CytRx Corporation, a biopharmaceutical research and development company specializing in oncology, announced positive updated results from its ongoing phase 2 clinical trial with aldoxorubicin for the treatment of unresectable glioblastoma multiforme (GBM), a deadly form of brain cancer.  The open-label, multisite trial is designed to investigate the preliminary efficacy and safety of aldoxorubicin in patients whose tumours have progressed following prior treatment with surgery, radiation and temozolomide.

Study subjects (n=18) have received between 1 and 14 cycles of aldoxorubicin, with 4 subjects continuing to receive aldoxorubicin treatment.  Subjects received either 350 mg/m2 (260 mg/m2 doxorubicin equivalent) (n=6) or 250 mg/m2 (185 mg/m2 doxorubicin equivalent) (n=12) of aldoxorubicin intravenously on Day 1, and every 21 days thereafter until discontinuation.  Notably, 2 subjects (11%) diagnosed with tumour progression following aldoxorubicin treatment (1 and 5 cycles, respectively) demonstrated no microscopic evidence of tumour tissue, a pathological complete response, when tissue was examined after resection.  Fourteen of 18 subjects discontinued aldoxorubicin treatment, although there is a significant possibility that some of the patients experienced pseudo-progression.  Pseudo-progression refers to post-treatment imaging changes in the tumour where the tumour appears larger compared to the pre-treatment baseline images.  These changes can be misleading in that the tumour appears to get worse (true progression), when in fact the changes may be the result of tumour destruction and related swelling around the tumour bed. Following discontinuation of aldoxorubicin treatment, 10 of 14 subjects received treatment with bevacizumab (Avastin) for 1 to 14 cycles.  Deaths have occurred in only 4 of 18 subjects (22%) to date, with survival duration so far of up to 10 plus months.

Aldoxorubicin was well tolerated at both dose levels with all adverse events consistent with known doxorubicin toxicities, but not cardiotoxity.  Grade 3 or 4 adverse events were comprised primarily of neutropenia, anaemia and fatigue and occurred mainly in the 350 mg/m2 dose group and were resolved before the next dose.  Only two aldoxorubicin-related serious adverse events have occurred in the trial, and both resolved successfully.

"GBM is the most common and aggressive malignant primary brain cancer in humans and carries an extremely poor prognosis for the vast majority of diagnosed patients. Prognosis at recurrence is especially poor," said Morris D. Groves, M.D., Neuro-Oncologist, Texas Oncology-Austin Brain Tumour Center and co-principal investigator of the trial.  "Pseudo-progression is commonly seen in CNS malignancies undergoing radiation therapy, and it mimics tumour progression, but it is thought to be a treatment-related reaction that could represent an active, inflammatory response against the tumour.  The findings from this trial are early but exciting; the finding of no tumour cells in the resected GBM tumour samples after treatment with aldoxorubicin is worth further investigation. This suggests, somewhat paradoxically, that by binding to albumin, aldoxorubicin may allow doxorubicin to cross the blood: brain barrier and into the malignancy."

"These results suggest the possibility that the administration of Avastin after treatment with aldoxorubicin could prolong survival in patients with relapsed GBM, and patient follow up is currently ongoing," said Daniel Levitt, M.D., Ph.D., CytRx executive vice president and chief medical officer.  "At the upcoming 2015 American Society of Clinical Oncology (ASCO) Annual Meeting, we will be convening with the study investigators to discuss the potential for a pivotal trial evaluating aldoxorubicin in combination with Avastin for the treatment of relapsed GBM, with survival as the primary endpoint.  We also look forward to submitting the results from this ongoing phase 2 clinical trial for presentation at a neuro-oncology-focused medical meeting in 2015."

The primary objective of this phase 2 trial is to determine progression-free survival (PFS) at 6 months and overall survival (OS) in patients with recurrent glioblastoma multiforme.  The principal secondary objective is to evaluate the safety of aldoxorubicin in study patients as assessed by the frequency and severity of adverse events.  Only patients who have not received prior treatment with bevacizumab (Avastin) are eligible to participate in the trial.  The clinical trial is expected to enroll up to 28 patients randomly assigned equally to receive either 350 mg/m2 (260 mg/m2 doxorubicin equivalent) or 250 mg/m2 (185 mg/m2 doxorubicin equivalent) of aldoxorubicin intravenously on Day 1, and every 21 days thereafter until evidence of tumour progression, unacceptable toxicity or withdrawal of consent.  Tumour response is monitored every 6 weeks by MRI until disease progression occurs.  The trial is being conducted at the John Wayne Cancer Center/Sarcoma Oncology Center in Santa Monica, CA, City of Hope in Duarte, CA, the Louisiana State University Health Sciences Center in New Orleans, LA, and Texas Oncology in Austin, TX.

This Phase 2 study follows positive confirmatory results reported in 2013 from a preclinical study in which aldoxorubicin demonstrated statistically significant efficacy (p<.0001) in the treatment of rapidly growing human brain (glioblastoma) cancer in the brains of animals.  In that study, animals treated with aldoxorubicin had median survival of more than 63 days, compared with approximately 25 days for animals treated with doxorubicin or saline.  In addition, because aldoxorubicin uptake was confined to the tumour in the brain rather than normal brain tissue, the principal investigator concluded that aldoxorubicin has the potential to safely shrink glioblastoma tumours, which could dramatically prolong patient survival.

Glioblastoma is the most common and most malignant primary brain tumor in adults and afflicts more than 12,000 new patients in the US annually.  The median survival after diagnosis is approximately 14 months, despite patients subsequently receiving surgical resection, radiotherapy and chemotherapy.  Limited efficacy of chemotherapeutic agents has been attributed to several contributing factors including insufficient drug delivery to the tumour site through the blood: brain barrier.

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 tumours concentrate albumin, thus increasing the delivery of the linker molecule with the attached doxorubicin to tumour sites. In the acidic environment of the tumour, 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.