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
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.
PRIMARY OBJECTIVES:
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)
SECONDARY OBJECTIVES:
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)
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: 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 study)
Multiple myeloma:
Lymphoma:
The following disease types are eligible:
For lymphoplasmacytic lymphoma patients without measurable lymphadenopathy, measurable disease can be defined by both of the following criteria:
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 ULN
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 curative
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:
Any of the following:
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 progression
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, temsirolimus)
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