Isatuximab and Bendamustine in Systemic Light Chain Amyloidosis

NCT04943302 | Withdrawn Phase 2 DMC

• 1 other identifier: 00001665
• Study Type: interventional
• Target: N/A
• Locations: 0 countries
• Sites: N/A

Brief Summary

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.

Conditions

Amyloidosis; Light Chain (AL) Amyloidosis

Keywords

isatuximab; bendamustine

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (6)

• Organ Response Rate

  36 Months

• Progression-Free Survival (PFS)

  36 Months

• Rates if Bone Marrow MRD

  36 Months

• Time to Next Treatment

  36 Months

• Toxicity of the Regimen

  36 Months

Study Arms (1)

Isatuximab + bendamustine

EXPERIMENTAL

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; Drug: Isatuximab

Interventions

Bendamustine Hydrochloride DRUG

To be given by IV at 70mg/m2 on cycle days 1 and 8 for up to 6 cycles

Isatuximab + bendamustine

Isatuximab DRUG

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

Isatuximab + bendamustine

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• Tufts Medical Center: lead
• Sanofi: collaborator

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Related Links

• Teva Pharmaceuticals International (bendamustine hydrochloride) \[package insert\]
• Sanofi Aventis US. Sarclisa (isatuximab-irfc) \[package insert\].

MeSH Terms

Conditions

Amyloidosis

Interventions

Bendamustine Hydrochloride; isatuximab

Condition Hierarchy (Ancestors)

Proteostasis Deficiencies; Metabolic Diseases; Nutritional and Metabolic Diseases

Intervention Hierarchy (Ancestors)

Butyrates; Acids, Acyclic; Carboxylic Acids; Organic Chemicals; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Benzimidazoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Officials

• Cindy Varga, MD

  Tufts Medical Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: 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.

Study Record Dates

• First Submitted: June 23, 2021
• First Posted: June 29, 2021
• Study Start: September 1, 2022
• Primary Completion: September 1, 2024
• Study Completion: January 1, 2026
• Last Updated: October 18, 2024

Record last verified: 2024-10

Data Sharing

• IPD Sharing: Will not share