# ACT IV

Source: https://onco.cc/trials/act-iv/  
OnCo record `act-iv` (Trial). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

ACT IV was a double-blind phase 3 test of rindopepimut, a vaccine against the EGFRvIII mutant protein, in 745 patients with newly diagnosed glioblastoma. It showed no benefit over a control vaccine, and because both arms beat historical expectations it taught the field how misleading historical-control comparisons can be.

## Summary

ACT IV, trial NCT01480479 sponsored by Celldex Therapeutics and reported in 2016, was a double-blind test of the EGFRvIII vaccine rindopepimut in newly diagnosed glioblastoma with minimal residual disease that showed no benefit, and it taught the field how misleading historical-control comparisons can be. It randomised 745 patients to rindopepimut or a control vaccine with temozolomide and found no difference in overall survival, while both arms outperformed historical expectations and EGFRvIII was lost at recurrence in most patients whichever arm they were in. OnCo links it to EGFR as a target, the EGFRvIII term, rindopepimut and the brain as a bottleneck, and the trial failed to replicate the phase 2 ACT III signal. Whether a single-antigen vaccine can ever work against a target the tumour so readily discards is the question its failure answered in the negative.

## Fields

- Kind: Trial
- Status: negative
- Last checked: 2026-09-06
- Registry id: NCT01480479
- Phase: 3
- Setting: Newly diagnosed EGFRvIII+ glioblastoma with minimal residual disease: rindopepimut + temozolomide vs control (KLH) + temozolomide
- Sponsor: Celldex Therapeutics
- Enrolled: 745
- Result: OS 20.1 vs 20.0 months; no benefit.
- Outcomes: Overall survival, minimal residual disease population: Rindopepimut + temozolomide 20.1 months vs Control + temozolomide 20 months, HR 1.01
- Replication: Failed to replicate the phase 2 ACT III signal; EGFRvIII loss at recurrence in both arms undermined the target.

## Sources

- ClinicalTrials.gov NCT01480479: https://clinicaltrials.gov/study/NCT01480479

## Connected records

- cancers: [Glioma & glioblastoma](https://onco.cc/cancers/glioblastoma/)
- technologies: [Off-the-shelf cancer vaccines](https://onco.cc/technologies/shared-antigen-vaccine/)
- targets: [EGFR](https://onco.cc/targets/egfr/)
- drugs: [Rindopepimut](https://onco.cc/drugs/rindopepimut/)
- companies: [Celldex Therapeutics](https://onco.cc/companies/celldex/)
- terms: [Blinding (double-blind, open-label, placebo-controlled)](https://onco.cc/terms/double-blind/), [Control arm and comparator (investigator's choice)](https://onco.cc/terms/control-arm/), [EGFRvIII](https://onco.cc/terms/egfrviii/), [External and synthetic control arms](https://onco.cc/terms/external-control-arm/), [Placebo](https://onco.cc/terms/placebo/), [Why trials fail: underpowered, wrong endpoint, control arm drift, subgroup fishing, crossover](https://onco.cc/terms/trial-failure-modes/)
- bottlenecks: [The brain: barrier and sanctuary](https://onco.cc/bottlenecks/b-brain-delivery/)

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