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Diffuse Large B Cell LymphomaPhase 1/2PLACARDNCT03873025

A Study of CXD101 in Combination With Pembrolizumab for Relapsed or Refractory Diffuse Large B-Cell Lymphoma

A Phase 1/2 study testing Pembrolizumab and CXD101 in people with Diffuse Large B Cell Lymphoma, run by University College, London.

Withdrawn

Withdrawn. The study stopped before anyone enrolled.

Official record
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Trial summary

Trial Subjects (patients), will receive single infusions of pembrolizumab in combination with CXD101 every 3 weeks for two years or until disease progression or unacceptable toxicity develops. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Diffuse Large B Cell Lymphoma
What is being tested?
Pembrolizumab and CXD101
Could I receive a placebo?
No, everyone receives an active treatment
How many people
0 participants
Where
No sites listed yet
Study dates
Oct 2019to Apr 2025
Phase
Phase 1/2
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
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Biopsy-confirmed DLBCL, relapsed/ refractory after ≥2 lines of prior therapy and not fit for ASCT or relapsed post ASCT. Eligible histologies include (a) diffuse large B-cell lymphoma NOS, (b) transformed indolent non-Hodgkin lymphoma (including Richter's transformation), (c) EBV positive DLBCL NOS, (d) high grade B-cell lymphoma with MYC and BCL2 and/or BCL6 translocations, (e) high grade B-cell lymphoma NOS \& (f) primary mediastinal B-cell lymphoma
  • Measurable disease (of >15mm in a node or >10mm in extranodal tissue)
  • Age 18 years or over
  • Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.
  • Adequate organ and bone marrow function: Hb >80g/L, neutrophils >1.0x10^9/L and platelets >75x10^9/L (without platelet transfusion support)
  • International normalised ratio (INR) or prothrombin time (PT) or Activated partial thromboplastin time (aPTT): ≤1.5 × ULN unless participant is receiving anticoagulant therapy as long as PT or aPTT is within therapeutic range of intended use of anticoagulants
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  • Adequate renal function: estimated creatinine clearance >60ml/min as calculated using the Cockroft-Gault equation
  • Adequate liver function, including:
  • Bilirubin ≤1.5 x upper limit of normal (ULN).
  • Aspartate or alanine transferase (AST or ALT) ≤2.5 x ULN
  • Negative serum or urine pregnancy test for women of childbearing potential (WOCBP)
  • Willing to comply with the contraceptive requirements of the trial
  • Written informed consent

Who cannot join

  • Post-transplant lymphoproliferative disorder
  • Women who are pregnant or breast feeding, or males expecting to conceive or father children at any point from the start of study treatment until 4 months after the last administration of study treatment
  • Patients with corrected QTc (QTcF or QTcB) interval >450msec
  • Clinically significant cardiac or respiratory disease:
  • Cardiac disease: Myocardial infarction, severe/unstable angina pectoris within 6 months prior to starting study treatment, NYHA class III-IV heart failure
  • Pulmonary disease causing ≥ grade 2 dyspnoea or patient requiring oxygen
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  • Known involvement of the central nervous system with lymphoma
  • Clinically significant active infection requiring antibiotic or antiretroviral therapy
  • Active autoimmune disease that has required systemic treatment in the past 2 years
  • History of (non-infectious) pneumonitis that required steroids or has current pneumonitis
  • History of immune hepatitis or myocarditis
  • Systemic anti-cancer therapy within 4 weeks prior to starting study treatment (12 weeks for CAR T-cells)
  • Prior radiotherapy within 2 weeks of start of study treatment. Participants must have recovered from all radiation-related toxicities, not require corticosteroids and not have had radiation pneumonitis.
  • Received a live vaccine within 30 days prior to starting study treatment
  • Have taken an IMP/investigational device within 4 weeks prior to starting study treatment
  • Major surgery within 4 weeks prior to starting study treatment
  • Prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g. CTLA-4, OX 40, CD137)
  • Prior allogeneic haematopoietic stem cell transplant, solid organ allogeneic transplant or allogeneic CAR T-cell therapy. Prior use of autologous CAR T-cell therapy is allowed but patient must be ≥ 12 weeks post infusion prior to starting study treatment
  • Diagnosis of prior immunodeficiency or organ-transplant requiring immunosuppressive therapy, or known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)-related illness
  • Positive serology for hepatitis B or C unless (as) hepatitis B positive due to vaccination (HBsAb positive, all other tests negative) or (b) past hepatitis B infection with low risk of reactivation (HBsAb positive \& HBcAb positive, other tests (including hepatitis B DNA) negative - PI/co-investigator approval needed
  • Severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients and/or a history of allergies to the excipients for CXD101
  • History or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the subject's participation for the full duration of the study, or is not in the best interest of the subject to participate, in the opinion of the treating investigator
  • Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the study
  • Non-haematological malignancy within the past 3 years with the exception of (a) adequately treated basal cell carcinoma, squamous cell skin cancer, or thyroid cancer (b) carcinoma in situ of the cervix or breast, (c) prostate cancer of Gleason grade 6 or less with stable prostate-specific antigen levels; or (d) cancer considered cured by surgical resection or unlikely to impact survival during the duration of the study such as localised transitional cell carcinoma of the bladder or benign tumours of the adrenal gland or pancreas
  • Current or prior use of immunosuppressive therapy within 7 days prior to start of treatment except the following: intranasal, inhaled, topical steroids or local steroid injections (eg. Intra-articular injection); systemic corticosteroids at physiologic doses (<10mg/day or less of prednisolone or equivalent)
  • Patient unable to swallow

