Trial record 1 of 1 for:
NCT04847453
Venetoclax, MLN9708 (Ixazomib Citrate) and Dexamethasone for the Treatment of Relapsed or Refractory Light Chain Amyloidosis
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The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. |
| ClinicalTrials.gov Identifier: NCT04847453 |
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Recruitment Status :
Recruiting
First Posted : April 19, 2021
Last Update Posted : March 17, 2023
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Sponsor:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
National Cancer Institute (NCI)
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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.
| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Recurrent AL Amyloidosis Refractory AL Amyloidosis | Procedure: Biospecimen Collection Procedure: Bone Marrow Aspiration and Biopsy Procedure: Computed Tomography Drug: Dexamethasone Drug: Ixazomib Citrate Procedure: Magnetic Resonance Imaging Procedure: Positron Emission Tomography Procedure: Transabdominal Ultrasound Drug: Venetoclax Procedure: X-Ray Imaging | Phase 1 |
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.
| Study Type : | Interventional (Clinical Trial) |
| Estimated Enrollment : | 24 participants |
| Allocation: | N/A |
| Intervention Model: | Single Group Assignment |
| Masking: | None (Open Label) |
| Primary Purpose: | Treatment |
| Official Title: | A Phase 1/1a Study of Venetoclax, MLN9708 (Ixazomib Citrate) and Dexamethasone for Relapsed/Refractory Light Chain Amyloidosis |
| Actual Study Start Date : | September 14, 2021 |
| Estimated Primary Completion Date : | September 30, 2024 |
| Estimated Study Completion Date : | September 30, 2024 |
Resource links provided by the National Library of Medicine
MedlinePlus related topics:
Amyloidosis
| Arm | Intervention/treatment |
|---|---|
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Experimental: Treatment (venetoclax, ixazomib citrate, dexamethasone)
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.
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Procedure: Biospecimen Collection
Undergo blood specimen collection
Other Names:
Procedure: Bone Marrow Aspiration and Biopsy Undergo bone marrow aspiration and biopsy Procedure: Computed Tomography Undergo CT scan
Other Names:
Drug: Dexamethasone Given PO
Other Names:
Drug: Ixazomib Citrate Given PO
Other Names:
Procedure: Magnetic Resonance Imaging Undergo MRI
Other Names:
Procedure: Positron Emission Tomography Undergo PET scan
Other Names:
Procedure: Transabdominal Ultrasound Undergo transabdominal ultrasound
Other Names:
Drug: Venetoclax Given PO
Other Names:
Procedure: X-Ray Imaging Undergo x-ray
Other Names:
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Primary Outcome Measures :
- Incidence of adverse events [ Time Frame: Up to 30 days ]Toxicity will be evaluated according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0.
- Maximum tolerated dose [ Time Frame: Up to the end of cycle 1 ]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) [ Time Frame: Up to the end of cycle 1 ]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) [ Time Frame: After cycles 3, 6, 9, and 12, and every 6 months thereafter up to 2.5 years ]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.
Other Outcome Measures:
- Expression of BCL-2, BCL-XL, BAX, BAK, BIM, NOXA, and MCL-1 [ Time Frame: Baseline ]Will be assessed by immunohistochemistry.
- Immune profile in the peripheral blood [ Time Frame: Before and during treatment ]Will be determined by mass cytometry.
- Hematologic response rates [ Time Frame: Up to 2.5 years ]Estimated using mass spectrometry to detect persistence of a monoclonal protein in the serum and urine.
- Characterization of CD138+ plasma cell with t(11;14) [ Time Frame: Up to 2.5 years ]
- Presence of minimal residual disease [ Time Frame: Up to 2.5 years ]Will be determined by Next Generation Sequencing in patients achieving a hematologic complete response.
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| Ages Eligible for Study: | 18 Years and older (Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
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, 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 failure to achieve at lease a very good partial response (VGPR) on the last line of therapy.
- 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 >= 20 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
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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
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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
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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;
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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
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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.
