Study of Carfilzomib for Multiple Myeloma Patients Who Are Relapsed/Refractory to Bortezomib-containing Treatments
Study of Carfilzomib for Multiple Myeloma Patients Who Are Relapsed/Refractory to Bortezomib-containing Treatments
This is a phase I/II multicenter, open label, nonrandomized study for patients with Multiple
 Myeloma (MM) who will receive treatment with carfilzomib in place of bortezomib using the
 same bortezomib-containing combination regimen to which a MM patient has progressed while
 receiving. This study will enroll 45 patients total. These patients will be resistant to
 bortezomib as demonstrated by progressive disease while on bortezomib or have relapsed within
 12 weeks of the last dose of bortezomib in a combination regimen. Patients will be
 sub-divided into 2 groups in this study, treatments containing (Group A) or not containing
 immunomodulatory drugs (IMiDs) (Group B). Thirty patient will be enrolled into Group A and 15
 patients into Group B for a total of 45 patients. Patients must have received 4 doses of a
 minimum of 1.0 mg/m^2 of bortezomib in no more than 4 weeks per cycle. Patients must have
 received at least one cycle meeting this definition and have shown progressive disease to be
 considered eligible. Patients who have been refractory to or relapsed within 12 weeks of the
 last dose of bortezomib in their most recent bortezomib-containing regimen that does not
 include either thalidomide or lenalidomide are eligible regardless of when patients received
 that regimen, as long as they meet the above criteria.

 Carfilzomib will subsequently replace bortezomib using the patient's most recent
 bortezomib-containing regimen to which the patient progressed while receiving. Patients will
 be eligible if they progressed from bortezomib with an alkylating agent (melphalan or
 cyclophosphamide), an anthracycline (doxorubicin or pegylated liposomal doxorubicin) and/or a
 glucocorticosteroid (prednisone, dexamethasone or medrol)and IMiD (thalidomide or
 lenalidomide). The study will consist of a screening period, followed by up to eight open
 label treatment cycles, a final assessment to occur 28 days after the end of the last
 treatment cycle, a follow-up period and maintenance cycles of single agent carfilzomib.

 Patient who complete the combination treatment period without progressive disease will be
 eligible for maintenance therapy with single-agent carfilzomib. During maintenance therapy
 carfilzomib will be administered at the same dose given during the last cycle of combination
 treatment.
Inclusion:

 Disease-related:

 1. Have a diagnosis of MM based on standard criteria

 2. Currently has MM with measurable disease, defined as a monoclonal immunoglobulin spike
 on serum electrophoresis of at least 0.5 gm/dL and/or urine monoclonal immunoglobulin
 amount of at least 200 mg/24 hours.

 3. Have relapsed within 12 weeks of receiving or is refractory to their most recent
 bortezomib-containing regimen as long as they meet the following criteria:

 -  Progressed from bortezomib-containing regimen either as a single agent or in
 combination with an alkylating agent (melphalan or cyclophosphamide), an
 anthracycline (doxorubicin or pegylated liposomal doxorubicin), IMiDs
 (thalidomide or lenalidomide), and/or a glucocorticosteroid (prednisone,
 dexamethasone or medrol)

 -  Bortezomib must have been administered at 4 doses of a minimum of 1.0 mg/m2 in no
 more than 28 days per cycle. Subjects must have received at least one cycle
 meeting this definition and have shown progressive disease to be considered
 eligible.

 -  Subject who have been refractory to their most recent bortezomib-containing
 regimen are eligible regardless of when the subject received that regimen, as
 long as they meet the above criteria and have been off the treatment for > 3
 weeks.

 Definition of refractory disease: patients who meet criteria for progressive disease
 while currently receiving treatment.

