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AmyloidosisPhase 2NCT04943302

Isatuximab and Bendamustine in Systemic Light Chain Amyloidosis

A Phase 2 study testing Bendamustine Hydrochloride and Isatuximab in people with Amyloidosis and Light Chain (AL) Amyloidosis, run by Tufts Medical Center.

Withdrawn

Withdrawn. The study stopped before anyone enrolled.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Amyloidosis, Light Chain (AL) Amyloidosis
What is being tested?
Bendamustine Hydrochloride and Isatuximab
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
0 participants
Where
No sites listed yet
Study dates
1 Sep 2022to Jan 2026
Phase
Phase 2
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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
Show all 20Show fewer
  • 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

Who cannot join

  • 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)
Show all 24Show fewer
  • 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.

About this study

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.

Read the detailed description

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.

Being tested
Bendamustine Hydrochloride, Isatuximab
Keywords
isatuximab, bendamustine
Medical subject headings
Amyloidosis

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Bendamustine HydrochlorideDrug

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

  • IsatuximabDrug

    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

Study groups in NCT04943302
Study groupRoleWhat they receive
Isatuximab + bendamustineExperimentalBendamustine 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.
Receives: Drug: Bendamustine Hydrochloride; Drug: Isatuximab

What is being measured

The primary outcome is the main question the study is designed to answer.

  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

    Measured: 36 Months

Secondary outcomes (6)

  1. 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

    Measured: 36 Months

  2. 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

    Measured: 36 Months

  3. 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.

    Measured: 36 Months

  4. Time to Next Treatment

    Time to next treatment

    Measured: 36 Months

  5. Toxicity of the Regimen

    Toxicity assessment with CTCAE v5.0

    Measured: 36 Months

  6. Peripheral Blood BCMA Levels (exploratory)

    Peripheral blood BCMA levels as assayed by the Comenzo Laboratory at Tufts Medical Center.

    Measured: 36 Months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted29 Jun 2021
  2. Study start1 Sep 2022
  3. Primary completionSep 2024 (estimated)
  4. Study completionJan 2026 (estimated)

Why it stopped: PI left institution. Study not moving forward in her absence.

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Sequential
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)
Enrolment
0 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT04943302
Sponsor's protocol ID
00001665
Status last verified
Oct 2024
First submitted
23 Jun 2021
Last updated
18 Oct 2024
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
No

Publications

  • Gertz MA. Immunoglobulin light chain amyloidosis: 2020 update on diagnosis, prognosis, and treatment. Am J Hematol. 2020 Jul;95(7):848-860. doi: 10.1002/ajh.25819. Epub 2020 Apr 28.

    PubMed 32267020

  • Quock TP, Yan T, Chang E, Guthrie S, Broder MS. Epidemiology of AL amyloidosis: a real-world study using US claims data. Blood Adv. 2018 May 22;2(10):1046-1053. doi: 10.1182/bloodadvances.2018016402.

    PubMed 29748430

  • Cornell RF, Zhong X, Arce-Lara C, Atallah E, Blust L, Drobyski WR, Fenske TS, Pasquini MC, Rizzo JD, Saber W, Hari PN. Bortezomib-based induction for transplant ineligible AL amyloidosis and feasibility of later transplantation. Bone Marrow Transplant. 2015 Jul;50(7):914-7. doi: 10.1038/bmt.2015.73. Epub 2015 Apr 27.

    PubMed 25915809

  • Gentile M, Vigna E, Recchia AG, Morabito L, Mendicino F, Giagnuolo G, Morabito F. Bendamustine in multiple myeloma. Eur J Haematol. 2015 Nov;95(5):377-88. doi: 10.1111/ejh.12609. Epub 2015 Jul 14.

    PubMed 26085055

  • Cheson BD, Rummel MJ. Bendamustine: rebirth of an old drug. J Clin Oncol. 2009 Mar 20;27(9):1492-501. doi: 10.1200/JCO.2008.18.7252. Epub 2009 Feb 17.

    PubMed 19224851

  • Flinn IW, van der Jagt R, Kahl BS, Wood P, Hawkins TE, Macdonald D, Hertzberg M, Kwan YL, Simpson D, Craig M, Kolibaba K, Issa S, Clementi R, Hallman DM, Munteanu M, Chen L, Burke JM. Randomized trial of bendamustine-rituximab or R-CHOP/R-CVP in first-line treatment of indolent NHL or MCL: the BRIGHT study. Blood. 2014 May 8;123(19):2944-52. doi: 10.1182/blood-2013-11-531327. Epub 2014 Mar 3.

    PubMed 24591201

  • Flinn IW, van der Jagt R, Kahl B, Wood P, Hawkins T, MacDonald D, Simpson D, Kolibaba K, Issa S, Chang J, Trotman J, Hallman D, Chen L, Burke JM. First-Line Treatment of Patients With Indolent Non-Hodgkin Lymphoma or Mantle-Cell Lymphoma With Bendamustine Plus Rituximab Versus R-CHOP or R-CVP: Results of the BRIGHT 5-Year Follow-Up Study. J Clin Oncol. 2019 Apr 20;37(12):984-991. doi: 10.1200/JCO.18.00605. Epub 2019 Feb 27.

