A Phase Ib Combination Study of Rituximab, TinostamustinEAnd CHeckpoint Inhibition With Pembrolizumab in Relapsed/Refractory DLBCL
NCT ID: NCT04279938
Last Updated: 2020-02-21
Study Results
The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.
Basic Information
Get a concise snapshot of the trial, including recruitment status, study phase, enrollment targets, and key timeline milestones.
WITHDRAWN
PHASE1
INTERVENTIONAL
2018-09-30
2021-01-31
Brief Summary
Review the sponsor-provided synopsis that highlights what the study is about and why it is being conducted.
Main study (part 2): Relapsed or refractory diffuse large B-cell lymphoma
Related Clinical Trials
Explore similar clinical trials based on study characteristics and research focus.
Study to Evaluate the Efficacy and Tolerability of Debio 1562 in Combination With Rituximab in Participants With Relapsed and/or Refractory DLBCL and Other Forms of NHL
NCT02564744
Ibrutinib in Combination With Lenalidomide and Rituximab in Participants With Relapsed or Refractory Diffuse Large B-Cell Lymphoma
NCT02077166
Treatment of Relapsed or Refractory Diffuse Large B Cell Lymphoma With Ociperlimab (BGB-A1217) in Combination With Tislelizumab (BGB-A317) or Rituximab
NCT05267054
Pembrolizumab in Combination With R-ICE Chemotherapy in Relapsed/Refractory Diffuse Large B-cell Lymphoma
NCT05221645
A Multi-Center Study of Ibrutinib in Combination With MEDI4736 in Subjects With Relapsed or Refractory Lymphomas
NCT02401048
Detailed Description
Dive into the extended narrative that explains the scientific background, objectives, and procedures in greater depth.
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.
Conditions
See the medical conditions and disease areas that this research is targeting or investigating.
Study Design
Understand how the trial is structured, including allocation methods, masking strategies, primary purpose, and other design elements.
NA
SINGLE_GROUP
TREATMENT
NONE
Study Groups
Review each arm or cohort in the study, along with the interventions and objectives associated with them.
Safety Run in & Main Efficacy Part
Part 1 (safety run-in) aims to evaluate the maximum tolerated dose (MTD) of tinostamustinein combination with pembrolizumab (200mg Q3W) and rituximab (375mg/m2 Q3W). The dose of tinostamustineestablished to be safe and tolerable in this combination will be used in part 2 of the trial (main efficacy part).
The aim of part 2 is to detect signals of anti-tumour activity and to further assess the safety of this combination treatment in r/r DLBCL. The study has a strong focus on correlative research in order to identify mechanisms of response and resistance to pembrolizumab and the pembrolizumab/R-tinostamustinecombination.
Tinostamustinein
Tinostamustine80-120mg IV Q3W (dose to be determined in part 1) for 6 cycles
Pembrolizumab
Pembrolizumab 200mg IV Q3W until disease progression or unacceptable toxicities (max. 2 years)
Rituximab
Rituximab 375 mg/m2 IV Q3W for 6 cycles
Interventions
Learn about the drugs, procedures, or behavioral strategies being tested and how they are applied within this trial.
Tinostamustinein
Tinostamustine80-120mg IV Q3W (dose to be determined in part 1) for 6 cycles
Pembrolizumab
Pembrolizumab 200mg IV Q3W until disease progression or unacceptable toxicities (max. 2 years)
Rituximab
Rituximab 375 mg/m2 IV Q3W for 6 cycles
Eligibility Criteria
Check the participation requirements, including inclusion and exclusion rules, age limits, and whether healthy volunteers are accepted.
Inclusion Criteria
* Previous treatment with at least 1 line of standard therapy
* Age 18 or over
* ECOG performance status 0/1 Measurable disease on cross-sectional imaging that is at least 1.5 cm in the longest diameter and measureable in two perpendicular dimensions
* Adequate organ function
* Resolution of prior systemic therapy related non-haematological AEs to grade (G) ≤ 1. Participants with ≤ G 2 neuropathy may be eligible.
* Consent to provide fresh tumour tissue during screening and treatment
Exclusion Criteria
* Autologous stem cell transplant (ASCT) within 12 weeks or other anticancer treatment within 3 weeks of commencing therapy
* Prior allogeneic transplant
* Known HIV, or active Hepatitis B/C infection
* Active systemic autoimmune disease
* No previous therapy with agents targeting immune checkpoint proteins
18 Years
ALL
Yes
Sponsors
Meet the organizations funding or collaborating on the study and learn about their roles.
Merck Sharp & Dohme LLC
INDUSTRY
Mundipharma-EDO GmbH
INDUSTRY
Royal Marsden NHS Foundation Trust
OTHER
Responsible Party
Identify the individual or organization who holds primary responsibility for the study information submitted to regulators.
Principal Investigators
Learn about the lead researchers overseeing the trial and their institutional affiliations.
Professor David Cunningham
Role: STUDY_CHAIR
The Royal Marsden Hospital NHS Foundation Trust
Locations
Explore where the study is taking place and check the recruitment status at each participating site.
The Royal Marsden NHS Foundation Trust
Sutton, Surrey, United Kingdom
Countries
Review the countries where the study has at least one active or historical site.
Other Identifiers
Review additional registry numbers or institutional identifiers associated with this trial.
REACH - Trial Number pending
Identifier Type: -
Identifier Source: org_study_id
More Related Trials
Additional clinical trials that may be relevant based on similarity analysis.