Acute Myeloid Leukemia, Recurrent Acute Myeloid Leukemia, Refractory Acute Myeloid Leukemia, Secondary Acute Myeloid Leukemia
Conditions
Brief summary
This phase Ib trial studies the side effects and best dose of navtemadlin when given together with decitabine and venetoclax in treating patients with acute myeloid leukemia that has come back after a period of improvement (recurrent), does not respond to treatment (refractory), or is newly diagnosed. Navtemadlin may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Chemotherapy drugs, such as decitabine, 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. 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. Giving navtemadlin, decitabine, and venetoclax together may work better than decitabine alone in treating patients with acute myeloid leukemia.
Detailed description
PRIMARY OBJECTIVE: I. To evaluate the toxicities of navtemadlin (KRT-232 \[AMG-232\]) in combination with decitabine (20 mg/m\^2 for 10 days), and venetoclax, and to determine the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D) of KRT-232 (AMG-232) in combination with a standard dose of decitabine and venetoclax. SECONDARY OBJECTIVES: I. To evaluate the pharmacokinetic (PK) profiles of KRT-232 (AMG-232), venetoclax, and decitabine when used in combination. II. To evaluate p53 signaling induced by KRT-232 (AMG-232), venetoclax, and decitabine as measured by MIC-1 induction. III. To correlate KRT-232 (AMG-232), venetoclax and decitabine exposure with pharmacodynamics endpoints (efficacy, toxicity, changes in p53 signaling). EXPLORATORY OBJECTIVES: I. To evaluate the response rate (RR) and progression free survival (PFS) of KRT-232 (AMG-232), venetoclax, and decitabine in acute myeloid leukemia (AML). II. To evaluate potential predictive biomarkers of response to KRT-232 (AMG-232), venetoclax, and decitabine in AML. III. To evaluate the pharmacodynamic (PD) effects of KRT-232 (AMG-232), venetoclax and decitabine in AML blasts. IV. To determine the variability of decitabine incorporation into genomic deoxyribonucleic acid (DNA) and correlate with systemic pharmacokinetics and exposure-response relationships. OUTLINE: This is a dose-escalation study of navtemadlin. Patients receive decitabine intravenously (IV) over 1 hour on days 1-10, navtemadlin orally (PO) once daily (QD) on days 1-7, and venetoclax PO QD on days 1-21. Treatment repeats every 28 days for up to 4 cycles in patients with evidence of persistent AML. Starting cycle 2, patients with no morphologic evidence of AML receive decitabine IV over 1 hour on days 1-5, navtemadlin PO QD on days 1-7, and venetoclax PO QD on days 1-14. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo bone marrow aspiration and biopsy, and blood sample collection throughout the trial. After completion of study treatment, patients are followed up for 30 days.
Interventions
PROCEDUREBiospecimen Collection
Undergo blood sample collection
PROCEDUREBone Marrow Aspiration
Undergo bone marrow aspiration
PROCEDUREBone Marrow Biopsy
Undergo bone marrow biopsy
DRUGDecitabine
Given IV
DRUGNavtemadlin
Given PO
DRUGVenetoclax
Given PO
Sponsors
National Cancer Institute (NCI)
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
* Relapsed/refractory AML (\>= 5% blasts in bone marrow or extramedullary leukemia); adverse cytogenetics, e.g., as defined by the Medical Research Council (MRC) Prognostic Groupings; secondary AML; organ dysfunction arising from significant co-morbidities not directly linked to leukemia; Eastern Cooperative Oncology Group \[ECOG\] = 2) or not willing to undergo intensive chemotherapy * Patients must have measurable disease as defined the presence of \>= 20% blasts in bone marrow or extramedullary leukemia * Eligible patient must show evidence of wild-type (WT) p53 as assessed by DNA sequencing; note, that since patients with AML have a rapidly proliferating disease, patient can be enrolled and begin treatment prior to obtaining the results of this test; patients who are found to the TP53 mutated will be removed from study and can continue on single agent decitabine; however patients will continue to be followed for toxicity * Age \>= 18 years; because no dosing or adverse event data are currently available on the use of KRT-232 (AMG-232) in patients \< 18 years of age, children are excluded from this study, but will be eligible for future pediatric trials * ECOG performance status =\< 2 (Karnofsky \>= 60%) * White blood count =\< 25 x 10\^9/L * Total bilirubin \< 1.5 x institutional upper limit of normal (ULN) (\< 2.0 x ULN for subjects with documented Gilbert's syndrome or \< 3.0 x ULN for subjects for whom the indirect bilirubin level suggests an extrahepatic source of elevation) * Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase \[SGOT\])/alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase \[SGPT\]) =\< 2.5 x ULN * Alkaline phosphatase \< 2.0 x ULN (if liver or bone