Feliciano Lopez's Swiss Open defence was ended with a shock defeat in the second round, while David Ferrer and Gilles Simon were among the seeds to tumble out of the German Tennis Championships.
Third seed Lopez was beaten 7-6 (7-5) 3-6 6-1 by world number 170 Yannick Hanfmann, the German competing in just his seventh ATP Tour match.
The Spaniard was unable to convert two break points that would have put him in position to serve out the first set and Hanfmann proved unforgiving in the decider, sending down five aces to take his total for the match to 13 and set up a quarter-final with Joao Sousa.
Fifth seed Paolo Lorenzi was unable to set up an all-Italian last-eight clash with Fabio Fognini, who rallied from a set down to beat Norbert Gombos, as he suffered a 7-6 (12-10) 3-6 6-4 defeat to Ernests Gulbis.
Ferrer went to the German Tennis Championships on the back of winning the Swedish Open but failed to make the most of a positive start against Federico Delbonis, the eighth-seeded Spaniard surrendering a 5-1 lead in the first set before being consigned to a 7-5 6-3 loss.
French duo Simon and Benoit Paire – seeded fourth and fifth respectively – were unable to advance to the quarter-finals. Simon provided moments of quality but was beaten 6-3 3-6 6-2 by Philipp Kohlschreiber, while Paire went down 6-4 7-6 (9-7) to Nicolas Kicker.
After a hard-fought 7-6 (7-4) 5-7 6-4 victory over Aljaz Bedene, Karen Khachanov is one of just two seeds remaining in Hamburg.