Study of the Combination of Panobinostat and Carfilzomib in Patients With Relapsed/Refractory Multiple Myeloma

In this open-label, non-randomized Phase I/II study, a maximum of 4 planned dose levels of
carfilzomib and panobinostat were evaluated to determine the maximum tolerated dose (MTD) to
administer. The MTD was not reached so patients in Phase II received treatment at dose level
4 to further assess efficacy. Response to treatment was evaluated after each 4-week cycle.
Those having an objective response or stable disease are continuing treatment until disease
progression or unacceptable toxicity occurs.

As the MTD in the 4 planned dose levels were not reached, a parallel Phase I study was
initiated to examine additional dose levels using a traditional 3+3 design. If these dose
levels are tolerable, then more patients will be recruited into an expansion cohort to
assess efficacy at the new dose level(s).

Inclusion Criteria:

1. Eligible participants must have multiple myeloma using standard criteria.

2. Patients must have measurable disease requiring systemic therapy defined as at least
one of the following:

- Serum M-protein ≥1 g/dl (≥10 g/l)

- Urine M-protein ≥200 mg/24 hrs

- Serum free light chain assay: involved free light chain level ≥10 mg/dl (≥100
mg/l) provided the serum free light chain ratio is abnormal

3. Must have progressed during or after at least one previous bortezomib-containing
treatment regimen. Patients who have received previous high-dose therapy/autologous
stem cell transplantation are eligible.

4. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.

5. Must meet the following laboratory criteria:

- Absolute neutrophil count (ANC) ≥1000/μL;

- Platelets ≥70,000/microL;

- AST or ALT and alkaline phosphatase (ALP) must be ≤ 2.5 x ULN, or ≤ 5 x ULN in
patients with plasmacytomas of the liver;

- Total bilirubin ≤ 1.5 x the institutional ULN;

- Serum creatinine ≤ 1.5 x ULN or calculated creatinine clearance ≥ 50 ml/min;

- Serum potassium, calcium, magnesium WNL (These may be corrected prior to
starting therapy, to make the patient eligible.)

6. Ability to swallow oral medications.

7. Baseline MUGA or ECHO must demonstrate left ventricular ejection fraction (LVEF) ≥
the lower limit of the institutional limits of normal.

8. Male or females ≥ 18 years of age.

9. Female patients must not be of child-bearing potential or must agree to use adequate
contraceptive measures.

10. Male patients willing to use adequate contraceptive measures.

11. Willingness and ability to comply with the trial and follow-up procedures.

12. Ability to understand the nature of this trial and give written informed consent.

Exclusion Criteria:

1. Currently receiving or have received systemic cancer therapy (chemotherapy, biologic
therapy) ≤ 21 days of initiating study therapy. For patients receiving small molecule
targeted therapy, study treatment may begin >21 days after last dose or >5 half lives
of previous treatment, whichever is shorter. Patients must have completed radiation
therapy ≥7 days prior to starting study treatment. Patients must have recovered from
or come to a new chronic stable baseline from all treatment-related toxicities.
Dexamethasone or other high-dose steroid therapy must be stopped ≥ days prior to
starting study treatment.

2. Previous treatment with HDAC, DAC, HSP90 or valproic acid for treatment of cancer.

3. Requires valproic acid for any medical condition during the study ≤5 days prior to
first panobinostat treatment.

4. Patient has not recovered from all therapy-related toxicities associated with prior
treatments to < Grade 2 CTCAE.

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

6. Patients with pleural effusions requiring thoracentesis or ascites requiring
paracentesis ≤14 days prior to study entry.

7. Patients using medications that have a risk of prolonging the QT interval or inducing
Torsade de Pointes if treatment cannot be discontinued or switched to a different
medication prior to receiving study drug.

8. Patients with > grade 2 diarrhea.

9. Patients with impaired cardiac function.

10. Infection requiring IV antibiotics.

11. Patients with > grade 2 peripheral neuropathy or with uncontrolled pain.

12. Women who are pregnant or lactating.

13. Any concurrent medical illness that may impair the ability of the patient to tolerate
study treatment and comply with the requirements of the study.

14. Mental condition that would prevent patient comprehension of the nature of, and risk
associated with, the study.

15. Use of any non-approved or investigational agent ≤30 days prior to administration of
the first dose of study drug. Patients may not receive any other investigational or
anti-cancer treatments while participating in this study.

16. Presence of other active cancers, or history of treatment for invasive cancer ≤ 5
years. Patients with stage I cancer who have received definitive local treatment at
least 3 years previously, and are considered unlikely to recur are eligible. All
patients with previously treated in situ carcinoma (i.e. non-invasive) are eligible,
as are patients with history of non-melanoma skin cancer.