Ruxolitinib in Treating Patients With Hypereosinophilic Syndrome or Primary Eosinophilic Disorders

Brief Title

Ruxolitinib in Treating Patients With Hypereosinophilic Syndrome or Primary Eosinophilic Disorders

Official Title

Phase 2 Study of Ruxolitinib in Idiopathic Hypereosinophilic Syndrome and Primary Eosinophilic Disorders

Brief Summary

      This phase II trial studies how well ruxolitinib works in treating patients with
      hypereosinophilic syndrome or primary eosinophilic disorders. Ruxolitinib may stop the growth
      of cancer cells by blocking some of the enzymes needed for cell growth.
    

Detailed Description

      PRIMARY OBJECTIVES:

      I. To determine the overall hematologic response rate to ruxolitinib in patients with
      hypereosinophilic syndrome and primary eosinophilic disorders.

      SECONDARY OBJECTIVES:

      I. To determine safety profile of ruxolitinib in patients with hypereosinophilic syndrome and
      primary eosinophilic disorders.

      II. To determine the proportion of patients on corticosteroids who are able to become
      corticosteroid-independent and/or reduce the dose by >= 50%.

      III. To evaluate the duration of response (DoR). IV. To evaluate the time-to-response (TTR).
      V. To evaluate progression-free survival (PFS) and overall survival.

      EXPLORATORY OBJECTIVES:

      I. To evaluate the ability of ruxolitinib to elicit morphologic and cytogenetic/molecular
      remissions in patients with baseline clonal abnormalities.

      II. To assess whether hematologic responses correlate with certain types of mutations on
      myeloid mutation panel testing and/or by flow immunophenotyping of T-cells in patients with
      lymphocyte-variant hypereosinophilia.

      III. To determine whether improvement in organ damage is observed in patients with baseline
      organ dysfunction.

      IV. To determine whether improvement in symptoms is observed based on a modified
      Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF).

      V. To evaluate biologic correlates of response including ribonucleic acid (RNA) sequencing
      (RNAseq) and JAK-STAT activation status (JAK2 and/or STAT3 phosphorylation) of eosinophils
      from whole blood and/or marrow.

      OUTLINE:

      Patients receive ruxolitinib orally (PO) twice daily (BID) on days 1-28. Treatment repeats
      for up to 6 cycles in the absence of disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up at 4-6 weeks and every 6 months
      for up to 3 years.
    

Study Phase

Phase 2

Study Type

Interventional


Primary Outcome

Overall response rate (ORR)

Secondary Outcome

 All cause mortality

Condition

BCR-JAK2 Fusion Protein Expression

Intervention

Ruxolitinib

Study Arms / Comparison Groups

 Treatment (ruxolitinib)
Description:  Patients receive ruxolitinib PO BID on days 1-28. Treatment repeats for up to 6 cycles in the absence of disease progression or unacceptable toxicity.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

25

Start Date

June 19, 2019

Completion Date

June 19, 2024

Primary Completion Date

April 30, 2021

Eligibility Criteria

        Inclusion Criteria:

          -  Subject with idiopathic hypereosinophilic syndrome must meet the following:

               -  Has as at least 2 readings with an absolute eosinophil count >= 1,500/mm^3 in the
                  preceding 3 months prior to starting ruxolitinib (one reading must be during the
                  screening period).

               -  Dependent, intolerant or refractory to corticosteroids OR has relapsed/refractory
                  disease to other therapy besides corticosteroids.

               -  Symptomatic from his/her disease OR has one or more signs of organ damage
                  (assessed by the investigator as possibly-related to eosinophilia or
                  biopsy-proven). This can include skin, lung, cardiac, central nervous system,
                  liver, or gastrointestinal (GI) involvement, or evidence of symptomatic hepatic
                  or splenic enlargement.

          -  Subject with lymphocyte-variant hypereosinophilia must meet the following

               -  Has at least 2 readings with an absolute eosinophil count >= 1,500/mm^3 in the
                  preceding 3 months prior to starting ruxolitinib (one reading must be during the
                  screening period).

               -  Dependent, intolerant or refractory to corticosteroids* OR has
                  relapsed/refractory disease to other therapy besides corticosteroids.

               -  Symptomatic from his/her disease OR has one or more signs of organ damage
                  (assessed by the investigator as possibly-related to eosinophilia or
                  biopsy-proven). This can include skin, lung, cardiac, central nervous system,
                  liver, or GI involvement, or evidence of symptomatic hepatic or splenic
                  enlargement

               -  Has abnormal T-lymphocyte immuno-phenotype by flow cytometry.

          -  Subject with chronic eosinophilic leukemia, not otherwise specified (CEL,NOS) must
             meet the following

               -  Has at least 2 readings with an absolute eosinophil count >= 500/mm^3 in the
                  preceding 3 months prior to starting ruxolitinib (one reading must be during the
                  screening period).

               -  Newly-diagnosed OR receiving corticosteroids OR has relapsed/refractory disease
                  to any therapy besides corticosteroids.

