Safety Study of the Selective Inhibitor of Nuclear Export (SINE) KPT-330 in Patients With Advanced Hematological Cancer

A Phase I Study of the Safety, Pharmacokinetics and Pharmacodynamics of Escalating Doses of the Selective Inhibitor of Nuclear Export/SINE™ Compound KPT-330 in Patients With Advanced Hematological Malignancies

The purpose of this research study is to find out more information relating to the highest dose of KCP-330 that can be given safely and side effects it may cause, to examine how the body affects KCP-330 concentrations in the blood (pharmacokinetics or PK), to examine the effects of KCP-330 on the body (pharmacodynamics or PDn) and to obtain information on its effectiveness in treating cancer.

Study Overview

• Status: Completed
• Conditions: Hematological Malignancies
• Intervention / Treatment: Drug: KPT-330

• Study Type: Interventional
• Enrollment (Actual): 286
• Phase: Phase 1

Contacts and Locations

Study Locations

• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2W 4N2
      • Tom Baker Cancer Centre
  • Ontario
    • Toronto, Ontario, Canada, M5T 2M9
      • Princess Margaret Hospital
• Denmark
  • Copenhagen, Denmark, 2100
    • Rigshospitalet
• United States
  • Florida
    • Tampa, Florida, United States, 33612
      • Moffitt Cancer Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Dana-Farber Cancer Institute
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine
  • New Jersey
    • Hackensack, New Jersey, United States, 07601
      • Hackensack University Medical Center
  • New York
    • New York, New York, United States, 10065
      • Weill Cornell Medical Center
  • Ohio
    • Canton, Ohio, United States, 44718
      • Gabrail Cancer Center Research
    • Columbus, Ohio, United States, 43210
      • The Ohio State University
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • Sarah Cannon Research Institute
  • Texas
    • Houston, Texas, United States, 77030
      • MD Anderson Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria

1. Malignancies that are refractory to or intolerant of established therapy known to provide clinical benefit. Patients must not be candidates for anti-tumor regimes known to provide clinical benefit.
2. All patients must have evidence of progressive disease on study entry. Previously untreated patients who are not chemotherapy candidates on Arm 2 may have advanced disease (without clear progression). There is no upper limit on the number of prior treatments provided that all inclusion criteria are met, and exclusion criteria are not met.

Exclusion Criteria

1. Radiation, chemotherapy, or immunotherapy or any other anticancer therapy ≤2 weeks prior to cycle 1 day 1 and mitomycin C and radioimmunotherapy 6 weeks prior to cycle 1 day 1.
2. Patients with active graft versus host disease after allogeneic stem cell transplantation. At least 3 months must have elapsed since completion of allogeneic stem cell transplantation except for patients with AML, where at least 2 months must have elapsed;
3. Known active hepatitis A, B, or C infection; or known to be positive for HCV RNA or HBsAg (HBV surface antigen);
4. Patients with active CNS malignancy. Asymptomatic small lesions are not considered active. Treated lesions may be considered inactive if they are stable for at least 3 months. Patient with malignant cells in their cerebrospinal fluid (CSF) without CNS symptom may be included.
5. Significantly diseased or obstructed gastrointestinal tract or uncontrolled vomiting or diarrhea.
6. Grade ≥2 peripheral neuropathy at baseline (within 14 days prior to cycle 1 day 1).
7. Macular degeneration, uncontrolled glaucoma, or markedly decreased visual acuity.
8. In the opinion of the investigator, patients who are significantly below their ideal body weight.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: selinexor	Drug: KPT-330; Other Names: Selinexor

