Recurrent Acute Myeloid Leukemia, Refractory Acute Myeloid Leukemia
Conditions
Brief summary
This phase II trial studies how well edicotinib (JNJ-40346527) works in treating participants with acute myeloid leukemia that has come back or does not respond to treatment. JNJ-40346527 may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.
Detailed description
PRIMARY OBJECTIVE: Evaluate preliminary efficacy of JNJ-40346527 in participants with relapsed/refractory AML. I. Best objective response rate (\> PR). SECONDARY OBJECTIVES: Assess safety and survival associated with JNJ-40346527 to treat participants with relapsed/refractory AML. Assess the duration of disease response associated with JNJ-40346527. I. Overall incidence of treatment-related and non-treatment related toxicity. II. Duration of response. III. 12-month event-free survival. IV. 12-month overall survival. EXPLORATORY OBJECTIVES: I. Evaluate the pharmacokinetics of JNJ-40346527 and effective inhibition of CSF-1R in marrow aspirates using plasma inhibitory assays, with established CSF-1R-sensitive cell lines. II. Identify the effect of JNJ-40346527 on leukemia cells and the immune microenvironment. III. Identify and quantify the specific subpopulation of cells that express CSF-1R in participants and correlate these with clinical response to JNJ-40346527. IV. Analyze the frequency of mutations using genomic deoxyribonucleic acid (DNA) from leukemia participants to determine if there is a genetic signature that predicts response to JNJ-40346527. V. Using ribonucleic acid (RNA) sequencing (RNAseq), identify an expression signature in CSF-1R+ cells that predicts patient response. VI. Evaluate the effect of JNJ-40346527 on immune cell populations (cytotoxic T cells, etc.) and phospho-signaling proteins by mass cytometry (CyTOF) analysis in pre- and post-treatment samples in order to identify biomarkers that predict patient response and prioritize potential combination strategies for future clinical trials. VII. Determine how leukemia cells change in response to CSF-1R inhibition by assessing cells collected pre- and post-treatment using an ex vivo sensitivity to a panel of small molecule inhibitors to determine what new drug sensitivities may emerge in AML cells after CSF-1R inhibition. OUTLINE: Participants receive JNJ-40346527 orally (PO) twice a day (BID) on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, participants are followed up within 2 weeks, at 4-6 weeks until death or minimum of 12 months.
Interventions
DRUGEdicotinib
Given PO
OTHERPharmacokinetic Study
Correlative studies
Sponsors
Oregon Health and Science University
Janssen, LP
The Leukemia and Lymphoma Society
OHSU Knight Cancer Institute
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
* 1\. Ability to understand and the willingness to sign a written informed consent document. * 2\. Age \>= 18 years at time of informed consent. Both men and women and members of all races and ethnic groups will be included. * 3\. Morphologically documented relapsed/refractory AML as defined by World Health Organization (WHO) criteria after at least 1 prior therapy for AML with the exception of hydroxyurea, and not felt to have curative treatment options per treating physician, or the patients themselves are unwilling to consider curative treatment options. * 4\. Sufficient and viable bone marrow aspirate or peripheral blood collection to use for the ex vivo sensitivity assay. * 5\. Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2. * 6\. Women must not be pregnant or breastfeeding. Women of childbearing potential must have a negative serum or urine pregnancy test within 14 days prior to start of study drug administration. * 7\. Participants must agree to use an adequate method contraception. * 8\. Must be able to take oral medications. * 9\. Adequate organ function as defined by the following: 1. Serum creatinine =\< 2 x the upper limit of normal (ULN), or glomerular filtration rate \> 20 ml/min as calculated by Cockcroft-Gault formula. 2. Serum potassium, magnesium, and calcium (corrected for albumin) within institutional normal limits or can be corrected with supplementation. 3. Total serum bilirubin =\< 2.5 x ULN. 4. Serum aspartate transaminase (AST) and/or alanine transaminase (ALT) =\< 2.5 x ULN.
Exclusion criteria
* 1\. Diagnosis of acute promyelocytic leukemia (APL, or AML M3 subtype). * 2\. Active central nervous system involvement with AML. * 3\. Concurrent active malignancy with expected survival of less than 1 year. For example, candidates with treated skin cancers, prostate cancer, breast cancer, etc. without metastatic disease are candidates for therapy since their expected survival exceeds that of relapsed or refractory AML. All subjects with concurrent malignancies will be reviewed by the principal investigator (PI) prior to enrollment. * 4\. Clinically significant graft versus host disease (GVHD) or active GVHD requiring initiation or escalation of treatment within 28-day screening period. * 5\. Clinically significant coagulation abnormality, such as disseminated intravascular coagulation. * 6\. Participants who are currently receiving any other investigational agents. * 7\. Previous treatment with CSF-1R kinase inhibitor or CSF-1R blocking antibody. * 8\. Known clinically significant liver disease defined as ongoing drug-induced liver injury, chronic active hepatitis C (HCV), chronic active hepatitis B (HBV), alcoholic liver disease, non-alcoholic steatohepatitis, primary biliary cirrhosis, extrahepatic obstruction caused by cholelithiasis, cirrhosis of the liver, portal hypertension, or history of autoimmune hepatitis. * 9\. Untreated HIV or active hepatitis C detectable by polymerase chain reaction (PCR), or chronic hepatitis B (patients positive for hepatitis B core antibody who are receiving intravenous immunoglobulin (IVIG) are eligible if hepatitis B \[HepB\] polymerase chain reaction \[PCR\] is negative). * 10\. Known history of cerebrovascular accident, myocardial infarction, or intracranial hemorrhage within 2 months of enrollment. * 11\. Clinically significant surgery within 2 weeks of enrollment. * 12\. Per PI discretion, active infection that is not well controlled by antibacterial or antiviral therapy. * 13\. Cancer-directed therapy within 2 weeks prior to starting treatment, with the exception of hydroxyurea, which is allowed to control white blood cell count. Hydroxyurea will be weaned as soon as clinically feasible. * 14\. Unwillingness to receive infusion of blood products. * 15\. Drugs that affect the CYP3A4 systems are allowed and essential for cancer patients, including anti-fungals but should be used with caution. * 16\. Patients with uncontrolled white blood cell count (defined as \> 50 K/cu mm not controlled with hydrea).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Best Objective Response Rate | first 2 cycles of study drug | An objective response is defined as achievement of a PR or any type of CR (CR, CRm, CRc, CRi) during a participant's first 2 cycles of study drug. Each participant's best disease response designation (amended from the IWG criteria specified by Cheson, 2003 JCO) during the first 2 cycles will be used when computing the best objective response rate. This rate will be reported alongside an exact confidence interval for each arm separately. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Treatment-related and Non-treatment Related Adverse Events Per National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0 | Start of study drug until 30 days after the last dose of study drug (while the participant remains on-study), which amounted to an average of 31 days for the 3 enrolled participants | The overall incidence of treatment-related and non-treatment-related toxicity (including serious and non-serious AEs). See the Adverse Event module of the Results section for a tabular summary of each toxicity event and associated system organ class. |
| Duration of Response | achievement of >=PR through end of study | For participants that achieve at least a partial response (PR), the length of time between start date of this response and progression. |
| Event-free Survival | study enrollment until last on-study disease assessment | Defined for all patients of a trial; measured from the date of entry into a study to the date of relapse from PR or CR or CRi, progression, or death from any cause; patients not known to have any of these events are censored on the date they were last examined. The Kaplan-Meier method will be used to estimate event-free survival. |
| Overall Survival | From study enrollment until end of participant follow-up (i.e., death or last contact), with the protocol specifying that [p]articipants will be followed … until death | Defined for all patients of a trial; measured from the date of entry into a study to the date of death from any cause; patients not known to have died at end of study are censored on the date they were last known to be alive. The Kaplan-Meier method will be used to estimate overall survival. |
Countries
United States
Participant flow
Recruitment details
Participants for this study were recruited from within the hematology and oncology practices participating research sites. There were 8 consented patients that were deemed screen failures and thus not enrolled on this trial. The reasons for screen failures were: patient chose alternative treatment (n=3), patient had insufficient sample for the ex vivo drug screen (n=3), patient was too sick to participate in the trial (n=1), and patient withdrew consent (n=1).
Pre-assignment details
All enrolled participants were included in the study and assigned to 1 of 2 arms according to their ex vivo sensitivity to study drug. Consented patients with indeterminate ex vivo sensitivity were considered screen failures. Although this was designed as a 2-arm trial (for purposes of stopping early for futility at the end of stage 1 of the study and of correlating pre-treatment ex vivo sensitivity with post-treatment clinical response), the study drug regimen was identical in the 2 arms.
