Acute Lymphoblastic Leukemia (Philadelphia Chromosome Positive), Chronic Myelogenous Leukemia, Hypereosinophilic Syndrome, Systemic Mastocytosis
Conditions
Keywords
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
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)
Interventions
DRUGNilotinib
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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). |
| 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). |
| 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. |
| 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. |
| 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. |
Countries
Australia, Austria, Belgium, Canada, Denmark, Finland, France, Germany, Hong Kong, Italy, Netherlands, New Zealand, Norway, Poland, Singapore, South Korea, Spain, Sweden, Switzerland, Taiwan, United Kingdom, United States
Participant flow
Recruitment details
The study was conducted at 100 centers in 22 countries.
Pre-assignment details
A total of 507 participants were randomized in the core study, out of which 136 participants entered the extension study.
Participants by arm
| Arm | Count |
|---|---|
| CML-CP With Prior Imatinib Only Adult participants PH+ CML-CP without prior TKI treatment with either resistant / intolerant to Imatinib received 400 mg Nilotinib orally twice daily up to the end of treatment (September-2012). | 321 |
| CML-AP With Prior Imatinib Only Adult participants PH+ CML-AP without prior TKI treatment with either resistant / intolerant to Imatinib received 400 mg Nilotinib orally twice daily up to the end of treatment (September-2012). | 137 |
| CML-CP Adult participants PH+ CML-CP in addition to prior TKI treatment with either resistant / intolerant to Imatinib received 400 mg Nilotinib orally twice daily up to the end of treatment (September-2012). | 49 |
| Total | 507 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Abnormal laboratory values | 1 | 0 | 0 |
| Overall Study | Administrative problems | 2 | 0 | 1 |
| Overall Study | Adverse Event | 10 | 2 | 3 |
| Overall Study | Death | 4 | 0 | 0 |
| Overall Study | Discontinued in core study without entering the extension study | 215 | 122 | 34 |
| Overall Study | Disease progression | 12 | 4 | 3 |
| Overall Study | Lost to Follow-up | 3 | 0 | 0 |
| Overall Study | Patient withdrew consent | 6 | 1 | 0 |
| Overall Study | Protocol Violation | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | CML-CP With Prior Imatinib Only | CML-AP With Prior Imatinib Only | CML-CP | Total |
|---|---|---|---|---|
| Age, Customized ≥35 to <55 years | 104 Participants | 49 Participants | 16 Participants | 169 Participants |
| Age, Customized <35 years | 22 Participants | 8 Participants | 3 Participants | 33 Participants |
| Age, Customized ≥55 to <65 years | 97 Participants | 39 Participants | 12 Participants | 148 Participants |
| Age, Customized ≥65 years | 98 Participants | 41 Participants | 18 Participants | 157 Participants |
| Sex: Female, Male Female | 159 Participants | 61 Participants | 25 Participants | 245 Participants |
| Sex: Female, Male Male | 162 Participants | 76 Participants | 24 Participants | 262 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 13 / 321 | 14 / 137 | 0 / 49 |
| other Total, other adverse events | 319 / 321 | 136 / 137 | 48 / 49 |
| serious Total, serious adverse events | 146 / 321 | 55 / 137 | 21 / 49 |
Outcome results
Primary
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.
Time frame: Up to End of the Treatment (Approximately 7.5 years)
Population: Full Analysis Set (FAS): All participants who received at least one dose of study medication.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| CML-CP With Prior Imatinib Only | Number of Participants Confirmed Overall Hematological Response (Phase II) | 76 Participants |
Primary
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).
Time frame: Up to End of the Treatment (Approximately 7.5 years)
Population: Full Analysis Set (FAS): All participants who received at least one dose of study medication
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| CML-CP With Prior Imatinib Only | Number of Participants With Major Cytogenetic Response (MCyR) | 191 Participants |
| CML-AP With Prior Imatinib Only | Number of Participants With Major Cytogenetic Response (MCyR) | 44 Participants |
| CML-CP | Number of Participants With Major Cytogenetic Response (MCyR) | 22 Participants |
Secondary
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.
