R2W: Randomised Trial in Waldenstrom's Macroglobulinaemia

Sponsor

University College, London (Other)

Overall Status

Completed

CT.gov ID

NCT01592981

Collaborator

(none)

Enrollment

Locations

Arms

Duration (Months)

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this trial is to assess tolerability and efficacy of the Bortezomib, Cyclophosphamide and Rituximab combination as initial therapy for previously untreated patients with symptomatic Waldenstrom's macroglobulinaemia.

Condition or Disease	Intervention/Treatment	Phase
Waldenstrom's Macroglobulinaemia	Drug: Bortezomib Drug: Cyclophosphamide Biological: Rituximab Drug: Fludarabine	Phase 2

Detailed Description

Waldenstrom macroglobulinaemia (WM) is a low grade nonHodgkin lymphoma characterised by bone marrow infiltration and the presence of an abnormal protein in the blood (IgM paraprotein. Most patients require treatment at presentation but there is no agreed standard of first line therapy. Current treatment is unsatisfactory with responses often incomplete and slow to attain, while recurrence is inevitable.

The aim of this study is to find out whether a new combination of Bortezomib (Velcade®), Cyclophosphamide and Rituximab (MabThera), is well tolerated and effective for patients with WM. R2W is a randomised, noncomparative, phase II trial of subcutaneous bortezomib, cyclophosphamide, rituximab (BCR, experimental arm) versus fludarabine, cyclophosphamide, rituximab (FCR, control arm) for initial therapy of WM. This is a two stage trial where six patients will be treated initially with BCR to assess tolerability. If BCR is considered tolerable, a further 50 patients will be randomised between BCR and FCR (2:1) in the second stage of the trial. Patients will receive 3 cycles of treatment and then be reassessed. Those with evidence of progression will stop trial treatment. All other patients will continue with a further 3 cycles (to a total of 6) unless there is a clear clinical contraindication to further treatment.

Study Design

Study Type:

Interventional

Actual Enrollment :

60 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Subcutaneous Bortezomib, Cyclophosphamide and Rituximab (BCR) Versus Fludarabine, Cyclophosphamide and Rituximab (FCR) for Initial Therapy of Waldenstrőm's Macroglobulinaemia (WM): a Randomized Phase II Trial

Study Start Date :

Jan 1, 2013

Actual Primary Completion Date :

Mar 1, 2017

Actual Study Completion Date :

Aug 2, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: bortezomib, cyclophosphamide, rituximab Bortezomib:1.6 mg/m2 s.c; days 1, 8, 15 of each cycle. Cyclophosphamide:250 mg/m2 oral; days 1, 8, 15 of each cycle. Rituximab: 375 mg/m2 i.v. infusion; days 1, 8, 15 and 22 of cycles 2 and 5 only. Cycle repeated every 28 days. After 3 cycles of treatment, patients are reassessed and those with evidence of progression stop trial treatment. All other patients continue with further 3 cycles (to a total of 6) unless a clear clinical contradiction to further treatment exist.	Drug: Bortezomib 1.6 mg/m2 subcutaneous bortezomib on days1, 8 and 15 of 28 days cycle Other Names: Velcade Drug: Cyclophosphamide Cyclophosphamide:250 mg/sq m, oral, days 1, 8 and 15 of each cycle in the experimental arm. Cyclophosphamide:250 mg/sq m, oral, days 1, 2 and 3 of each cycle in the control arm. Biological: Rituximab Rituximab: 375 mg/m2 i.v. infusion; days 1, 8, 15 and 22 of cycles 2 and 5 only Other Names: MabThera
Active Comparator: fludarabine, cyclophosphamide, rituximab Fludarabine:40 mg/sq m, oral, days 1,2 and 3 of each cycle. Cyclophosphamide:250 mg/sq m; oral, days 1, 2 and 3 of each cycle. Rituximab: 375 mg/sq m i.v. infusion days 1, 8, 15 and 22 of cycles 2 and 5 only. Cycle repeated every 28 days.After 3 cycles of treatment, patients are reassessed and those with evidence of progression stop trial treatment. All other patients continue with further 3 cycles (to a total of 6) unless a clear clinical contradiction to further treatment exist.	Drug: Cyclophosphamide Cyclophosphamide:250 mg/sq m, oral, days 1, 8 and 15 of each cycle in the experimental arm. Cyclophosphamide:250 mg/sq m, oral, days 1, 2 and 3 of each cycle in the control arm. Biological: Rituximab Rituximab: 375 mg/m2 i.v. infusion; days 1, 8, 15 and 22 of cycles 2 and 5 only Other Names: MabThera Drug: Fludarabine Fludarabine: 40 mg/sq m, oral, days 1, 2 and 3