metastases are present, \< 3.0 x ULN) * Body surface area (BSA)-normalized creatinine clearance \>= 30 mL/min/1.73 m\^2 (using Cockcroft-Gault creatinine clearance \[CrCl\]) * Prothrombin time (PT) or partial thromboplastin time (PTT) \< 1.5 x upper limit of normal (ULN), OR international normalized ratio (INR) \< 1.5 * Patient must be willing to submit the blood sampling and bone marrow sampling for the PK and PD analyses and exploratory biomarkers * The effects of KRT-232 (AMG-232) on the developing human fetus are unknown; for this reason and because decitabine is known to be teratogenic, women of child-bearing potential must agree to use adequate contraception prior to study entry and for the duration of study participation through 5 weeks (women) after receiving the last dose of KRT-232 (AMG-232); should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately; men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 3 months after completion of KRT-232 (AMG-232) administration * Adequate methods of effective birth control include sexual abstinence (men, women); vasectomy; or a condom with spermicide (men) in combination with barrier methods, hormonal birth control or intrauterine device (IUD) (women) * Ability to understand and the willingness to sign a written informed consent document * White blood cell (WBC) count =\< 25,000/uL before administration of decitabine on cycle 1 day 1; Note: hydroxyurea may be used to control the level of circulating leukemic blast cell counts to not lower than 10,000/uL during the study
Exclusion criteria
* Acute promyelocytic leukemia with t(15;17)(q22;q12) and/or PML-RARA molecular rearrangement * Patients with previously untreated AML with core binding factor (CBF) chromosomal aberrations (inv\[16\]/t\[16;16\] or t\[8;21\]); Note that patients with relapsed or refractory AML with CBF chromosomal aberrations will be eligible * Unresolved toxicities from prior anti-tumor therapy, defined as not having resolved to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 grade 0 or 1, or to levels dictated in the eligibility criteria with the exception of alopecia (grade 2 or 3 toxicities from prior antitumor therapy that are considered irreversible \[defined as having been present and stable for \> 6 months\], such as ifosfamide-related proteinuria, may be allowed if they are not otherwise described in the
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of toxicity | Up to 4 weeks | Will be evaluated according to National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. The maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) will be determined. Based on the toxicity observed, a derived variable, the occurrence of dose limiting toxicity, will be created. Will be correlated with MDM2 Inhibitor KRT-232 (KRT-232) (MDM2 inhibitor AMG-232 \[AMG-232\]) and decitabine exposure. Toxicities will be tabulated and reported according to dose level, grade, type, cycle, and attribution- and, if numbers permit, by whether the patient had newly diagnosed or previously treated acute myeloid leukemia (AML). Cumulative incidence curves will be used to estimate the proportion of patients who will discontinue therapy for reasons of toxicity or general inability to tolerate the regimen. The data from all patients treated at the RP2D, will be combined for a final summary and listing of toxicities observed. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Pharmacokinetics (PK) profile | Baseline, 1, 3, 5, 8 and 24 hours post dose on days 4 and 18 of course 1; baseline, 0.5 hour, prior to end of infusion, 0.25, 0.5, and 1 hour post infusion on days 1 and 4 of course 1 | Will be measured using liquid chromatography/tandem mass spectrometric method. Standard descriptive methods (point estimates and confidence intervals, scatterplots) will be used to summarize the baseline levels and the changes from baseline (i.e. after treatment). The individual PK parameters from a single dose will be estimated maximum concentration (Cmax), area under the curve (AUC), half-life (T1/2), apparent clearance, and apparent volume of distribution using non-compartmental or compartmental PK methods with the software WinNonlin. Cmax and AUC will be calculated for decitabine systemic exposure. |
| P53 activation | Up to 4 weeks | Will be measured by MIC-1 levels. For serum MIC-1 levels, each individual level will be normalized to the baseline level for that patient. Will be analyzed using nonparametric statistics. Significance for comparisons will be at the p \< 0.05 level. |
| Change in p53 signaling | Baseline to 30 days after end of study treatment | Will be correlated with KRT-232 (AMG-232) and decitabine exposure. Will be analyzed using nonparametric statistics. Significance for comparisons will be at the p \< 0.05 level. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORKevin R Kelly
City of Hope Comprehensive Cancer Center LAO
Outcome results
None listed