Open-Label, Phase 1/2 Study Evaluating the Relative Bioavailability/Bioequivalence of Different Formulations of Selinexor, the Impact of Hepatic Impairment on Selinexor Pharmacokinetics, and the Tolerability and Antitumor Activity of Selinexor Combination Treatment (SPRINT)
Overview
- Phase
- Phase 1
- Status
- Completed
- Sponsor
- Karyopharm Therapeutics Inc
- Enrollment
- 126
- Locations
- 11
- Primary Endpoint
- Monotherapy Period: Area Under the Concentration-Time Curve from Time Zero to Time of Last Concentration (AUC 0-t) of Selinexor in Patients with Normal, Moderate and Severe Hepatic Function
Overview
Brief Summary
This is a Phase 1/2, two-part, multi-arm, open-label study in patients with normal Hepatic Function (HF), with either Non-small cell lung cancer (NSCLC), who have had 1-2 prior lines of treatment, with 1 line containing a checkpoint Inhibitor (CPI); or patients with normal HF, with colorectal cancer (CRC) who have had 1-3 prior lines (KRAS wild-type [WT]) or 1-2 prior lines (mutant KRAS) of treatment with no CPI; or patients with impaired HF, with any solid tumor, who have had at least 1 prior line of treatment.
The study will comprise 2 treatment periods (monotherapy and combination therapy).
The purposes of this study, during Monotherapy period, are: (1) to determine the relative bioavailability of the 100 milligrams (mg) (Tablet B) and 20 mg (Tablet A) tablets of selinexor at 100 mg once weekly (QW) dose in patients with normal hepatic function; and (2) to assess the PK of selinexor after a single dose of 40 mg (2 × 20 mg), among patients with moderate and severe hepatic impairment, relative to 100 mg (5 × 20 mg), among patients with normal hepatic function; and, during the Combination therapy period, to assess the preliminary anti-tumor activity of selinexor in combination with docetaxel in patients with NSCLC and with pembrolizumab or folinic acid, 5-fluorouracil, and irinotecan (FOLFIRI) in patients with CRC.
Detailed Description
Up to 120 patients will be enrolled, of which, 20 with normal HF will be able to continue from Monotherapy to Combination therapy and up to 106 patients with normal HF will receive combination therapy in total. Patients with impaired hepatic function can only participate in the Monotherapy part of the study.
Monotherapy Period:
For the Monotherapy Period of Study KCP-330-027, patients with normal hepatic function (n=20), will be allocated to one of two test formulation treatment arms, and will receive a cross-over once weekly oral dosing, with either 1x100 mg or 5x20 mg selinexor, for 2 weeks, and then will have the option to move on to the combination treatment part of the study. Patients with either moderately or severely impaired hepatic functions will be treated with 2x20 mg selinexor weekly (with an option to increase the dose every 3 weeks by 20 mg increments, up to 80 mg).
For the assessment of hepatic impairment, participants with any type of advanced or metastatic solid tumor who have moderate or severe hepatic impairment will be enrolled in Moderate Hepatic Impairment (MHI) (n=8) and Severe Hepatic Impairment (SHI) (n=6) arms, respectively and will be treated with 2 × 20 mg selinexor, weekly.
For Weeks 1 and 2, following an overnight fast of at least 10 hours, patients will be fed a standard low-fat meal 30 minutes prior to administration of once weekly selinexor. Patients should finish the meal in 30 minutes or less; however, selinexor dose should be administered 30 minutes after start of the meal.
Blood sampling for selinexor PK analyses will be collected ≤10 minutes (m) pre selinexor dose, and at 15m (±5m), 30m (±5m), 1 hour (h) (±5m), 1.5h (±5m), 2h (±10m), 3h (±10m), 4h (±10m), 5h (±10m), 6h (±10m), 8h (±20m), 10h (±20m; optional), 24h (±1h), 30h (±1h), and 48h (±2h) post selinexor dose. Practitioners must record the actual clock time for selinexor dose, and each sample drawn.
