Charlie Hodgson makes his first start of the season as table-topping Saracens host Newcastle in the Aviva Premiership.
The stand-off has recovered from an Achilles injury to be fit to cover for England No 10 Owen Farrell, and will be partnered at half-back by Neil de Kock.
Elsewhere, centre Marcelo Bosch is handed a full debut while England internationals Alex Goode and David Strettle also feature.
Up-front, there are starts for Jamie George, Mouritz Botha, Jackson Wray and Will Fraser.
The Falcons show four changes to the side that starting in a narrow victory over London Irish last time out.
Captain Will Welch returns to the line-up, while prop Kieran Brookes replaces Oliver Tomaszczyk and there are also opportunities for fly-half Phil Godman and ex-Saracens wing Noah Cato.
London Irish v Northampton
New signing James O'Connor goes straight into the Irish line-up following his arrival from Australia earlier this week.
O'Connor features at full-back in a team captained by scrum-half Tomas O'Leary in the absence of lock George Skivington.
O'Leary will be partnered at half-back by Ian Humphreys and there is another opportunity for Wales international Ian Gough, who packs down at lock alongside Bryn Evans.
Saints head to the Madejski Stadium without England men Lee Dickson, Dylan Hartley, Courtney Lawes, Tom Wood and Ben Foden.
Rugby director Jim Mallinder has made two changes following last Saturday's destruction of Saracens, with full-back James Wilson replacing Foden and wing Tom Collins taking over from an injured Jamie Elliott.