A Study of Selinexor in Combination With Temozolomide and Anti-PD-1 Antibody in Patients With Relapsed/Refractory Primary Central Nervous System Lymphoma

The Efficiency and Safety of Selinexor in Combination With Temozolomide and Anti-PD-1 Antibody in Patients With Relapsed/Refractory Primary Central Nervous System Lymphoma: A Prospective, Single-arm, Open, Phase Ib/II Clinical Study

This study is a prospective, single-arm, open label, Phase Ib/II clinical study to evaluate the safety and efficacy of selinexor in combination with temozolomide and anti-PD-1 monoclonal antibody in patients with relapsed/refractory primary central nervous system lymphoma(PCNSL). Phase Ib used a "3+3" dose-climbing design to confirm the safety, maximum-tolerated dose (MTD,if any) and recommended phaseII dose (RP2D) of selinexor in combination with fixed dose of temozolomide and anti-PD-1 monoclonal antibody for 6 cycles. Phase II was a comprehensive evaluation of efficacy and safety. Subjects who achieved complete remission or partial remission were treated with anti-PD-1 monoclonal antibody maintenance therapy until disease progression or recurrence, intolerance of toxicity, death, loss of follow-up, withdrawal of notification (whatever happened first).

Study Overview

• Status: Recruiting
• Conditions: Relapsed/Refractory Primary Central Nervous System Lymphoma
• Intervention / Treatment: Drug: Selinexor; Drug: Temozolomide; Drug: Anti-PD-1 monoclonal antibody

• Study Type: Interventional
• Enrollment (Estimated): 38
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Wenbin Qian; Phone Number: +8613605801032; Email: qianwb@zju.edu.cn
• Study Contact Backup: Name: Xianggui Yuan; Phone Number: +8613989883884; Email: yuanxg@zju.edu.cn

Study Locations

• China
  • Zhejiang
    • Hanzhou, Zhejiang, China, 310009
      • Recruiting
      • 2nd Affiliated Hospital, School of Medicine, Zhejiang University
      • Contact: Wenbin Qian; Phone Number: +8613605801032; Email: qianwb@zju.edu.cn

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Aged between 18 and 75 (inclusive).
• Participants must be able to understand and be willing to sign a written informed consent document.
• Eastern Cooperative Oncology Group performance status 0 to 3.
• Life expectancy of ≥ 3 months (in the opinion of the investigator).
• Primary central nervous system lymphoma (PCNSL) of B-cell origin confirmed by pathology (histology or cytology)
• Measurable disease was defined as at least ≥1.0cm in short-diameter by enhanced MRI.
• Recurrent/refractory PCNSL: Must have received at least one systemic treatment with methotrexate-based treatment.
• Any non-hematological toxicity associated with previous treatment should return to grade 1 or normal (except hair loss according to NCI CTCAE version 5.0)

• Bone marrow and organ function meet the following criteria (no blood transfusion within 14 days prior to screening, no G-CSF, no medication correction) :

  1. Bone marrow function: absolute value of neutrophils ≥1.5×10^9/L, platelets ≥80×10^9/L, hemoglobin ≥80 g/L;
  2. Liver function: serum total bilirubin ≤1.5×ULN (≤3.0×ULN, if there is liver metastasis); Glutamic oxalic aminotransferase (AST) and glutamic pyruvic aminotransferase (ALT) ≤2.5×ULN (≤5.0×ULN, if there is liver metastasis);
  3. Coagulation function: International standardized ratio (INR) and activated partial thrombin time ≤1.5×ULN;
  4. Renal function: serum creatinine ≤1.5×ULN or estimated creatinine clearance ≥60 mL/min (male: Cr (ml/min) = (140-age) × body weight (kg) /72× serum creatinine concentration (mg/dl); Female: Cr (ml/min) = (140- age) × body weight (kg) /85× serum creatinine concentration (mg/dl)
• Women of reproductive potential must agree to use highly effective methods of birth control during the period of therapy and for 6 months after the last dose of the study drug. Men who are sexually active must agree to use highly effective contraception during the period of therapy and for 6 months after the last dose.
• Can accept multiple MRI/CT and lumbar puncture examination.
• Swallowing oral tablets/capsules without difficulty.
• Good compliance, willing to follow the visit schedule, dosing schedule, laboratory examination and other test procedure.