If a patient experiences emesis during the first 6 hours of the PK sampling, the PK results for that week will be excluded from the PK analysis dataset, and all testing timepoints must be re-collected during the following week (in this case, the same dosing formulation should be repeated on the following week, and other dosing formulation will be given the week after that).
Patients who will complete the Monotherapy Period will be reassessed for continuation to the Combination Therapy Period, as long as their Hepatic Function remains normal.
If a patient experiences significant toxicity related to selinexor and can't start the combination therapy immediately following monotherapy, dose interruption and weekly retesting are allowed for up to 21 days after the end of Monotherapy treatment visit. Patients requiring >21 days to recover from toxicities related to selinexor should be discussed with the Sponsor's Medical Monitor for documented approval to continue to the Combination Therapy Period. Reassessment may be extended then and following Medical Monitor approval up to 28 days.
Combination Therapy Period:
In the combination treatment period of the study, patients with normal hepatic functions will be allocated to one of 3 arms (with Arm C divided into 2 cohorts): Arm A (n= up to 40): Patients with NSCLC who have had up to 2 lines of prior systemic treatment with 1 line containing a CPI will receive 60 mg selinexor weekly, in combination with docetaxel 75 milligrams per meter square (mg/m^2) once every 3 weeks; Arm B (n= up to 40): Patients with CRC (KRAS WT) who have had up to 3 lines of prior systemic treatment or patients with CRC (KRAS mutant [KRAS Mut]) who have had up to 2 lines of prior systemic treatment, with no lines containing a checkpoint inhibitor (CPI) will receive 80 mg selinexor weekly, in combination with pembrolizumab 200 mg once every 3 weeks; Arm C (n<=26): Patients with CRC (regardless of KRAS status) who have had up to 2 lines of prior systemic treatment (regardless of CPI use) will receive either: (Cohort 1) selinexor 40 mg on days 1, 3, 15 and 18 in 28-day cycle + FOLFIRI; or (Cohort 2) selinexor 80 mg on days 1 and 15 in 28-day cycle + FOLFIRI.
Combination Therapy Period Patients will receive combination treatment until progressive disease (PD) or intolerable toxicity.
During both study periods, safety will be assessed through continuous reporting of adverse events (AEs), treatment-emergent adverse events (TEAEs), regularly scheduled clinical laboratory tests (hematologic and chemical), and physical examinations.
Tumor assessment will be performed with either computed tomography (CT) or magnetic resonance imaging (MRI) (CT with contrast preferred; for each patient, the imaging method should remain the same throughout the study).
Following treatment, patients will come in for a safety visit (approximately 30 days after the last dose of combination therapy) and will be followed for up to 2 years after that. Patients who discontinued due to PD will be followed for survival, and patients who discontinued for reasons other than PD will have tumor assessments until PD or until the start of new anti-neoplastic therapy, after which they will be followed for survival.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Sequential
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Common inclusion criteria for all patients:
- •Are greater than or equal to \[≥\] 18 years of age at the time of informed consent.
- •Have histologically confirmed solid tumor (any type of advanced or metastatic solid tumor for the Hepatic Impairment Arm of the Monotherapy Part), advanced or metastatic NSCLC or CRC and evidence of measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST v1.1).
- •Willing to provide signed written informed consent in accordance with federal, local, and institutional guidelines and comply with all requirements of the study.
- •Female patient of childbearing potential must have a negative serum pregnancy test at screening and agree to use highly effective (dual methods of) contraception throughout the study and for 4 months following the last dose of study drug; and male patients must use an effective barrier method of contraception throughout the study and for 4 months following the last dose of study drug if sexually active. Male patients must agree not to donate sperm during the study treatment period.
- •For the Monotherapy Part only (bioavailability/bioequivalence \[BA/BE\] and hepatic impairment \[HI\] arms):
- •Have received at least 1 line of systemic anticancer treatment unless there is no first-line standard of care therapy or standard of care therapy is contraindicated adjuvant or neoadjuvant therapy is not counted as one line of systemic therapy). Patients must have failed prior standard curative therapy for their disease, must be intolerant to or be ineligible for any potentially curative approved treatment, irrespective of line of therapy.
