Selinexor in Combination With Thalidomide and Dexamethasone in RRMM

Study Overview
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Brief Summary
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Multiple myeloma (MM) is an incurable plasma cell cancer that almost all patients eventually relapse despite advancement in treatment strategies. B-cell maturation antigen (BCMA) is a cell surface receptor that expressed primarily by malignant and normal plasma cells. This is a single-arm that includes escalation phase and expansion phase ,Selinexor in Combination withThalidomide and Dexamethasone to Treat Relapsed/Refractory Multiple Myeloma Patients.To evaluate efficacy and safety of Selinexor in combination with Thalidomide and Dexamethasone in RRMM patients received at least one prior lines of therapy

Detailed Description
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This is a single-arm and open-label phase Ib/IIa study of Relapsed/Refractory Multiple Myeloma patients who have received at least one prior lines of treatment therapy; Approximately 3-48 patients will be enrolled in the study. In dose escalation phase, patients with RRMM will be treated with thalidomide 100mg/d, dexamethasone 20mg biweekly, and escalating doses of oral ATG-010 weekly in a 3+3 design. ATG-010 dose level (DL) 1, 2 and 3 are 60, 80 and 100mg respectively. Then a phase 2 expansion at the recommended dose level based on phase 1b trial will be conducted to evaluate the efficacy, safety and tolerability. This arm is 4 weeks per cycle and include a total of 12 cycles.Selinexor RP2D，Thalidomide will be given at 100mg/d d1-28, and Dexamethasone 20 mg/d will be given on day 1, 2,8,9,15,16,22,23. If a patient develops partial intolerance to glucocorticoids (as determined by the Investigator) during the study, a dose reduction of dexamethasone maximum to 10 mg is permitted. If patients do not tolerate this dose, a potential discontinuation or further dose reduction would be allowed.

Official Title
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Phase Ib/II Study of ATG-010 in Combination With Thalidomide and Dexamethasone for Relapsed/Refractory Multiple Myeloma

