NCT02078349

Phase I Study of KPT330 in Asian Patients

An Investigator Sponsored Phase I Study of the Safety, Pharmacokinetics and Pharmacodynamics of Escalating Doses Followed by Dose Expansion of the Selective Inhibitor of Nuclear Export (SINE) Selinexor (KPT-330) in Asian Patients With Advanced or Metastatic Solid Tumor Malignancies

• Status: Completed
• Phase: Phase 1
• Study type: Interventional
• Enrollment: 120 (actual)
• Sponsor: National University Hospital, Singapore · Academic / Other
• Sex: All
• Age: 21 Years
• Healthy volunteers: Not accepted

Summary

This is an open-label, dose-escalation (Phase 1a) and expansion (Phase 1b) study to evaluate the safety and tolerability of KPT-330 and determine the recommended phase 2 dose (RP2D) in patients with solid tumor malignancies. The study drug KPT-330 or Selinexor works by blocking high levels of exporter proteins in cancer cells so that the tumor suppressor proteins (TSP, proteins that help to protect cells from becoming cancerous) and growth regulatory proteins (GRP, proteins that help control the growth of cells) will remain in the nucleus in its "activated" form. The idea for using this drug is that the blockage of this export of proteins from the nucleus should result in stopping the growth of tumor cells. Based on its mechanism of action, KPT-330 is a new class of drug called Selective Inhibitor of Nuclear Export (SINE). The purposes of this research study are to find out more information about the drug such as: the highest dose of KPT-330 that can be given safely, the side effects it may cause, to examine how the body affects the study drug concentrations in the blood (called pharmacokinetics or PK), to examine the effects of this study drug on the body (called pharmacodynamics or PD) and to gain some information on its usefulness in treating cancer. Benefits of the study include the chance of disease control for patients with treatment refractory cancer for which no other standard treatments are available. Common side effects (35-73%) in humans have mostly been mild and reversible. These include nausea, loss of appetite, fatigue, vomiting and weight loss.

