Safety and Efficacy of Selinexor in Combination With Pembrolizumab in Recurrent Advanced Melanoma

A Phase 2 Open-Label Multicenter Study to Evaluate the Safety and Efficacy of Selinexor in Combination With Pembrolizumab in Recurrent Advanced Melanoma

Approximately 40 participants with locally advanced or metastatic melanoma will be enrolled in 20 sites in the United States into 1 of the following 2 arms: Primary resistance to initial checkpoint inhibitor (CPI) therapy in Arm A and Acquired resistance to initial CPI therapy in Arm B. Participants who have disease progression (PD) after discontinuation of CPIs, especially in neoadjuvant or adjuvant therapy, will be considered to have acquired resistance in this study. Participants will receive study treatment (Selinexor and Pembrolizumab) until PD, intolerable toxicity or withdrawal from the study, whichever occurs first.

Study Overview

• Status: Terminated
• Conditions: Locally Advanced Unresectable or Metastatic Melanoma
• Intervention / Treatment: Drug: Selinexor; Drug: Pembrolizumab

• Study Type: Interventional
• Enrollment (Actual): 15
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • Los Angeles, California, United States, 90095
      • UCLA
    • Pasadena, California, United States, 91105
      • TOI Clinical Research
  • Florida
    • Plantation, Florida, United States, 33322
      • BRCR Global
  • Minnesota
    • Minneapolis, Minnesota, United States, 55404
      • Minnesota Oncology Hematology
  • Nebraska
    • North Platte, Nebraska, United States, 69101
      • Great Plains Health
  • New Jersey
    • Hackensack, New Jersey, United States, 07601
      • John Theurer Cancer Center at Hackensack University Medical Center
    • New Brunswick, New Jersey, United States, 08901
      • Rutgers Cancer Institute of New Jersey
  • New York
    • Albany, New York, United States, 12206
      • New York Oncology Hematology
    • New York, New York, United States, 10065
      • Memorial Sloan Kettering Cancer Center
  • Ohio
    • Cincinnati, Ohio, United States, 45242
      • OH Care Clinical Trials
    • Cleveland, Ohio, United States, 44144
      • Cleveland Clinic Foundation
  • Texas
    • Austin, Texas, United States, 78731
      • Texas Oncology-Austin Central
    • Dallas, Texas, United States, 75246
      • Texas Oncology - Baylor Sammons Center

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Age greater than or equal to (≥) 18 years at the time of informed consent.

• Participant must have a histologically confirmed diagnosis of locally advanced unresectable stage III or metastatic stage IV melanoma not amenable to local therapy.

  1. Participants must have confirmed PD per Response Evaluation Criteria in Solid Tumors (RECIST) on or within 12 weeks of the last dose of anti-PD-1/L1 monotherapy or combination therapy (including relatlimab or other anti-LAG-3 mAb) per Society for Immunotherapy in Cancer Guidelines (Kluger,2020).
  2. Arm A (primary resistance): participant has disease progression after receiving at least 6 weeks of prior anti-PD-1/L1 mAb with the best response as PD, or stable disease (SD) less than (<) 6 month (participants with a partial response [PR] or complete response [CR] who have disease progression within 6 months will be considered to have primary resistance in this study).
  3. Arm B (secondary/acquired resistance): participant has disease progression after receiving at least 6 months of prior anti-PD-1/L1 mAb with the best response as CR, PR, or SD greater than (>) 6 months (participants who have disease progression after neoadjuvant or adjuvant therapy, will be considered to have secondary resistance in this study).
  4. Participants who progress on or within 12 weeks after elective discontinuation of anti-PD-1/L1 mono or combination treatment in the absence of PD or treatment limiting toxicity must have confirmed PD per RECIST.
• Participants should have at least 1 prior line of CPI therapy but no more than 2.
• Measurable disease according to RECIST v1.1.
• Participants with stable previously treated brain metastases are permitted in this study.
• Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to (≤) 1.

