A systematic review of contemporary phase I trials in patients with lymphoma

Phase I trials represent the first step of the clinical evaluation of a new drug with the aim of assessing safety and preliminary antitumor activity (LoRusso et al., 2010, Ivy et al., 2010). Following a dramatic increase in the number of new agents and novel therapeutic combinations entering clinical evaluation over the last decade, significant efforts have been made aiming to redefine phase I trials designs and accelerate the clinical development of novel compounds (Le Tourneau et al., 2010). The use of disease specific phase I trials or expansion cohorts has been particularly successful. Hence, several new drugs have been evaluated in large phase I trials that following the establishment of a safe dose were expanded in large efficacy evaluation cohorts, bypassing the classical drug development sequence from phase I to phase II and phase III trials, eventually leading to multiple drugs approvals (Kwak et al., 2010, Chen et al., 2017, Armand et al., 2016, Ansell et al., 2015, Lesokhin et al., 2016, Younes et al., 2016).

Together with the expansion of new agents that have entered clinical evaluation for solid tumors, a sharp increase in new drugs developed for hematologic malignancies has also been observed, particularly for lymphomas.

This was supported by a better understanding of the biology of lymphomas, that has driven the development of several new small molecules, monoclonal antibodies, and, more recently, chimeric antigen receptor (CAR)-T cells (Ansell et al., 2015, Gopal et al., 2014, Wang et al., 2013, Younes et al., 2012, Neelapu et al., 2017, Schuster et al., 2019, Vitolo et al., 2017, Pro et al., 2012).

Historically, patients with lymphoma have been included in phase I trials together with patients with solid tumors. However, several phase I studies are nowadays specifically designed for patients with lymphomas. This is particularly appealing given the biology of lymphomas and the relative rarity of some specific lymphoma subtypes. In addition, even if the classical path of drug approval in oncology goes from phase I, to exploratory phase II, to randomized phase III studies, most of the recent drugs approvals in lymphomas were based on results of single arm phase II studies (Gopal et al., 2014, Wang et al., 2013, Younes et al., 2012, Pro et al., 2012, Byrd et al., 2013, Stathis et al., 2018), thus highlighting the importance of disease-specific phase I trials as a critical step in the evaluation of a new drug or drugs combination in lymphomas.

Most reviews of published phase I trials include trials enrolling mainly patients with solid tumors and may not reflect drug development in lymphomas (Arkenau et al., 2008, Arkenau et al., 2009, Schwaederle et al., 2016, Mackley et al., 2021). Furthermore, the increased number of new agents targeting specifically relevant pathogenetic pathways of lymphoid malignancies, as well as the lack of standard methodology criteria in hematologic malignancies highlight the need for specific guidelines.

Here, we present results of a systematic review of phase I trials specifically conducted for patients with lymphomas published between 2015 and 2020, aiming at describing their characteristics in terms of methodology used, agents investigated, their safety and preliminary antitumor activity.

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