Investigating the Safety and Efficacy of Rituximab and Pembrolizumab in Relapsed/Refractory Waldenström's Macroglobulinaemia

Study Overview
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Brief Summary
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This study is for patients who have previously been treated for Waldenström's macroglobulinaemia (WM) and their disease has either not responded (known as refractory disease) or has returned (known as relapsed disease). Through this study, the researchers would like to find out whether treating these patients with drugs called rituximab and pembrolizumab is a safe and effective combination for this disease. In this study, pembrolizumab and rituximab will be given together. In other studies pembrolizumab has been shown to be effective at treating diseases similar to WM. The researchers want to test whether giving pembrolizumab and rituximab together is safe and effective.

Official Title
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A Phase II Trial to Investigate the Safety and Efficacy of Rituximab and Pembrolizumab in Relapsed/Refractory Waldenström's Macroglobulinaemia

Conditions
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Waldenstrom Macroglobulinemia

Intervention / Treatment
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* Drug: Pembrolizumab
* Drug: Rituximab


Participation Criteria
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Eligibility Criteria
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Inclusion criteria Patients ≥18 years old Eastern Cooperative Oncology Group (ECOG) performance status 0-2 Presence of measurable disease, (defined as a serum IgM level of >0.5g/L) and fulfils other World Health Organisation (WHO) diagnostic criteria for WM Relapsed or refractory WM who have received ≥1 prior lines of therapy Adequate renal function: estimated creatinine clearance ≥ 30ml/min as calculated using the Cockroft-Gault equation Adequate liver function, including: Bilirubin ≤1.5x the upper limit of normal (ULN) Aspartate or alanine transferase (AST or ALT) ≤2.5 x ULN Adequate organ and bone marrow function: Neutrophils ≥0.75x109/L Platelets ≥50x109/L Willing to comply with the contraceptive requirements of the trial Negative serum or highly sensitive urine pregnancy test for women of childbearing potential (WOCBP) Written informed consent Exclusion criteria Refractory to rituximab as defined by progression on/within 6 months of finishing a rituximab based regimen Women who are pregnant or breastfeeding, or males expecting to conceive or father children at any point from the start of treatment until 4 months after the last administration of pembrolizumab Clinically significant cardiac disease within 6 months prior to registration including unstable angina or myocardial infarction, uncontrolled congestive heart failure (NYHA class III-IV), and unstable arrhythmias requiring therapy, with the exception of extra systoles or minor conduction abnormalities. Stable and controlled atrial fibrillation is not an exclusion. History of significant cerebrovascular disease in last 6 months Known central nervous system involvement of WM Clinically significant active infection requiring antibiotic or antiretroviral therapy (including Hepatitis B, C or human immunodeficiency virus (HIV)) Significant concurrent, uncontrolled medical condition including, but not limited to, renal, hepatic, haematological, gastrointestinal, endocrine, pulmonary, neurological, cerebral or psychiatric disease Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially curative therapy Active autoimmune disease apart from: Type I diabetes or thyroid disease, controlled on medication Skin conditions such as psoriasis, vitiligo or alopecia not requiring systemic treatment Auto-immune thrombocytopenia, thought to be secondary to WM, provided that platelet count meet the criteria specified above, on daily doses of corticosteroid ≤10mg prednisolone or equivalent Prior history of haemolytic anaemia (either warm or cold) History of colitis History of (non-infectious) pneumonitis that required steroids or has current pneumonitis Systemic anti-cancer therapy within 4 weeks prior to trial registration (except for BTK inhibitors, which may continue until cycle 1, day 1 of trial treatment) Received a T cell depleting antibody (e.g. Campath) within 3 months prior to starting treatment Received a live vaccine within 30 days prior to starting treatment Chronic or ongoing active infectious disease requiring systemic treatment such as, but not limited to, chronic renal infection, chronic chest infection with bronchiectasis, tuberculosis and active hepatitis Patients who have received treatment with any non-marketed drug substance or experimental therapy within 4 weeks prior to starting treatment (unless prior agreed with the TMG) Patients known or suspected of not being able to comply with a study protocol (e.g. due to alcoholism, drug dependency or psychological disorder) Positive serology for Hepatitis B defined as a positive test for HepB surface antigen (HBsAg). Note: patients who are HepB core antibody (HBcAb) positive will only be eligible for the study if the HepB virus deoxyribonucleic acid (HBV DNA) test is negative and patients are willing to undergo monthly monitoring for HBV reactivation Major surgery within 4 weeks prior to trial registration Prior therapy with an anti-PD-1,anti-PD-L1 or CTLA4 monoclonal antibody Prior allogeneic bone marrow transplantation Diagnosis of prior immunodeficiency or organ-transplant requiring immunosuppressive therapy or known HIV or acquired immunodeficiency syndrome (AIDS)-related illness 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 injections); systemic corticosteroids at physiologic doses (<10mg/ day of prednisolone or equivalent) Known or suspected hypersensitivity to components of pembrolizumab and/or rituximab (or other CD20 monoclonal antibody) Current participation in any other clinical trial of an investigational medicinal product (CTIMP)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: A single arm, non randomised phase II trial
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pembrolizumab and Rituximab<br> | Drug: Pembrolizumab<br>* 200 mg IV dose given on day 1 of a three week cycle<br>Drug: Rituximab<br>* 375 mg/m2 IV dose given up to 8 times in the trial<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of patients achieving at least a major response rate at 24 weeks post commencing treatment | defined as greater than 50% reduction in paraprotein | 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and tolerability of pembrolizumab and rituximab as assessed by the frequency of serious and non-serious adverse events, according to CTCAE v5.0 | As assessed by the number and grade of serious and non-serious adverse events, graded according to CTCAE v5.0 | until 5 months post last IMP administration | 
| Complete response rate at 24 weeks post commencing treatment |  | 24 weeks | 
| Very good partial response rate at 24 weeks post commencing treatment |  | 24 weeks | 
| Time to maximal response as determined by the time of registration to the maximal disease response |  | Assessed at 12 weeks, 24 weeks and 1 year after commencing treatment | 
| Time to next treatment | as determined by the time from registration to the next line of therapy | Assessed once per year after completing treatment (average of 1 year) | 
| Progression free survival (PFS) at 1 and 2 years |  | 1 and 2 years post commencing treatment | 
| Overall survival (OS) at 1 and 2 years |  | 1 and 2 years post commencing treatment | 
| Quality of Life - Change in quality of life (QoL) at 24 weeks post commencing treatment as assessed by EORTC QLQ-C30 questionnaire | Change in quality of life (QoL) at 24 weeks post commencing treatment as assessed by EORTC QLQ-C30 questionnaire. Daily activities and thoughts/feelings experienced by the patient over the week preceding questionnaire completion are graded on a scale from '1-not at all' to '4-very much'. Also rating of overall health and quality of life from '1-very poor' to '7-excellent' | 24 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Waldenstrom Macroglobulinemia, Relapsed, Refractory, Rituximab, Pembrolizumab