Combination Targeted Therapy Well Tolerated, Effective for Refractory Ewing’s Sarcoma Tumors

Combination Targeted Therapy Well Tolerated, Effective for Refractory Ewing’s Sarcoma Tumors

Released: 3/27/2012 1:00 PM EDT Embargo expired: 3/31/2012 2:30 PM EDT Source: American Association for Cancer Research (AACR)

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Newswise — CHICAGO — A combination of targeted therapies may be effective against relapsed or recurrent Ewing’s sarcoma or desmoplastic small-round-cell tumors, according to results of a phase I trial presented at the AACR Annual Meeting 2012, held here March 31 – April 4, and published simultaneously in Clinical Cancer Research, a journal of the American Association for Cancer Research.

“Ewing’s sarcoma (EWS) is the second most common bone malignancy striking children, adolescents and young adults in the prime of their lives,” said lead researcher Aung Naing, M.D., assistant professor in the department of investigational cancer therapeutics in the division of cancer medicine at The University of Texas MD Anderson Cancer Center in Houston, Texas. “More treatment options are needed for this disease, because relapse of the disease is quite frequent.

“When tested in the treatment of the EWS family of tumors, single-agent insulin growth factor-1 receptor (IGF-1R) inhibitors and the mTOR inhibitors given as monotherapy have produced variable outcomes.”

The researchers evaluated a subset of 20 patients, including 17 with EWS and three with desmoplastic small-round-cell tumors (DSRCT), who were treated as part of an expansion cohort from a phase I study of an IGF-1R inhibitor, cixutumumab, and the mTOR inhibitor temsirolimus.

All patients had been pretreated heavily before enrolling in the study. Researchers assigned patients to four-week cycles of 6 mg/kg cixutumumab and 25 mg to 37.5 mg of temsirolimus.

At a median follow-up of 8.9 months, they observed prolonged stable disease lasting more than six months and two complete responses in 29 percent of the patients with EWS. Notably, in one patient who had previously demonstrated a marked clinical response to a different IGF-1R targeted antibody before acquiring resistance, combining IGF-1R inhibition and mTOR inhibition induced a complete response, which provides strong evidence for synergy between mTOR and IGF-1R antagonists. Four responders developed grade 3 mucositis, myelosuppression or hyperglycemia, which were treated with supportive therapy.

“This study demonstrated early evidence that this combination can be considered for patients with relapsed and recurrent diseases,” Naing said. “Further studies in larger numbers of patients with EWS and DSRCT as well as additional investigation into underlying resistance mechanisms in individual patients are needed.”

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Presenter: Aung Naing, M.D.

Abstract Number: LB-124/CCR-12-0061

Title: Insulin Growth Factor-Receptor (IGF-1R) Antibody Cixutumumab Combined with the mTOR Inhibitor Temsirolimus in Patients with Refractory Ewing’s Sarcoma Family Tumors

Author Block: Aung Naing, Patricia LoRusso, Vivek Subbiah, Siqing Fu, David Hong, Peter Anderson, Robert Benjamin, Joseph Ludwig, Helen X. Chen, Austin Doyle, Razelle Kurzrock. UT MD Anderson Cancer Ctr., Houston, TX, Karmanos Cancer Institute, Detroit, MI, CTEP National Cancer Insititute, Rockville, MD, National Cancer Institute, Rockville, MD

Background: Temsirolimus was combined with cixutumumab, a fully human IgG1 monoclonal antibody directed at insulin growth factor-1 receptor (IGF-1R), on the basis of preclinical data suggesting that the combination could overcome resistance in Ewing’s sarcoma (EWS).

Methods: Patients received cixutumumab, 6 mg/kg IV weekly, and temsirolimus, 25 mg-37.5 mg IV weekly (4-week cycles), with restaging after 8 weeks. Median follow up was 8.9 months.

Results: Twenty patients (17 with EWS, 3 with desmoplastic small-round-cell tumor [DSCRT]) were enrolled. Twelve patients (60%) were men; median age, 24 years; median number of prior therapies, 6. Six patients previously received an IGF-1R inhibitor and two, temsirolimus. The most frequent toxicities, at least possibly drug-related, were thrombocytopenia (85%), mucositis (80%), hypercholesterolemia (75%), hypertriglyceridemia (70%), and hyperglycemia (65%) (mostly grade 1-2). Seven of 20 patients (35%) achieved stable disease (SD) >5 months or complete/partial (CR/PR) responses (duration = 5.6, 5.7, 8, 2 +, 18+, 15, 22+ months). Tumor regression of over 20% (100%, 100%, 27%, 23%, 23%) occurred in 5/17 (29%) EWS patients with time to treatment failure lasting 22, 2+, 15, 18 and 8 months, respectively. Biopsy samples of one patient taken at the time of emergence of resistance to a different IGF-1R inhibitor, demonstrated upregulation of mTOR pathway proteins, as determined by morphoproteomic analysis of the resistant tumor; and this particular patient achieved a CR with a time to treatment failure of 22 months on our trial. A second patient with EWS had a PR with prior IGF-1R treatment and then had a mixed response with remarkable regression in three lung modules after instituting cixutumumab and temsirolimus, but progression in a fourth lesion. Morphoproteomic analysis of this patient’s resistant tumor demonstrated upregulation of mTOR and ERK/MEK signals . The latter suggests the possibility that a combination of IGFR/mTOR and MEK inhibitors might warrant investigation in order to reverse resistance. Four of the seven best responders developed grade 3 mucositis, myelosuppression, or hyperglycemia, which was controlled while maintaining drug dose. Side effects of this regimen were well controlled with medication and the assistance of an endocrinologist, when necessary

Conclusions: This mechanism-based approach shows evidence of activity for temsirolimus and cixutumumab in EWS family tumors. The majority of best responders developed grade 3 side effects which were well controlled by supportive measures, suggesting that drug dose should not be compromised.

This study was supported by R21CA13763301A1 (Aung Naing), U01CA62461 (Razelle Kurzrock), and U01CA62487 (Patricia LoRusso)

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