Panobinostat, Carfilzomib, and Dexamethasone in Patients With Relapsed or Refractory Multiple Myeloma
Condition: Recurrent Plasma Cell Myeloma; Refractory Plasma Cell Myeloma
MeSH terms: Multiple Myeloma; Neoplasms, Plasma Cell
Intervention: Carfilzomib; Chemosensitivity Assay; Dexamethasone; Laboratory Biomarker Analysis; Panobinostat
Intervention description: Given IV; Undergo in vitro chemosensitivity testing; Given PO; Correlative studies; Given PO
Intervention MeSH terms: Dexamethasone; Dexamethasone acetate; Panobinostat; Ichthammol; BB 1101
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 9.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      This phase II trial studies how well panobinostat, carfilzomib, and dexamethasone work in
      treating patients with multiple myeloma that has come back (relapsed) or does not respond to
      treatment (refractory). Panobinostat may stop the growth of cancer cells by blocking some of
      the enzymes needed for cell growth. Chemotherapy drugs, such as carfilzomib and
      dexamethasone, work in different ways to stop the growth of cancer cells, either by killing
      the cells, by stopping them from dividing, or by stopping them from spreading. Using multiple
      myeloma cells from patients' blood samples, the researchers will do laboratory tests to look
      at how well each of the drugs, alone and in different combinations, kill multiple myeloma
      cells. If the laboratory tests work well, they may be used in the future to help plan
      treatment for future patients.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Diagnosis of multiple myeloma refractory to or relapsed after >= 1 line of prior
             therapy (International Myeloma Working Group [IMWG] criteria)

          -  Measurable disease, as indicated by one of the following:

               -  Serum monoclonal (M)-protein >= 1.0 g/dL

               -  Elevated involved free light chain >= 10 mg/dL as per IMWG criteria, and abnormal
                  ratio

               -  Urine Bence Jones protein > 200 mg/24 hour (hr)

          -  Absolute neutrophil count (ANC) >= 750/uL

          -  Platelet count >= 75,000/uL

          -  Hemoglobin >= 7 g/dL

          -  Creatinine =< 2.0 mg/dL or calculated creatinine clearance >= 30 mL/min

          -  Total bilirubin =< 1.5 x upper limit of normal (ULN) unless elevation is thought to be
             due to Gilbert's syndrome

          -  Serum glutamic-oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) and
             serum glutamate pyruvate transaminase (SPGT) (alanine aminotransferase [ALT]) =< 2.5 x
             ULN

          -  Patients must avoid consumption of grapefruit, pomegranates, starfruit, Seville
             oranges or products containing the juice of each during the entire study and
             preferably 7 days before the first dose of study medications; orange juice is allowed

          -  Women of child-bearing potential, defined as all women physiologically capable of
             becoming pregnant, should have a pregnancy test prior to the initiation of treatment
             and use highly effective methods of contraception during and for 3 months post study
             treatment; highly effective contraception methods include total abstinence, female
             sterilization, male sterilization, use of oral, injected, or implanted hormonal
             methods of contraception or placement of an intrauterine device (IUD) or intrauterine
             system (IUS) or other forms of hormonal contraception that have comparable efficacy;
             women using hormonal contraceptives should additionally use a barrier method of
             contraception; women are considered post-menopausal and not of child-bearing potential
             if they have had 12 months of natural amenorrhea or have had surgical bilateral
             oophorectomy (with or without hysterectomy), total hysterectomy, or tubal ligation at
             least 6 weeks ago

          -  Sexually active males must use a condom during intercourse while taking study drug and
             for 6 months after stopping treatment; males should not father a child in this period;
             a condom is required to be used also by vasectomized men as well as during intercourse
             with a male partner; female partners of sexually active men should also use an
             effective contraception during treatment and for 6 months after their male partner has
             stopped taking the drug

        Exclusion Criteria:

          -  Another bone marrow malignancy

          -  Another cancer with expected survival of < 2 years

          -  Active viral, bacterial, or fungal infection progressing on current treatment

          -  Clinically significant uncontrolled heart disease and/or recent cardiac event within 6
             months prior to enrollment, such as:

               -  History of angina pectoris, symptomatic pericarditis, or myocardial infarction

               -  Left ventricular ejection fraction (LVEF) < 45% as determined by echocardiogram
                  (ECHO) or multi gated acquisition (MUGA) scan

               -  History or presence of any significant, uncontrolled, or persistent cardiac
                  arrhythmias, e.g. ventricular, supraventricular, nodal arrhythmias or conduction
                  abnormality; stable atrial fibrillation within 6 months prior to randomization is
                  permitted

               -  Presence of unstable atrial fibrillation (ventricular response rate > 100 beats
                  per minute [bpm]); NOTE: patients with stable atrial fibrillation can be enrolled
                  provided they do not meet other cardiac exclusion criteria

               -  Resting heart rate < 50 bpm

               -  Complete left bundle branch block (LBBB), bifascicular block

               -  Congenital long QT syndrome

               -  Any clinically significant ST segment and/or T-wave abnormalities

               -  Corrected QT (QTcF) > 450 msec for males and > 470 msec for females using
                  Fridericia's correction on screening electrocardiogram (ECG)

               -  History of documented congestive heart failure (New York Heart Association
                  functional classification III-IV)

               -  Uncontrolled hypertension defined by a systolic blood pressure (SBP) >= 150 mmHg
                  and/or diastolic blood pressure (DBP) >= 100 mmHg with or without
                  antihypertensive medication; NOTE: initiation or adjustment of antihypertensive
                  medication(s) is allowed prior to screening

               -  Other clinically significant heart disease or vascular disease

          -  Currently taking medications that have known or definite risk of prolonging the QT
             interval or inducing Torsades de pointes (TdP); the medication must be discontinued or
             switched to a safe alternative medication prior to starting treatment; specific
             exception is allowed for patients on long-standing medications that have risk of
             prolonging QT interval or inducing TdP if screening ECG does not indicate a prolonged
             QT abnormality

          -  Impairment of gastrointestinal (GI) function or GI disease that may significantly
             alter the absorption of panobinostat or dexamethasone (e.g. ulcerative disease
             uncontrolled nausea, vomiting, malabsorption syndrome, obstruction, or stomach and/or
             small bowel resection)

          -  Unresolved diarrhea >= Common Terminology Criteria for Adverse Events (CTCAE) grade 2
             or a medical condition associated with chronic diarrhea (such as irritable bowel
             syndrome, inflammatory bowel disease)

          -  Major surgery =< 14 days prior to starting study treatment or side effects of surgery
             that have not recovered to < CTCAE grade 2