INCB18424 in Treating Young Patients With Relapsed or Refractory Solid Tumor, Leukemia, or Myeloproliferative Disease

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Children's Oncology Group
ClinicalTrials.gov Identifier:
NCT01164163
First received: July 15, 2010
Last updated: October 14, 2014
Last verified: August 2014
  Purpose

RATIONALE: INCB18424 (Ruxolitinib) may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

PURPOSE: This phase 1 clinical trial is studying the side effects and best dose of INCB18424 in treating young patients with relapsed or refractory solid tumor, leukemia, or myeloproliferative disease.


Condition Intervention Phase
Chronic Myeloproliferative Disorders
Leukemia
Myelodysplastic Syndromes
Myelodysplastic/Myeloproliferative Neoplasms
Unspecified Childhood Solid Tumor, Protocol Specific
Drug: ruxolitinib phosphate
Other: laboratory biomarker analysis
Other: pharmacological study
Phase 1

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase I Study of JAK Inhibition (INCB018424) in Children With Relapsed or Refractory Solid Tumors, Leukemias, and Myeloproliferative Neoplasms

Resource links provided by NLM:


Further study details as provided by Children's Oncology Group:

Primary Outcome Measures:
  • Maximum-tolerated dose and/or recommended phase II dose [ Time Frame: 28 days ] [ Designated as safety issue: Yes ]
  • Toxicity [ Time Frame: 30 days post treatment ] [ Designated as safety issue: Yes ]
  • Pharmacokinetics [ Time Frame: Up to 28 days ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Antitumor activity [ Time Frame: Up to 30 days post treatment ] [ Designated as safety issue: No ]
  • Toxicity and biologic activity [ Time Frame: Day 1 and Day 15 ] [ Designated as safety issue: No ]

Estimated Enrollment: 106
Study Start Date: September 2010
Estimated Primary Completion Date: May 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment (Ruxolitinib) Drug: ruxolitinib phosphate Other: laboratory biomarker analysis Other: pharmacological study

Detailed Description:

OBJECTIVES:

Primary

  • To estimate the maximum-tolerated dose and/or recommended phase II dose of oral JAK inhibitor INCB18424 administered continuously, twice daily to pediatric patients with relapsed or refractory solid tumors.
  • To define and describe the toxicities of this treatment administered on this schedule in pediatric patients with relapsed or refractory solid tumors, leukemias, or myeloproliferative neoplasms (MPNs).
  • To characterize the pharmacokinetics of this treatment in pediatric patients with relapsed or refractory solid tumors, leukemias, or MPNs.

Secondary

  • To preliminarily define the antitumor activity of this treatment within the confines of a phase I study.
  • To assess the biologic activity of oral JAK inhibitor INCB18424 upon JAK-STAT signaling in pediatric patients with relapsed or refractory solid tumors, leukemias, or MPNs.
  • To assess the cytotoxicity and biologic activity of oral JAK inhibitor INCB18424 upon phosphosignaling and mutation burden in pediatric patients whose leukemias or MPNs have known CRLF2 and/or JAK mutations.

OUTLINE: This is a multicenter, dose-escalation study.

Patients receive oral JAK inhibitor INCB18424 twice daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Patients with relapsed or refractory leukemia may receive intrathecal chemotherapy in course 2 and subsequent courses at the discretion of the treating physician.

Plasma, bone marrow, and blood samples may be collected at baseline, during course 1, and before subsequent courses for pharmacokinetic analysis and correlative biology studies.

After completion of study treatment, patients are followed up for 30 days.

  Eligibility

Ages Eligible for Study:   1 Year to 21 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

DISEASE CHARACTERISTICS:

  • Histologically confirmed diagnosis of one of the following:

    • Relapsed or refractory extracranial solid tumor
    • Relapsed or refractory leukemia

      • At least 25% blasts in the bone marrow (M3) with the exception of patients with acute myeloid leukemia (AML), who must have > 20% blasts in the bone marrow
    • Relapsed or refractory myeloproliferative neoplasm (MPN)

      • At original diagnosis or relapse
      • Current diagnostic criteria for MPNs include polycythemia vera, essential thrombocythemia, juvenile myelomonocytic leukemia, myelofibrosis, and atypical chronic myeloid leukemia
    • Relapsed or refractory leukemia or MPN that have confirmed JAK mutations and/or positive TSLPR surface staining

      • Testing for JAK mutations and/or confirmed positive flow cytometry surface staining for the thymic stromal lymphopoietin receptor (TSLPR; encoded by CRLF2); eligibility for part C will be contingent upon patients demonstrating overexpression of CRLF2 by flow cytometric methods measured at either JHU or U. Washington flow laboratories (therefore, pre-enrollment samples need to be sent to one of these laboratories after discussion with Dr. Loh) or if the patient has a CLIA lab documented alteration in JAK1 or JAK2, SH2B3, IL7RA, or another gene that would predict sensitivity to JAK inhibition.
  • Measurable or evaluable disease (for patients with solid tumors)
  • Current disease state is one for which there is no known curative therapy or therapy proven to prolong survival with an acceptable quality of life
  • No known active CNS involvement (radiographic or cytologic)

