Personalized Selinexor-based Therapy for Relapsed/Refractory Multiple Myeloma

• ClinicalTrials.gov Identifier: NCT04925193
• Recruitment Status: Recruiting
• First Posted: June 14, 2021
• Last Update Posted: February 5, 2024
• Sponsor: University of Colorado, Denver
• Collaborators: Karyopharm Therapeutics Inc; National Cancer Institute (NCI)
• Information provided by (Responsible Party): University of Colorado, Denver

Tracking Information

• First Submitted Date: May 19, 2021
• First Posted Date: June 14, 2021
• Last Update Posted Date: February 5, 2024
• Actual Study Start Date: November 18, 2021
• Estimated Primary Completion Date: November 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: June 7, 2021)

Overall Response rate [ Time Frame: Two years ]

To evaluate the overall response rate achieved with physician's choice selinexor-based combination therapy as measured by International Myeloma Working Group criteria (based on Kumar et al 2016)

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: June 7, 2021)

• MRD negative response rate [ Time Frame: 2 years ]
  To evaluate the minimal residual disease negative response rate achieved with physician's choice selinexor-based combination therapy assessed via NGS or multiparametric flow cytometry with sensitivity of 10-5.
• Progression Free Survival [ Time Frame: 2 years ]
  To evaluate the duration of progression free survival achieved with physician's choice selinexor-based combination therapy
• Overall Survival [ Time Frame: 2 years ]
  To evaluate the duration of overall survival achieved with physician's choice selinexor-based combination therapy
• Duration of Response [ Time Frame: 2 years ]
  To evaluate the duration of response achieved with physician's choice selinexor-based combination therapy
• Time to Next Treatment [ Time Frame: 2 years ]
  To evaluate the time to next treatment achieved with physician's choice selinexor-based combination therapy
• Safety and tolerability of selinexor [ Time Frame: 2 years ]
  To evaluate safety and tolerability of selinexor in combination with partner backbone agents using occurrence, nature and severity of Adverse Events

• Original Secondary Outcome Measures: Same as current

Current Other Pre-specified Outcome Measures (submitted: June 7, 2021)

• Reliability of My-DST testing to inform treatment choice [ Time Frame: 2 years ]
  Rate of assay failure
• Feasibility of My-DST testing to inform treatment choice [ Time Frame: 2 years ]
  Rate of identification of preferred partner therapy or combination
• Evaluation of My-DST related predictors of response [ Time Frame: 2 years ]
  ORR in patients with concordance or discordance between My-DST results and physicians selected regimen

• Original Other Pre-specified Outcome Measures: Same as current

Descriptive Information

• Brief Title: Personalized Selinexor-based Therapy for Relapsed/Refractory Multiple Myeloma
• Official Title: Personalized Selinexor-based Therapy for Relapsed/Refractory Multiple Myeloma

Brief Summary

Selinexor (KPT-330, Xpovio) is a first in class selective inhibitor of nuclear export which has been approved for use in relapsed and refractory multiple myeloma (RRMM). This trial will seek to evaluate the outcomes achieved with selinexor based combination in RRMM selected by physician's choice and compared prospectively to ex vivo drug sensitivity testing results. Participants will be enrolled and assigned into one of the following treatment arms:

Arm 1: Selinexor + pomalidomide + dexamethasone (SPd)

Arm 2: Selinexor + daratumumab + dexamethasone (SDd)

Arm 3: Selinexor + carfilzomib + dexamethasone (SKd)

Detailed Description

This study is a single institution, open-label phase II study to evaluate the overall response rate achieved with selinexor and dexamethasone based three drug combination therapy, selected by physician's choice, in patients with relapsed/refractory multiple myeloma.

Patients with RRMM will be eligible for enrollment. During screening, in addition to standard of care disease assessments, participant's bone marrow aspirate will be evaluated using a novel ex vivo Myeloma Drug Sensitivity Testing platform (My-DST). The following agents will be eligible for physician's choice, and in parallel evaluated for sample sensitivity in MyDST: pomalidomide, carfilzomib and daratumumab. Agents will be tested individually, in combination with selinexor and in combination with selinexor and dexamethasone. Results from MyDST will be not be available to investigators at time of treatment assignment, but will be evaluated to better characterize test performance and relationship with treatment outcomes.

Investigators will assign patients to one of the following treatment combinations: Selinexor/Pomalidomide/Dexamethsone (SPd), Selinexor/Daratumumab/Dexamethasone (SDd) or Selinexor/Carfilzomib/Dexamethasone (SKd). Investigators will use patient specific considerations such as prior therapeutic exposures, response to / tolerance of prior therapies and comorbid conditions which may increase risk for toxicity with specific agents to guide expert judgement in selecting partner agent for selinexor and dexamethasone. Treatment will continue until progression of disease, unacceptable toxicity or death.

This study will evaluate if physician's choice partner drug selection for selinexor based combination therapy in RRMM will lead to an overall response rate of 75% or higher.

• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Non-Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Multiple Myeloma in Relapse

Intervention

• Drug: Selinexor
  Selinexor is an oral, first-in-class, slowly reversible, potent selective inhibitor of nuclear export (SINE) compound that specifically blocks exportin 1 (XPO1).
• Drug: Pomalidomide
  Oral Table
• Drug: Daratumumab
  Injection
• Drug: Carfilzomib
  Injection
• Drug: Dexamethasone
  Oral tablet or injection

Study Arms

• Experimental: Arm 1 SPd
  • Selinexor 60 mg PO days 1, 8, 15
  • Pomalidomide 4 mg PO on days 1-21
  • Dexamethasone 40 mg PO or IV on days 1, 8, 15, 22
  • 28 day treatment cycles
  Interventions:

  • Drug: Selinexor
  • Drug: Pomalidomide
  • Drug: Dexamethasone
• Experimental: Arm 2 SDd
  • Selinexor 80 mg PO days 1, 8, 15
  • Daratumumab 1,800mg/30,000 units subcutaneous injection on days 1, 8, 15, 22 of cycles 1 and 2, days 1, 15 of cycles 3-6, day 1 of cycles >6
  • Dexamethasone 40 mg PO or IV days 1, 8, 15, 22
  • 28 day treatment cycle
  Interventions:

  • Drug: Selinexor
  • Drug: Daratumumab
  • Drug: Dexamethasone
• Experimental: Arm 3 SKd
  • Selinexor 80 mg PO days 1, 8, 15
  • Carfilzomib IV infusion 20 mg/m2 cycle 1, day 1, 56 mg/m2 cycle 1 day 8, 15. Cycle 2+ days 1, 8, 15.
  • Dexamethasone 40 mg IV or PO days 1, 8, 15, 22
  • 28 day treatment cycle
  Interventions:

  • Drug: Selinexor
  • Drug: Carfilzomib
  • Drug: Dexamethasone

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: June 7, 2021): 25
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: November 2025
• Estimated Primary Completion Date: November 2024 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Age ≥ 18 years
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. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of ≤ 2

4. Histologically confirmed diagnosis, measurable disease and evidence of disease progression of MM after 1 or more prior lines of therapy with either of the following:

   1. Documented evidence of PD after achieving at least SD for ≥ 1 cycle during a previous MM regimen (i.e., relapsed MM)
   2. ≤ 25% response (i.e, patient never achieved ≥ MR) or PD during or within 60 days from end of the most recent MM regimen (i.e., refractory MM)

5. Patients must have measurable disease as defined by at least one of the following:

   1. Serum M-protein ≥ 0.5 g/dL by serum protein electrophoresis (SPEP) or, for IgA myeloma, by quantitative IgA
   2. Urinary M-protein excretion at least 200 mg/24 hours
   3. Serum FLC ≥ 10 mg/dL, provided that FLC ratio is abnormal
   4. If no measurable disease by serum or urine, then the presence of a plasmacytoma of ≥2cm in one dimension prior to start of study can be used to follow response via radiologic imaging.

6. Adequate hepatic function:

   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 <2.5 × ULN.
7. Adequate renal function as determined by serum creatinine of ≤2 mg/dL OR estimated creatinine clearance of ≥ 20 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).

8. Adequate hematopoietic function within 7 days prior to C1D1: absolute neutrophil count ≥1000/mm3, hemoglobin ≥8 g/dL and platelet count ≥100,000/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 may receive 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) at any time.
   2. Patients may receive RBC and/or platelet transfusions as clinically indicated per institutional guidelines during the study.
9. 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:

1. Has received selinexor or another SINE (Specific Inhibitor of Nuclear Export) compound in a previous line of therapy.
2. 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.
3. 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.
4. Known intolerance, hypersensitivity, or contraindication to study drugs.
5. Pregnant or breastfeeding females.
6. Major surgery within 4 weeks prior to C1D1.

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

   1. Symptomatic ischemia, or
   2. Uncontrolled clinically significant conduction abnormalities (eg, patients with ventricular tachycardia on anti-arrhythmics are excluded; patients with first degree atrioventricular block or asymptomatic left anterior fascicular block/right bundle branch block will not be excluded), or
   3. Congestive heart failure of New York Heart Association Class ≥3 or known left ventricular ejection fraction <40%, or
   4. Myocardial infarction within 3 months prior to C1D1.
8. Subjects with active hepatitis B virus (Hep B) are allowed if antiviral therapy for hepatitis B has been given for >8 weeks and viral load is <100 IU/ml prior to first dose of trial treatment. Subjects with untreated hepatitis C virus (HCV) are allowed. Subjects with Human Immunodeficiency Virus (HIV) who have CD4+ T-cell counts ≥ 350 cells/µL and no history of AIDS-defining opportunistic infections in the last year are allowed.
9. 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, including prior gastric bypass or bowel resection procedures.
10. 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).
11. 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.
12. Contraindication to any of the required concomitant drugs or supportive treatments.
13. Patients unwilling or unable to comply with the protocol, including providing 24-hour urine samples for urine protein electrophoresis at the required time points.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Derek Schatz; 720-848-0628; derek.schatz@cuanschutz.edu

• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT04925193
• Other Study ID Numbers: 20-2202.cc; P30CA046934 ( U.S. NIH Grant/Contract )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: University of Colorado, Denver
• Original Responsible Party: Same as current
• Current Study Sponsor: University of Colorado, Denver
• Original Study Sponsor: Same as current

Collaborators

• Karyopharm Therapeutics Inc
• National Cancer Institute (NCI)

• Investigators: Not Provided
• PRS Account: University of Colorado, Denver
• Verification Date: February 2024