MCLA-117: a published within-patient escalation ladder

The Cycle 1 dose escalation scheme, and what it settles for this design

trial design

references

The MCLA-117 first-in-human Cycle 1 dose escalation scheme transcribed from the EHA 2020 e-poster, with the four features of it that bear on the scout-and-backfill design.

Published

September 6, 2026

Transcribed from an image of the poster, not from the poster. Every number below needs checking against the source before it is cited. Links are on the references page.

MCLA-117 (tepoditamab) is a CLEC12A x CD3 bispecific antibody. Its first-in-human phase 1 study in relapsed or refractory AML (NCT03038230) escalated within patients across four orders of magnitude, and is the precedent cited in Section 6 of the specification.

The Cycle 1 scheme

Cohorts 1 and 2, dosed on seven days in Cycle 1
Cohort	D1	D3	D5	D8	D11	D15	D22
1	25 µg	50 µg	100 µg	200 µg	300 µg	450 µg	675 µg
2	100 µg	200 µg	400 µg	750 µg	1000 µg	1250 µg	1500 µg

Cohorts 3 to 12, dosed on five days in Cycle 1
Cohort	D1	D4	D8	D15	D22
3	300 µg	1 mg	2 mg	2 mg	2 mg
4	600 µg	2 mg	6 mg	6 mg	6 mg
5	600 µg	2 mg	9 mg	9 mg	9 mg
6	1 mg	3 mg	15 mg	15 mg	15 mg
7	1 mg	3 mg	15 mg	25 mg	25 mg
8a	1 mg	3 mg	25 mg	40 mg	40 mg
8b	3 mg	10 mg	25 mg	40 mg	40 mg
9	5 mg	15 mg	25 mg	60 mg	60 mg
10	5 mg	15 mg	25 mg	120 mg	120 mg
11	5 mg	15 mg	25 mg	240 mg	240 mg
12	5 mg	15 mg	25 mg	400 mg	400 mg

Figure 1: MCLA-117 Cycle 1 dose escalation. Each line is one cohort’s within-patient ladder; the dose axis is logarithmic and spans the 25 µg first dose of cohort 1 to the 400 mg target dose of cohort 12.

What it settles

Within-patient traversal of four orders of magnitude is precedented and was executed. The programme ran from a 25 µg first dose to a 400 mg target dose, a factor of 16,000. Scout-and-backfill does not need to argue that a long ladder is possible.
The number of within-patient steps was not capped. Cohort 1 administers seven doses in 22 days and ends 27-fold above its own first dose, so the specification’s rejection of a rule such as “maximum three escalations” describes what this trial already did.
The first dose moved slowly while the target dose moved fast. Across the thirteen cohorts the D1 doses are 25, 100, 300, 600 and 600 µg, then 1, 1, 1, 3, 5, 5, 5 and 5 mg. The largest single increase in the D1 dose is 4-fold and most are 3-fold or less, while the D22 dose rises from 675 µg to 400 mg over the same sequence. The constraint sits on the first dose given to a patient who has had no drug, not on the ladder above it. This is the observation that changes the design, and Section 6 takes it up.
From cohort 9 the step-up prefix is fixed and only the target dose changes. Cohorts 9 to 12 all give 5 mg, 15 mg and 25 mg on D1, D4 and D8, and differ only in the D15/D22 target: 60, 120, 240 and 400 mg. That is the structure Section 7 assumes for the backfill regimen, a fixed step-up prefix with an escalating target, reached here empirically.

Observations 2 and 4 supply real values where Sections 13 and 15 carry assumptions: an escalation multiplier of roughly 2 to 3-fold per step, and five to seven steps inside a 28-day cycle.

Where the precedent and the simulated design differ

The step interval. Cohort 1 doses on D1, D3, D5, D8, D11, D15 and D22, so its first intervals are 2 and 3 days rather than 7. Scout-and-backfill holds the interval at one week, which makes the simulated ladder slower than the precedent rather than faster, and any acceleration it reports conservative on that axis. Whether a sub-weekly scout ladder is worth simulating is a later question; a 7-day interval is the v1 assumption because it is what the safety gate in Section 15 and the PD turnaround in Section 11 already support.

The figure

The escalation figure in Section 6 is drawn by make_escalation_figure.py, which carries the dose table above as its data. Change the table there and re-run it.