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A Study of Selinexor, in Combination With Carfilzomib, Daratumumab or Pomalidomide in Patients With Multiple Myeloma

NCT04661137

Description:

This is a prospective, 2-arm (with an additional exploratory arm), open-label, multicenter study looking at the response rate of patients receiving selinexor (KPT-330), in combination with carfilzomib, daratumumab or pomalidomide. Multiple Myeloma patients with documented disease progression or refractory disease while on current treatment with any carfilzomib-containing regimen (arm 1), any pomalidomide-containing regimen (arm 2) or any daratumumab-containing regimen (exploratory arm) will be included in the study. Patients will be assigned to the respective groups according to their current treatment. If a subject has received more than one of the above therapies, then assignment will be made at their physician's discretion (e.g treatment decision can be made based upon patient and physician preferred tolerance.). Patients will receive treatment until progressive disease (PD), death, toxicity that cannot be managed by standard of care, or withdrawal, whichever occurs first.

Related Conditions:
  • Multiple Myeloma
Recruiting Status:

Not yet recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: A Study of Selinexor, in Combination With Carfilzomib, Daratumumab or Pomalidomide in Patients With Multiple Myeloma
  • Official Title: A Phase 2B Study of Selinexor (KPT-330), in Combination With Carfilzomib, Daratumumab or Pomalidomide in Patients With Multiple Myeloma Relapsing on Current Therapy

Clinical Trial IDs

  • ORG STUDY ID: Pro2019-0125
  • SECONDARY ID: IST-318
  • NCT ID: NCT04661137

Conditions

  • Multiple Myeloma

Interventions

DrugSynonymsArms
Selinexor 60 MGKPT-330Pomalidomide-containing Regimen
Selinexor 80 MGKPT-330Carfilzomib-containing Regimen
Selinexor 100 MGKPT-330Exploratory/Daratumumab-containing Regimen
CarfilzomibKyprolisCarfilzomib-containing Regimen
PomalidomidePomalystPomalidomide-containing Regimen
DaratumumabDarzalexExploratory/Daratumumab-containing Regimen
DexamethasoneDextenza, Ozurdex, Neofordex, othersCarfilzomib-containing Regimen

Purpose

This is a prospective, 2-arm (with an additional exploratory arm), open-label, multicenter study looking at the response rate of patients receiving selinexor (KPT-330), in combination with carfilzomib, daratumumab or pomalidomide. Multiple Myeloma patients with documented disease progression or refractory disease while on current treatment with any carfilzomib-containing regimen (arm 1), any pomalidomide-containing regimen (arm 2) or any daratumumab-containing regimen (exploratory arm) will be included in the study. Patients will be assigned to the respective groups according to their current treatment. If a subject has received more than one of the above therapies, then assignment will be made at their physician's discretion (e.g treatment decision can be made based upon patient and physician preferred tolerance.). Patients will receive treatment until progressive disease (PD), death, toxicity that cannot be managed by standard of care, or withdrawal, whichever occurs first.

Detailed Description

      This is a Phase 2b, two-arm, open-label, multicenter study of Sd (selinexor 100, 80 or 60 mg)
      in combination with carfilzomib, or pomalidomide in patients with MM previously treated with
      carfilzomib or pomalidomide respectively, and refractory to prior treatment. An additional
      exploratory arm will focus on patients treated with SD in combination with daratumumab.

      This study will enroll approximately 96 patients overall (43 in each of the arms and 10
      additional patients in the exploratory arm. Patients will be assigned to the respective arms
      based on their previous treatment.

      Patients who are relapsed or refractory to their current carfilzomib-based regimen will be
      enrolled on Arm 1 and will receive the following treatment regimen on a 28-day cycle:

      Carfilzomib 56 mg/m2 on days 1, 8 and 15. They will also receive dexamethasone 40 mg (or 20
      mg if patient is ≥ 75 years old) once weekly and Selinexor 80 mg on days 1, 8 and 15.

      Patients who are relapsed or refractory to their current pomalidomide-based regimen will be
      enrolled on Arm 2 and will receive the following treatment regimen on a 28-day cycle:

      Pomalidomide 4 mg po daily for 21 days combined with Dexamethasone 40 mg (or 20 mg if patient
      is ≥ 75 years old) once weekly and Selinexor 60 mg days 1, 8 and 15.

      For arms 1 and 2, 13 patients will be accrued in each arm in the first stage. If there are 3
      or fewer responses in these 13 patients, the study will be stopped. Otherwise, 30 additional
      patients will be accrued for a total of 43 (in each arm).

