Clinical trial NCT04661137: 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
Study type: INTERVENTIONAL
Overall status: SUSPENDED
Phase: PHASE2
Conditions: Multiple Myeloma
Keywords: Selinexor
KPT-330
Lead sponsor: Hackensack Meridian Health
Sponsor class: OTHER
Collaborators: name: Karyopharm Therapeutics Inc
First posted: 2020-12-10
Enrollment: 96
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

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

Primary outcomes:
measure: Overall Response Rate (ORR) of patients receiving selinexor with carfilzomib and dexamethasone (Arm 1)
timeFrame: 30 Months
measure: Overall Response Rate (ORR) of patients receiving selinexor with pomalidomide and dexamethasone (Arm 2)
timeFrame: 30 Months
Secondary outcomes:
measure: Progression Free Survival (PFS)
timeFrame: 30 Months
measure: Overall Survival (OS)
timeFrame: 30 Months
measure: MRD Negativity
timeFrame: 30 Months
measure: Incidence of Adverse Events [Safety and Tolerability] using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), v 4.03.
timeFrame: 30 Months
measure: Time To Next Treatment (TTNT)
timeFrame: 30 Months
Other outcomes:
measure: Overall Response Rate (ORR) of patients receiving selinexor with daratumumab and dexamethasone
timeFrame: 30 Months
measure: Gut Microbiome analysis
timeFrame: 30 Months
measure: Immune cell subset analyses
timeFrame: 30 Months
measure: Analyses of cytokine markers
timeFrame: 30 Months
measure: Analyses of chemokine markers
timeFrame: 30 Months
measure: Analyses of inflammatory/anti-inflammatory markers
timeFrame: 30 Months
measure: Analyses of bacterial translocation markers
timeFrame: 30 Months
measure: Basic peripheral blood laboratory variables: Lymphocytes
timeFrame: 30 Months
measure: Basic peripheral blood laboratory variables: Eosinophils
timeFrame: 30 Months
measure: Basic peripheral blood laboratory variables: Monocytes
timeFrame: 30 Months
measure: Basic peripheral blood laboratory variables: Neutrophils
timeFrame: 30 Months
measure: Basic peripheral blood laboratory variables: Basophils
timeFrame: 30 Months
measure: Basic peripheral blood laboratory variables: LDH
timeFrame: 30 Months
measure: Basic peripheral blood laboratory variables: Neutrophil-to-lymphocyte ratio (NLR)
timeFrame: 30 Months
measure: Analyses of genetic profiles
timeFrame: 30 Months
measure: Analyses of markers of de novo or acquired resistance to treatment
timeFrame: 30 Months
Locations:
city: Washington
country: United States
facility: Lombardi Comprehensive Cancer Center
state: District of Columbia
city: Hackensack
country: United States
facility: John Theurer Cancer Center
state: New Jersey
Study officials:
affiliation: Hackensack Meridian Health
name: Noa Biran, MD
role: PRINCIPAL_INVESTIGATOR
References:
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citation: Du Bois D, Du Bois EF. A formula to estimate the approximate surface area if height and weight be known. 1916. Nutrition. 1989 Sep-Oct;5(5):303-11; discussion 312-3. No abstract available.
citation: Mosteller RD. Simplified calculation of body-surface area. N Engl J Med. 1987 Oct 22;317(17):1098. doi: 10.1056/NEJM198710223171717. No abstract available.
citation: Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, Carbone PP. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 1982 Dec;5(6):649-55. No abstract available.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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)
citation: 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.
citation: 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)