Clinical Trials /

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

NCT03557970

Description:

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.

Related Conditions:
  • Acute Myeloid Leukemia
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: CSF1R Inhibitor JNJ-40346527 in Treating Participants With Relapsed or Refractory Acute Myeloid Leukemia
  • Official Title: A Phase 2 Open-Label Study of the CSF-1R Inhibitor JNJ-40346527 in Patients With Relapsed/Refractory Acute Myeloid Leukemia (AML)

Clinical Trial IDs

  • ORG STUDY ID: STUDY00017583
  • SECONDARY ID: NCI-2018-00869
  • NCT ID: NCT03557970

Conditions

  • Recurrent Adult Acute Myeloid Leukemia
  • Refractory Acute Myeloid Leukemia

Interventions

DrugSynonymsArms
FMS Inhibitor JNJ-40346527JNJ-40346527Treatment (FMS inhibitor JNJ-40346527)

Purpose

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.

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.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (FMS inhibitor JNJ-40346527)ExperimentalParticipants 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.
  • FMS Inhibitor JNJ-40346527

Eligibility 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).
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Best objective response rate
Time Frame:Up to 84 days
Safety Issue:
Description: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

Measure: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
Safety Issue:
Description: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.
Measure:Duration of response
Time Frame:Up to 12 months
Safety Issue:
Description:For participants that achieve > partial response (PR), how long do they maintain this response before progression?
Measure:Event-free survival
Time Frame:At 12 months
Safety Issue:
Description:Time-to-event analysis (e.g., Kaplan-Meier and cumulative incidence curves) will be used to evaluate event-free survival.
Measure:Overall survival
Time Frame:Up to Death (or date of last contact)
Safety Issue:
Description:Time-to-event analysis (e.g., Kaplan-Meier and cumulative incidence curves) will be used to evaluate overall survival.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:OHSU Knight Cancer Institute

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