Description:
This phase I trial studies the side effects and best dose of PLX51107 and how well it works
with azacitidine in treating patients with acute myeloid leukemia or myelodysplastic
syndrome. PLX51107 may stop the growth of cancer cells by blocking some of the enzymes needed
for cell growth. Drugs used in chemotherapy, such as azacitidine, 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 PLX51107 and azacitidine may work better than
azacitidine alone in treating patients with acute myeloid leukemia or myelodysplastic
syndrome.
Title
- Brief Title: PLX51107 and Azacitidine in Treating Patients With Acute Myeloid Leukemia or Myelodysplastic Syndrome
- Official Title: A Phase I Study of PLX51107 (A Novel Bromodomain Inhibitor) in Combination With Azacytidine for Patients With Myelodysplastic Syndrome and Acute Myeloid Leukemia (AML)
Clinical Trial IDs
- ORG STUDY ID:
2018-0725
- SECONDARY ID:
NCI-2019-02517
- SECONDARY ID:
2018-0725
- SECONDARY ID:
P30CA016672
- NCT ID:
NCT04022785
Conditions
- Acute Myeloid Leukemia
- Myelodysplastic Syndrome
- Myelodysplastic/Myeloproliferative Neoplasm
- Myeloproliferative Neoplasm
Interventions
Drug | Synonyms | Arms |
---|
Azacitidine | 5 AZC, 5-AC, 5-Azacytidine, 5-AZC, Azacytidine, Azacytidine, 5-, Ladakamycin, Mylosar, U-18496, Vidaza | Treatment (BRD4 Inhibitor PLX51107, azacitidine) |
BRD4 Inhibitor PLX51107 | PLX 51107, PLX-51107, PLX51107 | Treatment (BRD4 Inhibitor PLX51107, azacitidine) |
Purpose
This phase I trial studies the side effects and best dose of PLX51107 and how well it works
with azacitidine in treating patients with acute myeloid leukemia or myelodysplastic
syndrome. PLX51107 may stop the growth of cancer cells by blocking some of the enzymes needed
for cell growth. Drugs used in chemotherapy, such as azacitidine, 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 PLX51107 and azacitidine may work better than
azacitidine alone in treating patients with acute myeloid leukemia or myelodysplastic
syndrome.
Detailed Description
PRIMARY OBJECTIVE:
I. To determine the minimum safe and biologically-effective dose of the combination of
PLX51107 and azacitidine (AZA).
SECONDARY OBJECTIVES:
I. To determine overall response rate (ORR) rate including CR (complete remission) + CRp
(complete remission with incomplete platelet recovery) + CRi (complete remission with
incomplete count recovery) + CRh (complete remission with partial hematologic recovery),
partial remission (PR) within 3 months of treatment initiation of PLX51107 and AZA
combination in patients with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML).
II. To investigate correlations of response to this combination with a pre-therapy,
on-therapy, and progression 81-gene panel of gene mutations in AML.
III. To determine the duration of response (DOR), event-free survival (EFS), overall survival
(OS), and number of patients bridged to stem cell transplant (SCT) and median duration to SCT
from the initiation of the combination.
OUTLINE: This is a dose-escalation study of PLX51107.
Patients receive PLX51107 orally (PO) once daily (QD) on days 1-21 and azacitidine
subcutaneously (SC) or intravenously (IV) over 15 minutes on days 8-14 and 22-28. Treatment
repeats every 28 days for up to 12 cycles in the absence of disease progression or
unacceptable toxicity.
After completion of study treatment, patients are followed up at 30 days, then every 6-12
months for 5 years.
Trial Arms
Name | Type | Description | Interventions |
---|
Treatment (BRD4 Inhibitor PLX51107, azacitidine) | Experimental | Patients receive PLX51107 PO QD on days 1-21 and azacitidine SC or IV over 15 minutes on days 8-14 and 22-28. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. | - Azacitidine
- BRD4 Inhibitor PLX51107
|
Eligibility Criteria
Inclusion Criteria:
- Diagnosis of
- AML (World Health Organization [WHO] classification definition of >= 20% blasts),
or
- MDS intermediate-2 score or with > 10% blasts, to include: MDS,
myeloproliferative neoplasm (MPN) with 10% blasts or more, or MDS/MPN 10% blasts
or more
- Patients who have received at least one prior therapy for AML or for MDS will be
eligible. Any prior therapy for AML or MDS will be counted as a prior salvage
- In the absence of rapidly progressing disease, the interval from prior treatment to
time of initiation of protocol therapy will be at least 2 weeks for cytotoxic agents
or at least 5 half-lives for cytotoxic/non-cytotoxic agents. The half-life for the
therapy in question will be based on published pharmacokinetic literature (abstracts,
manuscripts, investigator brochures, or drug-administration manuals) and will be
documented in the protocol eligibility document. The use of chemotherapeutic or
anti-leukemic agents is not permitted during the study with the following exceptions:
- Intrathecal (IT) therapy for patients with controlled central nervous system
(CNS) leukemia at the discretion of the principal investigator (PI). Controlled
CNS leukemia is defined by the absence of active clinical signs of CNS disease
and no evidence of CNS leukemia on the most recent 2 simultaneous cerebrospinal
fluid (CSF) evaluations
- Use of one dose of cytarabine (up to 2 g/m^2) or hydroxyurea for patients with
rapidly proliferative disease is allowed before the start of study therapy and
for the first four weeks on therapy. These medications will be recorded in the
case-report form.
