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

Sponsor

Children's Oncology Group (Other)

Overall Status

Completed

CT.gov ID

NCT01164163

Collaborator

National Cancer Institute (NCI) (NIH)

Enrollment

Locations

Arm

Patients Per Site

Study Details

Study Description

Brief 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.

Condition or Disease	Intervention/Treatment	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

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 Design

Study Type:

Interventional

Actual Enrollment :

49 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (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

Study Start Date :

Sep 1, 2010

Actual Primary Completion Date :

Oct 1, 2014

Arms and Interventions

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

Arm

Intervention/Treatment

Experimental: Treatment (Ruxolitinib)

Drug: ruxolitinib phosphate

Other: laboratory biomarker analysis

Other: pharmacological study

Outcome Measures

Primary Outcome Measures

Maximum-tolerated dose and/or recommended phase II dose [28 days]
Toxicity [30 days post treatment]
Pharmacokinetics [Up to 28 days]

Secondary Outcome Measures

Antitumor activity [Up to 30 days post treatment]
Toxicity and biologic activity [Day 1 and Day 15]

Eligibility Criteria

Criteria

Ages Eligible for Study:

1 Year to 21 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Locations

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