Time frame: From First Participant First Visit to Last Participant Last Visit (Approximately 7.5 years)
Population: Safety set: All participants who received at least one dose of study medication and had at least one post baseline safety assessment.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| CML-CP With Prior Imatinib Only | Number of Participants With Adverse Events and Serious Adverse Events to Evaluate Long Term Safety | Serious Adverse Events | 61 Participants |
| CML-CP With Prior Imatinib Only | Number of Participants With Adverse Events and Serious Adverse Events to Evaluate Long Term Safety | Adverse Events | 57 Participants |
| CML-AP With Prior Imatinib Only | Number of Participants With Adverse Events and Serious Adverse Events to Evaluate Long Term Safety | Serious Adverse Events | 26 Participants |
| CML-AP With Prior Imatinib Only | Number of Participants With Adverse Events and Serious Adverse Events to Evaluate Long Term Safety | Adverse Events | 17 Participants |
| CML-CP | Number of Participants With Adverse Events and Serious Adverse Events to Evaluate Long Term Safety | Serious Adverse Events | 5 Participants |
| CML-CP | Number of Participants With Adverse Events and Serious Adverse Events to Evaluate Long Term Safety | Adverse Events | 7 Participants |
Secondary
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.
Time frame: Up to End of the Treatment (Approximately 7.5 years)
Population: Full Analysis Set (FAS): All participants who received at least one dose of study medication
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| CML-CP With Prior Imatinib Only | Number of Participants With Complete Hematologic Response (Phase II) | 158 participants |
| CML-AP With Prior Imatinib Only | Number of Participants With Complete Hematologic Response (Phase II) | 76 participants |
| CML-CP | Number of Participants With Complete Hematologic Response (Phase II) | 27 participants |
Secondary
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).
Time frame: Up to End of the Treatment (Approximately 7.5 years)
Population: Full Analysis Set (FAS): All participants who received at least one dose of study medication
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| CML-CP With Prior Imatinib Only | Number of Participants With Overall Major Cytogenetic Responses (Phase II) | 191 participants |
| CML-AP With Prior Imatinib Only | Number of Participants With Overall Major Cytogenetic Responses (Phase II) | 44 participants |
| CML-CP | Number of Participants With Overall Major Cytogenetic Responses (Phase II) | 22 participants |
Secondary
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.
Time frame: Up to End of the Treatment (Approximately 7.5 years)
Population: Full Analysis Set (FAS): All participants who received at least one dose of study medication.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| CML-CP With Prior Imatinib Only | Overall Survival (OS) (Phase II) | NA months |
| CML-AP With Prior Imatinib Only | Overall Survival (OS) (Phase II) | 47.54 months |
| CML-CP | Overall Survival (OS) (Phase II) | NA months |
Secondary
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.
Time frame: Up to End of the Treatment (Approximately 7.5 years)
Population: Full Analysis Set (FAS): All participants who received at least one dose of study medication.~Major molecular response was not an efficacy variable for participants who received the CML-CP with prior imatinib and other TKI (Group B E8)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| CML-CP With Prior Imatinib Only | Participants With (MMR) Major Molecular Response (Phase II) | 106 Participants |
| CML-AP With Prior Imatinib Only | Participants With (MMR) Major Molecular Response (Phase II) | 18 Participants |
Secondary
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).
Time frame: Up to End of the Treatment (Approximately 7.5 years)
Population: Full Analysis Set (FAS): All participants who received at least one dose of study medication.~Time to progression was not an efficacy variable for participants who received the CML-CP with prior imatinib and other TKI (Group B E8).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| CML-CP With Prior Imatinib Only | Time to Progression (TTP) (Phase II) | 55.6 Months |
| CML-AP With Prior Imatinib Only | Time to Progression (TTP) (Phase II) | 15.9 Months |