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

• establish optimal doses of carfilzomib in mg/m^2 and panobinostat in mg in combination with each other (Phase I) [ Time Frame: 6 months ] [ Designated as safety issue: Yes ]
  The Phase I study will determine the maximum tolerated dose (MTD) of the combination of carfilzomib and panobinostat. The Phase I portion will follow a standard dose escalation design, beginning with 3 patients on dose level 1: carfilzomib 20 mg/m2 IV D1, 2 / 27 mg/m2 IV D8, 9, 15, 16 for cycle 1 and panobinostat 20 mg D 1, 3, 5, 15, 17, 19 for cycle 1; carfilzomib 27 mg/m2 IV D 1, 2, 8, 9, 15, 16 for cycle 2 and panobinostat 20 mg D 1, 3, 5, 15, 17, 19 for cycle 2. Patients will be assessed for dose-limiting toxicity (DLT) at each visit during Cycle 1 prior to receiving treatment.
• evaluate overall response (Phase II) [ Time Frame: 18 months ] [ Designated as safety issue: No ]
  To evaluate the overall response in patients with relapsed/refractory multiple myeloma treated with the combination of panobinostat and carfilzomib. (Phase II)The following restaging assessments will be done at baseline and every 2 cycles (8 weeks)to assess response: bone marrow aspiration/biopsy, skeletal survey, serum free light chain, serum immunoglobulin G, A, M, serum beta-2 microglobulin, SPEP & immunofixation, and UPEP & immunofixation.

• evaluate time-to-progression (TTP) [ Time Frame: 24 Months ] [ Designated as safety issue: No ]
  To evaluate time-to-progression (TTP)The following restaging assessments will be done at baseline and every 2 cycles (8 weeks)to assess if there is disease progression: bone marrow aspiration/biopsy, skeletal survey, serum free light chain, serum immunoglobulin G, A, M, serum beta-2 microglobulin, SPEP & immunofixation, and UPEP & immunofixation.
• evaluate progression-free-survival (PFS) [ Time Frame: 24 Months ] [ Designated as safety issue: No ]
  To evaluate progression-free-survival (PFS)The following restaging assessments will be done at baseline and every 2 cycles (8 weeks)to evalute progression-free-survival: bone marrow aspiration/biopsy, skeletal survey, serum free light chain, serum immunoglobulin G, A, M, serum beta-2 microglobulin, SPEP & immunofixation, and UPEP & immunofixation.
• evaluate overall-survival (OS) [ Time Frame: 24 Months ] [ Designated as safety issue: No ]
  To evaluate overall-survival (OS) After disease progression is documented, patients will be followed every 3 months for survival assessment.
• evaluate safety by assessing toxicities [ Time Frame: 24 months ] [ Designated as safety issue: No ]
  To evaluate safety by assessing possible toxicities of thrombocytopenia (platelets/mL), neutropenia (Absolute neutrophil/microL), febrile neutropenia (Absolute neutrophil count (ANC)/microL & temperature in degrees celcius), serum creatinine (Serum creatinine x ULN or calculated creatinine clearance ml/min), total bilirubin (Total bilirubin x the institutional ULN), diarrhea, vomiting, and average QTcF in msec from ECG's

Relapsed/refractory Multiple Myeloma (MM) is an incurable disorder with a poor prognosis. Carfilzomib is a novel proteasome inhibitor with activity in this setting. Panobinostat is a pan-deacetylase inhibitor which has shown synergistic cytotoxicity in vitro and in vivo with proteasome inhibitors. The combination should enhance the activity of both agents against myeloma cells. In the Phase I part of the trial, the optimal doses of the combination of carfilzomib and panobinostat will be determined. Assuming this combination is feasible, the Phase II portion will proceed, using the doses determined in Phase I. This trial will be conducted at multiple study sites by the Sarah Cannon Research Institute (SCRI) Oncology Research Consortium.

This is an open-label; non-randomized Phase I/II study of patients with relapsed or refractory multiple myeloma.

The Phase I study will determine the MTD of the combination of carfilzomib and panobinostat. The Phase I portion will follow a standard dose escalation design, beginning with dose level 1 (see Table 2). Patients will be assessed for dose-limiting toxicity (DLT) at each visit during Cycle 1 prior to receiving treatment. Dose modifications will not be permitted during Cycle 1 unless a patient experiences a DLT (see Section 5.2.2.). Treatment cycles will be administered at 28-day intervals. Panobinostat will be administered orally three times weekly during weeks 1 and 3 of each cycle (Days 1, 3, 5, 15, 17, 19). Carfilzomib will be administered intravenously on Days 1, 2, 8, 9, 15, and 16 of each cycle. During Cycle 1, the carfilzomib dose will be escalated after the Day 2 dose, if well tolerated.

