Waldenstrom Macroglobulinemia
Conditions
Keywords
Waldenstrom Macroglobulinemia, Relapsed, Refractory, Rituximab, Pembrolizumab
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.
Interventions
DRUGPembrolizumab
200 mg IV dose given on day 1 of a three week cycle
DRUGRituximab
375 mg/m2 IV dose given up to 8 times in the trial
Sponsors
Merck Sharp & Dohme LLC
University College, London
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
A single arm, non randomised phase II trial
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Patients Achieving at Least a Major Response Rate at 24 Weeks Post Commencing Treatment | 24 weeks | The primary outcome is the percentage of patients achieving at least a major response rate at 24 weeks post commencing treatment. A major response rate is defined as a greater than 50% reduction in paraprotein measurement - this is in line with international recognised response criteria for the disease under investigation. In this single arm study all patients receiving treatment were considered applicable for endpoint analysis. There is no comparison as there is only one arm. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 | — |
| Safety and Tolerability of Pembrolizumab and Rituximab as Assessed by the Frequency of Serious and Non-serious Adverse Events, According to CTCAE v5.0 | until 5 months post last IMP administration | As assessed by the number and grade of serious and non-serious adverse events, graded according to CTCAE v5.0 |
| 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 | 24 weeks | 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' |
| Time to Next Treatment | Assessed once per year after completing treatment (average of 1 year) | as determined by the time from registration to the next line of therapy |
Countries
United Kingdom
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Pembrolizumab and Rituximab 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 | 17 |
| Total | 17 |
Baseline characteristics
| Characteristic | Pembrolizumab and Rituximab | — |
|---|---|---|
| Age, Continuous | 70.4 years | — |
| ECOG Performance Status ECOG 0 | 9 Participants | — |
| ECOG Performance Status ECOG 1 | 7 Participants | — |
| ECOG Performance Status ECOG 2 | 1 Participants | — |
| Race and Ethnicity Not Collected | — | — Participants |
| Sex: Female, Male Female | 3 Participants | — |
| Sex: Female, Male Male | 14 Participants | — |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 5 / 17 |
| other Total, other adverse events | 17 / 17 |
| serious Total, serious adverse events | 10 / 17 |
Outcome results
Primary
Percentage of Patients Achieving at Least a Major Response Rate at 24 Weeks Post Commencing Treatment
The primary outcome is the percentage of patients achieving at least a major response rate at 24 weeks post commencing treatment. A major response rate is defined as a greater than 50% reduction in paraprotein measurement - this is in line with international recognised response criteria for the disease under investigation. In this single arm study all patients receiving treatment were considered applicable for endpoint analysis. There is no comparison as there is only one arm.
Time frame: 24 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pembrolizumab and Rituximab | Percentage of Patients Achieving at Least a Major Response Rate at 24 Weeks Post Commencing Treatment | 8 Participants |
Secondary
Complete Response Rate at 24 Weeks Post Commencing Treatment
Time frame: 24 weeks
Secondary
Overall Survival (OS) at 1 and 2 Years
Time frame: 1 and 2 years post commencing treatment
Secondary
Progression Free Survival (PFS) at 1 and 2 Years
Time frame: 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'
Time frame: 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
Time frame: until 5 months post last IMP administration
Secondary
Time to Maximal Response as Determined by the Time of Registration to the Maximal Disease Response
Time frame: 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
Time frame: Assessed once per year after completing treatment (average of 1 year)
Secondary
Very Good Partial Response Rate at 24 Weeks Post Commencing Treatment
Time frame: 24 weeks