Glutaminase Inhibitor CB-839 and Azacitidine in Treating Patients With Advanced Myelodysplastic Syndrome

NCT03047993 | Completed Phase 1 Results FDA Drug

• 3 other identifiers: 2016-0636NCI-2018-01243R01CA206210
• Study Type: interventional
• Target: 28
• Locations: 1 country
• Sites: 1

Brief Summary

This phase I/II trial studies the side effects of glutaminase inhibitor CB-839 in combination with azacitidine in treating patients with myelodysplastic syndrome that has spread to other places in the body. Glutaminase inhibitor CB-839 and azacitidine may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Conditions

Acute Myeloid Leukemia With Multilineage Dysplasia; Blasts 20-30 Percent of Bone Marrow Nucleated Cells; Blasts 20-30 Percent of Peripheral Blood White Cells; Chronic Myelomonocytic Leukemia; High Risk Myelodysplastic Syndrome; IPSS Risk Category Intermediate-2; Myelodysplastic Syndrome

Outcome Measures

Primary Outcomes (1)

• Number of Participants With a Response

  Response is Complete Remission (CR) + Partial Remission (PR) + Marrow CR = Complete Remission (CR) is \</=5% myeloblasts with normal maturation of all cell lines\* Persistent dysplasia will be noted, Peripheral blood; hemoglobin\>/=11 g/dL, Platelets \>/= 100x10\^9/L ,Neutrophils \>/=1.0 x 10\^9/L, Blasts = 0%. Partial Remission (PR) is all CR criteria if abnormal before treatment except: Bone marrow blasts decreased by \</=50% over pretreatment but still \>5% Cellularity and morphology not relevant. Marrow CR is Bone marrow: \</= 5% meyloblasts and decreased by \>/= 50% over pretreatment† Peripheral blood: if HI responses, they will be noted in addition to marrow CR.

  Up to 5 years, 4 months

Study Arms (1)

Treatment (glutaminase inhibitor CB-839, azacitidine)

EXPERIMENTAL

Patients receive glutaminase inhibitor CB-839 PO BID on days 1-28 and azacitidine SC or IV over 10-40 minutes on days 1-7.

Drug: Azacitidine; Drug: Glutaminase Inhibitor CB-839

Interventions

Azacitidine DRUG

Given IV or SC

Also known as: 5 AZC, 5-AC, 5-Azacytidine, 5-AZC, Azacytidine, Azacytidine, 5-, Ladakamycin, Mylosar, U-18496, Vidaza

Treatment (glutaminase inhibitor CB-839, azacitidine)

Glutaminase Inhibitor CB-839 DRUG

Given PO

Also known as: CB-839

Treatment (glutaminase inhibitor CB-839, azacitidine)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Signed, informed consent must be obtained prior to any study specific procedures
• Subjects with a histologically confirmed diagnosis of MDS, including both MDS and refractory anemia with excess blasts (RAEB)-T (acute myeloid leukemia \[AML\] with 20-30% blasts and multilineage dysplasia by French-American-British \[FAB\] criteria) by World Health Organization (WHO) and chronic myelomonocytic leukemia (CMML) are eligible
• Subjects with high-risk MDS (i.e. International Prognostic Scoring System \[IPSS\] Intermediate-2 or high-risk; or R-IPSS high or very-high risk). Patients with Intermediate-1 risk by IPSS or Intermediate risk by R-IPSS and with IDH1 or IDH2, or high-risk molecular features including TP53, ASXL1, EZH2, and/or RUNX1 mutations are also eligible
• Subjects with prior hypomethylating agent therapy exposure may be eligible based on discussion with the principal investigator (PI)
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
• Serum bilirubin =\< 2 x the upper limit of normal (ULN) (except for patients with Gilbert's disease)
• Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) =\< 3 x the laboratory ULN
• Creatinine clearance \> 30 mL/min based on the Cockcroft-Gault equation
• Able to understand and voluntarily sign a written informed consent, and willing and able to comply with protocol requirements
• Resolution of all treatment-related, non-hematological toxicities, except alopecia, from any previous cancer therapy to \< grade 1 prior to the first dose of study treatment
• Female patients of childbearing potential must have a negative serum or urine pregnancy test within 3 days of the first dose of study drug and agree to use dual methods of contraception during the study and for a minimum of 3 months following the last dose of study drug. Post-menopausal females (\>= 45 years old and without menses for \>= 1 year) and surgically sterilized females are exempt from these requirements. Male patients must use an effective barrier method of contraception during the study and for a minimum of 3 months following the last dose of study drug if sexually active with a female of childbearing potential

