| Purpose: |
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This study will evaluate the feasibility of combining four of the most active agents
available for the treatment of multiple myeloma. Further the investigators will attempt to
assess the activity of this combination.
Phase I/II studies of the novel proteasome inhibitor, carfilzomib, have shown it to have
significant activity in patients with advanced multiple myeloma, including patients with
bortezomib refractory disease. This drug, unlike bortezomib, has minimal neurotoxicity and
appears to have minimal gastrointestinal (GI) toxicity. Experience with the combination of
bortezomib, lenalidomide and dexamethasone has shown both neuropathy and chronic diarrhea to
be limiting.
Vorinostat is a histone deacetylase inhibitor with modest single agent activity in multiple
myeloma. Dysesthesia, GI issues and fatigue have been problematic in this patient
population. More recent studies combining vorinostat with lenalidomide and dexamethasone or
with bortezomib have demonstrated a much more robust activity, including in patients
refractory to lenalidomide or bortezomib-based combinations. Again, neuropathy, fatigue and
GI issues have been problematic.
The investigators own anecdotal experience with combinations of proteasome inhibitor,
histone deacetylase inhibitor, immunomodulators and dexamethasone has shown this combination
to be extremely active and well tolerated. The combination of vorinostat, carfilzomib,
lenalidomide and dexamethasone should offer the opportunity to maximize activity while
limiting toxicities, particularly neuropathy and GI.
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| Criteria: |
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Inclusion Criteria:
- Subjects must meet all of the following inclusion criteria to be eligible to enroll
in this study:
Disease related:
1. Symptomatic multiple myeloma
2. Relapsed and/or refractory multiple myeloma after at least one prior therapeutic
regimen for multiple myeloma
3. Prior treatment with immunomodulatory agents, proteasome inhibitors and histone
deacetylase inhibitors is permitted. (Patients who have used HDAC inhibitors,
including valproic acid , must have at least 5 half-lives wash out period before
beginning therapy with vorinostat on this protocol.)
4. Measurable disease, as indicated by one or more of the following:
- Serum M-protein ≥ 0.5 g/dL
- Urine Bence-Jones protein ≥ 200 mg/24 h
- If Serum Protein Electrophoresis is felt to be unreliable for routine M-protein
measurement (particularly for patients with IgA MM), then quantitative
immunoglobulin levels can be accepted.
- Serum free light chain ≥ 10 mg/dL (≥ 100 mg/L) and an abnormal free light chain
ratio
Demographic 5.Males and females ≥ 18 years of age 6.Life expectancy of more than three
months 7.Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2 (see Appendix B)
Laboratory 8.Adequate hepatic function, with bilirubin < 2 times the upper limit of normal
(ULN) and alanine aminotransferase (ALT) < 3 times ULN 9.Absolute neutrophil count (ANC) ≥
1,000/mm3 Hemoglobin ≥ 8 gm/dL Platelet count ≥ 50,000/ mm3 (≥ 30 × 109/L if myeloma
involvement in the bone marrow is > 50%)
- Screening ANC should be independent of granulocyte- and granulocyte/macrophage colony
stimulating factor (G-CSF and GM-CSF) support for at least 1 week and of pegylated G
CSF for at least 2 weeks.
- Subjects may receive red blood cell (RBC) or platelet transfusions, if clinically
indicated, in accordance with institutional guidelines
- Screening platelet count should be independent of platelet transfusions for at least
2 weeks 10.Calculated or measured creatinine clearance of ≥60 mL/minute, calculated
using the formula of Cockcroft and Gault [(140 - Age) x Mass (kg) / (72 x creatinine
mg/dL)]; multiply result by 0.85 (if female). Other generally accepted calculation
methods can be substituted.11.Potassium level 3.5-5.2 meq/L (institutional normal
range) Ethical/Other 12.Written informed consent in accordance with federal, local,
and institutional guidelines 13.Females of Child Bearing Potential* (FCBP) must have
a negative serum or urine pregnancy test, with a sensitivity of at least 50 mIU/mL
within 10-14 days and again within 24 hours prior to prescribing lenalidomide for
cycle 1 (prescription must be filled with 7 days) and must either commit to continued
abstinence from heterosexual intercourse or begin TWO methods of acceptable methods
of birth control, one highly effective method AND one additional effective method of
birth control (contraception) AT THE SAME TIME, at least 28 days before she starts
taking lenalidomide. FCBP must also agree to ongoing pregnancy Testing. (See
Appendix G: Risks of Fetal Exposure, Pregnancy Testing Guidelines and Acceptable
Birth Control Methods)
- A female of childbearing potential is a sexually mature female who: 1) has not
undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally
postmenopausal for at least 24 consecutive months (i.e., has had menses at any
time in the preceding 24 consecutive months).
