Multiple Myeloma
Conditions
Keywords
Elotuzumab, Multiple Myeloma, Phase 2
Brief summary
Despite the recent introduction of novel anti-multiple myeloma (MM) agents, high risk MM remains with poor prognosis and a therapeutic challenge. Elotuzumab (ELO) is a humanized monoclonal antibody that recognizes CS1/CD139, a molecule highly expressed in MM cells. The ELO (10 mg/kg), lenalidomide (LEN) and dexamethasone (DEX) combination achieves high overall response rates (ORR) and long progression-free survival (PFS) for patients with relapsed/refractory disease (RR) MM and those with impaired renal function. However, its efficacy for MM patients with high risk characteristics is still unknown. Pomalidomide (POM) is a recently approved immunomodulatory agent (IMiD) that produces response rates for high-risk RRMM patients when used in combination with DEX and other agents, including the proteasome inhibitor (PI) bortezomib (BTZ). POM has also demonstrated activity for LEN refractory patients. Carfilzomib (CFZ) is a potent second generation PI that has shown to be efficacious for IMiD and BTZ refractory patients as well as high risk patients carrying cytogenetic abnormalities. In this study, we propose to evaluate efficacy and safety of ELO in combination with POM, DEX and CFZ for high-risk RRMM patients.
Detailed description
This is a Phase 2, multicenter, open label, nonrandomized study with six patients safety lead-in cohort to evaluate efficacy and safety of elotuzumab in combination with pomalidomide, carfilzomib and dexamethasone among high risk relapsed and refractory multiple myeloma patients. This study will enroll previously treated patients that currently show evidence of progressive disease and have been diagnosed with high risk multiple myeloma. Thirty-nine patients will be enrolled in the study. First, six patients will be enrolled and used as a lead-in cohort for the safety evaluation and MTD re-determination (if necessary). The results of the safety lead-in cohort will be evaluated after the 6th patient has completed one full cycle of treatment. Recruitment of patients will be withheld during safety data analysis. Enrollment of the remaining 33 patients will be contingent upon safety committee's decision. The study consists of: 1) a screening period; 2) up to eight 28-day treatment cycles; 3) a final assessment to occur 28 days after the end of the last treatment cycle; and 4) a follow-up period. All drugs will be administered on a 28-day cycle schedule throughout the study. Subjects eligible for this study will receive treatment with study drug for a maximum of eight 28-day treatment cycles. Subjects are to be treated for 8 cycles of therapy without demonstrating PD.
Interventions
DRUGElotuzumab
Elotuzumab IV at 10mg/kg Elotuzumab IV at 20mg/kg
DRUGPomalidomide
Pomalidomide PO at 3mg
DRUGCarfilzomib
Carfilzomib 20mg/m2 IV Carfilzomib 56mg/m2 IV
DRUGDexamethasone
Dexamethasone 28mg PO Dexamethasone 40mg PO or IV Dexamethasone 8mg IV
Sponsors
Oncotherapeutics
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 be adults (age ≥ 18 years at the time of signing the informed consent document) and must meet all of the following inclusion criteria to be enrolled in the study: 1. ECOG/Zubrod performance status of 0-2 at study entry 2. Has a diagnosis of high-risk MM by showing any of the following a-f criteria: : 1. Presence of conventional cytogenetic markers such as deletion of 17p-p53, translocations involving t(14;16) and t(14;20) 2. Plasma cell leukemia (PCL) (\> 2.0 × 109/L circulating plasma cells by standard differential) 3. Extramedullary MM 4. Doubling in levels of a MM markers in the past 3 months such as any of the following criteria alone or in combination: i) Serum M-protein ≥ 1.0 g/dL, or ii) Urine M-protein ≥ 400 mg/24 hours, or iii) Only in patients who do not meet i or ii, then use serum free light chain (SFLC) \> 200 mg/L (involved light chain) and an abnormal kappa/lambda ratio 5. Refractoriness to their most recent lenalidomide-containing regimen and proteasome inhibitor-containing regimen. 6. Renal failure related to MM with creatinine clearance (CrCl) \>15 mL/min but \<30 mL/min as calculated by Cockcroft-Gault equation (Appendix 14.8). 3. Has previously received more than two lines of therapy including a lenalidomide-containing regimen and proteasome inhibitor-containing regimen. 4. Currently demonstrating progressive disease 5. Life expectancy greater than 3 months 6. Laboratory test results within these ranges at Screening and confirmed at enrollment prior to drug dosing on Cycle 1 Day 1: * ANC ≥ 1.5 x 109/L; if the bone marrow is extensively infiltrated ( ≥ 70% plasma cells) then ≥ 1.0 x 109/L * Platelet count ≥ 75 x 109/L; if the bone marrow is extensively infiltrated ( ≥ 70% plasma cells) then ≥ 50 x 109/L * Hemoglobin ≥ 8 g/dL 7. Women of childbearing potential (WOCBP†) must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 10-14 days prior to and again within 24 hours of starting study drug regimen † A WOCBP (women 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 (i.e., has had menses at any time in the preceding 24 consecutive months) WOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment with study drug (s) plus 5 half-lives of study drug plus 30 days (duration of ovulatory cycle) for a total of 120 days post-treatment completion. Subject must either commit to continued abstinence from heterosexual intercourse or begin TWO acceptable methods of birth control, one highly effective method and one additional effective method AT THE SAME TIME, and at least 28 days before she starts taking study drugs. WOCBP must also agree to ongoing pregnancy testing. All subjects must be counseled at a minimum of every 28 days about pregnancy precautions and risks of fetal exposure. See Section 10.3.5.2, Appendix 4 and Appendix 5. Males who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment with study drug plus 5 half-lives of the study drug plus 90 days (duration of sperm turnover) for a total of 154 days post-treatment completion. Men must agree to use a latex condom during sexual contact with a WOCBP even if they have had a vasectomy. All subjects must be counseled at a minimum of every 28 days about pregnancy precautions and risks of fetal exposure. See Section 10.3.5, Appendix 4 and Appendix 5 8. Able to take aspirin (acetylsalicylic acid, ASA) at 81 or 325 mg/daily as prophylactic anticoagulation (subjects intolerant to ASA may use warfarin or low molecular weight heparin) 9. Written informed consent in accordance with federal, local, and institutional guidelines 10. Able to adhere to the study visit schedule and other protocol requirements
Exclusion criteria
* Subjects meeting any of the following
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Treatment-Emergent Adverse Events (Safety and Tolerability) | 34 Months | Occurrence of adverse events throughout the study, graded via Common Terminology Criteria for Adverse Events (CTCAE) v 4.03 criteria (If necessary re-define MTD via the number of dose-limiting toxicities (DLTs) per dose level, of elotuzumab in combination with pomalidomide, carfilzomib and dexamethasone for high risk RRMM patients (based on six patients lead-in cohort if necessary). |
| Overall Rate of Response (Efficacy) | 34 Months | Efficacy of treatment will be assessed by the Overall response rate (ORR) \[ORR=complete response (CR†) + very good partial response (VGPR) + partial response (PR)\] Clinical benefit rate (CBR) \[CBR=CR† + VGPR + PR + minor response (MR)\]. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| PFS | 34 Months | Progression-free survival (PFS): time from initiation of therapy to progressive disease or death from any cause, whichever comes first |
| DOR | 34 Months | Duration of response (DOR): time from the first response (\> PR) to progressive disease |
| OS | 34 Months | Overall survival (OS): time from initiation of therapy to death from any cause or last follow-up visit. |
Countries
United States
Outcome results
None listed