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A Phase I/II Study of the Histone Deacetylase (HDAC) Inhibitor LBH589 (Panobinostat) in Combination With mTOR Inhibitor RAD001 (Everolimus) in Patients With Relapsed Multiple Myeloma or Lymphoma

Phase 1/Phase 2
18 Years
Open (Enrolling)
Hematopoietic/Lymphoid Cancer, Adult Nasal Type Extranodal NK/T-cell Lymphoma, Anaplastic Large Cell Lymphoma, Angioimmunoblastic T-cell Lymphoma, B-cell Adult Acute Lymphoblastic Leukemia, Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue, Hepatosplenic T-cell Lymphoma, Nodal Marginal Zone B-cell Lymphoma, Post-transplant Lymphoproliferative Disorder, Primary Central Nervous System Lymphoma, Recurrent Adult Burkitt Lymphoma, Recurrent Adult Diffuse Large Cell Lymphoma, Recurrent Adult Hodgkin Lymphoma, Recurrent Adult Lymphoblastic Lymphoma, Recurrent Adult T-cell Leukemia/Lymphoma, Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma, Recurrent Grade 1 Follicular Lymphoma, Recurrent Grade 2 Follicular Lymphoma, Recurrent Grade 3 Follicular Lymphoma, Recurrent Mantle Cell Lymphoma, Recurrent Marginal Zone Lymphoma, Recurrent Mycosis Fungoides/Sezary Syndrome, Recurrent Small Lymphocytic Lymphoma, Refractory Multiple Myeloma, Splenic Marginal Zone Lymphoma, T-cell Adult Acute Lymphoblastic Leukemia, Waldenstrom Macroglobulinemia

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Trial Information

A Phase I/II Study of the Histone Deacetylase (HDAC) Inhibitor LBH589 (Panobinostat) in Combination With mTOR Inhibitor RAD001 (Everolimus) in Patients With Relapsed Multiple Myeloma or Lymphoma


I. To determine the maximum tolerated doses (MTD) of LBH589 and RAD001 when used in
combination in patients with myeloma or lymphoma (Phase I).

II. Arm A: To evaluate the therapeutic activity of the combination of LBH589 with RAD001 in
patients with relapsed or refractory lymphoma. (Phase II)

III. Arm B: To evaluate the therapeutic activity of the combination of LBH589 with RAD001 in
patients with relapsed or refractory multiple myeloma (Phase II)


I. To further describe the toxicities associated with the combination of LBH589 with RAD001
in each arm independently.

II. To evaluate overall survival, progression-free survival, and duration of response in
each arm independently.


I. To evaluate the pharmacokinetic interaction of LBH589 and RAD001.

II. To assess the correlation between clinical (toxicity and/or tumor response or activity)
effects with the pharmacologic (pharmacokinetic/pharmacodynamic) parameters, and/or biologic
(correlative laboratory) results.


Patients receive oral panobinostat and oral everolimus once daily. Courses repeat every 28
days in the absence of disease progression or unacceptable toxicity. After completion of
study, patients are followed periodically for 2 years.

Inclusion Criteria


- Relapsed or refractory multiple myeloma requiring therapy (patients have failed, been
unable to tolerate, or refused other available active therapies)

- Biopsy-proven relapsed or refractory non-Hodgkin or Hodgkin lymphoma requiring
treatment (patients have failed, been unable to tolerate, or refused other available
active therapies)

- Patients should not have other treatment options considered curative

- For patients with lymphoma, a re-biopsy is necessary unless the patient has had a
previous biopsy < 6 months prior to treatment on this protocol if there has been no
intervening treatment

- Measurable lymphoma by CT scan or MRI as defined by at least 1 of the following: at
least 1 lesion that has a single diameter of >= 2 cm OR tumor cells in the blood >= 5
x109/L (skin lesions can be used if the area is >= 2cm in at least 1 diameter and
photographed with a ruler)

- The following disease types are eligible: transformed lymphomas, diffuse large B cell
lymphoma, mantle cell lymphoma, follicular lymphoma grade III, precursor B
lymphoblastic leukemia/lymphoma, mediastinal (thymic) large B-cell lymphoma, Burkitt
lymphoma/leukemia, precursor T-lymphoblastic leukemia/lymphoma, primary cutaneous
anaplastic large cell lymphoma

- The following disease types are eligible: anaplastic large cell lymphoma-primary
systemic type, small lymphocytic lymphoma/chronic lymphocytic leukemia, grades 1 & 2
follicular lymphoma, extranodal marginal zone B-cell lymphoma of MALT type, nodal
marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma, peripheral T
cell lymphoma (unspecified)

