# Dose and schedule optimisation trials specific to antibody-drug conjugates

Source: https://onco.cc/ideas/idea-tr1-adc-dose-and-schedule-optimisation/  
OnCo record `idea-tr1-adc-dose-and-schedule-optimisation` (Idea). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

Antibody-drug conjugates deliver chemotherapy payloads into tumours but cause lung, eye and nerve damage that tracks total exposure, and several were approved without an optimised dose. Randomised comparisons of lower doses, longer intervals and capped cumulative payload could keep the benefit while cutting these harms.

## Summary

Randomised dose and schedule comparisons for ADCs (e.g., lower dose per cycle, extended intervals, capped cumulative payload dose, response-adapted de-escalation) with PK of conjugate and free payload, tolerability estimands (ILD, ocular toxicity, neuropathy) and efficacy. The 5.4 versus 6.4 mg/kg trastuzumab deruxtecan comparison and dose modifications for several approved ADCs show dose was not optimised at approval.

## Fields

- Kind: Idea
- Last checked: 2026-09-08
- Hypothesis: Optimised ADC dosing will reduce grade 2+ exposure-driven toxicities by a third and discontinuation rates substantially, with non-inferior efficacy, for most ADCs tested.
- Rationale: ADC toxicity is largely payload-exposure-driven and cumulative, while efficacy depends on target saturation that occurs at lower doses; the therapeutic window is being wasted by MTD-based dosing.
- Proposed test: Two randomised phase 2/3 dose-comparison trials of approved ADCs with high discontinuation rates, with tolerability co-primary and efficacy non-inferiority.
- 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/)
- drugs: [Enfortumab vedotin](https://onco.cc/drugs/enfortumab-vedotin/), [Mirvetuximab soravtansine](https://onco.cc/drugs/mirvetuximab-soravtansine/), [Sacituzumab govitecan](https://onco.cc/drugs/sacituzumab-govitecan/), [Trastuzumab deruxtecan](https://onco.cc/drugs/trastuzumab-deruxtecan/)
- terms: [Drug-to-antibody ratio (DAR)](https://onco.cc/terms/dar/), [Interstitial lung disease (ILD) / pneumonitis](https://onco.cc/terms/ild/), [Payload (ADC)](https://onco.cc/terms/payload/)
- bottlenecks: [Toxicity and quality of life are undervalued](https://onco.cc/bottlenecks/b-toxicity-qol/), [Wrong doses](https://onco.cc/bottlenecks/b-dose-optimisation/)

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