- •Must have either normal hepatic function, or moderate or severe hepatic impairment (as defined by the NCI organ dysfunction working group (NCI-ODWG) criteria:
- •S20-100 and S100-20 arms: normal hepatic function (total bilirubin and aspartate aminotransferase \[AST\] less than or equal to \[≤\] upper limit of normal \[ULN\]).
- •Note: Patients with mild hepatic dysfunction (total bilirubin greater than \[\>\] 1 to 1.5 × ULN or AST \> ULN) may be included if liver function tests are stable for the past 3 months and enrollment is approved in writing by the Sponsor's Medical Monitor.
Exclusion Criteria
- •Common exclusion criteria for all patients:
- •Have inadequate hematopoietic function defined as (without transfusion or growth factor support within 7 days prior to first dose):
- •a. absolute neutrophil count (ANC) \<1.5 × 109/liter (L); platelet count (PLT) \<100 × 109/L; or hemoglobin (Hb) \<9 gram per deciliter (g/dL).
- •Have inadequate renal function defined as a calculated creatinine clearance (CrCl) of \<20 mL/min using the formula of Cockcroft and Gault.
- •Have any other medical condition especially any gastrointestinal (GI) dysfunctions or GI disease that could interfere with the absorption of selinexor (e.g., inability to swallow or retain oral medications, malabsorption syndrome, a history of GI surgery which may result in intestinal blind loop, significant gastroparesis, unresolved nausea, vomiting, or diarrhea \[National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Grade \>1\]).
- •Ongoing infection requiring parenteral antibiotics, antivirals, or antifungals on Day 1 dosing.
- •Prior exposure to a SINE compound or selinexor.
- •Insufficient time since or not recovered from procedures or anti-cancer therapy, defined as:
- •Not recovered from major surgery ≤21 days prior to Day 1 dosing. Minor procedures, such as biopsies, dental work, or placement of a port or intravenous (IV) line for infusion are permitted.
- •Have ongoing clinically significant anti-cancer therapy-related toxicities CTCAE Grade \>
Arms & Interventions
Monotherapy: Normal Hepatic Function (Selinexor)
(Closed for Enrollment)
Cohort 1:
- Week 1: selinexor 5 x 20-mg tablet daily;
- Week 2: selinexor 1 x 100-mg tablet daily
Cohort 2:
- Week 1: selinexor 1 x 100-mg tablet daily;
- Week 2: selinexor 5 x 20-mg tablet daily.
Intervention: Selinexor 100 mg (Drug)
Monotherapy: Impaired Hepatic Function (Selinexor)
Cohort 3:
Patients with Moderate Hepatic Impairment with any Solid Tumors;
- Selinexor 2 x 20-mg tablet once weekly (QW).
Cohort 4:
Patients with Severe Hepatic Impairment with any Solid Tumors;
- Selinexor 2 x 20-mg tablet QW.
Intervention: Selinexor 40 mg (Drug)
Combination Therapy: NSCLC Arm A: (Selinexor + Docetaxel)
(Closed for Enrollment)
Selinexor 60 mg oral dose QW and docetaxel 75 mg/m^2 intravenously (IV) once every 3 weeks (Non-small cell lung cancer [NSCLC] patients).
Intervention: Docetaxel (Drug)
Combination Therapy: NSCLC Arm A: (Selinexor + Docetaxel)
(Closed for Enrollment)
Selinexor 60 mg oral dose QW and docetaxel 75 mg/m^2 intravenously (IV) once every 3 weeks (Non-small cell lung cancer [NSCLC] patients).
Intervention: Selinexor 60 mg (Drug)
Combination Therapy: CRC Arm B: (Selinexor + Pembrolizumab)
(Closed for Enrollment)
Selinexor 80 mg oral does QW and pembrolizumab 200 mg IV every 3 weeks (Colorectal cancer [CRC] Patients).
