A Phase I Study of the Combination of Panobinostat and Carfilzomib in Patients With Relapsed and/or Refractory Multiple Myeloma

The purpose of this study is to find out what effects, good and/or bad, the combination of panobinostat and carfilzomib have on the patient's cancer. It will determine the side effects of different dose levels of panobinostat and carfilzomib and determine the best dose and schedule of the two drugs to recommend for future studies. The study will assess the effects of the drug on multiple myeloma. In addition, tests to study the way the drugs work will also be done.

The combination of the 2 drug classes have shown both pre-clinical (studies done in the lab) and clinical (studies done with people) effects against multiple myeloma. For this reason, these 2 drugs are being studied in combination to determine the side effects and anti-myeloma effects of the 2 drugs.

• Drug: Panobinostat
  standard 3+3 design Oral TIW 3 out of 4 weeks
• Drug: Carfilzomib

  standard 3+3 design

  Days 1/2, 8/9 and 15/16 every 4 weeks

• Drug: Panobinostat
  Panobinostat will be supplied as 5-mg or 20-mg pink/opaque-colored, hard gelatin capsules.Panobinostat is administered orally three times per week.
  Other Name: LBH589
• Drug: Carfilzomib
  Carfilzomib in Cycle 1 will be initiated at 20 mg/m^2 on Days 1 and 2 and escalated to 27mg/m^2 for Days 8, 9, 15, and 16 of Cycle 1 and for the duration of treatment. Carfilzomib will be administered by intravenous infusion on days 1, 2 and 8, 9 and 15, 16 of every 28 day cycle.
• Drug: Dexamethasone
  Dexamethasone (4mg) must be given prior to each carfilzomib infusion during Cycle 1. Dexamethasone pre-dose should continue through Cycle 2 if fever is observed post-dose, Cycle 2 Day 1, or thereafter associated with the infusion of carfilzomib.

Inclusion Criteria:

1. Male or female patients aged ≥ 18 years old 2. Diagnosis of MM following at least one prior therapy; there is no maximum number or prior therapies 3. Patients must have relapsed/ refractory disease and be in need of therapy with evidence of measurable disease defined as at least one of the following:

1. Serum M protein ≥ 0.5 g/dl (≥5g/l)
2. Urine M protein ≥ 200 mg/24 hours
3. Serum FLC assay: Involved FLC assay ≥ 10 mg/dl (≥100 mg/l) and an abnormal serum free light chain ratio (< 0.26 or > 1.65)

4. Measurable plasmacytoma (Prior biopsy is acceptable) 4. Ability to provide written informed consent obtained prior to participation in the study and any related procedures being performed 5. Patients must meet the following laboratory criteria:

   • ANC ≥ 1.0 x 109/L (growth factors cannot be used within 3 days of screening)
   • Hemoglobin ≥ 8 g/dl (PRBC transfusions cannot be used within 3 days of screening)
   • Platelets ≥ 75x 109/L (platelet transfusions cannot be used within 3 days of screening)
   • AST and ALT ≤ 2.5 x ULN
   • Serum bilirubin 1.5 x ULN
   • Serum potassium ≥ LLN
   • Total serum calcium [corrected for serum albumin] or ionized calcium ≥LLN. (treatment of hypercalcemia is allowed and subjects may enroll if hypercalcemia returns to normal with standard treatment)
   • Serum magnesium ≥ LLN
   • Serum phosphorus ≥ LLN
   • Creatinine clearance ≥ 30 ml/min (Crockcroft-Gault calculation)

   • Clinically euthyroid. Note: Patients are permitted to receive thyroid hormone supplements to treat underlying hypothyroidism.

     6. Baseline MUGA or ECHO must demonstrate LVEF ≥ the lower limit of the institutional normal.

     7. ECOG Performance Status of ≤ 2 8. Must be willing and able to undergo bone marrow aspirates per protocol (with or without bone marrow biopsy per institutional guidelines). The bone marrow aspirate/biopsy must be adequate to allow for comparison for the on-study efficacy assessments.

