A Phase I Study Of Panobinostat/Lenalidomide/Bortezomib/Dex for Relapsed And Relapsed/Refractory Multiple Myeloma
Phase: Phase 1
Diagnosis: Multiple Myeloma
NCT ID: NCT01965353
(View complete trial on ClinicalTrials.gov)
DFCI Protocol ID: 13-262
This research study is evaluating an investigational drug called Panobinostat (LBH589) in combination with the standard agents lenalidomide, bortezomib, and dexamethasone as a possible treatment for multiple myeloma.
Dana-Farber Cancer Institute, Brigham and Women's Hospital, Beth-Israel Deaconess Medical Center
Jacob Laubach, MD,
Dana-Farber Cancer Institute
Jacalyn Rosenblatt, MD,
Beth Israel Deaconess Medical Center
Dana-Farber Cancer Institute:
Kathleen Colson, 617-632-6303,
Beth-Israel Deaconess Medical Center:
Cancer Trials Call Center, 617-667-3060
- Patients must meet the following criteria on screening examination to be eligible to
participate in the study. All laboratory assessments should be performed within 21
days of initiation of protocol therapy unless otherwise specified.
- Participants must have a previous diagnosis of Multiple Myeloma, according to
International Myeloma Foundation 2003 Diagnostic Criteria
- Patients must have relapsed or relapsed and refractory disease after receiving 2 or
more lines of therapy.
- Relapse is the occurrence of any of the following: 1) >25% increase in M-protein from
the baseline levels; 2) reappearance of M-protein that had disappeared; or 3)
definite increase in the size and number of lytic bone lesions recognized on
radiographs (compression fractures per se do not constitute a relapse).
- Subjects will be considered refractory to therapy, as defined by progression during
treatment or within 60 days after the completion of salvage treatment. Subjects with
primary refractory disease, defined as disease that is non-responsive in patients
that have never achieved a minor response or better with any therapy are excluded.
- This includes: 1) non-responding, non-progressing; patients who never achieve MR or
better in whom there is no significant change in M protein and no evidence of
clinical progression; and 2) progressive; primary refractory, progressive disease
where patients meet criteria for true progressive disease (Durie 2006).
- Participants must have myeloma that is measurable. Measurable disease is defined as
one or more of the following:
- serum M-protein ≥ 0.5 g/dl,
- urine M-protein ≥ 200 mg/24 h, and/or
- serum FLC assay: involved FLC level ≥ 10 mg/dl with abnormal serum FLC ratio.
- Age ≥ 18 years at the time of signing informed consent.
- ECOG performance status <2 (Karnofsky >60%, see Appendix I)
- Females of childbearing potential (FCBP) must have a negative serum or urine
pregnancy test with a sensitivity of at least 50 mlU/mL 10 to14 days prior to therapy
and repeated again within 24 hours of starting lenalidomide and must either commit to
complete abstinence from heterosexual contact or begin TWO acceptable methods of
birth control, one highly effective method and one additional effective (barrier)
method, AT THE SAME TIME, at least 28 days before she starts taking lenalidomide.
FCBP must also agree to ongoing pregnancy testing. Men must practice complete
abstinence or agree to use a condom during sexual contact with a FCBP even if they
have had a successful vasectomy. All participants agree to enroll and comply with
the RevAssist® program for the prevention of pregnancy.
- A female of childbearing potential is a sexually mature female who: 1) has not
undergone a hysterectomy (the surgical removal of the uterus) or bilateral
oophorectomy (the surgical removal of both ovaries) or 2) has not been naturally
postmenopausal (amenorrhea following cancer therapy does not rule out childbearing
potential) for at least 24 consecutive months (i.e., has had menses at any time
during the preceding 24 consecutive months)
- Ability to understand and the willingness to sign a written informed consent
document. Voluntary written informed consent must be obtained before performance of
any study-related procedure not part of normal medical care, with the understanding
that consent may be withdrawn by the participant at any time without prejudice to
future medical care.
- Participants who exhibit any of the following conditions at screening will not be
eligible for admission into the study.
- Participants with primary refractory disease
- Participants who have a history of prior MM treatment with panobinostat, or an
- Participant has ≥ Grade 2 peripheral neuropathy on clinical examination within 21
days before initiation of protocol therapy.