    PubMed 30811293

  • Lentzsch S, Lagos GG, Comenzo RL, Zonder JA, Osman K, Pan S, Bhutani D, Pregja S, Sanchorawala V, Landau H. Bendamustine With Dexamethasone in Relapsed/Refractory Systemic Light-Chain Amyloidosis: Results of a Phase II Study. J Clin Oncol. 2020 May 1;38(13):1455-1462. doi: 10.1200/JCO.19.01721. Epub 2020 Feb 21.

    PubMed 32083996

  • Matsuda M, Gono T, Shimojima Y, Hoshii Y, Ikeda S. Phenotypic analysis of plasma cells in bone marrow using flow cytometry in AL amyloidosis. Amyloid. 2003 Jun;10(2):110-6. doi: 10.3109/13506120309041732.

    PubMed 12964418

  • Palladini G, Kastritis E, Maurer MS, Zonder J, Minnema MC, Wechalekar AD, Jaccard A, Lee HC, Bumma N, Kaufman JL, Medvedova E, Kovacsovics T, Rosenzweig M, Sanchorawala V, Qin X, Vasey SY, Weiss BM, Vermeulen J, Merlini G, Comenzo RL. Daratumumab plus CyBorD for patients with newly diagnosed AL amyloidosis: safety run-in results of ANDROMEDA. Blood. 2020 Jul 2;136(1):71-80. doi: 10.1182/blood.2019004460.

    PubMed 32244252

  • Jiang H, Acharya C, An G, Zhong M, Feng X, Wang L, Dasilva N, Song Z, Yang G, Adrian F, Qiu L, Richardson P, Munshi NC, Tai YT, Anderson KC. SAR650984 directly induces multiple myeloma cell death via lysosomal-associated and apoptotic pathways, which is further enhanced by pomalidomide. Leukemia. 2016 Feb;30(2):399-408. doi: 10.1038/leu.2015.240. Epub 2015 Sep 4.

    PubMed 26338273

  • Attal M, Richardson PG, Rajkumar SV, San-Miguel J, Beksac M, Spicka I, Leleu X, Schjesvold F, Moreau P, Dimopoulos MA, Huang JS, Minarik J, Cavo M, Prince HM, Mace S, Corzo KP, Campana F, Le-Guennec S, Dubin F, Anderson KC; ICARIA-MM study group. Isatuximab plus pomalidomide and low-dose dexamethasone versus pomalidomide and low-dose dexamethasone in patients with relapsed and refractory multiple myeloma (ICARIA-MM): a randomised, multicentre, open-label, phase 3 study. Lancet. 2019 Dec 7;394(10214):2096-2107. doi: 10.1016/S0140-6736(19)32556-5. Epub 2019 Nov 14.

    PubMed 31735560

  • Palladini G, Dispenzieri A, Gertz MA, Kumar S, Wechalekar A, Hawkins PN, Schonland S, Hegenbart U, Comenzo R, Kastritis E, Dimopoulos MA, Jaccard A, Klersy C, Merlini G. New criteria for response to treatment in immunoglobulin light chain amyloidosis based on free light chain measurement and cardiac biomarkers: impact on survival outcomes. J Clin Oncol. 2012 Dec 20;30(36):4541-9. doi: 10.1200/JCO.2011.37.7614. Epub 2012 Oct 22.

    PubMed 23091105

  • Palladini G, Hegenbart U, Milani P, Kimmich C, Foli A, Ho AD, Vidus Rosin M, Albertini R, Moratti R, Merlini G, Schonland S. A staging system for renal outcome and early markers of renal response to chemotherapy in AL amyloidosis. Blood. 2014 Oct 9;124(15):2325-32. doi: 10.1182/blood-2014-04-570010. Epub 2014 Aug 12.

    PubMed 25115890

  • Comenzo RL, Reece D, Palladini G, Seldin D, Sanchorawala V, Landau H, Falk R, Wells K, Solomon A, Wechalekar A, Zonder J, Dispenzieri A, Gertz M, Streicher H, Skinner M, Kyle RA, Merlini G. Consensus guidelines for the conduct and reporting of clinical trials in systemic light-chain amyloidosis. Leukemia. 2012 Nov;26(11):2317-25. doi: 10.1038/leu.2012.100. Epub 2012 Apr 5.

    PubMed 22475872

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Bendamustine Hydrochloride and Isatuximab in people with Amyloidosis and Light Chain (AL) Amyloidosis, run by Tufts Medical Center.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 20 inclusion and 24 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: withdrawn, as of the sponsor's last update on 18 Oct 2024. Status can change between updates, so confirm with the study contact before making plans.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study was withdrawn before enrolling participants, so there are no results.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Estimated Hematologic Response (time frame: 36 Months). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT04943302, which also lists 33 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 18 Oct 2024.

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