Source: Eur Urol  |  Posted 5 years ago

By Paula Moyer

ATLANTA, G.A. -- June 8, 2006 -- The investigative agent AP23573 has shown efficacy and tolerability in patients with advanced sarcomas, according to investigators who presented their findings here at the American Society of Clinical Oncology 2006 Annual Meeting (ASCO).

"There is a compelling single-agent efficacy of 25% in patients with a broad range of sarcomas," said principal investigator Sant P. Chawla, MD, adjunct member, bone and soft tumors division, John Wayne Cancer Institute, Santa Monica, California. "The progression-free survival rate was twice that of historical controls, and it was well tolerated with manageable side effects."

The mammalian target of rapamycin (mTOR) inhibitors have been shown to play a role in cell replication and angiogenesis, and several investigative teams are involved in the development of these agents against a variety of malignancies, Dr. Chawla said in a presentation on June 5[^]th[].

In their phase 2 study, Dr. Chawla and colleagues enrolled patients with advanced sarcoma regardless of whether or not the patients had received prior therapies. Subjects were divided into 4 cohorts based on histologic subtype. Treatment consisted of AP23573 at an intravenous dose of 12.5 mg for 5 days every 2 weeks.

The investigators used Response Evaluation Criteria in Solid Tumors (RECIST) guidelines to determine patient response to treatment and defined clinical benefit as complete or partial response or as stable disease for at least 16 weeks.

For each cohort, the investigators defined treatment as successful if the clinical benefit response rate was at least 25%. The team studied potential predictive markers of response by 18fluorodeoxyglucose-positron emission tomography (18FDG-PET) imaging, an analysis of mTOR pathway proteins in the tumoral tissue, and by measuring plasma cytokines and angiogenic factors.

The investigators treated 106 men and 107 women with AP23573, age range was 17 to 79 years (median 50 years).

The most frequent treatment-related adverse events included mucositis, rash, hyperlipidemia, fatigue, and thrombocytopenia.

Of the 212 patients for whom data were evaluable, 54 (26%) had a clinical benefit, including 5 partial responses among 3 patients with osteosarcoma, 1 with spindle cell sarcoma of the bone, and 1 with malignant fibrous histiocytoma.

Of the overall group, 76 patients (36%) were shown on 18FDG-PET to have rapid induction of partial metabolic responses following 3 to 5 days of study treatment.

Grade 3/4 toxicity events occurred in 6% of cases and consisted of mouth sores, fatigue, hypertriglyceridemia, anemia, and nausea.

The findings showed that AP23573 is well tolerated and efficacious. On the basis of these findings, the investigators are planning to conduct a phase 3 study, Dr. Chawla said.

The study was funded by ARIAD Pharmaceuticals, which is developing AP23573.

[[]Presentation title: Updated Results of a Phase II Trial of AP23573, a Novel mTOR Inhibitor, in Patients (Pts) With Advanced Soft Tissue or Bone Sarcomas. Abstract 9505[]]