Impact of age and comorbidity on safety outcomes in phase 1 trial participants for metastatic solid malignancies

Introduction

The number of phase 1 clinical trials has been increasing globally over the past decade. However, patient recruitment remains skewed towards younger populations with older adults remaining underrepresented, limiting generalizability. Few studies have systematically examined the role of comorbidities as a determinant of safety outcomes in phase 1 trials. Thus, we aimed to investigate the impact of age and comorbidity on safety outcomes of phase 1 trial participants.

Materials and Methods

This retrospective analysis examined electronic health records of patients aged ≥18 years enrolled in phase 1 trials for metastatic solid malignancies between January 2020 and May 2023. Patients were stratified into two age groups (<70 years vs. ≥70 years). Patients were classified as comorbid if they had Charlson Comorbidity Index (CCI) ≥3, Elixhauser Comorbidity Index (ECI) ≥4, or modified Elixhauser Comorbidity Index (mECI) >12. Eastern Cooperative Oncology Group (ECOG) performance status was also evaluated. Logistic regression models assessed associations between age, comorbidity, and safety outcomes: serious adverse events (SAE), dose-limiting toxicities (DLT), dose reductions/interruptions (DR/DI), cessation of treatment due to toxicity (COTT), and grade 3–5 toxicities.

Results

We included 229 patients, of whom 51 (22%) were aged ≥70 years. Among them, 79 (34%) experienced an SAE, 109 (48%) had DR/DI, 34 (15%) had COTT, 17 (7%) had DLT, and 99 (43%) developed grade 3–5 adverse events. Age was not significantly associated with a higher likelihood of adverse safety outcomes. However, patients with ECI ≥4 had significantly higher likelihood of SAE than those with ECI <4 (50% vs. 31%, p = 0.04, OR: 2.18, 95% CI: 1.08–4.44). Patients with ECOG ≥1 had higher likelihood of SAE than those with ECOG 0 (42% vs. 29%, p = 0.06, OR: 1.75, 95% CI: 1.01–3.05, p = 0.05). Patients with ECOG ≥1 had significantly higher likelihood of grade 3–5 adverse events than those with ECOG 0 (52% vs. 36%, p = 0.03, OR: 1.89, 95% CI: 1.11–3.23, p = 0.02). Other comorbidity indices were not significantly associated with safety outcomes.

Discussion

Age alone was not associated with safety outcomes in phase 1 clinical trials for metastatic solid malignancies. Instead, comorbidity burden and ECOG performance status were predictors of adverse events in our cohort of patients.