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs)	An adverse event (AE) was any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product during the course of a study and which does not necessarily have to have a causal relationship with this treatment. An Serious adverse event (SAE) was an AE resulting in any of the following outcomes: death; life-threatening event; required or prolonged inpatient hospitalization; persistent or significant disability/incapacity; congenital anomaly. TEAEs are any untoward medical incidence in a participant during administered study treatment, whether or not these events were related to study treatment.	From first dose of study drug administration to end of treatment (up to 27 months)
Recommended Phase 2 Dose (RP2D) of Selinexor	Recommended Phase 2 dose was determined by maximum tolerated dose (MTD). MTD was defined as the next lower dose level below the one in which > 1 of 3 participants or ≥ 2 of 6 participants experienced dose-limiting toxicity (DLT), provided that that dose level is ≤25% lower than the highest dose tested. If the projected MTD was >25% lower than the highest dose tested, then an additional cohort of ≥3 participants were added at a dose that was intermediate between the intolerable dose and the next lower dose.	From first dose of study drug administration to end of treatment (up to 27 months)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum Observed Plasma Concentration (Cmax) of Selinexor	Cmax was defined as the maximum observed concentration, taken directly from the plasma concentration.	0 (pre-dose), 0.5, 1, 2, 4, 8, 24 and 48 hours post-dose on Day 1, 8 of Cycle 1 and Days 15, 16 or 17 of Cycle 2
Time to Maximum Observed Concentration (Tmax) of Selinexor	Tmax was defined as time of first observation of Cmax, taken directly from the plasma concentration data.	0 (pre-dose), 0.5, 1, 2, 4, 8, 24 and 48 hours post-dose on Day 1, 8 of Cycle 1 and Days 15, 16 or 17 of Cycle 2
Average Concentration From Time 0 to 24 Hours (Cavg0-24h) of Selinexor	Cavg0-24h was defined as average concentration from time 0 to 24 hours.	0 (pre-dose), 0.5, 1, 2, 4, 8, 24 and 48 hours post-dose on Day 1, 8 of Cycle 1 and Days 15, 16 or 17 of Cycle 2
Area Under the Concentration-Time Curve From Time 0 to t (AUC0-t) of Selinexor	AUC0-t was defined as area under the concentration-time curve from time zero to the last non-zero concentration.	0 (pre-dose), 0.5, 1, 2, 4, 8, 24 and 48 hours post-dose on Day 1, 8 of Cycle 1 and Days 15, 16 or 17 of Cycle 2
Area Under the Concentration-Time Curve From Time 0 Extrapolated to Infinity (AUC0-inf) of Selinexor	AUC0-inf was defined as the area under the concentration-time curve from time zero to infinity (extrapolated).	0 (pre-dose), 0.5, 1, 2, 4, 8, 24 and 48 hours post-dose on Day 1, 8 of Cycle 1 and Days 15, 16 or 17 of Cycle 2
Apparent Volume of Distribution Uncorrected for Fraction Absorbed (Vd/F) of Selinexor	Apparent volume of distribution was calculated as Dose/ (kel *AUC0-inf), uncorrected for fraction absorbed, reported normalized by participant body weight (kilogram [kg]).	0 (pre-dose), 0.5, 1, 2, 4, 8, 24 and 48 hours post-dose on Day 1, 8 of Cycle 1 and Days 15, 16 or 17 of Cycle 2
Apparent Total Body Clearance, Uncorrected for Fraction Absorbed (Cl/F) of Selinexor	Cl/F was calculated as Dose/AUC0-inf, uncorrected for fraction absorbed, reported normalized by participant body weight (kg).	0 (pre-dose), 0.5, 1, 2, 4, 8, 24 and 48 hours post-dose on Day 1, 8 of Cycle 1 and Days 15, 16 or 17 of Cycle 2
Terminal Half-Life (t½) of Selinexor	t½ was, calculated as ln(2)/kel, where kel is elimination rate constant, calculated using linear regression on the terminal portion of the log-linear concentration versus time curve.	0 (pre-dose), 0.5, 1, 2, 4, 8, 24 and 48 hours post-dose on Day 1, 8 of Cycle 1 and Days 15, 16 or 17 of Cycle 2
Number of Participants With Overall Response of Selinexor	Objective response for each malignancy was defined using the disease response criteria by malignancy; For NHL (including DLBCL, PTCL, and CTCL), objective response included complete response (CR) and partial response (PR). For MM, objective response included stringent complete response (sCR), CR, very good partial response (VGPR), and PR. For WM, objective response included CR, VGPR, and PR. For CLL, ALL, and AML, objective response included complete remission and Partial remission. For CML, objective response includes complete cytogenic response, and complete hematologic response (CHR).	From first dose of study drug administration to end of treatment (up to 27 months)
Duration of Response	Duration of response was defined as the time from the first occurrence of objective response to first documented evidence of disease recurrence or progression. Participants without evidence of progression were censored at time of last evaluable disease assessment. Objective response was defined as any response of partial response/remission or better for all malignancies; for AML, a response of morphologic leukemia-free state is also included for ORR. Duration of response was calculated by Kaplan-Meier method.	From first dose of study drug administration to end of treatment (up to 27 months)
Progression-free Survival	Progression-free survival (PFS) was calculated from the date of first dose of study drug to first documented evidence of disease recurrence or progression or death due to any cause. Participants who were last known to be alive and without evidence of progression were censored at time of last evaluable disease assessment. If date of progression or death occurred after more than 1 missed disease assessment interval, participants were censored at the time of last evaluable disease assessment prior to the missed assessment.	Cycle 1 Day 1 to End of Treatment (up to 27 months)
Duration of at Least Stable Disease	Duration of at least stable disease was defined as the time from the date of first dose of study drug to first documented evidence of disease recurrence or progression. Participants without evidence of progression were censored at time of last evaluable disease assessment.	Cycle 1 Day 1 to End of Treatment (up to 27 months)
Overall Survival	Overall Survival was calculated from the date of first dose of study drug to date of death due to any cause. Participants who were last known to be alive were censored at time of last contact. Overall survival was calculated by Kaplan-Meier method.	Cycle 1 Day 1 to End of Treatment (up to 27 months)

