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Positive Survival Results Reported for Aldoxorubicin in Sarcoma Trial

Mid-stage data show superiority over doxorubicin

Positive overall survival (OS) results have been reported from a global, randomized, open-label, phase IIb trial investigating the efficacy and safety of aldoxorubicin (CytRx Corp.) compared with that of doxorubicin as first-line therapy in 123 patients with metastatic, locally advanced, or unresectable soft-tissue sarcoma (STS).

The widely used chemotherapeutic agent doxorubicin is delivered systemically and is highly toxic, which limits its dose to a level below its maximum therapeutic benefit. Doxorubicin also is associated with numerous adverse effects, especially the potential for damage to heart muscle at cumulative doses greater than 450 mg/m2.

Aldoxorubicin combines doxorubicin with a single-molecule linker that binds directly and specifically to circulating albumin, the most plentiful protein in the bloodstream. Protein-hungry tumors concentrate albumin, thereby increasing the delivery of the linker molecule with the attached doxorubicin to tumor sites. In the acidic environment of the tumor, but not the neutral environment of healthy tissues, doxorubicin is released. This allows larger doses (3.5 to 4 times) of doxorubicin to be administered while reducing its toxic effects. So far, there has been no evidence of clinically significant effects of aldoxorubicin on heart muscle, even at cumulative doses of the drug in excess of 2,000 mg/m2.

In the new study, subjects with advanced STS were randomly assigned to receive either aldoxorubicin 350 mg/m2 (n = 83) or doxorubicin 75 mg/m2 (n = 40) every 3 weeks for up to six cycles. The subjects were then followed every 6 weeks with computed tomography scans to monitor tumor size. The study’s primary endpoint was progression-free survival (PFS), and secondary endpoints included PFS at 6 months, the overall response rate (ORR), and OS.

In scans read by trial investigators, aldoxorubicin increased median PFS by approximately 79% (to 8.4 months) compared with 4.7 months with doxorubicin, meeting the study’s primary endpoint (hazard ratio [HR], 0.419; P = 0.0007). In a blinded central radiology review, aldoxorubicin increased median PFS by approximately 104% (to 5.7 months) compared with 2.8 months with doxorubicin, also meeting the study’s primary endpoint (HR, 0.584; P = 0.024).

Further, aldoxorubicin-treated patients demonstrated a 27% reduction in the risk of death compared with those treated with doxorubicin, the current standard-of-care in this indication. In addition, aldoxorubicin-treated patients demonstrated a 41% likelihood of surviving more than 2 years –– a two-fold increase compared with a 20% probability for doxorubicin-treated patients.

Median OS was 16.0 months for aldoxorubicin-treated patients compared with 14.4 months for doxorubicin-treated patients (P = 0.21). For treatment-naïve patients, representing 90% of the subjects in the study, median OS was 16.0 months in the aldoxorubicin group compared with 14.0 months in the doxorubicin group (P = 0.14).

In scans read by trial investigators, treatment with aldoxorubicin increased median PFS at 6 months by approximately 86% compared with doxorubicin, meeting this secondary primary endpoint (P = 0.002). In a blinded central radiology review, aldoxorubicin increased median PFS at 6 months by approximately 100% compared with doxorubicin, meeting this additional secondary endpoint (P = 0.02).

The ORR was 21.7% for aldoxorubicin-treated subjects (2.4% complete response [CR] and 19.3% partial response [PR]) compared with 5.0% for doxorubicin-treated subjects (0% CR and 5.0% PR). As assessed by a blinded central laboratory review, 23.8% of aldoxorubicin-treated subjects experienced a PR, whereas no doxorubicin-treated subjects had an objective response. In addition, a higher percentage of aldoxorubicin-treated subjects demonstrated tumor shrinkage compared with patients treated with doxorubicin, regardless of whether the scans were evaluated by investigators (65.4% vs. 41.2%) or by blinded reviewers (60.8% vs. 39.4%).

STS is a cancer that occurs in muscle, fat, blood vessels, tendons, fibrous tissues, and connective tissue. It can arise anywhere in the body at any age. According to the American Cancer Society, there are approximately 50 types of soft tissue sarcomas. In 2013, more than 11,400 new cases of STS were diagnosed in the U.S., and approximately 4,400 Americans died from the disease.

Source: CytRx; January 22, 2015.

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