PROJECT SUMMARY Delirium is the most common and distressing neuropsychiatric syndrome in cancer patients. It has a negative effect on symptom assessment, patient-clinician communication, decision making, and survival. Approximately 50% of patients with hyperactive or mixed delirium continue to be agitated despite low-dose haloperidol, which can be particularly distressing to patients and caregivers. Haloperidol dose escalation, neuroleptic rotation (from haloperidol to chlorpromazine), or combination therapy (haloperidol plus chlorpromazine) may provide good control of agitation. However, no delirium trials have ever been completed in the palliative cancer care setting; such trials are urgently needed to improve the quality of life of patients with this devastating syndrome. Our long-term goal is to develop evidence-based therapy for the palliation of delirium in cancer patients. The proposed study is a high-impact, three-arm, double-blind, double-dummy, randomized placebo-controlled trial to determine the effect of haloperidol dose escalation, neuroleptic rotation, and combination therapy in the treatment of refractory agitated delirium in cancer patients admitted to an acute palliative care unit (APCU). We hypothesize that neuroleptic rotation and combination therapy are effective for agitated delirium. The primary specific aim of this study is to assess the within-arm effect of haloperidol dose escalation, neuroleptic rotation, and combination therapy on agitation intensity (Richmond Agitation Sedation Scale [RASS]) over 24 hours in patients who did not experience a response to low-dose haloperidol. The second aim is to obtain preliminary estimates of the effects of these treatments on (1) the proportion of patients with target RASS -2 to +1, (2) delirium-related distress in nurses and caregivers, (3) symptom expression, (4) delirium severity, (5) the need for neuroleptics, (6) delirium recall, (7) adverse effects, and (8) end-of-life quality. In the third specific aim, we will obtain preliminary estimates of the between-arm effect size among haloperidol dose escalation, rotation to chlorpromazine, and combination therapy in the first 24 hours. After obtaining surrogate consent, we will administer the study medications under a titration scheme and monitor the participants closely until discharge. This study is highly innovative because (1) randomized trials for refractory agitated delirium have never been completed, (2) the patient population (i.e., cancer) is unique, (3) the treatment strategies (i.e., neuroleptic rotation/combined therapy) are previously untested, (4) the study setting (i.e., the APCU) is distinctive, and (5) the outcome measures (e.g., delirium-related distress) are novel. Successful completion of this proof-of- concept study will pave the way for a large randomized controlled trial that is adequately powered to confirm the optimal approach for refractory agitated delirium. This study is expected to have a positive effect on patient care by offering new evidence-based options for palliating refractory agitated delirium, thus enhancing our understanding of these interventions? effects on many clinically important delirium outcomes, reducing delirium- related distress, and ultimately, improving quality of life in advanced cancer patients and their caregivers.