Summary

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.

Objectives

PRIMARY OBJECTIVES:
I. To evaluate the safety and tolerability of venetoclax, MLN9708 (ixazomib citrate), and dexamethasone when used in combination.
II. To determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of venetoclax, MLN9708 (ixazomib citrate), and dexamethasone when used in combination.

SECONDARY OBJECTIVES:
I. To observe and record anti-tumor activity.
II. To obtain a preliminary estimate of the anti-light chain amyloidosis (AL) activity as assessed by incidence of complete hematologic response (CR) and overall hematologic response (partial response [PR], very good partial response [VGPR], and CR).
III. To estimate the organ-specific response rates, among patients with measurable organ disease, using standard criteria.
IV. To estimate progression free survival.

EXPLORATORY OBJECTIVES:
I. To evaluate expression of BCL-2, BCL-XL, and MCL-1 on the surface of plasma cells of patients with AL.
II. To describe the immune profile in the peripheral blood of patients with AL before and during treatment with venetoclax, MLN9708 (ixazomib citrate), and dexamethasone at multiple time points.
III. To estimate hematologic response rates using mass spectrometry to detect persistence of a monoclonal protein in the serum and urine.
IV. To characterize the genotype of the CD138+ plasma cell in patients with AL and t(11;14) and compare findings to those of patients with multiple myeloma and t(11;14) as reported in prior studies.
V. To determine presence of minimal residual disease by Next Generation Sequencing (NGS) in patients achieving a hematologic CR.

OUTLINE: This is a dose-escalation study of venetoclax and ixazomib citrate.

Patients receive venetoclax orally (PO) once daily (QD) on days 1-28, ixazomib citrate PO on days 1, 8 and 15, and dexamethasone PO on days 1, 8, 15 and 22. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients may undergo x-ray imaging and abdominal ultrasound during screening. Patients undergo bone marrow biopsy and/or aspiration as well as blood sample collection throughout the study. Patients may undergo computed tomography (CT) scans, and/or magnetic resonance imaging (MRI), and/or positron emission tomography (PET) scans throughout the study.

After completion of study treatment, patients are followed every 1-3 months until disease progression or death.

Eligibility

1. 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
2. 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
3. Patient requires therapy, as determined by the treating physician, following at least one line of treatment (No limit on the number of prior treatments)
4. 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
5. Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)
6. Leukocytes >= 3,000/mcL
7. 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
8. Platelets >= 75,000/mcL. Platelet transfusions to help patients meet eligibility criteria are not allowed within 2 weeks before study enrollment
9. Total bilirubin =< 1.5 x institutional upper limit of normal (ULN)
10. Aspartate aminotransferase (AST)(serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT)(serum glutamate pyruvate transaminase [SGPT]) =< 3 x institutional ULN
11. Creatinine Calculated clearance >= 15 mL/min using Cockcroft-Gault equation
12. Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial
13. For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated
14. 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
15. 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
16. 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
17. Life expectancy >= 3 months
18. Plasma cell burden =< 60%
19. Absence of bone lesions and other end organ disease consistent with multiple myeloma (patients with plasma cell burden between 10 and 60% without end organ disease can be included)
20. Measurable disease of AL amyloidosis as defined by at least one of the following: 1) serum or urine monoclonal protein >= 500 mg/dL by protein electrophoresis, or 2) serum free light chain >= 20 mg/L with an abnormal kappa:lambda ratio or the difference between involved and uninvolved free light chains (dFLC) >= 20 mg/L
21. It is not known what effects MLN9708 (ixazomib citrate), venetoclax, and dexamethasone have on human pregnancy or development of the embryo or fetus. Therefore, female patients participating in this study should avoid becoming pregnant, and male patients should avoid impregnating a female partner. Nonsterilized female patients of reproductive age group and male patients should use effective methods of contraception through defined periods during and after study treatment as specified below. *Female patients must meet 1 of the following: ** Postmenopausal for at least 1 year before the screening visit, or ** Surgically sterile, or ** If they are of childbearing potential, agree to practice 2 effective methods of contraception from the time of signing of the informed consent form through 90 days after the last dose of study drug, or ** Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [e.g., calendar, ovulation, symptothermal, postovulation methods] and withdrawal are not acceptable methods of contraception) * Male patients, even if surgically sterilized (i.e., status postvasectomy) must agree to 1 of the following: ** Practice effective barrier contraception during the entire study treatment period and through 90 days after the last dose of study drug, or ** Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [e.g., calendar, ovulation, symptothermal, postovulation methods for the female partner] and withdrawal are not acceptable methods of contraception)
22. Left ventricular ejection fraction >= 35% by echocardiogram.
23. Ability to understand and the willingness to sign a written informed consent document. Participants with impaired decision-making capacity (IDMC) who have a legally-authorized representative (LAR) and/or family member available will also be eligible

Treatment Sites in Georgia