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

Leukemia Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01164163
• Other study ID #: ADVL1011
• Secondary ID: COG-ADVL1011
• Status: Completed
• Phase: Phase 1
• First received: July 15, 2010
• Last updated: October 22, 2014
• Start date: September 2010

Study information

• Verified date: October 2014
• Source: Children's Oncology Group
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 49
• Est. primary completion date: October 2014
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 1 Year to 21 Years

Eligibility

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 Design

Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Chronic Myeloproliferative Disorders
• Leukemia
• Myelodysplastic Syndromes
• Myelodysplastic-Myeloproliferative Diseases
• Myelodysplastic/Myeloproliferative Neoplasms
• Myeloproliferative Disorders
• Neoplasms
• Preleukemia
• Unspecified Childhood Solid Tumor, Protocol Specific

Intervention

Drug:
• ruxolitinib phosphate

Other:
• laboratory biomarker analysis

• pharmacological study

Locations

Country	Name	City	State
United States	C.S. Mott Children's Hospital at University of Michigan Medical Center	Ann Arbor	Michigan
United States	AFLAC Cancer Center and Blood Disorders Service of Children's Healthcare of Atlanta - Egleston Campus	Atlanta	Georgia
United States	Children's Hospital Colorado Center for Cancer and Blood Disorders	Aurora	Colorado
United States	Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins	Baltimore	Maryland
United States	Warren Grant Magnuson Clinical Center - NCI Clinical Trials Referral Office	Bethesda	Maryland
United States	UAB Comprehensive Cancer Center	Birmingham	Alabama
United States	Dana-Farber/Harvard Cancer Center at Dana-Farber Cancer Institute	Boston	Massachusetts
United States	Children's Memorial Hospital - Chicago	Chicago	Illinois
United States	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio
United States	Simmons Comprehensive Cancer Center at University of Texas Southwestern Medical Center - Dallas	Dallas	Texas
United States	Baylor University Medical Center - Houston	Houston	Texas
United States	Riley's Children Cancer Center at Riley Hospital for Children	Indianapolis	Indiana
United States	St. Jude Children's Research Hospital	Memphis	Tennessee
United States	Midwest Children's Cancer Center at Children's Hospital of Wisconsin	Milwaukee	Wisconsin
United States	Masonic Cancer Center at University of Minnesota	Minneapolis	Minnesota
United States	Herbert Irving Comprehensive Cancer Center at Columbia University Medical Center	New York	New York
United States	Children's Hospital of Orange County	Orange	California
United States	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania
United States	Children's Hospital of Pittsburgh of UPMC	Pittsburgh	Pennsylvania
United States	Knight Cancer Institute at Oregon Health and Science University	Portland	Oregon
United States	UCSF Helen Diller Family Comprehensive Cancer Center	San Francisco	California
United States	Children's Hospital and Regional Medical Center - Seattle	Seattle	Washington
United States	Siteman Cancer Center at Barnes-Jewish Hospital - Saint Louis	St. Louis	Missouri
United States	Children's National Medical Center	Washington	District of Columbia

Sponsors (2)

Lead Sponsor	Collaborator
Children's Oncology Group	National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Maximum-tolerated dose and/or recommended phase II dose		28 days	Yes
Primary	Toxicity		30 days post treatment	Yes
Primary	Pharmacokinetics		Up to 28 days	No
Secondary	Antitumor activity		Up to 30 days post treatment	No
Secondary	Toxicity and biologic activity		Day 1 and Day 15	No