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

Metastatic Colorectal Cancer Clinical Trial

Official title:

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT04854434
• Other study ID #: XPORT-CRC-041
• Status: Terminated
• Phase: Phase 2
• Start date: June 29, 2021
• Est. completion date: June 24, 2022

Study information

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

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 13
• Est. completion date: June 24, 2022
• Est. primary completion date: June 24, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Colorectal Neoplasms
• Metastatic Colorectal Cancer

Intervention

Drug:
• Selinexor
Participants will receive selinexor oral tablets.
• Pembrolizumab
Participants will receive pembrolizumab intravenously.
• Trifluridine
Participants will receive trifluridine oral tablets as SOC.
• Tipiracil
Participants will receive tipiracil oral tablets as SOC.

Locations

Country	Name	City	State
United States	Valkyrie Clinical Trials	Los Angeles	California
United States	Christiana Care Health Services, Christiana Hospital	Newark	Delaware
United States	BRCR Global	Plantation	Florida

Sponsors (1)

Lead Sponsor	Collaborator
Karyopharm Therapeutics Inc

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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)
Secondary	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)
Secondary	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)
Secondary	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
Secondary	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
Secondary	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
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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