 Demographics:

 4. Age ≥ 18 years

 5. Life expectancy ≥ 3 months

 6. ECOG performance status 0-2 at study entry

 Laboratory tests (within 14 days prior to drug dosing on Cycle 1, Day 1)

 7. Absolute neutrophil count (ANC) ≥ 1.5 × 10^9/L; if the bone marrow is extensively
 infiltrated (> 70% plasma cells) then 1.0 x 109/L

 8. Hemoglobin ≥ 8 g/dL (subjects may be receiving red blood cell [RBC] transfusions in
 accordance with institutional guidelines)

 9. Platelet count ≥ 75 × 109/L; if the bone marrow is extensively infiltrated (> 70%
 plasma cells) then 50 x 10^9/L

 10. Creatinine clearance (CrCl) ≥ 30 mL/minute either measured or calculated. Subject with
 a creatinine > 15mL/min and < 30 mL/min due to significant myelomatous involvement of
 the kidneys may be enrolled in the study after receipt of approval from
 Oncotherapeutics.

 11. Adequate hepatic function, with AST (SGOT) and ALT (SGPT) 3 x upper limit of normal
 (ULN) or 5 x ULN if hepatic metastases are present and serum total bilirubin ≤ 1.5 x
 ULN

 12. Serum potassium > 3 and < 5

 Ethical/Other

 13. Written informed consent in accordance with federal, local, and institutional
 guidelines.

 14. Females of childbearing potential (FCBP) must agree to ongoing pregnancy testing and
 to practice contraception.

 15. Male subjects must agree to practice contraception.

 Exclusion:

 Disease-related

 1. Plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, monoclonal
 protein (M-protein) and skin changes (POEMS) syndrome

 2. Plasma cell leukemia

 3. Severe hypercalcemia, i.e., serum calcium 12 mg/dL (3.0 mmol/L) corrected for albumin

 4. Received the following prior therapy:

 -  Chemotherapy within 21 days of enrollment (6 wks for nitrosoureas)

 -  Corticosteroids (>10 mg/day prednisone or equivalent) within 21 days of
 enrollment

 -  Immunotherapy or antibody therapy as well as thalidomide, lenalidomide, arsenic
 trioxide, or bortezomib within 21 days before enrollment

 -  Radiation therapy within 21 days before enrollment, receipt of localized
 radiation therapy does not preclude enrollment

 -  Use of any other experimental drug or therapy within 28 days of enrollment

 Concurrent Conditions

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

 -  Unstable angina or myocardial infarction within 4 months prior to enrollment

 -  NYHA Class III or IV heart failure

 -  Uncontrolled angina

 -  Clinically significant pericardial disease

 -  Severe uncontrolled ventricular arrhythmias, sick sinus syndrome, or
 electrocardiographic evidence of acute ischemia or Grade 3 conduction system
 abnormalities unless subject has a pacemaker. Prior to study entry, any ECG
 abnormality at Screening has to be documented by the investigator as not
 medically relevant.

 6. Pregnant or lactating females

 7. Major surgery within 28 days prior to enrollment or has not recovered from side
 effects of such therapy (Kyphoplasty is not considered to be a major surgical
 procedure; however, the investigator is to discuss enrollment of a patient with a
 recent history of kyphoplasty with Oncotherapeutics).

 8. Acute active infection requiring treatment with systemic antibiotics, antivirals, or
 antifungals within 14 days prior to receiving first dose of study drug

 9. Known human immunodeficiency virus infection; baseline testing is not required

 10. Active hepatitis B or C infection; baseline testing is not required

 11. Uncontrolled hypertension or uncontrolled diabetes within 14 days prior to enrollment

 12. Nonhematologic malignancy within the past 5 years with the exception of a) adequately
 treated basal cell carcinoma, squamous cell skin cancer, or thyroid cancer; b)
 carcinoma in situ of the cervix or breast; c) prostate cancer of Gleason Grade 6 or
 less with stable prostate-specific antigen levels; or d) cancer considered cured by
 surgical resection or unlikely to impact survival during the duration of the study,
 such as localized transitional cell carcinoma of the bladder or benign tumors of the
 adrenal or pancreas

 13. Concurrent use of other anti-cancer agents or treatments

 14. Significant neuropathy (Grades 3-4, or Grade 2 with pain) within 14 days prior to
 enrollment

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

 16. Subjects with pleural effusions requiring thoracentesis or ascites requiring
 paracentesis within 14 days prior to enrollment

 17. Any other clinically significant medical disease or condition that, in the
 Investigator's opinion, may interfere with protocol adherence or a subject's ability
 to give informed