Arm

Intervention/Treatment

Experimental: bortezomib, cyclophosphamide, rituximab

Bortezomib:1.6 mg/m2 s.c; days 1, 8, 15 of each cycle. Cyclophosphamide:250 mg/m2 oral; days 1, 8, 15 of each cycle. Rituximab: 375 mg/m2 i.v. infusion; days 1, 8, 15 and 22 of cycles 2 and 5 only. Cycle repeated every 28 days. After 3 cycles of treatment, patients are reassessed and those with evidence of progression stop trial treatment. All other patients continue with further 3 cycles (to a total of 6) unless a clear clinical contradiction to further treatment exist.

Drug: Bortezomib

1.6 mg/m2 subcutaneous bortezomib on days1, 8 and 15 of 28 days cycle

Other Names:

Velcade

Drug: Cyclophosphamide

Cyclophosphamide:250 mg/sq m, oral, days 1, 8 and 15 of each cycle in the experimental arm. Cyclophosphamide:250 mg/sq m, oral, days 1, 2 and 3 of each cycle in the control arm.

Biological: Rituximab

Rituximab: 375 mg/m2 i.v. infusion; days 1, 8, 15 and 22 of cycles 2 and 5 only

Other Names:

MabThera

Active Comparator: fludarabine, cyclophosphamide, rituximab

Fludarabine:40 mg/sq m, oral, days 1,2 and 3 of each cycle. Cyclophosphamide:250 mg/sq m; oral, days 1, 2 and 3 of each cycle. Rituximab: 375 mg/sq m i.v. infusion days 1, 8, 15 and 22 of cycles 2 and 5 only. Cycle repeated every 28 days.After 3 cycles of treatment, patients are reassessed and those with evidence of progression stop trial treatment. All other patients continue with further 3 cycles (to a total of 6) unless a clear clinical contradiction to further treatment exist.

Drug: Cyclophosphamide

Cyclophosphamide:250 mg/sq m, oral, days 1, 8 and 15 of each cycle in the experimental arm. Cyclophosphamide:250 mg/sq m, oral, days 1, 2 and 3 of each cycle in the control arm.

Biological: Rituximab

Rituximab: 375 mg/m2 i.v. infusion; days 1, 8, 15 and 22 of cycles 2 and 5 only

Other Names:

MabThera

Drug: Fludarabine

Fludarabine: 40 mg/sq m, oral, days 1, 2 and 3

Outcome Measures

Primary Outcome Measures

Disease response [6 months (end of treatment)]
Number and percentage of patients who achieve disease response

Secondary Outcome Measures

Toxicity of grade 3 or higher adverse event [Up to 6 months after treatment start]
The number and percentage of patients who experience grade 3 or higher adverse event
Progression free survival [up to 5 years after treatment start]
Time from date of randomisation to the date of first progression, relapse or death from any cause
Overall survival [up to 5 years after treatment start]
Time form date of randomisation to the date of death from any cause
Quality of life (EQ-5D score) [at 3 and 6 months after treatment start]
Quality of life will be measured using patient-completed EQ-5D questionnaire