Exclusion Criteria:

• Pathological diagnosis was T cell lymphoma.
• Anti-tumor therapy with chemotherapy, radiotherapy, immunotherapy or antibody drugs, or Chinese herbal medicine with anti-tumor indications, small-molecule targeted therapy within 2 weeks, monoclonal antibody-coupled drugs or cytotoxin therapy within 10 weeks, and autologous stem cell transplantation within 6 months before the first administration.
• Participation in another clinical study with an investigational product during the 4 weeks prior to the first day of study treatment.
• Patients who use systemic adrenal corticosteroids for more than 5 days within 14 days prior to medication or who need to take >10mg of dexamethasone or equivalent drugs daily to control CNS disease.
• Active concurrent malignancy requiring active therapy.
• Prior treatment with temozolomide or anti-PD-1, anti-PD-L1, or anti-PD-L2 drugs within 6 months prior to initial administration
• Have uncontrolled or significant cardiovascular disease, including (but not limited to) : Any of the following: congestive heart failure (NYHA Class III or IV);myocardial infarction; unstable angina; or the presence of an arrhythmia requiring treatment at the time of screening with a left ventricular ejection fraction (LVEF) < 50% in the 6 months prior to initial dosing; Primary cardiomyopathy (e.g., dilated cardiomyopathy, hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, restricted cardiomyopathy, undefined cardiomyopathy); A clinically significant history of prolonged QTc, grade II type II atrioventricular block or grade III atrioventricular block, or QTc interphase (method F) > 470 msec (female) or > 480msec (male);Atrial fibrillation (EHRA grade ≥2b);Patients with unmanageable hypertension were deemed unsuitable for participation in the study.
• Uncontrolled infections or infections that require intravenous antibiotic treatment.
• Chronic hepatitis B carriers with active hepatitis B or C infection (hepatitis B: acute hepatitis B, untreated chronic hepatitis B virus infection, HBV-DNA≥ the detection limit of each center; Hepatitis C: HCV RNA positive) or syphilis. Notes: Non-active HBV surface antigen (HBsAg) carriers, subjects with active HBV infection and persistent anti-HBV inhibition (HBV DNA < each center detection limit), and subjects cured of HCV can be enrolled.
• Human immunodeficiency virus (HIV) infection
• Clinically significant gastrointestinal abnormalities that may affect drug intake, transport, or absorption (such as active gastrointestinal inflammation, chronic diarrhea, intestinal obstruction, etc.), or total gastrectomy or gastric banding surgery.
• Prior allogenic stem cell transplant.
• For female subjects, they are currently pregnant or breastfeeding.
• Allergy to the investigational drug or excipient.
• The patient has active mental illness, alcohol, drug or substance abuse.
• The presence of any life-threatening disease, medical condition, or organ system dysfunction that the investigator believes may affect the patient's safety or compliance with the study procedure.
• There are other conditions that the investigator considers inappropriate to participate in this clinical trial.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: selinexor-based treatment

Drug: Selinexor; Selinexor dose escalation: 40,60,80mg respectively every week, and dose expansion at the RP2D of Selinexor,every 3 weeks for 6 cycles.; Drug: Temozolomide; Temozolomide 150mg/m2 po d1-5 every 3 weeks for 6 cycles.; Drug: Anti-PD-1 monoclonal antibody; The dose of anti-PD-1 monoclonal antibody is fixed dose 200 mg intravenously every 3 weeks until until disease progression or recurrence, intolerance of toxicity, death, loss of follow-up, withdrawal of notification (whatever happened first).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Recommended phase 2 dose	To determine the recommended phase 2 dose for Selinexor.	Up to 21days
Objective response rate (ORR) for Phase II study	The objective response rate (ORR) is defined as the proportion of patients with CR or PR at the end of induction treatment.	18 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free survival (PFS)	PFS is defined as the duration of time from start of treatment to time of progression or death, whichever occurs first.	Up to 2 years after enrollment
Overall survival (OS)	OS is defined as the duration of time from start of treatment to time of death.	Up to 2 years after enrollment
Duration of response	The duration of overall response is measured from the time achieving ORR to time of progression, relapse or death, whichever occurs first.	Up to 2 years after enrollment

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
ctDNA mutation and mean ctDNA concentration in serum and cerebrospinal fluid	Types of ctDNA mutations and frequency are measured by next generation sequencing. The mean ctDNA concentration is the concentration of ctDNA expressed as mean tumor molecules /ml at specific time points.	Up to 2 years after enrollment
The levels of cytokine concentration in serum and cerebrospinal fluid	The levels of cytokine will be analyzed by ELISA in all patients recruited at Baseline and specific time point. The cytokine profile includes IL-6, IL-10, TNF-α, IFN-γ, IL-2 and IL-4	Up to 2 years after enrollment

Collaborators and Investigators

• Sponsor: Second Affiliated Hospital, School of Medicine, Zhejiang University

Study record dates

Study Major Dates

• Study Start (Actual): August 31, 2024
• Primary Completion (Estimated): August 31, 2026
• Study Completion (Estimated): August 31, 2028

Study Registration Dates

• First Submitted: August 7, 2024
• First Submitted That Met QC Criteria: August 13, 2024
• First Posted (Actual): August 15, 2024

Study Record Updates

• Last Update Posted (Actual): July 31, 2025
• Last Update Submitted That Met QC Criteria: July 28, 2025
• Last Verified: August 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; Immune System Diseases; Neoplasms by Histologic Type; Lymphatic Diseases; Lymphoproliferative Disorders; Immunoproliferative Disorders; Lymphoma; Antineoplastic Agents; Immunologic Factors; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents, Alkylating; Alkylating Agents; Temozolomide; Antibodies; Antibodies, Monoclonal
• Other Study ID Numbers: R202333

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No