A Phase 4 interventional study of Nilotinib in CML in Chronic Phase, sponsored by Novartis Pharmaceuticals. Completed at 320 sites in 26 countries. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2017-02-24.
Sponsored by Novartis Pharmaceuticals (part of Novartis) · Phase 4, Interventional, and Treatment
This study will assess the efficacy and safety of nilotinib in adult patients with newly diagnosed Philadelphia chromosome positive/BCR-ABL positive chronic myeloid leukaemia in chronic phase. The aim of the study is to confirm the rates of complete molecular remission (CMR) of nilotinib in newly diagnosed CML chronic phase patients in a pan-European population using the EUTOS standardized laboratories.
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Exclusion Criteria:
Other protocol-defined inclusion/exclusion criteria may apply
This was a single-arm study; therefore all participants received nilotinib (AMN107) 300 mg bid given as two 150 mg capsules twice daily.
Drug: Nilotinib
Nilotinib was supplied by Novartis as 150 mg hard gelatin capsules in bottles. Nilotinib was dosed on a flat scale and not dosed by body weight. This form of supply was continued for all participants entered into the core study.
Also known as: AMN107
Percentage of Participants With Molecular Response (MR4^0) at 18 Months
MR4\^0 was defined as either (i) detectable disease ≤ 0.01% BCR-ABL ratio (international scale (IS)) with mean ABL transcripts ≥ 10 000 or (ii) undetectable disease in complementary deoxyribonucleic acid (cDNA) with ≥ 10 000 ABL transcripts.
Time frame: at 18 months
Percentage of Participants Free From Progression to Accelerated Phase/Blast Crisis (AP/BC) at 12 and 24 Months
The following events were considered disease progression to AP/BC: Death due to disease under study; AP, as defined by any of the following: ≥ 15% blasts in the peripheral blood or bone marrow, but \< 30% blasts in both the peripheral blood and bone marrow, ≥ 30% blasts plus promyelocytes in peripheral blood or bone marrow, ≥ 20% basophils in the peripheral blood, Thrombocytopenia (\< 100 × 109/L) that was unrelated to therapy, Evidence of clonal evolution, as determined by medical review with consensus of the SSMC/DMC. BC was defined as: ≥ 30% blasts in peripheral blood or bone marrow, Appearance of extramedullary involvement other than hepatosplenomegaly proven by biopsy.
Time frame: at 12 and 24 months
Rate of Event Free Survival at 12 and 24 Months
EFS was defined as the time from the date of Day 1 (first treatment) + 1 day to the first occurrence of any of the following: Loss of complete hematologic response (CHR), Loss of CCyR, Death from any cause, Progression to the AP or BC of CML, Not achieving CHR up to 3 months (ie, 91 + 15 days), Not achieving CCyR up to 18 months (ie, 548 + 15 days), whichever is earlier.
Time frame: at 12 and 24 months
Percentage of Participants With Major Molecular Response (MMR) at, as Well as by, 12 and 24 Months
MMR was defined as BCR-ABL ratio (IS) ≤ 0.1% in a peripheral blood sample. BCR-ABL1 is an abnormal gene found in chronic myeloid leukemia (CML) and acute lymphoblastic leukemia (ALL). The chromosomal defect in the Philadelphia chromosome is a translocation, in which parts of two chromosomes, 9 and 22, swap places. The result is that a fusion gene is created by juxtapositioning the Abl1 gene on chromosome 9 to a part of the BCR ("breakpoint cluster region") gene on chromosome 22. Depending upon the breakpoints on the BCR gene, there are several forms of fusion proteins.
Time frame: 12 months, 24 months
Percentage of Participants With Complete Cytogenetic Response (CCyR) at, as Well as by, 12 and 24 Months
CCyR parameters were defined as 0% Philadelphia positive (Ph+) metaphases. Loss of CCyR was defined as a patient exceeding the CCyR criteria (ie, \> 0% Ph+ metaphases) at a subsequent visit after the patient had achieved CCyR.
Time frame: 12 and 24 months
Percentage of Participants With Major Cytogenetic Response (MCyR) at, as Well as by, 12 and 24 Months
Major cytogenetic response (MCyR) parameters were defined as 0 to 35% Philadelphia positive (Ph+) metaphases.