You may not qualify if:

• Any prior or coexisting medical condition that in the investigator's judgment will substantially increase the risk associated with the subject's participation in the study
• Psychiatric disorders or altered mental status precluding understanding of the informed consent process and/or completion of the necessary study procedures
• Active uncontrolled infection at study enrollment including known diagnosis of human immunodeficiency virus or chronic active hepatitis B or C infection
• Clinically significant gastrointestinal conditions or disorders that may interfere with study drug absorption, including prior gastrectomy
• Patients with known active central nervous system (CNS) disease, including leptomeningeal involvement
• Impaired cardiac function, uncontrolled cardiac arrhythmia, or clinically significant cardiac disease including the following: a) New York Heart Association grade III or IV congestive heart failure, b) myocardial infarction within the last 6 months
• Subjects with a corrected QT (QTc) \> 480 ms (QTc \> 510 msec for subjects with a bundle branch block at baseline)
• Nursing or pregnant women
• Subjects with known hypersensitivity to study drugs or their excipients

Sponsors & Collaborators

• M.D. Anderson Cancer Center: lead
• National Cancer Institute (NCI): collaborator

Study Sites (1)

M D Anderson Cancer Center

Houston, Texas, 77030, United States

Location

Related Publications (1)

• DiNardo CD, Verma D, Baran N, Bhagat TD, Skwarska A, Lodi A, Saxena K, Cai T, Su X, Guerra VA, Poigaialwar G, Kuruvilla VM, Konoplev S, Gordon-Mitchell S, Pradhan K, Aluri S, Hackman GL, Chaudhry S, Collins M, Sweeney SR, Busquets J, Rathore AS, Deng Q, Green MR, Grant S, Demo S, Choudhary GS, Sahu S, Agarwal B, Spodek M, Thiruthuvanathan V, Will B, Steidl U, Tippett GD, Burger J, Borthakur G, Jabbour E, Pemmaraju N, Kadia T, Kornblau S, Daver NG, Naqvi K, Short NJ, Garcia-Manero G, Tiziani S, Verma A, Konopleva M. Glutaminase inhibition in combination with azacytidine in myelodysplastic syndromes: a phase 1b/2 clinical trial and correlative analyses. Nat Cancer. 2024 Oct;5(10):1515-1533. doi: 10.1038/s43018-024-00811-3. Epub 2024 Sep 19.

  PMID: 39300320 DERIVED

Related Links

• MD Anderson Cancer Center

MeSH Terms

Conditions

Leukemia, Myelomonocytic, Chronic; Myelodysplastic Syndromes

Interventions

Azacitidine; CB-839

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Myelodysplastic-Myeloproliferative Diseases; Bone Marrow Diseases; Hematologic Diseases; Hemic and Lymphatic Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Aza Compounds; Organic Chemicals; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides

Results Point of Contact

• Title: Courtney DiNardo/Professor
• Organization: The University of Texas MD Anderson Cancer Center

cdinardo@mdanderson.org

713-794-1141

Study Officials

• Courtney DiNardo

  M.D. Anderson Cancer Center

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 3, 2017
• First Posted: February 9, 2017
• Study Start: November 15, 2017
• Primary Completion: March 16, 2023
• Study Completion: March 16, 2023
• Last Updated: May 14, 2024
• Results First Posted: May 14, 2024

Record last verified: 2024-04

Locations

US (1)