- The following disease types are eligible: anaplastic large cell lymphoma (T and null
cell type), lymphoplasmacytic lymphoma (Waldenstrom Macroglobulinemia), CNS lymphoma,
post-transplant lymphoproliferative disorders, mycosis fungoides/Sezary syndrome,
Hodgkin disease, primary effusion lymphoma, blastic NK-cell lymphoma, adult T-cell
leukemia/lymphoma, extranodal NK/T-cell lymphoma (nasal type)

- The following disease types are eligible: enteropathy-type T-cell lymphoma,
hepatosplenic T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma,
angioimmunoblastic T-cell lymphoma, anaplastic large cell lymphoma-primary cutaneous

- For lymphoplasmacytic lymphoma patients without measurable lymphadenopathy,
measurable disease can be defined by both of the following criteria: bone marrow
lymphoplasmacytosis with > 10% lymphoplasmacytic cells or aggregates, sheets,
lymphocytes, plasma cells, or lymphoplasmacytic cells on bone marrow biopsy AND
quantitative IgM monoclonal protein > 1,000 mg/dL

- Please contact study investigator and/or consult protocol document for specific
details on laboratory criteria

- Ability to understand and the willingness to sign a written informed consent document

- Life expectancy >= 12 weeks

- Willing to provide blood samples for research studies as required by the protocol

- Negative pregnancy test done =< 7 days prior to registration, for women of
childbearing potential only

- ECOG performance status (PS) 0, 1, or 2

- Patients with biopsy-proven CNS lymphoma at any time are not required to have a
re-biopsy to be eligible for this study

- Measurable multiple myeloma as defined by at least 1 of the following: serum
monoclonal protein >= 1.0 g/dL; >= 200 mg monoclonal protein in urine on 24-hour
electrophoresis; serum immunoglobulin free light chain >= 10 mg/dL and abnormal serum
immunoglobulin kappa to lambda free light chain ratio; OR monoclonal bone marrow
plasmacytosis >= 30% (evaluable disease)

- Willingness to return to Mayo Clinic


- Known positivity for human immunodeficiency virus (HIV) or hepatitis C with
uncontrolled disease (baseline testing for HIV and hepatitis C is not required)

- Candidate for potentially curative standard therapy

- Uncontrolled infection

- Therapy with myelosuppressive chemotherapy or biologic therapy <3 weeks unless the
patient has recovered from the nadir (lowest value of blood counts after
chemotherapy) of the previous treatment to a level that meets the inclusion
eligibility criteria of this protocol. NOTE: (patients who have received prior RAD001
therapy will be allowed but must meet above requirements)

- Receiving corticosteroids > 20 mg of prednisone per day (or equivalent)NOTE: Patients
may be receiving stable (not increased within the last month) chronic doses of
corticosteroids with a maximum dose of 20 mg of prednisone per day if they are being
given for disorders other than lymphoma (with the exception of CNS lymphoma, which
steroids are permitted at the lowest possible dose necessary and should not be
escalated during treatment) such as rheumatoid arthritis, polymyalgia rheumatica or
adrenal insufficiency or asthma.

- Persistent toxicities >= grade 2 from prior chemotherapy or biological therapy
regardless of interval since last treatment

- Patients with congenital long QT syndrome

- History or presence of sustained ventricular tachyarrhythmia (patients with a history
of atrial arrhythmia are eligible but should be discussed with the sponsor prior to

- Any history of ventricular fibrillation or torsade de pointes

- Bradycardia defined as HR < 50 bpm (patients with pacemakers are eligible if HR >= 50

- Right bundle branch block + left anterior hemiblock (bifascicular block)

- Patients with myocardial infarction or unstable angina =< 6 months prior to starting
study drug

- Other clinically significant heart disease (e.g., CHF NY Heart Association class III
or IV) , uncontrolled hypertension, history of labile hypertension, or history of
poor compliance with an antihypertensive regimen

- Pregnant women or women of reproductive ability who are unwilling to use effective

- Nursing women

- Men who are unwilling to use a condom (even if they have undergone a prior vasectomy)
while having intercourse with any woman, while taking the drug, and for 4 weeks after
stopping treatment

- Other concurrent chemotherapy, immunotherapy, radiotherapy, or any ancillary therapy
considered investigational (i.e., utilized for a non-FDA-approved indication and in
the context of a research investigation). NOTE: Patients may undergo palliative
concurrent radiation of myeloma lesions for pain control or impending fracture,
provided the lesion(s) by themselves do not constitute progression.

