Officials say the crash happened just before 2 a.m. near the City Avenue exit.
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Philadelphia police responded to a report of a two-car crash with entrapments and injuries.
At the scene, police discovered one car had swerved across multiple lanes of traffic and hit a second vehicle. The first car spun and overturned before coming to a halt on the right shoulder of an off-ramp.
The second car was struck in the rear and propelled forward into a bridge pillar on I-76 west.
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The driver of the first car, identified as 31-year-old Victor Spizzirri, was transported to Temple University Hospital with moderate injuries.
Police say the four members of the second car died in the crash and were pronounced dead at the scene.
There is no word yet on their identities.
Spizzirri displayed signs of impairment, according to police, and was arrested for homicide by vehicle while driving under the influence and related charges.