Isatuximab and Bendamustine in Systemic Light Chain Amyloidosis

Study Overview
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Brief Summary
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Patients with systemic light chain (AL) amyloidosis, particularly those who are ineligible for transplant or have relapsed/refractory disease, have limited treatment options. The combination of bendamustine and dexamethasone is well-tolerated and efficacious in patients with relapsed/refractory AL amyloidosis. Anti-CD38 antibodies have recently demonstrated great efficacy in AL amyloidosis. Adding isatuximab, a monoclonal antibody targeting CD38, to bendamustine would combine two mechanisms of targeting the clonal plasma cell without significant overlap in toxicity. This would provide a steroid minimizing and neurotoxic-free regimen for patients with AL amyloidosis. This study is a phase II clinical trial of isatuximab and bendamustine in newly diagnosed or relapsed/refractory AL amyloidosis. It is hypothesized that this combination will result in a high number of deep hematologic responses.

Detailed Description
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Systemic light-chain amyloidosis is a disorder in which clonal plasma cells produce misfolded immunoglobulin light chains that deposit in tissues resulting in organ dysfunction and ultimately death. The incidence in the United States is estimated to be 9.7 to 14.0 cases per million person-years with median survival from diagnosis between 6 months and 3 years. The standard of care for those who are eligible is high dose chemotherapy with ASCT. However, only 20-25% of patients are eligible for ASCT with another one-third of patients becoming eligible after bortezomib-based induction. Transplant ineligible patients and patients with relapsed disease after transplant are treated with evolving combinations of anti-plasma cell agents adapted from multiple myeloma including melphalan, cyclophosphamide, proteasome inhibitors, immunomodulatory agents with no therapies approved specifically for this disease. Bendamustine is an alkylating agent that has established anti plasma cell efficacy in both first-line and refractory multiple myeloma. Known for its efficacy and tolerability in a wide array of hematologic malignancies, toxicity profile consists of cytopenias, gastrointestinal side effects, and allergic reactions. In patients with indolent non-Hodgkin's lymphoma, bendamustine with rituximab showed superior 5 year event free survival compared to R-CHOP or R-CVP with a more tolerable toxicity profile. The tolerability of bendamustine made it an attractive agent for AL amyloidosis given the older patient population and co-existence of organ impairment. Efficacy of bendamustine in AL amyloidosis was recently demonstrated in a multicenter phase II study of 31 patients with relapsed/refractory AL amyloidosis who were given bendamustine 100mg/m2 on days 1 and 2 and dexamethasone 40mg weekly of 28 day cycle (2-12 cycles, median 4 cycles). Hematologic response of very good partial response (VGPR) or greater was achieved in 29% of patients (11% complete response) at median of 2.8 months and 29% achieved organ response. The median overall survival (OS) was 18.2 months, but the median OS was not reached among patients who achieved a hematologic partial response (PR) or better after 2 cycles at a median follow up of 14.9 months. Overall, treatment was well tolerated; the most common grade 3/4 toxicities were leukopenia, fatigue, renal dysfunction, rash, and mood symptoms. Plasma cells are known to express CD38, including the monoclonal plasma cells that result in AL amyloidosis. Monoclonal antibodies targeting CD38 have become standard of care in multiple myeloma and more recently have demonstrated safety and superior efficacy when combined with cyclophosphamide, bortezomib, and dexamethasone (CyBorD) compared to CyBorD alone in patients with newly diagnosed AL amyloidosis. Isatuximab is a monoclonal antibody that binds CD38 expressed on plasma cells and results in toxicity and lysis of the cell. Efficacy has been demonstrated in relapsed/refractory multiple myeloma based on a randomized, multicenter, phase 3 clinical trial comparing isatuximab, pomalidomide, and dexamethasone to pomalidomide and dexamethasone which resulted in a significant improvement in PFS (11.5 months vs. 6.5 months; HR 0.596; p=0.001). An ongoing trial, S1702, is investigating isatuximab in patients with relapsed or refractory AL amyloidosis (NCT03499808). This study proposes the combination of isatuximab and bendamustine as a neurotoxic-sparing and steroid-minimizing regimen for newly diagnosed or relapsed/refractory AL amyloidosis.

