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NCT01607892

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

Completed Phase 1 Results posted Last updated 26 January 2023
What this trial tests

Phase 1 trial testing KPT-330 in Hematological Malignancies in 286 participants. Completed in 13 October 2015.

Timeline
23 July 2012
Primary endpoint
13 October 2015
13 October 2015

Quick facts

Lead sponsorKaryopharm Therapeutics Inc
PhasePhase 1
StatusCompleted
Study typeINTERVENTIONAL
Allocationna
Designsingle group
Maskingnone
Primary purposetreatment
Enrollment286
Start date23 July 2012
Primary completion13 October 2015
Estimated completion13 October 2015
Sites12 locations across Denmark, Canada, United States

Drugs / interventions tested

Conditions studied

Sponsor

Karyopharm Therapeutics Inc — full company profile →

Who can join

18 and older, any sex, with Hematological Malignancies. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs) Primary · 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 thes

At Least One TEAE
GroupValue95% CI
Diffuse Large B-cell Lymphoma (DLBCL)58
Non-Hodgkin Lymphoma (NHL) Excluding DLBCL27
Multiple Myeloma (MM)81
Acute Myeloid Leukemia (AML)95
Other Hematological Malignancies (ALL, CML and CLL)24
At Least One Serious TEAE
GroupValue95% CI
Diffuse Large B-cell Lymphoma (DLBCL)33
Non-Hodgkin Lymphoma (NHL) Excluding DLBCL7
Multiple Myeloma (MM)52
Acute Myeloid Leukemia (AML)73
Other Hematological Malignancies (ALL, CML and CLL)13
Recommended Phase 2 Dose (RP2D) of Selinexor Primary · 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.

GroupValue95% CI
Advanced Hematological Malignancies.35
Maximum Observed Plasma Concentration (Cmax) of Selinexor Secondary · 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.

GroupValue95% CI
Selinexor (3 mg/m^2)49.0± NA
Selinexor (6 mg/m^2)50.0± 61.1
Selinexor (12 mg/m^2)149± 37.6
Selinexor (16.8 mg/m^2)205± 46.8
Selinexor (23 mg/m^2)262± 37.5
Selinexor (30 mg/m^2)387± 37.1
Selinexor (35 mg/m^2)407± 44.4
Selinexor (40 mg/m^2)416± 36.6
Selinexor (46 mg/m^2)670± 18.5
Selinexor (55 mg/m^2)583± 41.4
Selinexor (60 mg/m^2)668± 33.2
Selinexor (70 mg/m^2)800± 32.4
Time to Maximum Observed Concentration (Tmax) of Selinexor Secondary · 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.

GroupValue95% CI
Selinexor (3 mg/m^2)NA2.1 – 2.2
Selinexor (6 mg/m^2)4.02.1 – 7.7
Selinexor (12 mg/m^2)3.01.1 – 4.2
Selinexor (16.8 mg/m^2)2.080.92 – 8.5
Selinexor (23 mg/m^2)2.01.0 – 7.8
Selinexor (30 mg/m^2)2.00.72 – 4.4
Selinexor (35 mg/m^2)2.00.92 – 4.1
Selinexor (40 mg/m^2)4.02.0 – 7.5
Selinexor (46 mg/m^2)2.00.50 – 4.2
Selinexor (55 mg/m^2)2.91.0 – 8.0
Selinexor (60 mg/m^2)1.91.8 – 2.0
Selinexor (70 mg/m^2)2.01.0 – 4.0
Average Concentration From Time 0 to 24 Hours (Cavg0-24h) of Selinexor Secondary · 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.

GroupValue95% CI
Selinexor (3 mg/m^2)17.0± NA
Selinexor (6 mg/m^2)20.3± 94.8
Selinexor (12 mg/m^2)61.8± 39.9
Selinexor (16.8 mg/m^2)79.0± 61.8
Selinexor (23 mg/m^2)108± 46.8
Selinexor (30 mg/m^2)160± 38.0
Selinexor (35 mg/m^2)168± 54.0
Selinexor (40 mg/m^2)163± 29.2
Selinexor (46 mg/m^2)297± 26.3
Selinexor (55 mg/m^2)208± 19.1
Selinexor (60 mg/m^2)337± 4.2
Selinexor (70 mg/m^2)353± 26.2
Area Under the Concentration-Time Curve From Time 0 to t (AUC0-t) of Selinexor Secondary · 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.

