Aldoxorubicin - A New Approach to Cancer Treatment
Aldoxorubicin is a rationally-engineered cytotoxic which delivers well-established anti-cancer agent, doxorubicin, into the tumor. Currently in late-stage clinical trials, aldoxorubicin appears to overcome the key limitations of doxorubicin, including cumulative dose restrictions. Aldoxorubicin utilizes an acid-sensitive linker that selectively binds to albumin, which may allow the cytotoxic payload to preferentially accumulate in the tumor and potentially spare the surrounding healthy tissue. This mechanism leverages the tumor's low pH environment, and accompanying dependency upon circulating albumin to fuel growth, to enable the delivery of multifold times the standard dosing of doxorubicin.
Aldoxorubicin has now been tested in approximately 600 patients with cancer, and is currently being studied in ongoing clinical trials across multiple cancer indications including soft tissue sarcoma (STS) and small cell lung cancer (SCLC).
Pivotal, Global Phase 3 Clinical Trial of Aldoxorubicin in STS
In July 2016, we announced the initial analysis of top-line data from our on-going global, randomized Phase 3 clinical trial of aldoxorubicin as a treatment for patients with relapsed or refractory soft tissue sarcomas, or STS. The trial enrolled 433 patients at 79 sites in 15 countries including the U.S. and Canada. Aldoxorubicin performed better than investigator's choice for the entire study population, and narrowly missed statistical significance in progression-free survival, or PFS (p=0.12; HR=0.81, 95% CI 0.64-1.06), the trial's primary endpoint. All responses were determined by an independent, blinded central lab assessment of scans. Since the initial analysis, we have continued to follow patients for overall survival (OS), a secondary endpoint of the trial.
On November 29, 2016, we announced updated results from the Phase 3 clinical trial, which demonstrated a statistically significant improvement in PFS between aldoxorubicin and investigator's choice therapy in 246 patients with either leiomyosarcoma or liposarcoma, (p=0.007). The hazard ratio (HR) was 0.62 (95% CI 0.44-0.88), representing a 38% reduction in the risk of tumor progression for patients receiving aldoxorubicin versus investigator's choice. Leiomyosarcoma and liposarcoma, the two most common types of STS, accounted for 57% of the patients enrolled in the overall trial. Aldoxorubicin also demonstrated a statistically significant improvement in PFS over investigator's choice in 312 patients treated in North America (p=0.028; HR=0.71, 95% CI 0.53-0.97).
In the entire study population, aldoxorubicin achieved a statistically significant improvement in the disease control rate, or DCR (defined as objective response rate, or ORR, plus stable disease for at least four months) of 29.4% versus 20.5% for the patients treated with investigator's choice (p=0.030). In North American patients, the benefit was more pronounced, with aldoxorubicin-treated patients exhibiting a DCR of 32.9%, compared to 19.2% for patients treated with investigator's choice (p=0.007), an overall improvement of 71%. ORR in North American patients also favored aldoxorubicin over investigator's choice, 8.7% versus 3.3% (p=0.058).
Aldoxorubicin did not cause clinically significant cardiac, renal, or hepatic toxicities. For the global trial population, the most commonly reported adverse events were neutropenia and anemia consistent with prior clinical trials with aldoxorubicin. Grade 3 or higher adverse events were manageable with supportive care and occurred at a rate of 61% for patients receiving aldoxorubicin and 46% in patients treated with investigator's choice. Treatment-emergent adverse events leading to discontinuation occurred in 4.2% of patients treated with aldoxorubicin, compared to 6.3% for patients receiving investigator's choice. Serious adverse events, primarily febrile neutropenia that resolved and rarely led to treatment termination occurred more frequently in patients administered aldoxorubicin. Three treatment-related deaths occurred in aldoxorubicin-treated patient, while there were no deaths among patients receiving investigators' choice of drugs.
In March 2017, CytRx met with the U.S. FDA to discuss a regulatory strategy for submitting an New Drug Application or NDA for aldoxorubicin. CytRx and the FDA agreed that the aldoxorubicin NDA submission will be under the 505(b)(2) regulatory pathway. The FDA has not requested additional clinical trials prior to submitting the NDA. CytRx’s goal is to initiate a rolling NDA in Q4 2017.
Advancing Aldoxorubicin in Several Additional Tumor Types
In addition to STS, CytRx is also evaluating aldoxorubicin in a global Phase 2b clinical trial in second-line small-cell lung cancer, and a Phase 1b trial in combination with ifosfamide in patients with STS. CytRx has also completed trials with aldoxorubicin in patients with relapsed glioblastoma, Kaposi's sarcoma and in combination with gemcitabine.