Clinical trial NCT01607892: 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
Overall status: COMPLETED
Phase: PHASE1
Conditions: 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
Lead sponsor: Karyopharm Therapeutics Inc
Sponsor class: INDUSTRY
First posted: 2012-05-30
Enrollment: 286
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.


Eligibility criteria: 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.

Primary outcomes:
measure: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs)
timeFrame: From first dose of study drug administration to end of treatment (up to 27 months)
measure: Recommended Phase 2 Dose (RP2D) of Selinexor
timeFrame: From first dose of study drug administration to end of treatment (up to 27 months)
Secondary outcomes:
measure: Maximum Observed Plasma Concentration (Cmax) of Selinexor
timeFrame: 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
measure: Time to Maximum Observed Concentration (Tmax) of Selinexor
timeFrame: 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
measure: Average Concentration From Time 0 to 24 Hours (Cavg0-24h) of Selinexor
timeFrame: 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
measure: Area Under the Concentration-Time Curve From Time 0 to t (AUC0-t) of Selinexor
timeFrame: 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
measure: Area Under the Concentration-Time Curve From Time 0 Extrapolated to Infinity (AUC0-inf) of Selinexor
timeFrame: 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
measure: Apparent Volume of Distribution Uncorrected for Fraction Absorbed (Vd/F) of Selinexor
timeFrame: 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
measure: Apparent Total Body Clearance, Uncorrected for Fraction Absorbed (Cl/F) of Selinexor
timeFrame: 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
measure: Terminal Half-Life (t½) of Selinexor
timeFrame: 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
measure: Number of Participants With Overall Response of Selinexor
timeFrame: From first dose of study drug administration to end of treatment (up to 27 months)
measure: Duration of Response
timeFrame: From first dose of study drug administration to end of treatment (up to 27 months)
measure: Progression-free Survival
timeFrame: Cycle 1 Day 1 to End of Treatment (up to 27 months)
measure: Duration of at Least Stable Disease
timeFrame: Cycle 1 Day 1 to End of Treatment (up to 27 months)
measure: Overall Survival
timeFrame: Cycle 1 Day 1 to End of Treatment (up to 27 months)
Other outcomes:
Locations:
city: Tampa
country: United States
facility: Moffitt Cancer Center
state: Florida
city: Boston
country: United States
facility: Dana-Farber Cancer Institute
state: Massachusetts
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Hackensack
country: United States
facility: Hackensack University Medical Center
state: New Jersey
city: New York
country: United States
facility: Weill Cornell Medical Center
state: New York
city: Canton
country: United States
facility: Gabrail Cancer Center Research
state: Ohio
city: Columbus
country: United States
facility: The Ohio State University
state: Ohio
city: Nashville
country: United States
facility: Sarah Cannon Research Institute
state: Tennessee
city: Houston
country: United States
facility: MD Anderson Cancer Center
state: Texas
city: Calgary
country: Canada
facility: Tom Baker Cancer Centre
state: Alberta
city: Toronto
country: Canada
facility: Princess Margaret Hospital
state: Ontario
city: Copenhagen
country: Denmark
facility: Rigshospitalet
Study officials:
References:
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.
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.
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.
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.