               -  Has increased blasts in the blood or bone marrow (> 5% and < 20%), and/or a
                  clonal cytogenetic or molecular abnormality

                    -  Subjects with JAK2 mutations are included within this group.

          -  Subject with JAK2-rearranged eosinophilic neoplasm must meet the following

               -  Has at least 2 readings with an absolute eosinophil count >= 500/mm^3 in the
                  preceding 3 months prior to starting ruxolitinib (one reading must be during the
                  screening period).

               -  Newly-diagnosed OR receiving corticosteroids OR has relapsed/refractory disease
                  to any therapy besides corticosteroids.

                    -  This group includes subjects with PCM1-JAK2, BCR-JAK2, ETV6-JAK2 or other
                       JAK2 rearrangements.

          -  If receiving corticosteroids, must be a stable dose for >= 28 days prior to Day 1
             (unstable dosing not eligible).

          -  Eastern Cooperative Oncology Group (ECOG) performance status =< 3.

          -  Willing and able to review and execute informed consent (legally-authorized consent
             acceptable).

        Exclusion Criteria:

          -  Active life-threatening complication(s) from underlying eosinophilic disease (i.e.,
             leukostasis; acute thromboembolic disease including central nervous system (CNS)
             involvement; severe pulmonary or cardiac dysfunction). Stabilization of acute,
             life-threatening eosinophil-related co-morbidities will allow enrollment of the
             patient.

          -  World Health Organization (WHO)-defined myeloid neoplasm associated with eosinophilia
             other than CEL NOS and JAK2 rearranged neoplasms (e.g., myelodysplastic syndrome
             (MDS); myeloproliferative neoplasms (MPN); MDS/MPN overlap disorders; and systemic
             mastocytosis (SM).

          -  Reactive hypereosinophilia due to connective tissue disease, sarcoidosis or
             eosinophilic granulomatosis with polyangiitis.

          -  Organ-restricted ?tissue? eosinophilia with the absence of peripheral eosinophilia in
             the blood.

          -  Invasive malignancy over the previous 2 years except treated early stage carcinomas of
             the skin, completely resected intraepithelial carcinoma of the cervix, and completely
             resected papillary thyroid and follicular thyroid cancers.

          -  Myeloid or lymphoid neoplasm with eosinophilia and abnormalities of PDGFRA, PDGFRB or
             FGFR1.

          -  Anticipated to receive a hematopoietic stem cell transplant within the first 6 months
             of treatment on trial.

          -  Major surgery within 4 weeks prior to entering the study.

          -  Life expectancy of < 6 months.

          -  Known diagnosis of human immunodeficiency virus (HIV).

          -  Known diagnosis of chronic active hepatitis B or C (viral testing is not required).
             Subjects with a known history of hepatitis B and/or C are allowed on trial if at the
             time of enrollment, the virus is not active and undetected (testing required if there
             is a known history), and such patients are not actively receiving antiviral treatment
             specific for hepatitis B and/or C.

          -  Clinically serious infections requiring ongoing antibiotic therapy.

          -  Parasitic infection diagnosed within 24 weeks prior to enrollment.

          -  Platelet count =< 25 x 10^9/L at baseline.

          -  Alanine aminotransferase (ALT)/serum glutamate pyruvate transaminase (SGPT) > 4 x
             upper limit of normal (ULN) or direct bilirubin > 4 x ULN (if considered to be
             unrelated to the underlying eosinophilic disorder).

          -  End-stage renal function (creatinine clearance [CrCl] < 15 mL/min or glomerular
             filtration rate [GFR] < 15 mL/min) regardless of whether hemodialysis is required.

          -  Use of investigational or commercial therapies with the intent to treat the underlying
             eosinophilic disorder within 28 days of study start, including interferon; imatinib;
             alemtuzumab; cyclosporine; methotrexate; mepolizumab; benralizumab; or other antibody
             therapies.

          -  Use of hydroxyurea within 7 days of study start.

          -  Prior therapy with ruxolitinib or other JAK inhibitors.

          -  Previous allergic reactions to JAK inhibitors or excipients.

          -  Unwilling to commit to abstinence from heterosexual contact or agree to use and comply
             with highly effective contraception, 28 days prior to starting study drug, during the
             treatment period and for 12 weeks after discontinuation of study treatment.

          -  Females of childbearing potential who have a positive pregnancy test (urine or serum)
             during screening period.
      

Gender

All

Ages

18 Years - N/A

Accepts Healthy Volunteers

No

Contacts

Jason Gotlib, MD, MS, 6507231367, [email protected]

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT03801434

Organization ID

IRB-47457

Secondary IDs

NCI-2018-03723

Responsible Party

Sponsor

Study Sponsor

Stanford University

Collaborators

 Incyte Corporation

Study Sponsor

Jason Gotlib, MD, MS, Principal Investigator, Stanford Cancer Institute Palo Alto


Verification Date

January 2019