# Retire the 3+3: model-based dose finding that counts late and chronic side effects

Source: https://onco.cc/ideas/idea-tr1-model-based-dose-finding-with-late-toxicity/  
OnCo record `idea-tr1-model-based-dose-finding-with-late-toxicity` (Idea). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

The traditional way of finding a dose looks only at severe side effects in the first month. Modern statistical designs can use all patients' data and count the grumbling, long-lasting problems that make people quit months later.

## Summary

Phase 1 designs (BOIN, CRM, TITE variants) that incorporate late-onset toxicity, cumulative low-grade toxicity over multiple cycles, patient-reported tolerability and pharmacokinetics into dose selection, with a target of the 'optimal biological dose' rather than the MTD, and with backfill cohorts at lower doses. Regulators expect a model-based design; the 3+3 becomes the exception requiring justification.

## Fields

- Kind: Idea
- Last checked: 2026-09-08
- Hypothesis: Model-based designs incorporating late toxicity will recommend lower doses than 3+3 for the same agents in a substantial fraction of cases, and those doses will show lower real-world discontinuation.
- Rationale: For chronic oral therapies and immunotherapies, the toxicities that matter appear after cycle 1 and are often grade 2 but persistent; 3+3 is statistically inefficient and structurally blind to them.
- Proposed test: Re-analyse completed phase 1 datasets under TITE-BOIN with cumulative toxicity and compare recommended doses to the original; prospectively adopt in a sponsor's early-phase portfolio and track later dose changes.
- Maturity: early-clinical
- Actor: industry

## Sources

- Bottleneck evidence (Wrong doses): FDA Oncology Center of Excellence, Project Optimus: https://www.fda.gov/about-fda/oncology-center-excellence/project-optimus

## Connected records

- technologies: [Antibody-drug conjugate (ADC)](https://onco.cc/technologies/adc/), [Immune checkpoint inhibitors](https://onco.cc/technologies/checkpoint-inhibitor/), [Small-molecule kinase inhibitors](https://onco.cc/technologies/kinase-inhibitors/)
- people: [Ruth Plummer](https://onco.cc/people/ruth-plummer/)
- bottlenecks: [Trial design, endpoints and cost](https://onco.cc/bottlenecks/b-trial-design/), [Wrong doses](https://onco.cc/bottlenecks/b-dose-optimisation/)

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