Safety Study of KPT-330 (Selinexor) in Patients With Advanced or Metastatic Solid Tumor Cancer

Solid Tumor Clinical Trial

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 or Metastatic Solid Tumor Malignancies

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01607905
• Other study ID #: KCP-330-002
• Status: Completed
• Phase: Phase 1
• Start date: June 18, 2012
• Est. completion date: March 15, 2016

Study information

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

Clinical Trial Summary

Phase 1 study to evaluate the safety and tolerability of selinexor and determine the Recommended Phase 2 Dose (RP2D) of selinexor for advanced or metastatic solid tumor malignancies.

Description:

This is a phase 1a and phase 1b, open-label, dose-escalation study to evaluate the safety and tolerability of selinexor and determine the RP2D in patients with solid tumor malignancies.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 192
• Est. completion date: March 15, 2016
• Est. primary completion date: March 15, 2016
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Dose Escalation Phase: Patients with advanced or metastatic solid tumors for which no standard therapy is available. For Schedule 6 only: patients with colorectal cancer with liver metastasis.

Dose Expansion Phase: Previously treated, metastatic or advanced recurrent malignancy with 1 of the following diagnoses, which has been confirmed histologically or cytologically:

• Up to 12 patients with metastatic colorectal cancer with a history of progression or recurrence following prior fluoropyrimidine, irinotecan and platinum containing regimens as well as bevacizumab. In addition, patients with Kras wild type tumor must have received at least one EGFR blocker.

• Up to 6 patients with histological or cytological documentation of advanced ovarian, fallopian tube, or primary peritoneal carcinoma with a history of progression or recurrence following at least one prior platinum and one taxane based chemotherapy

• Up to 12 patients with incurable Squamous cell cancers as follows:

1. A minimum of 4 Squamous Non-Small Cell Lung Cancer (Sq-NSCLC)

2. A minimum of 4 Squamous Cell Carcinomas of the Head and Neck (Sq-HNC)

3. Squamous Cell Carcinoma of the Cervix (SqCC) All patient with Squamous Cell Carcinomas should have a documented history of progression or recurrence following at least one prior platinum based chemotherapy or chemotherapy/radiation containing regimen

• Up to 6 patients with castration-resistant prostate cancer (CRPC) that was pathologically confirmed as adenocarcinoma of the prostate and with evidence of metastatic disease on bone scan or other imaging. Patient must have progressive disease after at least one hormonal treatment and one cytotoxic therapy e.g. with docetaxel, mitoxantrone.

• Up to 12 patients with unresectable metastatic melanoma whose disease progressed on at least 1 prior systemic anticancer regimen (chemotherapy, biological or immunotherapy, or targeted therapy). Enrollment to this cohort may have been stopped before reaching 12 patients once the dose-escalation portion of the study was completed.

• Approximately 6 patients with advanced or metastatic solid tumors were to be enrolled on Schedule 8 at a starting dose of 35 mg/m^2 to assess general tolerability and activity of selinexor.

2. Dose Escalation Phase: Patients have exhausted, or be deemed to not benefit from, further conventional therapy and have evidence of progressive disease on study entry.

Both Dose Escalation and Expansion Phases: There is no upper limit on the number of prior treatments provided that all inclusion criteria are met and exclusion criteria are not met. Hormone ablation therapy is considered an anticancer regimen. Radiation and surgery are not considered anticancer regimes.

Exclusion Criteria:

1. Radiation, chemotherapy, or immunotherapy or any other anticancer therapy =3 weeks prior to cycle 1 day 1 and mitomycin C and radioimmunotherapy 6 weeks prior to cycle 1 day 1;

2. Except for patients with GBM/ AnaA in the Expansion Phase, patients with active CNS malignancy are excluded. Asymptomatic small lesions are not considered active. Treated lesions may be considered inactive if they are stable for at least 3 months.

