Clinical Trials /

Selinexor Treatment for Multiple Myeloma Patients Who Are Refractory to Lenalidomide-containing Therapy.

NCT04519476

Description:

This is a pilot study evaluating the safety and efficacy of selinexor among multiple myeloma (MM) patients that are refractory to lenalidomide-containing regimens with or without steroids.

Related Conditions:
  • Multiple Myeloma
Recruiting Status:

Not yet recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Selinexor Treatment for Multiple Myeloma Patients Who Are Refractory to Lenalidomide-containing Therapy.
  • Official Title: A Pilot Study Examining Selinexor's Ability to Overcome Resistance in Multiple Myeloma Patients Who Are Refractory to Lenalidomide-containing Therapy.

Clinical Trial IDs

  • ORG STUDY ID: IST-321
  • NCT ID: NCT04519476

Conditions

  • Refractory Multiple Myeloma

Interventions

DrugSynonymsArms
SelinexorKPT-330Selinexor/Lenalidomide/Steroids
LenalidomideRevlimidSelinexor/Lenalidomide/Steroids
MethylprednisoloneMedrolSelinexor/Lenalidomide/Steroids

Purpose

This is a pilot study evaluating the safety and efficacy of selinexor among multiple myeloma (MM) patients that are refractory to lenalidomide-containing regimens with or without steroids.

Detailed Description

      This is a pilot, multi-center, open-label study evaluating selinexor's ability to overcome
      resistance for multiple myeloma patients who are refractory to lenalidomide-containing
      therapies.

      Enrollment:

      The study will enroll up to a total of 22 Multiple Myeloma (MM) patients with progressive
      disease.

      Study Assessments:

      The study will consist of:

        1. screening period;

        2. study treatment until disease progression or intolerable toxicity;

        3. a final assessment to occur up to 28 days after the end of the last treatment cycle; and

        4. follow-up period.

      The screening period will be conducted within 14 days before baseline (baseline being day 1
      of cycle 1, before study drug administration). During this period, a medical history will be
      obtained along with complete physical examination including vital signs measurements, height,
      weight, Eastern Cooperative Oncology Group (ECOG) performance status, and 12-lead
      electrocardiogram (EKG). MM assessments will be performed, including β2 microglobulin (β2M),
      serum free light chain (SFLC) serum and urine protein electrophoresis, quantification of
      serum immunoglobulins, urine and serum immunofixation, and 24-hour total protein. An
      additional serum sample will be obtained for evaluation of biomarkers. In addition, a
      postero-anterior and lateral chest radiographs, skeletal survey, and a bone marrow aspirate
      (BM) and biopsy will be performed within 28 days of baseline. Clinical laboratory tests
      including hematology, clinical chemistry (blood urea nitrogen [BUN], serum creatinine, uric
      acid, lactate dehydrogenase [LDH], total bilirubin, alkaline phosphatase, aspartate
      aminotransferase [AST] and alanine aminotransferase [ALT]), electrolytes (potassium, sodium,
      chloride and calcium), random glucose, total protein, amylase, albumin, and urinalysis as
      well as serum pregnancy tests for females of child-bearing potential (FCBPs). Subjects will
      also be asked to fill out quality of life assessments at several time points during this
      study.

      Subjects eligible for this study will receive treatment with study drug until disease
      progression or intolerable toxicity does not allow ongoing treatment.

      Assessments:

      Schedule of assessments: Subjects that meet the inclusion/exclusion criteria during the
      screening period will continue to Day 1 of Cycle 1, when baseline evaluations will be
      conducted. Subjects who continue to meet the inclusion/exclusion criteria will be enrolled in
      the trial and study drug will be administered. During Cycle 1, subjects will also have study
      visits during which assessments will be performed on Days 8, 15 and 22. MM assessments will
      be performed on Day 22 during all subsequent cycles. Starting with Cycle 2, study visits will
      take place on Days 1 and 22. See Table 1

      Assessment overview: During the treatment period, each subject will have clinical laboratory
      tests performed to monitor for potential toxicity. Additional procedures performed at these
      visits will include monitoring for adverse events (AEs), review of concomitant medications
      and other support therapies (e.g. growth factors and transfusion), MM disease assessments,
      ECOG performance status, vital signs measurements, and physical examination. Subjects will
      remain on study until documentation of progressive disease (PD) as defined by the
      International Myeloma Working Group (IMWG) criteria. Subjects with stable disease will remain
      in the study. For subjects who show disappearance of urine and serum M-protein by protein
      electrophoresis and immunofixation on 2 consecutive assessments and the subject shows no
      other signs of disease activity, a bone marrow (BM) aspirate and biopsy will be required to
      confirm their CR. A BM aspirate and biopsy will not be required for subjects in any other
      response group categories.