Official Title
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Isatuximab and Bendamustine in Systemic Light Chain Amyloidosis

Conditions
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Amyloidosis, Light Chain (AL) Amyloidosis

Intervention / Treatment
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* Drug: Bendamustine Hydrochloride
* Drug: Isatuximab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 18 Histopathologically confirmed AL amyloidosis based on detection by polarizing microscopy of green birefringent material in Congo Red stained tissue specimens or characteristic electron microscopy appearance or immunohistohemical stain with anti-light chain anti-sera. Diagnosis cannot be based solely on congo red stain on bone marrow biopsy. Measurable disease (one of the following): Serum monoclonal protein ≥ 0.5g/dL Urine monoclonal protein >200mg/dL in 24 hour urine collection Clonal population of plasma cells in the bone marrow dFLC > 40mg/L Mayo Cardiac Amyloid Stage I-IIIA based on the Mayo 2004/European Addition criteria ECOG 0-2 ANC ≥ 1.0 x10^9/L Hemoglobin ≥ 8g/dL Platelet count ≥ 75 x10^9/L Calculated creatinine clearance ≥ 30mL/min based on the Cockcroft-Gault formula AST and ALT ≤ 2.5x ULN Serum bilirubin < 1.5x ULN Willingness to provide consent and participate in study activities Male participants must agree to use contraception during the intervention period and for at least 5 months after the last dose of isatuximab treatment and refrain from donating sperm during this period. Female participants may not be pregnant, not be breastfeeding, and at least one of the following conditions apply: Not a female of childbearing potential A female of childbearing potential who has a negative serum or urine pregnancy test with a sensitivity of at least 25 mIU/mL within 10 - 14 days prior to and again within 24 hours prior to starting study medication and before each cycle of study treatment and must either commit to continue abstinence from heterosexual intercourse or apply a highly effective method of birth control during the intervention period and for at least 5 months after the last dose of isatuximab treatment Exclusion Criteria: Resistant to prior anti CD38 antibody therapy as defined as either non-responsive or progression while on or within 60 days of discontinuation of treatment Received anti CD38 antibody in the previous 6 months Active symptomatic multiple myeloma as defined by IMWG. Smoldering multiple myeloma is permissible. Myocardial infarction within 6 months prior to enrollment. NYHA class IIIB or IV heart failure Mayo Cardiac Amyloid Stage IIIB based on the Mayo 2004/European Addition criteria (See Appendix A) Uncontrolled angina Severe uncontrolled ventricular arrhythmias Active conduction system abnormalities not including 1st degree AV-block, Wenckebach type 2nd degree heart block, or left bundle branch block. Use of other investigational drug within 14 days or 5 half-lives of the investigational drug prior to initiation of study intervention, whichever is longer. Any clinically significant, uncontrolled medical condition that, in the investigator's opinion, would expose the patient to excessive risk or may interfere with compliance or interpretation of the study results. Active systemic infection and severe infections requiring treatment with parenteral administration of antibiotics. Known to be HIV+ or to have hepatitis A, B, or C active infection Uncontrolled or active HBV infection: Patients with positive HBsAg and/or HBV DNA Patients can be eligible if anti-HBc IgG positive (with or without positive antiHBs) but HBsAg and HBV DNA are negative. If anti-HBV therapy in relation with prior infection was started before initiation of IMP, the anti-HBV therapy and monitoring should continue throughout the study treatment period. Patients with negative HBsAg and positive HBV DNA observed during screening period will be evaluated by a specialist for start of anti-viral treatment: study treatment could be proposed if HBV DNA becomes negative and all the other study criteria are still met. Active HCV infection: positive HCV RNA and negative anti HCV Patients with antiviral therapy for HCV started before initiation of IMP and positive HCV antibodies are eligible. The antiviral therapy for HCV should continue throughout the treatment period until seroconversion. Patients with positive anti-HCV and undetectable HCV RNA without antiviral therapy for HCV are eligible. Pregnancy or breastfeeding Treatment or diagnosis of another malignancy within 3 years of enrollment except complete resection of basal cell carcinoma or squamous cell carcinoma of the skin, an in situ malignancy, low risk prostate cancer. Hypersensitivity to bendamustine Hypersensitivity or history of intolerance to steroids, mannitol, pregelatinized starch, sodium stearyl fumarate, histidine (as base and hydrochloride salt), arginine hydrochloride, poloxamer 188, sucrose or any of the other components of study intervention that are not amenable to premedication with steroids and H2 blockers or would prohibit further treatment with these agents.

