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

• Sponsor: Ohio State University Comprehensive Cancer Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT01460940
• Collaborator: Celgene (Industry), Novartis (Industry)
• Enrollment: 24
• Locations: 2
• Arm: 1
• Duration (Months): 61.1
• Patients Per Site: 12
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

This phase II trial studies how well giving panobinostat together with lenalidomide works in treating patients with relapsed or refractory Hodgkin lymphoma. Panobinostat may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Biological therapies, such as lenalidomide, may stimulate the immune system in different ways and stop cancer cells from growing. Giving panobinostat together with lenalidomide may be an effective treatment for Hodgkin lymphoma

Condition or Disease	Intervention/Treatment	Phase
Adult Lymphocyte Depletion Hodgkin Lymphoma; Adult Lymphocyte Predominant Hodgkin Lymphoma; Adult Mixed Cellularity Hodgkin Lymphoma; Adult Nodular Lymphocyte Predominant Hodgkin Lymphoma; Adult Nodular Sclerosis Hodgkin Lymphoma; Recurrent Adult Hodgkin Lymphoma	Drug: panobinostat; Drug: lenalidomide	Phase 2

Detailed Description

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

Study Design

• Study Type: Interventional
• Actual Enrollment: 24 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Trial of Panobinostat and Lenalidomide in Patients With Relapsed or Refractory Hodgkin's Lymphoma
• Study Start Date: Oct 13, 2011
• Actual Primary Completion Date: Nov 16, 2016
• Actual Study Completion Date: Nov 16, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Lenalidomide and Panobinostat In the phase I trial, three patients will be enrolled at each dose level, starting at dose level 1 using a standard 3 + 3 dose escalation phase I design.	Drug: panobinostat; Administered orally Monday, Wednesday, Friday of every week for 4 weeks. A cycle is define as 28 days.; Other Names: HDAC inhibitor LBH589 hydroxamic acid ; Drug: lenalidomide; Lenalidomide will be administered orally daily on days 1-21. Lenalidomide will not be given on days 22-28. A cycle is define as 28 days.; Other Names: CC-5013 Revlimid

Outcome Measures

Primary Outcome Measures

1. Determine the Overall Response Rate (ORR), Including Complete Responses (CR) and Partial Responses (PR) [up to 24 months]

   Overall response rate (CR + PR) will be determined using the International response criteria with combined panobinostat and lenalidomide in patients with relapsed or refractory Hodgkin's lymphoma.

Secondary Outcome Measures

1. Assess the Safety and Tolerability of Combined Lenalidomide and Panobinostat in Patients With Previously Treated Hodgkin's Lymphoma. [up to 24 months]

   Safety and tolerability will be assessed for patients using the NIH-NCI Common Terminology Criteria (CTCAE) version 4.0

2. Progression-free Survival in Patients With Previously Treated Hodgkin's Lymphoma Receiving Combined Lenalidomide and Panobinostat [3-5 years]

   Determined from the date of start of therapy to death from any cause or censored at the last date the patient is known to be alive

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Washington University	Saint Louis	Missouri	United States	63110
2	The Ohio State University Medical Center	Columbus	Ohio	United States	43210

Sponsors and Collaborators

• Ohio State University Comprehensive Cancer Center
• Celgene
• Novartis

Investigators

• Principal Investigator: Kristie Blum, MD, Ohio State University

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Jamesline

Publications

None provided.

• Responsible Party: Ohio State University Comprehensive Cancer Center
• ClinicalTrials.gov Identifier: NCT01460940
• Other Study ID Numbers: OSU-10049; NCI-2011-03323
• First Posted: Oct 27, 2011
• Last Update Posted: Nov 14, 2017
• Last Verified: Nov 1, 2017

• Keywords provided by Ohio State University Comprehensive Cancer Center: refractory Hodgkin's lymphoma; panobinostat; lenalidomide
• Additional relevant MeSH terms: Lymphoma; Hodgkin Disease; Lenalidomide; Panobinostat; Histone Deacetylase Inhibitors

Study Results

Participant Flow

Arm/Group Title	Lenalidomide and Panobinostat
Arm/Group Description	In the phase I trial, three patients will be enrolled at each dose level, starting at dose level 1 using a standard 3 + 3 dose escalation phase I design. panobinostat: Administered orally Monday, Wednesday, Friday of every week for 4 weeks. A cycle is define as 28 days. lenalidomide: Lenalidomide will be administered orally daily on days 1-21. Lenalidomide will not be given on days 22-28. A cycle is define as 28 days.
Period Title: Overall Study
STARTED	24
COMPLETED	24
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Lenalidomide and Panobinostat
Arm/Group Description	In the phase I trial, three patients will be enrolled at each dose level, starting at dose level 1 using a standard 3 + 3 dose escalation phase I design. panobinostat: Administered orally Monday, Wednesday, Friday of every week for 4 weeks. A cycle is define as 28 days. lenalidomide: Lenalidomide will be administered orally daily on days 1-21. Lenalidomide will not be given on days 22-28. A cycle is define as 28 days.
Overall Participants	24
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	45
Sex: Female, Male (Count of Participants)
Female	7 29.2%
Male	17 70.8%
Region of Enrollment (participants) [Number]
United States	24 100%

