A Single-arm, Prospective Study of Cyclosporine in Combination With Carfilzomib and Dexamethasone in Patients With Relapsed Multiple Myeloma Refractory to Carfilzomib With High Expression of the Peptidylprolyl Isomerase A (PPIA) Gene in Myeloma Cells
Overview
- Phase
- Phase 1
- Intervention
- cyclosporine in combination with carfilzomib and dexamethasone
- Conditions
- Multiple Myeloma in Relapse
- Sponsor
- Tel-Aviv Sourasky Medical Center
- Enrollment
- 3
- Locations
- 1
- Primary Endpoint
- Number of Participants With Abnormal Laboratory Values and/or Adverse Events That Are Related to Treatment parameters.
- Status
- Completed
- Last Updated
- 9 months ago
Overview
Brief Summary
This phase 1, open-label, single-arm, prospective, single center study will evaluate the safety, tolerability and efficacy of cyclosporine in combination with carfilzomib and dexamethasone in patients with relapsed and refractory multiple myeloma (RRMM).
Detailed Description
This phase 1, open-label, single-arm, prospective, single center study will evaluate the safety, tolerability and efficacy of cyclosporine in combination with carfilzomib and dexamethasone in patients with relapsed and refractory multiple myeloma (RRMM). The patients will consist of adult men and women who have a confirmed diagnosis of RRMM, who have received at least two prior lines of therapy including carfilzomib, and were non responsive or refractory to carfilzomib as specified below, and who were found to have elevated expression of Peptidylprolyl Isomerase A (PPIA) in scRNA sequencing of their myeloma cells, and who meet other protocol outlined eligibility criteria. The patients will be treated with cyclosporine with dose titration based on repeated determinations of whole blood concentrations to achieve a target trough concentration of 250 ng/mL, in combination with carfilzomib plus dexamethasone. Patients may continue to receive treatment for 4 months or until disease progression or unacceptable toxicity, the earliest of them. Subjects will be followed for Adverse Events (AEs), clinical status-Overall response rate (ORR) as defined by International Myeloma Working Group (IMWG) criteria, Progression Free Survival (PFS), Duration of Response (DOR), Time to Progression (TTP), stringent Complete Response (sCR 0, Complete Response (CR), Very Goog Partial Response (VGPR), Partial Response (PR), Depth of Best Response (DpR), Time To Response (TTR), Progressive Disease (PD), Overall Survival (OS) and laboratory parameters for up to 4 months, unless they terminate early due to disease progression, unacceptable toxicity or due to meeting one of the withdrawal criteria
Investigators
Eligibility Criteria
Inclusion Criteria
- •Patients must meet all of the following inclusion criteria:
- •Male or female patients, 18 years of age or older.
- •Multiple myeloma diagnosed according to standard IMWG criteria.
- •Patients must have measurable disease defined by at least one of the following three measurements:
- •Serum M-protein 1 g/dL (10 g/L).
- •Urine M-protein 200 mg/24 hours.
- •Serum free light chain assay: involved free light chain level at least 100 mg/L, provided that the serum free light chain ratio is abnormal.
- •Patients received one or two prior lines of therapy which must have included bortezomib, lenalidomide-and daratumumab.
- •Patient received carfilzomib-based therapy either as their most recent line of therapy and within 3 months from study enrolment, and either failed to achieve a minor response after completing 2 cycles of carfilzomib based therapy, or are refractory to treatment.
- •Patients were found to have a high-expression level of PPIA, \>1.2 unique RNA molecules (UMI) per cell on average, by scRNA sequencing of their myeloma cells from bone marrow aspiration sample at study screening.
Exclusion Criteria
- •Patients meeting any of the following exclusion criteria are not eligible to participate in the study:
- •Patient underwent an allogeneic transplantation.
- •Major surgery within 14 days before enrolment.
- •Central nervous system involvement
- •Concomitant use of any other antineoplastic treatment with activity against MM (with the exception of ≤40 mg Dexamethasone per day or equivalent for no longer than 4 days).
- •Anti-myeloma therapy as follows prior to screening bone marrow aspiration:
- •Targeted therapy, within 14 days or at least 5 half-lives, whichever is less;
- •Monoclonal antibody treatment for multiple myeloma within 21 days;
- •Cytotoxic therapy within 14 days;
- •Proteasome inhibitor therapy within 14 days; note: no window is required for carfilzomib
Arms & Interventions
cyclosporine in combination with carfilzomib and dexamethasone
cyclosporine in combination with carfilzomib and dexamethasone in patients with relapsed multiple myeloma refractory to carfilzomib with high expression of the PPIA gene in myeloma cells
Intervention: cyclosporine in combination with carfilzomib and dexamethasone
Outcomes
Primary Outcomes
Number of Participants With Abnormal Laboratory Values and/or Adverse Events That Are Related to Treatment parameters.
Time Frame: follow-up 2 years post study
Number of Participants With Abnormal Laboratory Values and/or Adverse Events That Are Related to Treatment parameters.
Secondary Outcomes
- Mean % of levels in acceptable range will be calculated for the efficacy population.(follow-up 2 years post study)
- Extramedullary progression(follow-up 2 years post study)
- Depth of Best Response (DpR)(follow-up 2 years post study)
- Percentage of cyclosporine trough levels tests in acceptable range(follow-up 2 years post study)
- Overall Survival (OS)(follow-up 2 years post study)
- Overall response rate ORR(follow-up 2 years post study)
- Progression free survival PFS(follow-up 2 years post study)
- Duration of Response DOR(follow-up 2 years post study)
- Time to Response TTR(follow-up 2 years post study)
- Time to progression (TTP)(follow-up 2 years post study)