib. We performed the following biochemical measurements: whole-blood levels of ionized calcium, plasma levels of intact parathyroid hormone, and serum levels of total calcium, phosphate, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, magnesium, and markers of bone formation (bone alkaline phosphatase and osteocalcin) and bone resorption (N-telopeptide of collagen cross-links); urinalysis; and phosphate, calcium, and creatinine levels in "spot" urine specimens. RESULTS: Patients in the low-phosphate group (median serum phosphate level, 2.0 mg per deciliter [0.6 mmol per liter]; normal level, >2.5 mg per deciliter [0.8 mmol per liter]) had elevated parathyroid hormone levels and low-to-normal serum calcium levels, were younger, and were receiving a higher dose of imatinib than patients in the normal-phosphate group (median level, 3.2 mg per deciliter [1.0 mmol per liter]). Both groups had high levels of phosphate excreted in the urine and markedly decreased serum levels of osteocalcin and N-telopeptide of collagen cross-links. CONCLUSIONS: Hypophosphatemia, with associated changes in bone and mineral metabolism, develops in a proportion of patients taking imatinib for either chronic myelogenous leukemia or gastrointestinal stromal tumors. The drug may inhibit bone remodeling (formation and resorption), even in patients with normal serum phosphate levels.

Phase II study of doxorubicin and bevacizumab for patients with metastatic soft-tissue sarcomas.

PURPOSE: To evaluate the antitumor activity and tolerability of bevacizumab and doxorubicin in patients with metastatic soft-tissue sarcoma (STS). PATIENTS AND METHODS: Patients may have had up to one nonanthracycline line of therapy. Seventeen patients with metastatic STS were treated with doxorubicin at 75 mg/m2 intravenous (IV) push followed by bevacizumab 15 mg/kg IV every 3 weeks. Dexrazoxane was started for total doxorubicin dose exceeding 300 mg/m2. RESULTS: A total of 85 cycles of doxorubicin/bevacizumab were administered, median four cycles (range, one to 11), with three patients receiving one to four cycles of bevacizumab maintenance after reaching 600 mg/m2 doxorubicin. All 17 patients were assessable for response. Two partial responses (12%, 95% CI = 1% to 36%) were observed, lasting seven and 12 cycles of therapy. Eleven patients (65%) had stable disease for four cycles or more. Six patients developed cardiac toxicity grade 2 or greater, with four patients grade 2 (cumulative doxorubicin 75, 150, 300, 300 mg/m2, respectively), one grade 3 (total doxorubicin 591 mg/m2), and one grade 4 (total doxorubicin 420 mg/m2). One patient with extensive lung disease died of recurrent bilateral pneumothoraces, possibly treatment-related. CONCLUSION: The 12% response rate for these patients was no greater than that observed for single-agent doxorubicin. However, the 65% of patients with stable disease lasting four cycles or longer suggests further study is warranted in STSs. The observed cardiac toxicity, despite close monitoring and standard use of dexrazoxane, obliges a change in the dose and/or schedule in future studies of this combination.

A multicenter Phase II study of bortezomib in recurrent or metastatic sarcomas.

BACKGROUND: Based on evidence of activity in preclinical and Phase I studies, the authors undertook a study of bortezomib, a reversible proteasome inhibitor, for patients with metastatic sarcomas. METHODS: Two arms were opened, each using a Simon two-stage design. Arm A included patients with osteogenic sarcoma, Ewing sarcoma, and rhabdomyosarcoma. Arm B accrued patients with other types of soft tissue sarcomas. Patients were not allowed to have received previous chemotherapy for metastatic disease. The initial dose of bortezomib was a 1.5 mg/m2 intravenous push twice weekly followed by a rest week. The dose was escalated to 1.7 mg/m2 if patients tolerated Cycle 1 well. The dose escalation was eliminated due to toxicity observed in the first six patients. RESULTS: Painful neuropathy, myalgias, and asthenia were the most significant observed toxicities. The most frequent toxicities included fatigue, diarrhea, constipation, and nausea. Pharmacodynamic data from 18 patients with complete data collection did not show consistent differences between patients with or without Grade 2 or Grade 3 neuropathy (toxicity graded according the National Cancer Institute Common Toxicity Criteria). Arm A had low accrual and was closed. One confirmed partial response among 21 evaluable patients was observed on Arm B in a patient with leiomyosarcoma. Due to the inactivity of this agent, the study was closed after the first stage of accrual. CONCLUSIONS: Bortezomib has minimal activity in soft tissue sarcoma as a single agent. If studied further in sarcomas, bortezomib should be investigated in combination with agents with demonstrated preclinical synergy.