Approval Probability
TA Base Rate
Adjusted LOA
ML Risk
Also known as Tasigna, Nilotinib Hydrochloride, Nilotinib (AMN107), AMN107
Nilotinib · 31 trials · 25 indications
Centralised assessment of the BCR-ABL transcripts at 12 months since nilotinib initiation
Number of participants who remained in TFR (≥molecular response (MR) 4.0) without molecular relapse 12 months after entering the TFR phase (without re-starting nilotinib therapy) divided by the number of participants who entered the TFR phase and multiplied by 100. Molecular relapse during TFR is defined as the loss of major molecular response (MMR), or the confirmed loss of MR4.0 (defined by 3 consecutive tests less than MR4.0 assessed at 3 consecutive visits during TFR phase). Participants dropping out early from the study during the TFR phase were considered as unsuccessful TFR. Confidence intervals were calculated based on the Exact Clopper-Pearson method. MMR is defined as≥3.0 log reduction in BCR-ABL transcripts compared to the standardized baseline or ≤0.1% BCR-ABL. MR4.0 is defined as either detectable disease≤0.01% BCR-ABL or undetectable disease in cDNA with≥10,000 ABL transcripts
Major molecular response (MMR) was defined as a value of ≤ 0.1% of BCR-ABL ratio on the IS. The minimum number of control genes for a sample to be valid was 3000. For statistical comparison purpose, MMR was considered as a binary variable with patients achieving MMR grouped as 'responders' and patients not achieving MMR, patients with missing PCR evaluations or patients with atypical transcripts at baseline grouped as 'non-responders'. This endpoint was calculated based on the 12 month analysis.
MMR is defined as BCR-ABL ratio (%) on IS \<= 0.1% (corresponds to \>=3 log reduction of BCR-ABL transcripts from standardized baseline value). Clopper-Pearson method
The rate of confirmed best cumulative CMR was defined as the number of participants who had confirmed CMR during the first 12 months of treatment after the randomization date. Participants who achieved confirmed best cumulative CMR during the first 12 months were considered responders. Participants who dropped out early or who did not provide sufficient data for any reason were considered to be non-responders. The definition of CMR is undetectable BCR-ABL (fusion gene formed between bcr gene from chromosome 22 and abl gene from chromosome 9) where BCR-ABL ratio in % international scale (IS) ≤ 0.00001 by real-time quantitative polymerase chain reaction (RQ-PCR) where there was no detectable BCR-ABL and 1) the test had a sensitivity of at least 4.5 logs below the standardized baseline; 2) RQ-PCR negativity was confirmed on the next RQ-PCR sample (usually 3 months later); and 3) the date of confirmed CMR was the date of the first of two negative results with sensitivity \>4.5 logs.
CCyR was assessed from bone marrow samples. CCyr was defined as having 0% Philadelphia positive (Ph+) chromosome metaphases in bone marrow.
PFS was defined as the time from the date of start of treatment to the date of the first documented progression or death due to any cause. Progression is defined as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions
Neither sufficient shrinkage to qualify for Partial Response nor sufficient increase to qualify for Progression Disease, taking as reference the smallest sum of the longest diameter since the treatment started.
The primary efficacy variable was defined as the proportion of patients with a best overall response of CR by Week 16/Month 4 based on local assessment according to RECIST (Version 1.0). This is an at least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum longest diameter.
Complete response (CR) is the Disappearance of all target lesions.
MMR is defined as the percentage of participants in MMR (reduction of ≥ 3 logs in BCR-ABL transcripts compared to the standardized baseline established in IRIS, or ≤ 0.1% BCR-ABL/ABL % by international scale and measured by real-time quantitative polymerase chain reaction (RQ-PCR)) at 12 months.
MMR is defined as the percentage of participants in MMR (reduction of ≥ 3 logs in BCR-ABL transcripts compared to the standardized baseline established in IRIS, or ≤ 0.1% BCR-ABL/ABL % by international scale and measured by real-time quantitative polymerase chain reaction (RQ-PCR)) at 12 months.
