Relapsed or Refractory Diffuse Large B-cell Lymphoma Clinical Trial
Official title:
A Phase Ib Combination Study of Rituximab, TinostamustinEAnd CHeckpoint Inhibition With Pembrolizumab in Relapsed/Refractory DLBCL - REACH
Safety run-in (part 1): Relapsed or refractory B-cell Non-Hodgkin lymphoma (NHL)
Main study (part 2): Relapsed or refractory diffuse large B-cell lymphoma
The primary objective of the safety run-in phase (part 1) is to assess the safety and
tolerability of pembrolizumab in combination with R-tinostamustineand to recommend a safe and
tolerated dose of tinostamustinefor use in combination with 200mg pembrolizumab and 375mg/m2
rituximab Q3W in the main efficacy part of the study (part 2).
Part 2 (main study) The primary objective of part 2 is to assess efficacy of pembrolizumab in
combination with R-tinostamustineas determined by the best overall response rate (ORR) in
subjects with r/r DLBCL.
Hypothesis: The combination of pembrolizumab and R-tinostamustinewill act synergistically and
show high anti-tumour efficacy in subjects with r/r DLBCL. R-EDO-S101 will increase
pembrolizumab-mediated anti-tumour immunity by (A) tumour de-bulking with improved access of
immune cells into the tumour and reduced burden of tumour sub-clones and (B) epigenetic
priming of PD-1 inhibition through the histone deacetylase inhibitor (HDACi) component of
tinostamustine.
Secondary Objectives & Hypotheses
1. Objective: Safety and tolerability of pembrolizumab in combination with
R-tinostamustine.
Hypothesis: Combination of pembrolizumab with R-tinostamustinewill be safe and well
tolerated in r/r DLBCL patients.
2. Objective: Anti-tumour activity of pembrolizumab in combination with R-tinostamustineas
determined by CR rate, duration of response (DOR), progression-free survival (PFS) and
overall survival (OS).
Hypothesis: Combination of pembrolizumab with R-tinostamustinewill lead to deep and long
remissions. Continuation of pembrolizumab treatment as maintenance after completion of
induction therapy will demonstrate conversion of partial to complete response in some cases
and prolonged stabilization of disease.
Exploratory Objectives
1. Objective: Minimal residual disease (MRD) detection in circulating cell-free tumour DNA
(ctDNA) throughout treatment.
Hypothesis: MRD assessment will enable better measurement of the depth of response in
order to assess the effect of pembrolizumab after completion of
R-tinostamustine/pembrolizumab induction.
2. Objective: Dynamics of circulating immune cell subsets in the peripheral blood (PB)
throughout treatment.
Hypotheses:
- Detailed assessment of lymphocyte-, monocyte- and myeloid subsets and their protein
expression from pre-treatment until disease progression will give insights into
immunomodulation by pembrolizumab, and identify suitable pharmacodynamic markers
and mechanisms of pembrolizumab resistance.
- Assessment of PB T-cell function by synapse formation capacity and T-cell
exhaustion will demonstrate restoration of T-cell defects by pembrolizumab.
3. Objective: Detailed analyses of tumour microenvironment (TME) changes during treatment
and on progression.
Hypotheses: Changes in the composition and function of tumour-associated immune- and
stromal cells will elucidate mechanisms of action and resistance of pembrolizumab and
the combination.
4. Objective: Evaluation of tumour-derived biomarkers of response and resistance.
Hypotheses: Association of the molecular background of DLBCL (somatic mutations, mRNA
and protein expression, DNA methylation) with treatment response will help to identify
predictive biomarkers for future validation.
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