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

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ClinicalTrials.gov Identifier: NCT03873025
Recruitment Status : Not yet recruiting
First Posted : March 13, 2019
Last Update Posted : March 13, 2019
Sponsor:
Collaborators:
Celleron Therapeutics Ltd.
Merck Sharp & Dohme Corp.
Information provided by (Responsible Party):
University College, London

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.

Condition or disease Intervention/treatment Phase
Diffuse Large B Cell Lymphoma Combination Product: Pembrolizumab and CXD101 Phase 1 Phase 2

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).


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 45 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Estimated Study Start Date : October 2019
Estimated Primary Completion Date : April 2024
Estimated Study Completion Date : April 2025


Arm Intervention/treatment
Experimental: Pembrolizumab and CXD101

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.

Combination Product: Pembrolizumab and CXD101
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 Measures :
  1. 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) ]
    MTD to be defined as the highest dose level where 0 or 1 Dose limiting toxicity is observed in 6 patients

  2. Best Objective Response Rate [ Time Frame: From baseline to end of cycle 6 of treatment (approximately 18 weeks; each cycle lasts 21 days) ]
    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 :
  1. 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) ]
    Overall Response of the combination of CXD101 and Pembrolizumab

  2. Response Duration [ Time Frame: From start of treatment to time of disease progression (any time during study participation, minimum 3 years) ]
    Time from date of first response confirmation to the first date of progressive disease confirmation

  3. Best Overall Response at any time point [ Time Frame: From baseline to end of treatment (up to 2 years) ]
    Best Overall Response of CXD101 in combination with Pembrolizumab

  4. 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) ]
    CR, PR, MR, Stable Disease, Progressive Disease rates over 6 weeks of treatment

  5. Progression Free Survival [ Time Frame: 52 weeks after commencement of CXD101 and Pembrolizumab ]
    Progression Free Survival at 1 year

  6. Overall Survival [ Time Frame: 52 weeks after commencement of CXD101 and Pembrolizumab ]
    Overall survival at 1 year

  7. Incidence of treatment-emergent adverse events (safety and tolerability) [ Time Frame: From start of CXD101 and Pembrolizumab until 5 months post-treatment ]
    Adverse events to be reported during and after treatment, coded using CTCAE v5.0



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03873025


Contacts
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Contact: PLACARD Trial Coordinator +44 2076799860 ctc.placard@ucl.ac.uk
Contact: Lindsey Stevens +44 2076799868 l.stevens@ucl.ac.uk

Sponsors and Collaborators
University College, London
Celleron Therapeutics Ltd.
Merck Sharp & Dohme Corp.
Investigators
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Principal Investigator: Graham Collins Oxford University Hospitals NHS Trust

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Responsible Party: University College, London
ClinicalTrials.gov Identifier: NCT03873025     History of Changes
Other Study ID Numbers: UCL/17/0920
First Posted: March 13, 2019    Key Record Dates
Last Update Posted: March 13, 2019
Last Verified: March 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by University College, London:
Relapsed
Refractory
Additional relevant MeSH terms:
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Lymphoma
Lymphoma, B-Cell
Lymphoma, Large B-Cell, Diffuse
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Lymphoma, Non-Hodgkin
Pembrolizumab
Antineoplastic Agents, Immunological
Antineoplastic Agents