A phase I-Ib/II, open-label, multi-center study of the safety and efficacy of MBG453 as single agent and in combination with PDR001 in adult patients with advanced malignancies

MBG453 is a high-affinity, ligand-blocking, humanized anti-TIM-3 IgG4 antibody
which blocks the binding of TIM-3 to Phosphatidylserine. MBG453 shows
functional activity.
PDR001 is a high-affinity, ligand-blocking, humanized anti-PD-1 IgG4 antibody
that blocks the binding of PD-L1 and PD-L2 to PD-1. PDR001 shows functional
activity.


This first-in-humans study with MBG453 (alone and in combination with PDR001)
will characterize the safety, tolerability, pharmacokinetics, pharmacodynamics
and antitumor activity of MBG453 and MBG453 plus PDR001 administered i.v.
The first-in humans study with PDR001 is ongoing. In the first 6 patients no
DLTs, SAEs, dose reductions or dose interruptions during the first cycle of
treatment were seen.
The rationale for combining MBG453 with PDR001 is based on scientific evidence
in preclinical models. Several reports have shown that the cancer-induced
inhibitory modulation of T-cell activation is synergistically promoted by the
concurrent blockade of TIM-3 and PD-1.

Primary:
Phase I:
- To characterize the safety and tolerability of MBG453 as a single agent and
in combination with PDR001 and to identify recommended doses for future
studies. To further investigate the safety and tolerability of different doses
of MBG453 alone or in combination with PDR001 during the dose ranging part.

Phase II: To estimate the anti-tumor activity of MBG453 alone and in
combination with PDR001.

Secondary:
Both phases:
- to evaluate the preliminary anti-tumor activity of MBG453 as single agent and
in combination with PDR001.
- to make an initial comparison for the combination of MBG453 and PDR001
administered on a Q2W and Q4W dosing schedules.

Multicenter phase I-Ib/II open-label dose escalation study (phase I and Ib) and
dose expansion study (phase II) of MBG453 monotherapy (phase I) and MBG453 and
PDR001 combination therapy (phase Ib and II).

Phase Ib will commence after at least two cohorts in the dose escalation with
single agent have been completed and safety data suggests acceptable toxicity.
Once the MTD/RP2D of MBG453 as single agent and/or in combination with PDR001
is achieved, the phase II part will commence with selected indications
(melanoma, NSCLC and renal cell cancer).

Following declaration of the MTDs/RP2Ds for single agent and combination, and
only if efficacy has already been observed in the dose escalation parts, an
optional dose ranging part of the study may be opened. The dose ranging part
will only enroll patients not eligible for the phase II part of the study. The
dose ranging part may include the testing of different dose levels to better
understand the safety, tolerability and PK of MBG453 as single agent and in
combination with PDR001.

Should signs of anti-tumor activity be seen in the phase I dose escalation with
MBG453 as single agent, a phase II part will be opened in order to further
explore single agent efficacy at the recommended dose and schedule. Patients
with tumor types that have been shown to respond to single agent MBG453
(maximum of two indications) will be enrolled.

Treatment until disease progression or unacceptable side effects.

Follow-up for survival.

MBG453, intravenous every 2 weeks. Starting dose 80mg as single agent, 20mg in
combination with PDR001
PDR001, intravenous every 2 weeks. Starting dose 80mg


If necessary a once every 3 or once every 4 weeks schedule might be tested.

Risk: Adverse effects of MBG453 with or without PDR001 and potential risks
related to the assesments.

Burden: Cycles of 4 weeks. Cycle 1 and 3: five visits, Cycle 2: two visits,
from cycle 4 onwards two visits (in case of a once per 4 weeks dosing schedule:
1 visit per cycle).
Visit duration 1-4 hours.


Physical examination and vital signs: cycle 1: every week, cycle 2 and
subsequent cycles: every 2 weeks.
Blood tests for safety: cycle 1: 3 times, cycle 2: 2 times, from cycle 3
onwards: once per cycle. Additional blood draws: for PK, immunology biomarkers:
200 ml in total.
ECG: Screening, Cycles 1, 3 and 6 pre- and post infusion
Fresh tumorbiopsies at baseline, during treatment (cycle 3 and End of
Treatment).
CT-/MRIscan: every 2nd cycle until cycle 11. Thereafter every 3rd cycle.
Optional storage and use of the remaining blood and tissue for future research
after end of trial.