Back to resultsSafety Study of the Selective Inhibitor of Nuclear Export (SINE) KPT-330 in Patients With Advanced Hematological Cancer
Primary Purpose
Hematological Malignancies
Status
Completed
Phase
Phase 1
Locations
International
Study Type
Interventional
Intervention
KPT-330
Sponsored by
About this trial
This is an interventional treatment trial for Hematological Malignancies focused on measuring Selinexor, KPT-330, Multiple Myeloma, non-Hodgkin Lymphoma, Chronic Lymphocytic Leukemia, Waldenström's macroglobulinemia, Peripheral T-Cell Lymphoma, Cutaneous T-Cell Lymphoma, Chronic Myelocytic Leukemia, Acute Lymphoblastic Leukemia
Eligibility Criteria
Inclusion Criteria
- 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.
- 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
- 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.
- 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;
- Known active hepatitis A, B, or C infection; or known to be positive for HCV RNA or HBsAg (HBV surface antigen);
- 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.
- Significantly diseased or obstructed gastrointestinal tract or uncontrolled vomiting or diarrhea.
- Grade ≥2 peripheral neuropathy at baseline (within 14 days prior to cycle 1 day 1).
- Macular degeneration, uncontrolled glaucoma, or markedly decreased visual acuity.
- In the opinion of the investigator, patients who are significantly below their ideal body weight.
Sites / Locations
- Moffitt Cancer Center
- Dana-Farber Cancer Institute
- Washington University School of Medicine
- Hackensack University Medical Center
- Weill Cornell Medical Center
- Gabrail Cancer Center Research
- The Ohio State University
- Sarah Cannon Research Institute
- MD Anderson Cancer Center
- Tom Baker Cancer Centre
- Princess Margaret Hospital
- Rigshospitalet
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
selinexor
Arm Description
Outcomes
Primary Outcome Measures
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.
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.
Secondary Outcome Measures
Maximum Observed Plasma Concentration (Cmax) of Selinexor
Cmax was defined as the maximum observed concentration, taken directly from the plasma concentration.
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.
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.
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.
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).
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]).
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).
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.
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).
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.
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.
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.
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.
Full Information
NCT ID
NCT01607892
First Posted
May 16, 2012
Last Updated
January 24, 2023
Sponsor
Karyopharm Therapeutics Inc
1. Study Identification
Unique Protocol Identification Number
NCT01607892
Brief Title
Safety Study of the Selective Inhibitor of Nuclear Export (SINE) KPT-330 in Patients With Advanced Hematological Cancer
Official Title
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
Study Type
Interventional
2. Study Status
Record Verification Date
January 2023
Overall Recruitment Status
Completed
Study Start Date
July 23, 2012 (Actual)
Primary Completion Date
October 13, 2015 (Actual)
Study Completion Date
October 13, 2015 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Karyopharm Therapeutics Inc
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No
5. Study Description
Brief Summary
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Hematological Malignancies
Keywords
Selinexor, KPT-330, Multiple Myeloma, non-Hodgkin Lymphoma, Chronic Lymphocytic Leukemia, Waldenström's macroglobulinemia, Peripheral T-Cell Lymphoma, Cutaneous T-Cell Lymphoma, Chronic Myelocytic Leukemia, Acute Lymphoblastic Leukemia
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
286 (Actual)
8. Arms, Groups, and Interventions
Arm Title
selinexor
Arm Type
Experimental
Intervention Type
Drug
Intervention Name(s)
KPT-330
Other Intervention Name(s)
Selinexor
Primary Outcome Measure Information:
Title
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs)
Description
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.
Time Frame
From first dose of study drug administration to end of treatment (up to 27 months)
Title
Recommended Phase 2 Dose (RP2D) of Selinexor
Description
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.
Time Frame
From first dose of study drug administration to end of treatment (up to 27 months)
Secondary Outcome Measure Information:
Title
Maximum Observed Plasma Concentration (Cmax) of Selinexor
Description
Cmax was defined as the maximum observed concentration, taken directly from the plasma concentration.
Time Frame
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
Title
Time to Maximum Observed Concentration (Tmax) of Selinexor
Description
Tmax was defined as time of first observation of Cmax, taken directly from the plasma concentration data.
Time Frame
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
Title
Average Concentration From Time 0 to 24 Hours (Cavg0-24h) of Selinexor
Description
Cavg0-24h was defined as average concentration from time 0 to 24 hours.
