Panobinostat and Everolimus in Treating Patients With Recurrent Multiple Myeloma, Non-Hodgkin Lymphoma, or Hodgkin Lymphoma

Status:Active, not recruiting
Conditions:Cancer, Blood Cancer, Infectious Disease, Lymphoma, Hematology
Therapuetic Areas:Hematology, Immunology / Infectious Diseases, Oncology
Age Range:18 - Any
Start Date:June 2009
End Date:December 2019

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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

This phase I/II trial studies the side effects and best dose of panobinostat and everolimus
when given together and to see how well they work in treating patients with multiple myeloma,
non-Hodgkin lymphoma, or Hodgkin lymphoma that has come back. Panobinostat and everolimus may
stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.


I. To determine the maximum tolerated doses (MTD) of LBH589 (panobinostat) and RAD001
(everolimus) when used in combination in patients with myeloma or lymphoma. (Phase I) II. To
evaluate the therapeutic activity of the combination of LBH589 with RAD001 in patients with
relapsed or refractory lymphoma. (Arm A, phase II) III. To evaluate the therapeutic activity
of the combination of LBH589 with RAD001 in patients with relapsed or refractory multiple
myeloma. (Arm B, phase II)


I. To describe the toxicities associated with the combination of LBH589 with RAD001. (Phase
I) II. To further describe the toxicities associated with the combination of LBH589 with
RAD001 in each arm independently. (Phase II) III. To evaluate overall survival,
progression-free survival, and duration of response in each arm independently. (Phase II)


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.

OUTLINE: This is a phase I, dose-escalation study of panobinostat and everolimus followed by
a phase II study. (dose-escalation closed to accrual as of April 6, 2011)

Patients receive panobinostat orally (PO) once daily (QD) or on days 1, 3, 5, 15, 17, and 19
and everolimus PO QD on days 1-28. Courses repeat every 28 days in the absence of disease
progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 2 years.

Inclusion Criteria:

- Relapsed or refractory multiple myeloma requiring therapy, who have failed, unable to
tolerate, or refused other available active therapies

- Biopsy-proven relapsed or refractory non-Hodgkin lymphoma or Hodgkin disease requiring
treatment, who have failed, unable to tolerate, or refused other available active
therapies; patients should not have other treatment options considered curative;
(NOTE: 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; patients with biopsy-proven central nervous system [CNS]
lymphoma at any time are not required to have a re-biopsy to be eligible for this

- Multiple myeloma:

- Serum monoclonal protein >= 1.0 g/dL

- >= 200 mg of monoclonal protein in the urine on 24 hour electrophoresis

- Serum immunoglobulin free light chain >= 10 mg/dL AND abnormal serum
immunoglobulin kappa to lambda free light chain ratio

- Monoclonal bone marrow plasmacytosis >= 30% (evaluable disease) at time of

- Lymphoma:

- Measurable disease by computed tomography (CT) or magnetic resonance imaging
(MRI) or the CT portion of the positron emission tomography (PET)/CT; must have
at least one lesion that has a single diameter of >= 2 cm or tumor cells in the
blood >= 5 x 10^9/L; skin lesions can be used if the area is >= 2 cm in at least
one 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

- Anaplastic large cell lymphoma - primary systemic type

- Small lymphocytic lymphoma/chronic lymphocytic leukemia

- Follicular lymphoma, grades 1, 2

- Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue
(MALT) type

- Nodal marginal zone B-cell lymphoma

- Splenic marginal zone B-cell lymphoma

- Peripheral T cell lymphoma, unspecified.

- 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 natural killer (NK)-cell lymphoma

- Adult T-cell leukemia/lymphoma

- Extranodal NK/T-cell lymphoma, nasal type

- 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 type

- 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 immunoglobulin (Ig)M monoclonal protein > 1,000 mg/dL

- Absolute neutrophil count (ANC) >= 1000/uL

- Hemoglobin (Hgb) >= 9 g/dl

- Platelets (PLT) >= 75,000/uL

- Total bilirubin =< 1.5 x upper limit of normal (ULN) or if total bilirubin is > 1.5 x
ULN the direct bilirubin must be normal

- Aspartate aminotransferase (AST) =< 3 x ULN

- Creatinine =< 2.5 x ULN

- Serum potassium, magnesium and phosphorus >= lower limit of normal (LLN) and =< 1.2 x

- Ionized calcium >= LLN

- Thyroid-stimulating hormone (TSH) =< 1.5 x ULN; patients are permitted to receive
thyroid hormone supplements to treat underlying hypothyroidism

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

- Willingness to return to Mayo Clinic or National Cancer Institute, National Institutes
of Health (NIH) - Medical Oncology Branch, Center for Cancer Research (CCR)

- 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

- Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1 or 2

Exclusion Criteria:

- Candidate for known standard therapy for the patient's disease that is potentially

- Uncontrolled infection

- Therapy with myelosuppressive chemotherapy or biologic therapy < 3 weeks unless the
patient has recovered from the nadir 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

- Impaired cardiac function or clinically significant cardiac diseases, including any
one of the following:

- 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 enrollment)

- Any history of ventricular fibrillation or torsade de pointes

- Bradycardia defined as heart rate (HR) < 50 beats per minute (bpm;) patients with
pacemakers are eligible if HR >= 50 bpm

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

- 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., congestive heart failure [CHF]
New York [NY] Heart Association class III or IV, uncontrolled hypertension,
history of labile hypertension, or history of poor compliance with an
antihypertensive regimen)

- Any of the following:

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

- 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 (utilized for a non-Food and Drug Administration
[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

- Known positivity for human immunodeficiency virus (HIV) or hepatitis C with
uncontrolled disease; baseline testing for HIV is not required; Note: a detailed
assessment of Hepatitis B/C medical history and risk factors must be done at screening
for all patients; hepatitis b virus (HBV) deoxyribonucleic acid (DNA) and hepatitis C
virus (HCV) ribonucleic acid (RNA) polymerase chain reaction (PCR) testing are
required at screening for all patients with a positive medical history based on risk
factors and/or confirmation of prior HBV infection

- 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

- Thrombotic 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; NOTE: patients on chronic oxygen therapy, those with liver disease such as
cirrhosis, chronic hepatitis or chronic persistent hepatitis, or uncontrolled
infections will be excluded

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

- Receiving any medications or substances that are strong or moderate inhibitors of
CYP3A4; receiving any medications or substances that are inducers of CYP3A4

- 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

- Active bleeding tendency; NOTE: patients on therapeutic anticoagulation 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
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Scottsdale, Arizona 85259
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Scottsdale, AZ
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Bethesda, MD
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Rochester, Minnesota 55905
Rochester, MN
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