      Up to twenty-eight days after the last dose of study drug, subjects are to complete a final
      assessment (herein referred to as the End-of-Study treatment visit). Procedures to be
      conducted at this visit include a MM disease assessment, measurement of vital signs and
      weight, a complete physical examination, assessment of adverse events, a review of
      concomitant medications, assessment of ECOG performance status, hematology and clinical
      chemistry laboratory tests including electrolytes, total protein, amylase and albumin, and an
      assessment of response to treatment with the use of SFLC assay and ratio, serum and urine
      protein electrophoresis, quantification of serum immunoglobulins, urine and serum
      immunofixation, 24-hour total urine protein, and serum β2M. Subjects who withdraw from the
      study before the completion of the eight 28-day cycle evaluation periods will have all End-
      of-Study treatment assessments performed at their final visit.

      Following the End-of-Study treatment visit, subjects will be monitored for PD and survival by
      clinic visits every 3 months and every 6 months, respectively, until alternate therapy needs
      to be started or death intervenes.

      Dosing Regimens:

      All subjects enrolled will receive (Dose Level 0) 1) selinexor, PO, at 60 mg once weekly on
      days 1, 8, 15, and 22 of a 28-days cycle, 2) lenalidomide, PO, 10 mg daily on days 1-21 of a
      28-day cycle and 3) steroids at the same dose and schedule as the last
      lenalidomide-containing regimen if it contained steroids that they had failed to meet
      eligibility for this study.

      Recommended Concomitant Therapy:

      Subjects may receive full supportive care, including hydration prophylaxis, treatment with a
      5-HT3 antagonist and/or other anti-nausea agents, antibiotics, antivirals, vitamins, and
      supplements as appropriate. Patients should receive anti-platelet therapy with baby aspirin
      or other agents if they have additional risk factors for developing thrombotic events.

      Number of Patients (planned): 22

      Study Population: Multiple myeloma patients who are refractory to a lenalidomide-containing
      therapy
    

Trial Arms

NameTypeDescriptionInterventions
Selinexor/Lenalidomide/SteroidsExperimentalAll subjects enrolled will receive: 1) selinexor, PO, at 60 mg once weekly on days 1-28 of a 28-day cycle, 2) lenalidomide, PO, 10 mg daily on days 1-21 of 28-days cycle and 3) methylprednisolone at the same dose and schedule as the last lenalidomide-containing regimen if it contained steroids. If patient's qualifying lenalidomide-containing regimen contained different type of steroid (e.g. prednisone, dexamethasone, etc.) then patient on this study will receive methylprednisolone at the equivalent dose and schedule.
  • Selinexor
  • Lenalidomide
  • Methylprednisolone

Eligibility Criteria

        Inclusion Criteria:

          -  Patients must meet all of the following inclusion criteria to be eligible to enroll in
             this study:

               1. Age ≥ 18 year of age.

               2. 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.

               3. Able to adhere to the study visit schedule and other protocol requirements.

               4. ECOG Performance Status (PS) of ≤ 2.

               5. Has a diagnosis of MM based on standard criteria (9) as follows:

        Major criteria:

          1. Plasmacytomas on tissue biopsy.

          2. Bone marrow plasmacytosis (greater than 30% plasma cells).

          3. Monoclonal immunoglobulin spike on serum electrophoresis IgG greater than 3.5 g/dL or
             IgA greater than 2.0 g/dL or kappa or lambda light chain excretion greater than 1
             g/day on 24-hour urine protein electrophoresis.

        Minor criteria:

          1. Bone marrow plasmacytosis (10% to 30% plasma cells).

          2. Monoclonal immunoglobulin present but of lesser magnitude than given under major
             criteria.

          3. Lytic bone lesions.

          4. Normal IgM less than 50 mg/dL, IgA less than 100 mg/dL, or IgG less than 600 mg/dL.

             Any of the following sets of criteria will confirm the diagnosis of multiple myeloma:

             • any 2 of the major criteria

             • major criterion 1 plus minor criterion 2, 3, or 4

             • major criterion 3 plus minor criterion 1 or 3

             • minor criteria 1, 2, and 3, or 1, 2, and 4

        6. 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 7. 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 8 weeks 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 8. Previous exposure to lenalidomide: failed
             lenalidomide (> 10 mg)-containing regimen (lenalidomide- containing regimen could be
             any prior regimen and is not required to be a part of their most recent treatment) and
             have received a proteasome inhibitor, an immunomodulatory agent and an anti-CD38
             antibody therapy.

