Background: The anti-PD-1 combination therapy significantly improves clinical outcomes in patients with relapsed/refractory classical Hodgkin lymphoma (cHL), and up to 71% of patients who receive decitabine-plus-anti-PD-1 camrelizumab could achieve a complete response. However, a subset of patients is recalcitrant to decitabine-plus-camrelizumab and half of patients might experience disease progression within three years. Effective treatment regimens for those with relapsed or progressive cHL who failed decitabine-plus-camrelizumab are needed. This Phase II study was designed to assess the safety and efficacy of the combination of decitabine-plus-camrelizumab and chidamide, a histone deacetylase inhibitor, in decitabine-plus-camrelizumab resistant cHL patients. Methods: Patients with relapsed/refractory cHL who had primary resistance or progressed/relapsed on decitabine-plus-camrelizumab were enrolled and administrated with chidamide at 10 mg (days 1 to 4) and 20 mg (days 8, 11,15 and 18); plus decitabine at 10 mg (days 1 to 5); and camrelizumab at 200 mg (day 6), every 3 weeks. Safety was assessed by CTCAEv5.0, and antitumor response by PET-CT according to the revised Lugano classification. The primary endpoint was objective response rate. Recruitment is ongoing. This trial is registered with ClinicalTrial.gov number, NCT04233294. Results: Between January 19, 2020, and January 31, 2021, nineteen patients with relapsed/refractory cHL after relapse or progression on decitabine-plus-camrelizumab were enrolled. A median of 20 cycles of prior decitabine-plus-camrelizumab was given (range, 4-28). Fourteen patients completed response evaluation with a median follow-up of 5.7 months. All eligible patients received this triplet-agent regimen with a median of 8 cycles (range, 3 to 12). Thirteen of the fourteen evaluated patients (93%) had an objective response, including six acquiring a complete remission (43%) and seven reaching a partial response (50%). The most common adverse events were leukocytopenia (58%; grade 3: 16%), nausea (53%) and hypertriglyceridemia (26%). No immune-related adverse events were observed. Conclusions: The preliminary result shows a high objective response rate with the combination of chidamide, decitabine and camrelizumab in patients with resistance to decitabine-plus-camrelizumab therapy. The addition of chidamide to decitabine-plus-camrelizumab has an acceptable safety profile, and does not trigger immune-related adverse events. Clinical trial information: NCT04233294