A Phase I Trial to Assess the Effects of Food and Formulation on PK of KPT-330 in Patients With Sarcoma

Sarcoma Clinical Trial

Official title:

An Open-Label Phase IB Trial To Evaluate the Effects of Food and Formulation on Pharmacokinetics of the Oral Selective Inhibitor of Nuclear Export/SINE Compound KPT-330 in Patients With Soft-Tissue or Bone Sarcoma

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01896505
• Other study ID #: KCP-330-003
• Status: Completed
• Phase: Phase 1
• Start date: July 30, 2013
• Est. completion date: October 21, 2016

Study information

• Verified date: March 2023
• Source: Karyopharm Therapeutics Inc
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this research study is to find out more information such as: to determine the effects of high and low fat foods on the pharmacokinetics (PK) of oral KPT-330 tablets and to compare PK of capsules and tablets in Arms 1 and 2; to evaluate tumor response in sarcoma participants in Arm 3; to compare the PK of 60 milligrams (mg) of the new, 2nd generation tablet formulation and 60 mg of the selinexor suspension formula to the current, 1st generation tablets.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 54
• Est. completion date: October 21, 2016
• Est. primary completion date: October 21, 2016
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Patients must have histologically confirmed soft tissue or bone/cartilage sarcoma. Patients with sarcoma of small round blue cell tumor types are allowed. Gastrointestinal stromal tumors (GIST) are excluded.

2. Patients must have received at least one prior anticancer regimen for metastatic disease unless there is no other therapy available and evidence of progressive disease on study entry. Patients with stable disease will be included if there has been failure to respond to another drug(s) within the previous 3 months

Exclusion Criteria:

1. Patients with known liver metastases

2. Radiation, chemotherapy, immunotherapy, any other systemic anticancer therapy or participation in an investigational anti-cancer study = 3 weeks prior to initiation of therapy

3. Patients with known brain metastasis

4. Patients with any gastrointestinal dysfunctions that could interfere with the interpretation of the food effect data

5. Patients with known intolerance to low or high fat meals

6. In the opinion of the investigator, patients who are significantly below their ideal body weight

Related Conditions & MeSH terms

• Sarcoma

Intervention

Drug:
• KCP-330

Locations

Country	Name	City	State
Canada	Princess Margaret Hospital	Toronto	Ontario
United States	Memorial Sloan Kettering Cancer Centre	New York	New York

Sponsors (1)

