Daniel Levitt, Cytrx Corp.'s chief medical officer, told BioWorld Today that a two-month clinical hold placed on the trial in late 2014 apparently skewed the much-awaited data from Cytrx's phase III experiment comparing aldoxorubicin to investigator's-choice therapy in patients with relapsed or refractory soft tissue sarcomas (STS), and the results available so far show a miss on the primary endpoint of progression-free survival (PFS).

The hold "required a small change to the protocol and led to a substantial delay in the getting the study reapproved at the various ethics committees, institutional review boards, on study sites and in the [countries'] regulatory groups," Levitt said. "Even after we were taken off hold, which was within two months, [delays] ranged anywhere from one month up to six months. At the time of data cutoff, which was in March of this year, there is a lot of censoring that went on. We had, really, at that point about 200 patients who were still being censored."

Shares (NASDAQ:CYTR) were trading after-hours at 90 cents, down $1.61, or 64 percent.

Conducted under a special protocol assessment, the trial's analysis took place after 191 progression events. The clinical hold meant the analysis didn't have enough follow-up for almost two-thirds of patients who entered the study after the hold was resolved and enrollment started again. Almost half of all patients were excluded – censored – from the current PFS measure. Specifically, the results in hand show a median of 4.17 months and 4.04 months, respectively, for the pair (hazard ratio: 0.91). The Los Angeles-based company said it would do another PFS breakdown that will include longer patient follow-up and thus allow for all endpoints to mature.

On the plus side, objective response rate (ORR) and disease control rate (ORR plus stable disease ≥ 4 months), showed a near doubling in the aldoxorubicin arm compared to investigator's choice, including in patients previously treated 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, a secondary endpoint of the trial.

Treatment-related adverse events for aldoxorubicin were consistent with those observed in prior studies, Cytrx said, and the drug 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.

"We'll have [the new data package] analyzed in the fourth quarter," Levitt said. "We'll have a later date of cutoff, which will affect the censoring, and we are allowed to re-analyze the data, since all patients have been enrolled and placed on their specific treatment. We plan to meet in the fourth quarter with the FDA for an end-of-phase III meeting after we get the updated analysis, and discuss with them what they see for us going forward."

Only the FDA can decide "whether we have enough to submit to the agency for whatever indication they're willing to discuss with us, or whether we need to do any more work," he said. "Right now I can't answer that question. It would just be speculative."

In the study, aldoxorubicin went up against comparators that included ifosfamide and gemcitabine (additionally to dacarbazine, Votrient [pazopanib Glaxosmithkline plc (GSK)], and doxorubicin). The study completed enrollment of 433 patients last December, about a quarter ahead of schedule. Cytrx had said that, if the data warranted, a rolling NDA would start by the end of the year, with a launch possible in the second half of 2017. "All eyes are on pivotal phase III top-line results for aldoxorubicin in second-line STS in upcoming weeks," Jefferies analyst Chris Howerton wrote in a June 7 research report. If approved in second-line STS, aldoxorubicin will face competition from quarters beyond GSK's Votrient, approved in the U.S. and Europe in 2012 for the treatment of advanced STSs following prior chemotherapy.

Aldoxorubicin combines doxorubicin with a novel single-molecule linker that binds directly and specifically to circulating albumin. Since tumors concentrate albumin, delivery of the linker molecule with the attached doxorubicin is greater to the cancer site and – in the acidic environment of the tumor, but not the neutral environment of healthy tissues – doxorubicin is released as much greater possible doses with less toxicity.

"My interpretation is that this is an active drug," Levitt said, in patients previously treated with doxorubicin and those not. "Even based on the early analysis, looked to be as or more active, depending upon the specific endpoint that you're looking at, as any treatment being used for STS. Plus, the investigators on the control arm were allowed to tailor the type of treatment they were giving their patients to the specific sarcoma type, whereas we basically treated all comers."