Progression-free survival (PFS) is the time from date of randomization to the date of first documented progression or death due to any cause. If a participant has not had an event, progression-free survival is censored at the time of last adequate tumor assessment. Progression is defined according to Modified Response Evaluation Criteria in Solid Tumors (modified RECIST) criteria as at least a 20% increase in the sum of the longest diameter of target lesions, worsening of the non-target lesions or the appearance of one or more new lesions.
PFS is defined as the time from the first date of cross-over to nilotinib therapy from the control arm to the date of the first observation of documented disease progression. Tumor assessment was based on the local investigator's measurement using Modified Response Evaluation Criteria in Solid Tumors (modified RECIST) criteria. Progression is defined according to modified RECIST criteria as at least a 20% increase in the sum of the longest diameter of target lesions, worsening of the non-target lesions or the appearance of one or more new lesions.
MMR is defined as ≤ 0.1% BCR-ABL/control gene (ABL) % by international scale, or equivalent to ≥ 3 log reduction of BCR-ABL transcript from standardized baseline, measured by RQ-PCR (Real time quantitative polymerase chain reaction). BCR-ABL is the fusion gene from breakpoint cluster region and Abelson genes. A patient was counted as having MMR at 6 cycles if the patient met the MMR criteria at the Cycle 6 Visit.
MMR is defined as ≤ 0.1% BCR-ABL/control gene (ABL) % by international scale, or equivalent to ≥ 3 log reduction of BCR-ABL transcript from standardized baseline, measured by RQ-PCR (Real time quantitative polymerase chain reaction). BCR-ABL is the fusion gene from breakpoint cluster region and Abelson genes. A patient was counted as having MMR by 12 cycles if the patient met the MMR criteria at least once at any time between first study drug intake and Cycle 12 visit included.
Cytogenetic response is assessed as the percentage of Philadelphia positive (Ph+) metaphases in the bone marrow. Complete Cytogenetic Response (CCyR) is defined as 0% of Ph+ metaphases. A patient was counted as CCyR at 12 cycles if the patient met the CCyR criteria at the Cycle 12 Visit.
Percentage of particpants without confirmed loss of MMR within 6 months following nilotinib TFR is calculated by dividing the number of patients with no documented confirmed loss of MR4, in the first 6 months after starting nilotinib TFR phase by the number of patients who entered nilotinib TFR phase. Molecular relapse is defined as having a confirmed BCR-ABL ratio above MMR (2 consecutive BCR-ABL levels \>0.1% IS taken approximately 4 weeks apart).
Number of participants with adverse events (AEs) (any AE regardless of seriousness), serious adverse events (SAEs), Fatal SAEs and treatment related AEs.
TFR is defined as no confirmed loss of MR4 (Molecular response 4.0 log reduction from baseline) or loss of MMR (major molecular response) and no re-starting of nilotinib therapy within 12 months following cessation of nilotinib. Confirmed loss of MR4 is two consecutive BCR-ABL \> 0.01% IS. Loss of MMR does not require confirmation.
Major Molecular Response (MMR) was defined as BCR-ABL1\^IS ≤0.1%, on the International Scale \[BCR-ABL1IS\]) by 12 months. BCR is the Breakpoint Cluster Region gene / BCR gene product and ABL is the Abelson proto-oncogene. BCR-ABL is the Fusion gene from BCR and ABL/Protein product from BCR-ABL. Participants who withdrew prematurely or those who failed to provide data for the study for other reasons were designated as premature withdrawal or inevaluable, respectively, and were included in the ITT analysis as non-responders.
ORR was defined as the proportion of participants with a best overall response (BOR) of a confirmed complete response or partial response (CR+PR) determined by Response Evaluation Criteria in Solid Tumors (RECIST v1.0) based on local investigators' assessment (CT/MRI/photography). Per RECIST, CR: disappearance of all target lesions, all non-target lesions, and no new lesion; PR: a \>=30% decrease in the sum of the longest dimensions of the target lesions (TLs) taking as a reference the baseline sum, no unequivocal progression of non-TLs, and no new lesions. For CR or PR, tumor measurements must be confirmed by 2nd assessments at least 4 weeks apart.