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: Sequential Assignment
Interventional Model Description: Phase II, non-randomized, single institution study using a two-stage Simon optimal design. There will first be a safety run-in of 6 patients who will be evaluated for toxicity in cycle 1. Unexpected toxicities will trigger an early safety interim analysis to ensure the regimen is tolerable. In the first stage, 19 patients, including the 6 patients in the safety run-in, will be accrued. If 6 or fewer of these 19 patients achieves hematologic PR, the study will be stopped. Otherwise, up to 20 additional patients will be accrued for a maximum of 39 patients.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Isatuximab + bendamustine<br>Bendamustine will be administered by IV at a dose of 70mg/m2 on cycle days 1 and 8 for up to 6 cycles. Isatuximab will be administered by IV at a dose of 10mg/kg on cycle 1 days 1, 8, 15, and 22; cycle 2-6 days 1,8; and cycle 7-12 day 1. | Drug: Bendamustine Hydrochloride<br>* To be given by IV at 70mg/m2 on cycle days 1 and 8 for up to 6 cycles<br>Drug: Isatuximab<br>* To be given by IV at10mg/kg IV on cycle 1 days 1,8,15, and 22; cycle 2-6 days 1,8; and cycle 7-12 days 1<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Estimated Hematologic Response | Hematologic complete response + very good partial response (CR+VGPR) with definitions as follows: CR: Normalization of free light chain (FLC) ratio AND negative serum and urine immunofixation VGPR: Reduction in the difference between involved and uninvolved free light chains (dFLC) to <40mg/L Partial response (PR): Reduction in the dFLC to at least 50% No response (NR): Less than a PR | 36 Months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Organ Response Rate | Organ response rate as defined by: Kidneys: 30% reduction in 24-hour urine protein excretion or a drop of proteinuria below 0.5g/24h in the absence of progressive renal insufficiency, defined as a decrease in eGFR to 25% over baseline. Heart: Reduction of NT-proBNP of 30% and >300ng/L decrease from the starting value with baseline NT-proBNP ≥650ng/L OR reduction of BNP of 30% and >50ng/L from the starting value with baseline BNP ≥150ng/L. Liver: 50% decrease of an initially elevated alkaline phosphatase level or reduction in the size of the liver by at least 2cm (determined by physical exam, ultrasound, or computer tomography) Neuropathy: clinical improvement supported by clinical history, neurologic exam, orthostatic vital signs, resolution of severe constipation or reduction of diarrhea to less than 50% of previous movements/day, and EMG studies if indicated | 36 Months | 
| Progression-Free Survival (PFS) | PFS per the IMWG definition of progression of disease: From CR: Any detectable monoclonal protein or abnormal free light chain ratio (involved light chain must double) From PR: 50% increase in serum M protein to >0.5g/dL or 50% increase in urine M protein to >200mg/day (a visible peak must be present) Free light chain increase of 50% to >100mg/L | 36 Months | 
| Rates if Bone Marrow MRD | Bone marrow MRD negativity by NGS at a sensitivity of 1x10-6 at the time of complete response, end of treatment visit, and end of study visit. | 36 Months | 
| Time to Next Treatment | Time to next treatment | 36 Months | 
| Toxicity of the Regimen | Toxicity assessment with CTCAE v5.0 | 36 Months | 
| Peripheral Blood BCMA Levels (exploratory) | Peripheral blood BCMA levels as assayed by the Comenzo Laboratory at Tufts Medical Center. | 36 Months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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isatuximab, bendamustine