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

Primary Purpose

Diffuse Large B Cell Lymphoma

Status
Withdrawn
Phase
Phase 1
Locations
Study Type
Interventional
Intervention
Pembrolizumab and CXD101
Sponsored by
University College, London
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Diffuse Large B Cell Lymphoma focused on measuring Relapsed, Refractory

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  1. 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
  2. Measurable disease (of >15mm in a node or >10mm in extranodal tissue)
  3. Age 18 years or over
  4. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.
  5. Adequate organ and bone marrow function: Hb >80g/L, neutrophils >1.0x10^9/L and platelets >75x10^9/L (without platelet transfusion support)
  6. 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
  7. Adequate renal function: estimated creatinine clearance >60ml/min as calculated using the Cockroft-Gault equation
  8. Adequate liver function, including:

    1. Bilirubin ≤1.5 x upper limit of normal (ULN).
    2. Aspartate or alanine transferase (AST or ALT) ≤2.5 x ULN
  9. Negative serum or urine pregnancy test for women of childbearing potential (WOCBP)
  10. Willing to comply with the contraceptive requirements of the trial
  11. Written informed consent

Exclusion Criteria:

  1. Post-transplant lymphoproliferative disorder
  2. 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
  3. Patients with corrected QTc (QTcF or QTcB) interval >450msec
  4. Clinically significant cardiac or respiratory disease:

    1. Cardiac disease: Myocardial infarction, severe/unstable angina pectoris within 6 months prior to starting study treatment, NYHA class III-IV heart failure
    2. Pulmonary disease causing ≥ grade 2 dyspnoea or patient requiring oxygen
  5. Known involvement of the central nervous system with lymphoma
  6. Clinically significant active infection requiring antibiotic or antiretroviral therapy
  7. Active autoimmune disease that has required systemic treatment in the past 2 years
  8. History of (non-infectious) pneumonitis that required steroids or has current pneumonitis
  9. History of immune hepatitis or myocarditis
  10. Systemic anti-cancer therapy within 4 weeks prior to starting study treatment (12 weeks for CAR T-cells)
  11. 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.
  12. Received a live vaccine within 30 days prior to starting study treatment
  13. Have taken an IMP/investigational device within 4 weeks prior to starting study treatment
  14. Major surgery within 4 weeks prior to starting study treatment
  15. 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)
  16. 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
  17. Diagnosis of prior immunodeficiency or organ-transplant requiring immunosuppressive therapy, or known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)-related illness
  18. 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
  19. Severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients and/or a history of allergies to the excipients for CXD101
  20. 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
  21. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the study
  22. 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
  23. 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)
  24. Patient unable to swallow

Sites / Locations

    Arms of the Study

    Arm 1

    Arm Type

    Experimental

    Arm Label

    Pembrolizumab and CXD101

    Arm Description

    Initial 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.

    Outcomes

    Primary Outcome Measures

    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
    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

    Secondary Outcome Measures

    Overall Response Rate at the end of 4 cycles
    Overall Response of the combination of CXD101 and Pembrolizumab
    Response Duration
    Time from date of first response confirmation to the first date of progressive disease confirmation
    Best Overall Response at any time point
    Best Overall Response of CXD101 in combination with Pembrolizumab
    Best response at end of cycle 6 of treatment
    CR, PR, MR, Stable Disease, Progressive Disease rates over 6 weeks of treatment
    Progression Free Survival
    Progression Free Survival at 1 year
    Overall Survival
    Overall survival at 1 year
    Incidence of treatment-emergent adverse events (safety and tolerability)
    Adverse events to be reported during and after treatment, coded using CTCAE v5.0

    Full Information

    First Posted
    March 5, 2019
    Last Updated
    August 12, 2021
    Sponsor
    University College, London
    Collaborators
    Celleron Therapeutics Ltd., Merck Sharp & Dohme LLC
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    1. Study Identification

    Unique Protocol Identification Number
    NCT03873025
    Brief Title
    A Study of CXD101 in Combination With Pembrolizumab for Relapsed or Refractory Diffuse Large B-Cell Lymphoma
    Acronym
    PLACARD
    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
    Study Type
    Interventional

