LBH589 in Relapsed or Relapsed and Refractory Waldenstrom's Macroglobulinemia

Study Overview
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Brief Summary
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The purpose of this research study is to assess the overall response rate of LBH589 in patients with relapsed or refractory Waldenstrom's Macroglobulinemia. LBH589 is a newly discovered compound that has killed Waldenstrom cells in laboratory studies, however, it is not known if LBH589 will show the same activity in people with Waldenstrom's Macroglobulinemia. This drug has been used in research for the treatment of other types of cancer, such as multiple myeloma.

Detailed Description
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This phase II study is designed to assess the toxicity profile and the proportion of overall response in patients with relapsed or refractory WM. This will study the effect of single agent LBH589 on response in these patients. Efficacy measures will include both objective clinical measurements and investigator-reported outcomes. Response and time to event analyses will follow the criteria set forth in the International Waldenstrom consortium recommendations. Prior to the start of the study, investigators will assess disease and perform a CT scan of the chest, abdomen and pelvis. Response will be assessed after 2 cycles. If patients have stable disease or response, then they will continue on therapy until progression or unacceptable toxicity, being assessed every cycle until the sixth cycle and then every 3 months. Patients who show progression after 2 cycles will come off therapy and undergo event monitoring every 3 months. All responses will be assessed by M-protein quantification and immunofixation from serum and IgM monoclonal protein level. In addition, BM biopsies will be done at baseline, at the end of cycle 6 and at the end of all therapy. The protocol was amended because of concerns of toxicity to allow a starting dose of 25 mg; 12/36 (33%) patients were enrolled on the 25 mg dose.

Official Title
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Phase II Trial of LBH589 (Panobinostat) in Relapsed or Relapsed and Refractory Waldenstrom's Macroglobulinemia

Conditions
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Waldenstrom's Macroglobulinemia

Intervention / Treatment
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* Drug: LBH589


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female patients aged 18 years or older Must have received prior therapy for their WM, any number of prior therapies is allowed Must have symptomatic relapsed or refractory WM Measurable monoclonal IgM protein in the blood and presence of lymphoplasmacytic cells in the bone marrow during any previous bone marrow Laboratory values as described in the protocol Clinically euthyroid ECOG Performance Status of 2 or less Exclusion Criteria: Prior HDAC, DAC, HSP90 inhibitors or valproic acid for the treatment of cancer Patients who will need valproic acid for any medical condition during the study or within 5 days prior to first LBH589 treatment Peripheral neuropathy CTCAE grade 2 or higher Impaired cardiac function or clinically significant cardiac diseases Impairment of GI function or GI disease that may significantly alter the absorption of LBH589 Diarrhea > CTCAE grade 1 Other concurrent severe and/or uncontrolled medical conditions including abnormal laboratory values, that could cause unacceptable safety risks or compromise compliance with the protocol Patients using medications that have a relative risk of prolonging the QT interval or inducing torsade de pointes if treatment cannot be discontinued or switched to a different medication prior to starting study drug Patients who have received targeted agents within 2 weeks or within 5 half-lives of the agent and active metabolites (whichever is longer) and who have not recovered from side effects of those therapies Patients who have received chemotherapy or rituximab within 3 weeks or less; or radiation therapy to > 30% of marrow-bearing bone within 2 weeks or less prior to starting study treatment; or who have not yet recovered from side effects of such therapies Patients who have received corticosteroids 2 weeks or less prior to registration. Patients may be receiving chronic corticosteroids if they are being given for disorders other than than Waldenstrom's Macroglobulinemia Patients with active bleeding tendency or receiving any treatment with therapeutic doses of sodium warfarin or coumadin derivatives. Low doses of Coumadin to maintain line patency is allowed Patients who have undergone major surgery 4 weeks or less prior to starting study drug or who have not recovered from side effects of such therapy Women who are pregnant or breast feeding or women of childbearing potential not using an effective method of birth control Male patients whose sexual partners are women of childbearing potential not using effective methods of birth control Patients with prior malignancy within the last 5 years (except for basal or squamous cell carcinoma, or in situ cancer of the cervix) Patients with known positivity for human immunodeficiency virus (HIV) or hepatitis C; baseline testing for HIV and hepatitis C is not required Patients with a significant history of non-compliance to medical regimens or unwilling or unable to comply with the instructions given to him/her by the study staff

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: LBH589<br>30 mg three days a week (Mondays, Wednesdays and Fridays). 1 cycle was 28 days Dose modifications for attributable toxicities allowed for reduction to: 25 mg, 20 mg three times a week every week Or 20 mg three times a week every other week. No dose re-escalation was allowed. The protocol was amended on 6/15/2010 because of concerns of toxicity to allow a starting dose of 25 mg; 12/36 (33%) patients were enrolled on the 25 mg dose. | Drug: LBH589<br> <br> * Other names: panobinostat;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate | Overall response rate is percentage of participants with complete (CR), very good partial (VGPR), partial (PR), or minimal response (MR) as best response during treatment. CR Disappearance of monoclonal protein by immunofixation No histologic evidence of bone marrow involvement Resolution of any adenopathy/organomegaly (confirmed by CT scan), or signs or symptoms attributable to WM. Second immunofixation required for confirmation. VGPR -At least 90% reduction of serum monoclonal IgM concentration on protein electrophoresis. PR At least 50% reduction of serum monoclonal IgM concentration on protein electrophoresis and at least 50% decrease in adenopathy/organomegaly on physical examination or on CT scan. No new symptoms or signs of active disease. MR At least 25% but less than 50% reduction of serum monoclonal IgM by protein electrophoresis. No new symptoms or signs of active disease. | Assessed after 2nd cycle and then every subsequent cycle for 6 cycles. The median number of completed cycles of therapy was 5 (0- 32). As such observed up to  32 months. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Median Progression Free Survival | Progression free survival (PFS) is defined as the time from start of treatment to disease progression or death from any cause as estimated by Kaplan Meier methods. Patients who have not progressed and are alive are censored at the date the patient is known to be progression-free. | Assessed after 2nd cycle and then every subsequent cycle for 6 cycles and then every 3 months. If taken off treatment at cycle 2 for disease progression, assessed every 3 months. The median (range) follow up from treatment start is 7.7 month (0.9 - 29.7). | 
| Median Time to Progression | Time to progression (TTP) is defined as the time from start of treatment to progression. Patients who have not progressed are censored at the date the patient is last known to be progression free. | Assessed after 2nd cycle and then every subsequent cycle for 6 cycles and then every 3 months. If taken off treatment at cycle 2 for disease progression, assessed every 3 months. The median (range) follow up from treatment start is 7.7 month (0.9 - 29.7). | 
| Median Duration of Response | Duration of response DR is defined as the time from the date of first response after treatment to the date of disease progression Patients who have died for any cause or are alive without progression are censored at the date the patient is last know to be progression-free. Duration of response DR is defined as the time from the date of first response after treatment to the date of disease progression or death for any cause. Patients who are alive without progression are censored at the date the patient is last know to be progression-free. | Assessed after 2nd cycle and then every subsequent cycle for 6 cycles and then every 3 months. If taken off treatment at cycle 2 for disease progression, assessed every 3 months. The median (range) follow up from treatment start is 7.7 month (0.9 - 29.7). | 
| Number of Participants With Grade 3 and 4 Treatment-Related Thrombocytopenia | Grade 3 thrombocytopenia is defined as having 25,000-50,000 /uL platelets Grade 4 thrombocytopenia is defined as having < 25,000 /uL platelets | Assessed after 2nd cycle, every subsequent cycle for 6 cycles and then every 3 months. Once off-treatment, adverse events will be assessed for 30 days. The median (range) number of completed cycles of therapy was 5 (0- 32). Therefore, up to  33 months. | 
| Acetylated Histone H3 and Overall Response Association | Acetylated-histone-H3 levels were obtained through bone marrow biopsies and measured using established methods. This analysis aimed to analyze the association between overall response and percent change of acetylated histone h3 in samples using a paired t-test. | Bone marrow biopsies were obtained at the start of treatment (baseline) and after the 6th cycle. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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LBH589, WM, panobinostat, relapsed, waldenstrom, macroglobulinemia