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

• ClinicalTrials.gov Identifier: NCT04854434
• Recruitment Status: Active, not recruiting
• First Posted: April 22, 2021
• Last Update Posted: June 6, 2022
• Sponsor: Karyopharm Therapeutics Inc
• Information provided by (Responsible Party): Karyopharm Therapeutics Inc

Study Description

Brief 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.

Condition or disease	Intervention/treatment	Phase
Metastatic Colorectal Cancer	Drug: Selinexor; Drug: Pembrolizumab; Drug: Trifluridine; Drug: Tipiracil	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 78 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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
• Actual Study Start Date: June 29, 2021
• Estimated Primary Completion Date: July 2022
• Estimated Study Completion Date: April 2023

Arms and Interventions

Arm	Intervention/treatment
Experimental: Arm A: Selinexor 80 mg; Participants will receive a single dose of 80 milligrams (mg) of selinexor once weekly (QW) (4 oral tablets of 20 mg each) on Day 1 of each week (days 1, 8, 15, 22, 29, and 36 of each 42-day cycle) until progressive disease (PD), intolerable toxicity, or withdrawal from the study.	Drug: Selinexor; Participants will receive selinexor oral tablets.; Other Names: Xpovio; KPT-330
Experimental: Arm B: Selinexor 80 mg and Pembrolizumab 400 mg; Participants will receive a single dose of 80 mg of selinexor tablets QW (4 oral tablets of 20 mg each) of selinexor oral tablets QW on Day 1 of each week (days 1, 8, 15, 22, 29, and 36) in combination with pembrolizumab 400 mg intravenously (IV) once every 6 weeks of each 42-day cycle until PD, intolerable toxicity, or withdrawal from the study.	Drug: Selinexor; Participants will receive selinexor oral tablets.; Other Names: Xpovio; KPT-330; Drug: Pembrolizumab; Participants will receive pembrolizumab intravenously.; Other Name: Keytruda
Active Comparator: Arm C: Standard of care (SOC); Participants will receive combination of trifluridine and tipiracil 35 milligrams per square meter (mg/m^2) per dose (15 mg tablet + 20 mg tablet) as oral tablets twice daily (BID) (maximum 80 mg allowed 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.	Drug: Trifluridine; Participants will receive trifluridine oral tablets as SOC.; Drug: Tipiracil; Participants will receive tipiracil oral tablets as SOC.

Outcome Measures

Primary Outcome Measures :

1. Progression-free Survival (PFS) Based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 for Arm B and C [ Time Frame: From the date of randomization until disease progression or death, whichever occurs first (up to 3 years) ]

Secondary Outcome Measures :

1. Overall Survival (OS) for Arm A, B and C [ Time Frame: From the date of randomization up to death (up to 3 years) ]
2. Overall Response Rate (ORR) Based on RECIST 1.1 for Arm A, B and C [ Time Frame: From the date of randomization up to death (up to 3 years) ]
3. Progression-free Survival (PFS) at 6 Months for Arm A, B and C [ Time Frame: At 6 Months ]
4. Percent Overall Survival (OS) in 6 Months for Arm A, B and C [ Time Frame: 6 Months ]
5. Percent Overall Survival (OS) in 12 Months for Arm A, B and C [ Time Frame: 12 Months ]
6. Duration of Response (DOR) Based on RECIST 1.1 for Arm A, B and C [ Time Frame: From the date of randomization until disease progression or death, whichever occurs first (up to 3 years) ]
7. Disease Control Rate (DCR) Based on RECIST 1.1 for Arm A, B and C [ Time Frame: From the date of randomization up to death (up to 3 years) ]
8. Progression-free Survival (PFS) Based on RECIST 1.1 for Arm A and C [ Time Frame: From the date of randomization until disease progression or death, whichever occurs first (up to 3 years ]
9. Number of Participants With Adverse Events (AEs) by Occurrence, Nature, and Severity for Arm A, B and C [ Time Frame: From start of study drug administration up to follow-up (up to 3 years) ]
10. Number of Participants With Clinical Significant Changes in Vital Signs, Clinical Laboratory Values, Electrocardiogram (ECG) and Physical Examination Findings for Arm A, B and C [ Time Frame: From start of study drug administration up to follow-up (up to 3 years) ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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.

Contacts and Locations

Locations

United States, California

Valkyrie Clinical Trials

Los Angeles, California, United States, 90067

United States, Delaware

Christiana Care Health Services, Christiana Hospital

Newark, Delaware, United States, 19718

United States, Florida

BRCR Global

Plantation, Florida, United States, 33322

Sponsors and Collaborators

Karyopharm Therapeutics Inc

More Information

• Responsible Party: Karyopharm Therapeutics Inc
• ClinicalTrials.gov Identifier: NCT04854434
• Other Study ID Numbers: XPORT-CRC-041
• First Posted: April 22, 2021
• Last Update Posted: June 6, 2022
• Last Verified: June 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Colorectal Neoplasms; Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases; Trifluridine; Pembrolizumab; Antineoplastic Agents, Immunological; Antineoplastic Agents; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Antiviral Agents; Anti-Infective Agents