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Lymphoma, B-Cell

Waldenstrom Macroglobulinemia

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Ibrutinib

Tyrosine Kinase Inhibitors

Protein Kinase Inhibitors

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Tyrosine

Relapsed / refractory chronic lymphocytic leukemia and Waldenstrom macroglobulinaemia (lymphoplasmacytic lymphoma): 420 mg daily Relapsed / refractory mantle cell lymphoma: 560 mg daily Relapsed / refractory indolent B-cell non-Hodgkin lymphoma: 560 mg daily Treatment is continued until disease progression

King Hei Lu, MMedSc

Zoe Chan, BNs

Yok Lam Kwong, MD(HK)

Eric Tse, MBBS(HK), PhD(Cantab)

Yok Lam Kwong, MD(HK),

Efficacy and Safety of ibrutinib in patients with chronic lymphocytic leukemia and other indolent B-cell lymphomas who are chronic hepatitis B virus carriers or occult hepatitis B virus carriers

Ibrutinib is a selective oral Burton tyrosine kinase inhibitor. Through interfering with the downstream pathways of B-cell receptor signaling, it inhibits proliferation and induces apoptosis in many B-cell lymphoid malignancies. The clinical benefit of ibrutinib has been demonstrated in patients with relapsed/refractory chronic lymphocytic leukaemia, mantle cell lymphoma, small lymphocytic lymphoma, and other indolent B-cell non-Hodgkin lymphomas.

The pivotal trials of ibrutinib excluded HBsAg+ patients. Therefore, the effects of ibrutinib on HBsAg+ and anti-HBc+ patients remain entirely undefined. In view of the B-cell signaling inhibitory activity of ibrutinib, which might be more potent than rituximab in suppressing B-cells, HBV reactivation in patients exposed previously to HBV infection, including chronic HBV carriers and occult HBV carriers, could be a major clinical problem.

To enable ibrutinib to be prescribed in Asia and other regions of the world where HBV is endemic, evidence-based recommendations on prevention of HBV reactivation in at-risk populations, including chronic HBV carriers (HBsAg+), and occult HBV carriers (HBsAg- but anti-HBc+), are urgently needed.

The following treatment regimens will be adopted. Relapsed / refractory chronic lymphocytic leukemia and Waldenstrom macroglobulinaemia (lymphoplasmacytic lymphoma): 420 mg daily.

Relapsed / refractory mantle cell lymphoma: 560 mg daily. Relapsed / refractory indolent B-cell non-Hodgkin lymphoma: 560 mg daily. Treatment is continued until disease progression.

A total of 62 patients will be recruited, including 16 HBsAg+ patients, and 46 occult HBV carriers

Sample size calculation of occult HBV carriers For occult HBV carriers, the sample size is calculated according to the following information, based on our previous observations (as detailed in reference 3). The HBV reactivation rate in HBsAg-, anti-HBc+, anti-HBs+ patients is hypothesized to be 34%, which may increase to 68% in HBsAg-, anti-HBc+, but anti-HBs- patients \[3\]. Assuming a power of 80% and an alpha-risk of 0.1, together with the ratio of anti-HBs+ : anti-HBs- patients to be 2:1, we expect to recruit 42 HBsAg-, anti-HBc+ patients. With a dropout rate of 10%, the total number of patients to be recruited in this group will be 46.

Sample size calculation of HBsAg+ patients For HBsAg+ patients, the sample size is calculated according to the following information, based on our previous observations (as detailed in reference 3). The ratio of occult carriers (HBsAg-, anti-HBc+) : HBsAg+ patients is about 3: 1.3 Hence, the total number of HBsAg+ to be recruited will be 14 (42 divided by 3). With a drop-out rate of 10%, the total number of patients to be recruited in this group will be 16.

Approximate breakdown of number of patients in each category to be recruited Based on our previous observations on the proportions of low-grade B-cell lymphoid malignancies,8 an approximate breakdown of number of patients is as follows: follicular lymphoma (N=32), chronic lymphocytic leukemia/small lymphocytic lymphoma (N=11), marginal zone B-cell lymphoma (N=11), mantle cell lymphoma (N=5), and Waldenstrom macroglobulinemia (N=5).

Efficacy and Safety of Ibrutinib in Patients With CLL and Other Indolent B-cell Lymphomas Who Are Chronic Hepatitis B Virus Carriers or Occult Hepatitis B Virus Carriers

Efficacy and Safety of Ibrutinib in Patients With Chronic Lymphocytic Leukemia and Other Indolent B-cell Lymphomas Who Are Chronic Hepatitis B Virus Carriers or Occult Hepatitis B Virus Carriers

proportion of patients achieving CR or partial remission (PR)

Incidence of AE and SAE by severity grading as assessed according to CTCAE v4.03

Janssen, LP

The University of Hong Kong

Chair Professor

Antineoplastic Agents

Antirheumatic Agents

Cyclophosphamide

Fludarabine

Fludarabine phosphate

Rituximab

Bortezomib

Immunosuppressive Agents

Immunologic Factors

Antineoplastic Agents, Alkylating

Alkylating Agents

Antineoplastic Agents, Immunological

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.

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.

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

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.

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

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

Rebecca Auer

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.

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.

Randomised Trial in Waldenstrom's Macroglobulinaemia

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

Number and percentage of patients who achieve disease response

The number and percentage of patients who experience grade 3 or higher adverse event

Time from date of randomisation to the date of first progression, relapse or death from any cause

Time form date of randomisation to the date of death from any cause

Quality of life will be measured using patient-completed EQ-5D questionnaire

University College, London

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Efficacy and Safety of Ibrutinib in Patients With CLL and Other Indolent B-cell Lymphomas Who Are Chronic Hepatitis B Virus Carriers or Occult Hepatitis B Virus Carriers	NCT02991638	Chronic Lymphoc... Indolent B-cell... Chronic Hepatit... Lymphoma, Small... Mantle-Cell Lym... Waldenstrom's M... Follicular Lymp...	Ibrutinib	18 Years -	The University of Hong Kong
Efficacy and Safety of Ibrutinib in Patients With CLL and Other Indolent B-cell Lymphomas Who Are Chronic Hepatitis B Virus Carriers or Occult Hepatitis B Virus Carriers	NCT02991638	Chronic Lymphoc... Indolent B-cell... Chronic Hepatit... Lymphoma, Small... Mantle-Cell Lym... Waldenstrom's M... Follicular Lymp...	Ibrutinib	18 Years -	The University of Hong Kong
Randomised Trial in Waldenstrom's Macroglobulinaemia	NCT01592981	Waldenstrom's M...	Bortezomib Cyclophosphamid... Rituximab Fludarabine	18 Years -	University College, London
Randomised Trial in Waldenstrom's Macroglobulinaemia	NCT01592981	Waldenstrom's M...	Bortezomib Cyclophosphamid... Rituximab Fludarabine	18 Years -	University College, London
Randomised Trial in Waldenstrom's Macroglobulinaemia	NCT01592981	Waldenstrom's M...	Bortezomib Cyclophosphamid... Rituximab Fludarabine	18 Years -	University College, London

Spots Global Cancer Trial Database for waldenstrom's macroglobulinaemia