PATIENT CHARACTERISTICS:

  • Karnofsky performance status (PS) 50-100% (for patients > 16 years old) or Lansky PS 50-100% (for patients ≤ 16 years old)

    • Patients who are unable to walk because of paralysis, but who can actively sit up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance status
  • Patients with solid tumors* must meet the following criteria:

    • Peripheral ANC ≥ 1,000/mm^3
    • Platelet count ≥ 100,000/mm^3 (transfusion-independent, defined as > 7 days since prior platelet transfusions)
    • Hemoglobin ≥ 8.0 g/dL (may receive RBC transfusions)

      • Not refractory to to red cell or platelet transfusion
    • ALT ≤ 110 U/L NOTE: *Patients with solid tumors and known bone marrow metastatic disease are eligible for study, but not evaluable for hematologic toxicity. These patients must not be known to be refractory to RBC or platelet transfusions.
  • Patients with leukemia or MPNs must meet the following criteria:

    • Platelet count ≥ 20,000/mm^3 (may receive platelet infusions)
    • Hemoglobin ≥ 8.0 g/dL (may receive RBC transfusions)
    • ALT ≤ 225 U/L
  • Creatinine clearance or radioisotope GFR ≥ 70 mL/min OR serum creatinine based on age/gender as follows:

    • ≤ 0.6 mg/dL (for patients 1 to < 2 years old)
    • ≤ 0.8 mg/dL (for patients 2 to < 6 years old)
    • ≤ 1 mg/dL (for patients 6 to < 10 years old)
    • ≤ 1.2 mg/dL (for patients 10 to < 13 years old)
    • ≤ 1.4 mg/dL (for female patients ≥ 13 years old)
    • ≤ 1.5 mg/dL (for male patients 13 to < 16 years old)
    • ≤ 1.7 mg/dL (for male patients ≥ 16 years old)
  • Bilirubin (sum of conjugated + unconjugated) ≤ 1.5 times upper limit of normal for age
  • Serum albumin ≥ 2 g/dL
  • Not pregnant or nursing
  • Negative pregnancy test
  • Fertile patients must use effective contraception
  • Able to swallow crushed or whole tablets

    • Nasogastric or G tube administration is not allowed
  • Body surface area ≥ 0.65 m^2 (for patients at dose level -1, 1, and 2)
  • No uncontrolled infection, including patients with known active HIV or chronic hepatitis
  • No patients who, in the opinion of the investigator, may not be able to comply with the safety monitoring requirements of the study

PRIOR CONCURRENT THERAPY:

  • Fully recovered from the acute toxic effects of all prior anticancer therapy
  • At least 2 weeks since prior local palliative radiotherapy (small port)
  • At least 6 months since prior total-body irradiation (TBI), craniospinal radiotherapy, or radiotherapy to ≥ 50% of the pelvis (for patients with solid tumors)
  • At least 3 months since prior TBI, craniospinal radiotherapy, or radiotherapy to ≥ 50% of the pelvis (for patients with leukemia)
  • At least 3 months since prior stem cell transplantation or rescue without TBI and no evidence of active graft-vs-host disease
  • At least 6 weeks since other substantial bone marrow radiation
  • At least 3 weeks since prior myelosuppressive therapy (6 weeks for nitrosourea) (for patients with solid tumors)
  • At least 2 weeks since prior cytoxic chemotherapy (for patients with leukemia or MPNs)

    • Hydroxyurea may be initiated and continued for up to 24 hours before the start of study treatment
    • Intrathecal cytarabine (Ara-C) is not myelosuppressive chemotherapy
    • Patients with leukemia are permitted to receive intrathecal chemotherapy, including methotrexate or cytarabine, only if this is given at the time of diagnostic lumbar puncture at least 24 hours prior to the start of INCB018424
  • At least 2 weeks since prior long-acting hematopoietic growth factor (e.g., Neulasta) or 1 week for a short-acting growth factor

    • For agents that have known adverse events occurring beyond 1 week, this period must be extended beyond the time during which adverse events are known to occur (as discussed with the study chair)
  • At least 1 week since prior therapy with a biologic (antineoplastic) agent

    • For agents that have known adverse events occurring beyond 1 week, this period must be extended beyond the time during which adverse events are known to occur (as discussed with the study chair)
  • At least 3 half-lives of antibody since prior monoclonal antibody
  • No other concurrent investigational drugs
  • No other concurrent anticancer agents, including chemotherapy, radiotherapy, immunotherapy, or biologic therapy
  • No concurrent systemic steroids (i.e., prednisone > 10 mg)
  • No concurrent aspirin > 150 mg/day
  • No concurrent medications for myelofibrosis (e.g., hydroxyurea, interferon, thalidomide, busulfan, lenalidomide, or anagrelide)
  • No concurrent cyclosporine, tacrolimus, or other agents to prevent graft-vs-host disease after bone marrow transplant or organ rejection after transplant
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01164163