- Eastern Cooperative Oncology Group (ECOG) performance status 0-2
- Measured or calculated creatinine clearance >= 60 mL/min (unless considered due to
leukemia)
- Total bilirubin < 1.8 mg/dL (unless increase is due to hemolysis, congenital disorder,
or leukemia)
- Transaminases (serum glutamate pyruvate transaminase [SGPT]) < 2.5 x upper limit of
normal (ULN) (unless considered due to leukemia)
- Potassium levels should be within institutional normal limits (unless considered due
to leukemia)
- Magnesium levels should be within institutional normal limits (unless considered due
to leukemia)
- Calcium (normalized for albumin) levels should be within institutional normal limits
(unless considered due to leukemia)
- Ability to take oral medication
- Ability to understand and provide signed informed consent prior to any study-related
procedures and to comply with all study requirements
- Baseline left ventricular ejection fraction by echocardiogram (ECHO) or multigated
acquisition scan (MUGA) >= 50%
- Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy
test within 7 days. Men must agree not to father a child and agree to use a condom if
his partner is of child bearing potential
- WOCBP must use appropriate method(s) of contraception. WOCBP should use an adequate
method to avoid pregnancy until after the last dose of investigational drug. Women who
are not of childbearing potential (i.e., who are postmenopausal or surgically sterile)
as well as men with azoospermia do not require contraception
Exclusion Criteria:
- Patients with known significant impairment of gastrointestinal (GI) function or GI
disease that may significantly alter the absorption of PLX51107
- Patients with any other known concurrent severe and/or uncontrolled medical condition
including but not limited to diabetes, cardiovascular disease including hypertension,
renal disease, or active uncontrolled infection, which could compromise participation
in the study. Patients on active antineoplastic or radiation therapy for a concurrent
malignancy at the time of screening. Maintenance therapy, hormonal therapy, or steroid
therapy for well-controlled malignancy is allowed
- Patients with known positive human immunodeficiency virus (HIV), hepatitis B or C
infection by serology, with the exception of those with an undetectable viral load
within 3 months. (HIV testing and hepatitis B or C testing is not required prior to
study entry). Subjects with serologic evidence of prior vaccination to hepatitis B
virus (HBV) (i.e., hepatitis B virus surface antigen negative [HBs Ag-], and hepatitis
B surface antibody positive [HBs+]) may participate
- Patients with advanced malignant hepatic tumors
- Patients with known hypersensitivity to AZA or mannitol
- Women who are pregnant or are breast-feeding
- Patients who receive strong CYP3A4 and CYP2C8 inhibitors or inducers or CYP3A4
substrate drugs with a narrow therapeutic range, taken within 14 days or 5 drug
half-lives, whichever is longer, before start of study drug
- Patients who have received anti-cancer therapy within 14 days (or 5 half-lives) with
all toxicities resolved to grade 1 or less. No immune therapy or other biologic
therapy (other monoclonal antibodies or antibody-drug conjugates [ADCs]) within 28
days of cycle 1 day 1
Maximum Eligible Age: | N/A |
Minimum Eligible Age: | 18 Years |
Eligible Gender: | All |
Healthy Volunteers: | No |
Primary Outcome Measures
Measure: | Incidence of adverse events |
Time Frame: | Up to 5 years |
Safety Issue: | |
Description: | Toxicity type and severity will be summarized for each patient cohort using frequency tables. Per-treated analysis will be performed to include any patient who received the treatment regardless of the eligibility nor the duration or dose of the treatment received. |
Secondary Outcome Measures
Measure: | Overall response rate |
Time Frame: | Within 3 months of treatment initiation |
Safety Issue: | |
Description: | Will be defined as blast count reduction, hematologic improvement, partial remission, complete remission (CR), complete remission with incomplete count recovery, complete remission with incomplete platelet recovery, complete remission with partial hematologic recovery. Will be calculated and credible interval will be provided. Wilcoxon rank sum test or Fisher's exact test will be used to evaluate the association between patient prognostic factor (e.g. lab result and gene mutation) and response. |
Measure: | Gene mutations in acute myeloid leukemia |
Time Frame: | Up to 5 years |
Safety Issue: | |
Description: | Pre-therapy, on-therapy, and progression 81-gene panel of gene mutations will be correlated with response. |
Measure: | Duration of response |
Time Frame: | Number of days from the date of initial response to the date of first documented disease progression/relapse or death, whichever occurs first, assessed up to 5 years |
Safety Issue: | |
Description: | Will be estimated using the method of Kaplan and Meier. Comparison of time-to-event endpoints by important subgroups will be made using the log-rank test. |
Measure: | Event-free survival |
Time Frame: | Number of days from the date of treatment initiation to the date of documented treatment failure, relapses from CR, or death from any cause, whichever occurs first, assessed up to 5 years |
Safety Issue: | |
Description: | Will be estimated using the method of Kaplan and Meier. Comparison of time-to-event endpoints by important subgroups will be made using the log-rank test. |
Measure: | Overall survival |
Time Frame: | Time from treatment start until death or last follow up, assessed up to 5 years |
Safety Issue: | |
Description: | Will be estimated using the method of Kaplan and Meier. Comparison of time-to-event endpoints by important subgroups will be made using the log-rank test. |
Measure: | Number of patients bridged to stem cell transplant (SCT) |
Time Frame: | Up to 5 years |
Safety Issue: | |
Description: | |
Measure: | Median duration to SCT from initiation of combination |
Time Frame: | Up to 5 years |
Safety Issue: | |
Description: | |
Details
Phase: | Phase 1 |
Primary Purpose: | Interventional |
Overall Status: | Recruiting |
Lead Sponsor: | M.D. Anderson Cancer Center |
Last Updated
March 23, 2020