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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)
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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)
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- 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
Information from the National Library of Medicine
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04847453
Locations
| United States, California | |
| City of Hope Comprehensive Cancer Center LAO | Recruiting |
| Duarte, California, United States, 91010 | |
| Contact: Michael A. Rosenzweig mrosenzweig@coh.org | |
| Principal Investigator: Michael A. Rosenzweig | |
| City of Hope Comprehensive Cancer Center | Recruiting |
| Duarte, California, United States, 91010 | |
| Contact: Site Public Contact 800-826-4673 becomingapatient@coh.org | |
| Principal Investigator: Michael A. Rosenzweig | |
| University of California Davis Comprehensive Cancer Center | Recruiting |
| Sacramento, California, United States, 95817 | |
| Contact: Site Public Contact 916-734-3089 | |
| Principal Investigator: Aaron Rosenberg | |
| United States, Georgia | |
| Emory University Hospital/Winship Cancer Institute | Recruiting |
| Atlanta, Georgia, United States, 30322 | |
| Contact: Site Public Contact 404-778-1868 | |
| Principal Investigator: Craig C. Hofmeister | |
| United States, Maryland | |
| Johns Hopkins University/Sidney Kimmel Cancer Center | Recruiting |
| Baltimore, Maryland, United States, 21287 | |
| Contact: Site Public Contact 410-955-8804 jhcccro@jhmi.edu | |
| Principal Investigator: Carol A. Huff | |
| United States, Massachusetts | |
| Boston Medical Center | Recruiting |
| Boston, Massachusetts, United States, 02118 | |
| Contact: Site Public Contact 617-638-8265 | |
| Principal Investigator: Vaishali Sanchorawala | |
| Dana-Farber Cancer Institute | Recruiting |
| Boston, Massachusetts, United States, 02215 | |
| Contact: Site Public Contact 877-442-3324 | |
| Principal Investigator: Giada Bianchi | |
| United States, New York | |
| Montefiore Medical Center-Einstein Campus | Recruiting |
| Bronx, New York, United States, 10461 | |
| Contact: Site Public Contact 718-379-6866 eskwak@montefiore.org | |
| Principal Investigator: Ioannis Mantzaris | |
| Montefiore Medical Center-Weiler Hospital | Recruiting |
| Bronx, New York, United States, 10461 | |
| Contact: Site Public Contact 718-379-6866 eskwak@montefiore.org | |
| Principal Investigator: Ioannis Mantzaris | |
| Montefiore Medical Center - Moses Campus | Recruiting |
| Bronx, New York, United States, 10467 | |
| Contact: Site Public Contact 718-379-6866 eskwak@montefiore.org | |
| Principal Investigator: Ioannis Mantzaris | |
| United States, Ohio | |
| Ohio State University Comprehensive Cancer Center | Recruiting |
| Columbus, Ohio, United States, 43210 | |
| Contact: Site Public Contact 800-293-5066 Jamesline@osumc.edu | |
| Principal Investigator: Naresh Bumma | |
| United States, Virginia | |
| University of Virginia Cancer Center | Recruiting |
| Charlottesville, Virginia, United States, 22908 | |
| Contact: Site Public Contact 434-243-6303 uvacancertrials@hscmail.mcc.virginia.edu | |
| Principal Investigator: Laahn H. Foster | |
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
| Principal Investigator: | Michael A Rosenzweig | City of Hope Comprehensive Cancer Center LAO |
| Responsible Party: | National Cancer Institute (NCI) |
| ClinicalTrials.gov Identifier: | NCT04847453 |
| Other Study ID Numbers: |
NCI-2021-03038 NCI-2021-03038 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ) PHI-124 10440 ( Other Identifier: City of Hope Comprehensive Cancer Center LAO ) 10440 ( Other Identifier: CTEP ) UM1CA186717 ( U.S. NIH Grant/Contract ) |
| First Posted: | April 19, 2021 Key Record Dates |
| Last Update Posted: | March 17, 2023 |
| Last Verified: | December 2022 |
| Individual Participant Data (IPD) Sharing Statement: | |
| Plan to Share IPD: | Yes |
| 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. |
| URL: | https://grants.nih.gov/policy/sharing.htm |
| Studies a U.S. FDA-regulated Drug Product: | Yes |
| Studies a U.S. FDA-regulated Device Product: | No |
Additional relevant MeSH terms:
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Immunoglobulin Light-chain Amyloidosis Amyloidosis Proteostasis Deficiencies Metabolic Diseases Neoplasms, Plasma Cell Neoplasms by Histologic Type Neoplasms Lymphoproliferative Disorders Immunoproliferative Disorders Immune System Diseases Paraproteinemias Dexamethasone Dexamethasone acetate Venetoclax Ixazomib |
Ichthammol BB 1101 Glycine Anti-Inflammatory Agents Antiemetics Autonomic Agents Peripheral Nervous System Agents Physiological Effects of Drugs Gastrointestinal Agents Glucocorticoids Hormones Hormones, Hormone Substitutes, and Hormone Antagonists Antineoplastic Agents, Hormonal Antineoplastic Agents Protease Inhibitors |