If I remember right, route 15 above Frederick is a state bike route. From the looks of it when I've driven that way, it's not a pleasant ride - heavy traffic and no trees. Gmaps shows roads running parallel to 15 that are probably a good option (I think the Cannonball Century uses them). Maybe Old Frederick Rd. The farm country round there is fairly flat.
For Herndon to Frederick, you could cross at Whites' Ferry, Point of Rocks or Brunswick. My preference would be Point of Rocks (I don't know the way up from White's Ferry as well.)
W&OD to Leesburg to Clarkes Gap. Clarkes Gap Road to Waterford, then Loyalty, Taylorstown and Lovettsville Roads to the bridge at Point of Rocks. Also White's Ferry and C&O to Point of Rocks would work.
On the Maryland side, switch immediately to Ballenger Creek Pike at P.O.R. Takes you all the way to Frederick. Maybe someone else can suggest a way to get through Frederick, but Crestwood, New Design, Stadium, Market and Opposumtown Pike might work.