Purpose: The NIPU-trial investigates the effect of adding the telomerase vaccine UV1 to treatment with ipilimumab and nivolumab for patients with pleural mesothelioma (PM). Methods: In this phase 2 open-label trial, patients with PM progressing after first-line chemotherapy were randomised to receive ipilimumab and nivolumab alone (arm B) or combined with UV1 (arm A). The primary endpoint was progression-free survival (PFS) as determined by BICR. It was estimated that 69 PFS events were needed to detect a hazard ratio (HR) of 0.60 with 80% power and a one-sided alpha level of 0.10. Results: 118 patients were randomised. The median PFS determined by blinded independent central review (BICR) was 4.2 months (95%CI 2.9–9.8) in arm A and 4.7 months (95%CI 3.9–7.0) in arm B (HR 1.01, 80%CI 0.75–1.36 P = 0.979), after a median follow-up of 12.5 months (95%CI 9.7–15.6). The investigator-determined median PFS was 4.3 months (95%CI 3.0–6.8) in arm A and 2.9 months (95%CI 2.4–5.5) in arm B (HR 0.60, 80%CI 0.45–0.81 P = 0.025). Confirmed objective response rate (ORR) by BICR was 31% in arm A and 16% in arm B (odds ratio 2.44 80%CI 1.35–4.49 P = 0.056). After a median follow-up time of 17.3 months (95%CI 15.8–22.9), the OS was 15.4 months (95%CI 11.1–22.6) in arm A and 11.1 months (95%CI 8.8–18.1) in arm B, (HR 0.73, 80%CI 0.53–1.0, P = 0.197). Conclusion: The primary endpoint was not met. Predefined analyses of response rates are in favour of adding the vaccine.