Progression was defined by McDonald Criteria: A 25% increase in the sum of products of all measurable lesions over smallest sum observed (over baseline if no decrease) using the same techniques as baseline, OR clear worsening of any evaluable disease, OR appearance of any new lesion/site, OR clear clinical worsening OR failure to return for evaluation due to death or deteriorating condition (unless clearly unrelated to this cancer).
4-month progression-free survival rate was defined as the proportion of patients absent death or progression based on Response Evaluation Criteria In Solid Tumors Criteria (RECIST) before 4 months. Per RECIST 1.0 criteria: progressive disease (PD) is at least a 20% increase in the sum of longest diameter (LD) of target lesions taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. PD for the evaluation of non-target lesions is the appearance of one or more new lesions and/or unequivocal progression of non-target lesions.
Percentage of patients who experienced dose-limiting toxicities associated with Nilotinib as defined by the study protocol.
Occurrence of DLTs during cycle 1
Maximum Tolerated Dose (MTD) of Ruxolitinib with fixed dose of Nilotinib. Dose escalation will follow a 3+3 study design. The CTCAE v4.03 criteria will be used. Grade 4 toxicity will be accounted as dose limiting toxicity (DLT).
Major cytogenetic response defined by 35% or less of Philadelphia chromosomes by metaphase cytogenetics in marrow from CML and ALL patients
Determination of the maximum tolerated dose (MTD) and/or recommended Phase II dose (RP2D) of nilotinib in combination with LDE225
The full PK profiles of nilotinib in pediatric patients were assessed using serial sampling following a single 230 mg/m2 dose on Cycle 1 Day 1.
The full PK profiles of nilotinib in pediatric patients were assessed using serial sampling following a single 230 mg/m2 dose on Cycle 1 Day 1.
The full PK profiles of nilotinib in pediatric patients were assessed using serial sampling following a single 230 mg/m2 dose on Cycle 1 Day 1.
The full PK profiles of nilotinib in pediatric patients were assessed using serial sampling following a single 230 mg/m2 dose on Cycle 1 Day 1.
The steady-state PK profiles of nilotinib in pediatric patients were estimated using trough sampling following multiple 230 mg/m2 bid doses
The steady-state PK profiles of nilotinib in pediatric patients were estimated using trough sampling following multiple 230 mg/m2 bid doses
The full PK profiles of nilotinib in pediatric patients were assessed using serial sampling following a single 230 mg/m2 dose.
Assessed by AE evaluation, including safety laboratory and cardiac safety (ECG, cardiac enzymes, ECHO) measures.
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).
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.
| Arm | Type | Description |
|---|---|---|
| Nilotinib | ACTIVE_COMPARATOR | Control arm, this compound been licensed in this indication. |
| Peg-IFN alfa 2a (Pegasys®) and Nilotinib | EXPERIMENTAL | Arm testing the efficacy of a combination of nilotinib and Peg-IFN alfa 2a as frontline therapy for first line chronic phase CML patients. |
| Nilotinib 24-month treatment | EXPERIMENTAL | Participants were treated with nilotinib 300mg BID for 24 months and, thereafter, entered the 36-month TFR phase |
| Nilotinib 36-month treatment | EXPERIMENTAL | Participants were treated with nilotinib 300mg BID for 36 months and, thereafter, entered the 24-month TFR phase |
| Not randomized | EXPERIMENTAL | Participants were treated with nolotinib 300mg BID for 24 months, but did not achieve a sustained molecular response after 24 months of treatment. |
| Imatinib | ACTIVE_COMPARATOR | - |
| nilotinib 300mg bid (investigating arm) | EXPERIMENTAL | - |
| Nilotinb 400 mg bid (investigating arm) | EXPERIMENTAL | - |
| imatinib 400mg QD (control arm) | EXPERIMENTAL | - |
