Dose optimization for cancer treatments with considerations for late-onset toxicities.

Given that novel anticancer therapies have different toxicity profiles and mechanisms of action, it is important to reconsider the current approaches for dose selection. In an effort to move away from considering the maximum tolerated dose as the optimal dose, the Food and Drug Administration Project Optimus points to the need of incorporating long-term toxicity evaluation, given that many of these novel agents lead to late-onset or cumulative toxicities and there are no guidelines on how to handle them. Numerous methods have been proposed to handle late-onset toxicities in dose-finding clinical trials.

Incorporating patient-reported outcomes in dose-finding clinical trials with continuous patient enrollment.

Dose-finding clinical trials in oncology estimate the maximum tolerated dose (MTD), based on toxicity obtained from the clinician's perspective. While the collection of patient-reported outcomes (PROs) has been advocated to better inform treatment tolerability, there is a lack of guidance and methods on how to use PROs for dose assignments and recommendations. The PRO continual reassessment method (PRO-CRM) has been proposed to formally incorporate PROs into dose-finding trials.

Surv-CRM-12: A Bayesian phase I/II survival CRM for right-censored toxicity endpoints with competing disease progression.

The growing interest in new classes of anti-cancer agents, such as molecularly-targeted therapies and immunotherapies with modes of action different from those of cytotoxic chemotherapies, has changed the dose-finding paradigm. In this setting, the observation of late-onset toxicity endpoints may be precluded by treatment and trial discontinuation due to disease progression, defining a competing event to toxicity. Trial designs where dose-finding is modeled in the framework of a survival competing risks model appear particularly well-suited.

Mogamulizumab induces long-term immune restoration and reshapes tumour heterogeneity in Sézary syndrome.

Background: Mogamulizumab, an anti-CCR4 monoclonal antibody, has been shown to increase progression-free survival in cutaneous T-cell lymphoma.

Objectives: We hypothesized that besides the targeted depletion of Sézary cells (SCs), mogamulizumab may reshape the immune tumour microenvironment.

Methods: Both malignant and benign compartments from 26 patients with B2 stage Sézary syndrome before mogamulizumab initiation were prospectively analysed using KIR3DL2 and TCRVβ markers, serological markers and molecular assessments of clonality.

Dose-finding design and benchmark for a right censored endpoint.

Dose-finding trials aim to determine a safe dose to be tested in larger trials for efficacy. In oncology, designs generally assume conventional monotonic increasing dose-toxicity relationships, mostly with binary outcomes (e.g.