Related Conditions & MeSH terms

• Neoplasms
• Solid Tumor

Intervention

Drug:
• Selinexor
Participants in this study will receive selinexor orally at dose levels specified for their respective dose cohorts. Dosing will begin at 3 mg/m^2 twice a week and will escalate until the MTD or RP2D is determined. Cycles will be repeated in 4-week (28 days for schedule 1 to 7) and 3-week (21 days for schedule 8) intervals until progression of disease, unacceptable toxicity, or another discontinuation criterion is met. In the case of toxicity, dose adjustment will be permitted.
• Acetaminophen
Oral 500 mg (in Cycle 1, Week 1) to 1000 mg (in Cycle 1, Week 2 and onwards) of acetaminophen will be administered 1 hour prior to each selinexor dose up to 8 doses per cycle (28 days per cycle)

Locations

Country	Name	City	State
Canada	Princess Margaret Hospital	Toronto	Ontario
Denmark	Rigshospitalet	Copenhagen
United States	Gabrail Cancer Center	Canton	Ohio
United States	Karmanos Cancer Institute	Detroit	Michigan
United States	Memorial Sloan-Kettering Cancer Center	New York	New York
United States	Moffitt Cancer Center	Tampa	Florida

Sponsors (1)

Lead Sponsor	Collaborator
Karyopharm Therapeutics Inc

Countries where clinical trial is conducted

United States,  Canada,  Denmark, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)	An Adverse Event (AE) was defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. TEAE was defined as an adverse event with an onset that occurs after receiving study drug. A serious adverse event (SAE) was defined as an AE that meets one or more of the mentioned criteria; is fatal, life threatening, required in-patient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, congenital anomaly/birth defect, or important medical events. Number of participants with TEAEs and TESAEs were reported.	From start of study drug administration to 30 days after last dose of study treatment (maximum duration of 45 months)
Primary	Number of Participants With Treatment-related Treatment-emergent Adverse Events	An AE was defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. TEAE was defined as an adverse event with an onset that occurs after receiving study drug. A treatment-related AE was any untoward medical occurrence in a clinical investigation participant administered a medicinal product; the event had a causal relationship with the treatment or usage.	From start of study drug administration to 30 days after last dose of study treatment (maximum duration of 45 months)
Primary	Number of Participants With Treatment-emergent Adverse Events (TEAEs) Greater Than or Equal to Grade 3, Based on National Cancer Institute Common Terminology Criteria (NCI-CTCAE), Version 4.03	An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. As per NCI-CTCAE version 4.03, Grade 1: asymptomatic or mild symptoms, clinical or diagnostic observations only, intervention not indicated; Grade 2: moderate, minimal, local or noninvasive intervention indicated, limiting age-appropriate instrumental activities of daily life (ADL); Grade 3: severe or medically significant but not immediately life-threatening, hospitalization or prolongation of existing hospitalization indicated, disabling, limiting self-care ADL; Grade 4: life-threatening consequence, urgent intervention indicated; Grade 5: death related to AE. A treatment related AE was any untoward medical occurrence in a clinical investigation participant administered a product or medical device; the event had a causal relationship with the treatment or usage.	From start of study drug administration to 30 days after last dose of study treatment (maximum duration of 45 months)
Primary	Number of Participants Who Experienced Dose Limiting Toxicity (DLT)	Evaluation of DLTs was only conducted in participants who participated in the Dose-escalation Phase. A DLT was defined as any of the following, considered possibly related to drug administration, occurring in the first 28 days (or 21 days for participants on Schedule 8) at the target dose (ie, for Schedule 2 this meant the first 4 weeks after the 12 mg/m2 run-in week): Missed selinexor doses due to drug-related toxicities, discontinuation of a participant due to a toxicity that was at least possibly related to study drug before completing Cycle 1.	Cycle 1 only (28-day cycle)
Primary	Recommended Phase 2 Dose (RP2D)	The RP2D was the maximum tolerated dose (MTD) or less. MTD was defined as the next lower dose level below the one in which >1 of 3 participants or =2 of 6 participants experienced DLT, provided that dose level was =25 percent (%) lower than the highest (intolerable) dose tested. If the projected MTD was >25% lower than the highest dose tested, then an additional cohort of =3 participants was added at a dose that was intermediate between the intolerable dose and the next lower dose.	From start of study drug administration to 30 days after last dose of study treatment (maximum duration of 45 months)
