Venetoclax, MLN9708 (Ixazomib Citrate) and Dexamethasone for the Treatment of Relapsed or Refractory Light Chain Amyloidosis

Running, not enrolling · Phase 1

Conditions studied: Recurrent AL Amyloidosis, Refractory AL Amyloidosis

In brief

This phase I/Ia trial finds the best dose and side effects of venetoclax given in combination with ixazomib citrate and dexamethasone in treating patients with light chain amyloidosis that has come back (relapsed) or does not respond to treatment (refractory) and who have an abnormal genetic change \[translocation t(11;14)\]. Venetoclax is in a class of medications called B-cell lymphoma-2 (BCL-2) inhibitors. It may stop the growth of cancer cells by blocking Bcl-2, a protein needed for cancer cell survival. Ixazomib citrate is in a class of medications called proteasome inhibitors. It works by helping to kill cancer cells. Anti-inflammatory drugs such as dexamethasone reduce inflammation by lowering the body's immune response and are used with other drugs in the treatment of some types of cancer. Combination therapy with venetoclax, ixazomib citrate and dexamethasone may be effective in treatment of relapsed or refractory light chain amyloidosis.

Key facts

Study ID: NCT04847453
Run by: National Cancer Institute (NCI)
People needed: 24
Starts: 2022-08-03
Expected to finish: 2028-06-30
Last updated by the study team: 2026-07-31

Who can join

Age: 18 and older. Sex: any. Healthy volunteers: not accepted.

You may qualify if…

Histologically-proven systemic anti-light chain amyloidosis (AL) confirmed by positive Congo red staining with green birefringence on polarized light microscopy and evidence of a measurable clonal disease that requires active treatment. An underlying plasma cell disorder can be identified by one of the following: clonal plasma cells in the bone marrow (BM), monoclonal protein in the serum or urine, or abnormal free light chain ratio. For patients who are African-American or males >= 70 years with isolated cardiac involvement, mass spectrometry must be performed to confirm subtyping
Presence of t(11;14) by fluorescence in situ hybridization (FISH) on bone marrow biopsy, either confirmed at screening or documented with a prior biopsy
Patient requires therapy, as determined by the treating physician, following at least one line of treatment (No limit on the number of prior treatments)
Age >= 18 years. Because no dosing or adverse event data are currently available on the use of venetoclax in combination with MLN9708 (ixazomib citrate) and dexamethasone in patients < 18 years of age, children are excluded from this study
Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)
Leukocytes >= 3,000/mcL
Absolute neutrophil count >= 1,000/mcL. Screening absolute neutrophil count (ANC) should be independent of granulocyte- and granulocyte/macrophage colony stimulating factor (G-CSF and GM-CSF) support for at least 1 week and of pegylated G-CSF for at least 2 weeks
Platelets >= 75,000/mcL. Platelet transfusions to help patients meet eligibility criteria are not allowed within 2 weeks before study enrollment
Total bilirubin =< 1.5 x institutional upper limit of normal (ULN)
Aspartate aminotransferase (AST)(serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT)(serum glutamate pyruvate transaminase [SGPT]) =< 3 x institutional ULN
Creatinine Calculated clearance >= 15 mL/min using Cockcroft-Gault equation
Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial
For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated
Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load
Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial
AL Amyloidosis Cardiac Risk stage I, II or IIIa disease based on the 2013 European Modification of the 2004 Standard Mayo Clinic Staging in patients with advanced cardiac involvement (Dispenzieri et al., 2004; Wechalekar et al., 2013)
Staging system defined by: NT-proBNP cut off of < 332 pg/mL and troponin I cut-off of < 0.10 ng/mL (in the absence of troponin T, troponin I >= 0.1 ng/mL can be used) as thresholds for stages I, II and III; NT-proBNP =< 8500 pg/ml for stage IIIa
Stage I, both under threshold;
Stage I: Zero markers above threshold: NT-proBNP < 332 ng/L AND troponin T (TnT) =< 0.035 ng/mL; NT-proBNP < 332 ng/L AND TnI =< 0.1 ng/mL
Stage II, either troponin or NT-proBNP (but not both) over threshold;
Stage II: One marker above threshold: NT-proBNP >= 332 ng/L OR TnT >= 0.035 ng/mL; NT-proBNP >= 332 ng/L OR TnI >= 0.1 ng/mL
Stage III, both over threshold;
Stage IIIa, both over threshold but NT-proBNP =< 8500 pg/ml
Stage IIIa: Two markers above threshold: NT-proBNP >= 332 ng/L BUT =< 8,500 ng/L AND TnT >= 0.035 ng/mL; NT-proBNP >= 332 ng/L BUT =< 8,500 ng/L AND TnI >= 0.1 ng/mL
Stage IIIb: Two markers above threshold: NT-proBNP > 8,500 ng/L AND TnT >= 0.035 ng/mL; NT-proBNP > 8,500 ng/L AND TnI >= 0.1 ng/mL

