Multiple Myeloma in Relapse, Multiple Myeloma, Refractory
Conditions
Keywords
Multiple Myeloma, Multiple Myeloma, Refractory, Multiple Myeloma in Relapse
Brief summary
Selinexor, a first-in-class, oral selective exportin 1 (XPO1) inhibitor, has shown promise in pre-clinical and clinical studies. It functions by inhibiting the nuclear export protein XPO1, resulting in the accumulation of tumor suppressor proteins and inhibition of oncoprotein mRNAs, which is selectively lethal to myeloma cells. Selinexor has demonstrated activity in combination with various drugs, including glucocorticoids and proteasome inhibitors, leading to its FDA approval for the treatment of relapsed or refractory multiple myeloma.
Detailed description
Selinexor, a first-in-class, oral selective exportin 1 (XPO1) inhibitor, has shown promise in pre-clinical and clinical studies. It functions by inhibiting the nuclear export protein XPO1, resulting in the accumulation of tumor suppressor proteins and inhibition of oncoprotein mRNAs, which is selectively lethal to myeloma cells. Selinexor has demonstrated activity in combination with various drugs, including glucocorticoids and proteasome inhibitors, leading to its FDA approval for the treatment of relapsed or refractory multiple myeloma. Ruxolitinib, an oral JAK1/2 inhibitor, has been approved by the FDA for myelofibrosis treatment. Preliminary experiments have shown that Ruxolitinib, in combination with lenalidomide and dexamethasone, effectively inhibits MM cell proliferation. Additionally, the combination of Ruxolitinib and dexamethasone has demonstrated enhanced anti-MM effects. Clinical results indicate that Ruxolitinib in combination with steroids is well-tolerated in heavily treated MM patients. This proposed study aims to investigate the efficacy of a lower dose of Selinexor in combination with Ruxolitinib and methylprednisolone for patients with relapsed/refractory multiple myeloma. The study builds on the existing evidence of the individual and synergistic effects of Selinexor and Ruxolitinib, both in preclinical and clinical settings and seeks to provide a potential new treatment option for MM patients.
Interventions
DRUGMethylprednisolone
Glucocorticoid, steroid
DRUGSelinexor
Selinexor (KPT-330) is a first-in-class, oral selective exportin 1 (XPO1) inhibitor (1,2). Selinexor functions by binding with and inhibiting the nuclear export protein XPO1 (also called CRM1), leading to the accumulation of tumor suppressor proteins in t
DRUGRuxolitinib
elective inhibitor of Janus kinase (JAK)
Sponsors
Oncotherapeutics
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Healthy volunteers
No
Inclusion criteria
Patients must meet all the following inclusion criteria to be eligible to enroll in this study: 1\. Has a diagnosis of MM based on standard criteria as follows: Myeloma criteria: Must be At least 1 of 2 1. Clonal bone marrow plasma cells \>10% 2. Biopsy-proven bony or extramedullary plasmacytoma Active Myeloma criteria: Active Myeloma criteria: Must Meet At Least ONE of the Following: Meet at least one of the sub-criteria for #1 Evidence of End Organ Damage (a, b, c, or d), OR Meet sub-criteria #2. 60% or greater bone marrow plasma cells, OR Meet sub-criteria #3 Serum free light chain ratio, OR Meet sub-criteria #4 More than one focal lesion on MRI \> 5mm in size. 1. Evidence of end organ damage that can be attributed to the underlying plasma cell proliferative disorder, specifically 1. Hypercalcemia: serum calcium \>0.25 mmol/L (\>1mg/dL) higher than the upper limit of normal or \>2.75 mmol/L (\>11mg/dL) 2. Renal insufficiency: creatinine clearance \<40 mL per minute or serum creatinine \>177mol/L (\>2mg/dL) 3. Anemia: hemoglobin value of \>20g/L below the lowest limit of normal, or a hemoglobin value \<100g/L 4. Bone lesions: one or more osteolytic lesion on skeletal radiography, CT, or PET/CT. If bone marrow has \<10% clonal plasma cells, more than one bone lesion is required to distinguish from solitary plasmacytoma with minimal marrow involvement 2. 60% or greater clonal plasma cells on bone marrow examination 3. Serum involved / uninvolved free light chain ratio of 100 or greater, provided the absolute level of the involved light chain is at least 100 mg/L (a patient's involved free light chain either kappa or lambda is the one that is above the normal reference range; the uninvolved free light chain is the one that is typically in, or below, the normal range) 4. More than one focal lesion on MRI that is at least 5mm or greater in size The patient must have met the criteria for Active Myeloma at some stage following the diagnosis of Myeloma. Source documentation for both Myeloma and Active Myeloma will be required. 2\. Patients with relapsed/refractory multiple myeloma with at least three prior lines of therapy 3. Received an 1. Anti-CD38 antibody 2. Immunomodulatory agent (IMiD) 3. Proteasome inhibitor (PI) 4. Currently has MM with measurable disease, defined as: * a monoclonal immunoglobulin spike on serum electrophoresis of at least 0.5 g/dL and/or urine monoclonal protein levels of at least 200 mg/24 hours * for patients without measurable serum and urine M-protein levels, an involved SFLC \> 100 mg/L or abnormal SFLC ratio * for patients with IgD MM, a monoclonal immunoglobulin IgD of at least 5500 mg/L or meet other measurable disease eligibility criteria * for patients with IgA MM, total IgA of \> 700 mg/dL 5. Currently has progressive MM: MM patients that are relapsed or have refractory disease from at least 3 regimens or lines of therapy are eligible for enrollment provided they fulfill the other eligibility criteria: * patients are considered relapsed, when they progress greater than 60 days from their last dose of treatment * patients are refractory when they progress while currently receiving the treatment or within 8 weeks of its last dose 6. Adequate hepatic function within 14 days prior to C1D1: Total bilirubin \< 1.5 × upper limit of normal (ULN) (except patients with Gilbert's syndrome who must have a total bilirubin of \< 3 × ULN), and Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) normal to \< 2 × ULN. 7\. Adequate renal function within 14 days prior to C1D1 as determined by OR estimated CrCl of \> 60 mL/min, calculated using the Cockcroft and Gault formula (140 - Age) • Mass (kg)/ (72 • creatinine mg/dL); multiply by 0.85 if female (87)(Appendix 5). 