     9. Females of childbearing potential (FCBP - A female of childbearing potential is a sexually mature woman who: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months. Confirmation that the subject is not pregnant must be established by a negative serum -human chorionic gonadotropin (-hCG) pregnancy test result obtained during screening. Pregnancy testing is not required for post-menopausal or surgically sterilized women. FCBP must also agree to ongoing pregnancy testing. Men must agree to use a latex condom during sexual contact with a FCBP even if they have had a successful vasectomy.

   Exclusion Criteria:

   1. Prior HDAC, DAC, or valproic acid for the treatment of cancer 2. Prior treatment with carfilzomib 3. Daily requirement for corticosteroids > prednisone 10 mg /day or equivalent 4. Patients who will need valproic acid for any medical condition during the study or within 5 days prior to first panobinostat treatment 5. 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 but should be discussed with the Principal Investigator prior to enrollment)

   • History of congenital long QT syndrome

   • Any history of ventricular fibrillation or torsade de pointes

   • Bradycardia defined as HR< 50 bpm. Patients with pacemakers are eligible if HR ≥ 50 bpm.

   • ECG evidence of acute ischemia or grade 3 conduction system abnormalities. (unless subject has a pacemaker)

   • Screening ECG with a QTc > 450 msec (read by local cardiologist)
   • 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 , uncontrolled hypertension, history of labile hypertension, or history of poor compliance with an antihypertensive regimen) (Patients with a history of atrial arrhythmias may be eligible if they are controlled and approved by the Lead Principal Investigator) 4. Impairment of GI function or GI disease that may significantly alter the absorption of panobinostat. Inability to take oral medications, requirement for IV alimentation, active peptic ulcer disease or prior surgical procedures or bowel resection affecting absorption of oral medications.

     5. Patients with diarrhea > CTCAE grade 1 (increase of 4 stools per day over baseline mild increase in ostomy output compared to baseline).

     6. 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.

     7. 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 [allow 72 hour washout period]. (see Appendix I-table 1-1) 8. Concomitant use of CYP3A4 inhibitors (see Appendix I-table 2-1) 9. Patients who have received either vaccine or antibody based therapy within < 8 weeks; chemotherapy within < 4 weeks, IMiDs within 2 weeks; 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.

     10. Patients who have undergone major surgery ≤ 4 weeks prior to starting study drug or who have not recovered from side effects of such therapy.

     11. Peripheral blood stem cell transplant within 12 weeks of first dose of study treatment.

     12. Women who are pregnant or breast feeding or women of childbearing potential (WOCBP) not using an effective method of birth control.

     13. Male patients whose sexual partners are FCBP not using effective birth control.

     14. Patients with a prior malignancy with in the last 3 years (except for basal or squamous cell carcinoma, or in situ cancer or low risk prostate cancer after curative therapy or with > 90% remission at 5 years).

     15. Patients with known positivity for human immunodeficiency virus (HIV) or hepatitis C; baseline testing for HIV and hepatitis C is not required.

     16. 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.

     17. Significant neuropathy (≥ grade 3 or grade 2 with pain) within 14 days of initiation of therapy.

     18. Subjects with evidence of mucosal or internal bleeding, an active bleeding diathesis and or known platelet transfusion refractoriness.

     19. Patients with contraindications to any of the required concomitant drugs or supportive treatments, including hypersensitivity to anticoagulation and antiplatelet options, antiviral drugs, or tolerance to hydration due to pre-existing pulmonary of cardiac impairment.

     20. Patients with hypersensitivity to any of the components of the drug including allergy to Captisol (a cyclodextrin derivative used to solubilize carfilzomib), including voriconazole, ziprasidone, aripiprazole and amiodarone.

     21. Ongoing graft-versus-host disease.

• Multiple Myeloma Research Consortium
• Novartis
• Onyx Therapeutics, Inc.