Evaluation of the Omission of Dexamethasone in Premedication Regimens During Paclitaxel Treatment

Rationale Dexamethasone is administered alongside a H1-antagonist (e.g. cetirizine) to prevent hypersensitivity reactions (HSRs) during paclitaxel chemotherapy. However, the rationale seems limited and several studies have demonstrated no increase in HRSs after discontinuation of dexamethasone after the second paclitaxel administration. In addition, two studies have demonstrated the feasibility of lower doses of dexamethasone in paclitaxel premedication regimens. Furthermore, there seems to be no statistically significant association between the administration route (Intravenous (IV) or oral) or dose of dexamethasone and the HSR rate.

Dexamethasone may lead to serious side effects such as hyperglycemia, immune suppression, mood disturbances, sleeping disorders, and weight gain, thereby negatively affecting the patient's health-related quality of life (HRQoL).

Discontinuing dexamethasone might result in improved HRQoL, decreased healthcare costs, and more efficient premedication regimens. However, no head-to-head studies on dexamethasone's added value in preventing paclitaxel-induced HSRs have been performed. Therefore, the aim of our study is to demonstrate that the premedication regimen without dexamethasone is non-inferior to the standard of care premedication regimen with dexamethasone, based on the incidence of paclitaxel-induced HSRs (Common Terminology Criteria for Adverse Events (CTCAE) v5.0 grade ≥3).

Objective The primary objective is to evaluate the incidence of clinically relevant HSRs (grade ≥3 as per Common Terminology Criteria for Adverse Events; CTCAE version 5.0) during paclitaxel-based chemotherapy with a standard of care premedication regimen with dexamethasone compared to an experimental premedication regimen without dexamethasone.

Secondary objectives are: To determine the incidence and severity of HSRs (any grade) during paclitaxel-based chemotherapy with a standard of care premedication regimen with dexamethasone compared to an experimental premedication regimen without dexamethasone; To determine the number of paclitaxel administrations and cumulative dose until the first HSR occurrence (any grade); To determine the effect of dexamethasone omission on the patient's quality of life; To determine the incidence and severity of adverse events related to dexamethasone; To determine the cost-effectiveness of the premedication regimens with and without dexamethasone from a healthcare and societal perspective.

Main trial endpoints The primary outcome will be the percentage of patients who experience a clinically relevant HSR (CTCAE grade ≥3) during paclitaxel infusion (Yes/No), determined prospectively by the oncology medical staff (e.g. oncologist).

Secondary trial endpoints Secondary outcomes are: The severity of the HSR grades as defined by (CTCAE v.5.0); The incidence of the HSRs (all grades) as defined by (CTCAE v.5.0); The percentage (%) of patients that can be rechallenged (conform standard of care) after the occurrence of an HSR with or without dexamethasone; The number of paclitaxel administrations and cumulative dose (mg) until the first HSR occurrence; The incidence and severity of adverse events related to dexamethasone measured through the validated Dexamethasone Symptom Questionnaire (DSQ)(21); The patient quality of life measured using the EuroQol-5 dimensions-5 levels (EQ-5D-5L) and European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ C-30) scorings tools); The costs of the paclitaxel premedication regimen with and without dexamethasone from a healthcare and societal perspective.

Trial design This is a prospective, multicenter, randomized, non-inferiority trial.

Trial population In total, 500 patients (≥18 yo) with solid tumors (any indication) for whom paclitaxel-based chemotherapy is considered standard treatment will be included.

Interventions Eligible patients will be randomized 1:1 to receive either the local standard of care premedication regimen with dexamethasone or the experimental premedication regimen without dexamethasone during five administrations of paclitaxel. Patients will start with paclitaxel treatment on the physicians recommended dose as standard of care.

• The severity of the HSR grades as defined by (CTCAE v.5.0); [Time frame: Throughout the entire duration of the study, spanning five cycles (each cycle is 7 days) of paclitaxel treatment]
• The incidence of the HSRs (all grades) as defined by (CTCAE v.5.0); [Time frame: Throughout the entire duration of the study, spanning five cycles (each cycle is 7 days) of paclitaxel treatment]
• The percentage (%) of patients that can be rechallenged (according to standard of care procedures) after the occurrence of an HSR with or without dexamethasone; [Time frame: Throughout the entire duration of the study, spanning five cycles (each cycle is 7 days) of paclitaxel treatment]
• The incidence and severity of adverse events related to dexamethasone measured through the validated Dexamethasone Symptom Questionnaire (DSQ) [Time frame: Throughout the entire duration of the study, spanning five cycles (each cycle is 7 days) of paclitaxel treatment]
• The patient quality of life measured using the EuroQol-5 dimensions-5 levels (EQ-5D-5L) scorings tools. [Time frame: Throughout the entire duration of the study, spanning five cycles (each cycle is 7 days) of paclitaxel treatment]
• The patient quality of life measured using the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ C-30) scorings tools. [Time frame: Throughout the entire duration of the study, spanning five cycles (each cycle is 7 days) of paclitaxel treatment]
• • The total cost of treatment of both premedication regimens from a healthcare and societal perspective. [Time frame: Throughout the entire duration of the study, spanning five cycles (each cycle is 7 days) of paclitaxel treatment]