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
Conditions
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.
Detailed description
PRIMARY OBJECTIVES: I. To determine the safety, tolerability and clinical activity of glutaminase inhibitor CB-839 (CB-839) in combination with azacitidine (AZA) for patients with advanced myelodysplastic syndrome (MDS). SECONDARY OBJECTIVES: I. To explore the pharmacokinetics (PK) of CB-839 in combination with AZA. II. To explore the pharmacodynamics (PDn) of CB-839 in combination with AZA. III. To assess overall survival, event-free survival and duration of response of CB-839 in combination with AZA. OUTLINE: Patients receive glutaminase inhibitor CB-839 orally (PO) twice daily (BID) on days 1-28 and azacitidine subcutaneously (SC) or intravenously (IV) over 10-40 minutes on days 1-7. After completion of study treatment, patients are followed up at 28 days.
Interventions
DRUGAzacitidine
Given IV or SC
Given PO
Sponsors
National Cancer Institute (NCI)
M.D. Anderson Cancer Center
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* 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
Exclusion criteria
* 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With a Response | Up to 5 years, 4 months | 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Treatment (Glutaminase Inhibitor CB-839, Azacitidine) 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.
Azacitidine: Given IV or SC
Glutaminase Inhibitor CB-839: Given PO | 28 |
| Total | 28 |
Baseline characteristics
| Characteristic | Treatment (Glutaminase Inhibitor CB-839, Azacitidine) |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 18 Participants |
| Age, Categorical Between 18 and 65 years | 10 Participants |
| Age, Continuous | 70 years |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 3 Participants |
| Race (NIH/OMB) White | 24 Participants |
| Region of Enrollment United States | 28 participants |
| Sex: Female, Male Female | 6 Participants |
| Sex: Female, Male Male | 22 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 6 / 28 |
| other Total, other adverse events | 0 / 28 |
| serious Total, serious adverse events | 18 / 28 |
Outcome results
Primary
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.
Time frame: Up to 5 years, 4 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment (Glutaminase Inhibitor CB-839, Azacitidine) | Number of Participants With a Response | 11 Participants |