A Phase II Study Of Oral LBH589 In Adult Patients With Multiple Myeloma Who Have Received At Least Two Prior Lines Of Therapy And Whose Disease Is Refractory To The Most Recent Line Of Therapy
A Phase II Study Of Oral LBH589 In Adult Patients With Multiple Myeloma Who Have Received At Least Two Prior Lines Of Therapy And Whose Disease Is Refractory To The Most Recent Line Of Therapy
This study will evaluate the efficacy and safety of LBH589B in adult patients with multiple myeloma who have received at least two prior therapies and are refractory to their last therapy. Patients must have received in prior therapy either bortezomib or lenalidomide
Inclusion criteria:
Adults ≥ 18 years old
Subjects must have signed the consent form before undergoing any study specific screening procedures and before participation in this study. The subject must be fully informed by the investigator of the nature and potential risks of participation in this study.
Patients must have had a diagnosis of symptomatic multiple myeloma (from IMWG see (Kyle et al,2003) meeting all three of the following criteria:
Subjects must have received at least two prior lines of therapy and be refractory to the most recent line of therapy according to the following definitions: Refractory to most recent line of therapy Defined by disease progression during treatment or within 60 - 100 days after the completion of the most recent line of therapy. This includes the development of disease progression during maintenance or consolidation therapy with high dose glucocorticoids, or any other specific MM therapy Sixty days is counted from the point in time when the first response assessment is performed after completion of the last line of therapy. At a maximum, disease progression should be documented within 100 days after the last day of the last dose of any anti-MM therapy, including if last regimen of the most recent line of therapy was Autologous Stem Cell Transplant (ASCT). Stable disease patients also part of the IMWG definition are not eligible for this trial. At study screening, Progressive Disease (PD) will be assessed by comparing screening values or symptoms in reference to the baseline (values or symptoms) of their last line of therapy. Should a patient have experienced an initial response on their last line of therapy, PD should be assessed in reference to the lowest values of the initial confirmed response Minimal Response(MR) / Partial Response (PR) / Complete Response (CR).
Disease progression is defined by having one or more of the following:
Subjects must have previously been treated with bortezomib and at least one of the following: lenalidomide or thalidomide
Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) ≤ 2
Patients must have the following hematological laboratory values:
Patients must have the following renal function as shown by :
Patients must have adequate liver function as shown by:
Patients must have the following non-hematological laboratory values:
Baseline Multiple Uptake Gated Acquisition scan (MUGA) or echocardiogram (ECHO) must demonstrate Left Ventricular Ejection Fraction (LVEF) ≥ the lower limit of the institutional normal
Patients must be willing and able to undergo bone marrow aspirates as per protocol, with/without bone marrow biopsy according to their center's practice. The bone marrow aspirate /biopsy must be adequate to allow for comparison for the later efficacy response assessments.
Patients must have an M component at baseline above a minimum threshold of: 1g/dl (10g/L) for serum M component, or 200mg/24h urine M component.
Exclusion criteria:
Prior therapy with an Histone Deacetylase (HDAC) inhibitor for the treatment of Multiple Myeloma (MM)
Patients with non-secretory MM
Patients who have received allogenic stem cell transplantation < 12 months prior to study
Patients who have had prior allogenic stem cell transplantation and show evidence of active graft versus-host disease that requires immunosuppressive therapy
Patients with amyloidosis
Patients with peripheral neuropathy > grade 2
Impaired cardiac function or clinically significant cardiac diseases, including any one of the following:
Other clinically significant heart disease (e.g., Congestive Heart Failure (CHF NY) Heart Association class III or IV, uncontrolled hypertension, or history of poor compliance with an antihypertensive regimen)
Impairment of GI function or GI disease that may significantly alter the absorption of LBH589
Patients with unresolved diarrhea > CTCAE grade 1.
Other concurrent severe and/or uncontrolled medical conditions 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 torsades de pointes if the medications cannot be discontinued or switched to a different medication prior to starting study drug
Concomitant use of CYP3A4 inhibitors
Patients with an active bleeding diathesis or on any treatment with therapeutic doses of sodium warfarin (Coumadin®) or any other anti-vitamin K drug. Low doses of Coumadin® (e.g., ≤ 2 mg/day), or low doses of any other anti-vitamin K drug, for line patency is allowable
Patients who have received chemotherapy, radiation therapy or any investigational drugs, bortezomib or other immunomodulatory therapy (e.g., thalidomide, lenalidomide) or immunotherapy ≤ 3 weeks prior to starting study drug or who have not recovered from side effects of such therapy
Patients who have received high-dose corticosteroids as the only component of their most recent line of therapy
Patients who have received steroids (e.g., dexamethasone) ≤ 2 weeks prior to starting study treatment or who have not recovered from side effects of such therapy. Concomitant therapy medications that include corticosteroids are allowed if subjects receive < 20 mg of prednisone or equivalent as indicated for other medical conditions (and not as maintenance or an anticancer therapy for MM), or up to 100 mg of hydrocortisone as premedication for a administration of certain medications or blood products, while enrolled in this study.
Patients whose clinical condition would need valproic acid therapy during study or ≤ 5 days prior to starting drug
Patients who have undergone major surgery ≤ 4 weeks prior to starting study drug or who have not recovered from side effects of such therapy
Women who are pregnant or breast feeding or women of childbearing potential (WOCBP)not willing to use a double method of contraception during the study and for 3 months after treatment. One of these methods of contraception must be a barrier method. WOCBP are defined as women who have not undergone a hysterectomy or who have not been naturally postmenopausal for at least 12 consecutive months (i.e., who has had menses any time in the preceding 12 consecutive months). Women of childbearing potential must have a negative serum pregnancy test within 7 days of the first administration of oral LBH589
Male patients whose sexual partners are WOCBP not using a double method of contraception during the study and for 3 months after treatment. One of these methods of contraception must be a condom
Patients with a current second malignancy or a prior malignancy within the last 5 years except adequately treated basal cell or squamous cell skin cancer or in situ cervical cancer
Patients with any significant history of non compliance to medical regimens or unwilling or unable to comply with the protocol or unable to grant reliable informed consent.