| Control/cross-over to Nilotinib | ACTIVE_COMPARATOR | In core study phase, patients in this arm received Best Supportive Care (BSC) with or without imatinib or sunitinib at the last tolerated dose or at the investigator's choice until documented disease progression followed by cross-over to nilotinib arm. Patients entering the extension study on this control arm were permitted to cross over to nilotinib arm only upon documented disease progression. |
| Newly diagnosed and untreated Ph+ CML in first CP | EXPERIMENTAL | Diagnosis within 6 months of date of first cytogenetic analysis confirming Philadelphia chromosome with (9;22) translocation by standard conventional cytogenetic analysis. |
| Resistant/intolerant Ph+ CML in CP | EXPERIMENTAL | Resistant or Intolerant to either imatinib or dasatinib |
| Resistant/intolerant Ph+ CML in AP | EXPERIMENTAL | Resistant or intolerant to either imatinib or dasatinib - at the end no patients were enrolled in this arm. |
| Treatment Free Remission | EXPERIMENTAL | Patients entered a monitoring phase for 2 years and received 300 mg nilotinib mg bid. Patients who achieved MR4.5 entered a Consolidation Phase and were treated with nilotinib for 2 years. If MR4.5 was sustained during the Consolidation phase, patients were eligible to stop taking niltoinib during the treatment-free remission (TFR) phase. |
| DTIC | ACTIVE_COMPARATOR | 850 mg/m2 IV every 3 weeks |
| Level 1 | EXPERIMENTAL | Patients in this group will receive 100mg Nilotinib PO BID. |
| Level 2 | EXPERIMENTAL | Patients in this group will receive 200mg Nilotinib PO BID. |
| Level 3 | EXPERIMENTAL | Patients in this group will receive 300mg Nilotinib PO BID. |
| Level 4 | EXPERIMENTAL | Patients in this group will receive 400mg Nilotinib PO BID. |
| Nilotinib and Ruxolitinib | EXPERIMENTAL | The study included two strata, which were to be treated in parallel. The first stratum consisted of CML-patients in CP, which had been on nilotinib treatment before entering the study. These patients did not optimally respond to the previous treatment. The second stratum consisted of patients with CML in AP or BC and patients with relapsed/refractory Ph+ ALL and Ph+ ALL patients with MRD, with or without previous nilotinib treatment. Patients were treated with 300mg nilotinib BID during the escalation phase (12 months) with increasing doses of ruxolitinib. The dose expansion phase (12 months) began following the determination of the MTD of the combination and the decision to explore the cohort for confirmation of RPIID. In this phase, safety and tolerability of the MTD and/or potential RPIID was to be further evaluated, with the purpose of establishing that this dose is suitable for use in this patient group. |
| Nilotinib with Ruxolitinib | EXPERIMENTAL | Nilotinib: Given that recommended dose of Nilotinib for imatinib failed CML patients is 400mg twice daily, Nilotinib dose will remain fixed at 400mg bid throughout the cycles. Ruxolitinib: In the phase I part of the study, dose escalation will follow a 3+3 study design. Dose modifications will not occur, as the purpose of this study is to determine the maximum tolerated dose. Ruxolitinib will be given at one of 3 fixed dose levels for the duration of their treatment, either 10mg twice daily, 15mg twice daily or 20mg twice daily. |
| Nilotinib in conjunction with low dose interferon alfa | EXPERIMENTAL | - |
| Nilotinib + LDE225 | EXPERIMENTAL | The planned dose of nilotinib 400 mg b.i.d (twice a day) was selected for the combination as this is the dose approved for the treatment of the patient population that will be included in the present study. The starting dose for LDE225 chosen for the current study is 400 mg once daily(q.d.). The maximum dose of LDE225 that will be tested in combination with nilotinib is 800 mg once dail.y |
