A Phase 1/1a Study of Venetoclax, MLN9708 (ixazomib citrate) and Dexamethasone for Relapsed/Refractory Light Chain Amyloidosis

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.

Inclusion Criteria:

- 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

- Life expectancy >= 3 months

- Plasma cell burden =< 60%

- 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)

- 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

- 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)

- Left ventricular ejection fraction >= 35% by echocardiogram.

- 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

Exclusion Criteria:

- 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,
etavirine) 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