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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04661137
Recruitment Status : Recruiting
First Posted : December 10, 2020
Last Update Posted : February 4, 2022
Sponsor:
Collaborator:
Karyopharm Therapeutics Inc
Information provided by (Responsible Party):
Hackensack Meridian Health

Brief Summary:

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.


Condition or disease Intervention/treatment Phase
Multiple Myeloma Drug: Selinexor 60 MG Drug: Selinexor 80 MG Drug: Selinexor 100 MG Drug: Carfilzomib Drug: Pomalidomide Drug: Daratumumab Drug: Dexamethasone Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 96 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : March 16, 2021
Estimated Primary Completion Date : January 2023
Estimated Study Completion Date : January 2024


Arm Intervention/treatment
Experimental: Carfilzomib-containing Regimen

Carfilzomib 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.

Drug: Selinexor 80 MG
Selinexor 80 mg PO on days 1, 8 and 15
Other Name: KPT-330

Drug: Carfilzomib
56 mg/m2 IV on days 1, 8 and 15
Other Name: Kyprolis

Drug: Dexamethasone
20 mg if ≥ 75 years old and 40 mg if < 75 years old on days 1, 8, 15 and 22
Other Name: Dextenza, Ozurdex, Neofordex, others

Experimental: Pomalidomide-containing Regimen

Pomalidomide 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.

Drug: Selinexor 60 MG
Selinexor 60 mg PO on days 1, 8 and 15
Other Name: KPT-330

Drug: Pomalidomide
4 mg PO daily for 21 days
Other Name: Pomalyst

Drug: Dexamethasone
20 mg if ≥ 75 years old and 40 mg if < 75 years old on days 1, 8, 15 and 22
Other Name: Dextenza, Ozurdex, Neofordex, others

Experimental: Exploratory/Daratumumab-containing Regimen

Daratumumab 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.

Drug: Selinexor 100 MG
Selinexor 100 mg PO on days 1, 8, 15 and 22
Other Name: KPT-330

Drug: Daratumumab
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
Other Name: Darzalex

Drug: Dexamethasone
20 mg if ≥ 75 years old and 40 mg if < 75 years old on days 1, 8, 15 and 22
Other Name: Dextenza, Ozurdex, Neofordex, others




Primary Outcome Measures :
  1. Overall Response Rate (ORR) of patients receiving selinexor with carfilzomib and dexamethasone (Arm 1) [ Time Frame: 30 Months ]
    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)

  2. Overall Response Rate (ORR) of patients receiving selinexor with pomalidomide and dexamethasone (Arm 2) [ Time Frame: 30 Months ]
    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 :
  1. Progression Free Survival (PFS) [ Time Frame: 30 Months ]
    Duration from start of study treatment to PD or death [regardless of cause], whichever comes first

  2. Overall Survival (OS) [ Time Frame: 30 Months ]
    Duration from start of study treatment to death

  3. MRD Negativity [ Time Frame: 30 Months ]
    Rate of achievement of minimal residual disease (MRD) by multiparametric flow cytometry

  4. Incidence of Adverse Events [Safety and Tolerability] using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), v 4.03. [ Time Frame: 30 Months ]
    Incidence of Adverse Events [Safety and Tolerability] using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), v 4.03.

  5. Time To Next Treatment (TTNT) [ Time Frame: 30 Months ]
    Duration from start of study treatment to next treament


Other Outcome Measures:
  1. Overall Response Rate (ORR) of patients receiving selinexor with daratumumab and dexamethasone [ Time Frame: 30 Months ]
    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)

  2. Gut Microbiome analysis [ Time Frame: 30 Months ]
    To identify intestinal microbiota associated biomarkers that predict response and risk for development of treatment-related toxicities at baseline, on-treatment, post-treatment and relapse.

  3. Immune cell subset analyses [ Time Frame: 30 Months ]
    Changes from baseline in immune cell subsets in peripheral blood mononuclear and bone marrow mononuclear cells will be monitored.

