Selinexor and Backbone Treatments of Multiple Myeloma Patients
Title: A Phase 1b/2 Study of Selinexor (KPT-330) in Combination with Backbone Treatments for Resistant/Refractory Multiple Myeloma Lay Title: This study will independently assess the efficacy and safety of three combination therapies (with dose escalations in each arm) for the treatment of patients with relapsed/refractory multiple myeloma (RR MM). The combinations are: a) selinexor + dexamethasone + pomalidomide (SdP) b) selinexor + dexamethasone + bortezomib (SdB) c) selinexor + dexamethasone + lenalidomide (SdL)
Selinexor (KPT-330) is a first-in-class, oral, drug that has shown potent anti-myeloma activity in preclinical studies of MM and in an ongoing Phase 1 clinical study. There are two steps in this study, a Âdose-escalation phaseÂ and an Âexpansion phase.Â The dose-escalation phase is used to the best dose of these drugs and the best treatment schedule, based on how well the therapies work together and how safe they are when they are given together. The expansion phase will be used to see how well the best dose from the first phase works when given to a larger group of patients.
During screening, the study doctor will do a physical exam. The patient will have a skeletal survey done with x-ray in order to looks for soft tissue growths called plasmocytomas. The patient will have a bone marrow aspirate to see if the cancer has spread to the bone marrow. The patient will have blood samples and urine samples collected for routine test. The patient will have an eye examination, an electrocardiogram, and an echocardiogram.
If the patient qualifies for the study and chooses to participate they will return to the clinic on cycle 1 days 1, 8 and 15. On those days they will have blood collected for routine tests and physical exams done. They will also have blood collected for review of how drug is affecting their body. They may also have additional review of their urine and skeletal survey. On cycle 2, the patients will return on days 1 and 15. On those days they will have physical exams, urine and blood collected. They may also have skeletal survey done again if the doctor feels it is needed. They will also have bone marrow aspirate collected to see disease progression and a bone marrow biopsy may be done to better understand the myeloma. During the phase 1 portion of the study, additional blood samples will be collected to see how the drug is affecting the body. On cycle 3 and on, patients will return on day 1 where the patient will receive a physical exam, they will provide blood samples, urine samples, and bone marrow aspirate. They may also have skeletal survey done again if the doctor feels it is needed.
On the end of treatment visit, the patients will have physical exams, eye exams and will have blood and urine collected for routine tests. They may also have skeletal survey done again if the doctor feels it is needed.
Once off the treatment, patients will be contacted every 3 months and if their MM is not getting worse they will be asked to provide blood and urine samples, a bone marrow aspirate (and optionally a biopsy). If they had plasmocytomas they will be asked to undergo skeletal survey again to look for additional plasmocytomas. There is no maximum treatment limit and the patients may stay on the study drug for the extent of the st
Subjects who are 18 years old at the time of informed consent and have been diagnosed with Multiple Myeloma (MM) that has either come back or has not responded to treatment. For more information about the eligibility criteria for this trial, refer to the Health Professional version.
- Written informed consent signed in accordance with federal, local, and institutional guidelines.
- Age greater than or equal to (≥) 18 years at the time of informed consent.
- Histologically confirmed diagnosis with measurable disease for relapsed/refractory myeloma.
- Symptomatic MM, based on IMWG guidelines.
- Patients must have measurable disease as defined by at least one of the following:
- Serum M-protein ≥ 0.5 gram per deciliter (g/dL) by serum protein electrophoresis (SPEP) or, for immunoglobulin A (IgA) myeloma, by quantitative IgA
- Urinary M-protein excretion at least 200 mg/24 hours
- Serum free light chain (FLC) ≥ 100 milligram per liter (mg/L), provided that FLC ratio is abnormal
- If SPEP is felt to be unreliable for routine M-protein measurement (example, for IgA MM), then quantitative immunoglobulin (Ig) levels by nephelometry or turbidometry are acceptable
- Any non-hematological toxicities (except for peripheral neuropathy as described in exclusion criterion #22) that patients had from treatments in previous clinical studies must have resolved to less than or equal (≤) Grade 2 by C1D1.
- Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤ 2.