About this study

Official title: Phase Ib/II Trial of Histone Deacetylase Inhibitor CXD101 in Combination With Programmed Cell Death Protein-1 Inhibitor Pembrolizumab for Relapsed or Refractory Diffuse Large B-cell Lymphoma

Trial Subjects (patients), will receive single infusions of pembrolizumab in combination with CXD101 every 3 weeks for two years or until disease progression or unacceptable toxicity develops.

Read the detailed description

Trial Subjects (patients) who are deemed eligible for the trial will initially be entered into the safety run-in stage of the trial. Up to 12 patients will be registered into the safety run-in stage, in cohorts of 3 patients at a time.

3 patients will be registered initially and will be administered a single infusion of pembrolizumab (200mg, day 1) in combination with CXD101 (20mg twice daily days 1 to 5). This is dose level 0.

If 0 to 1 dose limiting toxicity (DLT) is observed, 3 more patients will be entered into the trial and treated at dose level 0. If 0 to 1 DLT is observed across all 6 patients, the maximum tolerated dose (MTD) will be declared and the expansion stage of the trial will be opened.

If more than 1 DLT is observed at dose level 0, 3 patients will be recruited and treated at dose level -1. The CXD101 dose will be reduced by 25% (20mg in the morning and 10mg in the evening, days 1 to 5), while the pembrolizumab dose will remain the same (200mg, day 1).

If 0 or 1 DLT is observed, 3 more patients will be recruited and treated at dose level -1. If 0 or 1 DLT is observed across all 6 patients the maximum tolerated dose will be declared and the expansion stage of the trial will be opened.

If more than 1 DLT is observed at dose level -1 the combination will be deemed excessively toxic and no further patients enrolled.

Once the MTD is declared, the cohort will be expanded and a further 33 patients will be treated at this dose level.

Patients will continue to receive pembrolizumab and CXD101 at 3 weekly intervals for a maximum of 2 years or until disease progression or unacceptable toxicity develops. Patients on pembrolizumab will be seen every 3 weeks during trial treatment. Patients who progress will be seen annually for disease status. Patients completing treating or who stop treatment early for reasons other than disease progression will be followed every 3 months for up to one year after the end of treatment, and annually thereafter until end of trial is declared (when the last patient has completed 1 year follow up).

Being tested
Pembrolizumab and CXD101
Keywords
Relapsed, Refractory
Medical subject headings
Lymphoma, Large B-Cell, Diffuse, Recurrence

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Pembrolizumab and CXD101Combination product

    Pembrolizumab is a humanised monoclonal antibody which targets the programmed cell death 1 (PD-1) receptor. It blocks a protective mechanism on cancer cells, and allow the immune system to destroy these cancer cells. CXD101 is a histone deacetylase (HDAC) inhibitor which kills cancer cells by blocking the vital functions of HDAC enzymes.

