Strategies for clinical development of monoclonal antibodies beyond first-in-human trials: tested doses and rationale for dose selection.

BACKGROUND: Our previous survey on first-in-human trials (FIHT) of monoclonal antibodies (mAbs) showed that, due to their limited toxicity, the recommended phase II dose (RP2D) was only tentatively defined. METHODS: We identified, by MEDLINE search, articles on single-agent trials of mAbs with an FIHT included in our previous survey. For each mAb, we examined tested dose(s) and dose selection rationale in non-FIHTs (NFIHTs). We also assessed the correlation between doses tested in the registration trials (RTs) of all FDA-approved mAbs and the corresponding FIHT results. RESULTS: In the 37 dose-escalation NFIHTs, the RP2D indication was still poorly defined. In phase II-III NFIHTs (n=103 on 37 mAbs), the FIHT RP2D was the only dose tested for five mAbs. For 16 mAbs, only doses different from the FIHT RP2D or the maximum administered dose (MAD) were tested and the dose selection rationale infrequently indicated. In the 60 RTs on 27 FDA-approved mAbs with available FIHT, the FIHT RP2D was tested only for two mAbs, and RT doses were much lower than the FIHT MAD. CONCLUSIONS: The rationale beyond dose selection in phase II and III trials of mAbs is often unclear in published articles and not based on FIHT data.

[Development of a therapeutic education program for prostate cancer patients undergoing new generation hormone therapy]. / Élaboration d'un programme d'éducation thérapeutique dédié aux patients atteints d'un cancer de la prostate sous hormonothérapie de nouvelle génération.

New generation hormone therapies (NGHT) is the gold standard treatment for metastatic prostate cancers and/or castration-resistant tumors. Four molecules have been approved: enzalutamide, abiraterone acetate, apalutamide and darolutamide. These treatments are oral therapies taken on a daily basis, which raise issues of adherence to treatment, adverse effects and drug interactions. Therapeutic educational programs for patients represent an emerging care activity that allows patients to acquire skills to better live with their disease and treatment. As of today, no such specific program to new generation hormone therapy in prostate cancer has been developed in France, which was the goal of our current study. This was conducted in three steps: i) identification of patients' educational needs through an exchange with a focus group of patients, ii) gathering of expert opinions on useful information to be given to patients on NGHT via a questionnaire submitted to GETUG members and iii) implementation of the program per se. Qualitative analysis of exchanges with the focus group of patients led to the identification of 7 meaning categories. Expert opinions regarding useful information to deliver to patients identified 13 key items. Based on these preliminary data concerning patients' educational needs, we set up the first french program dedicated to metastatic prostate cancer patients undergoing NGHT that included three therapeutic education workshops: "Experience of the disease", "Management of the treatment" and "Physical activity and diet".

High Content Screening Using New U2OS Reporter Cell Models Identifies Harmol Hydrochloride as a Selective and Competitive Antagonist of the Androgen Receptor.

Prostate cancer is the most commonly diagnosed malignancy in men. Its growth mainly relies on the activity of the androgen receptor (AR), justifying the use of androgen deprivation therapy as a gold standard treatment for the metastatic disease. Inhibition of the androgen axis using second generation antagonists has improved patients' survival, but is systematically confronted to resistance mechanisms, leading to a median survival that does not exceed 5 years. Counteracting this resistance has been the object of a large number of investigations, with a particular emphasis towards the identification of new AR inhibitors, whether they antagonize the receptor by a competitive or a non-competitive binding. To this end, many high content screens have been performed, to identify new non-steroidal AR antagonists, using a variety of approaches, but reported somewhat controversial results, depending on the approach and on the cell model that was used for screening. In our study, we used the U2OS osteosarcoma cells stably transfected with AR or ARv7 and a luciferase reporter as a previously validated model to screen the Prestwick Phytochemical library. The results of our screen identified ellipticine, harmol, and harmine hydrochloride as confirmed hits. Surprisingly, we could demonstrate that harmol hydrochloride, previously identified as a non-competitive inhibitor of AR or a weak inhibitor of androgen signaling, was actually a competitive antagonist of AR, which inhibits the growth of VCaP prostate cancer line, at concentrations for which it did not affect the growth of the AR negative DU145 and PC3 cells. Interestingly, we also report for the first time that harmol hydrochloride was selective for AR, as it could not alter the activity of other nuclear receptors, such as the glucocorticoid receptor (GR), the progesterone receptor (PR), or the mineralocorticoid receptor (MR). Additionally, we demonstrate that, conversely to enzalutamide, harmol hydrochloride did not show any agonistic activity towards the pregnane X receptor (PXR), a master regulator of drug metabolism. Together, our results shed light on the importance of the cellular context for the screening of new AR antagonists. They further indicate that some of the potential hits that were previously identified may have been overlooked.

Clinical Relevance of Routine Monitoring of Patient-reported Outcomes Versus Clinician-reported Outcomes in Oncology.

The National Cancer Institute Common Terminology Criteria for Adverse Events classification is the standard classification used by the physicians in oncology for reporting adverse events. This classification has evolved over the last years according to the emergence of new therapies. Reporting symptoms, quality of life (QoL) and toxicities via patient-reported outcomes (PROs) in clinical practice is not yet a standard of care, nevertheless many studies have been conducted recently to assess feasibility and impact of routine monitoring of PROs, which should enable for better management of toxicities and earlier detection of disease progression in a more patient-centered health care delivery system. The aim of this article was to discuss the advantages and limitations of both approaches, clinicians-reported outcomes and PROs. Growing evidence supports that the routine collection of PROs leads to improvement of QoL and overall survival of cancer patients.