Background: The ketamine is used to control refractory cancer pain as adjuvant to opioids. However, usefulness of ketamine has not yet been confirmed due to lack of previous studies. Additionally, most of prior studies were studied in heterogenous patients, and continuous intravenous infusion (CIVI) method was rare. The CIVI method using gradual dose titrations of ketamine is safe. So, it is suitable to terminally ill cancer patients who have available IV access but vulnerable to AEs. This phase II single-arm study investigated efficacy and safety of CIVI of Ketamine in these population. Methods: Cancer patients with expected limited survival time within several months and refractory cancer pain were enrolled. Refractory cancer pain indicates requirements of breakthrough analgesics ≥ 4 times/day or average pain score > personalized pain goal (PPG) in spite of intravenous Morphine Equivalent Daily Dose (MEDD) > 120 mg/day. The CIVI of ketamine was increased from 0.05 mg/kg/hr to 0.5 mg/kg/hr by 0.05 mg/kg/hr every 8hr when average pain score exceeded PPG or breakthrough was needed ≥ 2 times/8hr during 5 days. The primary end-point was overall pain response rate, which indicates complete response (both breakthrough ≤ 3/day and NRS ≤ PPG) plus partial response (breakthrough ≤ 3/day), without unacceptable toxicities. A total of 26 patients are needed to verify assumption of response rate of 40% with width of 0.4 for two-sided 95% CI and assuming 5% drop-out rate. This study was prematurely terminated at enrollment of 21 patients. Results: Among 21 enrolled patients between SEP 2019 and JAN 2023, 20 were analyzed except 1 due to early transfer. Most pain mechanisms were mixed type (n = 15, 75%), while some reported nociceptive pain (n = 3, 15%) or neuropathic pain (n = 2, 10%). The baseline background opioids were MEDD 186 mg/day (range, 124-592), number of breakthrough opioids were 5 (IQR, 5-7). The median PPG were 4 (range, 3-6). After application of ketamine, overall pain response rate was 45% (n = 9), complete pain response was 35% (n = 7) and partial pain response was 10% (n = 2). The other 11 were non-responders (six failed to achieve overall pain response despite of maximal dose or completing 5 days of ketamine, five patients discontinued the treatment due to AEs). AEs included confusion (n = 9, 45%), dizziness (n = 3, 15%), and hypertension (n = 2, 10%). Communication capacities were sustained in 10 patients and decreased in other 10 patients. OS were 21 days (95% CI, 18.1-23.9). Conclusions: Our study showed efficacies and safeties of gradually increasing CIVI of ketamine for terminally ill cancer patients with refractory cancer pain. The CIVI of ketamine can be a useful tool in these patients considering limited treatment options. Further studies comparing usefulness of CIVI of ketamine and usual practice with opioids escalation are needed (NCT03362073). Clinical trial information: NCT03362073.