Summary Radiotherapy using protons is an attractive option as it has the potential to better preserve healthy tissue compared to radiation with photons or electrons, and because trial outcomes indicate it can replace surgery for radical cancer treatments as well. Proton therapy makes use of the finite range of heavy charged particles with an intensity maximum at the end of their path (Bragg peak) followed by a sharp fall-off of the dose. However, predicting the proton range based on computed tomography (CT) scans carries an estimation uncertainty. For treatments with proximal critical organs and limited accessibility (head and neck), high heterogeneities (lung), or significant breath motion (liver) such uncertainty is too high and the therapy is in the best case challenging, if not impossible. New instrumentation is needed to monitor the location of the Bragg peak to 1-2 mm accuracy within several seconds in these challenging scenarios. We propose to use the novel Cerenkov Charge Induction (CCI) thallium bromide (TlBr) detectors for proton range verification (PRV) in proton therapy. CCI TlBr detectors combine the detection of Cerenkov light, which provides sub-nanosecond timing resolution with the conventional readout of semiconductor detectors, which provides excellent energy resolution and 3-D segmentation. Moreover, TlBr has a shorter attenuation length than most commonly used scintillation materials for prompt-gammas up to 6.1 MeV. CCI TlBr detectors provide a unique performance, as they offer simultaneous excellent performance in energy, time, and spatial resolution, that fits the needs of PRV in proton therapy. In this project, we will test the feasibility of using a non-collimated prompt gamma timing – Compton camera (PGT-CC) camera based on pixel CCI TlBr detectors for PRV in proton therapy. We will 1) manufacture pixel CCI TlBr detectors with optimized surface treatment to couple the photodetector and with highly-stable long- lasting electrodes; 2) characterize the detector features of pixel CCI TlBr devices in a benchtop setting using sealed sources, including energy, spatial, and timing resolution; 3) evaluate the performance of a PGT-CC camera for PRV made with pixel CCI TlBr detectors in a beamline with protons accelerated to 67.5 MeV; and 4) compare the performance of our PGT-CC camera prototype with gold standard techniques following realistic treatment protocols at a clinical beamline with protons accelerated to >200 MeV. The accomplishment of the aims of this project will determine the potential of CCI TlBr detectors to become the most competitive devices for PRV in proton therapy. A successful performance of the proposed detection system would allow to exploit the benefits of proton therapy in treatment regions that are currently very challenging, leading to increased treatment efficacy and lower toxicity in the healthy organs of the patients.