Background: Early phase clinical trials (EP-CTs) investigate novel treatment options in oncology, with recent advances in personalized therapy leading to improved outcomes and offering hope to patients with cancer. However, little research has sought to understand hope in EP-CT participants, thus we sought to study associations of patient-reported hope with prognostic understanding, quality of life (QOL), symptom burden, coping mechanisms, and financial wellbeing in EP-CT participants. Methods: We prospectively enrolled consecutive adults with cancer participating in EP-CTs at Massachusetts General Hospital from 04/2021-01/2023. Participants completed baseline surveys prior to treatment initiation that assessed hope (Herth Hope Index [HHI], higher scores indicate greater hope), prognostic awareness (Prognosis and Treatment Perceptions Questionnaire [PTPQ], QOL (Functional Assessment of Cancer Therapy-General), symptom burden (physical: Edmonton Symptom Assessment System [ESAS]; psychological: Patient Health Questionaire-4 [PHQ4]), coping mechanisms (Brief COPE), and financial wellbeing (Comprehensive Score for Financial Toxicity [COST]). We used descriptive statistics and regression models to explore associations of hope with patient characteristics as well as patient-reported prognostic awareness, QOL, symptom burden, coping, and financial wellbeing. Results: Of 221 eligible patients, we enrolled 204 (enrollment rate 92.3%, median age = 63.4 years [range 54.8-70.5]; 56.9% female, and 94.0% metastatic cancer). Most common cancer types were gastrointestinal (34.8%), breast (19.6%), and head and neck (10.3%). Patients had a mean HHI score of 27.2 (range 12.0-36.0), with 27.1% reporting their cancer is curable (mean hope scores were higher for those reporting curable vs incurable on the PTPQ: 28.8 vs 26.7, p = 0.016). Higher hope scores were associated with better QOL (B = 0.21, p < 0.001), lower symptom burden (ESAS-physical: B = -0.10, p < 0.001; PHQ4-depression: B = -2.10 p = < 0.001; PHQ4-anxiety: B = -0.99, p < 0.001), more adaptive coping strategies (self-blame [B = -1.34, p < 0.001]; acceptance [B = 1.30, p < 0.001], denial [B = -1.31, p < 0.001], support [B = 1.03, p < 0.001], active [B = 0.97. p < 0.001], disengage [B = -2.69, p < 0.001], religion [B = 0.63, p < 0.001]), and greater financial wellbeing (B = 0.10, p = 0.013). Conclusions: In this prospective cohort study, we found novel associations of higher hope scores with prognostic understanding, better QOL, lower symptom burden, more adaptive coping mechanisms, and greater financial wellbeing. Future studies should measure patient-reported hope and explore its role as a potential moderator of other outcomes in EP-CT participants.