ADVL1011, A Phase 1 Study of JAK Inhibition (INCB018424) in Children with Relapsed or Refractory Solid Tumors, Leukemias, and Myeloproliferative Neoplasms
This phase I 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.
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: Extracranial solid tumor Leukemia At least 25% blasts in the bone marrow (M3) 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 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 active CNS involvement (positive CSF cytology or known radiographic evidence of leptomeningeal dissemination) for patients with leukemia or MPNs PATIENT CHARACTERISTICS: Karnofsky performance status (PS) 50-100% (for patients greater than 16 years old) or Lansky PS 50-100% (for patients â?¤ 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 â?¥ 1,000/mm^3 Platelet count â?¥ 100,000/mm^3 (transfusion-independent, defined as greater than 7 days since prior platelet transfusions) Hemoglobin â?¥ 8.0 g/dL (may receive RBC transfusions) ALT â?¤ 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 â?¥ 20,000/mm^3 (may receive platelet infusions) Hemoglobin â?¥ 8.0 g/dL (may receive RBC transfusions) ALT â?¤ 225 U/L Creatinine clearance or radioisotope GFR â?¥ 70 mL/min OR serum creatinine based on age/gender as follows: â?¤ 0.6 mg/dL (for patients 1 to less than 2 years old) â?¤ 0.8 mg/dL (for patients 2 to less than 6 years old) â?¤ 1 mg/dL (for patients 6 to less than 10 years old) â?¤ 1.2 mg/dL (for patients 10 to less than 13 years old) â?¤ 1.4 mg/dL (for female patients â?¥ 13 years old) â?¤ 1.5 mg/dL (for male patients 13 to less than 16 years old) â?¤ 1.7 mg/dL (for male patients â?¥ 16 years old) Bilirubin (sum of conjugated + unconjugated) â?¤ 1.5 times upper limit of normal for age Serum albumin â?¥ 2 g/dL Corrected QT interval (QTc) less than 450 msec on ECG Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception Able to swallow crushed or whole tablets Body surface area â?¥ 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 6 months since prior total-body irradiation (TBI), craniospinal radiotherapy, or radiotherapy to â?¥ 50% of the pelvis 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 local palliative radiotherapy (small port) 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 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 patients who have been on an increasing dose of corticosteroids for the past week No other concurrent investigational drugs No other concurrent anticancer agents, including chemotherapy, radiotherapy, immunotherapy, or biologic therapy No concurrent systemic steroids (i.e., prednisone greater than 10 mg) No concurrent aspirin greater than 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
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.
05/22/2013 04:02 AM