Multiple Myeloma
Conditions
Keywords
multiple myeloma lenalidomide
Brief summary
Phase IIb clinical trial to determine if resistance to a lenalidomide containing regimen can be overcome by the addition of vorinostat, in patients with relapsed and refractory multiple myeloma.
Detailed description
lenalidomide has been investigated in combination with both lenalidomide and bortezomib regimens. "Investigational" means that the drug is still being studied and that the study doctors are trying to find out more about it; such as the safest dose to use, the side effects it may cause, and if the drug is effective for treating relapsed and/or refractory multiple myeloma. Lenalidomide is a drug that alters the immune system and it may also interfere with the development of tiny blood vessels that help support tumor growth. Therefore, in theory, it may reduce or prevent the growth of cancer cells. Lenalidomide is approved by the Food and Drug Administration (FDA) for the treatment of specific types of myelodysplastic syndrome (MDS) and in combination with dexamethasone for patients with multiple myeloma (MM) who have received at least 1 prior therapy. MDS and MM are cancers of the blood. It is currently being tested in a variety of cancer conditions. In this case it is considered experimental because the FDA has not approved this combination. Participants will receive 25mg of lenalidomide on days 1-21 every 28 days. Vorinostat is a drug that interferes with the life sustaining functions of the tumor cells. It has already received regulatory approval by the U.S. Food and Drug Administration (FDA) for the treatment of T-cell non-Hodgkin's Lymphoma in the United States. The usage of vorinostat in Multiple Myeloma is experimental (investigational) and has not been approved by the FDA, but studies in combination with proteasome inhibitors (bortezomib) and immunomodulatory (lenalidomide) agents are ongoing. Participants will receive either 400mg of vorinostat on days 1-7 and 15-21 every 28 days. Dexamethasone is a steroid that is known to cause cell death in multiple myeloma. Dexamethasone is FDA approved for the treatment of multiple myeloma and many other disease states. Participants will receive either Dexamethasone 40mg for those less than 75 years of age or 20mg for those aged 75 years and above on days 1, 8, 15 and 22 every 28 days In this research study the investigators are looking to evaluate the safety and efficacy of vorinostat when combined with lenalidomide and dexamethasone in treating relapsed and/or refractory multiple myeloma, refractory to lenalidomide.
Interventions
DRUGVorinostat, Lenalinomide and Dexamethasone
Vorinostat: 400 mg po days 1-7 and 15-21 Lenalidomide: 25 mg po days 1-21 \* Lenalidomide dose for patients with renal impairment (CrCL\<50ml/min) has be dose adjusted according to package insert Dexamethasone: 40mg po days 1, 8, 15 and 22 for patients aged less than 75 years, 20mg for those aged 75 years and above
Sponsors
Hackensack Meridian Health
Merck Sharp & Dohme LLC
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: * International Staging System symptomatic multiple myeloma, as recently defined (Kyle et al., 2009) or Durie-Salmon stage I-III multiple myeloma, after at least one (1) prior anti-myeloma regimen. * Refractory to lenalidomide (administered either with dexamethasone or in combination with other agents); refractory will be defined as no response (\<MR) or PD on or within 60 days of discontinuing a prior lenalidomide-containing regimen. * Measurable monoclonal protein by serum or urine; or FLC level ≥ 10mg/dL (with abnormal FLC ratio), or measurable extramedullary plasmacytomas: * No prior HDAC inhibitor * Age ≥ 18 years * Performance status ECOG 0-3 * Acceptable organ function as defined by: * Bilirubin \<2 x upper limit of normal * ALT and AST \<2.5 x upper limit of normal * Serum creatinine \<3.0 mg/dL * ANC ≥1.0 x 109/L * Platelet count ≥50 x 109/L * QTc interval ≤ 470ms * Non-pregnant and non-lactating * Life expectancy of more than six months * Written informed consent in accordance with federal, local and institutional guidelines * 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). * 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) * All study participants must be registered into the mandatory RevAssist® program and be willing and able to comply with the requirements of RevAssist®. * 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. * 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), Pradaxa® or be treated with full-dose, low molecular weight heparin, as if to treat deep venous thrombosis (DVT)/pulmonary embolism.
