ASCO 2006 Abstract #9515

 

A PHASE II MULTICENTER TRIAL OF

IMATINIB MESYLATE (IM) IN PATIENTS WITH

AGGRESSIVE FIBROMATOSIS

 

R. Chugh, R. G. Maki, D. G. Thomas, D. Reinke, J. K. Wathen, S. Patel, D. A. Priebat, P. A. Meyers, R. S. Benjamin, L. H. Baker

 

BACKGROUND: Aggressive fibromatosis (desmoid tumors, AF) are uncommon, locally aggressive, connective tissue neoplasms. Existing literature on systemic treatment of AF is sparse and consists mostly of case reports and small case-series. Based on previous observation of regression of AF treated with IM and tumoral expression of IM targets, SARC (Sarcoma Alliance for Research through Collaboration) included the treatment of AF onto a multi-institution phase II trial of IM in sarcoma. Here we report early clinical and laboratory results of the AF group.

METHODS: Eligible patients had histologically proven AF, unresectable or difficult to resect without considerable functional impairment. Patients were treated with IM 300 mg po BID (BSA>1.5m²). The primary endpoint was complete (CR) or partial response (PR) at two months or stable disease (SD) or better at four months. Tumor DNA was extracted from available formalin fixed paraffin embedded tissue specimens and analyzed via allelic PCR and genomic DNA sequence analysis for specific point mutations in PDGFRa exons 12/14/18, PDGFRß exons 12/18, KIT exons 9/11/13/17, and bRAF. Results: 51 patients were enrolled from 10/02 to 12/05 at 5 institutions, with 45 patients currently evaluable. The median age is 37 (range 14-67), and median number of prior therapies is 1 (range 0-3). 36 patients (80%) reached the primary endpoint of CR/PR at 2 months or SD or better at 4 months. The median time to treatment failure is 6.8 months (95% C.I. 5.8-17.1). Thus far, the maximum change in the largest dimension of the tumor ranged from a 21% increase to a 45% decrease. In 22 available tumor specimens, deletions within PDGFRaE12 and E18 were noted in 1 and 3 patients, respectively, while a wildtype genotype was found in other regions.

CONCLUSIONS: IM has activity in AF, the mechanism of which remains unclear. While this is the largest reported phase II trial of AF, further improvement in evaluating clinical efficacy in this disease is clearly necessary. We plan an analysis of the maximum change in largest tumor dimension for each patient, which will be particularly beneficial in AF as responses often occur late. We have not as yet identified a laboratory predictor of clinical benefit. Further investigation of other potential targets in fresh tissue is warranted.

CITATION: Journal of Clinical Oncology, 2006 ASCO Annual Meeting Proceedings Part I. Vol 24, No. 18S (June 20 Supplement), 2006: 9515

 

 

 

 

ASCO 2006 Abstract #9514

A SARC MULTICENTER PHASE III

STUDY OF GEMCITABINE (G)

VS. GEMCITABINE AND DOCETAXEL (g+D) IN

PATIENTS WITH METASTATIC SOFT TISSUE SAROMAS (sts)

 

 R. G. Maki, M. L. Hensley, J. K. Wathen, S. R. Patel, D. A. Priebat, S. Okuno, D. Reinke, P. F. Thall, R. S. Benjamin, L. H. Baker, h. on behalf of SARC: Sarcoma Alliance for Research through Collaboration

 

 

Abstract:

BACKGROUND: We sought to compare the response of metastatic STS to G vs. G+D in a phase III study using a novel Bayesian adaptive randomization strategy.

METHODS: Entry criteria included non-GIST STS diagnosis, age > 10, measurable disease, < 3 prior regimens, normal organ function, and Grade (Gr) < 1 neuropathy. Pts were stratified by histology (leiomyosarcoma [LMS] vs. other), and history of prior pelvic radiation (PPR) or not, yielding 4 diagnostic subgroups. Therapy was G 1200 mg/m² (over 120 min, d1+d8) or G 900 mg/m² (over 90 min, d1+d8) and docetaxel (100 mg/m² d8) q21d; all pts received (peg)-filgrastim starting d9. 25% dose reductions were employed for PPR or toxicity. The primary endpoint was tumor response (CR, PR, or 24+ weeks stable), using a double-blind Bayesian adaptive randomization procedure to incrementally assign more pts to the superior treatment arm, while accounting for possible treatment-subgroup interactions. Although this study is not based on a 1:1 randomized phase III design, enrolling ~120 pts would show a difference between a response rate (RR) of 10% for G and 30% with G+D with a power of 0.8 and two-sided alpha of 0.05.