14. Men must agree to use a latex condom during sexual contact with a FCBP even
if they have had a successful vasectomy (See Appendix G: Risks of Fetal
Exposure, Pregnancy Testing Guidelines and Acceptable Birth Control Methods) 15.
All study participants must be registered into the mandatory RevAssist® program
and be willing and able to comply with the requirements of RevAssist®.
16. Subjects must adhere to the study visit schedule and other protocol
requirements and receive outpatient treatment and laboratory monitoring at the
institute that administers the drug 17. Subjects must agree to take
enteric-coated aspirin 81-325 mg orally daily, or if history of prior thrombotic
disease or allergy to aspirin, must be fully anticoagulated with warfarin (INR
2-3) or be treated with full-dose, low molecular weight heparin, as if to treat
deep venous thrombosis (DVT)/pulmonary embolism.
Exclusion Criteria:
- Subjects who meet any of the following exclusion criteria are not eligible to be
enrolled in this study:
Disease related
1. Subjects with non-secretory or hyposecretory multiple myeloma, defined as <0.5 g/dL
M-protein in serum and <200 mg/24 hr Bence Jones protein in urine and serum free
light chain <10mg/dL (<100 mg/L)
2. Corticosteroid therapy in a dose equivalent to dexamethasone ≥ 4 mg/day or prednisone
≥20 mg/day within 3 weeks prior to first dose
3. Concurrent use of histone deacetylase inhibitor (eg. Valproic acid)
4. Use of any other experimental drug or therapy within 28 days of baseline
5. POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and
skin changes)
6. Plasma cell leukemia
7. Waldenström's macroglobulinemia
8. Chemotherapy with approved or investigative anticancer therapeutics, including
steroid therapy dose as defined above, within 3 weeks prior to first dose
9. Radiation therapy or immunotherapy within 4 weeks prior to first dose; localized
radiation therapy within 1 week prior to first dose
10. Planned radiation therapy that occurs after the start of treatment
11. Participation in an investigational therapeutic study within 3 weeks or within 5 drug
half-lives (t1/2) prior to first dose, whichever time is greater.
Concurrent conditions
12. Pregnant or lactating females (Lactating females must agree not to breast feed while
taking lenalidomide or vorinostat).
13. History of allergy to boron or mannitol
14. Major surgery within 3 weeks prior to first dose
15. Congestive heart failure (New York Heart Association class III to IV), symptomatic
ischemia, conduction abnormalities uncontrolled by conventional intervention or
myocardial infarction in the previous six months
16. Uncontrolled hypertension
17. Acute active infection requiring systemic antibiotics, antivirals, or antifungals
within two weeks prior to first dose
18. Known or suspected HIV infection, known HIV seropositivity, or active hepatitis A,
B, or C infection
19. Non-hematologic malignancy within the past three years except a) adequately treated
basal cell or squamous cell skin cancer, b) carcinoma in situ of the cervix, or
c) prostate cancer < Gleason Grade 6 with stable prostate specific antigen (PSA)
levels
20. Serious psychiatric or medical conditions that could interfere with treatment
21. Significant neuropathy (Grade 3, Grade 4, or Grade 2 with pain) at the time of the
first dose and/or within 14 days before enrollment
22. Contraindication to any of the required concomitant drugs, including proton-pump
inhibitor (e.g., lansoprazole), antiviral agents, enteric-coated aspirin or other
anticoagulant, or if a history of prior thrombotic disease, warfarin or low molecular
weight heparin
23. Subjects in whom the required program of oral and intravenous fluid hydration is
contraindicated, e.g., due to pre-existing pulmonary, cardiac, or renal impairment
24. Subjects with pleural effusions requiring thoracentesis or ascites requiring
paracentesis
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