| Group 1 | EXPERIMENTAL | 1 year to \< 10 years pediatric patients with newly diagnosed CP-Ph+ CML, or CP or AP-Ph+ CML resistant/intolerant to imatinib and/or dasatinib, or relapsed/refractory Ph+ ALL (acute lymphoblastic leukemia) treated at the proposed dose of 230 mg/m2 bid. |
| Group 2 | EXPERIMENTAL | \>= 10 years to \<18 years pediatric patients with newly diagnosed CP-Ph+ CML, or CP or AP-Ph+ CML resistant/intolerant to imatinib and/or dasatinib, or relapsed/refractory Ph+ ALL (acute lymphoblastic leukemia) treated at the proposed dose of 230 mg/m2 bid. |
| Monotherapy: AMN107 | EXPERIMENTAL | initial dose of imatinib (dose level 1) was 400 mg bid was administered orally on a continuous daily schedule and was not escalated during the study |
| Combination Therapy: AMN107 + Imatinib | ACTIVE_COMPARATOR | six possible doses of Nilotinib (100 mg once daily (qd), 200 mg qd, 400 mg qd, 200 mg bid, 300 mg bid, and 400 mg bid). four possible doses of Imatinib (0 mg, 400 mg qd, 600 mg qd, and 400 mg bid).the initial dose of nilotinib (dose level 1) was 200 mg qd and could have been escalated up to 400 mg bid |
| CML-CP With Prior Imatinib Only | EXPERIMENTAL | Imatinib-resistant / intolerant PH+ CML-CP patients |
| CML-AP With Prior Imatinib Onl | EXPERIMENTAL | Imatinib-resistant / intolerant PH+ CML-AP patients |
| CML-CP | EXPERIMENTAL | Imatinib-resistant / intolerant PH+ CML-CP patients |
| Name | Type | Description |
|---|---|---|
| Nilotinib (Tasigna ®), capsules of 150 mg | DRUG | Nilotinib 2 capsules of 150 mg orally twice daily at 12 hours difference, fasting (minimum 1 hour before or 2 hours after a meal) for at least 36 months |
| Nilotinib (Tasigna ®) and Pegylated interferon alfa 2a (Pegasys®) | DRUG | * Nilotinib 2 capsules of 150 mg orally twice daily at 12 hours difference, fasting (minimum 1 hour before or 2 hours after a meal) for at least 36 months and * Pegylated interferon alfa 2a subcutaneously once a week (auto-injection syringes of 135 and 90 micrograms) at 30 micrograms/week the first month alone (= priming procedure), then at 30 micrograms/2weeks the first month of combination to nilotinib and then at 45 micrograms/week thereafter until month 24 after nilotinib initiation. |
| Nilotinib | DRUG | Participants received a daily oral nilotinib dose of 300 mg BID, given as two 150 mg capsules BID. |
| Imatinib | DRUG | - |
| Nilotinib (AMN107) | DRUG | - |
| imatinib (STI571) | DRUG | - |
| Best Supportive Care (BSC) +/- imatinib or sunitinib | OTHER | Can include pain medication, localized radiotherapy, nutritional support, and/or oxygen therapy and blood transfusions. Imatinib or sunitinib can be administered at the last tolerated dose and regimen or at the Investigator's choice. |
| DTIC | DRUG | DTIC was supplied locally as sterile powder for i.v. infusion. |
| Nilotinib 100mg | DRUG | Patients will begin dabrafenib (150mg PO BID) and trametinib (2mg PO once daily) or encorafenib (450 mg PO) and binimetinib (45 mg PO BID) on day one and will continue for 28 days. After 7 days, nilotinib will be added at 100mg PO BID and will continue for 21 days. For each subsequent cycle, nilotinib will be given for 28 days. |
| Nilotinib 200mg | DRUG | Patients will begin dabrafenib (150mg PO BID) and trametinib (2mg PO once daily) or encorafenib (450 mg PO) and binimetinib (45 mg PO BID) on day one and will continue for 28 days. After 7 days, nilotinib will be added at 200mg PO BID and will continue for 21 days. For each subsequent cycle, nilotinib will be given for 28 days. |
| Nilotinib 300mg | DRUG | Patients will begin dabrafenib (150mg PO BID) and trametinib (2mg PO once daily) or encorafenib (450 mg PO) and binimetinib (45 mg PO BID) on day one and will continue for 28 days. After 7 days, nilotinib will be added at 300mg PO BID and will continue for 21 days. For each subsequent cycle, nilotinib will be given for 28 days. |