Time Frame
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
Title
Area Under the Concentration-Time Curve From Time 0 to t (AUC0-t) of Selinexor
Description
AUC0-t was defined as area under the concentration-time curve from time zero to the last non-zero concentration.
Time Frame
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
Title
Area Under the Concentration-Time Curve From Time 0 Extrapolated to Infinity (AUC0-inf) of Selinexor
Description
AUC0-inf was defined as the area under the concentration-time curve from time zero to infinity (extrapolated).
Time Frame
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
Title
Apparent Volume of Distribution Uncorrected for Fraction Absorbed (Vd/F) of Selinexor
Description
Apparent volume of distribution was calculated as Dose/ (kel *AUC0-inf), uncorrected for fraction absorbed, reported normalized by participant body weight (kilogram [kg]).
Time Frame
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
Title
Apparent Total Body Clearance, Uncorrected for Fraction Absorbed (Cl/F) of Selinexor
Description
Cl/F was calculated as Dose/AUC0-inf, uncorrected for fraction absorbed, reported normalized by participant body weight (kg).
Time Frame
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
Title
Terminal Half-Life (t½) of Selinexor
Description
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.
Time Frame
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
Title
Number of Participants With Overall Response of Selinexor
Description
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).
Time Frame
From first dose of study drug administration to end of treatment (up to 27 months)
Title
Duration of Response
Description
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.
Time Frame
From first dose of study drug administration to end of treatment (up to 27 months)
Title
Progression-free Survival
Description
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.
Time Frame
Cycle 1 Day 1 to End of Treatment (up to 27 months)
Title
Duration of at Least Stable Disease
Description
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.
Time Frame
Cycle 1 Day 1 to End of Treatment (up to 27 months)
Title
Overall Survival
Description
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.
Time Frame
Cycle 1 Day 1 to End of Treatment (up to 27 months)
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria
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.
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
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.
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;
Known active hepatitis A, B, or C infection; or known to be positive for HCV RNA or HBsAg (HBV surface antigen);
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.
Significantly diseased or obstructed gastrointestinal tract or uncontrolled vomiting or diarrhea.
Grade ≥2 peripheral neuropathy at baseline (within 14 days prior to cycle 1 day 1).
Macular degeneration, uncontrolled glaucoma, or markedly decreased visual acuity.
In the opinion of the investigator, patients who are significantly below their ideal body weight.
Facility Information:
Facility Name
Moffitt Cancer Center
City
Tampa
State/Province
Florida
ZIP/Postal Code
33612
Country
United States
Facility Name
Dana-Farber Cancer Institute
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02215
Country
United States
Facility Name
Washington University School of Medicine
City
Saint Louis
State/Province
Missouri
ZIP/Postal Code
63110
Country
United States
Facility Name
Hackensack University Medical Center
City
Hackensack
State/Province
New Jersey
ZIP/Postal Code
07601
Country
United States
Facility Name
Weill Cornell Medical Center
City
New York
State/Province
New York
ZIP/Postal Code
10065
Country
United States
Facility Name
Gabrail Cancer Center Research
City
Canton
State/Province
Ohio
ZIP/Postal Code
44718
Country
United States
Facility Name
The Ohio State University
City
Columbus
State/Province
Ohio
ZIP/Postal Code
43210
Country
United States
Facility Name
Sarah Cannon Research Institute
City
Nashville
State/Province
Tennessee
ZIP/Postal Code
37203
Country
United States
Facility Name
MD Anderson Cancer Center
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States
Facility Name
Tom Baker Cancer Centre
City
Calgary
State/Province
Alberta
ZIP/Postal Code
T2W 4N2
Country
Canada
Facility Name
Princess Margaret Hospital
City
Toronto
State/Province
Ontario
ZIP/Postal Code
M5T 2M9
Country
Canada
Facility Name
Rigshospitalet
City
Copenhagen
ZIP/Postal Code
2100
Country
Denmark
12. IPD Sharing Statement
Plan to Share IPD
Yes
Citations:
PubMed Identifier
29203585
Citation
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.
Results Reference
derived
PubMed Identifier
28468797
Citation
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.
Results Reference
derived
PubMed Identifier
28336527
Citation
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.
Results Reference
derived
PubMed Identifier
23752175
Citation
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.
Results Reference
derived
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Safety Study of the Selective Inhibitor of Nuclear Export (SINE) KPT-330 in Patients With Advanced Hematological Cancer
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