      Finally, in the exploratory arm, we will enroll up to 10 patients who are relapsed or
      refractory to their current daratumumab-based regimen. Patients enrolled on the exploratory
      arm will receive the following treatment regimen on a 28-day cycle:

      Daratumumab on current schedule (16 mg/kg IV days 1,8,15,22 for cycles 1-2; days 1 and 15 for
      cycles 3-6; day 1 for cycle 7 and on) combined with Dexamethasone 40 mg once weekly (or 20 mg
      if patient is ≥ 75 years old) and Selinexor 100 mg once weekly.

      The Investigator may remove a patient from study treatment using criteria described in
      Section 10.2. Patients may decide to discontinue study treatment for any reason. Patients who
      elect to discontinue study treatment should be encouraged to continue in the study so that
      follow-up information on disease progression, other antineoplastic therapy, symptoms and
      survival status may be obtained. However, patients may elect to withdraw consent and decline
      further participation in the trial at any time.

      The Investigator must determine the primary reason for a patient's discontinuation of study
      treatment and record this information on the electronic case report form (eCRF). Patients who
      are prematurely withdrawn from study treatment are not eligible to re-initiate study
      treatment on this protocol at a later date.
    

Trial Arms

NameTypeDescriptionInterventions
Carfilzomib-containing RegimenExperimentalCarfilzomib 56 mg/m2 on days 1, 8 and 15. Dexamethasone 20 mg if ≥ 75 years old and 40 mg if < 75 years old on days 1, 8, 15 and 22. Selinexor 80 mg on days 1, 8 and 15.
  • Selinexor 80 MG
  • Carfilzomib
  • Dexamethasone
Pomalidomide-containing RegimenExperimentalPomalidomide 4 mg po daily for 21 days. Dexamethasone 20 mg if ≥ 75 years old and 40 mg if < 75 years old on days 1, 8, 15 and 22. Selinexor 60 mg on days 1, 8 and 15.
  • Selinexor 60 MG
  • Pomalidomide
  • Dexamethasone
Exploratory/Daratumumab-containing RegimenExperimentalDaratumumab on current schedule (16 mg/kg IV days 1, 8, 15 and 22 for cycles 1-2; days 1 and 15 for cycles 3-6; day 1 for cycle 7 and on). Dexamethasone 20 mg if ≥ 75 years old and 40 mg if < 75 years old on days 1, 8, 15 and 22. Selinexor 100 mg on days 1, 8, 15 and 22.
  • Selinexor 100 MG
  • Daratumumab
  • Dexamethasone

Eligibility Criteria

        Inclusion Criteria:

          1. Age ≥18 years at time of informed consent.

          2. Histologically confirmed MM and evidence of disease progression while on one of the
             below MM regimens:

               -  Arm 1: Refractory to or disease progression while on a carfilzomib-containing
                  regimen

               -  Arm 2: Refractory to or disease progression while on a pomalidomide-containing
                  regimen

               -  Exploratory Arm: Refractory to or disease progression while on a
                  daratumumab-containing regimen

          3. Measurable disease as defined: Serum M-protein ≥ 0.5 g/dL; urine M-protein excretion
             at least 200 mg/24h; serum FLC ≥ 100 mg/L, provided that FLC is abnormal; if serum
             protein electrophoresis is felt to be unreliable for routine M-protein measurement
             (i.e. IgA MM) then quantitative Ig levels by nephelometry or turbidometry are
             acceptable; for non-secretory disease, bone marrow plasma cells ≥ 20% or a
             biopsy-proven target lesion by PET/CT or MRI is acceptable

          4. Documented evidence of disease progression (by IMWG criteria) or refractory disease on
             the current treatment as defined as:

               -  Achieving SD or less for ≥ 1 cycle during treatment with regimens stated in #2
                  (i.e. relapsed) OR

               -  <25% response (i.e. never achieved MR) or PD during or within 60 days from the
                  end-of most recent MM regimen as listed in #2 (i.e. refractory).

          5. Any non-hematological toxicities (except for peripheral neuropathy) that patients
             experienced from treatments in previous regimens have resolved to Grade 2 or less by
             Cycle 1 Day 1.

          6. ECOG 2 or less

          7. Adequate hepatic function within 28 days prior to C1D1:

               1. 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

               2. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) normal to <2
                  × ULN.

          8. Adequate renal function within 28 days prior to C1D1 as determined by estimated
             creatinine clearance of ≥ 30 mL/min, calculated using the Cockcroft and Gault formula
             (140 - Age) • Mass (kg)/ (72 • creatinine mg/dL); multiply by 0.85 if female
             (Cockcroft 1976).

          9. Adequate hematopoietic function within 7 days prior to C1D1: total white blood cell
             (WBC) count ≥1500/mm3, absolute neutrophil count ≥1000/mm3, hemoglobin ≥8.5 g/dL and
             platelet count ≥75,000/mm3 (patients for whom <50% of bone marrow nucleated cells are
             plasma cells) or ≥50,000/mm3 (patients for whom ≥50% of bone marrow nucleated cells
             are plasma cells).