Conditions
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Multiple Myeloma

Intervention / Treatment
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* Drug: Selinexor
* Drug: Thalidomide
* Drug: Dexamethasone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must meet all of the following inclusion criteria to be eligible to enroll in this study: Known and written informed consent (ICF) voluntarily. Age ≥ 18 years and ≤ 75 years. Patients with multiple myeloma who have received first-line treatment (induction, autologous transplantation and maintenance as the same first-line treatment) and achieved at least partial remission in induction. At or after accepting first-line regimen, subjects must have progression disease (PD) recorded which is determined by researcher according to IMWG criteria. Any clinically significant non-hematological toxicities (except for hair loss, peripheral neuropathy, which is otherwise stipulated in Article 13 of the exclusion criteria) that relevant to previous therapies must have resolved to ≤Grade 2 prior to first dose of study drug. Adequate hepatic function: total bilirubin < 2× upper limit of normal (ULN) (for patients with Gilbert's syndrome, a total bilirubin of < 3× ULN is required), AST < 2.5× ULN, and ALT < 2.5× ULN. Adequate renal function: estimated creatinine clearance ≥ 20 mL/min (calculated using the formula of Cockroft-Gault). Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, 1, or 2. Measurable MM as defined by at least one of the following: Serum M-protein (SPEP) ≥ 10 g/L 24 hours-Urinary M-protein excretion ≥ 0.2 g (200 mg) Serum FLC ≥ 100 mg/L with abnormal FLC ratio Expected survival is more than 6 months. Adequate hematopoietic function (no blood transfusion within 2 weeks and no G-CSF/GM-CSF supportive treatment within 1 week prior to screening test): Hemoglobin level ≥ 80 g/L ANC ≥ 1,000/mm3 (1.0×109/L) Platelet count ≥ 75,000/mm3 (75×109/L) Female patients of childbearing potential must meet below two criteria: must agree to use effective contraception methods since signature in ICF, throughout the study and for 3 months following the last dose of study treatment. must have a negative serum pregnancy test at screening. Note: A woman is considered of childbearing potential following menarche and until becoming postmenopausal (defined as no menstrual period for a minimum of 12 months) or permanently sterile (having undergone a hysterectomy, bilateral salpingectomy or bilateral oophorectomy). A woman who is taking oral contraceptive or using intrauterine device is considered of childbearing potential. Male patients (including those who have received vasectomy) must use a condom if sexually active with a female of child-bearing potential throughout the study and for 3 months following the last dose of study treatment. Exclusion Criteria: Patients who meet any of the following criteria will not be enrolled: Asymptomatic (smoldering) MM. Plasma cell leukemia. Documented active amyloidosis. Previously refractory or intolerant to immunomodulators. Pregnancy or breastfeeding. Major surgery was performed within 4 weeks prior to the first study. Patients with active, unstable cardiovascular diseases, fits any of the following: Symptomatic ischemia, or Uncontrolled clinically-significant conduction abnormalities (e.g., patients with ventricular tachycardia on antiarrhythmics are excluded; patients with first-degree atrioventricular (AV) block or asymptomatic left anterior fascicular block/right bundle branch block (LAFB/RBBB) are allowed), or Congestive heart failure (CHF) of New York Heart Association (NYHA) ≥ Grade 3, or Acute myocardial infarction (AMI) within 3 months prior to the first dose of study drug. Uncontrolled active infection within 1 week prior to the first dose of study drug. Known HIV positive. Known active hepatitis A, B, or C infection; or known positive for HCV RNA or HBsAg. (Note: patients with HBsAg negative but HBc Ab positive need further HBV-DNA test, excluded if HBV-DNA ≥103 , if HBV-DNA <103 need anti-viral drugs) Prior malignancy that required treatment or has shown evidence of recurrence (except for skin basal-cell carcinoma and in-situ carcinoma including squamous cell carcinoma, bladder cancer in situ, endometrial cancer in situ, cervical cancer in situ/atypical hyperplasia, prostate cancer incidental finding (T1a or T1b), or breast cancer in situ) within 5 years prior to the first dose of study drug. Active GI dysfunction interfering with the ability to swallow tablets, or any GI dysfunction that could interfere with absorption of study treatment. Grade ≥ 3 peripheral neuropathy, and Grade ≥ 2 painful neuropathy, within 3 weeks prior to the first dose of study drug. Previous history of deep vein thrombosis. Serious, active psychiatric, or medical conditions which, in the opinion of the Investigator, could interfere with study treatment. Participation in an investigational anti-cancer clinical study within 3 weeks or 5 half-lives (T1/2) prior to the first dose of study drug. Received ASCT within 12 weeks prior to the first dose of study drug or previous allogeneic stem cell transplantation (no time limitation). Treatment with an approved or trial anticancer drug was given within 4 weeks prior to the first study. Known intolerance to or contraindication for glucocorticoid therapy. Prior exposure to a SINE compound.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Selinexor in combination with thalidomide and Dexamethasone<br>Selinexor in combination with thalidomide and Dexamethasone. Thalidomide will be given at 100mg/d d1-28,and Dexamethasone 20 mg/d will be given on day 1, 2,8,9,15,16,22,23. Treatment will be administered in 28-day cycles,include a total of 12 cycles. Selinexor dose escalation: 60, 80, 100mg respectively on day 1,8,15,22 for 4-week cycles. Then Selinexor will be given at the recommended dose level on phase II. | Drug: Selinexor<br>* Selinexor (ATG-010# is a first-in-class, oral selective exportin 1 (XPO1) inhibitor (1,2). Selinexor functions by binding with and inhibiting the nuclear export protein XPO1 (also called CRM1), leading to the accumulation of tumor suppressor proteins in the cell nucleus along with inhibition of translation of oncoprotein mRNAs.<br>* Other names: ATG-010;Drug: Thalidomide<br>* 100mg/d, Po. on day1-28<br>* Other names: fǎn yìng tíng;Drug: Dexamethasone<br>* 20 mg/d Po. on day 1, 2,8,9,15,16,22,23<br>* Other names: Dex;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR) | ORR in each arm: partial response (PR) + very good partial response (VGPR) + complete response (CR) | Assessed from the date of first dose of study treatment until the date that PD assessed up to 12months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of Response (DOR) | Duration from the first observation of at least PR to time of disease progression, or deaths due to disease progression, whichever occurs first. | 12 months | 
| Disease Control Rate (DCR) | Disease Control Rate (DCR=CBR+Stable Disease[SD; for a minimum of 12 weeks]) | 12 months | 
| Progression-Free Survival (PFS) | Duration from start of study treatment to PD or death (regardless of cause), whichever comes first | 12 months | 
| Overall Survival (OS) | The estimates of Kaplan-Meier | 12 months | 
| Minimal Residual Disease (MRD) | To evaluate the minimal residual disease in CR and sCR patients | 12 months | 
| Clinical Benefit Rate (CBR) | Clinical Benefit Rate (CBR=ORR+Minor Response [MR]) | 12 months | 
| Number of Participants with Adverse Events | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs) | From first dose of study drug administration to end of treatment (up to 12 months) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Selinexor, ATG-010, Multiple Myeloma, Relapsed/Refractory Multiple Myeloma, Thalidomide