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

Waldenstrom Macroglobulinemia Clinical Trial

— PembroWM  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03630042
• Other study ID #: UCL/18/0131
• Secondary ID: 2018-001767-23MI
• Status: Completed
• Phase: Phase 2
• Start date: September 6, 2019
• Est. completion date: June 1, 2023

Study information

• Verified date: September 2023
• Source: University College, London
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 17
• Est. completion date: June 1, 2023
• Est. primary completion date: September 21, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion criteria

1. Patients =18 years old

2. Eastern Cooperative Oncology Group (ECOG) performance status 0-2

3. 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

4. Relapsed or refractory WM who have received =1 prior lines of therapy

5. Adequate renal function: estimated creatinine clearance = 30ml/min as calculated using the Cockroft-Gault equation

6. Adequate liver function, including:

• Bilirubin =1.5x the upper limit of normal (ULN)

• Aspartate or alanine transferase (AST or ALT) =2.5 x ULN

7. Adequate organ and bone marrow function:

• Neutrophils =0.75x109/L

• Platelets =50x109/L

8. Willing to comply with the contraceptive requirements of the trial

9. Negative serum or highly sensitive urine pregnancy test for women of childbearing potential (WOCBP)

10. Written informed consent

Exclusion criteria

1. Refractory to rituximab as defined by progression on/within 6 months of finishing a rituximab based regimen

2. 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

3. 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.

4. History of significant cerebrovascular disease in last 6 months

5. Known central nervous system involvement of WM

6. Clinically significant active infection requiring antibiotic or antiretroviral therapy (including Hepatitis B, C or human immunodeficiency virus (HIV))

7. Significant concurrent, uncontrolled medical condition including, but not limited to, renal, hepatic, haematological, gastrointestinal, endocrine, pulmonary, neurological, cerebral or psychiatric disease

8. 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

9. 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

10. Prior history of haemolytic anaemia (either warm or cold)

11. History of colitis

12. History of (non-infectious) pneumonitis that required steroids or has current pneumonitis

13. 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)

14. Received a T cell depleting antibody (e.g. Campath) within 3 months prior to starting treatment

15. Received a live vaccine within 30 days prior to starting treatment

16. 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

17. 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)

18. Patients known or suspected of not being able to comply with a study protocol (e.g. due to alcoholism, drug dependency or psychological disorder)

19. 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

20. Major surgery within 4 weeks prior to trial registration

21. Prior therapy with an anti-PD-1,anti-PD-L1 or CTLA4 monoclonal antibody

22. Prior allogeneic bone marrow transplantation

23. Diagnosis of prior immunodeficiency or organ-transplant requiring immunosuppressive therapy or known HIV or acquired immunodeficiency syndrome (AIDS)-related illness

24. 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)

25. Known or suspected hypersensitivity to components of pembrolizumab and/or rituximab (or other CD20 monoclonal antibody)

26. Current participation in any other clinical trial of an investigational medicinal product (CTIMP)

Related Conditions & MeSH terms

• Waldenstrom Macroglobulinemia

Intervention

Drug:
• Pembrolizumab
200 mg IV dose given on day 1 of a three week cycle
• Rituximab
375 mg/m2 IV dose given up to 8 times in the trial

Locations

Country	Name	City	State
United Kingdom	Royal Bournemouth Hospital, University Hospitals Dorset NHS Foundation Trust	Bournemouth	Dorset
United Kingdom	Bristol Haematology & Oncology Medical Centre, University Hospitals Bristol and Weston NHS Foundation Trust	Bristol
United Kingdom	St Bartholomew's Hospital, Barts Health NHS Trust	London	Greater London
United Kingdom	UCLH, Univeristy College London Hospitals NHS Foundation Trust	London	Greater London
United Kingdom	The Christie Hospital, The Christie NHS Foundation Trust	Manchester	Greater Manchester
United Kingdom	Norfolk and Norwich University Hospital, Norfolk and Norwich University Hospitals NHS Foundation Trust	Norwich
United Kingdom	Churchill Hospital, Oxford Univeristy NHS Foundation Trust	Oxford	Oxfordshire
United Kingdom	Derriford Hospital, Univeristy Hospitals Plymouth NHS Trust	Plymouth	Devon
United Kingdom	Torbay and South Devon NHS Foundation Trust	Torquay	Devon

Sponsors (2)

Lead Sponsor	Collaborator
University College, London	Merck Sharp & Dohme LLC

Country where clinical trial is conducted

United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	Complete response rate at 24 weeks post commencing treatment		24 weeks
Secondary	Very good partial response rate at 24 weeks post commencing treatment		24 weeks
Secondary	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
Secondary	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)
Secondary	Progression free survival (PFS) at 1 and 2 years		1 and 2 years post commencing treatment
Secondary	Overall survival (OS) at 1 and 2 years		1 and 2 years post commencing treatment
Secondary	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