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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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ClinicalTrials.gov Identifier: NCT01607892
Recruitment Status : Completed
First Posted : May 30, 2012
Results First Posted : April 1, 2021
Last Update Posted : April 1, 2021
Sponsor:
Information provided by (Responsible Party):
Karyopharm Therapeutics Inc

Tracking Information
First Submitted Date  ICMJE May 16, 2012
First Posted Date  ICMJE May 30, 2012
Results First Submitted Date  ICMJE February 1, 2021
Results First Posted Date  ICMJE April 1, 2021
Last Update Posted Date April 1, 2021
Actual Study Start Date  ICMJE July 23, 2012
Actual Primary Completion Date October 13, 2015   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 5, 2021)
  • Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs) [ Time Frame: From first dose of study drug administration to end of treatment (up to 27 months) ]
    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 [ Time Frame: From first dose of study drug administration to end of treatment (up to 27 months) ]
    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.
Original Primary Outcome Measures  ICMJE
 (submitted: May 25, 2012)
Number of participants with Adverse Events [ Time Frame: 2 and 12 months ]
Severity of Adverse Events
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: March 5, 2021)
  • Maximum Observed Plasma Concentration (Cmax) of Selinexor [ 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 ]
    Cmax was defined as the maximum observed concentration, taken directly from the plasma concentration.
  • Time to Maximum Observed Concentration (Tmax) of Selinexor [ 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 ]
    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 [ 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 ]
    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 [ 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 ]
    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 [ 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 ]
    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 [ 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 ]
    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 [ 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 ]
    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 [ 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 ]
    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 [ Time Frame: From first dose of study drug administration to end of treatment (up to 27 months) ]
    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 [ Time Frame: From first dose of study drug administration to end of treatment (up to 27 months) ]
    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 [ Time Frame: Cycle 1 Day 1 to End of Treatment (up to 27 months) ]
    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 [ Time Frame: Cycle 1 Day 1 to End of Treatment (up to 27 months) ]
    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 [ Time Frame: Cycle 1 Day 1 to End of Treatment (up to 27 months) ]
    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.
Original Secondary Outcome Measures  ICMJE
 (submitted: May 25, 2012)
Area under the plasma concentration versus time curve (AUC) of KPT-330 [ Time Frame: 2 and 12 months ]
Changes in AUC over time
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Safety Study of the Selective Inhibitor of Nuclear Export (SINE) KPT-330 in Patients With Advanced Hematological Cancer
Official Title  ICMJE 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
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.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Hematological Malignancies
Intervention  ICMJE Drug: KPT-330
Other Name: Selinexor
Study Arms  ICMJE Experimental: selinexor
Intervention: Drug: KPT-330
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: March 5, 2021)
286
Original Estimated Enrollment  ICMJE
 (submitted: May 25, 2012)
72
Actual Study Completion Date  ICMJE October 13, 2015
Actual Primary Completion Date October 13, 2015   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Canada,   Denmark,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01607892
Other Study ID Numbers  ICMJE KCP-330-001
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Responsible Party Karyopharm Therapeutics Inc
Study Sponsor  ICMJE Karyopharm Therapeutics Inc
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Michael Kauffman, MD, Ph.D Karyopharm Therapeutics Inc
PRS Account Karyopharm Therapeutics Inc
Verification Date March 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP