Multiple Myeloma
Conditions
Brief summary
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.
Detailed description
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.
Interventions
DRUGVorinostat, Lenalidomide, Carfilzomib, Dexamethasone
Dose Escalation Schema Cohort Carfilzomib (mg/m2) Lenalidomide (mg) Vorinostat (mg) Dexamethasone (mg) 1. 15 15 300 40 2. 20 15 300 40 3. 20 25 300 40 4. 20/27\* 25 300 40 5. 20/27\* 25 400 40
Sponsors
Hackensack Meridian Health
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Safety and dose of carfilzomib, lenalidomide, vorinostat and dexamethasone for MM | Within 30 days of the last administration of study treatment | Primary Objective: To evaluate safety and establish the maximum tolerated dose (MTD) \[and/or a protocol defined dose below the MTD\] of carfilzomib, lenalidomide, vorinostat and dexamethasone in relapsed and/or refractory multiple myeloma subjects. Secondary Objectives: To observe evidence of efficacy (response rate, duration of response, time to progression, time to next treatment) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall response rate (ORR) Time to next treatment (TTNT) Time to progression (TTP) Duration of response (DOR | Within 30 days of the last administration of study treatment | Secondary Objectives: To observe evidence of efficacy (response rate, duration of response, time to progression, time to next treatment) |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORDavid Siegel, MD, PhD
Hackensack Meridian Health
Outcome results
None listed