Drug manufacturer XBiotech has cancelled the phase III XCITE study of MABp1 (Hutruo; formerly Xilonix) in patients with advanced colorectal cancer, following a second prospectively planned, unblinded analysis.
The company released a statement June 12 announcing the decision. XBiotech said its independent data monitoring committee determined that data were not sufficient to meet efficacy or the threshold for continuation, which involved a prospectively defined acceptance boundary for the interim analysis of less than or equal toP= .08.
The committee did not have safety concerns about MABp1, a novel monoclonal antibody that specifically targets antiinterleukin 1-alpha (IL-1α). IL-1α is a potent inflammatory mediator of chronic inflammation that is secreted by cells in response to infection or injury and also by many types of tumors.
“We are obviously disappointed with these findings,” said John Simard, XBiotech president and CEO. “In the coming weeks, the company plans to analyze the data extensively to further understand the primary and secondary endpoint data, as well as to identify populations that may have benefited from the therapy.”
Results from XCITE were presented at the 2016 World Congress of Gastrointestinal Cancer.1However, there were questions surrounding those results even at the time. Dirk Arnold, MD, Instituto CUF de Oncologia in Lisbon, said the findings were unreliable due to the study’s methodology. Furthermore, he said that the benefit associated with MABp1 was unclear and that potential clinical consequences could not yet be determined.
"The jury is still out on whether the study made sense but as the results do not bear close inspection, they also cannot be relied upon," Arnold said. "It’s not yet clear whether there is any benefit in translating this trial into practice."
The trial was designed to evaluate MABp1 in patients with mCRC who were refractory to prior standard oxaliplatin and irinotecan chemotherapy. The primary endpoints were symptom control-based objective response (OR; primary endpoint), new criteria, and IL-1α blockade. Eligible patients were required to exhibit functional impairment or display multiple symptoms known to be associated with poorer outcomes, including pain, fatigue, ECOG performance status of 1 or 2, weight loss, and/or elevated systemic inflammation.
Patients were not allowed to use treatments during the trial that could affect outcome, including chemotherapy or steroids.
There were 207 patients assigned to MABp1 and 102 patients to placebo. All patients received best supportive care (BSC). Disease control status was objectively described by lean body mass evaluation using dual-energy X-ray absorptiometry and the EORTC-Quality of Life Questionnaire 30 (QLQC30)
Investigators said measures of improved health status correlated with improvement in nearly all self-reported and laboratory-based measures of health, such as reduced systemic inflammation. Patients receiving MABp1 showed improved symptom control (secondary endpoint). Additionally, MABp1-treated patients showed better control of paraneoplastic thrombocytosis (P= .003) and reduced IL-6 mediated systemic inflammation compared with placebo (P= .004).
As assessed by the newly developed criteria of symptom control-based OR, the response to treatment with MABp1 was 33% versus 19% with placebo (P= .0045). This improvement in response should correlate with improved overall survival (OS), but the study was not designed to directly compare OS between the 2 arms. Furthermore, all patients in the placebo arm crossed over to receive MABp1 after 8 weeks, confounding the survival results.
Incidence of adverse events (AEs) was similar in each arm, with the most common AEs being abdominal pain, peripheral edema, fatigue, anemia, constipation, decrease in weight, asthenia, decreased appetite, and nausea. Responses to MABp1 were associated with improvements in lean body mass, fatigue, and pain, which may be in line with the mechanism of action, investigators said.
XBiotech said it is continuing with other studies exploring MABp1, including a phase III study European study presented at this year’s ASCO Annual Meeting.2
In that trial, 309 patients were assigned to MABp1 or placebo in a 2:1 ratio. The composite primary endpoint assessed the rate of patients achieving stabilization or improvement in lean body mass and 2 of 3 symptom measures (pain, fatigue, appetite loss) from screening to assessment at 8 weeks. Nearly two-thirds (62%) of patients assigned to placebo crossed-over at 8 weeks, thus making a comparison for OS between the 2 study groups impossible.
Patients who completed 8 weeks of therapy were considered on protocol and included in this analysis (82%). Almost twice as many on protocol patients assigned to MABp1 achieved the primary endpoint compared with placebo (40% vs 23%; relative risk, 1.76; 95% CI, 1.14-2.72; one-tailedP= .003). Thirty-eight patients in the MABp1 group and 19 patients in the placebo group discontinued prior to 8 weeks because of disease progression, including 17 and 11 deaths, respectively.
Median survival was 11.7 months for patients who reached the primary endpoint versus 5.7 months for those who did not (HR, 0.39;P<.0001).