Aldoxorubicin prolonged progression-free survival (PFS) in patients with liposarcoma and leiomyosarcoma (L-sarcoma) compared with standard treatments in a phase III study (Abstract 11000). The drug was also found to be a good alternative to standard therapies for treatment of relapsed or refractory soft tissue sarcomas (STS). Furthermore, with the regimen given in this trial, aldoxorubicin had minimal cardiac toxicity compared with doxorubicin, presenter Sant P. Chawla, MD, of the Sarcoma Oncology Center, said at the Sarcoma Oral Abstract Session on June 2. With the response to the drug demonstrated in this international study, and “its impressive lack of cumulative cardiotoxicity,” he said, “aldoxorubicin may be a superior anthracycline for treating advanced STS.”
Aldoxorubicin is a novel anthracycline that, administered intravenously, binds covalently to albumin in the circulation. The albumin carries the drug to the tumor site and is taken up by the tumor, Dr. Chawla explained. In the acidic environment of the tumor, the link with albumin is cleaved, and doxorubicin is released. In a previous randomized, phase II study including 126 patients with untreated metastatic STS, a doubling of PFS was seen in the group treated with aldoxorubicin compared with doxorubicin. There was no cumulative cardiotoxicity in the aldoxorubicin group with a median dose equivalent to 1,500 mg/m2 of doxorubicin.
Dr. Chawla presented a phase III study that compared 350 mg/m2 of aldoxorubicin (equivalent to 260 mg/m2 of doxorubicin) every 3 weeks with investigator’s choice (IC) of pazopanib, gemcitabine/docetaxel, dacarbazine, doxorubicin, or ifosfamide, administered according to each study site’s standard practice. The primary endpoint was PFS. Secondary endpoints included overall response rate (ORR), disease control rate (DCR, defined as ORR plus stable disease for 4 months or longer), overall survival (OS), PFS at 4 and 6 months, and adverse events. Prespecified analyses were also conducted based on geography (North America and Australia vs. Europe, Israel, and Chile), sarcoma type, and previous doxorubicin treatment.
Of the 433 patients randomly assigned, 218 received aldoxorubicin and 215 received IC. The groups were well balanced demographically; notably, approximately two-thirds of the patients in each group had received previous treatment with doxorubicin.
Median PFS in the intent-to-treat population was 4.11 months in the aldoxorubicin group and 2.96 months in the IC group (p = 0.0870). Among patients with L-sarcoma, median PFS was 5.32 months in the aldoxorubicin group and 2.96 in the IC group (p = 0.0070). The difference between median PFS in patients in North America and Australia receiving aldoxorubicin and IC was also statistically significant, favoring the former (4.21 vs. 2.96, respectively; p = 0.0225).
OS was similar between the aldoxorubicin and IC groups (12.88 vs. 12.16 months, respectively; p = 0.8555). ORR was almost double in the aldoxorubicin group compared with IC (8.3% vs. 4.2%, respectively; p = 0.1106) and more than double in patients with L-sarcoma (10.0 vs. 4.0, respectively; p = 0.0790).
Discussant Vinod Ravi, MD, of The University of Texas MD Anderson Cancer Center, said, “The most important takeaway from this study is that aldoxorubicin has a very favorable toxicity profile compared to doxorubicin. … Hematologic toxicity is fairly comparable, but there is a sharp drop in the cardiac toxicity.”
Aldoxorubicin “has a great deal of value and should potentially replace doxorubicin as a next-generation anthracycline,” Dr. Ravi said. “There is published phase II data and subset analysis showing promising activity.” He speculated that failure to reach the primary endpoint in the phase III trial (despite a trend favoring aldoxorubicin), in contrast with the phase II trial, was “related to the complex trial design and the heterogeneous population with prior exposure to doxorubicin, and this may not be the appropriate subset to address this question.”