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

Study Overview
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Brief Summary
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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)

Official Title
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A Phase IA/II Multicenter, Dose-escalation Study of Oral AMN107 on a Continuous Daily Dosing Schedule in Adult Patients With Imatinib-resistant/Intolerant CML in Chronic or Accelerated Phase or Blast Crisis, Relapsed/Refractory Ph+ ALL, and Other Hematologic Malignancies.

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

Intervention / Treatment
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* Drug: Nilotinib


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CML-CP With Prior Imatinib Only<br>Imatinib-resistant / intolerant PH+ CML-CP patients | Drug: Nilotinib<br> <br> |
| Experimental: CML-AP With Prior Imatinib Onl<br>Imatinib-resistant / intolerant PH+ CML-AP patients | Drug: Nilotinib<br> <br> |
| Experimental: CML-CP<br>Imatinib-resistant / intolerant PH+ CML-CP patients | Drug: Nilotinib<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Major Cytogenetic Response (MCyR) | 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). | Up to End of the Treatment (Approximately 7.5 years) | 
| Number of Participants Confirmed Overall Hematological Response (Phase II) | 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. | Up to End of the Treatment (Approximately 7.5 years) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Overall Major Cytogenetic Responses (Phase II) | 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). | Up to End of the Treatment (Approximately 7.5 years) | 
| Number of Participants With Complete Hematologic Response (Phase II) | 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. | Up to End of the Treatment (Approximately 7.5 years) | 
| Participants With (MMR) Major Molecular Response (Phase II) | 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. | Up to End of the Treatment (Approximately 7.5 years) | 
| Time to Progression (TTP) (Phase II) | 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). | Up to End of the Treatment (Approximately 7.5 years) | 
| Overall Survival (OS) (Phase II) | 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. | Up to End of the Treatment (Approximately 7.5 years) | 
| Number of Participants With Adverse Events and Serious Adverse Events to Evaluate Long Term Safety | 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. | From First Participant First Visit to Last Participant Last Visit (Approximately 7.5 years) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CML in blast crisis, CML in chronic phase, CML in accelerated phase, Gleevec resistance, Gleevec intolerant, Gleevec and CML, imatinib resistance, imatinib intolerant, Hypereosinophilic Syndrome, Systemic Mastocytosis, Chronic eosinophilic syndrome, Philadelphia chromosome positive acute lymphoblastic leukemia, HES, CEL, CML, SM, Ph+ ALL refractory to standard therapy, Ph+ALL relapsed, AMN107A