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

This study is currently recruiting participants.
Verified March 2014 by Mayo Clinic
Sponsor:
Information provided by:
Mayo Clinic
ClinicalTrials.gov Identifier:
NCT00918333
First received: June 1, 2009
Last updated: March 20, 2014
Last verified: March 2014

June 1, 2009
March 20, 2014
June 2009
January 2016   (final data collection date for primary outcome measure)
  • Toxicity, as assessed by NCI CTCAE v3.0 (phase I) [ Designated as safety issue: Yes ]
  • Proportion of confirmed tumor responses (i.e., CR, CRu, sCR, VGPR, or PR) (phase II) [ Time Frame: Using up to 12 cycles of treatment ] [ Designated as safety issue: No ]
Same as current
Complete list of historical versions of study NCT00918333 on ClinicalTrials.gov Archive Site
  • Survival time [ Designated as safety issue: No ]
  • Progression-free survival [ Designated as safety issue: No ]
  • Duration of response [ Designated as safety issue: No ]
  • Pharmacologic (pharmacokinetic/pharmacodynamic) parameters and biological (correlative laboratory) results and correlation to differences between responders and non-responders [ Time Frame: Before and after treatment ] [ Designated as safety issue: No ]
Same as current
Not Provided
Not Provided
 
Panobinostat and Everolimus in Treating Patients With Recurrent Multiple Myeloma, Non-Hodgkin Lymphoma, or Hodgkin Lymphoma
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

RATIONALE: Panobinostat and everolimus may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

PURPOSE: This phase I/II trial is studying the side effects and best dose of panobinostat and everolimus when given together and to see how well they work in treating patients with recurrent multiple myeloma, non-Hodgkin lymphoma, or Hodgkin lymphoma.

PRIMARY OBJECTIVES:

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)

SECONDARY OBJECTIVES:

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.

TERTIARY OBJECTIVES:

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:

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.

Interventional
Phase 1
Phase 2
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
  • 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
  • Drug: panobinostat
    Given orally
    Other Names:
    • Faridak
    • HDAC inhibitor LBH589
    • histone deacetylase inhibitor LBH589
    • LBH589
  • Drug: everolimus
    Given orally
    Other Names:
    • 42-O-(2-hydroxy)ethyl rapamycin
    • Afinitor
    • RAD001
  • Other: laboratory biomarker analysis
  • Other: pharmacological study
    Other Name: pharmacological studies
  • Other: flow cytometry
  • Other: immunohistochemistry staining method
    Other Name: immunohistochemistry
  • Other: western blotting
    Other Names:
    • Blotting, Western
    • Western Blot
Experimental: Arm I
Patients receive oral panobinostat (Monday, Wednesday, Friday) and oral everolimus once daily.
Interventions:
  • Drug: panobinostat
  • Drug: everolimus
  • Other: laboratory biomarker analysis
  • Other: pharmacological study
  • Other: flow cytometry
  • Other: immunohistochemistry staining method
  • Other: western blotting
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
109
Not Provided
January 2016   (final data collection date for primary outcome measure)

Inclusion

  • 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 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 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

Exclusion

  • 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 enrollment)
  • Any history of ventricular fibrillation or torsade de pointes
  • Bradycardia defined as HR < 50 bpm (patients with pacemakers are eligible if HR >= 50 bpm)
  • 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 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 (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, temsirolimus)
  • 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
Both
18 Years and older
No
Not Provided
United States
 
NCT00918333
MC0886, NCI-2009-00934, 08-004746, MC0886, CLBH589BUS17T
Yes
Shaji K. Kumar, M.D., Mayo Clinic Cancer Center
Mayo Clinic
Not Provided
Study Chair: Shaji K. Kumar, M.D. Mayo Clinic
Principal Investigator: Joseph R. Mikhael, M.D. Mayo Clinic in Arizona
Mayo Clinic
March 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP