AXAL Immunotherapy Well-Tolerated in Recurrent Metastatic Cervical Cancer

Axalimogene filolisbac (ADXS11-001 or AXAL), a live attenuated bioengineered bacteria-vectored vaccine immunotherapy, is well tolerated and appears to be associated with promising overall survival among women with persistent/recurrent metastatic cervical cancer (PRmCC), despite poor response rates, according to results from a single-arm, phase II clinical trial presented at the 2016 American Society of Clinical Oncology (ASCO) Annual Meeting, held June 3–7 in Chicago (abstract 5516).

The study (NCT 01266460) was halted temporarily by the US Food and Drug Administration (FDA) when a study participant’s blood tested positive for the bioengineered live attenuated Listeria monocytogenes that serves as the AXAL immunotherapy vector, 3 years after treatment (read more on next page).

“In patients with PRmCC and progression following ≥ 1 prior lines of systemic therapy, ADXS11-001 is well tolerated and demonstrates a 38.5% rate of 12-month survival,” lead study author Warner King Huh, MD, of the University of Alabama, Birmingham, and coauthors reported in a poster presentation.

The findings “suggest consistent survival benefit in a heavily bevacizumab-pretreated population, particularly among those patients receiving three or more doses of immunotherapy,” they wrote.

Patients treated with first-line platinum-based doublet chemotherapy and bevacizumab can survive up to 17 months but there are limited treatment options after first-line therapies fail and these patients face a median overall survival of only 7.3 months.

AXAL immunotherapy employs a live attenuated L. monocytogenes “bioengineered to secrete a HPV-16 E7 protein fused with a truncated fragment of listeriolysin O,” the study authors reported. The therapy “targets HPV-transformed cells, inducing antitumor T-cell immunity and breaking immune tolerance within the tumor microenvironment.”

In Stage 1 of the study, 26 patients enrolled between January 2012 and May 2014 received up to three doses of 1 × 10⁹ colony forming units administered every 28 days. Eighteen patients received the maximum of three doses.

The 12-month survival rate of 38.5% in Stage 1 of the trial exceeds prior historical trial results with this patient population, according to the authors. Among patients who received three per-protocol doses, 12-month survival was 55.6% with a 12.1-month median overall survival rate.

Adverse events (all grades, 1–4) affecting at least four patients (15%) in Stage 1 included: chills, fatigue, fever, nausea, headache, hypotension, vomiting, cytokine release syndrome, myalgia, abdominal pain, and general pain.

Objective responses in Stage 1 of the study included no complete or partial responses, and 7 patients with stable disease (27%); 10 patients experienced disease progression (38%). Six patients (23%) received no evaluation.

Stage 2 was therefore amended to allow continuous cycles of AXAL beyond three doses. For Stage 2 of the trial, 24 patients were enrolled.

One 66-year-old woman who received three doses of AXAL in Stage 2 experienced a durable complete response, the authors noted.

FDA Temporarily Halts Trial

The trial was temporarily halted by the FDA on October 1, 2015 for a safety amendment review, after a study participant’s blood tested positive for Listeria 3 years after participating in the trial.

The patient “had a dramatic response and lived for 3 years-and remember, most of these patients have died within a year,” study coauthor Bradley J. Monk, MD, FACS, told Cancer Network. Dr. Monk is also the lead cervical cancer advisor for Advaxis Inc, the company producing AXAL.

The woman had a low-grade fever but was not septic and did not have listeriosis, Dr. Monk said. The hospital conducted a routine blood culture, which yielded Listeria. A sample was sent to the Centers for Disease Control and Prevention in Atlanta for genotyping, and scientists there confirmed that it was the attenuated ADXS11-001 strain she had been administered as a study participant.

“It was concerning enough to the FDA that the FDA said, Let’s halt the program, let’s investigate,” said Dr. Monk. “So they investigated.”

The FDA discovered that the patient had been in a serious car accident at the time she was receiving treatment on trial. Her injuries had required an orthopedic implant and bone graft.

“So the theory was-is, today-that that was probably a biofilm-sort of situation, where that foreign body had been colonized,” said Dr. Monk.

The trial protocol was therefore amended with an eligibility restriction that excludes patients with “foreign objects” like prosthetic implants, a requirement to extend antibiotic prophylaxis until completion of study treatment, and more surveillance cultures.

As a result of the clinical hold, 10 study participants who had not experienced disease progression had to discontinue AXAL treatment.

The FDA’s hold was lifted in December 2015, but because so many Stage 2 patients had discontinued AXAL treatment during the FDA’s clinical hold, the sponsors decided to re-enroll a new cohort of patients. A new enrollment effort will begin this summer.

The study was sponsored by Advaxis Inc and the Gynecologic Oncology Group, which is now part of NRG Oncology.