(T1130-10-63) Retrospective Safety Evaluation of Tyrosine Kinase Inhibitor Products When Administered in Single Dose in Crossover Studies to Healthy Volunteers

Purpose: Tyrosine Kinases (TKs) are multi-targeted anticancer drugs with activity towards receptors involved in tumorigenesis, tumor progression, and metastatic progression. TKs have emerged as major targets of drug discovery in precision oncology. Since the approval of the first Tyrosine Kinase Inhibitor (TKI) by the Food and Drug Administration (FDA) in 2001, some clinical challenges have emerged including important toxicity profiles of certain TKIs. This raises safety concerns for the patient population who are chronic users of TKIs but also for healthy volunteers (HVs) who are administered TKIs for the purpose of clinical trials, whether in the context of new investigational product (IP) or bioequivalence (BE, generic investigational product) studies. Regulatory Agencies requirements to conduct BE studies with TKIs are not always concordant in terms of design and study population. Our Contract Research Organization (CRO) has gained considerable experience in conducting BE studies with different TKIs since 2010 in HVs. Our aim was to perform a retrospective evaluation of the safety profile of these studies in order to support and facilitate the conduction of different phase I studies with TKIs in HVs.

Methods: We selected 8 different TKIs for which our CRO had performed more than 1 clinical trial between 2010 and 2022. A total of 53 bioequivalence studies were included, in which IPs were administered to over 1700 HVs. This retrospective evaluation describes the safety profile of immediate release formulations (tablet and capsule) of afatinib, dasatinib, erlotinib, gefitinib, ibrutinib, imatinib, nilotinib, and sunitinib when orally administered to HVs, in the context of single dose crossover studies. Designs included 2, 3-, or 4-treatment periods with clinical conduct under fasting and/or fed conditions. Safety assessments included the incidence of Treatment Emergent Adverse Events (TEAE), physical exams, clinical laboratory tests, and dropout monitoring.

Results: Of the 1733 subjects who participated in the crossover BE clinical trials, less than 1% were prematurely discontinued for safety reasons by the Principal Investigator (PI). Ibrutinib showed, among the IPs tested, “the highest” percentage of withdrawal subjects (3.1%), but only 2 were removed from studies for TEAE reason. The other 7 IPs exhibited a percentage of discontinued subjects equal to or below 1.2%. Approximately 28% of subjects reported a TEAE in which only 1% of subjects reported a severe drug related AE. The most commonly reported TEAEs included headache, nausea, fatigue, and diarrhea. Changes in laboratory tests accounted for less than 3% of TEAEs. In general, for each IP, the percentages of TEAEs reported were similar regardless of the administration of food and no increase of TEAEs was observed with the number of IP administrations.

Conclusion: The safety profile analysis of the 53 studies confirmed that the 8 TKIs, administered at single dose, were safe and well tolerated in HVs. This data is in line with literature in TKIs, and supports the conduct of more TKI studies in HVs in phase I clinical trials.