Exclusion criteria
* Subjects must not meet any of the following
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate (PR or Better) of Vorinostat in Combination With Lenalidomide and Dexamethasone in Patients With Relapsed/Refractory MM Refractory to a Previous Lenalidomide Containing Regimen | On treatment portion of study is completed after 12 cycles (each cycle is 28 days in duration) and one month of follow up. Patients may be followed for up to two years after last dose of lenalidomide and vorinostat for disease status and survival. | Defined as: 1. Progression on therapy OR within 60 days after the last dose of a lenalidomide containing regimen OR 2. No clinical response (\<MR) on a lenalidomide containing regimen An overall response rate of 25% or more will be acceptable, while an overall response of less than or equal to 16% will be considered unacceptable. Response will be assessed according to a modified International Working Group Uniform Response Criteria (Durie et al., 2006) * Complete Response: Negative immunofixation on the serum and urine and Disappearance of any soft tissue plasmacytomas and ⩽5% plasma cells in bone marrow * Very Good Partial Response- Serum and urine M-component detectable by immunofixation but not on electrophoresis or 90 or greater reduction in serum M-component plus urine M-component \<100 mg per 24 h * Partial Response- ⩾50% reduction of serum M-protein and reduction in 24-h urinary M-protein by ⩾90% or to \<200 mg per 24 h. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORDavid Siegel, M.D., Ph.D
Hackensack Meridian Health
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Vorinostat, Lenalinomide, Dexamethasone Vorinostat: 400 mg po days 1-7 and 15-21 Lenalidomide: 25 mg po days 1-21 \* Lenalidomide dose for patients with renal impairment (CrCL\<50ml/min) has be dose adjusted according to package insert Dexamethasone: 40mg po days 1, 8, 15 and 22 for patients aged less than 75 years, 20mg for those aged 75 years and above
Vorinostat, Lenalinomide and Dexamethasone: Vorinostat: 400 mg po days 1-7 and 15-21 Lenalidomide: 25 mg po days 1-21
\* Lenalidomide dose for patients with renal impairment (CrCL\<50ml/min) has be dose adjusted according to package insert
Dexamethasone: 40mg po days 1, 8, 15 and 22 for patients aged less than 75 years, 20mg for those aged 75 years and above | 25 |
| Total | 25 |
Baseline characteristics
| Characteristic | Vorinostat, Lenalinomide, Dexamethasone |
|---|---|
| Age, Continuous | 65 years |
| Region of Enrollment United States | 25 participants |
| Sex: Female, Male Female | 7 Participants |
| Sex: Female, Male Male | 18 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| other Total, other adverse events | 25 / 25 |
| serious Total, serious adverse events | 6 / 25 |
Outcome results
Primary
Overall Response Rate (PR or Better) of Vorinostat in Combination With Lenalidomide and Dexamethasone in Patients With Relapsed/Refractory MM Refractory to a Previous Lenalidomide Containing Regimen
Defined as: 1. Progression on therapy OR within 60 days after the last dose of a lenalidomide containing regimen OR 2. No clinical response (\<MR) on a lenalidomide containing regimen An overall response rate of 25% or more will be acceptable, while an overall response of less than or equal to 16% will be considered unacceptable. Response will be assessed according to a modified International Working Group Uniform Response Criteria (Durie et al., 2006) * Complete Response: Negative immunofixation on the serum and urine and Disappearance of any soft tissue plasmacytomas and ⩽5% plasma cells in bone marrow * Very Good Partial Response- Serum and urine M-component detectable by immunofixation but not on electrophoresis or 90 or greater reduction in serum M-component plus urine M-component \<100 mg per 24 h * Partial Response- ⩾50% reduction of serum M-protein and reduction in 24-h urinary M-protein by ⩾90% or to \<200 mg per 24 h.
Time frame: On treatment portion of study is completed after 12 cycles (each cycle is 28 days in duration) and one month of follow up. Patients may be followed for up to two years after last dose of lenalidomide and vorinostat for disease status and survival.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Vorinostat, Lenalinomide, Dexamethasone | Overall Response Rate (PR or Better) of Vorinostat in Combination With Lenalidomide and Dexamethasone in Patients With Relapsed/Refractory MM Refractory to a Previous Lenalidomide Containing Regimen | 6 Participants |