Detailed description

This is a single-centre, phase 1a (dose escalation) and 1b (doses expansion) study to evaluate the safety and tolerability of oral Selinexor in Asian patients with advanced solid malignancies. After the initial screening visit and registration in the study, each patient will be assigned to 3 different schedules, a starting dose of 50 mg/m2 (Schedule 1) given once weekly ; 40 mg/m2 (Schedule 2) with a twice weekly dosing schedule and three times a week at 20mg/m2 (Schedule 3) dosing schedule have been chosen for this study. For Schedule 2, drug administration will occur twice weekly, on days 1 and 3 of the first two weeks (e.g. Monday and Wednesday or Tuesday and Thursday) and for Schedule 3, drug administration will occur three times a week on days 1, 3 and 5 (ie: Monday, Wednesday and Friday). For Schedule 1, one cycle is 4 weeks with 4 doses of Selinexor. In Schedule 2, one cycle is 3 weeks with 4 doses of Selinexor. In Schedule 3, one cycle is 4 weeks with 12 doses of Selinexor. Dose will be escalated using a 3+3 design. Patients who have difficulty tolerating treatment (e.g., due to anorexia, nausea, or fatigue) at any dose level may have their dose reduced by 4-10 mg/m(2) increments to a lowest dose of 11 mg/m(2). Aggressive use of supportive medications is often sufficient to mitigate or eliminate tolerability problems.Supportive care including antinausea/ anti-emetic therapy, acid suppression (H2-blockers and/or proton pump inhibitors), glucocorticoids, anti-diarrheal therapy, and other standard treatments may be administered as per institutional guidelines both prophylactically and for symptomatic patients. A 3+3 design will be used for the dose escalation. A minimum of 3 patients will be enrolled per cohort. Once 3 patients are enrolled in a cohort and have completed at least six days of dosing at the target dose, up to 3 additional patients may be added to that cohort. After up to 6 patients have been accrued to a dose level, that dose level will be closed to accrual until safety assessment of all the 3 to 6 patients is performed through a safety cohort meeting at the end of cycle 1. If the dose level is well tolerated during these 4 weeks at the target dose, then dose escalation will be performed in the next cohort. Dose escalation in the 3+3 design will proceed as follows: * At least 3 patients will be entered into the cohort. Once 3 patients are enrolled in a cohort and have completed at least six days of dosing at the target dose, up to 3 additional patients may be added to that cohort. * If none of the patients in this cohort experience DLT during the 4 weeks at the target dose, dose escalation will be continued as per protocol design * If one of patients experiences first cycle DLT, up to three additional patients will be added to this cohort (maximum 6 will be evaluated in this cohort) and if no additional patients experience DLT (i.e. only 1 out of 6 patients in the cohort experience DLT), dose escalation as per protocol will be allowed. * If a DLT is observed in 2 or more subjects in a cohort of 3 or 6 subjects at a dose level, and a lower dose level has not been tested, then an additional 3 subjects will be enrolled at a lower dose level. * If, following dose escalation, 2 patients in the cohort experience first cycle DLT, this dose will be labelled as Maximally Tolerated Dose (MTD) and the RP2D will be the previous dose at which \<= 1/6 patients experienced a DLT. If only 3 subjects were treated at the previous lower dose level, then an additional 3 subjects will also be recruited for a total of 6 subjects at that dose level. * However an additional cohort of patients may be enrolled at a dose between MTD and the dose below it. If dose level 3 is reached and criteria for determining MTD are not met, further dose escalation for each dose level may occur after discussion with the investigators, Karyopharm and the PI.If one patient in a cohort develops a DLT in Cycle 1, at least 5 additional patients will be enrolled at that dose level. If there are no additional DLTs at that dose level, then doses will be escalated by up to 30-40% and all subsequent cohorts will include \>=3 patients. If one DLT occurs in the first 3 patients enrolled in a cohort, an additional 3 patients will be enrolled. If another DLT occurs at this dose level (i.e., 2 DLTs/6 patients), this dose will be considered the MTD, and the RP2D is defined as the dose level below this dose, provided that that dose level is \<=25% lower than the highest (intolerable) dose tested. This protocol is designed to guide maximal escalation, while ensuring patient safety. In order to achieve this, during each safety cohort review meeting with the investigators, Karyopharm, and PI, a decision will be made on the dose escalation scheme. The recommended phase 2 dose (RP2D) is defined as the next lower dose level below MTD. The MTD is the dose level in which \> 1 of 3 patients or \>= 2 of 6 patients experience DLT, provided that that dose level is \<=25% lower than the highest (intolerable) dose tested. If the projected RP2D is \> 25% lower than the highest dose tested, then an additional cohort of \>=3 patients will be added at a dose that is intermediate between the intolerable dose and the next lower dose. Once RP2D is reached, approximately 60 patients may be enrolled in the Dose Expansion cohort. The dose schedule for the Dose Expansion Phase will be the same as that for the Dose Escalation Phase. There is no maximum duration of participation for any patient enrolled in this study. However it is anticipated that for patients remaining on study for prolonged periods, an Extension study protocol will be made available in the near future.The dose used in the expansion phases of the study will be the RP2D (or lower doses) as determined in the dose escalation phases of the study.

Conditions

• Solid Tumors

Interventions

Type	Name	Description
DRUG	KPT-330	Each dose will consist of KPT-330 (Selinexor) for oral administration on an mg/m2 basis, and should be based on the patient's actual calculated body surface area (BSA) at baseline. Patients with a BSA \>2.5 m(2) will receive a dose based upon a 2.5 m(2) BSA.

Timeline

• Start date: 2014-02-01
• Primary completion: 2020-03-20
• Completion: 2020-03-20
• First posted: 2014-03-05
• Last updated: 2020-09-10

Locations

1 site across 1 country: Singapore