Time frame: 12 and 24 months
Percentage of Participants Free From Progression to AP/BC With MR4^0 at 12 Months
The following events were considered disease progression to AP/BC: Death due to disease under study; AP, as defined by any of the following: ≥ 15% blasts in the peripheral blood or bone marrow, but \< 30% blasts in both the peripheral blood and bone marrow, ≥ 30% blasts plus promyelocytes in peripheral blood or bone marrow, ≥ 20% basophils in the peripheral blood, Thrombocytopenia (\< 100 × 109/L) that was unrelated to therapy, Evidence of clonal evolution, as determined by medical review with consensus of the SSMC/DMC. BC was defined as: ≥ 30% blasts in peripheral blood or bone marrow, Appearance of extramedullary involvement other than hepatosplenomegaly proven by biopsy.
Time frame: at 12 months
Percentage of Participants With Event Free Survival in Participants Achieving MR4^0 at 12 Months
EFS was defined as the time from the date of Day 1 (first treatment) + 1 day to the first occurrence of any of the following: Loss of complete hematologic response (CHR), Loss of CCyR, Death from any cause, Progression to the AP or BC of CML, Not achieving CHR up to 3 months (i.e. 91 + 15 days).
Time frame: at 12 months
Percentage of Participants With Progression Free Survival (PFS) at 12 and 24 Months
PFS was defined by the study protocol as the time from the date of start of study drug to the date of earliest progression to AP/BC, or the date of death from any cause.
Time frame: 12 months, 24 months
Rate of Molecular Response (MR4^0) at, as Well as by, 12 and 24 Months
MR4\^0 was defined as either (i) detectable disease ≤ 0.01% BCR-ABL ratio (international scale (IS)) with mean ABL transcripts ≥ 10 000 or (ii) undetectable disease in complementary deoxyribonucleic acid (cDNA) with ≥ 10 000 ABL transcripts.
Time frame: 12 and 24 months
Rate of Molecular Response (MR4^5) at, as Well as by, 12 and 24 Months
MR4\^5 was defined as either (i) detectable disease ≤ 0.0032% BCR-ABL ratio (IS) with mean ABL transcripts ≥ 32 000 or (ii) undetectable disease in cDNA with ≥ 32 000 ABL transcripts).
Time frame: 12 and 24 months
Rate of Complete Hematologic Response (CHR) at, as Well as by, 12 and 24 Months
CHR was defined as all of the following present for ≥ 4 weeks in the peripheral blood: WBC count \< 10 x 109/L, Platelet count \< 450 x 109/L, No circulating peripheral blood blasts, promyelocytes, myelocytes, or metamyelocytes in the peripheral blood, The presence of \< 5% basophils, No evidence of disease-related symptoms and extramedullary disease, including spleen and liver. Loss of CHR was defined as the appearance of any of the following after having achieved a CHR confirmed by a second determination ≥ 4 weeks later (unless associated with progression to AP/BC or death, which was considered to be a confirmed loss of CHR event on its own): WBC count that increased to \> 20.0 x 109/L, Platelet count that increased to ≥ 600 x 109/L, Any palpable spleen, defined as size of spleen below costal margin \> 5 cm, Appearance of \> 5% myelocytes plus metamyelocytes, or any promyelocytes or blasts in the peripheral blood.
Time frame: 12 months, 24 months
Percentage of Participants With Overall Survival at 12 and 24 Months
OS was defined as the time between the date of Day 1 (first treatment) and the date of death from any cause. Deaths which occurred after the 24-month time window and which were occasionally reported by some Investigators were excluded from the analysis. This is in agreement with the protocol stating that patients were to be followed for survival and progression to AP/BC up to 24 months after the participants treatment start.
Time frame: 12 months, 24 months
Rate of Molecular Response (MR4^0) by 18 Months
MR4\^0 was defined as either (i) detectable disease ≤ 0.01% BCR-ABL ratio (international scale (IS)) with mean ABL transcripts ≥ 10 000 or (ii) undetectable disease in complementary deoxyribonucleic acid (cDNA) with ≥ 10 000 ABL transcripts. BCR = Breakpoint Cluster Region gene/BCR gene product BCR-ABL is fusion gene formed from the ABL gene from chromosome 9 fusing with the BCR gene on chromosome 22, the gene product is BCR-ABL tyrosine kinase
Time frame: by 18 months
Rate of Molecular Response (MR4^5) by 18 Months
MR4\^5 was defined as either (i) detectable disease ≤ 0.0032% BCR-ABL ratio (IS) with mean ABL transcripts ≥ 32 000 or (ii) undetectable disease in cDNA with ≥ 32 000 ABL transcripts). BCR = Breakpoint Cluster Region gene/BCR gene product BCR-ABL is fusion gene formed from the ABL gene from chromosome 9 fusing with the BCR gene on chromosome 22, the gene product is BCR-ABL tyrosine kinase
Time frame: by 18 months
Percentage of Participants With Progression Free Survival in Participants Achieving MR4^0 at 12 Months
PFS was defined by the study protocol as the time from the date of start of study drug to the date of earliest progression to AP/BC, or the date of death from any cause.
