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

A Phase I Study of JAK Inhibition (INCB018424) in Children With Relapsed or Refractory Solid Tumors, Leukemias, and Myeloproliferative Neoplasms

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.

Study Overview

• Status: Completed
• Conditions: Unspecified Childhood Solid Tumor, Protocol Specific; Myelodysplastic Syndromes; Leukemia; Chronic Myeloproliferative Disorders; Myelodysplastic/Myeloproliferative Neoplasms
• Intervention / Treatment: Other: pharmacological study; Other: laboratory biomarker analysis; Drug: ruxolitinib phosphate

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.

• Study Type: Interventional
• Enrollment (Actual): 49
• Phase: Phase 1

Contacts and Locations

Study Locations

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

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year to 21 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Treatment (Ruxolitinib)	Other: pharmacological study; Other: laboratory biomarker analysis; Drug: ruxolitinib phosphate

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Maximum-tolerated dose and/or recommended phase II dose	28 days
Toxicity	30 days post treatment
Pharmacokinetics	Up to 28 days

Secondary Outcome Measures

Outcome Measure	Time Frame
Antitumor activity	Up to 30 days post treatment
Toxicity and biologic activity	Day 1 and Day 15

Collaborators and Investigators

• Sponsor: Children's Oncology Group
• Collaborators: National Cancer Institute (NCI)

Study record dates

Study Major Dates

• Study Start: September 1, 2010
• Primary Completion (Actual): October 1, 2014

Study Registration Dates

• First Submitted: July 15, 2010
• First Submitted That Met QC Criteria: July 15, 2010
• First Posted (Estimate): July 16, 2010

Study Record Updates

• Last Update Posted (Estimate): October 23, 2014
• Last Update Submitted That Met QC Criteria: October 22, 2014
• Last Verified: October 1, 2014

More Information

Terms related to this study

• Keywords: unspecified childhood solid tumor, protocol specific; primary myelofibrosis; chronic myelomonocytic leukemia; previously treated myelodysplastic syndromes; juvenile myelomonocytic leukemia; childhood myelodysplastic syndromes; relapsing chronic myelogenous leukemia; refractory chronic lymphocytic leukemia; polycythemia vera; essential thrombocythemia; recurrent childhood acute lymphoblastic leukemia; recurrent childhood acute myeloid leukemia; myelodysplastic/myeloproliferative neoplasm, unclassifiable; atypical chronic myeloid leukemia, BCR-ABL1 negative; childhood acute promyelocytic leukemia (M3); acute myeloid leukemia/transient myeloproliferative disorder
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms by Histologic Type; Disease; Bone Marrow Diseases; Hematologic Diseases; Precancerous Conditions; Neoplasms; Syndrome; Myelodysplastic Syndromes; Leukemia; Preleukemia; Myeloproliferative Disorders; Myelodysplastic-Myeloproliferative Diseases
• Other Study ID Numbers: ADVL1011; COG-ADVL1011 (Other Identifier: Children's Oncology Group)