GroupValue95% CI
Selinexor (3 mg/m^2)331± NA
Selinexor (6 mg/m^2)564± 41.9
Selinexor (12 mg/m^2)1459± 20.5
Selinexor (16.8 mg/m^2)1829± 23.3
Selinexor (23 mg/m^2)2774± 36.7
Selinexor (30 mg/m^2)3461± 26.9
Selinexor (35 mg/m^2)3901± 29.2
Selinexor (40 mg/m^2)4481± 23.8
Selinexor (46 mg/m^2)5228± 21.6
Selinexor (55 mg/m^2)5601± 36.2
Selinexor (60 mg/m^2)5282± 57.9
Selinexor (70 mg/m^2)5466± 45.7
Area Under the Concentration-Time Curve From Time 0 Extrapolated to Infinity (AUC0-inf) of Selinexor Secondary · 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).

GroupValue95% CI
Selinexor (3 mg/m^2)348± NA
Selinexor (6 mg/m^2)733± NA
Selinexor (12 mg/m^2)1529± 18.7
Selinexor (16.8 mg/m^2)1867± 23.6
Selinexor (23 mg/m^2)2645± 1111
Selinexor (30 mg/m^2)3513± 26.0
Selinexor (35 mg/m^2)3948± 28.6
Selinexor (40 mg/m^2)4552± 23.7
Selinexor (46 mg/m^2)5284± 21.0
Selinexor (55 mg/m^2)6089± 32.3
Selinexor (60 mg/m^2)6964± 12.2
Selinexor (70 mg/m^2)7803± 8.5
Apparent Volume of Distribution Uncorrected for Fraction Absorbed (Vd/F) of Selinexor Secondary · 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 \[kg\]).

GroupValue95% CI
Selinexor (3 mg/m^2)1.6± NA
Selinexor (6 mg/m^2)1.5± NA
Selinexor (12 mg/m^2)1.9± 21.2
Selinexor (16.8 mg/m^2)1.9± 29.9
Selinexor (23 mg/m^2)1.9± 34.1
Selinexor (30 mg/m^2)1.7± 24.1
Selinexor (35 mg/m^2)2.0± 30.3
Selinexor (40 mg/m^2)1.7± 29.1
Selinexor (46 mg/m^2)1.8± 12.9
Selinexor (55 mg/m^2)1.9± 27.9
Selinexor (60 mg/m^2)1.6± 23.0
Selinexor (70 mg/m^2)1.7± 13.4
Apparent Total Body Clearance, Uncorrected for Fraction Absorbed (Cl/F) of Selinexor Secondary · 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).

GroupValue95% CI
Selinexor (3 mg/m^2)0.19± NA
Selinexor (6 mg/m^2)0.21± NA
Selinexor (12 mg/m^2)0.21± 26.6
Selinexor (16.8 mg/m^2)0.22± 22.8
Selinexor (23 mg/m^2)0.20± 54.9
Selinexor (30 mg/m^2)0.21± 25.3
Selinexor (35 mg/m^2)0.22± 25.9
Selinexor (40 mg/m^2)0.23± 26.2
Selinexor (46 mg/m^2)0.22± 12.9
Selinexor (55 mg/m^2)0.20± 24.6
Selinexor (60 mg/m^2)0.19± 27.5
Selinexor (70 mg/m^2)0.22± 7.8
Terminal Half-Life (t½) of Selinexor Secondary · 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.

GroupValue95% CI
Selinexor (3 mg/m^2)NA5.5 – 6.1
Selinexor (6 mg/m^2)NA4.4 – 5.1
Selinexor (12 mg/m^2)6.24.2 – 7.8
Selinexor (16.8 mg/m^2)6.13.1 – 8.7
Selinexor (23 mg/m^2)6.93.5 – 12.0
Selinexor (30 mg/m^2)5.83.9 – 8.4
Selinexor (35 mg/m^2)6.24.6 – 10.4
Selinexor (40 mg/m^2)4.82.7 – 9.8
Selinexor (46 mg/m^2)5.74.1 – 6.8
Selinexor (55 mg/m^2)6.65.4 – 10.1
Selinexor (60 mg/m^2)5.94.3 – 5.9
Selinexor (70 mg/m^2)5.25.0 – 6.0
Number of Participants With Overall Response of Selinexor Secondary · 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).