Intervention: Pembrolizumab (Drug)
Combination Therapy: CRC Arm B: (Selinexor + Pembrolizumab)
(Closed for Enrollment)
Selinexor 80 mg oral does QW and pembrolizumab 200 mg IV every 3 weeks (Colorectal cancer [CRC] Patients).
Intervention: Selinexor 80 mg (Drug)
Combination Therapy: CRC Arm C: (Selinexor + FOLFIRI)
(Closed for Enrollment)
Cohort 1:
Selinexor 40 mg oral dose Days 1, 3, 15 and 18 in a 28-day cycle and FOLFIRI (irinotecan 180 mg/m^2; leucovorin 400 mg/m^2; 5- fluorouracil (5-FU) 400 mg/m^2 bolus then 5-FU 2400 mg/m^2 continuous over 46-48 hours; IV on Day 1 and 15 in a 28-day cycle) (CRC Patients).
Cohort 2:
Selinexor 80 mg oral dose Days 1 and 15 in a 28-day cycle and FOLFIRI (irinotecan 180 mg/m^2; leucovorin 400 mg/m^2; 5-FU 400 mg/m^2 bolus then 5-FU 2400 mg/m^2 continuous over 46-48 hours; IV on Day 1 and 15 in a 28-day cycle) (CRC Patients).
Intervention: FOLFIRI (Drug)
Combination Therapy: CRC Arm C: (Selinexor + FOLFIRI)
(Closed for Enrollment)
Cohort 1:
Selinexor 40 mg oral dose Days 1, 3, 15 and 18 in a 28-day cycle and FOLFIRI (irinotecan 180 mg/m^2; leucovorin 400 mg/m^2; 5- fluorouracil (5-FU) 400 mg/m^2 bolus then 5-FU 2400 mg/m^2 continuous over 46-48 hours; IV on Day 1 and 15 in a 28-day cycle) (CRC Patients).
Cohort 2:
Selinexor 80 mg oral dose Days 1 and 15 in a 28-day cycle and FOLFIRI (irinotecan 180 mg/m^2; leucovorin 400 mg/m^2; 5-FU 400 mg/m^2 bolus then 5-FU 2400 mg/m^2 continuous over 46-48 hours; IV on Day 1 and 15 in a 28-day cycle) (CRC Patients).
Intervention: Selinexor 40 mg (Drug)
Combination Therapy: CRC Arm C: (Selinexor + FOLFIRI)
(Closed for Enrollment)
Cohort 1:
Selinexor 40 mg oral dose Days 1, 3, 15 and 18 in a 28-day cycle and FOLFIRI (irinotecan 180 mg/m^2; leucovorin 400 mg/m^2; 5- fluorouracil (5-FU) 400 mg/m^2 bolus then 5-FU 2400 mg/m^2 continuous over 46-48 hours; IV on Day 1 and 15 in a 28-day cycle) (CRC Patients).
Cohort 2:
Selinexor 80 mg oral dose Days 1 and 15 in a 28-day cycle and FOLFIRI (irinotecan 180 mg/m^2; leucovorin 400 mg/m^2; 5-FU 400 mg/m^2 bolus then 5-FU 2400 mg/m^2 continuous over 46-48 hours; IV on Day 1 and 15 in a 28-day cycle) (CRC Patients).
