Panobinostat and Carfilzomib in Treating Participants With Relapsed or Refractory Multiple Myeloma

PRIMARY OBJECTIVES:

I. To determine the maximum recommended dose (MRD) of the combination of carfilzomib and
panobinostat in patients with relapsed/refractory multiple myeloma (RRMM). (Phase I) II. To
determine the overall response rate (stable disease [SD], minimal response [MR], partial
response [PR], very good partial response [VGPR], near complete response/complete response
[nCR/CR] of the combination. (Phase Ib)

SECONDARY OBJECTIVES:

I. To determine the overall response rate (ORR), stable disease (SD), minimal response (MR),
partial response (PR), very good partial response (VGPR), near complete response/complete
response (nCR/CR). (Phase I) II. To determine the time to progression (TTP). (Phase I and Ib)
III. To determine the progression free survival (PFS). (Phase I and Ib) IV. To determine the
time to best response. (Phase I and Ib) V. To determine time to next therapy. (Phase I and
Ib) VI. To determine duration of response. (Phase I and Ib) VII. To determine the overall
response rate (SD, MR, PR, VGPR, nCR/CR) of the combination. (Phase Ib) VIII. To assess the
safety of the combination. (Phase Ib)

OUTLINE: This is a phase I and Ib dose escalation study.

Participants receive carfilzomib intravenously (IV) over 30 minutes on days 1, 2, 8, 9, 15,
and 16 and panobinostat orally (PO) once daily (QD) on days 1, 3, 5, 8, 10, and 12 of each
course. Courses repeat every 28 days for up to 8 courses in the absence of disease
progression or unacceptable toxicity. After 8 courses, participants may continue carfilzomib
IV on days 1, 2, 15, and 16, and panobinostat PO on days 1, 3, 5, 8, 10, and 12 of each
course. If the disease becomes worse, participants can receive carfilzomib on the original
dosing schedule (days 1, 2, 8, 9, 15, and 16 of each course).

After completion of study treatment, participants are followed up at 30 days.

Inclusion Criteria:

- Relapsed/refractory MM with failure to at least two lines of MM treatment which must
include at least one immunomodulatory imide drugs (IMiD) (thalidomide, lenalidomide)
and proteasome inhibitor (bortezomib) and measurable levels of myeloma paraprotein in
serum (>= 0.5 g/dl), urine (>= 0.2 g excreted in a 24-hour collection sample), or
abnormal free light chain (FLC) ratio. Oligo or non secretory myeloma patients may be
included, if there is measurable plasmacytosis in the bone marrow biopsy or measurable
extramedullary disease.

- Ability to provide written informed consent obtained prior to participation in the
study and any related procedures being performed.

- Absolute neutrophil count (ANC) >= 1.0 x 10^9/L within 28 days of starting therapy.

- Hemoglobin >= 8 g/dl (transfusions are permitted) within 28 days of starting therapy.

- Platelet count > 70,000 cells/mm^3 for patients with < 50% of bone marrow plasma cells
or platelet count > 25,000 cells/mm^3 for patients in whom > 50% of the bone marrow
nucleated cells were plasma cells within 28 days of starting therapy.

- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x upper
limit of normal (ULN) within 28 days of starting therapy.

- Serum bilirubin =< 2 x ULN within 28 days of starting therapy.

- Eastern Cooperative Oncology Group (ECOG) performance status of =< 2.

- Creatinine clearance (CrCl) >= 30 mL/minute within 28 days prior to registration,
either measured or calculated using a standard formula (e.g., Cockcroft and Gault).

- Multiple gated acquisition (MUGA) or echocardiogram (ECHO) must demonstrate left
ventricular ejection fraction (LVEF) >= 45%.

- Female patients who: are postmenopausal for at least 1 year before the screening
visit, OR are surgically sterile, OR if they are of childbearing potential, agree to
practice 2 effective methods of contraception, at the same time, from the time of
signing the informed consent through 30 days after the last dose of study drug, or
agree to completely abstain from heterosexual intercourse. Male patients, even if
surgically sterilized (i.e., status post vasectomy), who: agree to practice effective
barrier contraception during the entire study treatment period and through 30 days
after the last dose of study drug, OR agree to completely abstain from heterosexual
intercourse.

Exclusion Criteria:

- Valproic acid for the treatment of cancer.

- Patients who will need valproic acid for any medical condition during the study or
within 5 days prior to first panobinostat treatment.

- Impaired cardiac function or clinically significant cardiac diseases, including any
one of the following:

- History or presence of sustained ventricular tachyarrhythmia. (Patients with a
history of atrial arrhythmia are eligible)

- Any history of ventricular fibrillation or torsade de pointes

- Bradycardia defined as heart rate (HR) < 50 bpm. Patients with pacemakers are
eligible if HR >= 50 bpm.

- Screening electrocardiogram (ECG) with a corrected QT interval (QTc) or QTcF >
450 msec

- Right bundle branch block + left anterior hemiblock (bifascicular block)

- Patients with myocardial infarction or unstable angina =< 6 months prior to
starting study drug

- Other clinically significant heart disease (e.g., congestive heart failure [CHF]
New York Heart Association [NYHA] class III or IV, uncontrolled hypertension,
history of labile hypertension, or history of poor compliance with an
antihypertensive regimen).

- Impairment of gastrointestinal (GI) function or GI disease that may significantly
alter the absorption of panobinostat.

- Patients with diarrhea > Common Terminology Criteria for Adverse Events (CTCAE) grade
2.

- Other concurrent severe and/or uncontrolled medical conditions (e.g., uncontrolled
diabetes or active or uncontrolled infection) including abnormal laboratory values,
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 torsade de pointes if treatment cannot be discontinued or switched to a
different medication prior to starting study drug.

- Patients who have received chemotherapy within =< 2 weeks by time of cycle 1 day 1 of
therapy on trial; or radiation therapy to > 30% of marrow-bearing bone within 2 weeks
prior to starting study treatment; or who have not yet recovered from side effects of
such therapies.

- Female patients who are lactating or have a positive serum or urine pregnancy test
during the screening period.

- Patients 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
staff.

- Known history of allergy to Captisol (a cyclodextrin derivative used to solubilize
carfilzomib).