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About
This phase I trial studies the best dose of CB-839 HCl when given together with carfilzomib and dexamethasone in treating patients with multiple myeloma that has come back or does not respond to previous treatment. CB-839 HCl and carfilzomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as dexamethasone work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving CB-839 HCl, carfilzomib, and dexamethasone may work better in treating patients with multiple myeloma.
Full description
PRIMARY OBJECTIVES:
I. To determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) of glutaminase inhibitor CB-839 hydrochloride (CB-839 HCl) in combination with carfilzomib and dexamethasone.
SECONDARY OBJECTIVES:
I. Evaluate the safety and tolerability of CB-839 HCl in combination with carfilzomib and dexamethasone.
II. To determine the overall response rate (ORR) associated with the combination of CB-839 HCl with carfilzomib and dexamethasone.
CORRELATIVE RESEARCH OBJECTIVES:
I. Evaluate plasma pharmacokinetic (PK) profiles of CB-839 HCl and carfilzomib when used in combination.
II. To perform molecular profiling assays on malignant and normal tissues, including, but not limited to, whole exome sequencing (WES), messenger ribonucleic acid (RNA) sequencing (RNAseq), circulating cell free (cf) deoxyribonucleic acid (DNA) analysis, flow cytometry assessments, immunohistochemical (IHC) staining, and metabolomics-based assessments in order to identify potential predictive and prognostic biomarkers, and identify resistance mechanisms using genomic DNA, RNA, flow cytometry, IHC, and metabolomics-based assessment platforms.
III. To contribute genetic analysis data from de-identified biospecimens to Genomic Data Commons (GDC), a well annotated cancer molecular and clinical data repository, for current and future research.
IV. To bank CD138+ multiple myeloma (MM) cells from the bone marrow, and blood (for cfDNA analysis) obtained from patients at the Experimental Therapeutics Clinical Trials Network (ETCTN) Biorepository at Nationwide Children's Hospital.
OUTLINE: This is a dose escalation study of glutaminase inhibitor CB-839 hydrochloride.
Patients receive glutaminase inhibitor CB-839 hydrochloride orally (PO) every 12 hours on days 1-28, dexamethasone PO on days 1, 2, 8, 9, 15, 16, and 23, and carfilzomib intravenously (IV) over 10 minutes on days 1, 2, 8, 9, 15, and 16. 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 and then periodically for up to 1 year.
Enrollment
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Inclusion criteria
Patients must have relapsed and/or refractory myeloma and be experiencing disease relapse
Patients must have measurable disease by International Myeloma Working Group (IMWG) criteria (any of the following):
At least two prior lines of therapy and all patients should have at least been exposed to a proteasome inhibitor (PI), an immunomodulatory drug (IMiD), and an anti-CD38 antibody
Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)
Leukocytes >= 3,000/mcL
Absolute neutrophil count >= 1,000 cells/mm3 without growth factors (within 14 days of enrollment)
Hemoglobin >= 8 g/dL (within 14 days of enrollment)
Platelets >= 50,000 cells/mm3 (>= 30,000 cells/mm3 if bone marrow plasma cells >= 50% at enrollment)
Total bilirubin =< 1.5 x 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 =< institutional ULN OR glomerular filtration rate (GFR) >= 40 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal
Willingness to undergo interim bone marrow biopsy/aspiration for clinical purposes
Negative pregnancy test done =< 7 days prior to registration, for women of childbearing potential only
Ability to understand and the willingness to sign a written informed consent document
Exclusion criteria
Patients who are refractory or intolerant to carfilzomib (prior carfilzomib exposure accepted)
Patients who have received recent prior chemotherapy with:
Patients who have not recovered from adverse events (AEs) due to prior anti-cancer therapy (i.e., have residual toxicities > grade 1 except peripheral neuropathy)
Patients who are receiving any other investigational agents
History of allergic reactions attributed to compounds of similar chemical or biologic composition to CB-839 HCl, carfilzomib, or dexamethasone
Patients with uncontrolled intercurrent illness
Any of the following:
Pregnant women or women of reproductive ability who are unwilling to use two effective methods of contraception from the time of signing the informed consent form through 4 months after the last dose of study drug
Nursing women
And men who are unwilling to use birth control while taking the drug and for 4 months after stopping treatment
Adverse cardiac history (unstable angina, myocardial infarction less than 4 months, New York Heart Association [NYHA] class III or IV congestive heart failure [CHF], ejection fraction [EF] < 40%, uncontrolled arrhythmias)
Concomitant high dose corticosteroids other than what is part of treatment protocol (concurrent use of corticosteroids). EXCEPTION: Patients may be on chronic steroids (maximum dose 10 mg/day prednisone equivalent) if they are being given for disorders other than myeloma, e.g., adrenal insufficiency, rheumatoid arthritis, etc
Central nervous system (CNS) involvement
Concurrent amyloid light-chain (AL) amyloidosis
Diagnosed or treated for another malignancy within 2 years before study enrollment or previously diagnosed with another malignancy and have any evidence of residual disease. Patients with nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone complete resection
Patient has >= grade 3 peripheral neuropathy or grade 2 with pain on clinical examination during the screening period
Major surgery within 14 days before study registration
On concurrent treatment with an HIV protease inhibitor
Any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment according to this protocol
Known gastrointestinal (GI) disease or GI procedure that could interfere with the oral absorption or tolerance of CB-839 HCl including difficulty swallowing, refractory vomiting, gastric resection or bypass, or duodenal/jejunal resection
Primary purpose
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36 participants in 1 patient group
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Data sourced from clinicaltrials.gov
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