Time frame: 12 months
| Milestone | Nilotinib |
|---|---|
| Started | 1089 |
| Itt mr (b2a2 &/or b3a2 +ve pts only) | 1056 |
| Itt cyr (ph+ patients only) | 983 |
| Completed | 881 |
| Not completed | 208 |
| Withdrew: Adverse event | 117 |
| Withdrew: Withdrawal by subject | 27 |
| Withdrew: Disease progression | 17 |
| Withdrew: Protocol violation | 11 |
| Withdrew: Lost to follow-up | 9 |
| Withdrew: New cancer therapy | 9 |
| Withdrew: Abnormal laboratory values | 6 |
| Withdrew: Abnormal test procedure results | 4 |
| Withdrew: Administratie problems | 4 |
| Withdrew: Death | 4 |
MR4\^0 was defined as either (i) detectable disease ≤ 0.01% BCR-ABL ratio (international scale (IS)) with mean ABL transcripts ≥ 10 000 or (ii) undetectable disease in complementary deoxyribonucleic acid (cDNA) with ≥ 10 000 ABL transcripts.
| Percentage of Participants | Nilotinib |
|---|---|
| Percentage of Participants With Molecular Response (MR4^0) at 18 Months | 38.3 |
The following events were considered disease progression to AP/BC: Death due to disease under study; AP, as defined by any of the following: ≥ 15% blasts in the peripheral blood or bone marrow, but \< 30% blasts in both the peripheral blood and bone marrow, ≥ 30% blasts plus promyelocytes in peripheral blood or bone marrow, ≥ 20% basophils in the peripheral blood, Thrombocytopenia (\< 100 × 109/L) that was unrelated to therapy, Evidence of clonal evolution, as determined by medical review with consensus of the SSMC/DMC. BC was defined as: ≥ 30% blasts in peripheral blood or bone marrow, Appearance of extramedullary involvement other than hepatosplenomegaly proven by biopsy.
| Percentage of participants | Nilotinib |
|---|---|
| Pts free from progression to AP/BC at 12 months | 99.4 |
| Pts free from progression to AP/BC at 24 months | 99.4 |
EFS was defined as the time from the date of Day 1 (first treatment) + 1 day to the first occurrence of any of the following: Loss of complete hematologic response (CHR), Loss of CCyR, Death from any cause, Progression to the AP or BC of CML, Not achieving CHR up to 3 months (ie, 91 + 15 days), Not achieving CCyR up to 18 months (ie, 548 + 15 days), whichever is earlier.
| Percentage of participants | Nilotinib |
|---|---|
| Percentage of participants with EFS at 12 months | 71.7 |
| Percentage of participants with EFS at 24 months | 69.1 |
MMR was defined as BCR-ABL ratio (IS) ≤ 0.1% in a peripheral blood sample. BCR-ABL1 is an abnormal gene found in chronic myeloid leukemia (CML) and acute lymphoblastic leukemia (ALL). The chromosomal defect in the Philadelphia chromosome is a translocation, in which parts of two chromosomes, 9 and 22, swap places. The result is that a fusion gene is created by juxtapositioning the Abl1 gene on chromosome 9 to a part of the BCR ("breakpoint cluster region") gene on chromosome 22. Depending upon the breakpoints on the BCR gene, there are several forms of fusion proteins.
| Percentage of participants | Nilotinib |
|---|---|
| at 12 months | 56.2 |
| at 24 months | 61.1 |
| by 12 months | 68.8 |
| by 24 months | 80.3 |
CCyR parameters were defined as 0% Philadelphia positive (Ph+) metaphases. Loss of CCyR was defined as a patient exceeding the CCyR criteria (ie, \> 0% Ph+ metaphases) at a subsequent visit after the patient had achieved CCyR.
