| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Relapsed and refractory Diffuse Large B-cell Lymphoma |
|
| E.1.1.1 | Medical condition in easily understood language |
| Diffuse Large B-cell Lymphoma, a aggressive form of lymphoma, that has previously been treated and either returned or failed to respond to treatment |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10012822 |
| E.1.2 | Term | Diffuse large B-cell lymphoma refractory |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10012821 |
| E.1.2 | Term | Diffuse large B-cell lymphoma recurrent |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | Information not present in EudraCT |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Safety run in stage (phase Ib): To determine the maximum dose of CXD101 that can be given to patients, when given together with pembrolizumab
Dose expansion stage (phase II): To determine the percentage of patients who enter complete remission (CR) or partial remission (PR) during the first 6 cycles (18 weeks) of trial treatment (CXD101 and pembrolizumab) |
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| E.2.2 | Secondary objectives of the trial |
To investigate the length of time taken for a patient's disease to relapse after treatment with CXD101 and pembrolizumab
To find out how long patients live after treatment with CXD101 and pembrolizumab
To find out whether patients whose disease responds well (CR or PR) relapse, and if so, how long this takes to happen
To determine the percentage of patients who enter CR or PR at any time during treatment with CXD101 and pembrolizumab
To assess whether patients with a complete or partial response to CXD101 and pembrolizumab take longer for their disease to progress than those who have a minimal response or stable disease
To investigate what side effects patients experience from treatment with CXD101 and pembrolizumab
To investigate whether PET scanning is an effective way of checking response to trial treatment
To investigate whether patients with different subtypes of diffuse large B-cell lymphoma respond in the same way to trial treatment
To investigate whether the type of lym |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1.Biopsy-confirmed DLBCL, relapsed/ refractory after ≥2 lines of prior therapy and not suitable for ASCT or relapsed post ASCT. Eligibile 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
g.Other WHO classified variants of DLBCL may be permitted with the agreement of at least two TMG clinicians.
2.Measurable disease (of > 15mm in a node or > 10mm in extranodal tissue)
3.Age ≥ 18 years
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:
a.Bilirubin ≤1.5 x upper limit of normal (ULN).
b.Aspartate or alanine transferase (AST or ALT) ≤2.5x 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
|
|
| E.4 | Principal 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:
a. Cardiac disease: Myocardial infarction, severe/unstable angina pectoris within 6 months prior to starting study treatment, NYHA class III-IV heart failure
b. 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 for radiation toxicity 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 or anti-PD-L1 or anti PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg. 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 (a) 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 – see section 6.2.3 in the protocol for more details
19.Severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients and/or a history of allergies to the excipients of 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 (some exceptions apply - listed in trial protocol)
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 tablets
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| E.5 End points |
| E.5.1 | Primary end point(s) |
1. Safety run in Stage (phase Ib): Safety and toxicity of CXD101 in combination with pembrolizumab as assessed by CTCAE v5.0, most notably events defined as dose limiting toxicities occurring in the first cycle of treatment
2. Phase II: Best overall response rate (defined as CR and PR) to CXD101 and pembrolizumab over 6 cycles of treatment, assessed by CT and PET-CT using the RECIL criteria |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. During first cycle (21 days) of trial treatment
2. After 6 cycles of treatment (18 weeks after starting treatment) |
|
| E.5.2 | Secondary end point(s) |
1. Overall response rate at the end of 4 cycles
2. Duration of response in patients achieving CR or PR, as determined by the time from first response to disease progression
3. Complete response (CMR), partial response (PR), minor response (MR), stable disease (SD), progressive disease (PD) rates, as assessed by CT and confirmed by PET-/CT as per RECIL criteria over 6 cycles of treatment (18-weeks)
4. Best overall response at any time point
5. Progression Free Survival (PFS) at 1 year
6. Overall Survival (OS) at 1 year
7. Toxicity of the combination of CXD101 and pembrolizumab as assessed by CTCAE v5.0
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. After 4 cycles of treatment (12 weeks after starting trial treatment)
2. Continuously throughout trial
3. After 6 cycles of treatment (18 weeks after starting treatment)
4. Continuously throughout trial treatment and at end of treatment (Up to 140 weeks after starting trial treatment)
5. 1 year after starting trial treatment
6. 1 year after starting trial treatment
7. Continuously through trial treatment and up to 5 months after stopping trial treatment (or later if the patient suspects late toxicity beyond the AE/SAE reporting window) |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
| Phase Ib/II - dose finding safety run in followed by expansion at maximum tolerated dose |
|
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
| E.8.2.2 | Placebo | Information not present in EudraCT |
| E.8.2.3 | Other | Information not present in EudraCT |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 10 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| End of trial will be declared when the final data item for the final patient is received by the UCL CTC (i.e. it is anticipated that this will be when the final patient treated with pembrolizumab and CXD101 completes their 1 year follow up visit). |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 5 |
| E.8.9.2 | In all countries concerned by the trial days | 31 |
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