| Nilotinib 400mg | DRUG | Patients will begin dabrafenib (150mg PO BID) and trametinib (2mg PO once daily) or encorafenib (450 mg PO) and binimetinib (45 mg PO BID) on day one and will continue for 28 days. After 7 days, nilotinib will be added at 400mg PO BID and will continue for 21 days. For each subsequent cycle, nilotinib will be given for 28 days. |
| Dabrafenib | DRUG | All patients will begin dabrafenib (150mg PO BID) on day one and will continue for 28 days. |
| Trametinib | DRUG | All patients will begin trametinib (2mg PO once daily) on day one and will continue for 28 days. |
| Encorafenib | DRUG | encorafenib will be administered orally 450mg once daily for 28 consecutive days |
| Binimetinib | DRUG | binimetinib will be administered orally 45mg twice daily for 28 consecutive days |
| Ruxolitinib | DRUG | Ruxolitinib was supplied by Novartis as 5 mg, 15 mg, and 20 mg tablets. Medication labels were in German and complied with the legal requirements of Germany. They included storage conditions for the drug but no information about the patient. The investigator emphasized compliance and instructed the patient to take ruxolitinib exactly as prescribed. |
| Nilotinib, interferon-alfa | DRUG | - |
| Nilotinib + LDE225 | DRUG | Nilotinib is an aminopyrimidine ATP-competitive inhibitor of the protein tyrosine kinaseactivity of BCR-ABL. |
| Tasigna | DRUG | - |
| Nilotinib, Imatinib | DRUG | Nilotinib 50 mg and 200 mg gelatin capsules and Imatinib 100 mg and 400 mg film-coated tablets in bottles.. Medication labels for each study drug complied with the legal requirements of each country, were printed in the local language. |
Inclusion Criteria: * Male and female patients * CP-CML, positive Philadelphia chromosome or positive BCR-ABL (M-bcr transcript), diagnosed less than 3 months prior to study entry * Age of at least 18 years-old and less than 65 years * Patient for whom treatment with Nilotinib is expected * No othe...
Nilotinib is a small molecule oncology drug developed by Novartis AG (ticker NVS). It is studied in chronic myeloid leukemia (CML), including chronic phase CML, as well as gastrointestinal stromal tumor and glioma. Nilotinib is also known by the brand name Tasigna and by the research code AMN107.
Nilotinib is studied for the treatment of chronic myeloid leukemia, including chronic phase CML, and for Philadelphia positive acute lymphoblastic leukemia in patients resistant to tyrosine kinase inhibitor therapy. It has also been evaluated in gastrointestinal stromal tumor and glioma. Nilotinib is an investigational agent in these settings.
Nilotinib targets ABL1 and BCR as a tyrosine kinase inhibitor. By inhibiting these targets, it is designed to interfere with the signaling that drives chronic myeloid leukemia and related Philadelphia chromosome positive leukemias. This mechanism underlies its study in CML and other hematologic malignancies.
Nilotinib is developed by Novartis AG, which trades under the ticker NVS. Novartis is the sponsor behind the clinical program evaluating nilotinib across chronic myeloid leukemia, gastrointestinal stromal tumor, and glioma. The drug is also marketed under the brand name Tasigna.
Nilotinib is in Phase 2 development according to the current program data, and it is an investigational agent still being studied in clinical trials. Its trial record includes Phase 1, Phase 2, and Phase 3 studies. It should not be assumed to be approved for the indications under investigation.
Nilotinib has been studied in nine clinical trials with about 1,947 total participants. Notable studies include NCT02201459, a Phase 3 trial of nilotinib with or without peg-IFN in first line chronic phase CML, and NCT04903119, a recruiting Phase 1 trial in metastatic melanoma with BRAF mutation.
Yes, Tasigna is a brand name for nilotinib. Nilotinib is also known as nilotinib hydrochloride, AMN107, and nilotinib 300 mg or 150 mg capsules. These names refer to the same active drug developed by Novartis, so searches for Tasigna and AMN107 point to nilotinib.