Phase II Trial of nab-Sirolimus in Patients With Advanced Malignant Perivascular Epithelioid Cell Tumors (AMPECT): Long-Term Efficacy and Safety Update.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.nab-Sirolimus is approved in the United States for the treatment of metastatic or locally advanced malignant perivascular epithelioid cell tumor (PEComa) on the basis of the primary analysis results of the phase II Advanced Malignant Perivascular Epithelioid Cell Tumors (AMPECT) trial (ClinicalTrials.gov identifier: NCT02494570). Results from the primary analysis were previously published; however, the median duration of response (mDOR) had not been reached at that time. Here, 3 years after the primary analysis, we report final efficacy and safety data (data cutoff: April 29, 2022). At study completion, the confirmed overall response rate (by independent radiologist review using RECIST v1.1) was 38.7% (95% CI, 21.8 to 57.8), with an additional converted confirmed complete response (n = 2). Median progression-free survival remained the same at 10.6 months (95% CI, 5.5 to 41.2). The mDOR was reached at 39.7 months (95% CI, 6.5 to not reached [NR]), and the median overall survival at completion was 53.1 months (95% CI, 22.2 to NR). The most common treatment-related adverse events (TRAEs) were stomatitis (82.4%) and fatigue and rash (each 61.8%). No new or unexpected adverse events occurred, and no grade ≥4 TRAEs were reported. These results highlight the long-term clinical benefit of nab-sirolimus in patients with advanced malignant PEComa, with a DOR of >3 years.

nab-Sirolimus for Patients With Malignant Perivascular Epithelioid Cell Tumors.

PURPOSE: Malignant perivascular epithelioid cell tumor (PEComa) is a rare aggressive sarcoma, with no approved treatment. To our knowledge, this phase II, single-arm, registration trial is the first prospective clinical trial in this disease, investigating the safety and efficacy of the mammalian target of rapamycin inhibitor nab-sirolimus (AMPECT, NCT02494570). PATIENTS AND METHODS: Patients with malignant PEComa were treated with nab-sirolimus 100 mg/m2 intravenously once weekly for 2 weeks in 3-week cycles. The primary end point was objective response rate evaluated by independent radiology review. Key secondary end points included duration of response, progression-free survival, and safety. A key exploratory end point was tumor biomarker analysis. RESULTS: Thirty-four patients were treated (safety evaluable), and 31 were evaluable for efficacy. The overall response rate was 39% (12 of 31; 95% CI, 22 to 58) with one complete and 11 partial responses, 52% (16 of 31) of patients had stable disease, and 10% (3 of 31) had progressive disease. Responses were of rapid onset (67% by week 6) and durable. Median duration of response was not reached after a median follow-up for response of 2.5 years, with 7 of 12 responders with treatment ongoing (range, 5.6-47.2+ months). Twenty-five of 31 patients had tumor mutation profiling: 8 of 9 (89%) patients with a TSC2 mutation achieved a confirmed response versus 2 of 16 (13%) without TSC2 mutation (P < .001). The median progression-free survival was 10.6 months (95% CI, 5.5 months to not reached), and the median overall survival was 40.8 months (95% CI, 22.2 months to not reached). Most treatment-related adverse events were grade 1 or 2 and were manageable for long-term treatment. No grade ≥ 4 treatment-related events occurred. CONCLUSION: nab-Sirolimus is active in patients with malignant PEComa. The response rate, durability of response, disease control rate, and safety profile support that nab-sirolimus represents an important new treatment option for this disease.

nab-Paclitaxel in patients with advanced solid tumors and hepatic dysfunction: a pilot study.

OBJECTIVE: This pilot open-label clinical study evaluated the safety and pharmacokinetics of albumin-bound paclitaxel (nab-paclitaxel) in patients with advanced solid tumors and hepatic dysfunction. RESEARCH DESIGN/METHODS: Dosing was determined according to baseline bilirubin levels as described in the package insert for Taxol((R)) (paclitaxel), and patients received 130, 200 or 260 mg/m(2) nab-paclitaxel every 3 weeks. RESULTS: Thirty patients with elevated baseline bilirubin and aspartate aminotransferase levels received nab-paclitaxel. The most commonly-occurring grade 3/4 adverse events were neutropenia and fatigue. Grade 3/4 neutropenia occurred in 10, 30 and 30% of patients receiving 130, 200 and 260 mg/m(2) nab-paclitaxel, respectively. Grade 3 fatigue presented in 50 and 30% patients receiving 130 and 200 mg/m(2) nab-paclitaxel, respectively (no grade 4 event). Only one (10%) patient had a grade 3 sensory neuropathy in the 260 mg/m(2) nab-paclitaxel arm. Treatment-related grade 3 bilirubinemia and elevated aspartate aminotransferase was observed in patients receiving 130 mg/m(2) (30 and 10%, respectively) and 260 mg/m(2) nab-paclitaxel (20 and 10%, respectively). One patient had a grade 4 bilirubinemia in the 200 mg/m(2) nab-paclitaxel arm. Total bilirubin levels were inversely correlated to paclitaxel clearance (p < 0001). CONCLUSIONS: nab-Paclitaxel has an acceptable tolerability profile in patients with solid tumors and hepatic dysfunction. The safety and pharmacokinetic results support the same dose modification scheme recommended for cremophor-based paclitaxel.