| Percentage of participants | Nilotinib |
|---|---|
| at 12 months | 72.4 |
| at 24 months | 65.6 |
| By Month 12 | 82.5 |
| By Month 24 | 89.0 |
Major cytogenetic response (MCyR) parameters were defined as 0 to 35% Philadelphia positive (Ph+) metaphases.
| Percentage of participants | Nilotinib |
|---|---|
| at 12 months | 73.8 |
| at 24 months | 66.2 |
| by 12 months | 86.7 |
| by 24 months | 91.4 |
The following events were considered disease progression to AP/BC: Death due to disease under study; AP, as defined by any of the following: ≥ 15% blasts in the peripheral blood or bone marrow, but \< 30% blasts in both the peripheral blood and bone marrow, ≥ 30% blasts plus promyelocytes in peripheral blood or bone marrow, ≥ 20% basophils in the peripheral blood, Thrombocytopenia (\< 100 × 109/L) that was unrelated to therapy, Evidence of clonal evolution, as determined by medical review with consensus of the SSMC/DMC. BC was defined as: ≥ 30% blasts in peripheral blood or bone marrow, Appearance of extramedullary involvement other than hepatosplenomegaly proven by biopsy.
| Percentage of participants | Nilotinib |
|---|---|
| Percentage of Participants Free From Progression to AP/BC With MR4^0 at 12 Months | 100.0 |
EFS was defined as the time from the date of Day 1 (first treatment) + 1 day to the first occurrence of any of the following: Loss of complete hematologic response (CHR), Loss of CCyR, Death from any cause, Progression to the AP or BC of CML, Not achieving CHR up to 3 months (i.e. 91 + 15 days).
| Percentage of participants | Nilotinib |
|---|---|
| Percentage of Participants With Event Free Survival in Participants Achieving MR4^0 at 12 Months | 87.0 |
PFS was defined by the study protocol as the time from the date of start of study drug to the date of earliest progression to AP/BC, or the date of death from any cause.
| Percentage of participants | Nilotinib |
|---|---|
| at 12 months | 99.2 |
| at 24 months | 99.0 |
MR4\^0 was defined as either (i) detectable disease ≤ 0.01% BCR-ABL ratio (international scale (IS)) with mean ABL transcripts ≥ 10 000 or (ii) undetectable disease in complementary deoxyribonucleic acid (cDNA) with ≥ 10 000 ABL transcripts.
| Percentage of participants | Nilotinib |
|---|---|
| at 12 months | 30.7 |
| at 24 months | 40.2 |
| by month 12 | 36.9 |
| by month 24 | 55.0 |
MR4\^5 was defined as either (i) detectable disease ≤ 0.0032% BCR-ABL ratio (IS) with mean ABL transcripts ≥ 32 000 or (ii) undetectable disease in cDNA with ≥ 32 000 ABL transcripts).
| Percentage of participants | Nilotinib |
|---|---|
| at 12 months | 15.2 |
| at 24 months | 21.9 |
| by 12 months | 20.6 |
| by 24 months | 38.4 |
CHR was defined as all of the following present for ≥ 4 weeks in the peripheral blood: WBC count \< 10 x 109/L, Platelet count \< 450 x 109/L, No circulating peripheral blood blasts, promyelocytes, myelocytes, or metamyelocytes in the peripheral blood, The presence of \< 5% basophils, No evidence of disease-related symptoms and extramedullary disease, including spleen and liver. Loss of CHR was defined as the appearance of any of the following after having achieved a CHR confirmed by a second determination ≥ 4 weeks later (unless associated with progression to AP/BC or death, which was considered to be a confirmed loss of CHR event on its own): WBC count that increased to \> 20.0 x 109/L, Platelet count that increased to ≥ 600 x 109/L, Any palpable spleen, defined as size of spleen below costal margin \> 5 cm, Appearance of \> 5% myelocytes plus metamyelocytes, or any promyelocytes or blasts in the peripheral blood.
| Percentage of prticipants | Nilotinib |
|---|---|
| by Month 24 | 89.1 |
| at 12 months | 82.7 |
| at 24 months | 75.5 |
| by Month12 | 86.2 |
OS was defined as the time between the date of Day 1 (first treatment) and the date of death from any cause. Deaths which occurred after the 24-month time window and which were occasionally reported by some Investigators were excluded from the analysis. This is in agreement with the protocol stating that patients were to be followed for survival and progression to AP/BC up to 24 months after the participants treatment start.