- Renal insufficiency, defined as creatinine clearance < 60 mL/min (either actual or
calculated value), within 21 days of initiation of protocol therapy. The
Cockgroft-Gault formula should be used for calculating creatinine clearance values:
140-age) x Body mass (kg) x 0.85 (female) or 1.0 (male)/serum creat (mg/dL) x 72
- Platelet count <75,000cells/mm3at time of screening evaluation. Transfusion may not
be used to meet platelet eligibility criteria within 7 days of obtaining screening
- Participants with an absolute neutrophil count (ANC) < 1500 cells/mm3 at time of
screening evaluation. Growth factor may not be used to meet ANC eligibility criteria
within 7 days of obtaining screening evaluation.
- Participants with hemoglobin level < 8.0 g/dL, at time of screening. Transfusion may
not be used to meet eligibility criteria within 7 days of obtaining screening
- Participants with hepatic impairment, defined as bilirubin > 1.5 x institutional
upper limit of normal (ULN) or AST (SGOT), ALT (SGPT), or alkaline phosphatase > 2x
institutional ULN, within 21 days of initiation of protocol therapy. Patients with
benign hyperbilirubinemia (e.g., Gilbert's syndrome) are eligible
- Other ongoing anti-myeloma therapy. Patients may be receiving concomitant therapy
with bisphosphonates and low dose corticosteroids (e.g., prednisone up to but no more
than 10 mg p.o. q.d. or its equivalent) for symptom management and comorbid
conditions. Doses of corticosteroid should be stable for at least 7 days prior to
- Concomitant use of drugs that may cause a prolongation of the QTcF or inducing
torsade de pointes if treatment cannot be discontinued or switched to a different
medication prior to starting study drug. If these drugs become medically necessary
during study, they must be used with caution.
- Concomitant use of CYP3A4 inhibitors at time of screening. If use of CYP3A4
inhibitors becomes medically necessary during study, they must be used with caution.
- Anti-myeloma therapy, including radiotherapy, within 2 weeks or within 5 half-lives
of the agent and active metabolites (whichever is longer) prior to Day 1 and who have
not recovered from side effects (to ≤ Grade 1) of those therapies.
- Known significant cardiac abnormalities, including:
- History or presence of sustained ventricular tachyarrythmia. (Participants with a
history of atrial arrhythmia are eligible but should be discussed with the
investigator prior to enrollment).
- Any history of ventricular fibrillation or torsade de pointes
- Bradycardia defined as HR < 50 bpm. Participants with pacemakers are eligible if HR ≥
- QTcF interval ≥ 450 milliseconds on screening ECG;
- Right bundle branch block + left anterior hemiblock (bifascicular block)
- Participants 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)
- Serious, intercurrent illness including, but not limited to, clinically relevant
active infection, known active hepatitis B or C viral infection, known HIV infection,
uncontrolled diabetes mellitus, or serious co-morbid medical conditions such as
chronic restrictive pulmonary disease, and cirrhosis.
- Any condition, including laboratory abnormalities, that in the opinion of the
investigator places the subject at unacceptable risk if he/she were to participate in
- Prior malignancy (within the last 5 years) except for adequately treated basal cell
or squamous cell skin cancer, or in situ cervical cancer
- Known hypersensitivity to acyclovir or similar anti-viral drug
- POEMS syndrome (plasma cell dyscrasias with polyneuropathy, organomegaly,
endocrinopathy, monoclonal protein (M-protein) and skin changes) or AL Amyloidoses
- Known intolerance to steroid therapy
- Participants who have had prior allogeneic stem cell transplantation with evidence of
active graft-versus-host disease requiring immunosuppressive therapy
- Participants receiving any other investigational agents.
- Participants with known brain metastases.
- Poor tolerability or known allergy to any of the study drugs or compounds of similar
chemical or biologic composition to lenalidomide, bortezomib, panobinostat and/or
- Female participants pregnant or breast-feeding.
- Impairment of GI function or GI disease that may significantly alter the absorption
- Participants with diarrhea > CTCAE grade 2
- Participants who have undergone major surgery ≤ 4 weeks prior to starting study drug
or who have not recovered from side effects of the surgery.
- Participants 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