Non-small Cell Lung Cancer
Conditions
Brief summary
This study is being done to evaluate the safety of the investigational study drug, selinexor when given with docetaxel to patients who have been previously treated for advanced KRAS mutant lung cancer.
Detailed description
This is a phase 1/2 single-arm, non-blinded, multi-institutional study. Selinexor will be administered once weekly starting one week before chemotherapy initiation (to permit pharmacodynamic assessment of selinexor alone and in combination with chemotherapy).This study will compare safety and outcomes with historical controls (docetaxel monotherapy).
Interventions
DRUGSelinexor
Selinexor once weekly oral or twice weekly oral
DRUGDocetaxel
Docetaxel once every 3 weeks (75 mg/m2 IV)
Sponsors
Karyopharm Therapeutics Inc
University of Texas Southwestern Medical Center
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Docetaxel will be given once every 3 weeks. Treatment will be administered in 21-day cycles. Dose limiting toxicities (DLTs) will be assessed based on the first cycle (7-day lead-in plus 21-day cycle = 28 days) toxicity using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events \[NCI CTCAE\] version 4.03. A standard 3 + 3 dose escalation paradigm will be used.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients must meet all of the following inclusion criteria to be eligible to enroll in this study: 1. Written informed consent in accordance with federal, local, and institutional guidelines. The patient must provide informed consent prior to the first screening procedure. However, the Investigator should not repeat procedures that are performed as part of standard of care (SOC), if they are within the screening window and are done prior to signing the ICF. 2. Age ≥ 18 years 3. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 4. Histologically or cytologically confirmed advanced (stage 4, according to the American Joint Committee on Cancer \[AJCC\] version 7.0 Staging manual) NSCLC 5. Molecular identification of a KRAS mutation (codons 12, 13, or 61 mutations detected by sequencing) by a CLIA-certified assay (source documentation required). 6. Tissue available for analysis at time of enrollment for biomarker analysis: 10 unstained slides plus 1 H+E slide. If archival tumor tissue is not available in select cases, subjects may be permitted to enroll on the study with prior approval of the study PI. 7. At least one and up to two previous lines of systemic cytotoxic therapy for advanced NSCLC, of which one must have been a platinum-based doublet therapy. Up to four total previous lines of systemic therapy (including immunotherapy and molecularly targeted therapy) for advanced NSCLC. 8. Radiographic or clinical disease recurrence or progression during or after the last line of systemic therapy 9. Adequate hematologic function (absolute neutrophil count \[ANC\] ≥ 1500 cells/µL; hemoglobin ≥ 9 g/dL; platelets ≥ 100,000/µL. Patients may be transfused with PRBCs up to 7 days prior to when enrollment labs are drawn to achieve Hgb ≥9.0 mg/dL. 10. Adequate renal function (calculated creatinine clearance ≥ 30 mL/min using the Cockcroft-Gault equation) 11. Adequate hepatic function (total bilirubin ≤ upper limit of normal \[ULN\], alanine aminotransferase \[ALT\] ≤ 2 × ULN and aspartate aminotransferase \[AST\] ≤ 2 × ULN). ALT and/or AST may be ≤ 5 × ULN if due to liver metastases. If ALT or AST is \> 2 and ≤ 5 × ULN in patients with liver metastases, alkaline phosphatase must be ≤ 2.5 × ULN (unless elevated alkaline phosphatase clearly due to skeletal-rather than hepatic-process; eg, normal GGT, presence of multiple bone metastases, absence of bulky and/or central liver metastases). Patients with Gilbert's syndrome are allowed if total bilirubin ≤ 2 × ULN and direct bilirubin is ≤ ULN. 12. Female patients of childbearing potential must agree to use 2 methods of contraception (including 1 highly effective and 1 effective method of contraception) and have a negative serum pregnancy test at Screening. Male patients must use an effective barrier method of contraception if sexually active with a female of childbearing