- Advaxis Inc. disclosed along with its fourth quarter results that a Phase 1/2 trial of its immunotherapy drug axalimogene filolisbac, also known as axal, in combination with AstraZeneca plc's Imfinzi has been placed on clinical hold by the Food and Drug Administration.
- The agency notified the company on March 9 after a patient in the study died due to respiratory failure. The death, considered a Grade 5 Serious Adverse Event, occurred on Feb. 27.
- The biotech's stock fell more than 15% in value Tuesday morning to trade below the company's 52-week low.
Enrollment and dosing have stopped in the trial of patients with advanced, recurrent or refractory human papillomavirus (HPV)-associated cervical cancer and HPV-associated head and neck cancer. Advaxis noted the hold does not affect any of its other clinical trials.
Management said on a call with investors the patient who died was a cervical cancer patient who had previously received 11 standard doses of axal and 21 doses of AstraZeneca's Imfinzi (durvalumab).
At the last treatment, the patient had been given Imfinzi before Advaxis' drug and developed a case of hypotension, which eventually required intensive care. The patient eventually progressed to respiratory failure.
Advaxis said it's working with AstraZeneca and the FDA "to review this event in detail and to resolve this clinical hold."
While the first part of the study has been completed, the extension phase has also been put on hold.
"It should be noted that over 250 patients have received axal and approximately 700 doses have been delivered across multiple trials in HPV-associated cancers to-date, and that this is the first time we have seen this type of event," said Advaxis interim CEO Tony Lombardo on the March 12 call.
AstraZeneca's Imfinzi (durvalumab) "has seen some other problems as well, but this is an atypical presentation for what they are used to seeing as well, added Advaxis CSO Robert Petit. "We are still trying to get to the bottom."
Jefferies analyst Biren Amin implied in a note to clients that the problem might actually be with Imfinzi, and not caused by axal.
"We reviewed the BLA for durva and noted 0.8% (11/1,414) death rate within 30 [days] due to respiratory failure in the safety database. This also corresponds [with] SAE reports of 1% respiratory failure in trials for durva, pembro, and avelumab that we reviewed, suggesting 1% incidence across most PD-1/L1s," he wrote. "In some cases, the SAEs were reported as cardiorespiratory arrest, which suggests cardiac etiology and would also align [with] hypotension as reported for the deceased patient in axal + durva study."
AstraZeneca said in a statement to BioPharma Dive the exact cause of death is still under investigation. "We remain confident in the safety profile of durvalumab and our clinical trial programmes with this medicine are ongoing," said a company spokesperson.
Axal is also under investigation in combination Bristol-Myers Squibb Co.'s PD-1 inhibitor Opdivo (nivolumab) as a treatment for recurrent metastatic cervical cancer who have failed at least one prior line of systemic chemotherapy. The trial is still expected to start before the end of 2018.
Advaxis did note it will not invest in any further development of programs for head and neck cancer or anal cancer, but that it is looking at "alternative funding" for those programs.