• Adequate bone marrow function at screening, defined as:

  1. Absolute neutrophil count (ANC) ≥1.5 * 10^9 per liter (L).
  2. Hemoglobin ≥10 gram per deciliter (gm/dL) (≥6.2 millimoles per liter [mmol/L]).
  3. Platelet count ≥100 * 10^9/L.
• Serum direct bilirubin ≤1.5 * upper limit of normal (ULN); aspartate transaminase (AST) and alanine transaminase (ALT) ≤2.5 * ULN (with confirmed liver metastases: AST and ALT ≤5 * ULN).
• Calculated creatinine clearance (CrCl) ≥15 milliliters per minute (mL/min) based on the Cockcroft and Gault formula.
• Female participants of childbearing potential must have a negative serum pregnancy test at screening and agree to use highly effective methods of contraception throughout the study and for at least four months following the last dose of study treatment. Childbearing potential excludes: Age >50 years and naturally amenorrhoeic for >1 year, or previous bilateral salpingo-oophorectomy, or hysterectomy.
• Male participants who are sexually active must use highly effective methods of contraception throughout the study and for at least four months following the last dose of study treatment. Male participants must agree not to donate sperm during the study treatment period.
• Written informed consent signed in accordance with federal, local, and institutional guidelines.

Exclusion Criteria:

• Metastatic uveal or ocular melanoma.
• Active central nervous system (CNS) metastases or other CNS (e.g., meningeal) involvement.

• Participants must have resolution or improvement of immune-mediated treatment related adverse reactions related to prior treatment(s) to Grade ≤1 without steroid maintenance therapy or his or her previous baseline prior to the corresponding CPI therapy

  a. History of immune-mediated treatment related adverse reactions leading to discontinuation of prior anti-programmed death protein 1 (PD-1), anti-programmed death protein ligand 1 (PD-L1), or anti programmed death protein ligand 2 (PD-L2) monoclonal antibodies (mAbs) or severe hypersensitivity reaction to any mAb or any excipients which in the opinion of the Investigator precludes future use of anti-PD-1/PDL1 therapy.

• Concurrent systemic steroid therapy higher than physiologic dose (>10 milligrams per day [mg/day] of prednisone or equivalent).
• Previous treatment with selinexor or other exportin 1 (XPO1) inhibitors.

• Insufficient time since or not recovered from procedures or anti-cancer therapy, defined as:

  1. Not recovered from major surgery ≤28 days prior to Day 1 dosing. Minor procedures, such as biopsies, dental work, or placement of a port or intravenous (IV) line for infusion are permitted.
  2. 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
  3. Had last dose of previous anti-cancer therapy ≤14 days prior to Day 1 dosing
  4. Palliative radiotherapy >14 days prior to the study is allowed
  5. 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 (e.g., nasal spray influenza vaccine) ≤14 days prior to the intended C1D1.
• Impairment of gastrointestinal (GI) function or GI disease that could significantly alter the absorption of selinexor (e.g., vomiting, or diarrhea that is CTCAE version 5.0 grade >1).
• Life expectancy less than (<) 4 months based on the opinion of the Investigator
• Active pneumonitis requiring steroid therapy.
• Uncontrolled (i.e., clinically unstable) infection requiring parenteral antibiotics, antivirals, or antifungals within 7 days prior to first dose of study treatment; however, prophylactic use of these agents is acceptable (including parenteral).
• Any life-threatening illness, medical condition, or organ system dysfunction which, in the Investigator's opinion, could compromise the participant's safety, prevent the participant from giving informed consent, or being compliant with the study procedures.
• Female participants who are pregnant or lactating.
• Active hepatitis B virus treated with antiviral therapy for hepatitis B within 8 weeks with a viral load >100 international units per milliliter (IU/mL).
• Untreated hepatitis C virus positive without documentation of negative viral load per institutional standard.
• Human immunodeficiency virus positive with CD4+T-cells ≤350 cells per microliter, positive viral load per institutional standard, and a history of acquired immunodeficiency syndrome defining opportunist infections in the last year.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm A: Primary resistance to Initial CPI Therapy; Participants will receive a dose of 80 milligrams (mg) selinexor orally once weekly (QW) and a dose of pembrolizumab 400 mg intravenously (IV) once in every six weeks (Q6W), both on Day 1 of a 6-week cycle until progressive disease (PD), intolerable toxicity or withdrawal from the study, whichever occurs first.	Drug: Selinexor; Dose and formulation: 80 mg (4 tablets of 20 mg); Other Names: KPT-330; XPOVIO®; Drug: Pembrolizumab; Dose and formulation: 400 mg (25 milligrams per milliliter [mg/mL]) Solution; Other Names: KEYTRUDA®
Experimental: Arm B: Acquired Resistance to Initial CPI Therapy; Participants will receive a dose of 80 mg selinexor orally once weekly (QW) and a dose of pembrolizumab 400 mg IV Q6W, both on Day 1 of a 6-week cycle until PD, intolerable toxicity or withdrawal from the study, whichever occurs first.	Drug: Selinexor; Dose and formulation: 80 mg (4 tablets of 20 mg); Other Names: KPT-330; XPOVIO®; Drug: Pembrolizumab; Dose and formulation: 400 mg (25 milligrams per milliliter [mg/mL]) Solution; Other Names: KEYTRUDA®