  Hide Study Locations
Locations
United States, Alabama
UAB Comprehensive Cancer Center
Birmingham, Alabama, United States, 35294
United States, California
Children's Hospital of Orange County
Orange, California, United States, 92868
UCSF Helen Diller Family Comprehensive Cancer Center
San Francisco, California, United States, 94115
United States, Colorado
Children's Hospital Colorado Center for Cancer and Blood Disorders
Aurora, Colorado, United States, 80045
United States, District of Columbia
Children's National Medical Center
Washington, District of Columbia, United States, 20010-2970
United States, Georgia
AFLAC Cancer Center and Blood Disorders Service of Children's Healthcare of Atlanta - Egleston Campus
Atlanta, Georgia, United States, 30322
United States, Illinois
Children's Memorial Hospital - Chicago
Chicago, Illinois, United States, 60611
United States, Indiana
Riley's Children Cancer Center at Riley Hospital for Children
Indianapolis, Indiana, United States, 46202
United States, Maryland
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Baltimore, Maryland, United States, 21231-2410
Warren Grant Magnuson Clinical Center - NCI Clinical Trials Referral Office
Bethesda, Maryland, United States, 20892-1182
United States, Massachusetts
Dana-Farber/Harvard Cancer Center at Dana-Farber Cancer Institute
Boston, Massachusetts, United States, 02115
United States, Michigan
C.S. Mott Children's Hospital at University of Michigan Medical Center
Ann Arbor, Michigan, United States, 48109-0286
United States, Minnesota
Masonic Cancer Center at University of Minnesota
Minneapolis, Minnesota, United States, 55455
United States, Missouri
Siteman Cancer Center at Barnes-Jewish Hospital - Saint Louis
St. Louis, Missouri, United States, 63110
United States, New York
Herbert Irving Comprehensive Cancer Center at Columbia University Medical Center
New York, New York, United States, 10032
United States, Ohio
Cincinnati Children's Hospital Medical Center
Cincinnati, Ohio, United States, 45229-3039
United States, Oregon
Knight Cancer Institute at Oregon Health and Science University
Portland, Oregon, United States, 97239-3098
United States, Pennsylvania
Children's Hospital of Philadelphia
Philadelphia, Pennsylvania, United States, 19104
Children's Hospital of Pittsburgh of UPMC
Pittsburgh, Pennsylvania, United States, 15213
United States, Tennessee
St. Jude Children's Research Hospital
Memphis, Tennessee, United States, 38105
United States, Texas
Simmons Comprehensive Cancer Center at University of Texas Southwestern Medical Center - Dallas
Dallas, Texas, United States, 75390
Baylor University Medical Center - Houston
Houston, Texas, United States, 77030-2399
United States, Washington
Children's Hospital and Regional Medical Center - Seattle
Seattle, Washington, United States, 98105
United States, Wisconsin
Midwest Children's Cancer Center at Children's Hospital of Wisconsin
Milwaukee, Wisconsin, United States, 53226
Sponsors and Collaborators
Children's Oncology Group
Investigators
Principal Investigator: Mignon Loh, MD University of California, San Francisco
  More Information

Additional Information:
No publications provided

Responsible Party: Children's Oncology Group
ClinicalTrials.gov Identifier: NCT01164163     History of Changes
Other Study ID Numbers: ADVL1011, COG-ADVL1011
Study First Received: July 15, 2010
Last Updated: October 14, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by Children's Oncology Group:
unspecified childhood solid tumor, protocol specific
recurrent childhood acute lymphoblastic leukemia
recurrent childhood acute myeloid leukemia
refractory chronic lymphocytic leukemia
relapsing chronic myelogenous leukemia
childhood myelodysplastic syndromes
previously treated myelodysplastic syndromes
atypical chronic myeloid leukemia, BCR-ABL1 negative
chronic myelomonocytic leukemia
juvenile myelomonocytic leukemia
myelodysplastic/myeloproliferative neoplasm, unclassifiable
polycythemia vera
essential thrombocythemia
childhood acute promyelocytic leukemia (M3)
acute myeloid leukemia/transient myeloproliferative disorder
primary myelofibrosis

Additional relevant MeSH terms:
Leukemia
Myelodysplastic Syndromes
Myelodysplastic-Myeloproliferative Diseases
Myeloproliferative Disorders
Neoplasms
Preleukemia
Syndrome
Bone Marrow Diseases
Disease
Hematologic Diseases
Neoplasms by Histologic Type
Pathologic Processes
Precancerous Conditions

ClinicalTrials.gov processed this record on October 20, 2014