Collaborators and Investigators

• Sponsor: Karyopharm Therapeutics Inc

Publications and helpful links

General Publications

• Chen C, Siegel D, Gutierrez M, Jacoby M, Hofmeister CC, Gabrail N, Baz R, Mau-Sorensen M, Berdeja JG, Savona M, Savoie L, Trudel S, Areethamsirikul N, Unger TJ, Rashal T, Hanke T, Kauffman M, Shacham S, Reece D. Safety and efficacy of selinexor in relapsed or refractory multiple myeloma and Waldenstrom macroglobulinemia. Blood. 2018 Feb 22;131(8):855-863. doi: 10.1182/blood-2017-08-797886. Epub 2017 Dec 4.
• Kuruvilla J, Savona M, Baz R, Mau-Sorensen PM, Gabrail N, Garzon R, Stone R, Wang M, Savoie L, Martin P, Flinn I, Jacoby M, Unger TJ, Saint-Martin JR, Rashal T, Friedlander S, Carlson R, Kauffman M, Shacham S, Gutierrez M. Selective inhibition of nuclear export with selinexor in patients with non-Hodgkin lymphoma. Blood. 2017 Jun 15;129(24):3175-3183. doi: 10.1182/blood-2016-11-750174. Epub 2017 May 3. Erratum In: Blood. 2020 Jul 9;136(2):259.
• Garzon R, Savona M, Baz R, Andreeff M, Gabrail N, Gutierrez M, Savoie L, Mau-Sorensen PM, Wagner-Johnston N, Yee K, Unger TJ, Saint-Martin JR, Carlson R, Rashal T, Kashyap T, Klebanov B, Shacham S, Kauffman M, Stone R. A phase 1 clinical trial of single-agent selinexor in acute myeloid leukemia. Blood. 2017 Jun 15;129(24):3165-3174. doi: 10.1182/blood-2016-11-750158. Epub 2017 Mar 23. Erratum In: Blood. 2020 Jul 9;136(2):259.
• Schmidt J, Braggio E, Kortuem KM, Egan JB, Zhu YX, Xin CS, Tiedemann RE, Palmer SE, Garbitt VM, McCauley D, Kauffman M, Shacham S, Chesi M, Bergsagel PL, Stewart AK. Genome-wide studies in multiple myeloma identify XPO1/CRM1 as a critical target validated using the selective nuclear export inhibitor KPT-276. Leukemia. 2013 Dec;27(12):2357-65. doi: 10.1038/leu.2013.172. Epub 2013 Jun 11.

Study record dates

Study Major Dates

• Study Start (Actual): July 23, 2012
• Primary Completion (Actual): October 13, 2015
• Study Completion (Actual): October 13, 2015

Study Registration Dates

• First Submitted: May 16, 2012
• First Submitted That Met QC Criteria: May 25, 2012
• First Posted (Estimate): May 30, 2012

Study Record Updates

• Last Update Posted (Estimate): January 26, 2023
• Last Update Submitted That Met QC Criteria: January 24, 2023
• Last Verified: January 1, 2023

More Information

Terms related to this study

• Keywords: Multiple Myeloma; Acute Lymphoblastic Leukemia; Chronic Lymphocytic Leukemia; KPT-330; Peripheral T-Cell Lymphoma; Selinexor; Waldenström's macroglobulinemia; non-Hodgkin Lymphoma; Cutaneous T-Cell Lymphoma; Chronic Myelocytic Leukemia
• Additional Relevant MeSH Terms: Neoplasms by Site; Hematologic Diseases; Neoplasms; Hematologic Neoplasms
• Other Study ID Numbers: KCP-330-001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No