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

Primary Purpose

AL Amyloidosis

Status
Recruiting
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Biospecimen Collection
Bone Marrow Aspiration and Biopsy
Computed Tomography
Dexamethasone
Ixazomib Citrate
Magnetic Resonance Imaging
Positron Emission Tomography
Transabdominal Ultrasound
Venetoclax
X-Ray Imaging
Sponsored by
National Cancer Institute (NCI)
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for AL Amyloidosis

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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. Patients must have measurable disease with dFLC >= 4 mg/dL (40mg/L). For patients who are African-American, mass spectrometry must be performed to confirm subtyping
  • Presence of t(11;14) by fluorescence in situ hybridization (FISH) on bone marrow biopsy, to be confirmed at screening.
  • Evidence of relapsed, refractory, or progressive disease following at least one line of treatment as defined by National Comprehensive Cancer Network (NCCN) guidelines (no limit on the number of prior treatments). Hematologic relapse/progression is defined by the reappearance of a detectable monoclonal protein or abnormal serum free light-chain ratio after having achieved a hematologic complete response or a 50% increase in serum M protein or urine M protein to > 0.5 g/dL or > 200 mg/day, respectively, or a free light-chain increase of 50% to >100 mg/L in those with stable disease or partial response. Refractory disease is progression on a previous line of therapy without response
  • 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
  • Calculated clearance >= 30 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 >= 50 mg/L with an abnormal kappa:lambda ratio or the difference between involved and uninvolved free light chains (dFLC) ≥40 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)
  • 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

Sites / Locations

  • City of Hope Comprehensive Cancer Center LAORecruiting
  • City of Hope Comprehensive Cancer CenterRecruiting
  • University of California Davis Comprehensive Cancer CenterRecruiting
  • Emory University Hospital/Winship Cancer InstituteRecruiting
  • Johns Hopkins University/Sidney Kimmel Cancer CenterRecruiting
  • Boston Medical CenterRecruiting
  • Dana-Farber Cancer InstituteRecruiting
  • Montefiore Medical Center-Einstein CampusRecruiting
  • Montefiore Medical Center-Weiler Hospital
  • Montefiore Medical Center - Moses CampusRecruiting
  • Ohio State University Comprehensive Cancer CenterRecruiting
  • University of Pittsburgh Cancer Institute (UPCI)Recruiting
  • Huntsman Cancer Institute/University of UtahRecruiting
  • University of Virginia Cancer CenterRecruiting
  • Virginia Commonwealth University/Massey Cancer CenterRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Treatment (venetoclax, ixazomib citrate, dexamethasone)

Arm Description

Patients receive venetoclax PO 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 CT scans, and/or MRI, and/or PET scans throughout the study.

Outcomes

Primary Outcome Measures

Incidence of adverse events
Toxicity will be evaluated according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0.
Maximum tolerated dose
Defined as the dose for which the isotonic estimate of the toxicity rate is closest to the target toxicity rate.
Recommended phase 2 dose (RP2D)
Will be based on the assessment of toxicities during cycle 1 that meet criteria for dose-limiting toxicities (DLT).

Secondary Outcome Measures

Overall response rate (complete hematologic response)
Will be estimated based on the patients enrolled in the dose-escalation as well as the dose-expansion stage, using Clopper-Pearson confidence interval. Hematologic complete response rate will be evaluated according to the consensus guidelines in treatment response.

Full Information

First Posted
April 15, 2021
Last Updated
September 15, 2023
Sponsor
National Cancer Institute (NCI)
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1. Study Identification

Unique Protocol Identification Number
NCT04847453
Brief Title
Venetoclax, MLN9708 (Ixazomib Citrate) and Dexamethasone for the Treatment of Relapsed or Refractory Light Chain Amyloidosis
Official Title
A Phase 1/1a Study of Venetoclax, MLN9708 (Ixazomib Citrate) and Dexamethasone for Relapsed/Refractory Light Chain Amyloidosis
Study Type
Interventional

2. Study Status

Record Verification Date
September 2023
Overall Recruitment Status
Recruiting
Study Start Date
August 3, 2022 (Actual)
Primary Completion Date
September 30, 2024 (Anticipated)
Study Completion Date
September 30, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
National Cancer Institute (NCI)

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief 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.
Detailed Description
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
AL Amyloidosis