A maximum of three dose levels will be evaluated.Approximately 24 patients will be enrolled during the Phase I portion to establish the MTD.

In the Phase II portion of this study, patients with relapsed/refractory multiple myeloma will receive treatment with the panobinostat and carfilzomib combination established during Phase I. Patients will be reevaluated for response to treatment after each cycle (4 weeks). Patients with objective response or stable disease will continue treatment, with subsequent reevaluations every 4 weeks, until disease progression or unacceptable toxicity occurs.

Up to 54 eligible patients will be treated in the Phase I/II study.

• Drug: Phase I Dose level -1; Carfilzomib and panobinstat
  Carfilzomib Cycle 1: 15 mg/m2 IV D1, 2 /20 mg/m2 IV D8, 9, 15, 16 Carfilzomib Cycle 2 to progression: 20 mg/m2 IV D 1, 2, 8, 9, 15, 16 Panobinostat Cycle 1: 20 mg D 1, 3, 5, 15, 17, 19 Panobinostat Cycle 2 to progression:20 mg D 1, 3, 5, 15, 17, 19
• Drug: Phase I Dose Level 1, Carfilzomib and Panobinostat
  Carfilzomib Cycle 1: 20 mg/m2 IV D1, 2 / 27 mg/m2 IV D8, 9, 15, 16 Carfilzomib Cycle 2 to progression: 27 mg/m2 IV D 1, 2, 8, 9, 15, 16 Panobinostat Cycle 1: 20 mg D 1, 3, 5, 15, 17, 19 Panobinostat Cycle 2 to progression: 20 mg D 1, 3, 5, 15, 17, 19
• Drug: Phase I Dose Level 2; carfilzomib and panobinostat
  Carfilzomib Cycle 1: 20 mg/m2 IV D1, 2 / 36 mg/m2 IV D8 ,9, 15, 16 Carfilzomib Cycle 2 to progression: 36 mg/m2 IV D 1, 2, 8, 9, 15, 16 Panobinostat Cylce 1: 20 mg D 1, 3, 5, 15, 17, 19 Panobinostat Cylce 2 to progression: 20 mg D 1, 3 ,5, 15, 17, 19
• Drug: Phase 1 Dose level 3; carfilzomib and panobinostat
  Carfilzomib cycle 1: 20 mg/m2 IV D 1, 2 / 36 mg/m2 IV D8, 9, 15, 16 Carfilzomib cycle 2 to progression: 45 mg/m2 IV D 1 ,2, 8 ,9, 15, 16 Panobinostat cycle 1: 20 mg D 1, 3, 5, 15, 17, 19 Panobinostat cycle 2 to progression: 20 mg D 1, 3, 5, 15, 17, 19
• Drug: Phase I dose level 4; carfilzomib and panobinostat
  Carfilzomib cycle 1: 20 mg/m2 IV D 1, 2 / 36 mg/m2 IV D8, 9, 15, 16 Carfilzomib cycle 2 to progression: 45 mg/m2 IV D 1 ,2, 8 ,9, 15, 16 Panobinostat cycle 1: 30 mg D 1, 3, 5, 15, 17, 19 Panobinostat cycle 2 to progression: 30 mg D 1, 3, 5, 15, 17, 19
• Drug: Phase II Dose Level TBD; carfilzomib and panobinostat
  Panobinostat PO TBD Days 1, 3, 5, 15, 17 and 19 Carfilzomib IV TBD Days 1, 2 escalating on Days 8, 9, 15, and 16 Treatment cycles will be repeated every 28 days

Inclusion Criteria:

1. Eligible participants must have multiple myeloma using standard criteria (Appendix B).

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. (See Appendix A).

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 >/=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 >/=ays 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 >/=ays 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 (see Appendix F).
8. Patients with > grade 2 diarrhea.

9. Patients with impaired cardiac function, including any of the following conditions:

   • History or presence of sustained ventricular tachyarrhythmia.
   • Any history of ventricular fibrillation or Torsade de pointes.
   • Bradycardia defined as HR <50 bpm. Patients with pacemakers are eligible if HR >/=bpm.
   • Screening ECG with a QTc >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. CHF NY Heart Association class III or IV (Appendix D), uncontrolled hypertension, history of labile hypertension, or history of poor compliance with an antihypertensive regimen).
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.

• Onyx Therapeutics, Inc.
• Novartis