Date: 2016-11-29
Type of information: Results
phase: 3
Announcement: results
Company: CytRx Corporation (USA - CA)
Product: aldoxorubicin
Action
mechanism: antineoplastic agent/anthracycline. 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 many side effects, especially the potential for damage to heart muscle at cumulative doses greater than 450 mg/m2. Aldoxorubicin combines doxorubicin with a novel single-molecule linker that binds directly and specifically to circulating albumin, the most plentiful protein in the bloodstream. Protein-hungry tumors concentrate albumin, thus 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 for greater doses (3 ½ to 4 times) of doxorubicin to be administered while reducing its toxic side effects. In studies thus far there has been no evidence of clinically significant effects of aldoxorubicin on heart muscle, even at cumulative doses of drug well in excess of 2,000 mg/m2.
Disease: soft tissue sarcoma
Therapeutic area: Cancer - Oncology
Country: Australia, Canada, Chile, Denmark, France, Hungary, Israel, Italy, Netherlands, Poland, Russian Federation, Spain, USA
Trial
details: The randomized, controlled Phase 3 trial enrolled 433 patients at 79 sites in 15 countries including the U.S. and Canada. Patients with metastatic, locally advanced or unresectable soft tissue sarcomas who had either not responded to, or who had progressed following treatment with one or more systemic regimens of non-adjuvant chemotherapy were randomized 1:1 to be treated with aldoxorubicin or the investigator's choice of an approved chemotherapeutic regimen, including doxorubicin, ifosfamide, dacarbazine, pazopanib (Votrient®), or gemcitabine plus docetaxel. The primary endpoint of the study is PFS. Secondary endpoints include overall survival, response rates and safety. The Phase 3 trial is being conducted in accordance with a Special Protocol Assessment which was granted by the FDA. Leiomyosarcoma and liposarcoma are the two most common types of STS and accounted for 57% of the patients enrolled in the trial. (NCT02049905)
Latest
news: * On November 29, 2016, CytRx Corporation announced positive updated results from its pivotal Phase 3 clinical trial evaluating aldoxorubicin compared to investigator's choice in patients with relapsed or refractory soft tissue sarcomas (STS). The study, which enrolled 433 patients, demonstrated a statistically significant improvement in progression-free survival (PFS) between aldoxorubicin and investigator's choice therapy in 246 patients with leiomyosarcoma and 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. Aldoxorubicin 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). Notably, aldoxorubicin performed better than investigator's choice for the entire study population and narrowly missed statistical significance (p=0.12; HR=0.81, 95% CI 0.64-1.06). All responses were determined by an independent, blinded central lab assessment of scans. CytRx plans to submit the results of this clinical trial for presentation at an upcoming major scientific meeting. In the entire study population, aldoxorubicin achieved a statistically significant improvement in the disease control rate (DCR; defined as objective response rate (ORR) plus stable disease for at least 4 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 even 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). Of note, no objective responses were observed in patients treated with Votrient® (pazopanib). Patients continue to be followed for overall survival (OS), a secondary endpoint, and CytRx expects the OS data to be available in 2017. Pre-specified analyses were based on sarcoma histopathology and geography. The geographic analysis includes patients from North America (defined as the United States, Canada and Australia, per the trial statistical analysis plan). The 312 patients treated in North America comprise 72% of the total trial population, including 296 patients from the United States, 8 patients from Canada and 8 patients from Australia. The 246 patients with leiomyosarcoma or liposarcoma comprise 57% of the total trial population. 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 hypertension occurred in patients receiving Votrient® (pazopanib). 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. Importantly, 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. Treatment-related deaths occurred in one aldoxorubicin-treated patient and in no patients receiving investigators' choice drugs. Based on these results, CytRx expects to submit a New Drug Application (NDA) with the FDA for aldoxorubicin as a treatment for patients with relapsed or refractory STS in 2017. * On July 11, 2016, CytRx announced the results of an analysis of its global, randomized, Phase 3 clinical trial of aldoxorubicin compared to investigator's choice therapy in patients with relapsed or refractory soft tissue sarcomas (STS). In accordance with the FDA-granted special protocol assessment, the current analysis occurred following 191 progression events. Because enrollment was interrupted by a partial clinical hold in November 2014, this analysis did not provide for sufficient follow-up for the nearly two-thirds of patients who entered the Phase 3 study after the hold was resolved and enrollment resumed. This resulted in nearly half of all patients being censored (excluded) from the current progression free survival (PFS) evaluation. CytRx expects to conduct a second analysis, which will include longer patient follow-up and allow for greater maturation of all endpoints. The Company expects to announce the results of this evaluation and hold an end-of-Phase 3 meeting with the FDA in the fourth quarter of 2016. The partial clinical hold was related to a single patient enrolled in a compassionate use study, which was subsequently resolved successfully. For the current evaluation, the study did not show a significant difference between aldoxorubicin and investigator's choice therapy for PFS, with a median of 4.17 months and 4.04 months, respectively, for the study's primary endpoint (hazard ratio: 0.91). However, the most immediate indications of therapeutic activity, objective response rate (ORR) and disease control rate (ORR + stable disease ? 4 months), showed a near doubling in the aldoxorubicin arm compared to investigator's choice, including in patients who previously received treatment with doxorubicin. Disease control rate for aldoxorubicin was significantly greater than investigator's choice therapy in the intent-to-treat population (p=0.048) as well as in patients who received prior doxorubicin (p=0.0415). Patients continue to be followed for overall survival (OS), a secondary endpoint of the trial. Treatment-related adverse events for aldoxorubicin were consistent with those observed in prior studies. Aldoxorubicin was not associated with clinically significant cardiac, kidney or liver toxicities. The Company plans to present updated results of the study at an upcoming medical meeting.