- Adequate hepatic function within 28 days prior to C1D1:
- For SPd, SRd, and SPEd: Total bilirubin < 2* upper limit of normal (ULN) (except patients with Gilbert's syndrome [hereditary indirect hyperbilirubinemia] who must have a total bilirubin of ≤ 3* ULN) and both aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 2.5* ULN
- For SVd, SPVd, SDd, SNd, SBd and SDPd: Total bilirubin of < 1.5* ULN (except patients with Gilbert's syndrome [hereditary indirect hyperbilirubinemia] who must have a total bilirubin of ≤ 3* ULN) and both AST and ALT < 2.0* ULN
- For SKd: Total bilirubin < 2* ULN (except patients with Gilbert's syndrome [hereditary indirect hyperbilirubinemia] who must have a total bilirubin of ≤ 3* ULN) and both AST and ALT < 3.0* ULN
- Adequate renal function within 28 days prior to C1D1. Estimated creatinine clearance
(CrCl) calculated using the formula of Cockroft and Gault (1976):
- ≥ 20 milliliter per minute (mL/min) for SVd, SDd, and SKd arms
- ≥ 30 mL/min for SNd and SBd arms
- ≥ 45 mL/min for SPd, SPVd, SPEd and SDPd arms
60 mL/min for SRd arm
- Adequate hematopoietic function within 28 days prior to C1D1: total white blood cell
(WBC) count ≥ 1,500/millimeter cube (mm^3), absolute neutrophil count (ANC) ≥
1,000/mm^3, hemoglobin (Hb) ≥ 8.0 g/dL, and platelet count ≥ 100,000/mm^3.
- SPVd (Arm 4) and SKd (Arm 6) only: platelet count ≥150,000.
- Female patients of childbearing potential must have a negative serum pregnancy test at Screening. Female patients of childbearing potential and fertile male patients must use highly effective methods of contraception throughout the study and for 1 week following the last dose of study treatment. SPd (Arm 1) Only:
- Relapsed or refractory MM with:
- Documented evidence of progressive disease (PD) after achieving at least stable disease (SD) for ≥ 1 cycle during a previous MM regimen (i.e., relapsed MM)
- ≤ 25 percent (%) response (i.e., patients never achieved ≥ MR) or PD during or within 60 days from the end of the most recent MM regimen (i.e., refractory MM)
- Previously undergone ≥ 2 cycles of lenalidomide and a PI (in separate therapeutic regimens [not for maintenance] or in combination)
- In the expansion arm at RP2D, patients must not be pomalidomide refractory SVd (Arm 2) Only:
- Relapsed or refractory MM with:
- Documented evidence of relapse after ≥ 1 previous line of therapy
- Not refractory to bortezomib in their most recent line of therapy SRd in RRMM (Arm 3) Only:
- Patients who received ≥ 1 prior therapeutic regimen (prior lenalidomide is allowed as long as patient's MM was not refractory to prior lenalidomide; patients whose MM was refractory to lenalidomide maintenance regimens will be allowed in this cohort). SPVd (Arm 4) Only:
- Patients who received 1- 3 prior lines of therapy, including ≥ 2 cycles of lenalidomide and have demonstrated disease progression on their last therapy (may include prior bortezomib, as long as the patient's MM was not refractory to bortezomib therapy), but patients must be pomalidomide-naïve in the Dose Expansion at RP2D (Cohort 4.3 ONLY). SDd (Arm 5) Only:
- Patients who received ≥ 3 prior lines of therapy, including a PI and an immunomodulatory agent (IMiD), or patients with MM refractory to both a PI and an IMiD.
