Clinical Trials /

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

NCT03873025

Description:

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.

Related Conditions:
  • Diffuse Large B-Cell Lymphoma
  • Diffuse Large B-Cell Lymphoma, Not Otherwise Specified
  • Double-Hit Lymphoma
  • EBV-Positive Diffuse Large B-Cell Lymphoma, Not Otherwise Specified
  • Mediastinal Large B-Cell Lymphoma
  • Richter Syndrome
  • Transformed Lymphoma
  • Triple-Hit Lymphoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: UCL/17/0920
  • NCT ID: NCT03873025

Conditions

  • Diffuse Large B Cell Lymphoma

Purpose

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).
    

Trial Arms

NameTypeDescriptionInterventions
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.

    Eligibility Criteria

            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. ECOG PS of 2 is
                 allowed if due to lymphoma
    
              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. Clinically significant myocardial infarction, severe/unstable angina pectoris within 6
                 months, NYHA class III-IV heart failure or significant pulmonary disease
    
              4. Known involvement of the central nervous system
    
              5. Clinically significant active infection requiring antibiotic or antiretroviral therapy
    
              6. Active autoimmune disease that has required systemic treatment in the past 2 years
                 (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive
                 drugs). Replacement therapy (e.g. thyroxine, insulin, or physiologic corticosteroid
                 replacement therapy for adrenal or pituitary insufficiency etc.) is not considered a
                 form of systemic treatment
    
              7. History of (non-infectious) pneumonitis that required steroids or has current
                 pneumonitis
    
              8. History of immune hepatitis or myocarditis
    
              9. Systemic anti-cancer therapy within 4 weeks prior to trial registration.
    
             10. 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. A 1 week washout is permitted for palliative radiation
                 (≤2 weeks of radiotherapy) to non-CNS disease
    
             11. Received a live vaccine within 30 days prior to starting study treatment
    
             12. Have taken an IMP/investigational device within 4 weeks prior to starting study
                 treatment
    
             13. Major surgery within 4 weeks prior to trial registration
    
             14. 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)
    
             15. Prior allogeneic haematopoietic stem cell transplant. Prior CAR T-cell therapy is
                 allowed
    
             16. Diagnosis of prior immunodeficiency or organ-transplant requiring immunosuppressive
                 therapy, or known human immunodeficiency virus (HIV) or acquired immunodeficiency
                 syndrome (AIDS)-related illness
    
             17. Known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] reactive)
                 or known active Hepatitis C virus (defined as HCV RNA detected) infection
    
             18. Severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients
                 and/or a history of allergies to the excipients for CXD101
    
             19. 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
    
             20. Has known psychiatric or substance abuse disorders that would interfere with
                 cooperation with the requirements of the study
    
             21. Has a known additional malignancy that is progressing or has required active treatment
                 within the past 3 years. Note: Patients with basal cell carcinoma of the skin,
                 squamous cell carcinoma of the skin or carcinoma in situ (e.g. ductal carcinoma in
                 situ of the breast, cervical cancer in situ) that have undergone potentially curative
                 therapy are not excluded
    
             22. 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)
    
             23. Patient unable to swallow
          
    Maximum Eligible Age:N/A
    Minimum Eligible Age:18 Years
    Eligible Gender:All
    Healthy Volunteers:No

    Primary Outcome Measures

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

    Secondary Outcome Measures

    Measure:Overall Response Rate at the end of 4 cycles
    Time Frame:From baseline to end of cycle 4 of treatment (approximately 12 weeks; each cycle lasts 21 days)
    Safety Issue:
    Description:Overall Response of the combination of CXD101 and Pembrolizumab
    Measure:Response Duration
    Time Frame:From start of treatment to time of disease progression (any time during study participation, minimum 3 years)
    Safety Issue:
    Description:Time from date of first response confirmation to the first date of progressive disease confirmation
    Measure:Best Overall Response at any time point
    Time Frame:From baseline to end of treatment (up to 2 years)
    Safety Issue:
    Description:Best Overall Response of CXD101 in combination with Pembrolizumab
    Measure:Best response at end of cycle 6 of treatment
    Time Frame:From baseline to end of cycle 6 of treatment (approximately 18 weeks; each cycle lasts 21 days)
    Safety Issue:
    Description:CR, PR, MR, Stable Disease, Progressive Disease rates over 6 weeks of treatment
    Measure:Progression Free Survival
    Time Frame:52 weeks after commencement of CXD101 and Pembrolizumab
    Safety Issue:
    Description:Progression Free Survival at 1 year
    Measure:Overall Survival
    Time Frame:52 weeks after commencement of CXD101 and Pembrolizumab
    Safety Issue:
    Description:Overall survival at 1 year
    Measure:Incidence of treatment-emergent adverse events (safety and tolerability)
    Time Frame:From start of CXD101 and Pembrolizumab until 5 months post-treatment
    Safety Issue:
    Description:Adverse events to be reported during and after treatment, coded using CTCAE v5.0

    Details

    Phase:Phase 1/Phase 2
    Primary Purpose:Interventional
    Overall Status:Not yet recruiting
    Lead Sponsor:University College, London

    Trial Keywords

    • Relapsed
    • Refractory

    Last Updated