Panobinostat, Carfilzomib, and Dexamethasone in Patients With Relapsed or Refractory Multiple Myeloma

PRIMARY OBJECTIVES:

I. To correlate in vitro drug sensitivity testing with clinical response by determining the
rate of in vitro drug sensitivity to panobinostat, carfilzomib, and dexamethasone singly and
in combination, doublets and triplets.

SECONDARY OBJECTIVES:

I. To monitor response rates (partial response [PR], very good partial response [VGPR], and
complete response) using the International Myeloma Working Group Uniform Response Criteria
for Multiple Myeloma.

EXPLORATORY OBJECTIVES:

I. Progression free survival and overall survival will be assessed for up to 3 years after
last dose.

OUTLINE:

Patients receive panobinostat orally (PO) on days 1, 3, 5, 15, 17, and 19. Patients also
receive carfilzomib intravenously (IV) and dexamethasone PO on days 1, 2, 8, 9, 15, and 16.
Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or
unacceptable toxicity. Patients also undergo collection of blood and/or bone marrow samples
for testing via in vitro chemosensitivity assay.

After completion of study treatment, patients are followed up every 3 months for up to 3
years.

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 free light chain as per IMWG criteria, and abnormal ratio

- Urine Bence Jones protein > 200 mg/24 hr

- Absolute neutrophil count (ANC) of >= 1,000/uL

- Platelet count of >= 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

- The following laboratory values must be, or corrected to with supplements, over the
lower limit of normal before starting treatment:

- Serum sodium

- Potassium

- Magnesium

- Phosphorus

- 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

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 enrollment 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 females using Fridericia's
correction on screening electrocardiogram (ECG) by mean value of triplicate ECGs

- 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 risk prolonging the QT interval or inducing Torsades
de pointes; the medication must be discontinued or switched to a safe alternative
medication prior to starting treatment

- 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 who have not recovered
from side effects to < grade 2 CTCAE

- Women who are pregnant or breast feeding or women of childbearing potential (WOCBP)
not using an effective method of birth control; 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. who has had menses anytime in
the proceeding 12 consecutive months); women of childbearing potential must have a
negative serum pregnancy test within 24 hrs of receiving the first dose of study
medication

- Male patients whose sexual partners are WOCBP not using effective birth control