| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Relapsed and refractory Waldenström's Macroglobulinaemia |
|
| E.1.1.1 | Medical condition in easily understood language |
| Waldenström's Macroglobulinaemia, a rare type of lymphoma, that has previously been unsuccessful treated |
|
| 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 | 10047801 |
| E.1.2 | Term | Waldenstrom's macroglobulinaemia |
| 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 |
| •To determine how effective the combination of drugs rituximab and pembrolizumab is at treating patients with Waldenström’s macroglobulinaemia (WM) that has either failed to respond to initial treatment (refractory) or which has returned after initially responding to treatment (relapsed). |
|
| E.2.2 | Secondary objectives of the trial |
•To assess the number and severity of side effects experienced by patients receiving trial treatment (rituximab and pembrolizumab) for their refractory/relapsed WM
•To determine the percentage of patients whose disease improves after trial treatment
•To determine how long after registration the best response to trial treatment is seen in patients
•After the patient has stopped trial treatment, what is the average length of time until another treatment is needed for their WM?
•To determine the effect of trial treatment on the patient's quality of life
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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:
o Bilirubin ≤1.5x the upper limit of normal (ULN)
o Aspartate or alanine transferase (AST or ALT) ≤2.5 x ULN
7. Adequate organ and bone marrow function:
o Neutrophils ≥0.75x109/L
o 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
|
|
| E.4 | Principal 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:
o Type I diabetes or thyroid disease, controlled on medication
o Skin conditions such as psoriasis, vitiligo or alopecia not requiring systemic treatment
o 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)
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Percentage of patients achieving an overall response rate (defined as complete response (CR), very good partial response (VGPR), partial response (PR) or minor response (MR) i.e. a greater than 25% reduction in the serum IgM level) at 24 weeks post commencing treatment. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 24 weeks after starting treatment |
|
| E.5.2 | Secondary end point(s) |
1. Safety and tolerability of pembrolizumab and rituximab as assessed by the frequency of serious and non-serious adverse events, graded according to CTCAE v5.0
2. Complete response (CR) rate at 24 weeks post commencing treatment
3. Very good partial response (VGPR) rate at 24 weeks post commencing treatment
4. Time to maximal response, as determined by the time of registration to the maximal disease response
5. Time to next treatment, as determined by the time from registration to the next line of therapy
6. Progression free survival (PFS) at 1 and 2 years
7. Overall survival (OS) at 1 and 2 years
8. Change in quality of life (QoL) at 24 weeks post commencing treatment
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Continuously through trial and at end of trial
2. 24 weeks after starting treatment
3. 24 weeks after starting treatment
4. End of trial
5. End of trial
6. 1 and 2 years after starting treatment
7. 1 and 2 years after starting treatment
8. 24 weeks after starting treatment
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|
| 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) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| 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 | 8 |
| 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
|
| The end of the trial will be when the last patient has completed 2 years of follow up. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 1 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 1 |
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