Background: Therapy for advanced refractory malignancies remains a major challenge. As the combination of ICI and CT has been shown in some cancers to be superior to CT alone, and as ICI, CT, and TT have efficacy, but divergent toxicity; this combination was chosen for treating patients with such diseases. Methods: Treatment was highly personalized and was designed based on diagnosis, prior therapy and eligibility for TT. ICI included pembrolizumab in 7 (2 in combination with ipilimumab), nivolumab in 10, and atezolizumab in 2. Chemotherapy was given in 28-day cycles. Multiagent CT cycles were given in 17, and single-agent in 2.13 received platinum and 10 taxanes. TT included erlotinib 4, cituxumab 2, bevacizumab 2, dabrafenib/trametinib 3, crizotinib 1, alectinib 1, sorafenib 1, everolimus 1. 4 were not eligible for TT. Results: From 04/2016 to 10/2018 19 consecutive patients (PT) were treated; median (M), age 62 (27-82), ECOG PS 2 (0-4), female 15/male 4. Tumor type; lung 8, pancreas 3, lymphoma 2, melanoma 2, cholangioCA 1, ureter 1, cervix 1, Glioblastoma Multiforme 1. 13 PT had prior therapy, M2(1-11). 7 had prior ICI, 3 prior TT. Disease was bulky in 6. Response was based on PET evaluation with tumor regression depicted after cycle #1. 11 achieved CR (57%), M 6⁺ months (1⁺-15⁺), 7 PR (37%), M 4 months (1⁺-7) and 1 SD 7 months. 3 intracranial metastases; 2 CR, 1 PR. Response was seen in extensive prior therapy, bulky disease, poor performance, and prior ICI. No unexpected side effects were observed. Grade 3-4 adverse events; 12.7%, primarily hematologic. Conclusions: The personalized combination of ICI, CT, and TT in advanced refractory diverse cancer diseases is associated with high clinical activity. Further evaluation in clinical trials is strongly indicated.