On September 21, 2015 CytRx Corporation (Nasdaq: CYTR), a biopharmaceutical research and development company specializing in oncology, reported that JAMA Oncology, the prestigious peer-reviewed Journal of the American Medical Association (JAMA), has published a paper on September 17, 2015 entitled "First-Line Aldoxorubicin vs Doxorubicin in Metastatic or Locally Advanced Unresectable Soft-Tissue Sarcoma: A Phase 2b Randomized Clinical Trial (Press release, CytRx, SEP 21, 2015, View Source [SID:1234507508])." Schedule your 30 min Free 1stOncology Demo! This paper discusses the design, methodology and results from CytRx’s completed multicenter, randomized, open-label global Phase 2b clinical trial investigating the efficacy and safety of aldoxorubicin compared with doxorubicin as first-line therapy in patients with metastatic or locally advanced unresectable soft tissue sarcomas (STS). It concludes that aldoxorubicin is the first single-agent therapy that has shown significantly superior efficacy over doxorubicin in the primary and secondary endpoints of progression-free survival and overall tumor response rate. Additionally, patients treated with aldoxorubicin exhibited manageable adverse effects, had no unexpected events, and did not exhibit evidence of acute cardiotoxicity.
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The full publication can be accessed online here.
"The publication of our global Phase 2b clinical trial results in JAMA Oncology underscores the significance of aldoxorubicin as a potential new therapy for STS as we make progress on our global, pivotal Phase 3 clinical trial for this indication," said Steven A. Kriegsman, CytRx’s Chairman and CEO. "The fact that aldoxorubicin is the first single chemotherapy to demonstrate statistically significant improvement in progression-free survival, progression-free survival at 6 months and tumor response underscores our confidence in the potential of this drug to benefit patients with advanced STS. We are confident that the publication of these results in a major, peer-reviewed journal will increase aldoxorubicin’s awareness in the STS community."
About the Aldoxorubicin Phase 2b Trial Design
In this international, open-label, 123-patient, 31-center Phase 2b trial, patients with advanced soft tissue sarcomas were randomized 2:1 to receive either 350 mg/m2 of aldoxorubicin (83 patients) or 75 mg/m2 of doxorubicin (40 patients) every 3 weeks for up to 6 cycles. Patients were then followed every 6 weeks with CT scans to monitor tumor size. Two approaches were used to evaluate efficacy of aldoxorubicin: assessment by the study investigators, as well as assessment by a blinded central laboratory review. The primary endpoint was progression-free survival (PFS) and secondary endpoints include PFS at 6 months for each group, overall response (complete and partial) rate (ORR) and overall survival (OS). A 2:1 randomization scheme was chosen to extend safety information for aldoxorubicin; because doxorubicin has well-documented safety and efficacy data, the doxorubicin arm served to demonstrate patient responses to the drug similar to those evaluated in other studies.
Summarization of Trial Results
An analysis of the trial data revealed the following results, as previously reported:
Primary endpoint results, as determined by both the trial investigators and by blinded central radiology review, found that subjects treated with aldoxorubicin demonstrated highly statistically significantly better clinical outcomes than subjects that received standard doxorubicin therapy for their soft tissue sarcomas. In scans read by trial investigators, PFS results demonstrated that treatment with aldoxorubicin increased median PFS approximately 80% to 8.3 months, compared to 4.6 months with doxorubicin, meeting the study’s primary endpoint (HR=0.419; p=0.0007). In the blinded central radiology review, PFS results demonstrated that treatment with aldoxorubicin increased median PFS approximately 107% to 5.6 months, compared to 2.7 months with doxorubicin, also meeting the study’s primary endpoint (HR=0.60; p=0.0228).
Progression-free survival at 6 months effectively doubled for those receiving aldoxorubicin compared to doxorubicin. By blinded central radiology review, the PFS at 6 months was 45.7% for aldoxorubicin-treated patients compared to 22.9% for those receiving doxorubicin. As evaluated by investigators, PFS at 6 months was 68% and 33% for patients receiving aldoxorubicin or doxorubicin respectively.
Overall survival (OS) was assessed as a prospectively planned secondary endpoint although the trial was not powered to show a statistically significant outcome. Aldoxorubicin-treated patients demonstrated a 27 percent reduction in the risk of death compared to patients treated with doxorubicin (HR 0.73: 95% confidence interval 0.44-1.20), the current standard-of-care in this indication. In addition, aldoxorubicin-treated patients demonstrated a 41% likelihood of surviving more than 2 years, a 2-fold increase, compared to a 20% probability for doxorubicin-treated patients. Median OS was 15.8 months (95% CI, 13.1-NR) for aldoxorubicin-treated patients versus 14.3 months (95% CI, 8.6-20.6) for doxorubicin treated patients (p=0.21). For treatment-naïve patients, representing 90% of the patients in the clinical trial, median OS was 16.0 months (95% CI, 13.1-NR) for aldoxorubicin-treated patients versus 14.0 months (95% confidence interval 8.7-20.1) for doxorubicin treated patients (p=0.14).
ORR as determined by the investigators was 23% for aldoxorubicin subjects (2% complete response) versus 5.0% for doxorubicin subjects (0% complete response). As assessed by blinded central lab review, 25% of aldoxorubicin subjects had a partial response while 0.0% of doxorubicin subjects exhibited any objective response. In addition, a higher percentage of aldoxorubicin-treated subjects demonstrated tumor shrinkage compared to patients treated with doxorubicin, regardless of whether the scans were evaluated by investigators (66% vs. 44%) or by blinded reviewers (63% vs. 41%).
Adverse events were of a type consistent with known doxorubicin toxicities. The majority of adverse events resolved prior to the following cycle with no treatment discontinuation. Aldoxorubicin-treated subjects did experience a higher percentage of Grade 3 or 4 treatment emergent adverse events (TEAEs) of neutropenia (29% vs. 12%).
No clinically significant cardiotoxicity was seen with aldoxorubicin while approximately 10% of doxorubicin patients had clinically significant cardiotoxicity. Most importantly, there was no clinically significant reduction in cardiac function in the aldoxorubicin patients despite receiving doses up to 4 times the standard dose of doxorubicin.
About Soft Tissue Sarcoma
Soft tissue sarcoma is a cancer occurring in muscle, fat, blood vessels, tendons, fibrous tissues and connective tissue, and 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 were diagnosed in the U.S. and approximately 4,400 Americans died from this disease. In addition, approximately 40,000 new cases and 13,000 deaths in the U.S. and Europe are part of a growing underserved market.
About Aldoxorubicin
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.