               1. Patients receiving hematopoietic growth factor support, including erythropoietin,
                  darbepoetin, granulocyte-colony stimulating factor (G-CSF), granulocyte
                  macrophage-colony stimulating factor (GM-CSF), and platelet stimulators (eg,
                  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.

               2. Patients must have:

                    -  At least a 2-week interval from the last red blood cell (RBC) transfusion
                       prior to the Screening hemoglobin assessment, and

                    -  At least a 1-week interval from the last platelet transfusion prior to the
                       Screening platelet assessment.

             However, patients may receive RBC and/or platelet transfusions as clinically indicated
             per institutional guidelines during the study.

         10. Female patients of childbearing potential must have a negative serum pregnancy test at
             Screening. Female patients of childbearing potential and fertile male patients who are
             sexually active with a female of childbearing potential must use highly effective
             methods of contraception throughout the study and for 3 months following the last dose
             of study treatment.

        Exclusion Criteria:

          -  Patients meeting any of the following exclusion criteria are not eligible to enroll in
             this study:

               1. Smoldering MM

               2. Radiation therapy, chemotherapy or immunotherapy other than above stated regimens
                  in #2 ≤2 weeks prior to C1D1. Patients on long-term glucocorticosteroids during
                  screening do not require a washout period. Prior RT is permitted for treatment of
                  fractures or to prevent fractures as well as for pain management.

               3. Active graft versus host disease after allogeneic stem cell transplant.

               4. Life expectancy <3 months.

               5. Known active hepatitis A, B, or C infection; or known to be positive for
                  hepatitis C virus ribonucleic acid (RNA) or hepatitis B virus surface antigen.

               6. Has any concurrent medical condition or disease (eg, uncontrolled active
                  hypertension, uncontrolled active diabetes, active systemic infection, etc.) that
                  is likely to interfere with study procedures.

               7. Uncontrolled active infection requiring parenteral antibiotics, antivirals, or
                  antifungals within 1 week prior to Cycle 1 Day 1 (C1D1). Patients on prophylactic
                  antibiotics or with a controlled infection within 1 week prior to C1D1 are
                  acceptable.

               8. Known intolerance, hypersensitivity, or contraindication to glucocorticoids.

               9. Pregnant or breastfeeding females.

              10. Body surface area (BSA) <1.4 m2 at baseline, calculated by the Dubois (Dubois
                  1916) or Mosteller (Mosteller 1987) method.

              11. Any active gastrointestinal dysfunction interfering with the patient's ability to
                  swallow tablets, or any active gastrointestinal dysfunction that could interfere
                  with absorption of study treatment.

              12. Inability or unwillingness to take supportive medications such as anti-nausea and
                  anti-anorexia agents as recommended by the National Comprehensive Cancer Network®
                  (NCCN) Clinical Practice Guidelines in Oncology (CPGO) (NCCN CPGO) for antiemesis
                  and anorexia/cachexia (palliative care).

              13. Any active, serious psychiatric, medical, or other conditions/situations that, in
                  the opinion of the Investigator, could interfere with treatment, compliance, or
                  the ability to give informed consent.

              14. Contraindication to any of the required concomitant drugs or supportive
                  treatments.

              15. Patients unwilling or unable to comply with the protocol
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Overall Response Rate (ORR) of patients receiving selinexor with carfilzomib and dexamethasone (Arm 1)
Time Frame:30 Months
Safety Issue:
Description:ORR will include patients who experience partial response (PR), very good partial response (VGPR), complete response (CR), or stringent complete response (sCR), based on International Myeloma Working Group (IMWG) response criteria (Kumar 2016)

Secondary Outcome Measures

Measure:Progression Free Survival (PFS)
Time Frame:30 Months
Safety Issue:
Description:Duration from start of study treatment to PD or death [regardless of cause], whichever comes first
Measure:Overall Survival (OS)
Time Frame:30 Months
Safety Issue:
Description:Duration from start of study treatment to death
Measure:MRD Negativity
Time Frame:30 Months
Safety Issue:
Description:Rate of achievement of minimal residual disease (MRD) by multiparametric flow cytometry
Measure:Safety and Tolerability
Time Frame:30 Months
Safety Issue:
Description:Safety and tolerability using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), v 4.03.
Measure:Time To Next Treatment (TTNT)
Time Frame:30 Months
Safety Issue:
Description:Duration from start of study treatment to next treament

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Hackensack Meridian Health

Trial Keywords

  • Selinexor
  • KPT-330

Last Updated

December 10, 2020