A Study of Oral AMN107 in Adults With Chronic Myelogenous Leukemia (CML) or Other Hematologic Malignancies

Phase 1

Completed

Conditions: Chronic Myelogenous Leukemia
Acute Lymphoblastic Leukemia (Philadelphia Chromosome Positive)
Hypereosinophilic Syndrome
Systemic Mastocytosis

Interventions: Drug: Nilotinib

Registration Number: NCT00109707

Lead Sponsor: Novartis Pharmaceuticals

Brief Summary: The purpose of this trial is to assess the efficacy, safety, tolerability, biologic activity, and pharmacokinetics of AMN107 in six groups of patients with one of the following conditions:

Relapsed/refractory Ph+ Acute lymphoblastic leukemia (ALL) (arm 1)

Group A - Imatinib failure only (arms 2, 3 and 4)

* imatinib-resistant or intolerant CML - Chronic Phase (CP)

* imatinib-resistant or intolerant CML - Accelerated Phase (AP)

* imatinib-resistant or intolerant CML - Blast Crisis (BC)

Group B - Imatinib and other TKI failure (arms 2, 3 and 4)

* imatinib-resistant or intolerant CML - Chronic Phase (CP)

* imatinib-resistant or intolerant CML - Accelerated Phase (AP)

* imatinib-resistant or intolerant CML - Blast Crisis (BC)

Hypereosinophilic syndrome/chronic eosinophilic leukemia (HES/CEL) (arm 5)

Systemic mastocytosis (Sm) (arm 6)

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 507

Inclusion Criteria

Main inclusion criteria include:

Patients with CML in blast crisis, CML in accelerated phase defined as never in blast crisis phase, or CML in chronic phase defined as never been in blast crisis phase or accelerated phase who have: *developed progressive disease during therapy with at least 600 mg of imatinib per day, -OR- *patients with CML on imatinib therapy, at any dose, developing progressive disease and the presence of a genetic mutation likely to result in imatinib resistance -OR- *have developed an intolerance to imatinib
Relapsed or refractory Ph+ ALL
Hypereosinophilic syndrome/chronic eosinophilic leukemia.
Systemic mastocytosis who have a clinical indication for treatment.
Prior imatinib therapy for patients with Ph+ ALL, HES/CEL and SM is permitted but is not required
CML patients who have been treated with an investigational tyrosine kinase inhibitor who otherwise meet the definition of imatinib-resistance or intolerance are eligible
Written informed consent prior to any study procedures being performed

Exclusion Criteria

Impaired cardiac function
Patients with severe/chronic or uncontrolled medical conditions (including but not limited to diabetes, infections, GI impairment, CNS infiltration, liver and kidney disease)
Prior and concomitant use of certain medications (including but not limited to warfarin, chemotherapy, hematopoietic colony-stimulating growth factors, medications that can affect electrocardiogram test results, other investigational drugs )
Women who are pregnant or breastfeeding
Patients with a history of another primary malignancy that is currently clinically significant or currently requires active intervention.
Patients unwilling to comply with the protocol.
Known diagnosis of human immunodeficiency virus (HIV) infection

Other protocol-defined inclusion/exclusion criteria may apply

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
CML-AP With Prior Imatinib Onl	Nilotinib	Imatinib-resistant / intolerant PH+ CML-AP patients
CML-CP With Prior Imatinib Only	Nilotinib	Imatinib-resistant / intolerant PH+ CML-CP patients
CML-CP	Nilotinib	Imatinib-resistant / intolerant PH+ CML-CP patients

Primary Outcome Measures

Name	Time	Method
Number of Participants With Major Cytogenetic Response (MCyR)	Up to End of the Treatment (Approximately 7.5 years)	Major Cytogenetic Response (MCyR) is defined as Complete Cytogenetic Response (CCyR: 0% Ph-chromosome-positive cells in metaphase in bone marrow) or Partial Cytogenetic Response (PCyR: 1-35% Ph-chromosome-positive cells in metaphase in bone marrow).
Number of Participants Confirmed Overall Hematological Response (Phase II)	Up to End of the Treatment (Approximately 7.5 years)	Hematologic response is defined as the percentage of participants in complete hematologic response (defined as the following present for at least 4 weeks: WBC count \<10 x 109/L, Platelet count \<450 x 109/L, Basophils \<5%, No blasts and promyelocytes in peripheral blood, Myelocytes + metamyelocytes \< 5% in peripheral blood, No evidence of extramedullary disease, including spleen and liver). Hematological response was a primary outcome measure for Arm CML-AP with prior imatinib only.