Participants by arm
| Arm | Count |
|---|---|
| Assay Positive Participants with ex vivo sensitivity to study drug according to a cell viability assay performed on participant bone marrow or peripheral blood cells. Sensitivity is defined as an IC50 that is \<=20% of the median IC50. | 1 |
| Assay Negative Participants lacking ex vivo sensitivity to study drug according to a cell viability assay performed on participant bone marrow or peripheral blood cells. Lack of sensitivity is defined as an IC50 that is \>20% of the median IC50. | 2 |
| Total | 3 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 0 | 1 |
| Overall Study | Physician Decision | 0 | 1 |
| Overall Study | Study closure | 1 | 0 |
Baseline characteristics
| Characteristic | Assay Negative | Total | Assay Positive |
|---|---|---|---|
| Age, Continuous | 60 years | 63 years | 72 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 2 Participants | 3 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 2 Participants | 3 Participants | 1 Participants |
| Sex: Female, Male Female | 0 Participants | 1 Participants | 1 Participants |
| Sex: Female, Male Male | 2 Participants | 2 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 1 | 1 / 2 |
| other Total, other adverse events | 1 / 1 | 2 / 2 |
| serious Total, serious adverse events | 1 / 1 | 0 / 2 |
Outcome results
Primary
Best Objective Response Rate
An objective response is defined as achievement of a PR or any type of CR (CR, CRm, CRc, CRi) during a participant's first 2 cycles of study drug. Each participant's best disease response designation (amended from the IWG criteria specified by Cheson, 2003 JCO) during the first 2 cycles will be used when computing the best objective response rate. This rate will be reported alongside an exact confidence interval for each arm separately.
Time frame: first 2 cycles of study drug
Population: According to the protocol, only those participants who have completed at least 1 cycle of study agent and have response measurements will be evaluable for objective response. Since the only participant with a recorded disease response designation did not complete 1 cycle of study drug, there are no evaluable participants for this trial's primary outcome.
Secondary
Duration of Response
For participants that achieve at least a partial response (PR), the length of time between start date of this response and progression.
Time frame: achievement of >=PR through end of study
Population: No participants achieved a response while on study so duration of response cannot be computed.
Secondary
Event-free Survival
Defined for all patients of a trial; measured from the date of entry into a study to the date of relapse from PR or CR or CRi, progression, or death from any cause; patients not known to have any of these events are censored on the date they were last examined. The Kaplan-Meier method will be used to estimate event-free survival.
Time frame: study enrollment until last on-study disease assessment
Population: EFS cannot be calculated due to a lack of disease response information.
Secondary
Incidence of Treatment-related and Non-treatment Related Adverse Events Per National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0
The overall incidence of treatment-related and non-treatment-related toxicity (including serious and non-serious AEs). See the Adverse Event module of the Results section for a tabular summary of each toxicity event and associated system organ class.
Time frame: Start of study drug until 30 days after the last dose of study drug (while the participant remains on-study), which amounted to an average of 31 days for the 3 enrolled participants
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Assay Positive | Incidence of Treatment-related and Non-treatment Related Adverse Events Per National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0 | Treatment-related AE's (any grade) | 0 Participants |
| Assay Positive | Incidence of Treatment-related and Non-treatment Related Adverse Events Per National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0 | Non-treatment-related AE's (any grade) | 1 Participants |
| Assay Negative | Incidence of Treatment-related and Non-treatment Related Adverse Events Per National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0 | Treatment-related AE's (any grade) | 0 Participants |
| Assay Negative | Incidence of Treatment-related and Non-treatment Related Adverse Events Per National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0 | Non-treatment-related AE's (any grade) | 2 Participants |
Secondary
Overall Survival
Defined for all patients of a trial; measured from the date of entry into a study to the date of death from any cause; patients not known to have died at end of study are censored on the date they were last known to be alive. The Kaplan-Meier method will be used to estimate overall survival.
Time frame: From study enrollment until end of participant follow-up (i.e., death or last contact), with the protocol specifying that [p]articipants will be followed … until death
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Assay Positive | Overall Survival | NA months |
| Assay Negative | Overall Survival | 6.6 months |