Selinexor for Treatment of Light Chain Amyloidosis With Relapsed/Refractory Disease

Study Overview
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Brief Summary
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The purpose of this study is to test the safety and efficacy of Selinexor and Dexamethasone and see what effects it has on AL amyloidosis.

Official Title
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Selinexor for Treatment of Light Chain Amyloidosis With Relapsed/Refractory Disease

Conditions
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Amyloid, Amyloidosis, AL Amyloidosis

Intervention / Treatment
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* Drug: Selinexor
* Drug: Dexamethasone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of primary AL amyloidosis Relapsed and/or refractory AL amyloidosis Measurable disease Male or female patients 18 years or older Able to give voluntary written consent Eastern Cooperative Oncology Group performance status and/or other performance status 0, 1, or 2. Absolute neutrophil count (ANC) ≥ 1,000/mm3 and platelet count ≥ 75,000/mm3. Total bilirubin ≤ 1.5 × the upper limit of the normal range (ULN). Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 × ULN. Calculated creatinine clearance ≥ 30 mL/min Exclusion Criteria: Non-AL amyloidosis Clinically overt myeloma Prior exposure to Selinexor Clinically significant cardiac disease Severe obstructive airway disease Female patients who are lactating or have a positive serum pregnancy test during the screening period Planned high-dose chemotherapy and autologous stem cell transplantation within 6, 28-day treatment cycles after starting on treatment Failure to have fully recovered (ie, ≤ Grade 1 toxicity) from the reversible effects of prior chemotherapy. Major surgery within 14 days before enrollment. Radiotherapy within 14 days before enrollment. Infection requiring systemic intravenous antibiotic therapy or other serious infection within 14 days before study enrollment. Systemic treatment, within 14 days before the first dose, with strong CYP3A inducers (rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, phenobarbital, see Appendix 11.7), or use of Ginkgo biloba or St. John's wort. Positive for human immunodeficiency virus (HIV), hepatitis B, and hepatitis C Serious medical or psychiatric illness GI disease or GI procedure that could interfere with the oral absorption or tolerance including difficulty swallowing Diagnosed or treated for another malignancy within 2 years before study enrollment or previously diagnosed with another malignancy and have any evidence of residual disease. Patients with nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone complete resection. Participation in another clinical trials involving investigational agents within 30 days of starting this trial Peripheral neuropathy (grade 2 with pain or grade 3 or higher).

Ages Eligible for Study
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Minimum Age: 18 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/ dexamethasone (Sd)<br>Selinexor • 60mg PO once weekly on days 1, 8, 15, 22 until disease progression or toxicity Dexamethasone • 20 mg PO administered 30-60 minutes prior to selinexor on days 1, 2, 8, 9, 15, 16, 22, 23 | Drug: Selinexor<br>* Selinexor will be given orally at a dose of 60mg once weekly on the first day of the week (day 1, 8, 15, and 22) for Cycle 1 and up to Cycle 12.<br>Drug: Dexamethasone<br>* Dexamethasone will be given orally at a dose of 20mg, if tolerated, or at a reduced dose if required, 30 to 60 minutes prior to selinexor for first 2 days of each week only (days 1, 2, 8, 9, 15, 16, 22, and 23 of each cycle).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Compare number of dose limiting toxicity (DLT) occurence to measure safety and toxicity | Safety and toxicity will be determined by how many occurrence of dose limiting toxicity (DLT) occured during 12 months of treatment for each subject | approximately 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Compare Hematologic Overall Response Rate (ORR) | Comparing proportion of subjects with Complete Response (CR), Very Good Partial Response (VGPR), Partial Response (PR), No Response (NR) and Progressive Disease (PD) | approximately 12 months | 
| Hematologic Very Good Partial Response (VGPR) or better rate | Percentage of subjects that achieved Very Good Partial Response (VGPR) or better response | approximately 12 months | 
| Hematologic Complete Response (CR) rate | Percentage of subjects that achieved Complete Response (CR) | approximately 12 months | 
| Stringent dFLC response rate | Percentage of subjects that has stringent dFLC (dFLC is defined as the difference in involved amyloidogenic and uninvolved serum-free light chains). | approximately 12 months | 
| Number of patients with peripheral blood mass spectrometry for monoclonal protein detection (MALDI-TOF) | For each subject, detection of monoclonal protein will be analyzed at screening, day 1 of each cycle (only when in ≥VGPR), at each end of treatment (EOT) visits, and day 1 of each post-treatment follow, up until PD or 24 months, whichever occurs first. | End of Study (approximately 3 years) | 
| minimal residual disease (MRD) negative CR/VGPR rate | Percentage of subjects that is MRD negative when in complete response (CR) and Very Good Partial Response (VGPR) | approximately 12 months | 
| Percentage of participants with organ response | Organ response for kidney and cardiac is defined as the proportion of baseline organ involved participants who achieve organ response in each corresponding organ. Organ response defined for cardiac: N-terminal brain pronatriuretic peptide (NT-proBNP) response (> 30% and > 300 nanogram per liter [ng/L] decrease in participants with baseline NT-proBNP >= 650 ng/L) or New York Heart Association (NYHA) class response (>= 2 class decrease in participants with baseline NYHA class 3 or 4); for kidney: decrease in proteinuria by >=30% or below 0.5 grams /24 hours without renal progression. | End of Study (approximately 3 years) | 
| Median hematologic Progression Free Survival (PFS) | Median estimate of months that participants have progression free survival and median estimate is calculated using the Kaplan-Meier methodology | End of Study (approximately 3 years) | 
| Time to first hematologic response | Measured in months between the date of enrollment and the first efficacy evaluation at which the participant has met the criteria for hematologic complete response. | approximately 12 months | 
| Time to best hematologic response | Measured in months between the date of enrollment and the best hematologic response the subject achieved while on treatment | approximately 12 months | 
| Time to hematologic progression | Measured in months between the date of enrollment and the first efficacy evaluation at which the participant has met the criteria for hematologic progression | End of Study (approximately 3 years) | 
| Duration of hematologic response | Duration of hematologic response is defined as the time between the date of initial documentation of hematologic response (i.e. Complete Response, Very Good Partial Response, Partial Response, No Response and Progressive Disease) to the date of the next hematologic response | End of Study (approximately 3 years) | 
| Time to next therapy | Measured in months from the date of enrollment to the start date of subsequent treatment for AL amyloidosis | End of Study (approximately 3 years) | 
| Median organ Progression Free Survival (PFS) | Measured in months between the date of enrollment and the first efficacy evaluation at which the participant has met the criteria for hematologic complete response. | End of Study (approximately 3 years) | 
| Time to organ response | Measured in months between the date of enrollment and the organ response | approximately 12 months | 
| Time to organ progression | Measured in months between the date of organ response to organ progression | End of Study (approximately 3 years) | 
| Duration of organ response | Measured in months between the date of initial documentation of organ response to organ progression | End of Study (approximately 3 years) |