8\. Adequate hematopoietic function within 14 days prior to C1D1: total WBC count ≥1500/mm3, ANC ≥1000/mm3, hemoglobin ≥8.5 g/dL and platelet count ≥75,000/mm3 (patients for whom \<50% of BM nucleated cells are plasma cells) or ≥50,000/mm3 (patients for whom ≥50% of BM nucleated cells are plasma cells). 9\. Patients receiving hematopoietic growth factor support, including erythropoietin, darbepoetin, G-CSF, GM-CSF, and platelet stimulators (e.g., eltrombopag, romiplostim, or interleukin-11) must have a 2-week interval between growth factor support and the Screening assessments, but they may receive growth factor support during the study. 10\. Patients must have: * At least a 2-week interval from the last red blood cell (RBC) transfusion prior to the start of study treatment * At least a 1-week interval from the last platelet transfusion prior to the start of study treatment * However, patients may receive RBC and/or platelet transfusions as clinically indicated per institutional guidelines during the study 11. Female patients of childbearing potential (FCBP) must have a negative serum pregnancy test at Screening. Female patients of childbearing potential and fertile male patients who are sexually active must use highly effective methods of contraception throughout the study and for one month following the last dose of study treatment. Male patients must agree not to donate sperm during the study treatment period. Specifically: * FCBP† must have a negative serum or urine pregnancy test with a sensitivity of at least 25 mIU/mL within 10 - 14 days prior to and again within 24 hours of starting treatment and must either commit to continued abstinence from heterosexual intercourse or use 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 therapy. FCBP must also agree to ongoing pregnancy testing. Men must agree to use a latex condom during sexual contact with a FCBP 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. † A FCBP (female 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) 12. Able to take antiplatelet therapy if platelet count is above 30 x 109/L. Options include aspirin (acetylsalicylic acid, ASA) at 81 or 325/mg/daily, warfarin low molecular weight hepairin, Pradaza, Eliquis, or Xarelto. 13\. Patients with history of human immunodeficiency virus (HIV) are eligible if they have CD4+ T cell counts ≥350 cells/µL, negative viral load per institutional standard, and no history of acquired immunodeficiency syndrome (AIDS)-defining opportunistic infections in the last year. 14\. Patients with untreated hepatitis C virus (HCV) are eligible if there is a documentation of negative viral load per institutional standard. 15\. Age ≥ 18 years of age. 16. Willing and able to provide written informed consent in accordance with federal, local, and institutional guidelines. The patient must provide informed consent prior to the first screening procedure. 17\. 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 |
|---|---|---|
| 1. Maximum Tolerated Dose (MTD): | 30 months | ● A standard 3 + 3 dose escalation schedule will be used for all escalations |
| 2. Recommended phase 2 dose (RP2D) | 30 months | Primary objective of a phase 1 study is to define a safe and tolerable dose to use in further studies designed to determine efficacy, the Recommended Phase 2 Dose (RP2D) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 1. Overall Response Rate ([ORR]=CR+VGPR+PR) | 30 months | ORR is a measure of how many patients in a study experience a significant reduction or complete disappearance of their cancer following treatment, essentially indicating the percentage of patients who have a partial or complete response to the therapy being tested. ORR is calculated by adding the number of patients with a Complete Response + Very Good Partial Response + Partial Response. |
| 2. Clinical Benefit Rate ([CBR]=CR+VGPR+PR+MR) | 30 months | The percentage of patients with advanced cancer who experience a complete or partial response to a treatment. CBR is calculated by adding the number of patients with Complete Response (CR) + Very Good Partial Response (VGPR) + Partial Response (PR) + Minor Response. |
| 3. To determine disease parameters for study treatment: | 30 months | * Time to progression (TTP) - define as the time from the initiation of therapy to progressive disease * Progression-free survival (PFS) - defined as the time from initiation of therapy to progressive disease or death from any cause, whichever occurs first * Time to first response - defined as the time from the initiation of therapy to the first evidence of confirmed clinical benefit defined as \> minimal response (MR, including patients who achieved a complete response (CR), very good partial response (VGPR), partial response (PR), or MR * DOR - defined as the time from the first response to progressive disease * Overall survival (OS) - Overall survival, defined as the time from initiation of therapy to death from any cause or last follow-up visit |
Other
| Measure | Time frame | Description |
|---|---|---|
| Background and rationale for assessment of serum B cell maturation antigen levels (sBCMA) | 30 months | Only for MM patients participating in the optional biomarker including sBCMA analysis study. To evaluate the ability of MM-related biomarkers including sBCMA, to serve as: * Diagnostic biomarker by determining specificity and sensitivity in MM patients * Prognostic biomarker by determining its ability to predict the probable course of the disease including its recurrence. * Stratification biomarker by examining its ability to predict clinical outcomes of MM patients |
Countries
United States
Contacts
Primary ContactRichard Bailey
Backup ContactYohana Sebhat
Outcome results
None listed