Venetoclax, MLN9708 (Ixazomib Citrate) and Dexamethasone for the Treatment of Relapsed or Refractory Light Chain Amyloidosis
ID de estudio #: NCT04847453
condición: Recurrent AL Amyloidosis, Refractory AL Amyloidosis
Estado: Aún no está reclutandopropósito:
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 may stop the growth of tumor cells by blocking Bcl-2, a protein that helps cancer cells survive. 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.
intervención: Bone Marrow Aspiration and Biopsy, Dexamethasone, Ixazomib Citrate, Venetoclax
última actualización: 17 de Septiembre de 2021
fecha de inicio: 17 de Septiembre de 2021
finalización estimada: 30 de Septiembre de 2024
última actualización: 15 de Septiembre de 2021
fase de desarrollo: la Fase 1 de ATLAS
tamaño / inscripción: 6
descripción del estudio: OBJETIVOS PRINCIPALES:
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.
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 using standard criteria. IV. To estimate progression free survival.
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.
After completion of study treatment, patients are followed up at 30 days, every month for 1 year, then samples are collected every month until disease progression.
- Incidencia de eventos adversos
Toxicity will be evaluated according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0.
- 30 días antes de su llegada
Dosis máxima tolerada
Defined as the dose for which the isotonic estimate of the toxicity rate is closest to the target toxicity rate.
- Up to the end of cycle 1
Recommended phase 2 dose (RP2D)
Will be based on the assessment of toxicities during cycle 1 that meet criteria for dose-limiting toxicities (DLT).
- Up to the end of cycle 1
- Overall response rate (complete hematologic response)
After cycles 3, 6, 9, and 12, and every 6 months thereafter up to 2.5 years
criterios de inclusión:
• Sexos elegibles: todos
Histologically-proven systemic 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 difference in free light chain (dFLC) > 5mg/dL ( 50 mg/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
Estado funcional del Eastern Cooperative Oncology Group (ECOG) =< 2 (Karnofsky >= 60%)
Leucocitos >= 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
Objective, measurable organ involvement defined by one or more of the following:
Kidney: albuminuria >= 500 mg/day in a 24-hour urine specimen
Heart: presence of a mean left ventricular wall thickness on echocardiogram greater than 12 mm, or unexplained low voltage (< 5mV) on electrocardiogram (ECG), or NT-proBNP > 332 ng/L in the absence of impaired renal function (estimated glomerular filtration rate [eGFR] < 45 mL/min), or prior heart biopsy showing amyloid deposition
Liver: hepatomegaly on physical exam or imaging, or infiltrative pattern on imaging typical of amyloidosis, with elevated alkaline phosphatase > 1.5 X Upper Limit of Normal (ULN), or prior liver biopsy showing amyloid deposition
Gastrointestinal (GI) tract: biopsy showing amyloid deposition along with symptoms such as GI bleeding or persistent diarrhea (> 4 loose stools/day)
Autonomic or peripheral nervous system: defined as orthostasis, symptoms of nausea, dysgeusia, recurrent diarrhea or constipation, abnormal sensory and/or motor finding on neurologic exam, gastric atony by gastric emptying scan
Soft tissue: defined as symptomatic macroglossia or soft tissue deposits requiring therapy. Note: skin or lymph node involvement, carpal tunnel syndrome, or bone marrow amyloid as the sole clinical manifestations of amyloidosis are not sufficient for inclusion
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
Los pacientes con una neoplasia maligna previa o concurrente cuya historia natural o tratamiento no tienen el potencial de interferir con la evaluación de seguridad o eficacia del régimen de investigación son elegibles para este ensayo.
AL Amyloidosis Cardiac Risk stage I, II or IIIa disease
Staging system defined by: NT-proBNP cut off of < 332 pg/mL and troponin I cut-off of < 0.10 ng/mL as thresholds for stages I, II and III; NT-proBNP < 8500 pg/ml for stage IIIa
Estadio I, ambos bajo umbral;
Stage II, either troponin or NT-proBNP (but not both) over threshold;
Estadio III, ambos por encima del umbral;
Stage IIIa, both over threshold but NT-proBNP < 8500 pg/ml
Esperanza de vida >= 3 meses
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 will be include)
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) >= 50 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
Criterio de exclusión: Criterios:
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 chemotherapy or radiotherapy 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 with NT-Pro BNP > 8500 pg/mL
Patients with grade 3 or worse diarrhea
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