A Study to Evaluate the Safety and Efficacy of Selinexor With or Without Pembrolizumab Versus Standard of Care in Previously Treated Metastatic Colorectal Cancer With RAS Mutations

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the efficacy and safety of selinexor alone or with pembrolizumab in participants with advanced or metastatic colorectal cancer (CRC). Approximately 78 participants with advanced or metastatic CRC will be enrolled, and randomized (1:1:1) into three arms A (selinexor only), B (selinexor and pembrolizumab), and C (standard of care [Combination of trifluridine and tipiracil]). Randomization will be based on stratification factors: Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 versus 2. The end of treatment (EoT) visit will occur less than or equal to (<=30) days post-treatment discontinuation. A survival follow-up visit will be performed every 3 months from EoT and will continue for 12 months.

Official Title
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A Phase 2 Open-Label Multicenter Study to Evaluate the Safety and Efficacy of Selinexor With or Without Pembrolizumab Versus Standard of Care in Previously Treated Metastatic Colorectal Cancer With RAS Mutations

Conditions
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Metastatic Colorectal Cancer

Intervention / Treatment
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* Drug: Selinexor
* Drug: Pembrolizumab
* Drug: Trifluridine
* Drug: Tipiracil


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants have histologically proven diagnosis of unresectable metastatic colorectal cancer with a known rat sarcoma (RAS) mutation. Participants have measurable disease according to RECIST 1.1 criteria. Have received 2-3 prior lines of systemic anticancer treatment (adjuvant or neoadjuvant therapy is not counted as one line of systemic therapy). Participants with stable previously treated brain metastases are allowed. ECOG performance status of 0-2 at the time of screening. Age ≥ 18 years at the time of signing informed consent Life expectancy of at least 3 months. Female participants of childbearing potential must agree to use dual methods of contraception and have a negative serum pregnancy test at screening, and male participants must use an effective barrier method of contraception if sexually active throughout the study and for 4 months after the last dose of selinexor or pembrolizumab or 6 months after trifluridine and tipiracil. Written informed consent signed in accordance with federal, local, and institutional guidelines. Exclusion Criteria: Prior treatment with a selective inhibitor of nuclear export (SINE) compound or selinexor. Prior treatment with immune checkpoint inhibitors. Participants with microsatellite instability high (MSI-H) or deficient mismatch repair (dMMR). Known allergy to any of study drugs (selinexor, pembrolizumab, and trifluridine and tipiracil) or the excipient of pembrolizumab. Significant cardiovascular impairment, defined as: Left ventricular ejection fraction ≤ 40 percent (%) Active congestive heart failure (New York Heart Association [NYHA]) Class ≥ 3 Unstable angina or myocardial infarction within 3 months of enrollment Serious and potentially life-threatening arrhythmia Impaired hematopoietic function (any of the following would result in exclusion): Absolute neutrophil count (ANC) less than (<) 1500/cubic millimeter (mm^3) Platelet count < 100,000/ mm^3 Hemoglobin (Hb) < 10 gram per deciliter (g/dL) Significant renal impairment, defined as: calculated creatinine clearance (CrCl) of < 30 milliliter per minute (mL/min) using the formula of Cockcroft and Gault. Impaired hepatic function defined as: total bilirubin greater than (>) 1.5 × upper limit of normal (ULN) and aspartate transaminase (AST) > 2.5 x ULN, AST > 2.5 x ULN; for Arm B, unless bilirubin elevation is related to Gilbert's Syndrome for which bilirubin must be ≤ 4 x ULN. Participants with a diagnosis of immunodeficiency or are receiving systemic steroid therapy (>10 mg/day of prednisone or equivalent) or any other form of immunosuppressive therapy. Participants with active autoimmune disease requiring systemic treatment during the past 2 years. Participants with controlled type I and type II diabetes mellitus, and endocrinopathies such as hypothyroidism on stable hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are allowed. Note: The Investigator needs to evaluate the participants medical history to confirm that they are eligible to receive the combination with pembrolizumab per these criteria. 