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

Multiple Myeloma Clinical Trial

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 Details — Status: Recruiting

Administrative data

• NCT number: NCT04661137
• Other study ID #: Pro2020-0369
• Secondary ID: IST-318
• Status: Recruiting
• Phase: Phase 2
• Start date: March 16, 2021
• Est. completion date: January 2025

Study information

• Verified date: January 2024
• Source: Hackensack Meridian Health
• Contact: Palka Anand
• Phone: 551-996-3040
• Email: Palka.Anand[@]hmhn.org
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 96
• Est. completion date: January 2025
• Est. primary completion date: January 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Multiple Myeloma
• Neoplasms, Plasma Cell

Intervention

Drug:
• Selinexor 60 MG
Selinexor 60 mg PO on days 1, 8 and 15
• Selinexor 80 MG
Selinexor 80 mg PO on days 1, 8 and 15
• Selinexor 100 MG
Selinexor 100 mg PO on days 1, 8, 15 and 22
• Carfilzomib
56 mg/m2 IV on days 1, 8 and 15
• Pomalidomide
4 mg PO daily for 21 days
• 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
• Dexamethasone
20 mg if = 75 years old and 40 mg if < 75 years old on days 1, 8, 15 and 22

Locations

Country	Name	City	State
United States	John Theurer Cancer Center	Hackensack	New Jersey
United States	Lombardi Comprehensive Cancer Center	Washington	District of Columbia

Sponsors (2)

Lead Sponsor	Collaborator
Hackensack Meridian Health	Karyopharm Therapeutics Inc

Country where clinical trial is conducted

United States, 

References & Publications (12)

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.

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.

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.

Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976;16(1):31-41. doi: 10.1159/000180580. — View 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. — View 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.

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)

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.

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)

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.

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. — View 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. — View Citation

* Note: There are 12 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Overall Response Rate (ORR) of patients receiving selinexor with daratumumab and dexamethasone	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)	30 Months
Other	Gut Microbiome analysis	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.	30 Months
Other	Immune cell subset analyses	Changes from baseline in immune cell subsets in peripheral blood mononuclear and bone marrow mononuclear cells will be monitored.	30 Months
Other	Analyses of cytokine markers	Cytokines will be quantified in plasma samples by multiplex ELISA and other readout assays.	30 Months
Other	Analyses of chemokine markers	Chemokines will be quantified in plasma samples by multiplex ELISA and other readout assays.	30 Months
Other	Analyses of inflammatory/anti-inflammatory markers	Inflammation/anti-inflammation markers will be quantified in plasma samples by multiplex ELISA and other readout assays.	30 Months
Other	Analyses of bacterial translocation markers	Bacterial translocation markers will be quantified in plasma samples by multiplex ELISA and other readout assays.	30 Months
Other	Basic peripheral blood laboratory variables: Lymphocytes	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).	30 Months
Other	Basic peripheral blood laboratory variables: Eosinophils	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).	30 Months
Other	Basic peripheral blood laboratory variables: Monocytes	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).	30 Months
Other	Basic peripheral blood laboratory variables: Neutrophils	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).	30 Months
Other	Basic peripheral blood laboratory variables: Basophils	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).	30 Months
Other	Basic peripheral blood laboratory variables: LDH	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).	30 Months
Other	Basic peripheral blood laboratory variables: Neutrophil-to-lymphocyte ratio (NLR)	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).	30 Months
Other	Analyses of genetic profiles	Exploratory analysis to identify molecular genomic determinants of response or resistance to selinexor in the treatment combinations to define biomarkers	30 Months
Other	Analyses of markers of de novo or acquired resistance to treatment	Exploratory analysis to identify mechanisms of de novo or acquired resistance to selinexor in combination with carfilzomib, pomalidomide or daratumumab.	30 Months
Primary	Overall Response Rate (ORR) of patients receiving selinexor with carfilzomib and dexamethasone (Arm 1)	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)	30 Months
Primary	Overall Response Rate (ORR) of patients receiving selinexor with pomalidomide and dexamethasone (Arm 2)	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)	30 Months
Secondary	Progression Free Survival (PFS)	Duration from start of study treatment to PD or death [regardless of cause], whichever comes first	30 Months
Secondary	Overall Survival (OS)	Duration from start of study treatment to death	30 Months
Secondary	MRD Negativity	Rate of achievement of minimal residual disease (MRD) by multiparametric flow cytometry	30 Months
Secondary	Incidence of Adverse Events [Safety and Tolerability] using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), v 4.03.	Incidence of Adverse Events [Safety and Tolerability] using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), v 4.03.	30 Months
Secondary	Time To Next Treatment (TTNT)	Duration from start of study treatment to next treament	30 Months