potential. For both male and female patients, effective methods of contraception must be used throughout the study and for 3 months following the last dose of study treatment. Female patients of child-bearing potential must have a negative serum pregnancy test at screening and agree to use 2 reliable methods of contraception throughout the study and for 3 months after their last dose of medication. Female patients are considered NOT of childbearing potential if they have a history of surgical sterility (including hysterectomy and/or bilateral oophorectomy, but not tubal ligation alone) or evidence of post-menopausal status defined as any of the following: * Natural menopause with last menses \>1 year ago * Radiation-induced oophorectomy with last menses \>1 year ago * Chemotherapy-induced menopause with last menses \>1 year ago. Male patients and their partners must use 2 reliable methods of contraception, at least one of them a barrier method (if sexually active with a female of child-bearing potential). 13. Measurable disease according to RECIST v1.1 14. Previously treated (surgery and/or radiation therapy) or untreated brain metastases are eligible, provided that patients are asymptomatic and not requiring escalating doses of corticosteroids. 15. Previous treatment-associated clinically significant toxicities resolved to CTCAE grade ≤2 (except alopecia) or to their baseline. NOTE: Prior immunotherapy-related endocrinopathy controlled with ongoing medical management (eg, hypothyroidism, adrenal insufficiency, diabetes) is permitted 16. At least 3 weeks or 5 half-lives, whichever is shorter, since receiving systemic anticancer therapy, including investigational agents, prior to starting study therapy. At least 2 weeks since receiving radiation therapy prior to starting study therapy
Exclusion criteria
* Patients meeting any of the following
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Dose Limiting Toxicities (DLT) | Each 21 day cycle for 2 years | A DLT was any Grade 3 or 4 adverse event (AE) using the Common Terminology Criteria for Adverse Events Version 4.0 (CTCAE 4.0). DLTs were collected to determine the Maximum-Tolerated Dose (MTD). \*\*DLT will include the following when considered to be at least possibly related to study drug administration: 1) \> 1 missed doses (out of 4 doses) of study treatment during cycle 1 due to study treatment related toxicities 2) Discontinuation of study therapy before completion of Cycle 1, due to study-drug related toxicity. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Tumor Size Will be Assessed Using the RECIST v1.1 | Each 21 day cycle for 2 years | To evaluate the efficacy of selinexor monotherapy and in combination with docetaxel in patients with advanced KRAS mutant NSCLC. Tumor size will be assessed at baseline and every 2 cycles (ie, after 7 weeks for first 2 cycles, and then every 6 weeks) during the treatment period using the Response Evaluation Criteria in Solid Tumors RECIST v1.1 criterion. |
Countries
United States
Participant flow
Pre-assignment details
41 subjects consented;1 screen failed prior to receiving treatment. Participants started at dosing selinexor 60 mg + docetaxel 75 mg/m2. The second dose level was 80 mg +docetaxel 75 mg/m2 to which 4 subjects were assigned. Then 33 patients enrolled and started on Dose expansion: selinexor 60 mg weekly plus docetaxel 75 mg/m2 3 weekly. No data was collected or analyzed for the selinexor Monotherapy cohort, study was halted due to funding.
Participants by arm
| Arm | Count |
|---|---|
| Dose Escalation: Selinexor 60 mg + Docetaxel Dose Escalation Phase: Selinexor 60 mg and in Combination With Docetaxel '3x3' Dose escalation (cycle = 21 days). Selinexor once weekly oral administration (cohorts 60mg, 80mg) Docetaxel once every 3 weeks (75mg/m2 IV).
cohort escalation until MTD (maximum tolerated dose) is established. | 3 |
| Dose Escalation: Selinexor 80 mg + Docetaxel Dose Escalation Phase: Selinexor 800 mg and in Combination With Docetaxel '3x3' Dose escalation (cycle = 21 days). Selinexor once weekly oral administration (cohorts 60mg, 80mg) Docetaxel once every 3 weeks (75mg/m2 IV).
