This was not an easy fix. Hats off to my mechanic.
157,000 miles mix of highway and local. Got the dreaded P0300 running down the interstate light throttle. Blinking CEL went out under load or coasting. For the CEL to be on & flashing, had to be steady / light throttle. My mechanic's scanner displayed random misfires on all cylinders, but more so from #s 1 & 6. All sensors checked out ok. Smoked the intake...no leaks. Cleaned the injectors, replaced the plugs, checked coil packs, grounds, & plug wires. Nothing was making sense, so he put in a reman ECM along with all the updates. Still got the P0300. With the help of his friend (who makes his living traveling to shops diagnosing), they found the timing chain had excessive slop. Super loose. The crankshaft turned 40 degrees before the chain started to turn the cam. Under steady/light throttle, the crank and cam were just rockin' & rollin' (floating) back and forth causing the code.
New timing chain fixed it. Runs as good as new now. I didn't realize the slow degradation of performance until the new chain went in.

Side note......... After the chain replacement, no more P0300, but then got a P0101 (MAF sensor) code. WTF ??. I replaced the MAF with a new Delphi one & still had P0101. No snorkel leaks. My mechanic put back in the original ECM and no more MAF P0101 code. I hate aftermarket parts. Give me genuine GM any day.

 

@ 40° I would recommend replacing the timing chain too. I just wouldn't have thought about checking for it. Nice find.

 

I am having the same problem for the last 8-9 months on my chevy 07 3500 express. the p0300 on constantly now, won't go away. CEL comes on giving it throttle up a hilll at 60 mph, but goes out on coasting down the other side of the hill. (i replaced all the same parts with oems, also smoked the intake... cleaned the injectors, and MAF. cleaned ecu ground. replaced the plugs, coil packs, grounds, & plug wires. new cam position sensor, and new crankshaft position sensor. ). you reported " the timing chain had excessive slop. ...The crankshaft turned 40 degrees before the chain started to turn the cam. Under steady/light throttle, the crank and cam were just rockin' & rollin' (floating) back and forth causing the code,,." this threat is really helpful to me :
how does a shop check for "excessive timing chain slop" ? is that the same as 'crankshaft whiplash ?" what's the cost and labor hours to replace the timing chain ? my mechanic has been told by GM HQ service to check for 'crankshaft whiplash which sounds like the "40 degrees out" that your van was showing. your help is really welcome-- this is a work van that subs as an EMT support van on weekends. it's been virtually unusable due to the p0300 s because i don't want to risk getting stuck with it 300 miles away from home.

 

The repair page says they used a lab scope to compare crank sensor and cam sensor variation to find the 40 degrees of slop. My cost was $2100 which included the timing set, oil pump, water pump, belt, oil & filter, antifreeze, diagnosis & labor. The oil pump, water pump, & belt had to come off for the timing chain, so they were replaced.
I know they spent many, many hours on diagnosing this, so it turned out to be a bargain for me.
Hope this helps

 

In the old days with distributors, we just popped the cap off and turned the crank. Now you have to pull a valve cover to observe the valve train movement while turning the crank back and forth.

 

Correct about the old days. Things were much simpler. Now, if you have access to a scope, you can let the sensors do the work & you don't have to pull a valve cover.
Without a scope though, you're putting a degree wheel on the crank (if you want to know the exact amount of slop) & pulling a valve cover.