Randomised Trial in Waldenstrom's Macroglobulinaemia (R2W)

This study is currently recruiting participants. (see Contacts and Locations)
Verified March 2013 by University College, London
Sponsor:
Information provided by (Responsible Party):
University College, London
ClinicalTrials.gov Identifier:
NCT01592981
First received: May 3, 2012
Last updated: March 26, 2013
Last verified: March 2013
  Purpose

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 Intervention Phase
Waldenstrom's Macroglobulinaemia
Drug: Bortezomib
Drug: Cyclophosphamide
Biological: Rituximab
Drug: Fludarabine
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: 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

Resource links provided by NLM:


Further study details as provided by University College, London:

Primary Outcome Measures:
  • Disease response [ Time Frame: 6 months (end of treatment) ] [ Designated as safety issue: No ]
    Number and percentage of patients who achieve disease response


Secondary Outcome Measures:
  • Toxicity [ Time Frame: Up to 6 months after treatment start ] [ Designated as safety issue: Yes ]
    The number and percentage of patients who experience grade 3 or higher adverse event

  • Progression free survival [ Time Frame: up to 5 years after treatment start ] [ Designated as safety issue: No ]
    Time from date of randomisation to the date of first progression, relapse or death from any cause

  • Overall survival [ Time Frame: up to 5 years after treatment start ] [ Designated as safety issue: No ]
    Time form date of randomisation to the date of death from any cause

  • Quality of life [ Time Frame: at 3 and 6 months after treatment start ] [ Designated as safety issue: No ]
    Quality of life will be measured using patient-completed EQ-5D questionnaire


Estimated Enrollment: 56
Study Start Date: January 2013
Estimated Study Completion Date: July 2021
Estimated Primary Completion Date: July 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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 Name: 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 Name: 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 Name: MabThera
Drug: Fludarabine
Fludarabine: 40 mg/sq m, oral, days 1, 2 and 3

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01592981

Contacts
Contact: R2W Trial Coordinator +44 207 679 9860 ctc.r2w@ucl.ac.uk

Locations
United Kingdom
Birmingham Heartlands Hospital Not yet recruiting
Birmingham, United Kingdom, B9 5SS
Principal Investigator: Guy Pratt         
St James University Hospital Recruiting
Leeds, United Kingdom, LS9 7TF
Principal Investigator: Roger Owen         
St Bartolomew's Hospital Recruiting
London, United Kingdom, EC1A 7BE
Principal Investigator: Rebecca Auer         
University College Hospital Not yet recruiting
London, United Kingdom, NW1 2BU
Principal Investigator: Shirley D'Sa         
Sponsors and Collaborators
University College, London
  More Information

No publications provided

Responsible Party: University College, London
ClinicalTrials.gov Identifier: NCT01592981     History of Changes
Other Study ID Numbers: UCL/11/0353
Study First Received: May 3, 2012
Last Updated: March 26, 2013
Health Authority: United Kingdom: Medicines and Healthcare Products Regulatory Agency

Keywords provided by University College, London:
Waldenstrom's macroglobulinaemia
bortezomib
cyclophosphamide
rituximab

Additional relevant MeSH terms:
Waldenstrom Macroglobulinemia
Neoplasms, Plasma Cell
Neoplasms by Histologic Type
Neoplasms
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Paraproteinemias
Blood Protein Disorders
Hematologic Diseases
Hemorrhagic Disorders
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Rituximab
Bortezomib
Fludarabine
Fludarabine phosphate
Cyclophosphamide
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Immunosuppressive Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on September 30, 2014