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 IV line for infusion are permitted. Have ongoing clinically significant anti-cancer therapy-related toxicities Common Terminology Criteria for Adverse Events (CTCAE) Grade > 1. In specific cases, participants whose toxicity has stabilized or with Grade 2 non-hematologic toxicities can be allowed following documented approval by the Sponsor's Medical Monitor. Had last dose of previous anti-cancer therapy ≤14 days prior to Day 1 dosing. Palliative radiotherapy > 14 days prior to the study is allowed. Received investigational drugs in other clinical trials within 28 days, or 5 half-lives of the investigational drug (whichever is shorter), prior to Cycle 1 Day 1 (C1D1). Live-attenuated vaccine against an infectious disease (e.g., nasal spray influenza vaccine) ≤ 14 days prior to the intended C1D1. Female participants who are pregnant or lactating. Active, ongoing or uncontrolled active infection requiring parenteral antibiotics, antivirals, antifungals within 1 week of Screening. Participants with autoimmune disease, a medical condition that requires systemic corticosteroids or other immunosuppressive medication; or a history of interstitial lung disease. Any gastrointestinal dysfunctions that could interfere with the absorption of selinexor (e.g. bowel obstruction, inability to swallow tablets, malabsorption syndrome, unresolved nausea, vomiting, diarrhea CTCAE > grade 1). In the opinion of the investigator, participants who are below their ideal body weight and would be unduly impacted by changes in their weight. Serious psychiatric or medical conditions that could interfere with participation in the study or in the opinion of the Investigator would make study involvement unreasonably hazardous. Concurrent therapy with approved or investigational anticancer therapeutic including topical therapies.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A: Selinexor 80 mg<br>Participants received a single dose of selinexor 80 mg (4 tablets of 20 mg) orally QW on Day 1 of each week of a 42-day cycle (i.e., on Days 1, 8, 15, 22, 29, and 36 of each 42-day cycle) until PD, intolerable toxicity, or withdrawal from the study (maximum exposure: 33 weeks). | Drug: Selinexor<br>* Participants will receive selinexor oral tablets.<br>* Other names: KPT-330;|
| Experimental: Arm B: Selinexor 80 mg and Pembrolizumab 400 mg<br>Participants received a single dose of selinexor 80 mg (4 tablets of 20 mg) orally QW on Day 1 of each week of a 42-day cycle (i.e., on Days 1, 8, 15, 22, 29, and 36 of each 42-day cycle) in combination with pembrolizumab 400 mg IV once every 6 weeks of each 42-day cycle until PD, intolerable toxicity, or withdrawal from the study (maximum exposure: 30 weeks). | Drug: Selinexor<br>* Participants will receive selinexor oral tablets.<br>* Other names: KPT-330;Drug: Pembrolizumab<br>* Participants will receive pembrolizumab intravenously.<br>* Other names: Keytruda;|
| Active Comparator: Arm C: Standard of care (SOC)<br>Participants received combination of trifluridine and tipiracil 35 mg/m^2/dose tablets orally BID (maximum 80 mg per dose) as SOC on Days 1 through 5 and Days 8 through 12 of each 28-day cycle until PD, intolerable toxicity, or withdrawal from the study (maximum exposure: 11 weeks). | Drug: Trifluridine<br>* Participants will receive trifluridine oral tablets as SOC.<br>Drug: Tipiracil<br>* Participants will receive tipiracil oral tablets as SOC.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Arm B and C: Progression-free Survival (PFS) as Assessed by the Investigator Per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 | PFS was defined as the time from the date of randomization until disease progression or death due to any cause, whichever occurs first. PFS was assessed by the investigator per RECIST 1.1. As per RECIST 1.1 criteria, 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. | From the date of randomization until disease progression or death, whichever occurs first (up to 8 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Arm A, B and C: Overall Survival (OS) | OS was defined as time from the date of randomization to death due to any cause. | From the date of randomization up to death (up to 8 months) | 
| Arm B and C: Overall Response Rate (ORR) | ORR was defined as the percentage of participants who achieve complete response (CR) or partial response (PR) or or initiating a new antineoplastic therapy. ORR was assessed by RECIST 1.1 as defined by the Investigator based on radiologic criteria. Per RECIST 1.1 criteria, CR was defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) had reduction in short axis to <10 mm. PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. | From the date of randomization until the documentation of CR or PR, whichever occurs first (up to 8 months) | 