  4. Analyses of cytokine markers [ Time Frame: 30 Months ]
    Cytokines will be quantified in plasma samples by multiplex ELISA and other readout assays.

  5. Analyses of chemokine markers [ Time Frame: 30 Months ]
    Chemokines will be quantified in plasma samples by multiplex ELISA and other readout assays.

  6. Analyses of inflammatory/anti-inflammatory markers [ Time Frame: 30 Months ]
    Inflammation/anti-inflammation markers will be quantified in plasma samples by multiplex ELISA and other readout assays.

  7. Analyses of bacterial translocation markers [ Time Frame: 30 Months ]
    Bacterial translocation markers will be quantified in plasma samples by multiplex ELISA and other readout assays.

  8. Basic peripheral blood laboratory variables: Lymphocytes [ Time Frame: 30 Months ]
    Basic peripheral blood laboratory value of absolute and relative lymphocytes obtained in routine clinical care will be evaluated prior to treatment, on-treatment, post-treatment, relapse and at development of severe AE (>3 score).

  9. Basic peripheral blood laboratory variables: Eosinophils [ Time Frame: 30 Months ]
    Basic peripheral blood laboratory value of absolute and relative eosinophils obtained in routine clinical care will be evaluated prior to treatment, on-treatment, post-treatment, relapse and at development of severe AE (>3 score).

  10. Basic peripheral blood laboratory variables: Monocytes [ Time Frame: 30 Months ]
    Basic peripheral blood laboratory value of absolute and relative monocytes obtained in routine clinical care will be evaluated prior to treatment, on-treatment, post-treatment, relapse and at development of severe AE (>3 score).

  11. Basic peripheral blood laboratory variables: Neutrophils [ Time Frame: 30 Months ]
    Basic peripheral blood laboratory value of absolute and relative neutrophils obtained in routine clinical care will be evaluated prior to treatment, on-treatment, post-treatment, relapse and at development of severe AE (>3 score).

  12. Basic peripheral blood laboratory variables: Basophils [ Time Frame: 30 Months ]
    Basic peripheral blood laboratory value of absolute and relative basophils obtained in routine clinical care will be evaluated prior to treatment, on-treatment, post-treatment, relapse and at development of severe AE (>3 score).

  13. Basic peripheral blood laboratory variables: LDH [ Time Frame: 30 Months ]
    Basic peripheral blood laboratory value of LDH obtained in routine clinical care will be evaluated prior to treatment, on-treatment, post-treatment, relapse and at development of severe AE (>3 score).

  14. Basic peripheral blood laboratory variables: Neutrophil-to-lymphocyte ratio (NLR) [ Time Frame: 30 Months ]
    Basic peripheral blood laboratory value of absolute neutrophil-to-lymphocyte ratio (NLR) obtained in routine clinical care will be evaluated prior to treatment, on-treatment, post-treatment, relapse and at development of severe AE (>3 score).

  15. Analyses of genetic profiles [ Time Frame: 30 Months ]
    Exploratory analysis to identify molecular genomic determinants of response or resistance to selinexor in the treatment combinations to define biomarkers

  16. Analyses of markers of de novo or acquired resistance to treatment [ Time Frame: 30 Months ]
    Exploratory analysis to identify mechanisms of de novo or acquired resistance to selinexor in combination with carfilzomib, pomalidomide or daratumumab.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04661137


Contacts
Layout table for location contacts
Contact: Palka Anand 551-996-3040 Palka.Anand@hmhn.org
Contact: Kristin Ivanovski 551-996-5231 Kristin.Ivanovski@hmhn.org