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Response Rate (ORR) Assessed as Per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1	ORR was defined as the percentage of participants who achieved complete response (CR) or partial response (PR). 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) with reduction in short axis to less than (<)10 millimeter (mm). PR was defined as at least a 30 percentage (%) 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 24 months)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free Survival (PFS) as Per RECIST v 1.1	PFS was defined as time from date of first treatment to the date of first confirmed progressive disease (PD), assessed by RECIST 1.1 is objectively documented or death due to any cause. 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.	From the date of randomization until disease progression or death, due to any cause (up to 24 months)
Overall Survival (OS)	OS was defined as the time from date of first study treatment until death due to any cause. If death event did not occur during the follow-up period, the participant was censored at the date of discontinuation from the study (i.e. withdrawal of consent), or date of last participating visit (e.g., a telephone contact with participant status being alive) on or before database cutoff date, whichever occurs first.	From the date of first study treatment up to death (up to 24 months)
Complete Response Rate (CRR)	Complete response rate was defined as percentage of participants who had achieved a complete response (CR) per RECIST 1.1. As per RECIST version 1.1, CR was defined as disappearance of all target lesions, any pathological lymph nodes (whether target or non-target) with reduced in the short axis to <10 mm.	Up to 101 weeks
Duration of Response (DOR) as Per RECIST v 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. Per RECIST 1.1 criteria, CR was defined as disappearance of all target lesions, any pathological lymph nodes (whether target or non-target) with 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. 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.	From first occurrence of CR or PR until disease progression or death, whichever occurs first (up to 24 months)
Percentage of Participants With Disease Control Rate (DCR) as Per RECIST v 1.1	Disease control rate was defined as percentage of participants who have a response of CR, PR, or at least 12 continuous weeks of stable disease (SD) 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) with 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. Percentage values were rounded off.	Up to 24 months
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 serious adverse event (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 the study treatment up to 24 months
Number of Participants With Clinically Significant Abnormalities in Clinical Laboratory Parameters	Clinical laboratory parameters included clinical chemistry, hematology and urinalysis. Number of participants with clinically significant laboratory abnormalities which were deemed clinically significant by the investigator were reported.	From start of the study treatment up to 24 months
Number of Participants With Clinically Significant Changes in Vital Signs	Vital signs included body temperature, blood pressure (systolic blood pressure and diastolic blood pressure). Measurements were made after the participant had been resting supine for a minimum of 5 minutes. The clinically significant change assessment was based on investigator's judgment. Number of participants with clinically significant change from baseline in vital signs values were reported.	From start of the study treatment up to 24 months
Number of Participants With Clinically Significant Changes in Physical Examination	Number of participants with clinically significant physical examination abnormalities including general appearance, dermatological, head, eyes, ears, nose, throat, respiratory, cardiovascular, abdominal, lymph nodes, musculoskeletal, and neurological examinations. Number of participants with clinically significant physical examination abnormalities which were deemed clinically significant by the investigator were reported.	From start of the study treatment up to 24 months
Number of Participants With Severity of Adverse Events Assessed Using the NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0	AEs are graded using the following criteria using Common Terminology Criteria for Adverse events v5.0: Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated; Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL; Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care ADL; Grade 4: Life-threatening consequences; urgent intervention indicated; Grade 5: Death related to AE.	From start of the study treatment up to 24 months

Collaborators and Investigators

• Sponsor: Karyopharm Therapeutics Inc

Study record dates

Study Major Dates

• Study Start (Actual): May 12, 2021
• Primary Completion (Actual): September 22, 2023
• Study Completion (Actual): September 22, 2023

Study Registration Dates

• First Submitted: February 22, 2021
• First Submitted That Met QC Criteria: February 22, 2021
• First Posted (Actual): February 24, 2021

Study Record Updates

• Last Update Posted (Actual): August 23, 2024
• Last Update Submitted That Met QC Criteria: August 22, 2024
• Last Verified: August 1, 2024

More Information

Terms related to this study

• Keywords: Pembrolizumab; Karyopharm; KPT-330; Selinexor; Locally advanced unresectable or metastatic melanoma; Recurrent advanced melanoma
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroendocrine Tumors; Nevi and Melanomas; Skin Neoplasms; Melanoma; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Pembrolizumab
• Other Study ID Numbers: XPORT-MEL-033

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No