You may not qualify if…

Patients who have had major surgery or radiotherapy within 14 days prior to entering the study. If the involved radiotherapy field is small, 7 days will be considered a sufficient interval between treatment and administration of the MLN9708 (ixazomib citrate)
Patients who have had anti-plasma cell therapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study
Patients who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities > grade 1) with the exception of alopecia
Patients who are receiving any other investigational agents, within 30 days of the start of this trial and throughout the duration of this trial
Patients with central nervous system involvement
History of allergic reactions attributed to compounds of similar chemical or biologic composition to venetoclax, MLN9708 (ixazomib citrate) (including boron or boron-containing products) or dexamethasone
Strong or moderate CYP3A inhibitors (e.g., erythromycin, ciprofloxacin, diltiazem, fluconazole, verapamil), or strong CYP3A inducers (e.g., carbamazepine, phenytoin, rifampin, St. John's wort), or moderate CYP3A inducers (e.g., bosentan, efavirenz, etravirine) should be avoided
Venetoclax should be administered using caution with substrates or inhibitors of P-glycoprotein (P-gp)
Patients with uncontrolled intercurrent illness including, but not limited to: ongoing or active serious or systemic infection (within 14 days prior to study enrollment), active hepatitis B or C virus infection, hypertension, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or myocardial infarction (within the past 6 months)
Patients with psychiatric illness/social situations that would limit compliance with study requirements
Female patients who are lactating or have a positive serum pregnancy test during the screening period are excluded from this study because MLN9708 (ixazomib citrate) is a proteasome inhibitor with the potential for embryo-lethal effects, and an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with MLN9708 (ixazomib citrate). Patients must stop breastfeeding while on MLN9708 (ixazomib citrate) and until 90 days have passed since their last dose. These potential risks may also apply to other agents used in this study
Known gastrointestinal disease or gastrointestinal procedure that could interfere with the oral absorption or tolerance of MLN9708 (ixazomib citrate), including difficulty swallowing
Peripheral neuropathy that is >= grade 3, or grade 2 with pain on clinical examination during the screening period
Patients that have previously been treated with MLN9708 (ixazomib citrate). Patients who have received prior treatment with venetoclax
Patients without measurable disease by serum free light chain, serum m-spike or urine monoclonal protein
Patients with New York Heart Association classification III/IV. Patients with advanced cardiac amyloidosis, Mayo stage IIIB based on European Modification of the 2004 Standard Mayo Clinic Staging in patients with advanced cardiac involvement with NT-Pro BNP > 8500 pg/mL (Wechalekar et al., 2013)
Patients with grade 3 or worse diarrhea

Where it is running

City of Hope Comprehensive Cancer Center — Duarte, California, United States
University of California Davis Comprehensive Cancer Center — Sacramento, California, United States
Emory University Hospital/Winship Cancer Institute — Atlanta, Georgia, United States
Johns Hopkins University/Sidney Kimmel Cancer Center — Baltimore, Maryland, United States
Boston Medical Center — Boston, Massachusetts, United States
Dana-Farber Cancer Institute — Boston, Massachusetts, United States
Montefiore Medical Center-Einstein Campus — The Bronx, New York, United States
Montefiore Medical Center-Weiler Hospital — The Bronx, New York, United States
Montefiore Medical Center - Moses Campus — The Bronx, New York, United States
UNC Lineberger Comprehensive Cancer Center — Chapel Hill, North Carolina, United States
Ohio State University Comprehensive Cancer Center — Columbus, Ohio, United States
UPMC Hillman Cancer Center — Pittsburgh, Pennsylvania, United States
University of Texas at Austin — Austin, Texas, United States
Huntsman Cancer Institute/University of Utah — Salt Lake City, Utah, United States
University of Virginia Cancer Center — Charlottesville, Virginia, United States
VCU Massey Comprehensive Cancer Center — Richmond, Virginia, United States

Full record on ClinicalTrials.gov

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