| Percentage of participants | Nilotinib |
|---|---|
| at 12 months | 99.6 |
| at 24 months | 98.9 |
MR4\^0 was defined as either (i) detectable disease ≤ 0.01% BCR-ABL ratio (international scale (IS)) with mean ABL transcripts ≥ 10 000 or (ii) undetectable disease in complementary deoxyribonucleic acid (cDNA) with ≥ 10 000 ABL transcripts. BCR = Breakpoint Cluster Region gene/BCR gene product BCR-ABL is fusion gene formed from the ABL gene from chromosome 9 fusing with the BCR gene on chromosome 22, the gene product is BCR-ABL tyrosine kinase
| Percentage of participants | Nilotinib |
|---|---|
| Rate of Molecular Response (MR4^0) by 18 Months | 48.5 |
MR4\^5 was defined as either (i) detectable disease ≤ 0.0032% BCR-ABL ratio (IS) with mean ABL transcripts ≥ 32 000 or (ii) undetectable disease in cDNA with ≥ 32 000 ABL transcripts). BCR = Breakpoint Cluster Region gene/BCR gene product BCR-ABL is fusion gene formed from the ABL gene from chromosome 9 fusing with the BCR gene on chromosome 22, the gene product is BCR-ABL tyrosine kinase
| Percentage of participants | Nilotinib |
|---|---|
| Rate of Molecular Response (MR4^5) by 18 Months | 31.6 |
PFS was defined by the study protocol as the time from the date of start of study drug to the date of earliest progression to AP/BC, or the date of death from any cause.
| Percentage of participants | Nilotinib |
|---|---|
| at 12 months | 99.2 |
| at 24 months | 99.0 |
Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Nilotinib | — | 207/1,089 (19%) | 841/1,089 (77.2%) |
| Event | Nilotinib |
|---|---|
| Atrial fibrillationCardiac disorders | 13/1089 |
| Coronary artery diseaseCardiac disorders | 7/1089 |
| Angina pectorisCardiac disorders | 6/1089 |
| PancreatitisGastrointestinal disorders | 6/1089 |
| PyrexiaGeneral disorders | 6/1089 |
| AnaemiaBlood and lymphatic system disorders | 5/1089 |
| VomitingGastrointestinal disorders | 5/1089 |
| Back painMusculoskeletal and connective tissue disorders | 5/1089 |
| HeadacheNervous system disorders | 5/1089 |
| DyspnoeaRespiratory, thoracic and mediastinal disorders | 5/1089 |
| Event | Nilotinib |
|---|---|
| RashSkin and subcutaneous tissue disorders | 233/1089 |
| PruritusSkin and subcutaneous tissue disorders | 180/1089 |
| HeadacheNervous system disorders | 163/1089 |
| FatigueGeneral disorders | 150/1089 |
| NauseaGastrointestinal disorders | 122/1089 |
| AlopeciaSkin and subcutaneous tissue disorders | 115/1089 |
| NasopharyngitisInfections and infestations | 113/1089 |
| ThrombocytopeniaBlood and lymphatic system disorders | 111/1089 |
| MyalgiaMusculoskeletal and connective tissue disorders | 99/1089 |
| AstheniaGeneral disorders | 97/1089 |
The intent-to-treat (ITT) population consisted of all participants who received at least one dose of study drug.
| Age, Continuous(Years) | Nilotinib |
|---|---|
| Mean | 51.6 ± 14.87 |
| Gender(Participants) | Nilotinib |
|---|---|
| Female | 447 |
| Male | 642 |
| Race/Ethnicity, Customized(Participants) | Nilotinib |
|---|---|
| Caucacian | 1045 |
| Black | 6 |
| Oriental | 5 |
| Native American | 2 |
| Other | 31 |
| Weight at baseline(Kg) | Nilotinib |
|---|---|
| Mean | 77.47 ± 15.730 |
| ECOG performance score(Participants) | Nilotinib |
|---|---|
| No restrictions (0) | 867 |
| Only light work (1) | 199 |
| Only self care (2) | 21 |
| Limited self care (3) | 0 |
| Completely disabled (4) | 0 |
| Missing | 2 |
Showing the first 100 of 320 sites across 26 countries.
This study is completed, as verified in Dec 2016. You cannot join it, but the record below documents what was studied.
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Studies of the drug tested here: Nilotinib