A Phase 2 Trial of the Efficacy and Safety of Elotuzumab in Combination With Pomalidomide, Carfilzomib and Dexamethasone Among High Risk Relapsed/ Refractory Multiple Myeloma Patients
Overview
- Phase
- Phase 2
- Status
- Terminated
- Sponsor
- Oncotherapeutics
- Enrollment
- 13
- Locations
- 6
- Primary Endpoint
- Incidence of Treatment-Emergent Adverse Events (Safety and Tolerability)
Overview
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.
Study Design
- Study Type
- Interventional
- Allocation
- Na
- Intervention Model
- Single Group
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- All
- Accepts 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:
- •ECOG/Zubrod performance status of 0-2 at study entry
- •Has a diagnosis of high-risk MM by showing any of the following a-f criteria: :
- •Presence of conventional cytogenetic markers such as deletion of 17p-p53, translocations involving t(14;16) and t(14;20)
- •Plasma cell leukemia (PCL) (\> 2.0 × 109/L circulating plasma cells by standard differential)
- •Extramedullary MM
- •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
- •Refractoriness to their most recent lenalidomide-containing regimen and proteasome inhibitor-containing regimen.
- •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).
- •Has previously received more than two lines of therapy including a lenalidomide-containing regimen and proteasome inhibitor-containing regimen.
Exclusion Criteria
- •Subjects meeting any of the following exclusion criteria are not to be enrolled in the study:
- •POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes) 19
- •Waldenström's macroglobulinemia
- •Received the following prior therapy:
- •Chemotherapy within 3 weeks of study drugs (6 weeks for nitrosourea, melphalan or monoclonal antibodies)
- •Corticosteroids (\>10 mg/daily prednisone or equivalent) within 3 weeks of study drugs
- •Immunomodulatory therapy within one week before study drugs
- •Antibody therapy within 3 weeks before study drugs
- •Extensive radiation therapy (total maximum radiation doses of 50Gy to any individual site or 30Gy for the disseminated MM of bone) within 3 weeks before study drugs. Receipt of localized radiation therapy does not preclude enrollment.
- •Cytotoxic chemotherapy with approved or investigational anticancer therapeutics within 3 weeks prior to first dose
Arms & Interventions
Elo Pom Car and Dex
Drug dosing and administration:
All drugs are administered on a 28-day cycle.
Elotuzumab: 10 mg/kg IV on Days 1,8,15 and 22 Cycles 1 and 2. 20 mg/kg on Day 1 of Cycles 3 and beyond.
Pomalidomide: 3 mg PO on days 1-21
Carfilzomib: 20 mg/m2 IV on days 1 of cycle 1. 56 mg/m2 IV on days 8 and 15 of cycle 1 and Days 1, 8 and 15 of the remaining seven cycles.
Dexamethasone: On days 1,8,15,22 of Cycle 1-2 and day 1 of Cycle 3 and every day 1 thereafter, pre-treatment with 28 mg PO 3-24 hours prior to the start of ELO. On days 8,15,22 of Cycle 3 and beyond, 40mg of DEX PO or IV. On Day 8 and 15 of Cycle 3 and beyond, pre-treatment with DEX 40mg PO or IV at least 30 min and no more than 4 hours prior to the start of CFZ.
Intervention: Elotuzumab (Drug)
Elo Pom Car and Dex
Drug dosing and administration:
All drugs are administered on a 28-day cycle.
Elotuzumab: 10 mg/kg IV on Days 1,8,15 and 22 Cycles 1 and 2. 20 mg/kg on Day 1 of Cycles 3 and beyond.
Pomalidomide: 3 mg PO on days 1-21
Carfilzomib: 20 mg/m2 IV on days 1 of cycle 1. 56 mg/m2 IV on days 8 and 15 of cycle 1 and Days 1, 8 and 15 of the remaining seven cycles.
Dexamethasone: On days 1,8,15,22 of Cycle 1-2 and day 1 of Cycle 3 and every day 1 thereafter, pre-treatment with 28 mg PO 3-24 hours prior to the start of ELO. On days 8,15,22 of Cycle 3 and beyond, 40mg of DEX PO or IV. On Day 8 and 15 of Cycle 3 and beyond, pre-treatment with DEX 40mg PO or IV at least 30 min and no more than 4 hours prior to the start of CFZ.
Intervention: Pomalidomide (Drug)
Elo Pom Car and Dex
Drug dosing and administration:
All drugs are administered on a 28-day cycle.
Elotuzumab: 10 mg/kg IV on Days 1,8,15 and 22 Cycles 1 and 2. 20 mg/kg on Day 1 of Cycles 3 and beyond.
Pomalidomide: 3 mg PO on days 1-21
Carfilzomib: 20 mg/m2 IV on days 1 of cycle 1. 56 mg/m2 IV on days 8 and 15 of cycle 1 and Days 1, 8 and 15 of the remaining seven cycles.
Dexamethasone: On days 1,8,15,22 of Cycle 1-2 and day 1 of Cycle 3 and every day 1 thereafter, pre-treatment with 28 mg PO 3-24 hours prior to the start of ELO. On days 8,15,22 of Cycle 3 and beyond, 40mg of DEX PO or IV. On Day 8 and 15 of Cycle 3 and beyond, pre-treatment with DEX 40mg PO or IV at least 30 min and no more than 4 hours prior to the start of CFZ.
Intervention: Carfilzomib (Drug)
Elo Pom Car and Dex
Drug dosing and administration:
All drugs are administered on a 28-day cycle.
Elotuzumab: 10 mg/kg IV on Days 1,8,15 and 22 Cycles 1 and 2. 20 mg/kg on Day 1 of Cycles 3 and beyond.
Pomalidomide: 3 mg PO on days 1-21
Carfilzomib: 20 mg/m2 IV on days 1 of cycle 1. 56 mg/m2 IV on days 8 and 15 of cycle 1 and Days 1, 8 and 15 of the remaining seven cycles.
Dexamethasone: On days 1,8,15,22 of Cycle 1-2 and day 1 of Cycle 3 and every day 1 thereafter, pre-treatment with 28 mg PO 3-24 hours prior to the start of ELO. On days 8,15,22 of Cycle 3 and beyond, 40mg of DEX PO or IV. On Day 8 and 15 of Cycle 3 and beyond, pre-treatment with DEX 40mg PO or IV at least 30 min and no more than 4 hours prior to the start of CFZ.
Intervention: Dexamethasone (Drug)
Outcomes
Primary Outcomes
Incidence of Treatment-Emergent Adverse Events (Safety and Tolerability)
Time Frame: 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)
Time Frame: 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 Outcomes
- PFS(34 Months)
- OS(34 Months)
- DOR(34 Months)