Purpose: The safety, pharmacokinetics and efficacy of elraglusib, a GSK-3b small molecule inhibitor, as monotherapy or combined with chemotherapy, in patients with relapsed or refractory solid tumors or hematologic malignancies was studied. Patients and Methods: Elraglusib (intravenously twice weekly in three-week cycles) monotherapy dose-escalation was followed by dose-escalation with eight chemotherapy regimens (gemcitabine, doxorubicin, lomustine, carboplatin, irinotecan, gemcitabine/nab-paclitaxel, paclitaxel/carboplatin, and pemetrexed/carboplatin) in patients previously exposed to the same chemotherapy. Results: Patients received monotherapy (n=67) or combination therapy (n=171) elraglusib doses 1-15 mg/kg twice weekly. The initial recommended phase 2 dose (RP2D) of elraglusib was 15 mg/kg twice weekly and was defined, without DLT observation, due to fluid volumes necessary for drug administration. The RP2D was subsequently reduced to 9.3 mg/kg once weekly to reduce elraglusib-associated central/peripheral vascular access catheter blockages. Other common elraglusib-related adverse events (AE) included transient visual changes and fatigue. Grade 3 treatment-emergent AE occurred in 55.2% and 71.3% of patients on monotherapy and combination therapy, respectively. Part 1 monotherapy (n=62) and part 2 combination (n=138) patients were evaluable for response. In part 1, a patient with melanoma had a complete response, and a patient with acute T-cell leukemia/lymphoma had a partial response (PR). In part 2, 7 PRs were observed, and the median progression-free survival and overall survival were 2.1 (95% CI, 2-2.6) and 6.9 (95% CI, 5.7-8.4) months, respectively. Conclusions: Elraglusib had a favorable toxicity profile as monotherapy and combined with chemotherapy and was associated with clinical benefit supporting further clinical evaluation in combination with chemotherapy.