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
24 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Treatment (venetoclax, ixazomib citrate, dexamethasone)
Arm Type
Experimental
Arm Description
Patients receive venetoclax PO 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 CT scans, and/or MRI, and/or PET scans throughout the study.
Intervention Type
Procedure
Intervention Name(s)
Biospecimen Collection
Other Intervention Name(s)
Biological Sample Collection, Biospecimen Collected, Specimen Collection
Intervention Description
Undergo blood specimen collection
Intervention Type
Procedure
Intervention Name(s)
Bone Marrow Aspiration and Biopsy
Intervention Description
Undergo bone marrow aspiration and biopsy
Intervention Type
Procedure
Intervention Name(s)
Computed Tomography
Other Intervention Name(s)
CAT, CAT Scan, Computed Axial Tomography, Computerized Axial Tomography, Computerized axial tomography (procedure), Computerized Tomography, CT, CT Scan, tomography
Intervention Description
Undergo CT scan
Intervention Type
Drug
Intervention Name(s)
Dexamethasone
Other Intervention Name(s)
Aacidexam, Adexone, Aknichthol Dexa, Alba-Dex, Alin, Alin Depot, Alin Oftalmico, Amplidermis, Anemul mono, Auricularum, Auxiloson, Baycadron, Baycuten, Baycuten N, Cortidexason, Cortisumman, Decacort, Decadrol, Decadron, Decadron DP, Decalix, Decameth, Decasone R.p., Dectancyl, Dekacort, Deltafluorene, Deronil, Desamethasone, Desameton, Dexa-Mamallet, Dexa-Rhinosan, Dexa-Scheroson, Dexa-sine, Dexacortal, Dexacortin, Dexafarma, Dexafluorene, Dexalocal, Dexamecortin, Dexameth, Dexamethasone Intensol, Dexamethasonum, Dexamonozon, Dexapos, Dexinoral, Dexone, Dinormon, Dxevo, Fluorodelta, Fortecortin, Gammacorten, Hemady, Hexadecadrol, Hexadrol, Lokalison-F, Loverine, Methylfluorprednisolone, Millicorten, Mymethasone, Orgadrone, Spersadex, TaperDex, Visumetazone, ZoDex
Intervention Description
Given PO
Intervention Type
Drug
Intervention Name(s)
Ixazomib Citrate
Other Intervention Name(s)
MLN-9708, MLN9708, Ninlaro
Intervention Description
Given PO
Intervention Type
Procedure
Intervention Name(s)
Magnetic Resonance Imaging
Other Intervention Name(s)
Magnetic Resonance, Magnetic resonance imaging (procedure), Magnetic Resonance Imaging Scan, Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance, MR, MR Imaging, MRI, MRI Scan, NMR Imaging, NMRI, Nuclear Magnetic Resonance Imaging
Intervention Description
Undergo MRI
Intervention Type
Procedure
Intervention Name(s)
Positron Emission Tomography
Other Intervention Name(s)
Medical Imaging, Positron Emission Tomography, PET, PET Scan, Positron emission tomography (procedure), Positron Emission Tomography Scan, Positron-Emission Tomography, proton magnetic resonance spectroscopic imaging, PT
Intervention Description
Undergo PET scan
Intervention Type
Procedure
Intervention Name(s)
Transabdominal Ultrasound
Other Intervention Name(s)
abdominal ultrasound, TUS
Intervention Description
Undergo transabdominal ultrasound
Intervention Type
Drug
Intervention Name(s)
Venetoclax
Other Intervention Name(s)
ABT-0199, ABT-199, ABT199, GDC-0199, RG7601, Venclexta, Venclyxto
Intervention Description
Given PO
Intervention Type
Procedure
Intervention Name(s)
X-Ray Imaging
Other Intervention Name(s)
Conventional X-Ray, Diagnostic Radiology, Medical Imaging, X-Ray, Plain film radiographs, Radiographic Imaging, Radiographic imaging procedure (procedure), Radiography, RG, Static X-Ray, X-Ray
Intervention Description
Undergo x-ray
Primary Outcome Measure Information:
Title
Incidence of adverse events
Description
Toxicity will be evaluated according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0.
Time Frame
Up to 30 days
Title
Maximum tolerated dose
Description
Defined as the dose for which the isotonic estimate of the toxicity rate is closest to the target toxicity rate.
Time Frame
Up to the end of cycle 1
Title
Recommended phase 2 dose (RP2D)
Description
Will be based on the assessment of toxicities during cycle 1 that meet criteria for dose-limiting toxicities (DLT).
Time Frame
Up to the end of cycle 1
Secondary Outcome Measure Information:
Title
Overall response rate (complete hematologic response)
Description
Will be estimated based on the patients enrolled in the dose-escalation as well as the dose-expansion stage, using Clopper-Pearson confidence interval. Hematologic complete response rate will be evaluated according to the consensus guidelines in treatment response.
Time Frame
After cycles 3, 6, 9, and 12, and every 6 months thereafter up to 2.5 years
Other Pre-specified Outcome Measures:
Title
Expression of BCL-2, BCL-XL, BAX, BAK, BIM, NOXA, and MCL-1
Description
Will be assessed by immunohistochemistry.
Time Frame
Baseline
Title
Immune profile in the peripheral blood
Description
Will be determined by mass cytometry.
Time Frame
Before and during treatment
Title
Hematologic response rates
Description
Estimated using mass spectrometry to detect persistence of a monoclonal protein in the serum and urine.
Time Frame
Up to 2.5 years
Title