- Patients must not have received prior anti-cluster of differentiation 38 (anti-CD38) monoclonal antibodies (Cohort 5.3 ONLY - Dose Expansion at RP2D). SKd (Arm 6) Only:
- Patients may have received prior PIs; however, their MM must NOT be refractory to carfilzomib. SRd in NDMM (Arm 7) Only:
- Patients must have symptomatic myeloma per IMWG guidelines with either CRAB criteria (calcium elevation, renal failure, anemia, lytic bone lesions) or myeloma-defining events and need systemic therapy. No prior systemic therapy for NDMM is permitted other than pulse dose dexamethasone (maximum dose of 160 mg) or corticosteroid equivalent. SNd (Arm 8) Only:
- Patients must have MM that relapsed after 1 - 3 prior lines of therapy (may not include those with MM refractory to bortezomib or carfilzomib but patients must be ixazomib-naïve). SPEd (Arm 9) Only:
- Patients who received ≥ 2 prior therapies, including lenalidomide and a proteasome inhibitor (in separate or the same regimens), but patients must be pomalidomide-naive and elotuzumab-naive in the Dose Expansion at RP2D (Cohort 9.3 ONLY). SBd (Arm 10) Only:
- Patients who have MM that was refractory to an IMiD, a proteasome inhibitor, and refractory or intolerant (or both) to an anti-CD38 monoclonal antibody. Patients must be belantamab mafodotin-naive in the Dose Expansion cohort at RP2D (Cohort 10.3 ONLY). SDPd (Arm 11) Only: Patients who received 1-3 prior therapies, including lenalidomide and a proteasome inhibitor (in separate or the same regimen), but patients must be pomalidomide-naive and daratumumab-naive in the Dose Expansion cohort at RP2D (Cohort 11.3 ONLY).
Patients meeting any of the following exclusion criteria are not eligible to enroll in this
- Smoldering MM.
- MM that does not express M-protein or FLC (i.e., non-secretory MM is excluded), and quantitative immunoglobulin levels cannot be used instead.
- Documented active systemic amyloid light chain amyloidosis.
- Active plasma cell leukemia.
- Red Blood Cell (RBC) and platelet transfusions and blood growth factors within 14 days of C1D1.
- Radiation, chemotherapy, or immunotherapy or any other anticancer therapy ≤ 2 weeks prior to C1D1, and radio-immunotherapy within 6 weeks prior to C1D1. Patients on long-term glucocorticoids during Screening do not require a washout period. Prior radiation is permitted for treatment of fractures or to prevent fractures as well as for pain management.
- Patients with history of spinal cord compression with residual paraplegia (Dose Escalation Phase only).
- Treatment with an investigational anti-cancer therapy within 3 weeks prior to C1D1.
- Prior autologous stem cell transplantation < 1 month, or allogeneic stem cell transplantation < 3 months prior to C1D1.
- Active graft versus host disease after allogeneic stem cell transplantation.
- Life expectancy < 3 months.
- Major surgery within 4 weeks prior to C1D1.
- Active, unstable cardiovascular function:
- Symptomatic ischemia, or
- Uncontrolled clinically-significant conduction abnormalities (e.g., patients with ventricular tachycardia on antiarrhythmics are excluded; patients with 1st degree atrioventricular (AV) block or asymptomatic left anterior fascicular block/right bundle branch block (LAFB/RBBB) will not be excluded), or
- Congestive heart failure (CHF) of New York Heart Association (NYHA) Class ≥ 3, or
- Myocardial infarction (MI) within 3 months prior to C1D1
- Ejection fraction (EF) < 50% at Screening
- Uncontrolled active hypertension.
- Uncontrolled active infection requiring parenteral antibiotics, antivirals, or antifungals within one week prior to first dose.
- Known active hepatitis A, B or C.
- Known human immunodeficiency virus (HIV) infection or HIV seropositivity.
- Any active gastrointestinal dysfunction that prevents the patient from swallowing tablets or interferes with absorption of study treatment.
- Currently pregnant or breastfeeding.
- A serious active psychiatric or active medical condition which, in the opinion of the Investigator, could interfere with treatment.
- Hypersensitivity to any of the treatments for the arm in which the patient is enrolled.
- SVd Arm (Arm 2), SPVd (Arm 4), and SNd Arm (Arm 8) only: Prior history of neuropathy Grade > 2, or Grade ≥ 2 neuropathy with pain at Screening (within 28 days prior to C1D1).
- Patients who are eligible for the selinexor PK Run-in only: Treatment with moderate or strong inhibitors/inducers of CYP3A within 7 days prior to Day 1 of the PK Run-in period.
- Patients who are eligible for the selinexor PK Run-in only: Not able to receive a strong CYP3A4 inhibitor due to concomitant medications.
- SKd arm only: HBs Ag + plus HBc Ab + even though no active hepatitis B virus (HBV) hepatitis. If HBs Ag - plus HBc Ab +, treating physician needs to contact the medical monitor.
- Prior exposure to a selective inhibitor of nuclear export (SINE) compound, including selinexor. SBd (Arm 10): Only:
- Current corneal epithelial disease except mild punctate keratopathy.
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