Intervention: Selinexor 80 mg (Drug)
Outcomes
Primary Outcomes
Monotherapy Period: Area Under the Concentration-Time Curve from Time Zero to Time of Last Concentration (AUC 0-t) of Selinexor in Patients with Normal, Moderate and Severe Hepatic Function
Time Frame: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 24, 30, and 48 hours post-dose on Days 1 and 8
Monotherapy Period: Area Under the Concentration-Time Curve from Time Zero Extrapolated to Infinity (AUC 0-inf) of Selinexor in Patients with Normal, Moderate and Severe Hepatic Function
Time Frame: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 24, 30, and 48 hours post-dose on Days 1 and 8
Combination Therapy Period: Arm C: Number of Patients With Adverse Events (AEs)
Time Frame: From start of study drug administration up to survival follow-up (Up to 36 months)
Monotherapy Period: Maximum Plasma Concentration (Cmax) of Selinexor in Patients with Normal, Moderate and Severe Hepatic Function
Time Frame: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 24, 30, and 48 hours post-dose on Days 1 and 8
Combination Therapy Period: Arm A and B: Overall Response Rate (ORR) as Assessed by Response Criteria in Solid Tumors Version 1.1 (RECIST 1.1)
Time Frame: Up to 36 months
Secondary Outcomes
- Combination Therapy Period: Overall Survival (OS): Arms A and C as Assessed by RECIST 1.1 and Arm B as Assessed by iRECIST(Up to 36 months)
- Monotherapy Period: Time to Maximum Observed Concentration (Tmax) of Selinexor in Patients with Normal, Moderate and Severe Hepatic Impairment(Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 24, 30, and 48 hours post-dose on Days 1 and 8)
- Monotherapy Period: Terminal Elimination Rate Constant (Lambda z) of Selinexor in Patients with Normal, Moderate and Severe Hepatic Impairment(Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 24, 30, and 48 hours post-dose on Days 1 and 8)
- Monotherapy Period: Apparent Clearance (CL/F) of Selinexor in Patients with Normal, Moderate and Severe Hepatic Impairment(Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 24, 30, and 48 hours post-dose on Days 1 and 8)
- Combination Therapy Period: Arm C: Overall Response Rate (ORR) as Assessed by RECIST 1.1(Up to 36 months)
- Monotherapy Period: Terminal Half-Life (t1/2) of Selinexor in Patients with Normal, Moderate and Severe Hepatic Impairment(Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 24, 30, and 48 hours post-dose on Days 1 and 8)
- Monotherapy Period: Apparent Volume of Distribution (Vd/F) of Selinexor in Patients with Normal, Moderate and Severe Hepatic Impairment(Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 24, 30, and 48 hours post-dose on Days 1 and 8)
- Monotherapy Period: Fraction Unbound (fu) of Selinexor (Tablet A) in Plasma(Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 24, 30, and 48 hours post-dose on Days 1 and 8)
- Monotherapy Period: Maximum Free-Drug Concentration (Cmaxu) of Selinexor (Tablet A) in Plasma(Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 24, 30, and 48 hours post-dose on Days 1 and 8)
- Monotherapy Period: Area Under the Free-Drug Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUCu) of Selinexor (Tablet A) in Plasma(Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 24, 30, and 48 hours post-dose on Days 1 and 8)
- Monotherapy Period: Apparent Free-drug Clearance (CLu/F) of Selinexor (Tablet A) in Plasma(Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 24, 30, and 48 hours post-dose on Days 1 and 8)
- Monotherapy Period: Apparent Free-drug Volume of Distribution (Vu/F) of Selinexor (Tablet A) in Plasma(Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 24, 30, and 48 hours post-dose on Days 1 and 8)
- Combination Therapy Period: Progression-free Survival (PFS): Arms A and C as Assessed by RECIST 1.1 and Arm B as Assessed by iRECIST(Up to 36 months)
- Combination Therapy Period: Duration of Response (DOR): Arms A and C as Assessed by RECIST 1.1 and Arm B as Assessed by iRECIST(Up to 36 months)
- Combination Therapy Period: Disease Control Rate (DCR): Arms A and C: as Assessed by RECIST 1.1 and Arm B as Assessed by iRECIST(Up to 36 months)
- Monotherapy Period: Number of Patients With Adverse Events (AEs)(From start of study drug administration up to survival follow-up (up to 36 months))
- Combination Therapy Period: Arm A and B: Number of Patients With Adverse Events (AEs)(From start of study drug administration up to survival follow-up (up to 36 months))