A Multicenter, randomized, double-blind, placebo controlled phase III study of panobinostat in combination with bortezomib and dexamethasone in patients with relapsed multiple myeloma
Donna M. Weber
The goal of this clinical research study is to learn if the combination of panobinostat, bortezomib, and dexamethasone is safe and results in a better anti-myeloma activity than bortezomib and dexamethasone alone.
Disease Group: Myeloma
Treatment Agent: Bortezomib,Dexamethasone,Panobinostat
Treatment Location: Both at MDACC & and Other Sites
Primary objective To compare progression-free survival (PFS), in patients treated with Panobinostat (PAN) in combination with bortezomib/ dexamethasone (BTZ/Dex) vs. patients treated with placebo in combination with BTZ/Dex. Key secondary objective To compare overall survival (OS) Other secondary objectives • To compare ORR (overall response rate) comprising CR, nCR and PR • To compare nCR plus CR rate (near complete response plus + complete response) • To compare MRR (minor response rate) • To compare TTR (time to response) • To compare TTP (time to progression) • To assess duration of response (DOR from first occurring PR or better) • To assess safety of the combination therapy • To assess health-related quality of life and symptoms of multiple myeloma Exploratory objectives To assess very good partial response (VGPR) rate To assess stringent CR (sCR) rate
IRB Review and Approval Date: 01/12/2011
Recruitment Status: Not Accepting
Projected Accrual: 762
1) Patient has a previous diagnosis of multiple myeloma, based on IMWG
2003 definitions all three of the following criteria had been met: a.
Monoclonal immunoglobulin (M component) on electrophoresis, and on
immunofixation on serum or on total 24 hour urine (or demonstration of M
protein in cytoplasm of plasma cell for non secretory myeloma) . b. Bone
marrow (clonal) plasma cells >/= 10% or biopsy proven plasmacytoma c.
Related organ or tissue impairment (CRAB symptoms: anemia,
hypercalcemia, lytic bone lesions, renal insufficiency, hyperviscosity,
amyloidosis or recurrent infections)
2) Patient with 1 to 3 prior lines of therapy who requires retreatment of myeloma for one of the 2 conditions below: a. Relapsed, defined by disease that recurred in a patient that responded under a prior therapy, by reaching a MR or better, and had not progressed under this therapy nor up to 60 days of last dose of this therapy. Patients priorly treated by BTZ may be eligible. b. Relapsed-and-refractory to a therapy provided that meets both conditions: patient has relapsed to at least one prior line; and patient was refractory to another line (except BTZ), by either not reaching a MR, or progressed while under this therapy, or within 60 days of its last dose
3) Patient has measurable disease at study screening defined by at least one of the following measurements: Serum M-protein >/= 1 g/dL (>/= 10 g/L); Urine M-protein >/= 200 mg/24 h
4) Patient treated with local radiotherapy with or without concomitant exposure to steroids for pain control or management of cord/nerve root compression, is eligible. Two weeks must have lapsed since last date of radiotherapy, which is recommended to be a limited field. Patient who require concurrent radiotherapy should have entry to the protocol deferred until the radiotherapy is completed and 2 weeks have passed since the last date of therapy
5) Patient’s age is >/= 18 years at time of signing the informed consent
6) Patient has an Eastern Cooperative Oncology Group (ECOG) performance status (PS) </= 2
7) Patient has the following laboratory values within 3 weeks before starting study drug (lab tests may be repeated, as clinically indicated, to obtain acceptable values before failure at screening is concluded but supportive therapies are not to be administered within the week prior to screening tests for ANC or platelet count) a. Absolute neutrophil count (ANC) >/= 1.5 x 10^9 /L; b. Platelet count >/= 100 x 10^9 /L; c. Serum potassium, magnesium, phosphorus , within normal limits (WNL) for institution d. Total calcium (corrected for serum albumin) or ionized calcium greater or equal to lower normal limits (> LLN) for institution, and not higher than CTCAE grade 1 in case of elevated value. e. AST/SGOT and ALT/SGPT </= 2.5 x ULN f. Serum total bilirubin </= 1.5 ULN (or </= 3.0 x ULN if patient has Gilbert syndrome) g. Serum creatinine levels </= 1.5 x ULN, or calculated creatinine clearance >/= 60 ml/min
8) Continued from # 7 : Note: Potassium, calcium, magnesium, and/or phosphorus supplements may be given to correct values that are < LLN.
