Relapsed or Refractory Diffuse Large B-cell LymphomaPhase 1NCT04279938
A Phase Ib Combination Study of Rituximab, TinostamustinEAnd CHeckpoint Inhibition With Pembrolizumab in Relapsed/Refractory DLBCL
A Phase 1 study testing Tinostamustinein, Pembrolizumab and Rituximab in people with Relapsed or Refractory Diffuse Large B-cell Lymphoma, run by Royal Marsden NHS Foundation Trust at 1 site in United Kingdom.
Trial summary
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 Read more about this study
- Who is it for?
- Ages 18 years and olderHealthy volunteers can take part
- Conditions the study is for
- Relapsed or Refractory Diffuse Large B-cell Lymphoma
- What is being tested?
- Tinostamustinein, Pembrolizumab and Rituximab
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 0 participants
- Where
- 1 siteUnited Kingdom
- Study dates
- Sep 2018to Jan 2021
- Phase
- Phase 1
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- Healthy volunteers accepted
- Adult, Older adult
Who may be able to join
- Histologically proven CD20+ DLBCL (including transformed lymphoma)
- 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
Who cannot join
- CNS or leptomeningeal involvement
- 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
Trial locations and contacts
1 site in 1 country.
United Kingdom1 site
The Royal Marsden NHS Foundation Trust
Sutton, Surrey, SM2 5PT
About this study
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
Read the detailed description
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
- 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.
- 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
- 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.
- 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.
- 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.
- 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.
- Being tested
- Tinostamustinein, Pembrolizumab, Rituximab
- Medical subject headings
- Recurrence, Lymphoma, Large B-Cell, Diffuse
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
TinostamustineinDrug
Tinostamustine80-120mg IV Q3W (dose to be determined in part 1) for 6 cycles
PembrolizumabDrug
Pembrolizumab 200mg IV Q3W until disease progression or unacceptable toxicities (max. 2 years)
RituximabDrug
Rituximab 375 mg/m2 IV Q3W for 6 cycles
| Study group | Role | What they receive |
|---|---|---|
| Safety Run in & Main Efficacy Part | Other | 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. Receives: Drug: Tinostamustinein; Drug: Pembrolizumab; Drug: Rituximab |
What is being measured
The primary outcome is the main question the study is designed to answer.
Number of participants with treatment-related adverse events as assessed by CTCAE v4.0
Part 1 (safety run-in): To assess the safety and tolerability of pembrolizumab in combination with R-tinostamustineand to recommend a safe and tolerated dose of tinostamustinefor use in part 2 in combination with 200mg pembrolizumab and 375mg/m2 rituximab .
Part 2 (main study): To assess efficacy of pembrolizumab in combination with R-tinostamustineas determined by best overall response in subjects with relapsed/refractory (r/r) DLBCL.
Measured: 2.3 years
Secondary outcomes (1)
Secondary Objectives
Anti-tumour activity of pembrolizumab in combination with R-tinostamustineas determined by complete response rate (CR), duration of response (DOR), progression-free survival (PFS) and overall survival (OS)
- To assess the safety profile of pembrolizumab in combination with R-tinostamustinein subjects with r/r DLBCL
- Exploratory biomarkers of response and resistance to pembrolizumab in combination with R-tinostamustine
Measured: 2.3 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted21 Feb 2020
- Study startSep 2018 (estimated)
- Primary completionMar 2020 (estimated)
- Study completionJan 2021 (estimated)
Why it stopped: Safety data on drug
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Relapsed or Refractory Diffuse Large B-cell LymphomaStudies of the same condition, open and under way.
- More trials run by Royal Marsden NHS Foundation TrustThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 0 participants (actual)
Sponsor and investigators
- Lead sponsor
- Royal Marsden NHS Foundation Trust
- Sponsor type
- University, hospital or other
- Collaborators
- Merck Sharp & Dohme LLC, Mundipharma-EDO GmbH
- Responsible party
- Sponsor
- Investigators
- Professor David Cunningham, Study chair, The Royal Marsden Hospital NHS Foundation Trust
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04279938
- Sponsor's protocol ID
- REACH - Trial Number pending
- Status last verified
- Feb 2020
- First submitted
- 12 Jan 2018
- Last updated
- 21 Feb 2020
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 21 Feb 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase Ib Combination Study of Rituximab, TinostamustinEAnd CHeckpoint Inhibition With Pembrolizumab in Relapsed/Refractory DLBCL - REACH
- ClinicalTrials.gov ID
- NCT04279938
- Acronym / sponsor ID
- REACH - Trial Number pending
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- WithdrawnReason stopped: Safety data on drug
- Enrolment
- 0 participants (actual)
- Lead sponsor
- Royal Marsden NHS Foundation TrustUniversity, hospital or other
- Collaborators
- Merck Sharp & Dohme LLC, Mundipharma-EDO GmbH
- Study start
- Sep 2018 (estimated)
- Primary completion
- Mar 2020 (estimated)
- Study completion
- Jan 2021 (estimated)
- First posted
- 21 Feb 2020 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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
Detailed description
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
- 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.
- 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
- 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.
- 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.
- 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.
- 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.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Safety Run in & Main Efficacy Part | Other | Drug: Tinostamustinein, Drug: Pembrolizumab, Drug: RituximabPart 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. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (7 listed)
- Histologically proven CD20+ DLBCL (including transformed lymphoma)
- 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
Key exclusion criteria (6 listed)
- CNS or leptomeningeal involvement
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| TinostamustineinTinostamustine80-120mg IV Q3W (dose to be determined in part 1) for 6 cycles | Drug | Safety Run in & Main Efficacy Part |
| PembrolizumabPembrolizumab 200mg IV Q3W until disease progression or unacceptable toxicities (max. 2 years) | Drug | Safety Run in & Main Efficacy Part |
| RituximabRituximab 375 mg/m2 IV Q3W for 6 cycles | Drug | Safety Run in & Main Efficacy Part |
Primary outcome
Number of participants with treatment-related adverse events as assessed by CTCAE v4.0
Time frame: 2.3 years
Part 1 (safety run-in): To assess the safety and tolerability of pembrolizumab in combination with R-tinostamustineand to recommend a safe and tolerated dose of tinostamustinefor use in part 2 in combination with 200mg pembrolizumab and 375mg/m2 rituximab . Part 2 (main study): To assess efficacy of pembrolizumab in combination with R-tinostamustineas determined by best overall response in subjects with relapsed/refractory (r/r) DLBCL.
1 secondary outcome
Secondary Objectives
Time frame: 2.3 years
Results and safety
The study was withdrawn before enrolling participants, so there are no results.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 21 Feb 2020.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Professor David Cunningham study chair
The Royal Marsden Hospital NHS Foundation Trust
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Tinostamustinein, Pembrolizumab and Rituximab in people with Relapsed or Refractory Diffuse Large B-cell Lymphoma, run by Royal Marsden NHS Foundation Trust at 1 site in United Kingdom.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 7 inclusion and 6 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: withdrawn, as of the sponsor's last update on 21 Feb 2020. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United Kingdom. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study was withdrawn before enrolling participants, so there are no results.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 (time frame: 2.3 years). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 21 Feb 2020.