Overview
Safety and Efficacy of Selinexor in Combination With Pembrolizumab in Recurrent Advanced Melanoma
Status:
Recruiting
Recruiting
Trial end date:
2024-11-01
2024-11-01
Target enrollment:
0
0
Participant gender:
All
All
Summary
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.Phase:
Phase 2Accepts Healthy Volunteers?
NoDetails
Lead Sponsor:
Karyopharm Therapeutics IncTreatments:
Pembrolizumab
Criteria
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.