Multiple Myeloma in Relapse, Multiple Myeloma, Refractory
Conditions
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
Interventions
DRUGcyclosporine in combination with carfilzomib and dexamethasone
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.
Sponsors
Weizmann Institute of Science
Tel-Aviv Sourasky Medical Center
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
single-arm, prospective study
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Patients must meet all of the following inclusion criteria: 1. Male or female patients, 18 years of age or older. 2. Multiple myeloma diagnosed according to standard IMWG criteria. 3. 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. 4. Patients received one or two prior lines of therapy which must have included bortezomib, lenalidomide-and daratumumab. 5. 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. 6. 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. 7. Patients must meet the following clinical laboratory criteria: * Absolute neutrophil count (ANC) ≥1,000/mm3 and platelet count≥75,000/mm3. Platelet transfusions to help patients meet eligibility criteria are not allowed within 3 days of enrolment. * Total bilirubin ≤1.5 the upper limit of the normal range (ULN). * Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤3 ULN. * Calculated creatinine clearance ≥45 mL/min 8. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2. 9. Female patients who: * Are postmenopausal for at least 24 months before the screening visit, OR * Are surgically sterile, OR * Who are of childbearing potential, and agree to practice two effective methods of contraception (1 highly effective method and 1 additional effective method) at the same time, from the time of signing the informed consent through 90 days after the last dose of study treatment, OR agree to completely abstain from heterosexual intercourse. Females of childbearing potential (FCBP) must have a negative serum or urine pregnancy test with a sensitivity of at least 25 milli International Units/mL within 10 to 14 days of initiation of Cycle 1 and again within 24 hours of starting Cycle 1. FCBP must also agree to ongoing pregnancy testing. All patients must be counseled at a minimum of every 28 days about pregnancy precautions and risks of fetal exposure. 10. Male patients, even if surgically sterilized (i.e., status postvasectomy), who: * Agree to completely abstain from heterosexual intercourse, OR * Agree to practice effective barrier contraception (i.e., latex condom) during sexual contact with a FCBP, even if they have had a successful vasectomy, throughout the entire study treatment period and through 4 months after the last dose of study treatment. 11. Voluntary written consent must be given before performance of any study-related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care. 12. Patient is willing and able to adhere to the study visit schedule and other protocol requirements. \-
Exclusion criteria
* Patients meeting any of the following
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Abnormal Laboratory Values and/or Adverse Events That Are Related to Treatment parameters. | follow-up 2 years post study | Number of Participants With Abnormal Laboratory Values and/or Adverse Events That Are Related to Treatment parameters. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression free survival PFS | follow-up 2 years post study | The time from first dose to the date of the first documented tumor progression or death due to any cause. PFS will be determined by an investigator, based upon laboratory data, as defined by the IMWG criteria |
| Duration of Response DOR | follow-up 2 years post study | The time between the date of first response to the date of the first objectively documented tumor progression as assessed by study steering committee according to modified IMWG criteria or death due to any cause prior to subsequent anti-cancer therapy. |
| Time to Response TTR | follow-up 2 years post study | The time from the first dose to the date of the first sCR, CR, VGPR, or PR. |
| Depth of Best Response (DpR) | follow-up 2 years post study | According to IMWG criteria. |
| Overall response rate ORR | follow-up 2 years post study | Proportion of patients who achieve a best overall response of stringent complete response , complete response, very good partial response, or partial response as defined using the IMWG criteria |
| Overall Survival (OS) | follow-up 2 years post study | Time between the date of first dose and the date of death due to any cause |
| Extramedullary progression | follow-up 2 years post study | Kaplan Meyer test will be applied to test for differences between the groups in Progression Free Survival |
| Percentage of cyclosporine trough levels tests in acceptable range | follow-up 2 years post study | will be calculated for each patient. |
| Mean % of levels in acceptable range will be calculated for the efficacy population. | follow-up 2 years post study | — |
| Time to progression (TTP) | follow-up 2 years post study | Time from initiation of treatment to documented PD |
Countries
Israel
Outcome results
None listed