Clinical trial NCT01607905: Safety Study of KPT-330 (Selinexor) in Patients With Advanced or Metastatic Solid Tumor 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 or Metastatic Solid Tumor Malignancies
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Solid Tumor
Keywords: Selinexor
KPT-330
Squamous Cell Carcinoma
Glioblastoma multiforme
Adenocarcinoma
Melanoma
Colorectal cancer
Gynecological cancer
Castrate-resistant Prostate Cancer
Other solid tumors
Lead sponsor: Karyopharm Therapeutics Inc
Sponsor class: INDUSTRY
First posted: 2012-05-30
Enrollment: 192
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

Detailed 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)
timeFrame: From start of study drug administration to 30 days after last dose of study treatment (maximum duration of 45 months)
measure: Number of Participants With Treatment-related Treatment-emergent Adverse Events
timeFrame: From start of study drug administration to 30 days after last dose of study treatment (maximum duration of 45 months)
measure: 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
timeFrame: From start of study drug administration to 30 days after last dose of study treatment (maximum duration of 45 months)
measure: Number of Participants Who Experienced Dose Limiting Toxicity (DLT)
timeFrame: Cycle 1 only (28-day cycle)
measure: Recommended Phase 2 Dose (RP2D)
timeFrame: From start of study drug administration to 30 days after last dose of study treatment (maximum duration of 45 months)
Secondary outcomes:
measure: Maximum Observed Plasma Concentration (Cmax) of Selinexor
timeFrame: Cycle1, Day1: Pre-dose, 30, 60, 120, 240, 480 minutes
measure: Time of Maximum Observed Concentration in Plasma (Tmax) of Selinexor
timeFrame: Cycle1, Day1: Pre-dose, 30, 60, 120, 240, 480 minutes
measure: Area Under the Concentration Time Curve From the Time of Dosing to Time in Plasma (AUC0-t) of Selinexor
timeFrame: Cycle1, Day1: Pre-dose, 30, 60, 120, 240, 480 minutes
measure: Area Under the Concentration Time Curve From the Time of Dosing Extrapolated to Infinity (AUC0-inf) of Selinexor
timeFrame: Cycle1, Day1: Pre-dose, 30, 60, 120, 240, 480 minutes
measure: Elimination Half-Life (t1/2) of Selinexor
timeFrame: Cycle1, Day1: Pre-dose, 30, 60, 120, 240, 480 minutes
measure: Apparent Total Body Clearance (CL/F) of Selinexor
timeFrame: Cycle1, Day1: Pre-dose, 30, 60, 120, 240, 480 minutes
measure: Apparent Volume of Distribution of Selinexor (Vd/F)
timeFrame: Cycle1, Day1: Pre-dose, 30, 60, 120, 240, 480 minutes
measure: Number of Participants With Best Overall Response (BOR)
timeFrame: Up to maximum duration of 45 months
measure: Percentage of Participants With Objective Response
timeFrame: Up to maximum duration of 45 months
measure: Duration of Stable Disease (SD)
timeFrame: From first dose of study drug administration to first documented evidence of disease recurrence or progression (maximum duration of 45 months)
measure: Progression-free Survival (PFS)
timeFrame: From start of study drug administration until PD or discontinuation from the study or death (maximum duration of 45 months)
measure: Overall Survival (OS)
timeFrame: From first dose of study drug administration to date of death (maximum duration of 45 months)
Other outcomes:
Locations:
city: Tampa
country: United States
facility: Moffitt Cancer Center
state: Florida
city: Detroit
country: United States
facility: Karmanos Cancer Institute
state: Michigan
city: New York
country: United States
facility: Memorial Sloan-Kettering Cancer Center
state: New York
city: Canton
country: United States
facility: Gabrail Cancer Center
state: Ohio
city: Toronto
country: Canada
facility: Princess Margaret Hospital
state: Ontario
city: Copenhagen
country: Denmark
facility: Rigshospitalet
Study officials:
References:
citation: Machlus KR, Wu SK, Vijey P, Soussou TS, Liu ZJ, Shacham E, Unger TJ, Kashyap T, Klebanov B, Sola-Visner M, Crochiere M, Italiano JE Jr, Landesman Y. Selinexor-induced thrombocytopenia results from inhibition of thrombopoietin signaling in early megakaryopoiesis. Blood. 2017 Aug 31;130(9):1132-1143. doi: 10.1182/blood-2016-11-752840. Epub 2017 Jun 19.