- Active other malignancy requiring treatment that would interfere with the assessments
of response of the lymphoma or myeloma to protocol treatment - Inability to
swallow or impairment of gastrointestinal function or gastrointestinal disease that
may significantly alter the absorption of the drugs (e.g., ulcerative disease,
uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small bowel
resection) that would preclude use of oral medications

- Thrombolic or embolic events such as a cerebrovascular accident including transient
ischemic attacks within the past 6 months

- Any severe and/or uncontrolled medical conditions or other conditions that, in the
treating physician's opinion, could adversely impact their ability to participate in
the study

- Patients on chronic oxygen therapy, with liver disease (e.g., cirrhosis, chronic
hepatitis, or chronic persistent hepatitis), or uncontrolled infections

- Known hypersensitivity to RAD001 (everolimus) or other rapamycins (sirolimus,

- Concomitant use of CYP3A4 inhibitors

- Using medications that have a relative risk of prolonging the QT interval or inducing
torsades de pointes if treatment cannot be discontinued or switched to a different
medication prior to starting study drug

- Active bleeding tendency. NOTE: Patients on therapeutic anticoagulatin should be
monitored carefully to maintain therapeutic level of anticoagulation to avoid
increased risk of bleeding due to concurrent drug induced thrombocytopenia. It is
suggested that patients who require anticoagulation therapy while on therapy use low
molecular weight heparin (LMWH).

- Major surgery =< 4 weeks prior to registration or have not recovered from side
effects of such therapy

- Screening ECG with a QTcFredericia (QTcF) > 450 msec

Type of Study:


Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Toxicity, as assessed by NCI CTCAE v3.0 (phase I)

Safety Issue:


Principal Investigator

Shaji K. Kumar, M.D.

Investigator Role:

Study Chair

Investigator Affiliation:

Mayo Clinic


United States: Food and Drug Administration

Study ID:




Start Date:

June 2009

Completion Date:

Related Keywords:

  • Hematopoietic/Lymphoid Cancer
  • Adult Nasal Type Extranodal NK/T-cell Lymphoma
  • Anaplastic Large Cell Lymphoma
  • Angioimmunoblastic T-cell Lymphoma
  • B-cell Adult Acute Lymphoblastic Leukemia
  • Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue
  • Hepatosplenic T-cell Lymphoma
  • Nodal Marginal Zone B-cell Lymphoma
  • Post-transplant Lymphoproliferative Disorder
  • Primary Central Nervous System Lymphoma
  • Recurrent Adult Burkitt Lymphoma
  • Recurrent Adult Diffuse Large Cell Lymphoma
  • Recurrent Adult Hodgkin Lymphoma
  • Recurrent Adult Lymphoblastic Lymphoma
  • Recurrent Adult T-cell Leukemia/Lymphoma
  • Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma
  • Recurrent Grade 1 Follicular Lymphoma
  • Recurrent Grade 2 Follicular Lymphoma
  • Recurrent Grade 3 Follicular Lymphoma
  • Recurrent Mantle Cell Lymphoma
  • Recurrent Marginal Zone Lymphoma
  • Recurrent Mycosis Fungoides/Sezary Syndrome
  • Recurrent Small Lymphocytic Lymphoma
  • Refractory Multiple Myeloma
  • Splenic Marginal Zone Lymphoma
  • T-cell Adult Acute Lymphoblastic Leukemia
  • Waldenström Macroglobulinemia
  • Burkitt Lymphoma
  • Hodgkin Disease
  • Immunoblastic Lymphadenopathy
  • Leukemia
  • Leukemia, Lymphocytic, Chronic, B-Cell
  • Leukemia, Lymphoid
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma
  • Leukemia, T-Cell
  • Leukemia-Lymphoma, Adult T-Cell
  • Lymphoma
  • Lymphoma, Follicular
  • Lymphoma, Large B-Cell, Diffuse
  • Lymphoma, Non-Hodgkin
  • Lymphoproliferative Disorders
  • Waldenstrom Macroglobulinemia
  • Multiple Myeloma
  • Neoplasms, Plasma Cell
  • Mycoses
  • Mycosis Fungoides
  • Sezary Syndrome
  • Lymphoma, B-Cell
  • Lymphoma, T-Cell
  • Lymphoma, T-Cell, Cutaneous
  • Lymphoma, Large-Cell, Anaplastic
  • Lymphoma, B-Cell, Marginal Zone
  • Lymphoma, Mantle-Cell
  • Lymphoma, Extranodal NK-T-Cell



Mayo ClinicRochester, Minnesota  55905
Mayo Clinic Scottsdale-PhoenixScottsdale, Arizona  85259
Metabolism Branch, NCI, NIHBethesda, Maryland  20892