A Phase II Trial of Panobinostat and Lenalidomide in Patients With Relapsed or Refractory Hodgkin's Lymphoma

PRIMARY OBJECTIVES: I. Determine the overall response rate (ORR), including complete
responses (CR) and partial responses (PR), with combined lenalidomide and panobinostat in
patients with relapsed or refractory Hodgkin's lymphoma. SECONDARY OBJECTIVES: I. Assess the
safety and tolerability of combined lenalidomide and panobinostat in patients with previously
treated Hodgkin's lymphoma. II. Determine progression-free survival (PFS) in patients with
previously treated Hodgkin's lymphoma receiving combined lenalidomide and panobinostat. III.
Evaluate changes in natural killer (NK) cell number and function, plasma cytokines, gene
expression profile of peripheral blood, and plasma proteins via proteomics, before, during,
and after lenalidomide and panobinostat therapy. IV. Determine levels of histone acetylation
before and after treatment with panobinostat. V. Determine the pharmacokinetics of
lenalidomide in the presence of panobinostat. VI. To collect deoxyribonucleic acid (DNA)
samples for potential later analysis of associations between outcomes and polymorphisms in
genes coding for drug metabolizing enzymes, transporters and molecular targets of
lenalidomide or panobinostat. OUTLINE: Patients receive panobinostat orally (PO) on days 1,
3, and 5 of weeks 1-4 and lenalidomide PO on days 1-7 of weeks 1-3. Courses repeat every 28
days in the absence of disease progression or unacceptable toxicity. After completion of
study treatment, patients are followed up at least every 3 months for 2 years, and then every
6 months for 3-5 years

Inclusion Criteria:

- Histologically confirmed classical or lymphocyte predominant Hodgkin's lymphoma that
is relapsed or refractory after at least one prior chemotherapy; patients with
Hodgkin's lymphoma may have one of the following World Health Organization (WHO)
subtypes:

- Nodular sclerosis Hodgkin's lymphoma

- Mixed cellularity Hodgkin's lymphoma

- Lymphocyte-rich Hodgkin's lymphoma

- Lymphocyte-deplete Hodgkin's lymphoma

- Nodular Lymphocyte-predominant Hodgkin's lymphoma

- Patients must have relapsed or progressed after at least one prior cytotoxic
chemotherapy

- Previous autologous or allogeneic stem cell transplantation is permitted

- Previous treatment with either single agent panobinostat or lenalidomide is
permitted

- Absolute neutrophil count (ANC) >= 1200/μL

- Platelets >= 100,000/μl

- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x upper
limit normal (ULN)

- Serum bilirubin =< 1.5 x ULN

- Calculated creatinine clearance >= 60ml/min by Cockcroft-Gault estimation of CrCI

- Measurable Disease must be present either on physical examination or imaging studies;
non-measurable disease alone is not acceptable; any tumor mass > 1 cm is acceptable;
lesions that are considered non-measurable include the following:

- Bone lesions

- Leptomeningeal disease

- Ascites

- Pleural/pericardial effusion

- Inflammatory breast disease

- Lymphangitis cutis/pulmonis

- Bone marrow involvement (involvement by non-Hodgkin lymphoma should be noted)

- Baseline multi gated acquisition (MUGA) or echocardiogram (ECHO) must demonstrate left
ventricular ejection fraction (LVEF) >= 45%

- Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2

- Able to provide written informed consent obtained prior to participation in the study
and any related procedures being performed

- Females of childbearing potential (FCBP)† must have a negative serum or urine
pregnancy test with a sensitivity of at least 50 mIU/mL within 10 - 14 days and again
within 24 hours prior to starting Cycle 1 of lenalidomide (prescriptions must be
filled within 7 days as required by RevAssist) and must either commit to continued
abstinence from heterosexual intercourse or begin TWO acceptable methods of birth
control, one highly effective method and one additional effective method AT THE SAME
TIME, at least 28 days before she starts taking lenalidomide. FCBP must also agree to
ongoing pregnancy testing. Men must agree to use a latex condom during sexual contact
with a FCBP even if they have had a successful vasectomy.

- Able to take aspirin (81 or 325 mg) daily as prophylactic anticoagulation (patients
intolerant of aspirin or at increased risk of venous thrombosis may use warfarin or
low molecular weight heparin)

Exclusion Criteria:

- Patients who are candidates for high dose chemotherapy and autologous stem cell
transplantation with curative intent should not be enrolled

- Patients with active central nervous system (CNS) lymphoma

- Use of valproic acid for any medical condition while receiving protocol treatment or
within 5 days prior to first panobinostat dose

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

- History or presence of sustained ventricular tachyarrhythmia; (patients with a
history of atrial arrhythmia are eligible but should be discussed with Novartis
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 QTc > 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)

- Impairment of gastrointestinal (GI) function or GI disease that may significantly
alter the absorption of panobinostat

- Patients with diarrhea > Common Terminology Criteria for Adverse Events (CTCAE) grade
2

- Other concurrent severe and/or uncontrolled medical conditions (e.g., uncontrolled
diabetes or active or uncontrolled infection) 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

- Known hypersensitivity to thalidomide or lenalidomide.

- The development of erythema nodosum if characterized by a desquamating rash while
taking thalidomide or similar drugs

- Pregnant or breastfeeding females

- Patients with known positivity for human immunodeficiency virus (HIV) or hepatitis B
or C; baseline testing for HIV and hepatitis C is not required. Patients who are
seropositive because of hepatitis B virus vaccine are eligible.

- Concurrent use of other anti-cancer agents or treatments

- Patients with any 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