| Arm A and C: Overall Response Rate (ORR) | ORR was defined as the percentage of participants who achieve CR or PR or or initiating a new antineoplastic therapy. ORR was assessed by RECIST 1.1 as defined by the Investigator based on radiologic criteria. Per RECIST 1.1 criteria, CR was defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) had reduction in short axis to <10 mm. PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. | From the date of randomization until the documentation of CR or PR, whichever occurs first (up to 8 months) | 
| Arm A, B and C: Progression-free Survival (PFS) at 6 Months | PFS at 6 months was defined as the time from the date of randomization without disease progression at 6 months as assessed by the investigator per RECIST 1.1. As per RECIST 1.1 criteria, PD was defined as at least a 20% increase in the sum of the longest diameter (SLD), taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions. | At 6 Months | 
| Arm A, B and C: Percentage of Participants With Overall Survival (OS) at 6 Months | OS was defined as the time from the first dose date to date of death due to any cause. Participant was considered as event (overall survival) free if participant was not died and was alive at 6 months. | At 6 Months | 
| Arm A, B and C: Percentage of Participants With Overall Survival (OS) at 12 Months | OS was defined as the time from the first dose date to date of death due to any cause. Participant was considered as event (overall survival) free if participant was not died and was alive at 12 months. | At 12 Months | 
| Arm B and C: Duration of Response (DOR) Based on Response Evaluation Criteria in Solid Tumors Version 1.1 | DOR was defined as the time from first occurrence of CR or PR until the first date of PD per RECIST version 1.1 or death. CR was defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) had reduction in short axis to <10 mm. PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. | From first occurrence of CR or PR until disease progression or death, whichever occurs first (up to 8 months) | 
| Arm A and C: Duration of Response (DOR) Based on Response Evaluation Criteria in Solid Tumors Version 1.1 | DOR was defined as the time from first occurrence of CR or PR until the first date of PD per RECIST version 1.1 or death. CR was defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) had reduction in short axis to <10 mm. PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. | From first occurrence of CR or PR until disease progression or death, whichever occurs first (up to 8 months) | 
| Arm B and C: Percentage of Participants With Confirmed Disease Control Rate as Per Response Evaluation Criteria in Solid Tumors Version 1.1 | Disease control rate was defined as participants who achieved best overall response of CR, PR, or at least 12 continuous weeks of stable disease (SD) as assessed by investigator as per RECIST v 1.1. As per RECIST v 1.1 before PD or initiating a new antineoplastic therapy, CR was defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (at least a 20% increase in the sum of diameters of target lesions) taking as reference the smallest sum diameters while on study. | From the date of randomization up to death (up to 8 months) | 
| Arm A and C: Percentage of Participants With Confirmed Disease Control Rate as Per Response Evaluation Criteria in Solid Tumors Version 1.1 | Disease control rate was defined as participants who achieved best overall response of CR, PR, or at least 12 continuous weeks of stable disease (SD) as assessed by investigator as per RECIST v 1.1. As per RECIST v 1.1 before PD or initiating a new antineoplastic therapy, CR was defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (at least a 20% increase in the sum of diameters of target lesions) taking as reference the smallest sum diameters while on study. | From the date of randomization up to death (up to 8 months) | 
| Arm A, B and C: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs | An adverse event was defined as any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of study treatment, whether or not considered related to the study treatment. A SAE was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. A TEAE was defined as those AEs that develop or worsen after the first dose of study drug. TEAEs included both serious and non-serious TEAEs. | From start of study drug administration up to 12 months |