             9. Adequate hepatic function within 28 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.

             10. Adequate renal function within 28 days prior to C1D1 as determined by serum
             creatinine of ≤1.5 mg/dL 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 (10)(Appendix 5).

             11. Adequate hematopoietic function within 7 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).

             12. 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.

             13. 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 14. Patients must be registered into the
             mandatory REVLIMID REMS™ program and be willing and able to comply with the
             requirements of the REVLIMID REMS™ program.

             15. 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 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, 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) Able to take aspirin
                  (acetylsalicylic acid, ASA) at 81 or 325 mg/daily as antiplatelet therapy if
                  platelet count is above 30 x 109/L (subjects intolerant to ASA may use warfarin
                  or low molecular weight heparin)

        Exclusion Criteria:

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

               1. Has received selinexor or another XPO1 inhibitor previously.

               2. Prior malignancy that required treatment or has shown evidence of recurrence
                  (except for non-melanoma skin cancer or adequately treated cervical carcinoma in
                  situ) during the 5 years prior to randomization. Cancer treated with curative
                  intent for >5 years previously and without evidence of recurrence will be
                  allowed.

               3. Has any concurrent medical condition or disease (e.g., uncontrolled active
                  hypertension, uncontrolled active diabetes, active systemic infection, POEMS
                  syndrome [polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and
                  skin changes], primary amyloidosis, etc.) that is likely to interfere with study
                  procedures.

               4. 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.

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

               6. Known hypersensitivity to compounds of similar chemical or biological composition
                  to thalidomide and lenalidomide or steroids.

               7. Concurrent use of other anti-cancer agents or treatments.

               8. The development of erythema nodosum if characterized by a desquamating rash while
                  taking thalidomide or similar drugs.

               9. Severe hypercalcemia, i.e., serum calcium ≥ 12 mg/dL (3.0 mmol/L) corrected for
                  albumin

              10. Any condition, including the presence of laboratory abnormalities, which places
                  the subject at unacceptable risk if he/she were to participate in the study or
                  confounds the ability to interpret data from the study.

              11. Pregnant or breastfeeding females.

              12. BSA <1.4 m2 at baseline, calculated by the Dubois (58) or Mosteller (59) method.

              13. Life expectancy of less than 3 months.

              14. Major surgery within 4 weeks prior to C1D1.

              15. Active, unstable cardiovascular function, as indicated by the presence of:

             1. Symptomatic ischemia, or 2. Uncontrolled clinically significant conduction
             abnormalities (e.g., patients with ventricular tachycardia on anti-arrhythmic are
             excluded; patients with first degree atrioventricular block or asymptomatic left
             anterior fascicular block/right bundle branch block will not be excluded), or 3. CHF
             of New York Heart Association Class ≥3 or known left ventricular ejection fraction <
             40%, or 4. MI within 3 months prior to C1D1. 16. Known active HIV infection or HIV
             seropositivity. 17. 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.

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

             19. 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).

             20. 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.

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

             22. 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
Time Frame:30 months
Safety Issue:
Description:Overall Response Rate ([ORR]=CR +VGPR+ PR)

Secondary Outcome Measures

Measure:Adverse Events Occurrences
Time Frame:30 months
Safety Issue:
Description:Occurrence of adverse events throughout the study, graded via CTCAE v.5.0
Measure:Time to progression (TTP)
Time Frame:30 months
Safety Issue:
Description:defined as the time from the initiation of therapy to progressive disease
Measure:Progression-free survival (PFS)
Time Frame:30 months
Safety Issue:
Description:defined as the time from initiation of therapy to progressive disease or death from any cause, whichever occurs first
Measure:Time to first response
Time Frame:30 months
Safety Issue:
Description: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
Measure:Duration of Response (DOR)
Time Frame:30 months
Safety Issue:
Description:defined as the time from the first response to progressive disease
Measure:Overall survival (OS)
Time Frame:30 months
Safety Issue:
Description:defined as the time from initiation of therapy to death from any cause or last follow-up visit

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Oncotherapeutics

Trial Keywords

  • Selinexor
  • Lenalidomide-Refractory
  • Multiple Myeloma

Last Updated

August 18, 2020