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])."

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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.

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.

On September 21, 2015 BioInvent International (OMXS: BINV) reported that the company and its partner, the University of Pennsylvania, have decided to expand their planned clinical Phase II study with the antibody BI-505 by, among other things, including a control group (Press release, BioInvent, SEP 21, 2015, View Source [SID:1234507507]). This will increase the study data quality and accelerate the path for approval of a potential new drug for multiple myeloma.

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"The interest that leading researchers and clinicians at the University of Pennsylvania are showing in this potentially groundbreaking treatment for multiple myeloma makes it possible to conduct the planned study in a time and cost efficient way. The increased patient numbers will not significantly impact the schedule nor BioInvent’s costs for the study," says Michael Oredsson, President and CEO of BioInvent.

As a result of more effective treatments being available, the multiple myeloma survival rate has increased significantly over the past 20 years. However, neither existing nor new drugs in clinical development are expected to be able to eliminate all myeloma cells, and residual cells lead to relapse in the vast majority of patients with the disease. Data from preclinical studies indicate that the mechanism-of-action of BioInvent’s antibody BI-505, to engage the immune system to seek up and attack stressed cancer cells, has the potential to significantly improve responses and prevent or delay relapse. The positive safety profile of BI-505, which has been documented in an earlier clinical trial, is an important factor in making BI-505 well-suited for patients who are undergoing autologous stem cell transplant (ASCT).

The Phase II controlled study will include patients undergoing ASCT and chemotherapy with high-dose melphalan (HDM). The number of patients receiving supplementary treatment with BI-505 will be increased to 45 patients, up from the previously announced 30. In addition, a control group of a total of 45 patients will be added to the study. These patients will receive the standard of care treatment. Altogether the number of patients in the study is being tripled compared to the previously communicated plan. The greater patient numbers will allow for a more accurate evaluation of the effect of supplementary therapy with BioInvent’s antibody. The study will begin with a safety evaluation of five patients, which is in keeping with the original plan, and will also include an interim analysis.

The clinical effect of BI-505 will be evaluated 100 days after transplantation and after one year. All patients will also be monitored for up to five years to evaluate progression-free survival.

Despite the more ambitious plan, it will be possible to initiate the study in accordance with the previously communicated schedule.

"We are enthusiastic about the potential for BI-505 to prevent or delay relapse of multiple myeloma. This new and more ambitious study design will generate robust clinical data, facilitating the future development of a new approach in myeloma for our patients.," says Brendan Weiss, MD and Assistant Professor of Medicine at the University of Pennsylvania.

To the editors:

About BI-505 and multiple myeloma
In the western world, an average of 5.6 new cases of multiple myeloma per 100,000 people are registered every year, which is equivalent to around 60,000 new cases a year. Multiple myeloma is an incurable cancer for which there are no good drugs to prevent the relapses that affect all patients after treatment with cytotoxic drugs or after a stem cell transplant. Expression of the adhesion protein ICAM-1 (also called CD54), is elevated in myeloma cells, which makes it a suitable target for a drug candidate. The BI-505 drug candidate is a human antibody that specifically binds to ICAM-1. BI-505 affects tumours in two ways – by inducing cell death of myeloma cells and by engaging the patient’s immune cells, known as macrophages, to attack myeloma cells. Macrophages are abundant in the bone marrow of myeloma patients, where they are thought to contribute to disease progression and development of resistance to currently available drugs. BI-505 has the ability to get macrophages to attack myeloma cells and has, in several relevant animal models, proved to be more effective at killing tumours than existing drugs. The good safety profile and the effectiveness of the substance against cancer cells that do not bind to tumours, even where these are expressed in low quantities, makes BI-505 especially suitable in preventing multiple myeloma relapses.

On September 19, 2015 Genmab A/S (OMX: GEN) reported that the U.S. Food and Drug Administration (FDA) has granted Priority Review to the supplemental Biologics License Application (sBLA) for ofatumumab (Arzerra) as maintenance therapy of patients with relapsed chronic lymphocytic leukemia (CLL) (Press release, Genmab, SEP 19, 2015, View Source [SID:1234507503]).

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The application was submitted to the FDA by Novartis under our ofatumumab collaboration in July 2015.

Priority Review is an FDA designation for drugs that treat a serious condition and may provide a significant improvement in safety or efficacy. The FDA aims to complete its review of the ofatumumab sBLA within the time set by the Prescription Drug User Fee Act (PDUFA) and has given a target date for completion of their review of January 21, 2016.

"We are very pleased that the FDA has granted Priority Review for ofatumumab, which means ofatumumab could potentially be available as a maintenance therapy for patients suffering from relapsed CLL relatively soon," said Jan van de Winkel, Ph.D., Chief Executive Officer of Genmab. "We look forward to receiving FDA’s feedback on the application."

The application is based on interim results from a Phase III study, PROLONG (OMB112517) which evaluated ofatumumab maintenance therapy versus no further treatment in patients with a complete or partial response after second or third line treatment for CLL. Results from this trial were presented at the 2014 American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting.

About CLL
CLL, the most commonly diagnosed adult leukemia in Western countries, accounts for approximately 1 in 4 cases of leukemia1,2. Most CLL patients experience disease progression despite initial response to therapy and may require additional treatment3.

About Ofatumumab (Arzerra)
Ofatumumab is a human monoclonal antibody that is designed to target the CD20 molecule found on the surface of chronic lymphocytic leukemia (CLL) cells and normal B lymphocytes.

In the United States, Arzerra is approved for use in combination with chlorambucil for the treatment of previously untreated patients with CLL for whom fludarabine-based therapy is considered inappropriate. In the European Union, Arzerra is approved for use in combination with chlorambucil or bendamustine for the treatment of patients with CLL who have not received prior therapy and who are not eligible for fludarabine-based therapy. In more than 50 countries worldwide, Arzerra is also indicated as monotherapy for the treatment of patients with CLL who are refractory after prior treatment with fludarabine and alemtuzumab.
Arzerra is not approved anywhere in the world as maintenance therapy for relapsed chronic lymphocytic leukemia.
Please see full Prescribing Information, including Boxed WARNING for Arzerra (ofatumumab).

Arzerra is marketed under a collaboration agreement between Genmab and Novartis.