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CSF1R Inhibitor JNJ-40346527 in Treating Participants With Relapsed or Refractory Acute Myeloid Leukemia

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ClinicalTrials.gov Identifier: NCT03557970
Recruitment Status : Recruiting
First Posted : June 15, 2018
Last Update Posted : March 13, 2019
Sponsor:
Information provided by (Responsible Party):
Elie Traer, OHSU Knight Cancer Institute

Brief Summary:
This phase II trial studies how well FMS inhibitor JNJ-40346527 works in treating participants with acute myeloid leukemia that has come back or does not respond to treatment. FMS inhibitor JNJ-40346527 may stop the growth of cancer cells by blocking some of the microenvironmental signals needed for cell growth.

Condition or disease Intervention/treatment Phase
Recurrent Adult Acute Myeloid Leukemia Refractory Acute Myeloid Leukemia Drug: FMS Inhibitor JNJ-40346527 Other: Pharmacokinetic Study Phase 2

Detailed Description:

PRIMARY OBJECTIVES:

Evaluate preliminary efficacy of JNJ-40346527 in participants with relapsed/refractory AML.

1. 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.

  1. Overall incidence of treatment-related and non-treatment related toxicity.
  2. Duration of response.
  3. 12-month event-free survival.
  4. 12-month overall survival.

EXPLORATORY OBJECTIVES:

  1. 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.
  2. Identify the effect of JNJ-40346527 on leukemia cells and the immune microenvironment.
  3. 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.
  4. Using ribonucleic acid (RNA) sequencing (RNAseq), identify an expression signature in CSF-1R+ cells that predicts patient response.
  5. 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.
  6. 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 FMS inhibitor JNJ-40346527 orally (PO) twice a day (BID) on days 1-28. Courses 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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 100 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 2 Open-Label Study of the CSF-1R Inhibitor JNJ-40346527 in Patients With Relapsed/Refractory Acute Myeloid Leukemia (AML)
Actual Study Start Date : October 5, 2018
Estimated Primary Completion Date : December 20, 2022
Estimated Study Completion Date : December 30, 2023


Arm Intervention/treatment
Experimental: Treatment (FMS inhibitor JNJ-40346527)
Participants receive FMS inhibitor JNJ-40346527 PO BID on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Drug: FMS Inhibitor JNJ-40346527
Given PO
Other Name: JNJ-40346527

Other: Pharmacokinetic Study
Correlative studies
Other Name: PHARMACOKINETIC, PK Study




Primary Outcome Measures :
  1. Best objective response rate [ Time Frame: Up to 84 days ]
    A Simon 2-stage minimax design will be used to determine best objective response. The best objective response and exact confidence interval will be determined using the binomial distribution for each arm separately. Response assessment will be based on best objective response rates within the first 2 cycles of study drug, including complete response (CR), CR with inadequate bone marrow recovery, partial response, stable disease, or progressive disease.


Secondary Outcome Measures :
  1. Incidence of treatment-related and non-treatment related adverse events per National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 [ Time Frame: Up to 30 days after last dose of study drug ]
    The overall incidence of treatment-related and non-treatment related toxicity and the exact confidence interval will be estimated. In addition, each toxicity event will be tabulated and summarized by severity and major organ site.

  2. Duration of response [ Time Frame: Up to 12 months ]
    For participants that achieve > partial response (PR), how long do they maintain this response before progression?

  3. Event-free survival [ Time Frame: At 12 months ]
    Time-to-event analysis (e.g., Kaplan-Meier and cumulative incidence curves) will be used to evaluate event-free survival.

  4. Overall survival [ Time Frame: Up to Death (or date of last contact) ]
    Time-to-event analysis (e.g., Kaplan-Meier and cumulative incidence curves) will be used to evaluate overall survival.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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/hour (h) 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).

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03557970


Contacts
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Contact: Elie Traer, MD 503-494-7999 traere@ohsu.edu

Locations
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United States, Oregon
OHSU Knight Cancer Institute Recruiting
Portland, Oregon, United States, 97239
Contact: Elie Traer, MD    503-494-7999    traere@ohsu.edu   
Principal Investigator: Elie Traer, MD         
United States, Texas
UT Southwestern/Simmons Cancer Center-Dallas Not yet recruiting
Dallas, Texas, United States, 75390
Contact: Robert Collins    214-648-3060    robert.collins@utsouthwestern.edu   
Sub-Investigator: Robert Collins         
Sponsors and Collaborators
OHSU Knight Cancer Institute
Investigators
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Principal Investigator: Elie Traer, MD OHSU Knight Cancer Institute

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Responsible Party: Elie Traer, Principal Investigator, OHSU Knight Cancer Institute
ClinicalTrials.gov Identifier: NCT03557970     History of Changes
Other Study ID Numbers: STUDY00017583
NCI-2018-00869 ( Registry Identifier: NCI CTRP )
First Posted: June 15, 2018    Key Record Dates
Last Update Posted: March 13, 2019
Last Verified: March 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Neoplasms by Histologic Type
Neoplasms