Clinical trial NCT03630042: Investigating the Safety and Efficacy of Rituximab and Pembrolizumab in Relapsed/Refractory Waldenström's Macroglobulinaemia
Official title: A Phase II Trial to Investigate the Safety and Efficacy of Rituximab and Pembrolizumab in Relapsed/Refractory Waldenström's Macroglobulinaemia
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Waldenstrom Macroglobulinemia
Keywords: Waldenstrom Macroglobulinemia
Relapsed
Refractory
Rituximab
Pembrolizumab
Lead sponsor: University College, London
Sponsor class: OTHER
Collaborators: name: Merck Sharp & Dohme LLC
First posted: 2018-08-14
Enrollment: 17
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: A single arm, non randomised phase II trial
Primary purpose: TREATMENT

Brief 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.


Eligibility criteria: 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)

Primary outcomes:
measure: Percentage of Patients Achieving at Least a Major Response Rate at 24 Weeks Post Commencing Treatment
timeFrame: 24 weeks
Secondary outcomes:
measure: Safety and Tolerability of Pembrolizumab and Rituximab as Assessed by the Frequency of Serious and Non-serious Adverse Events, According to CTCAE v5.0
timeFrame: until 5 months post last IMP administration
measure: Complete Response Rate at 24 Weeks Post Commencing Treatment
timeFrame: 24 weeks
measure: Very Good Partial Response Rate at 24 Weeks Post Commencing Treatment
timeFrame: 24 weeks
measure: Time to Maximal Response as Determined by the Time of Registration to the Maximal Disease Response
timeFrame: Assessed at 12 weeks, 24 weeks and 1 year after commencing treatment
measure: Time to Next Treatment
timeFrame: Assessed once per year after completing treatment (average of 1 year)
measure: Progression Free Survival (PFS) at 1 and 2 Years
timeFrame: 1 and 2 years post commencing treatment
measure: Overall Survival (OS) at 1 and 2 Years
timeFrame: 1 and 2 years post commencing treatment
measure: Quality of Life - Change in Quality of Life (QoL) at 24 Weeks Post Commencing Treatment as Assessed by EORTC QLQ-C30 Questionnaire
timeFrame: 24 weeks
Other outcomes:
Locations:
city: Plymouth
country: United Kingdom
facility: Derriford Hospital, Univeristy Hospitals Plymouth NHS Trust
state: Devon
city: Torquay
country: United Kingdom
facility: Torbay and South Devon NHS Foundation Trust
state: Devon
city: Bournemouth
country: United Kingdom
facility: Royal Bournemouth Hospital, University Hospitals Dorset NHS Foundation Trust
state: Dorset
city: London
country: United Kingdom
facility: St Bartholomew's Hospital, Barts Health NHS Trust
state: Greater London
city: London
country: United Kingdom
facility: UCLH, Univeristy College London Hospitals NHS Foundation Trust
state: Greater London
city: Manchester
country: United Kingdom
facility: The Christie Hospital, The Christie NHS Foundation Trust
state: Greater Manchester
city: Oxford
country: United Kingdom
facility: Churchill Hospital, Oxford Univeristy NHS Foundation Trust
state: Oxfordshire
city: Bristol
country: United Kingdom
facility: Bristol Haematology & Oncology Medical Centre, University Hospitals Bristol and Weston NHS Foundation Trust
city: Norwich
country: United Kingdom
facility: Norfolk and Norwich University Hospital, Norfolk and Norwich University Hospitals NHS Foundation Trust
Study officials:
affiliation: Oxford University Hospitals NHS Trust
name: Jaimal Kothari
role: PRINCIPAL_INVESTIGATOR
References: