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

NCT03873025 | Withdrawn Phase 1 DMC

• 1 other identifier: UCL/17/0920
• Study Type: interventional
• Target: N/A
• Locations: 0 countries
• Sites: N/A

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.

Conditions

Diffuse Large B Cell Lymphoma

Keywords

Relapsed; Refractory

Outcome Measures

Primary Outcomes (2)

• 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

  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)

• 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

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

Secondary Outcomes (7)

• Overall Response Rate at the end of 4 cycles

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

• Response Duration

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

• Best Overall Response at any time point

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

• Best response at end of cycle 6 of treatment

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

• Progression Free Survival

  52 weeks after commencement of CXD101 and Pembrolizumab

Study Arms (1)

Pembrolizumab and CXD101

EXPERIMENTAL

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

Interventions

Pembrolizumab and CXD101 COMBINATION_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.

Pembrolizumab and CXD101

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• University College, London: lead
• Celleron Therapeutics Ltd.: collaborator
• Merck Sharp & Dohme LLC: collaborator

MeSH Terms

Conditions

Lymphoma, Large B-Cell, Diffuse; Recurrence

Interventions

pembrolizumab

Condition Hierarchy (Ancestors)

Lymphoma, B-Cell; Lymphoma, Non-Hodgkin; Lymphoma; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Study Officials

• Graham Collins

  Oxford University Hospitals NHS Trust

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 5, 2019
• First Posted: March 13, 2019
• Study Start: October 1, 2019
• Primary Completion: April 1, 2024
• Study Completion: April 1, 2025
• Last Updated: August 17, 2021

Record last verified: 2021-08

Data Sharing

• IPD Sharing: Will not share