Study groups in NCT03873025
Study groupRoleWhat they receive
Pembrolizumab and CXD101ExperimentalInitial dose ('dose level 0'):- Single 200mg pembrolizumab IV infusion (day 1) in combination with oral CXD101 20mg twice daily PO (days 1 to 5) given in 21-day cycles for 2 years or until termination of treatment due to disease progression or unacceptable toxicity. Reduced dose level ('Dose level -1'; if >1 DLT observed at dose level 0): Single 200mg pembrolizumab IV infusion (day 1) in combination with oral CXD101 given twice daily, 20mg in the morning and 10mg in the evening (days 1 to 5) given in 21-day cycles for 2 years or until termination of treatment due to disease progression or unacceptable toxicity.
Receives: Combination Product: Pembrolizumab and CXD101

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Safety run in: Determine the maximum tolerated dose of CXD101 given in combination with pembrolizumab

    MTD to be defined as the highest dose level where 0 or 1 Dose limiting toxicity is observed in 6 patients

    Measured: During first cycle of CXD101 + pembrolizumab (each cycle lasts 21 days; assessment will take into account dose limiting toxicities reported at any time during the first 21 days of treatment)

  2. Best Objective Response Rate

    Proportion of patients achieving CR or PR during the first 6 cycles of CXD101 in combination with pembrolizumab using the RECIL criteria

    Measured: From baseline to end of cycle 6 of treatment (approximately 18 weeks; each cycle lasts 21 days)

Secondary outcomes (7)

  1. Overall Response Rate at the end of 4 cycles

    Overall Response of the combination of CXD101 and Pembrolizumab

    Measured: From baseline to end of cycle 4 of treatment (approximately 12 weeks; each cycle lasts 21 days)

  2. Response Duration

    Time from date of first response confirmation to the first date of progressive disease confirmation

    Measured: From start of treatment to time of disease progression (any time during study participation, minimum 3 years)

  3. Best Overall Response at any time point

    Best Overall Response of CXD101 in combination with Pembrolizumab

    Measured: From baseline to end of treatment (up to 2 years)

  4. Best response at end of cycle 6 of treatment

    CR, PR, MR, Stable Disease, Progressive Disease rates over 6 weeks of treatment

    Measured: From baseline to end of cycle 6 of treatment (approximately 18 weeks; each cycle lasts 21 days)

  5. Progression Free Survival

    Progression Free Survival at 1 year

    Measured: 52 weeks after commencement of CXD101 and Pembrolizumab

  6. Overall Survival

    Overall survival at 1 year

    Measured: 52 weeks after commencement of CXD101 and Pembrolizumab

  7. Incidence of treatment-emergent adverse events (safety and tolerability)

    Adverse events to be reported during and after treatment, coded using CTCAE v5.0

    Measured: From start of CXD101 and Pembrolizumab until 5 months post-treatment

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted13 Mar 2019
  2. Study startOct 2019 (estimated)
  3. Primary completionApr 2024 (estimated)
  4. Study completionApr 2025 (estimated)

Why it stopped: There are insufficent funds to open the trial and start recruiting patients due to the impact of the COVID-19 pandemic.

Resources

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 1/2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
0 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03873025
Sponsor's protocol ID
UCL/17/0920
Acronym
PLACARD
Status last verified
Aug 2021
First submitted
5 Mar 2019
Last updated
17 Aug 2021
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
No

Questions about this trial

What is this clinical trial studying?

A Phase 1/2 study testing Pembrolizumab and CXD101 in people with Diffuse Large B Cell Lymphoma, run by University College, London.

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 13 inclusion and 26 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 17 Aug 2021. Status can change between updates, so confirm with the study contact before making plans.

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 combined 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.

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

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?

Safety run in: Determine the maximum tolerated dose of CXD101 given in combination with pembrolizumab (time frame: During first cycle of CXD101 + pembrolizumab (each cycle lasts 21 days; assessment will take into account dose limiting toxicities reported at any time during the first 21 days of treatment)). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03873025.

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 17 Aug 2021.

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