cohort escalation until MTD (maximum tolerated dose) is established. | 4 |
| Dose Expansion Phase: Selinexor 60 + Docetaxel Dose Expansion Phase: Selinexor 60 mg and in Combination With Docetaxel Selinexor once weekly oral administration Docetaxel once every 3 weeks (75 mg/m2 IV) | 33 |
| Total | 40 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 |
|---|---|---|---|---|---|---|---|---|
| Dose Escalation:Selinexor 80mg+Docetaxel | Dose not tolerated by the subject | 0 | 4 | 0 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Dose Escalation: Selinexor 60 mg + Docetaxel | Dose Escalation: Selinexor 80 mg + Docetaxel | Dose Expansion Phase: Selinexor 60 + Docetaxel | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 2 Participants | 3 Participants | 15 Participants | 20 Participants |
| Age, Categorical Between 18 and 65 years | 1 Participants | 1 Participants | 18 Participants | 20 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants | 4 Participants | 32 Participants | 39 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants | 0 Participants | 1 Participants | 4 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) White | 0 Participants | 3 Participants | 30 Participants | 33 Participants |
| Region of Enrollment United States | 3 participants | 4 participants | 33 participants | 40 participants |
| Sex: Female, Male Female | 3 Participants | 3 Participants | 17 Participants | 23 Participants |
| Sex: Female, Male Male | 0 Participants | 1 Participants | 16 Participants | 17 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk |
|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 3 | 0 / 4 | 0 / 0 | 0 / 33 | 0 / 0 | 0 / 0 | 0 / 0 |
| other Total, other adverse events | 3 / 3 | 4 / 4 | 0 / 0 | 33 / 33 | 0 / 0 | 0 / 0 | 0 / 0 |
| serious Total, serious adverse events | 0 / 3 | 4 / 4 | 0 / 0 | 0 / 33 | 0 / 0 | 0 / 0 | 0 / 0 |
Outcome results
Primary
Number of Participants With Dose Limiting Toxicities (DLT)
A DLT was any Grade 3 or 4 adverse event (AE) using the Common Terminology Criteria for Adverse Events Version 4.0 (CTCAE 4.0). DLTs were collected to determine the Maximum-Tolerated Dose (MTD). \*\*DLT will include the following when considered to be at least possibly related to study drug administration: 1) \> 1 missed doses (out of 4 doses) of study treatment during cycle 1 due to study treatment related toxicities 2) Discontinuation of study therapy before completion of Cycle 1, due to study-drug related toxicity.
Time frame: Each 21 day cycle for 2 years
Population: The study was halted prior to participants receiving selinexor monotherapy. No data was collected or analyzed for the selinexor Monotherapy Cohort.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Selinexor in Combination With Docetaxel Cohort | Number of Participants With Dose Limiting Toxicities (DLT) | selinexor, 80 mg | 3 Participants |
| Selinexor in Combination With Docetaxel Cohort | Number of Participants With Dose Limiting Toxicities (DLT) | selinexor, 60 mg | 37 Participants |
| Selinexor Monotherapy Cohort | Number of Participants With Dose Limiting Toxicities (DLT) | selinexor, 80 mg | 0 Participants |
| Selinexor Monotherapy Cohort | Number of Participants With Dose Limiting Toxicities (DLT) | selinexor, 60 mg | 0 Participants |
Secondary
Tumor Size Will be Assessed Using the RECIST v1.1
To evaluate the efficacy of selinexor monotherapy and in combination with docetaxel in patients with advanced KRAS mutant NSCLC. Tumor size will be assessed at baseline and every 2 cycles (ie, after 7 weeks for first 2 cycles, and then every 6 weeks) during the treatment period using the Response Evaluation Criteria in Solid Tumors RECIST v1.1 criterion.
Time frame: Each 21 day cycle for 2 years
Population: 32 patients were evaluable for disease. This was a 3+3 dose escalation study, participants started at dosing selinexor 60 mg + docetaxel 75 mg/m2. Dose tolerated for 3 patients. 2nd dose level of 80 mg +docetaxel 75 mg/m2 was not tolerated and data was not collected. The remainder of the patients enrolled were then started on selinexor 60 mg weekly plus docetaxel 75 mg/m2 3 weekly. No data was collected or analyzed for the selinexor Monotherapy cohort, study was halted due to funding.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Selinexor in Combination With Docetaxel Cohort | Tumor Size Will be Assessed Using the RECIST v1.1 | 25 Participants |
| Selinexor Monotherapy Cohort | Tumor Size Will be Assessed Using the RECIST v1.1 | 0 Participants |
| Selinexor 100 mg and in Combination With Docetaxel | Tumor Size Will be Assessed Using the RECIST v1.1 | 0 Participants |
| Selinexor 40 mg Monotherapy | Tumor Size Will be Assessed Using the RECIST v1.1 | 0 Participants |
| Selinexor 60 mg Monotherapy | Tumor Size Will be Assessed Using the RECIST v1.1 | 0 Participants |
| Selinexor 80 mg Monotherapy | Tumor Size Will be Assessed Using the RECIST v1.1 | 0 Participants |