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Age ≥ 18 years
Confirmed diagnosis of WM (according to consensus panel / WHO criteria) with measurable IgM paraprotein
Previously untreated disease at any stage requiring therapy at the discretion of the treating physician. Suggested criteria for initiating treatment include:
haematological suppression to Hb <10 g/dl, or neutrophils <1.5x109/l or platelets <150x109/l
clinical evidence of hyperviscosity
bulky lymphadenopathy and/or bulky splenomegaly
presence of B symptoms
No previous chemotherapy (prior plasma exchange and steroids are permissible)
Performance status grade 0 - 2
Life expectancy of greater than 6 months
Informed consent
Agreed compliance with recommended contraceptive precautions where appropriate

Exclusion Criteria:

Lymphoplasmacytic lymphoma with no detectable serum IgM paraprotein
Severe pre-existing neuropathy (> grade 2)
Autoimmune cytopenias
Evidence of active Hepatitis B or C infection (patients with evidence of past HepB infection may be eligible - see appendix 6)
Serological positivity for HIV
Pregnant or lactating women
Life expectancy severely limited by other illness
Renal failure (creatinine clearance <30 ml/min)
Severe impairment of liver function: alkaline phosphatase/bilirubin >2.5 times upper limit of normal (ULN), ALT/AST >2.5 times ULN not related to lymphoma (patients with Gilbert syndrome are eligible)
History of allergic reaction to compounds containing boron or mannitol
Known hypersensitivity to murine compounds.
Diagnosed or treated for a malignancy other than WM within 5 years before day 1 of Cycle 1 with the exception of complete resection of basal cell carcinoma, squamous cell carcinoma of the skin or any other in situ malignancy
Active systemic infection requiring treatment
Concurrent treatment with another investigational agent
Severe or life-threatening cardiac, pulmonary, neurological, psychiatric or metabolic disease

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	Basingstoke & North Hampshire Hospital	Basingstoke	United Kingdom
2	Royal United Hospital	Bath	United Kingdom
3	Birmingham Heartlands Hospital	Birmingham	United Kingdom	B9 5SS
4	City Hospital	Birmingham	United Kingdom
5	Pilgrim Hospital	Boston	United Kingdom
6	Colchester General Hospital	Colchester	United Kingdom
7	Darent Valley Hospital	Dartford	United Kingdom
8	Dewsbury and District Hospital	Dewsbury	United Kingdom
9	Royal Devon and Exeter Hospital	Exeter	United Kingdom
10	Grantham and District Hospital	Grantham	United Kingdom
11	St James University Hospital	Leeds	United Kingdom	LS9 7TF
12	Leicester Royal Infirmary	Leicester	United Kingdom
13	Lincoln County Hospital	Lincoln	United Kingdom
14	Royal Liverpool University Hospital	Liverpool	United Kingdom
15	St Bartolomew's Hospital	London	United Kingdom	EC1A 7BE
16	University College Hospital	London	United Kingdom	NW1 2BU
17	King's College Hospital	London	United Kingdom
18	Northwick Park Hospital	London	United Kingdom
19	Royal Free Hospital	London	United Kingdom
20	Maidstone Hospital	Maidstone	United Kingdom
21	Derriford Hospital	Plymouth	United Kingdom
22	Pontefract Hospital	Pontefract	United Kingdom
23	Queen's Hospital	Romford	United Kingdom
24	Salisbury District Hospital	Salisbury	United Kingdom
25	Musgrove Park Hospital	Taunton	United Kingdom
26	Torbay Hospital	Torquay	United Kingdom
27	Tunbridge Wells Hospital	Tunbridge Wells	United Kingdom
28	Pinderfields Hospital	Wakefield	United Kingdom
29	Sandwell Hospital	West Bromwich	United Kingdom
30	Royal Hampshire County Hospital	Winchester	United Kingdom