Secondary Outcome Measures

Name	Time	Method
Number of Participants With Complete Hematologic Response (Phase II)	Up to End of the Treatment (Approximately 7.5 years)	A Complete Hematologic Response (CHR) is obtained when all the following criteria are met: WBC ≤ institutional ULN; platelets ≤ 450,000/mm3; ≤20% basophils in peripheral blood; no blasts or promyelocytes in PB cells; \< 5% myelocytes plus metamyelocytes in PB cells; no extra-medullary involvement including no hepatomegaly or splenomegaly.
Participants With (MMR) Major Molecular Response (Phase II)	Up to End of the Treatment (Approximately 7.5 years)	MMR was defined for participants who demonstrated a reduction in BCR-ABL/control gene % transcripts to ≤0.1% based on international scale. The control gene used may have been either BCR or ABL.
Number of Participants With Adverse Events and Serious Adverse Events to Evaluate Long Term Safety	From First Participant First Visit to Last Participant Last Visit (Approximately 7.5 years)	Adverse events (AEs) were defined as any unfavorable and unintended diagnosis, symptom, sign (including an abnormal laboratory finding), syndrome or disease which either occurs during study, having been absent at baseline, or, if present at baseline, appears to worsen. Serious adverse events (SAEs) were defined as any untoward medical occurrences that result in death, are life threatening, require (or prolong) hospitalization, cause persistent or significant disability/incapacity, result in congenital anomalies or birth defects, or are other conditions which in judgement of investigators represent significant hazards.
Number of Participants With Overall Major Cytogenetic Responses (Phase II)	Up to End of the Treatment (Approximately 7.5 years)	Cytogenetic responses (CyRs) in CML are based on the percentage of Ph+ metaphases in bone marrow; a value of 0% Ph+ metaphases defines a complete cytogenetic response (CCyR) and \>0% to 35% defines a major cytogenetic response (MCyR). Achievement of CCyR is associated with a significant survival advantage in participants with CML-CP. MCyR was categorized as either CCyR or partial cytogenetic response (PCyR).
Overall Survival (OS) (Phase II)	Up to End of the Treatment (Approximately 7.5 years)	OS was calculated for all participants as the time between the start of nilotinib and death. Participants were followed for survival after discontinuation, every 3 months, and were included in the analysis of OS. Censoring was at the date of the last contact for discontinued participants and followed up for survival.
Time to Progression (TTP) (Phase II)	Up to End of the Treatment (Approximately 7.5 years)	Time to Progression was defined as the time from the start of nilotinib to the earliest date of Disease Progression (PD), discontinuation due to PD or death. Disease progression was defined as an increase in the number of circulating leukemic cells via cytogenetic assessment using real-time quantitative reverse transcriptase polymerase chain reaction (PCR).

Trial Locations

Locations (25): Sidney Kimmel Comprehensive Cancer Center/Johns Hopkins Med. Div.of Hematologic Malignancie
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Baltimore, Maryland, United States
Stanford University Medical Center
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Stanford, California, United States
University of Chicago Medical Center Dept. of U. of Chicago Hosp(3)
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Chicago, Illinois, United States
Dana Farber Cancer Institute
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Boston, Massachusetts, United States
Vanderbilt University Medical Center, Clinical Trials Center Investigational Drug Services
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Nashville, Tennessee, United States
University of Illinois at Chicago Divisionof Hematology/Oncology
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Chicago, Illinois, United States
Oregon Health Sciences University
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Portland, Oregon, United States
MD Anderson Cancer Center/University of Texas
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Houston, Texas, United States
Swedish Cancer Institute
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Seattle, Washington, United States
City of Hope National Medical Center
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Duarte, California, United States
Indiana Blood and Marrow Institute Dept of Indiana Blood&Mar (2)
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Beech Grove, Indiana, United States
Wayne State University
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Detroit, Michigan, United States
University of Rochester Medical Center
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Rochester, New York, United States
Duke University Medical Center
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Durham, North Carolina, United States
Roswell Park Cancer Institute Rosewell SC
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Buffalo, New York, United States
Memorial Sloan Kettering Cancer Center
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New York, New York, United States
The Jones Clinic
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Germantown, Tennessee, United States
Novartis Investigative Site
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Newcastle upon Tyne, United Kingdom
Hackensack University Medical Center
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Hackensack, New Jersey, United States
University of Colorado Hospital
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Aurora, Colorado, United States
H. Lee Moffitt Cancer Center & Research Institute Dept.of H. Lee Moffitt
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Tampa, Florida, United States
Ochsner Clinic Foundation
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New Orleans, Louisiana, United States
University of Michigan Health System Clinical Trials Office
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Ann Arbor, Michigan, United States
Mayo Clinic - Rochester
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Rochester, Minnesota, United States
Wake Forest University Baptist Medical Center
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Winston-Salem, North Carolina, United States