8 Oct 2018
$AFMD puts 2 #AFM11 trials on clinical hold for SAEs in 3 patients:
• 2 life-threatening AEs in clinicaltrials.gov/ct2/show/NCT02… (R/R NHL)
• 1 death in clinicaltrials.gov/ct2/show/NCT02… (R/R B-ALL)
A trial such as this demands the closest and most concrete analysis we can bring to it. 7/
[my abstract below]
So now I need a dose-response model for toxicity that incorporates BOTH:
(a) ordinal toxicities AND
(b) inter-individual heterogeneity.
Several extant models already do (a), and I’ll discuss their connections with my own model below.
But (b) is a new requirement. 12/
The key to this notationally is to posit that a DLT occurs at the boundary between CTCAE grades 2–3, and to write: 13/
MTDᵢ ≡ MTDᵢᵍ, g=3
MTDᵢ¹ = max dose patient i can tolerate before getting a Grade 1 toxicity
MTDᵢ² = max dose patient i can tolerate before getting a Grade 2 toxicity
MTDᵢ⁵ = max dose patient i can tolerate before getting a Grade 5 (fatal) toxicity. 14/
log MTDᵢ ~ 𝒩(μ,τ), τ ≡ 1/σ².
MTDᵢᵍ = rᵢ⁽ᵍ⁻³⁾·MTDᵢᵍ (Eq. 3)
effectively assumes that the grading system is superbly aligned with the underlying dose-response. 17/
log rᵢ ~ 𝒩(log r₀, τᵣ) , τᵣ≫1.
How much easier would this elicitation be, conducted in terms of #titration in the individual patient! 26/
But now back to my own priors, inferred from the actual design of the trial. To begin, the prior on μ:
μ ~ 𝒰[2.9, 7.5]
aimed to center
log MTDᵢ ~ 𝒩(μ,τ)
at a median of log(180), the Cohort 5 target dose [ng/kg/week] ±1 order of magnitude either side. 27/
CV ~ 𝒩(0.5, σ=1/6).
I argue that adopting a dose-escalation design requires holding an expectation that CV is modest. The σ=1/6 puts CV>1 in the normal distribution’s 3σ upper tail. 29/
r₀ ~ 𝒰(1, 5).
Both endpoints here are safely outside the bounds of reason. 30/
While μ≈5 puts median MTDᵢ around e⁵≈150 ng/kg weekly, close to the Cohort 5 dose of 180, finding CV≈1 is a ‘surprise’, and the r₀≈1.3 deserves at least some comment. 36/
But it DOES conflict in retrospect with the 3⨉ multiplier between dose levels (and the 3⨉ step-up dosing) in this trial. 39/
Beneath the retrospective surface of this discussion is a prospective opportunity:
Since this model may be used in this same way at EVERY dosing decision, it actually forms a basis for designing and implementing dose-#titration trials with ordinal outcomes! /44