Secondary	Maximum Observed Plasma Concentration (Cmax) of Selinexor	Cmax was defined as maximum observed concentration, taken directly from the plasma concentration data.	Cycle1, Day1: Pre-dose, 30, 60, 120, 240, 480 minutes
Secondary	Time of Maximum Observed Concentration in Plasma (Tmax) of Selinexor	Tmax was defined as time of first observation of Cmax, taken directly from the plasma concentration data.	Cycle1, Day1: Pre-dose, 30, 60, 120, 240, 480 minutes
Secondary	Area Under the Concentration Time Curve From the Time of Dosing to Time in Plasma (AUC0-t) of Selinexor	AUC0-t was defined as area under the concentration-time curve from time zero to the last non-zero concentration.	Cycle1, Day1: Pre-dose, 30, 60, 120, 240, 480 minutes
Secondary	Area Under the Concentration Time Curve From the Time of Dosing Extrapolated to Infinity (AUC0-inf) of Selinexor	AUC0-inf was defined as area under the concentration-time curve from time zero to infinity (extrapolated). It was calculated as AUC0-t + Ct/kel, where: Ct = the last observed non-zero concentration and Kel = elimination rate constant.	Cycle1, Day1: Pre-dose, 30, 60, 120, 240, 480 minutes
Secondary	Elimination Half-Life (t1/2) of Selinexor	t1/2 was defined as elimination half-life, it was calculated as ln(2)/kel, where In = natural logarithm and kel = elimination rate constant.	Cycle1, Day1: Pre-dose, 30, 60, 120, 240, 480 minutes
Secondary	Apparent Total Body Clearance (CL/F) of Selinexor	CL/F was calculated as Dose/AUC0-inf, uncorrected for fraction absorbed; reported normalized by participant body weight (kilogram).	Cycle1, Day1: Pre-dose, 30, 60, 120, 240, 480 minutes
Secondary	Apparent Volume of Distribution of Selinexor (Vd/F)	Vd/F was calculated as Dose/(kel * AUC0-inf), uncorrected for fraction absorbed; reported normalized by participant body weight (kilogram).	Cycle1, Day1: Pre-dose, 30, 60, 120, 240, 480 minutes
Secondary	Number of Participants With Best Overall Response (BOR)	BOR is response recorded from start of treatment until disease progression/recurrence. Best lesion response was defined by Recist Criteria V1 (for target and non-target lesions) and RANO criteria (for glioblastoma multiforme): complete response (CR)- disappearance of all target lesions. Any pathological lymph nodes (target/non target) must have reduction in short axis to less than (<) 10 mm; partial response (PR)- at least 30% decrease in sum of diameters of target lesions, taking as reference the baseline sum longest diameter; stable disease (SD)- steady state of disease. Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD; progressive disease (PD): at least 20% increase in sum of diameters of measured lesions taking as references smallest sum of diameters recorded since treatment started. In addition to relative increase of 20%, sum must also demonstrate an absolute increase of at least 5 mm, or appearance of one or more new lesions.	Up to maximum duration of 45 months
Secondary	Percentage of Participants With Objective Response	Objective response rate (ORR) was determined as percentage of participants who had either CR or PR, as defined by RECIST v1.1 (for solid tumors). CR was defined as disappearance of all target lesions. Any pathological lymph nodes (target/non target) must have reduction in short axis to <10 mm and PR was defined as at least 30% decrease in sum of diameters of target lesions. ORR was calculated as a proportion and included a 2 sided 95% CI using the exact (Clopper-Pearson) method.	Up to maximum duration of 45 months
Secondary	Duration of Stable Disease (SD)	Duration of stable disease was defined as the time from the date of first dose to first documented radiologic evidence of disease recurrence or progression, as defined by RECIST v1.1 (for solid tumors) or RANO criteria (for GBM and AnaA).	From first dose of study drug administration to first documented evidence of disease recurrence or progression (maximum duration of 45 months)
Secondary	Progression-free Survival (PFS)	Progression-free survival was calculated from the date of first dose of study treatment to first documented evidence of disease recurrence or progression or death due to any cause. Patients who are last known to be alive and without evidence of progression will be censored at time of last evaluable disease assessment. If date of progression or death occurred after more than 1 missed disease assessment interval, patients are censored at the time of last evaluable disease assessment prior to the missed assessment. Progressive disease 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 start of study drug administration until PD or discontinuation from the study or death (maximum duration of 45 months)
Secondary	Overall Survival (OS)	OS was calculated from the date of first dose to date of death. Participants who were still alive prior to the data cutoff for final efficacy analysis, or who dropout prior to study end, were censored at the day they were last known to be alive. The OS was calculated using the Kaplan-Meier method.	From first dose of study drug administration to date of death (maximum duration of 45 months)