FDA hits Advaxis with clinical hold after death in AstraZeneca combination trial

The events leave Advaxis facing the conundrum of why a patient who had previously tolerated both drugs died of respiratory failure. (FDA)

The FDA has placed a clinical hold on a study of Advaxis’ axalimogene filolisbac and AstraZeneca’s PD-L1 checkpoint inhibitor Imfinzi. Regulatory officials took the action upon learning a cervical cancer patient developed respiratory failure and died after receiving the combination.

Enrollment and dosing in the trial are now on hold while Advaxis, AstraZeneca and the investigator figure out what happened in the phase 1/2 trial of patients with HPV-associated cancers. 

The patient who died had advanced refractory metastatic cervical cancer that progressed following treatment with other therapies. After entering the trial about one year ago, the patient received six combination cycles—11 doses of listeria-based cancer vaccine axalimogene filolisbac and 21 hits of Imfinzi. The first five cycles passed without incident. That changed with the most recent round of treatment.


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Medical problems began following the first dose of Imfinzi but were managed, Advaxis CSO Robert Petit said on a call with investors. The patient then received an administration of axalimogene filolisbac. The situation escalated from there. 

After receiving treatment for hypotension, the patient was hospitalized and thereafter developed respiratory failure. Efforts to stop the worsening of the patient’s condition fell short and she died.

The events leave Advaxis facing the conundrum of why a patient who had previously tolerated both drugs died of respiratory failure. Prior studies suggest Imfinzi may be the culprit. One patient had died of respiratory failure in AstraZeneca’s phase 3 trial of Imfinzi in lung cancer at the time it reported data in September, and analysts at Jefferies uncovered other incidents linked to the drug and checkpoint inhibitors in general.

"We reviewed the BLA for [Imfinzi] and noted 0.8% 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 [Imfinzi], [Keytruda] and [Bavencio] that we reviewed, suggesting 1% incidence across most PD-1/L1s. 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 Advaxis' trial]," the analysts wrote.

The full implications of the death for Advaxis will only become clear following the investigation. For now, the clinical hold has halted enrollment in the phase 1/2 trial at about 25 participants. Other trials of Advaxis’ candidate are progressing as normal. 

Shares in Advaxis fell 23% in after-hours trading.

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