Cediranib active in alveolar soft part sarcoma

WAILEA, Hawaii — A randomized phase 2 trial designed to assess the effect of cediranib for patients with alveolar soft part sarcoma met its primary endpoint, according to results of the CASPS trial presented at Connective Tissue Oncology Society Annual Meeting.

Cediranib (AstraZeneca), an oral VEGF receptor tyrosine kinase inhibitor, appeared associated with a significant change in sum of target marker lesions compared with placebo. Cediranib-treated patients also achieved superior PFS and OS outcomes.

“CASPS confirms the significant activity of cediranib against alveolar soft part sarcoma,” Ian Judson, MD, of Royal Marsden Hospital in London, said during a presentation.

Alveolar soft part sarcoma — which accounts for 0.5% to 1% of soft tissue sarcomas — often occurs in young individuals. The disease — characterized by long latency periods, slow progression, and spontaneous stabilization and regression — often does not respond to conventional chemotherapy, according to study background.

Cediranib has exhibited activity in alveolar soft part sarcoma in single-arm phase 2 trials.

In the CASPS trial, Judson and colleagues enrolled 48 patients (median age, 31 years; interquartile range, 27-45; 52.1% female) aged 16 years or older treated at one of 12 centers in the United Kingdom, Spain or Australia. Patients had ECOG performance status of 0 (52.1%) or 1 (45.8%).

All patients had histologically confirmed disease, progressive disease within 6 months prior to randomization, and measurable metastatic disease as determined by RECIST version 1.1.

The most common sites of primary disease were the upper leg (41.7%) and arm (14.6%).

Investigators excluded patients with inadequate bone marrow reserve, as well as inadequate liver, renal or cardiac function. Other exclusion criteria included history of other malignancies, significant gastrointestinal impairment, hemorrhage within the prior 4 weeks, thrombosis within the previous 3 months or poorly controlled hypertension.

Twenty patients (41.7%) had received prior TKI treatment.

Researchers randomly assigned patients 2:1 to cediranib 30 mg daily or placebo. Follow-up occurred every 4 weeks, with tumor assessments every 8 weeks. Study assignment was unblinded at 24 weeks, or earlier if the patient progressed. Patients assigned placebo had the option to cross over to cediranib.

Percentage change in the sum of target marker lesion diameters from randomization to week 24 — or sooner if the patient progressed — served as the primary objective. Secondary objectives included PFS, OS, safety and tolerability.

The primary endpoint analysis included 28 patients assigned cediranib and 16 patients assigned placebo. Researchers also examined outcomes among 42 patients (27 assigned cediranib and 15 assigned placebo) who had not received prior cediranib therapy.

The study met its primary endpoint, as researchers reported significantly greater median change in sum of target marker lesions among all evaluable patients (-8.3% vs. 13.4%; P = .0013) and in the cediranib-naïve population (-4.4% vs. 14.4%; P = .0026).

An assessment of best responses at 24 weeks or upon progression in the evaluable population showed six patients, all of whom were assigned cediranib, achieved partial response. Median duration of response exceeded 26 months (95% CI, 4-undefined), and three patients still had not progressed at the time of analysis.

Thirty-one patients — 19 assigned cediranib and 12 assigned placebo — achieved stable disease. Seven patients — three assigned cediranib and four assigned placebo — experienced progressive disease.

Cediranib-treated patients achieved longer median PFS (10.8 months vs. 3.7 months; HR = 0.58; 90% CI, 0.33-1.03) and a higher rate of 12-month PFS (47.7% vs. 22.5%). Median OS had not been reached (HR for cediranib vs. placebo = 0.66; 95% CI, 0.25-1.75). Researchers reported a higher 12-month OS rate in the cediranib group (93.6% vs. 66%), despite the fact patients assigned placebo could cross over to cediranib upon progression.

The most common any-grade adverse events included diarrhea (90.3% for cediranib vs. 37.5% for placebo), hypertension (83.9% vs. 56.3%), fatigue (54.8% vs. 37.5%), nausea (38.7% vs. 18.8%) and dyspnea (35.5% vs. 18.8%).

The most common grade 3 or higher adverse events included hypertension (19.4% vs. 0%), increased GGT level (6.5% vs. 6.3%), diarrhea (6.5% vs. 0%), asthenia (3.2% vs. 0) and fatigue (3.2% vs. 0%).

“Side effects were generally manageable with dose reductions and antihypertensives,” Judson said. – by Mark Leiser

For more information:

Judson I, et al. Abstract 2774046. Presented at: Connective Tissue Oncology Society Annual Meeting; Nov. 8-11, 2017; Maui.

Di sclosure: Judson reports no relevant financial disclosures. Please see the abstract for a list of all other researchers’ relevant financial disclosures.