RESULTS: 122 pts were randomized; 119 pts had evaluable outcomes. Median number of prior regimens was 1; median number of cycles was 4 (range 1-26). 49 pts were adaptively randomized to G and 73 to G+D, indicating superiority of G+D. Of 119 evaluable pts, 27% (G) and 32% (G+D) showed response as defined. The odds of pts with LMS receiving G+D instead of G increased from 1:1 at the start of the study to ~6:1 at its completion. RR was 10% (G) vs. 16% (G+D) (p=0.15, Fisher exact test). Consistent with the RR outcomes, progression free survival (PFS) was 6.2 m (G+D, K-M 95%CI 3.6-8.8) vs. 2.6 m (G, 95%CI 2.0-3.2). Overall survival (OS) was 18.0 m (G+D, K-M 95%CI 11.7-24.1) vs. 11.2 m (G, 95%CI 6.8-15.5). Pts receiving G+D had a higher rate of discontinuation due to toxicity than those receiving G (p<0.01, log rank). Conclusions: We observed substantial clinical activity in this pre-treated STS population. G+D yields superior PFS and OS to G, but at the price of increased toxicity. Adaptive randomization is an effective method that substantively reduces the number of pts receiving inferior therapy.

CITATION: Journal of Clinical Oncology, 2006 ASCO Annual Meeting Proceedings Part I. Vol 24, No. 18S (June 20 Supplement), 2006: 9514

 

ASCO 2004 Abstract #9013

ACTIVITY OF IMATINIB MESYLATE IN

DESMOID TUMORS: INTERIM ANALYSIS

OF A SARCOMA ALLIANCE FOR

RESEARCH THRU COLLABORATION (SARC)

PHASE II MULTICENTER TRIAL

L. H. Baker, K. Wathen, R. Chugh, D. Thomas, P. F. Thall, R. G. Maki, B. L. Samuels, P. A. Meyers, D. A. Priebat, R. S. Benjamin; University of Michigan, Ann Arbor, MI; M.D. Anderson Cancer Center, Houston, TX; Memorial Sloan Kettering Cancer Center, New York, NY; University of Illinois at Chicago, Chicago, IL; Washington Hospital Center, Washington, DC

BACKGROUND: Desmoid tumors (aggressive fibromatosis) are rare clonal neoplastic proliferations of connective tissues. Although classified as benign, local aggressiveness can lead to significant impairment. Standard treatment involves wide surgical resection and/or radiation therapy. In cases of unresectable or recurrent disease, tamoxifen, chemotherapy, and NSAIDs have been used with varying success. We and others have previously reported desmoid tumors expressing c-kit, PDGFRa, and/or PDGFRß. We reported two patients with extraabdominal desmoid tumors treated with the selective tyrosine kinase inhibitor imatinib (Gleevec®) with significant shrinkage. SARC, in association with the Connective Tissue Oncology Society, initiated a prospective phase II trial in patients with desmoid tumors, or one of nine sarcoma subtypes. Here, we report specifically on patients with desmoid tumors.

METHODS: Patients > 10 years old with desmoid tumors that were not curable by surgical management or in whom curative surgery would lead to undesirable functional impairment were eligible. Imatinib was prescribed at 300 mg BID (BSA>1.5m²), 200 mg BID (BSA=1.0-1.49m²), or 100 mg BID (BSA<1.0m²). Response outcomes at two and four months were collected. Rules for early termination within each disease type were based on a hierarchical Bayesian probability model accounting for correlation of the responses of the 10 disease types. Tissue specimens were analyzed by immunohistochemistry for expression of c-kit, PDGFRa, PDGFRß, AKT, PTEN, FKHR, and beta catenin. Tumor DNA was analyzed for PDGFRa exon 18 and APC mutations by allelic discrimination PCR.

RESULTS: 26 patients with desmoid tumors have been enrolled with 22 currently evaluable. Two and four month progression-free survival rates of patients are 91% (20/22) and 78% (14/18), respectively. We have found polymorphisms/mutations of PDGFRa exon 18.

CONCLUSIONS: Imatinib appears to be a promising agent in the management of unresectable or difficult to resect desmoid tumors. We postulate that responsiveness is a function of alteration of that gene or other downstream effectors.

CITATION: Journal of Clinical Oncology, 2004 ASCO Annual Meeting Proceedings (Post-Meeting Edition). Vol 22, No 14S (July 15 Supplement), 2004: 9013

 

ASCO 2004 Abstract #9001

 A IMATINIB MESYLATE IN SOFT TISSUE AND BONE SARCOMAS: INTERIM RESULTS OF A SARCOMA ALLIANCE FOR RESEARCH THRU COLLABORATION (sarc) PHASE II MULTICENTER TRIAL

R. Chugh, D. Thomas, K. Wathen, P. F. Thall, R. S. Benjamin, R. S. Maki, B. L. Samuels, M. L. Keohan, D. A. Priebat, L. H. Baker; University of Michigan, Ann Arbor, MI; M.D. Anderson Cancer Center, Houston, TX; Memorial Sloan Kettering Cancer Center, New York, NY; University of Illinois at Chicago, Chicago, IL; Columbia University, New York, NY; Washington Hospital Center, Washington, DC

BACKGROUND: The success of imatinib (Gleevec®) in gastrointestinal stromal tumor (GIST) is proof that a small oncogene targeted molecule can have significant benefit in a solid tumor. Sarcomas, other than GIST, also overexpress one or more of the tyrosine kinases inhibited by imatinib. We are performing a multi-institutional study to evaluate imatinib activity in nine different sarcoma subtypes and desmoid tumors.