Complete response
GroupValue95% CI
Diffuse Large B-cell Lymphoma (DLBCL)5
Non-Hodgkin Lymphoma (NHL) Excluding DLBCL1
Multiple Myeloma (MM)0
Acute Myeloid Leukemia (AML)0
Other Hematological Malignancies (ALL, CML and CLL)0
Partial response
GroupValue95% CI
Diffuse Large B-cell Lymphoma (DLBCL)7
Non-Hodgkin Lymphoma (NHL) Excluding DLBCL8
Multiple Myeloma (MM)6
Acute Myeloid Leukemia (AML)0
Other Hematological Malignancies (ALL, CML and CLL)0
Morphologic complete remission
GroupValue95% CI
Diffuse Large B-cell Lymphoma (DLBCL)0
Non-Hodgkin Lymphoma (NHL) Excluding DLBCL0
Multiple Myeloma (MM)0
Acute Myeloid Leukemia (AML)4
Other Hematological Malignancies (ALL, CML and CLL)0
Partial remission
GroupValue95% CI
Diffuse Large B-cell Lymphoma (DLBCL)0
Non-Hodgkin Lymphoma (NHL) Excluding DLBCL0
Multiple Myeloma (MM)0
Acute Myeloid Leukemia (AML)3
Other Hematological Malignancies (ALL, CML and CLL)1
Complete cytogenetic response
GroupValue95% CI
Diffuse Large B-cell Lymphoma (DLBCL)0
Non-Hodgkin Lymphoma (NHL) Excluding DLBCL0
Multiple Myeloma (MM)0
Acute Myeloid Leukemia (AML)0
Other Hematological Malignancies (ALL, CML and CLL)0
Complete hematological response
GroupValue95% CI
Diffuse Large B-cell Lymphoma (DLBCL)0
Non-Hodgkin Lymphoma (NHL) Excluding DLBCL0
Multiple Myeloma (MM)0
Acute Myeloid Leukemia (AML)0
Other Hematological Malignancies (ALL, CML and CLL)0
Duration of Response Secondary · 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.

GroupValue95% CI
Diffuse Large B-cell Lymphoma (DLBCL)335.548 – NA
Non-Hodgkin Lymphoma (NHL) Excluding DLBCL25136 – NA
Multiple Myeloma (MM)18057 – NA
Acute Myeloid Leukemia (AML)7629 – NA
Other Hematological Malignancies (ALL, CML and CLL)NANA – NA

Adverse events — posted to ClinicalTrials.gov

Time frame: From first dose of study drug administration to end of treatment (up to 27 months). Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Diffuse Large B-cell Lymphoma (DLBCL)
Serious: 33/58 (57%)
Deaths:
Non-Hodgkin Lymphoma (NHL) Excluding DLBCL
Serious: 7/27 (26%)
Deaths:
Multiple Myeloma (MM)
Serious: 52/81 (64%)
Deaths:
Acute Myeloid Leukemia (AML)
Serious: 73/95 (77%)
Deaths:
Other Hematological Malignancies (ALL, CML and CLL)
Serious: 13/24 (54%)
Deaths:

Serious adverse events (147 terms)

ReactionSystemDiffuse Large B-cell Lymph…Non-Hodgkin Lymphoma (NHL)…Multiple Myeloma (MM)Acute Myeloid Leukemia (AML)Other Hematological Malign…
SepsisInfections and infestations
Febrile neutropeniaBlood and lymphatic system disorders
PneumoniaInfections and infestations
FatigueGeneral disorders
PyrexiaGeneral disorders
DehydrationMetabolism and nutrition disorders
Malignant neoplasm progressionNeoplasms benign, malignant and unspecified (incl cysts and polyps)
ThrombocytopeniaBlood and lymphatic system disorders
Acute kidney injuryRenal and urinary disorders
Lung infectionInfections and infestations
BacteraemiaInfections and infestations
DeathGeneral disorders
Confusional stateGeneral disorders
Respiratory failureRespiratory, thoracic and mediastinal disorders
VomitingGastrointestinal disorders
Staphylococcal infectionInfections and infestations
EmbolismVascular disorders
HypotensionVascular disorders
AstheniaGeneral disorders
Disease progressionGeneral disorders
Multiple organ dysfunction syndromeGeneral disorders
DeliriumPsychiatric disorders
FallInjury, poisoning and procedural complications
Aspartate aminotransferase increasedInvestigations
TachycardiaCardiac disorders
Other adverse events (114 terms — click to expand)