Lead Sponsor	Collaborator
Karyopharm Therapeutics Inc

Countries where clinical trial is conducted

United States,  Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Area Under the Concentration-time Curve From the Time Zero to the Last Non-zero Concentration (AUC0-t) of Selinexor	AUC0-t was defined as area under the concentration-time curve from time zero to the last non-zero concentration.	Day 1 of weeks 1-3 in Cycle 1: Pre-dose (within 10 minutes before swallowing study drug), 15, 30 minutes, 1, 1.5, 2, 3, 4, 5, 6, 8, 10,18, 24, and 48 hours post-dose
Primary	Area Under the Concentration Time Curve From the Time Zero to Extrapolated to Infinity (AUC0-inf) of Selinexor	AUC0-inf was defined as area under the concentration-time curve from time zero to infinity (extrapolated), AUC0-inf was calculated as AUC0-t + Ct/ elimination rate constant (kel), where: Ct = the last observed non- zero concentration.	Day 1 of weeks 1-3 in Cycle 1: Pre-dose (within 10 minutes before swallowing study drug), 15, 30 minutes, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 18, 24, and 48 hours post-dose
Primary	Maximum Observed Plasma Concentration (Cmax) of Selinexor	Cmax was defined as maximum observed concentration, taken directly from the plasma concentration data.	Day 1 of weeks 1-3 in Cycle 1: Pre-dose (within 10 minutes before swallowing study drug), 15, 30 minutes, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 18, 24, and 48 hours post-dose
Primary	Time of First Maximum Observed Concentration (Tmax) of Selinexor	Tmax was defined as time of first observation of Cmax, taken directly from the plasma concentration data.	Day 1 of weeks 1-3 in Cycle 1: Pre-dose (within 10 minutes before swallowing study drug), 15, 30 minutes, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 18, 24, and 48 hours post-dose
Primary	Terminal Phase Half-Life (t1/2) of Selinexor	t1/2 was the terminal phase half-life, it was calculated as ln(2)/kel.	Day 1 of weeks 1-3 in Cycle 1: Pre-dose (within 10 minutes before swallowing study drug), 15, 30 minutes, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 18, 24, and 48 hours post-dose
Primary	Apparent Total Body Clearance (CL/F) of Selinexor	Apparent total body clearance was calculated as Dose/AUC0-inf, uncorrected for fraction absorbed; reported normalized by participant body weight (kilogram [kg]).	Day 1 of weeks 1-3 in Cycle 1: Pre-dose (within 10 minutes before swallowing study drug), 15, 30 minutes, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 18, 24, and 48 hours post-dose
Primary	Apparent Volume of Distribution (Vd/F) of Selinexor	Vd/F was calculated as Dose/ (kel *AUC0-inf), uncorrected for fraction absorbed; reported normalized by participant body weight (kg).	Day 1 of weeks 1-3 in Cycle 1: Pre-dose (within 10 minutes before swallowing study drug), 15, 30 minutes, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 18, 24, and 48 hours post-dose
Secondary	Percentage of Participants With Best Overall Response According to Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 Criteria	Best overall response rate was defined as the percentage of participants who achieved complete response (CR), and partial response (PR), as assessed by the RECIST v1.1 criteria. CR was defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non target) must have reduction in the short axis to less than (<) 10 millimeter (mm). PR was defined as At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum longest diameter (LD).	From the date of first documented response until the date of documented progression or last disease assessment (up to 39 months)
Secondary	Duration of Stable Disease as Per RECIST v1.1 Criteria	Duration of at least stable disease was defined as the time from the date of first dose of study treatment to first documented radiologic evidence of disease recurrence or progression as per RECIST v1.1 Criteria. Participants without evidence of progression were censored at time of last disease assessment. Progressive Disease (PD) was defined as at least a 20% increase in the sum of diameters of measured lesions taking as references the smallest sum of diameters recorded since the treatment started. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Appearance of one or more new lesions also constituted progressive disease.	From the date of first dose of study treatment to first documented radiologic evidence of disease recurrence or progression, censored date (up to 39 months)
Secondary	Progression Free Survival (PFS) as Per RECIST v1.1 Criteria	PFS was defined as the time from the date of randomization until the first date of Independent Review Committee (IRC)-confirmed PD per RECIST v1.1, or death due to any cause. PD was defined as at least a 20% increase in the sum of the longest diameter (SLD), taking as reference the smallest sum of the longest diameter (SLD) recorded from baseline or the appearance of 1 or more new lesions. Participants who were last known to be alive and without evidence of progression were censored at time of last disease assessment. If date of progression or death occurred after more than 1 missed disease assessment interval, or 30 days after end of treatment, participants were censored at the time of last evaluable disease assessment prior to the missed assessment.	From first dose of study treatment to time of disease progression or death, censored date (up to 39 months)
Secondary	Overall Survival (OS)	OS was defined as the time from date first dose of study treatment to the date of death. Participants who were still alive prior to the data cutoff for final efficacy analysis, or who dropped out prior to study end, were censored at the day they were last known to be alive.	From first dose of study treatment to death, censored date (up to 39 months)
Secondary	Time to Progression (TTP)	TTP was defined as the time from date of first dose of study treatment to first documented evidence of disease recurrence or progression, or death due to disease progression, whichever occurred first. Participants without evidence of progression were censored at time of last evaluable disease assessment.	From first dose of study treatment to first documented evidence of disease recurrence or progression, or death, censored date (up to 39 months)
Secondary	Number of Participants With Growth Modulation Index (GMI) Less Than or Equal to (<=) 1.33 and Greater Than (>) 1.33	GMI was defined as the ratio between the TTP with selinexor and the TTP with the most recent prior treatment. GMI was calculated, using a previously described threshold of 1.3 or greater as a sign of potential drug activity and improved overall survival.	Up to 39 months
Secondary	Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs	An AE was any untoward medical occurrence in a 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. SAE defined as any AE, occurring at any dose (including after the informed consent form was signed and prior to dosing) that and regardless of causality that: results in death, is life-threatening (participant was at immediate risk of death from event as it occurred), requires in-patient hospitalization (formal admission to a hospital for medical reasons) or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, results in a congenital anomaly/birth defect. TEAE was defined as any AE with onset or worsening of a pre-existing condition on or after the first administration of study treatment through 30 days following last dose or any event considered drug-related by the investigator through the end of the study.	From screening up to 30 days post last study drug dose (up to 39 months)
Secondary	Number of Participants With Treatment-Emergent Adverse Events (TEAEs) by Severity	AE was defined as the appearance of (or worsening of any pre-existing) undesirable sign, symptom, or medical condition that occur after participant's signed informed consent obtained. TEAE was defined as any AE with onset or worsening of a pre-existing condition on or after the first administration of study treatment through 28 days following last dose or any event considered drug-related by the investigator through the end of the study. Grade refers to the severity of the AE. The CTCAE displays Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1: mild, Grade 2: moderate, Grade 3: severe, Grade 4: life-threatening, and Grade 5: death.	From screening up to 30 days post last study drug dose (up to 39 months)
Secondary	Number of Participants With Clinically Significant Laboratory Abnormalities	Number of participants with clinically significant laboratory abnormalities including clinical chemistry, hematology, coagulation and urinalysis. Number of participants with clinically significant laboratory abnormalities which were deemed clinically significant by the investigator were reported.	From screening up to 30 days post last study drug dose (up to 39 months)
Secondary	Number of Participants With Clinically Significant Changes in Vital Signs	Vital signs included blood pressure (systolic blood pressure and diastolic blood pressure). Measurements were made after the participant had been resting supine for a minimum of 5 minutes. Clinically significant findings were defined as such in the opinion of the investigator occurring at any time on treatment from normal pre-dose based on the condition met (Yes/No). Number of participants with clinically significant changes in vital signs with condition (Yes) were only reported.	From screening up to 30 days post last study drug dose (up to 39 months)
Secondary	Number of Participants With Clinically Significant Changes in Electrocardiogram (ECGs)	Twelve lead ECGs were obtained after the participant has rested in a supine position for at least 5 minutes. Clinically significant findings were defined as such in the opinion of the investigator or designated physician occurring at any time on treatment from normal pre-dose.	From screening up to 30 days post last study drug dose