9) Patient has provided written informed consent prior to any screening procedures
10) Patient is able to swallow capsules
11) Patient must be able to adhere to the study visit schedule and other protocol requirements
12) Women of childbearing potential (WOCBP) must have a negative serum pregnancy test within 7 days prior to start of study treatment
1) Patients who have progressed under all prior lines of anti MM therapy
2) Patients who have been refractory to prior BTZ (i.e. did not achieve at least a MR, or have progressed under it or within 60 days of last dose)
3) Allogeneic stem cell transplant recipient presenting with graft versus host disease either active or requiring immunosuppression
4) Patient has shown intolerance to bortezomib or to dexamethasone or components of these drugs or has any contraindication to one or the other drug, following locally applicable prescribing information
5) Patient has grade >/= 2 peripheral neuropathy or grade 1 peripheral neuropathy with pain on clinical examination within 14 days before randomization
6) Patient received prior treatment with DAC inhibitors including panobinostat
7) Patient needing valproic acid for any medical condition during the study or within 5 days prior to first administration of panobinostat/study treatment.
8) Patient taking any anti-cancer therapy concomitantly (bisphosphonates are permitted only if commenced prior to the start of screening period)
9) Patient has secondary primary malignancy < 3 years of first dose of study treatment (except for treated basal or squamous cell carcinoma, or in situ cancer of the cervix).
10) Patient who received: a. prior anti-myeloma chemotherapy or medication including IMiDs and Dex </= 3 weeks prior to start of study. b. experimental therapy or biologic immunotherapy including monoclonal antibodies </= 4 weeks prior to start of study. c. prior radiation therapy </= 4 weeks or limited field radiotherapy </= 2 weeks prior start of study.
11) Patient has not recovered from all therapy-related toxicities associated with above listed treatments to < grade 2 CTCAE.
12) Patient has undergone major surgery </= 2 weeks prior to starting study drug or who have not recovered from side effects of such therapy to < grade 2 CTCAE
13) Patients with evidence of mucosal or internal bleeding
14) Patient has unresolved diarrhea >/= CTCAE grade 2
15) Patient has impaired cardiac function, including any one of the following: a. LVEF < LLN of institutional norm, as determined by ECHO or MUGA b. obligate use of a permanent cardiac pacemaker c. congenital long QT syndrome d. history or presence of ventricular tachy-arrhythmias e. resting bradycardia defined as < 50 beats per minute f. QTcF > 450 msec on screening ECG g. complete left bundle branch block (LBBB), bifascicular block h. any clinically significant ST segment and/or T-wave abnormalities i. presence of unstable atrial fibrillation (ventricular response rate > 100 bpm). Patients with stable atrial fibrillation can be enrolled provided they do not meet other cardiac exclusion criteria. j. myocardial infarction or unstable angina pectoris </= 6 months prior to starting study drug k. symptomatic congestive heart failure (New York Heart Association class III-IV) l. other clinically significant heart disease and vascular disease (e.g. uncontrolled hypertension
16) Patient taking medications with relative risk of prolonging the QT interval or inducing Torsade de pointes, if such treatment cannot be discontinued or switched to a different medication prior to starting study drug
17) Patient has impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of panobinostat (e.g. ulcerative disease, uncontrolled nausea, vomiting, malabsorption syndrome, obstruction, or stomach and/or small bowel resection)
18) Patient has any other concurrent severe and/or uncontrolled medical conditions (e.g., uncontrolled diabetes, active or uncontrolled infection, chronic obstructive or chronic restrictive pulmonary disease including dyspnea at rest from any cause, uncontrolled thyroid dysfunction) that could cause unacceptable safety risks or compromise compliance with the protocol
19) Patient has a known history of HIV seropositivity or history of active/treated hepatitis B or C (a test for screening is not required)
20) 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 3 months after the study evaluation completion treatment, of which one must be a barrier method. WOCBP are defined as sexually mature women who have not undergone a hysterectomy or who have not been naturally postmenopausal for at least 12 consecutive months (i.e. patient has had menses at any time in the preceding 12 consecutive months.
21) Patient is a male not willing to use a barrier method of contraception (a condom) during the study and for 3 months after the study evaluation completion treatment.
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Donna M. Weber
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