Characterization of CD138+ plasma cell with t(11;14)
Time Frame
Up to 2.5 years
Title
Presence of minimal residual disease
Description
Will be determined by Next Generation Sequencing in patients achieving a hematologic complete response.
Time Frame
Up to 2.5 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Michael A Rosenzweig
Organizational Affiliation
City of Hope Comprehensive Cancer Center LAO
Official's Role
Principal Investigator
Facility Information:
Facility Name
City of Hope Comprehensive Cancer Center LAO
City
Duarte
State/Province
California
ZIP/Postal Code
91010
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Michael A. Rosenzweig
Email
mrosenzweig@coh.org
First Name & Middle Initial & Last Name & Degree
Michael A. Rosenzweig
Facility Name
City of Hope Comprehensive Cancer Center
City
Duarte
State/Province
California
ZIP/Postal Code
91010
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Site Public Contact
Phone
800-826-4673
Email
becomingapatient@coh.org
First Name & Middle Initial & Last Name & Degree
Michael A. Rosenzweig
Facility Name
University of California Davis Comprehensive Cancer Center
City
Sacramento
State/Province
California
ZIP/Postal Code
95817
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Site Public Contact
Phone
916-734-3089
First Name & Middle Initial & Last Name & Degree
Aaron Rosenberg
Facility Name
Emory University Hospital/Winship Cancer Institute
City
Atlanta
State/Province
Georgia
ZIP/Postal Code
30322
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Site Public Contact
Phone
404-778-1868
First Name & Middle Initial & Last Name & Degree
Craig C. Hofmeister
Facility Name
Johns Hopkins University/Sidney Kimmel Cancer Center
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21287
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Site Public Contact
Phone
410-955-8804
Email
jhcccro@jhmi.edu
First Name & Middle Initial & Last Name & Degree
Carol A. Huff
Facility Name
Boston Medical Center
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02118
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Site Public Contact
Phone
617-638-8265
First Name & Middle Initial & Last Name & Degree
Vaishali Sanchorawala
Facility Name
Dana-Farber Cancer Institute
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02215
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Site Public Contact
Phone
877-442-3324
First Name & Middle Initial & Last Name & Degree
Giada Bianchi
Facility Name
Montefiore Medical Center-Einstein Campus
City
Bronx
State/Province
New York
ZIP/Postal Code
10461
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Site Public Contact
Phone
718-379-6866
Email
eskwak@montefiore.org
First Name & Middle Initial & Last Name & Degree
Nishi N. Shah
Facility Name
Montefiore Medical Center-Weiler Hospital
City
Bronx
State/Province
New York
ZIP/Postal Code
10461
Country
United States
Individual Site Status
Suspended
Facility Name
Montefiore Medical Center - Moses Campus
City
Bronx
State/Province
New York
ZIP/Postal Code
10467
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Site Public Contact
Phone
718-379-6866
Email
eskwak@montefiore.org
First Name & Middle Initial & Last Name & Degree
Nishi N. Shah
Facility Name
Ohio State University Comprehensive Cancer Center
City
Columbus
State/Province
Ohio
ZIP/Postal Code
43210
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Site Public Contact
Phone
800-293-5066
Email
Jamesline@osumc.edu
First Name & Middle Initial & Last Name & Degree
Naresh Bumma
Facility Name
University of Pittsburgh Cancer Institute (UPCI)
City
Pittsburgh
State/Province
Pennsylvania
ZIP/Postal Code
15232
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Site Public Contact
Phone
412-647-8073
First Name & Middle Initial & Last Name & Degree
Kathleen A. Dorritie
Facility Name
Huntsman Cancer Institute/University of Utah
City
Salt Lake City
State/Province
Utah
ZIP/Postal Code
84112
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Site Public Contact
Phone
888-424-2100
Email
cancerinfo@hci.utah.edu
First Name & Middle Initial & Last Name & Degree
Amandeep Godara
Facility Name
University of Virginia Cancer Center
City
Charlottesville
State/Province
Virginia
ZIP/Postal Code
22908
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Site Public Contact
Phone
434-243-6303
Email
uvacancertrials@hscmail.mcc.virginia.edu
First Name & Middle Initial & Last Name & Degree
Laahn H. Foster
Facility Name
Virginia Commonwealth University/Massey Cancer Center
City
Richmond
State/Province
Virginia
ZIP/Postal Code
23298
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Site Public Contact
Email
CTOclinops@vcu.edu
First Name & Middle Initial & Last Name & Degree
Hashim Mann

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing Plan Description
NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page.
IPD Sharing URL
https://grants.nih.gov/policy/sharing.htm

Learn more about this trial

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

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