Outcome Measures

1. Primary Outcome

Title	Determine the Overall Response Rate (ORR), Including Complete Responses (CR) and Partial Responses (PR)
Description	Overall response rate (CR + PR) will be determined using the International response criteria with combined panobinostat and lenalidomide in patients with relapsed or refractory Hodgkin's lymphoma.
Time Frame	up to 24 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Lenalidomide and Panobinostat
Arm/Group Description	In the phase I trial, three patients will be enrolled at each dose level, starting at dose level 1 using a standard 3 + 3 dose escalation phase I design. panobinostat: Administered orally Monday, Wednesday, Friday of every week for 4 weeks. A cycle is define as 28 days. lenalidomide: Lenalidomide will be administered orally daily on days 1-21. Lenalidomide will not be given on days 22-28. A cycle is define as 28 days.
Measure Participants	24
Number [percentage of patients]	16.7

2. Secondary Outcome

Title	Assess the Safety and Tolerability of Combined Lenalidomide and Panobinostat in Patients With Previously Treated Hodgkin's Lymphoma.
Description	Safety and tolerability will be assessed for patients using the NIH-NCI Common Terminology Criteria (CTCAE) version 4.0
Time Frame	up to 24 months

Outcome Measure Data

Analysis Population Description

Grade 3-4 toxicities

Arm/Group Title	Lenalidomide and Panobinostat
Arm/Group Description	In the phase I trial, three patients will be enrolled at each dose level, starting at dose level 1 using a standard 3 + 3 dose escalation phase I design. panobinostat: Administered orally Monday, Wednesday, Friday of every week for 4 weeks. A cycle is define as 28 days. lenalidomide: Lenalidomide will be administered orally daily on days 1-21. Lenalidomide will not be given on days 22-28. A cycle is define as 28 days.
Measure Participants	24
neutropenia	58.3
thrombocytopenia	41.7
febrile neutropenia	25.0
hypophosphatemia	25.0

3. Secondary Outcome

Title	Progression-free Survival in Patients With Previously Treated Hodgkin's Lymphoma Receiving Combined Lenalidomide and Panobinostat
Description	Determined from the date of start of therapy to death from any cause or censored at the last date the patient is known to be alive
Time Frame	3-5 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Lenalidomide and Panobinostat
Arm/Group Description	In the phase I trial, three patients will be enrolled at each dose level, starting at dose level 1 using a standard 3 + 3 dose escalation phase I design. panobinostat: Administered orally Monday, Wednesday, Friday of every week for 4 weeks. A cycle is define as 28 days. lenalidomide: Lenalidomide will be administered orally daily on days 1-21. Lenalidomide will not be given on days 22-28. A cycle is define as 28 days.
Measure Participants	24
Median (95% Confidence Interval) [months]	3.8

Adverse Events

Arm/Group Title	Lenalidomide and Panobinostat
Arm/Group Description	In the phase I trial, three patients will be enrolled at each dose level, starting at dose level 1 using a standard 3 + 3 dose escalation phase I design. panobinostat: Administered orally Monday, Wednesday, Friday of every week for 4 weeks. A cycle is define as 28 days. lenalidomide: Lenalidomide will be administered orally daily on days 1-21. Lenalidomide will not be given on days 22-28. A cycle is define as 28 days.
All Cause Mortality
	Lenalidomide and Panobinostat
	Affected / at Risk (%)	# Events
Total	0/24 (0%)
Serious Adverse Events
	Lenalidomide and Panobinostat
	Affected / at Risk (%)	# Events
Total	17/24 (70.8%)
Blood and lymphatic system disorders
Thrombocytopenia	1/24 (4.2%)	1
Neutropenia	3/24 (12.5%)	3
Gastrointestinal disorders
Dehydration	1/24 (4.2%)	1
Nausea/vomiting	1/24 (4.2%)	1
Infections and infestations
Febrile Neutropenia	4/24 (16.7%)	4
Infection without Neutropenia	2/24 (8.3%)	2
Investigations
Fatigue	1/24 (4.2%)	1
Metabolism and nutrition disorders
Hyponatremia	1/24 (4.2%)	1
Hyperbilirubinemia/Transaminitis	1/24 (4.2%)	1
Psychiatric disorders
Altered Mental Status	1/24 (4.2%)	1
Skin and subcutaneous tissue disorders
Rash	1/24 (4.2%)	1
Other (Not Including Serious) Adverse Events
	Lenalidomide and Panobinostat
	Affected / at Risk (%)	# Events
Total	24/24 (100%)
Blood and lymphatic system disorders
Febrile Neutropenia	2/24 (8.3%)	2
Thrombocytopenia	9/24 (37.5%)	9
Infections and infestations
Neutropenia	11/24 (45.8%)	11
Infection without Neutropenia	2/24 (8.3%)	2
Investigations
Lymphopenia	6/24 (25%)	6
Metabolism and nutrition disorders
Hypokalemia	2/24 (8.3%)	2
Hypophosphatemia	2/24 (8.3%)	2
Hyperbilirubinemia/Transaminitis	2/24 (8.3%)	2

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.