Locations
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United States, District of Columbia
Lombardi Comprehensive Cancer Center Recruiting
Washington, District of Columbia, United States, 20007
Contact: Melin Vranesic    202-687-0160    mv764@georgetown.edu   
Contact: Elizabeth Pendergrass    202-784-0038    eaw109@georgetown.edu   
Principal Investigator: David Vesole, MD, PhD         
United States, New Jersey
John Theurer Cancer Center Recruiting
Hackensack, New Jersey, United States, 07601
Contact: Palka Anand    551-996-3040    Palka.Anand@hmhn.org   
Contact: Kristin Ivanovski    551-996-5231    Kristin.Ivanovski@hmhn.org   
Principal Investigator: Noa Biran, MD         
Sponsors and Collaborators
Hackensack Meridian Health
Karyopharm Therapeutics Inc
Investigators
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Principal Investigator: Noa Biran, MD Hackensack Meridian Health
Publications:
Fridericia L. Die Systolendauer im elektrokardiogramm bei normalen menschen und bei herzkranken. [The duration of systole in the electrocardiogram of normal subjects and of patients with heart disease.]. Acta Medica Scandinavica. 1920;53:469-86.
Bahlis N, Chen C, Sebag M et al. A Phase 1B/2 Study of Selinexor in combination with backbone therapies for treatment of relapsed/refractory multiple myeloma. EHA Learning Center. Abstract P277. June 10, 2016.
Jakubowiak A, Jasielec J, Rosenbaum CA et al. Final Results of Phase 1 MMRC Trial of Selinexor, Carfilzomib, and Dexamethasone in Relapsed/Refractory MM. Blood 2016. 128;973.
Chari A, et al. Results of the Pivotal STORM Study (Part 2) in Penta-Refractory Multiple Myeloma (MM): Deep and Durable Responses with Oral Selinexor Plus low dose Dexamethasone in Patients with Penta-Refractory MM. Blood. 2018. ASH Abstract 598.
Gasparetto C, et al. Deep and Durable Respones with Selinexor, Daratumumab and Dexamethasone (SDd) in Patients with MM Previously Exposed to Proteasome Inhibitors and Immunomodulatory Drugs: Results of the Phase 1B Study of SDd. Blood 2018. ASH Abstract 599.
Gasparetteo C, Lipe B, Tuchman S, et al. Once weekly selinexor, carfilzomib, and dexamethasone (SKd) in patients with relapsed/refractory multiple myeloma (MM). Poster presented at the 2020 American Society of Clinical Oncology Virtual Annual Meeting. J Clin Oncol 38:2020 (suppl; abstr 8530)
Chen CI, Bahlis N, Gasparetto C, et al. Selinexor, pomalidomide, and dexamethasone (SPd) in patients with relapsed or refractory multiple myeloma. Presented at: American Society of Hematology Annual Meeting; Orlando, Florida. December 6-10, 2019.
Gasparetto C, Lentzsch S, Schiller GJ et al). Selinexor, daratumumab and dexamethasone in patients with relapsed/refractory multiple myeloma (MM). Poster presented at the 2020 American Society of Oncology Virtual Annual Meeting. J Clin Oncol 38: 2020 (Suppl abstr 8510)

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Responsible Party: Hackensack Meridian Health
ClinicalTrials.gov Identifier: NCT04661137    
Other Study ID Numbers: Pro2020-0369
IST-318 ( Other Identifier: Karyopharm )
First Posted: December 10, 2020    Key Record Dates
Last Update Posted: February 4, 2022
Last Verified: February 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Hackensack Meridian Health:
Selinexor
KPT-330
Additional relevant MeSH terms:
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Multiple Myeloma
Neoplasms, Plasma Cell
Neoplasms by Histologic Type
Neoplasms
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Paraproteinemias
Blood Protein Disorders
Hematologic Diseases
Hemorrhagic Disorders
Lymphoproliferative Disorders
Immunoproliferative Disorders
Immune System Diseases
Dexamethasone
Daratumumab
Pomalidomide
Anti-Inflammatory Agents
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Gastrointestinal Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Immunologic Factors
Angiogenesis Inhibitors