ReactionSystemDiffuse Large B-cell Lymph…Non-Hodgkin Lymphoma (NHL)…Multiple Myeloma (MM)Acute Myeloid Leukemia (AML)Other Hematological Malign…
FatigueGeneral disorders
NauseaGastrointestinal disorders
Decreased appetiteMetabolism and nutrition disorders
ThrombocytopeniaBlood and lymphatic system disorders
AnaemiaBlood and lymphatic system disorders
DiarrhoeaGastrointestinal disorders
VomitingGastrointestinal disorders
HyponatraemiaMetabolism and nutrition disorders
Weight decreasedInvestigations
DyspnoeaRespiratory, thoracic and mediastinal disorders
NeutropeniaBlood and lymphatic system disorders
ConstipationGastrointestinal disorders
DehydrationMetabolism and nutrition disorders
EpistaxisRespiratory, thoracic and mediastinal disorders
HypercreatininaemiaMetabolism and nutrition disorders
PyrexiaGeneral disorders
DysgeusiaNervous system disorders
HypokalaemiaMetabolism and nutrition disorders
Oedema peripheralGeneral disorders
Vision blurredEye disorders
DizzinessNervous system disorders
HypotensionVascular disorders
Back painMusculoskeletal and connective tissue disorders
HypomagnesaemiaMetabolism and nutrition disorders
CoughRespiratory, thoracic and mediastinal disorders
HyperglycaemiaMetabolism and nutrition disorders
HypocalcaemiaMetabolism and nutrition disorders
StomatitisGastrointestinal disorders
HeadacheNervous system disorders
Confusional statePsychiatric disorders
LeukopeniaBlood and lymphatic system disorders
Muscular weaknessMusculoskeletal and connective tissue disorders
AstheniaGeneral disorders
ArthralgiaMusculoskeletal and connective tissue disorders
Febrile neutropeniaBlood and lymphatic system disorders
HypophosphataemiaMetabolism and nutrition disorders
Abdominal painGastrointestinal disorders
HyperkalaemiaMetabolism and nutrition disorders
Alanine aminotransferase increasedInvestigations
Aspartate aminotransferase increasedInvestigations

Most-reported serious reactions: Sepsis, Febrile neutropenia, Pneumonia, Fatigue, Pyrexia, Dehydration, Malignant neoplasm progression, Thrombocytopenia.

Data from ClinicalTrials.gov NCT01607892 adverse events section.

Sponsor's own description

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.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

  1. Molecular landscape of acute myeloid leukemia in younger adults and its clinical relevance.
    Grimwade D, Ivey A, Huntly BJ. · · 2016 · cited 308× · PMID 26660431 · DOI 10.1182/blood-2015-07-604496
  2. CRM1 inhibition induces tumor cell cytotoxicity and impairs osteoclastogenesis in multiple myeloma: molecular mechanisms and therapeutic implications.
    Tai YT, Landesman Y, Acharya C, Calle Y, et al · · 2014 · cited 259× · PMID 23588715 · DOI 10.1038/leu.2013.115
  3. XPO1-dependent nuclear export as a target for cancer therapy.
    Azizian NG, Li Y. · · 2020 · cited 183× · PMID 32487143 · DOI 10.1186/s13045-020-00903-4
  4. Prognostic impact and targeting of CRM1 in acute myeloid leukemia.
    Kojima K, Kornblau SM, Ruvolo V, Dilip A, et al · · 2013 · cited 176× · PMID 23564911 · DOI 10.1182/blood-2012-08-447581
  5. KPT-330 inhibitor of CRM1 (XPO1)-mediated nuclear export has selective anti-leukaemic activity in preclinical models of T-cell acute lymphoblastic leukaemia and acute myeloid leukaemia.
    Etchin J, Sanda T, Mansour MR, Kentsis A, et al · · 2013 · cited 159× · PMID 23373539 · DOI 10.1111/bjh.12231
  6. Genome-wide studies in multiple myeloma identify XPO1/CRM1 as a critical target validated using the selective nuclear export inhibitor KPT-276.
    Schmidt J, Braggio E, Kortuem KM, Egan JB, et al · · 2013 · cited 132× · PMID 23752175 · DOI 10.1038/leu.2013.172
  7. A phase 1 clinical trial of single-agent selinexor in acute myeloid leukemia.
    Garzon R, Savona M, Baz R, Andreeff M, et al · · 2017 · cited 127× · PMID 28336527 · DOI 10.1182/blood-2016-11-750158
  8. Selective inhibitors of nuclear export (SINE)--a novel class of anti-cancer agents.
    Parikh K, Cang S, Sekhri A, Liu D. · · 2014 · cited 124× · PMID 25316614 · DOI 10.1186/s13045-014-0078-0

Verify or expand the search:

Other trials of KPT-330

Trials testing the same drug.

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Trials by the same sponsor.

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Data sources for this page

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Primary sources · FDA · ClinicalTrials.gov · EMA · SEC EDGAR · ChEMBL · Wikidata · full sourcing