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LBH589 in Relapsed or Relapsed and Refractory Waldenstrom's Macroglobulinemia

Primary Purpose

Waldenstrom's Macroglobulinemia

Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
LBH589
Sponsored by
Dana-Farber Cancer Institute
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Waldenstrom's Macroglobulinemia focused on measuring LBH589, WM, panobinostat, relapsed, waldenstrom, macroglobulinemia

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Rocky Mountain Cancer Centers
  • Dana-Farber Cancer Institute

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

LBH589

Arm Description

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.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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.
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.
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.
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
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.

Full Information

First Posted
July 9, 2009
Last Updated
January 10, 2021
Sponsor
Dana-Farber Cancer Institute
Collaborators
Brigham and Women's Hospital, Novartis
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1. Study Identification

Unique Protocol Identification Number
NCT00936611
Brief Title
LBH589 in Relapsed or Relapsed and Refractory Waldenstrom's Macroglobulinemia
Official Title
Phase II Trial of LBH589 (Panobinostat) in Relapsed or Relapsed and Refractory Waldenstrom's Macroglobulinemia
Study Type
Interventional

2. Study Status

Record Verification Date
January 2021
Overall Recruitment Status
Completed
Study Start Date
July 2009 (Actual)
Primary Completion Date
September 2011 (Actual)
Study Completion Date
November 2012 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Dana-Farber Cancer Institute
Collaborators
Brigham and Women's Hospital, Novartis

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Waldenstrom's Macroglobulinemia
Keywords
LBH589, WM, panobinostat, relapsed, waldenstrom, macroglobulinemia

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
39 (Actual)

8. Arms, Groups, and Interventions

Arm Title
LBH589
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
LBH589
Other Intervention Name(s)
panobinostat
Primary Outcome Measure Information:
Title
Overall Response Rate
Description
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.
Time Frame
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 Measure Information:
Title
Median Progression Free Survival
Description
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.
Time Frame
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).
Title
Median Time to Progression
Description
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.
Time Frame
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).
Title
Median Duration of Response
Description
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.
Time Frame
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).
Title
Number of Participants With Grade 3 and 4 Treatment-Related Thrombocytopenia
Description
Grade 3 thrombocytopenia is defined as having 25,000-50,000 /uL platelets Grade 4 thrombocytopenia is defined as having < 25,000 /uL platelets
Time Frame
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.
Title
Acetylated Histone H3 and Overall Response Association
Description
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.
Time Frame
Bone marrow biopsies were obtained at the start of treatment (baseline) and after the 6th cycle.

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Irene Ghobrial, MD
Organizational Affiliation
Dana-Farber Cancer Institute
Official's Role
Principal Investigator
Facility Information:
Facility Name
Rocky Mountain Cancer Centers
City
Denver
State/Province
Colorado
ZIP/Postal Code
80220
Country
United States
Facility Name
Dana-Farber Cancer Institute
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02115
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
23287861
Citation
Ghobrial IM, Campigotto F, Murphy TJ, Boswell EN, Banwait R, Azab F, Chuma S, Kunsman J, Donovan A, Masood F, Warren D, Rodig S, Anderson KC, Richardson PG, Weller E, Matous J. Results of a phase 2 trial of the single-agent histone deacetylase inhibitor panobinostat in patients with relapsed/refractory Waldenstrom macroglobulinemia. Blood. 2013 Feb 21;121(8):1296-303. doi: 10.1182/blood-2012-06-439307. Epub 2013 Jan 3.
Results Reference
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LBH589 in Relapsed or Relapsed and Refractory Waldenstrom's Macroglobulinemia

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