PURPOSE: Even with antiemetic prophylaxis, patients undergoing cancer chemotherapy often still experience chemotherapy-induced nausea and vomiting (CINV). Neurokinin-1 (NK-1) receptor antagonists will prevent CINV effectively but are not affordable for patients of low socioeconomic status. METHODS: In this group sequential, response adaptive randomized double-blinded clinical trial, patients of low socioeconomic who cannot afford NK-1 receptor antagonists, planned for highly emetogenic chemotherapy (HEC) agents received olanzapine 5 mg plus pregabalin 75 mg or placebo orally for five days add-on to standard antiemetic therapy (injection ondansetron 8 mg + injection dexamethasone 12 mg on day one followed by oral dexamethasone 8 mg on days 2 to 4). The primary outcome was the difference in the proportion of patients with "overall no nausea" between groups. Following the interim analysis, the allocation ratio was modified, resulting in more patients being assigned to the well-performing arm. RESULTS: Initially, 30 patients were equally randomized into two groups. As the experimental group performed well in the interim analysis, the allocation ratio was changed to 2:1 for the subsequent period. Finally, the experimental group (n = 36) performed better in terms of "overall no nausea" than the control group(n = 18) (41.6% vs. 5.5%, p = 0.008). Sedation and dizziness were significantly greater in the experimental group compared to the standard-of-care group. CONCLUSION: Olanzapine 5 mg plus pregabalin 75 mg add-on to a combination of dexamethasone and ondansetron will significantly prevent the incidence of CINV compared to a combination of dexamethasone and ondansetron alone. However, the combination is associated with sedation and dizziness as adverse events. TRIAL REGISTRATION: Clinical trial registry-India (CTRI/2021/08/035451). Registration Date: 05/08/2021.