    2. Study Status

    Record Verification Date
    August 2021
    Overall Recruitment Status
    Withdrawn
    Why Stopped
    There are insufficent funds to open the trial and start recruiting patients due to the impact of the COVID-19 pandemic.
    Study Start Date
    October 2019 (Anticipated)
    Primary Completion Date
    April 2024 (Anticipated)
    Study Completion Date
    April 2025 (Anticipated)

    3. Sponsor/Collaborators

    Responsible Party, by Official Title
    Sponsor
    Name of the Sponsor
    University College, London
    Collaborators
    Celleron Therapeutics Ltd., Merck Sharp & Dohme LLC

    4. Oversight

    Studies a U.S. FDA-regulated Drug Product
    No
    Studies a U.S. FDA-regulated Device Product
    No
    Data Monitoring Committee
    Yes

    5. Study Description

    Brief 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.
    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).

    6. Conditions and Keywords

    Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
    Diffuse Large B Cell Lymphoma
    Keywords
    Relapsed, Refractory

    7. Study Design

    Primary Purpose
    Treatment
    Study Phase
    Phase 1, Phase 2
    Interventional Study Model
    Single Group Assignment
    Masking
    None (Open Label)
    Allocation
    N/A
    Enrollment
    0 (Actual)

    8. Arms, Groups, and Interventions

    Arm Title
    Pembrolizumab and CXD101
    Arm Type
    Experimental
    Arm Description
    Initial 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.
    Intervention Type
    Combination Product
    Intervention Name(s)
    Pembrolizumab and CXD101
    Intervention Description
    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.
    Primary Outcome Measure Information:
    Title
    Safety run in: Determine the maximum tolerated dose of CXD101 given in combination with pembrolizumab
    Description
    MTD to be defined as the highest dose level where 0 or 1 Dose limiting toxicity is observed in 6 patients
    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)
    Title
    Best Objective Response Rate
    Description
    Proportion of patients achieving CR or PR during the first 6 cycles of CXD101 in combination with pembrolizumab using the RECIL criteria
    Time Frame
    From baseline to end of cycle 6 of treatment (approximately 18 weeks; each cycle lasts 21 days)
    Secondary Outcome Measure Information:
    Title
    Overall Response Rate at the end of 4 cycles
    Description
    Overall Response of the combination of CXD101 and Pembrolizumab
    Time Frame
    From baseline to end of cycle 4 of treatment (approximately 12 weeks; each cycle lasts 21 days)
    Title
    Response Duration
    Description
    Time from date of first response confirmation to the first date of progressive disease confirmation
    Time Frame
    From start of treatment to time of disease progression (any time during study participation, minimum 3 years)
    Title
    Best Overall Response at any time point
    Description
    Best Overall Response of CXD101 in combination with Pembrolizumab
    Time Frame
    From baseline to end of treatment (up to 2 years)
    Title
    Best response at end of cycle 6 of treatment
    Description
    CR, PR, MR, Stable Disease, Progressive Disease rates over 6 weeks of treatment
    Time Frame
    From baseline to end of cycle 6 of treatment (approximately 18 weeks; each cycle lasts 21 days)
    Title
    Progression Free Survival
    Description
    Progression Free Survival at 1 year
    Time Frame
    52 weeks after commencement of CXD101 and Pembrolizumab
    Title
    Overall Survival
    Description
    Overall survival at 1 year
    Time Frame
    52 weeks after commencement of CXD101 and Pembrolizumab
    Title
    Incidence of treatment-emergent adverse events (safety and tolerability)
    Description
    Adverse events to be reported during and after treatment, coded using CTCAE v5.0
    Time Frame
    From start of CXD101 and Pembrolizumab until 5 months post-treatment

    10. Eligibility

    Sex
    All
    Minimum Age & Unit of Time
    18 Years
    Accepts Healthy Volunteers
    No
    Eligibility Criteria
    Inclusion Criteria: 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 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 Exclusion Criteria: 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 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
    Overall Study Officials:
    First Name & Middle Initial & Last Name & Degree
    Graham Collins
    Organizational Affiliation
    Oxford University Hospitals NHS Trust
    Official's Role
    Principal Investigator

    12. IPD Sharing Statement

    Plan to Share IPD
    No

    Learn more about this trial

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

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