Relapsed/Refractory Primary Central Nervous System Lymphoma
Conditions
Brief summary
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).
Interventions
DRUGSelinexor
Selinexor dose escalation: 40,60,80mg respectively every week, and dose expansion at the RP2D of Selinexor,every 3 weeks for 6 cycles.
DRUGTemozolomide
Temozolomide 150mg/m2 po d1-5 every 3 weeks for 6 cycles.
DRUGAnti-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).
Sponsors
Second Affiliated Hospital, School of Medicine, Zhejiang University
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Recommended phase 2 dose | Up to 21days | To determine the recommended phase 2 dose for Selinexor. |
| Objective response rate (ORR) for Phase II study | 18 weeks | The objective response rate (ORR) is defined as the proportion of patients with CR or PR at the end of induction treatment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free survival (PFS) | Up to 2 years after enrollment | PFS is defined as the duration of time from start of treatment to time of progression or death, whichever occurs first. |
| Duration of response | Up to 2 years after enrollment | The duration of overall response is measured from the time achieving ORR to time of progression, relapse or death, whichever occurs first. |
| Overall survival (OS) | Up to 2 years after enrollment | OS is defined as the duration of time from start of treatment to time of death. |
Other
| Measure | Time frame | Description |
|---|---|---|
| ctDNA mutation and mean ctDNA concentration in serum and cerebrospinal fluid | Up to 2 years after enrollment | 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. |
| The levels of cytokine concentration in serum and cerebrospinal fluid | Up to 2 years after enrollment | 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 |
Countries
China
Contacts
Primary ContactXianggui Yuan
Backup ContactWenbin Qian
Outcome results
None listed