Neoplasms

Blood and Lymph Conditions

All Conditions

Symptoms and General Pathology

Rare Diseases

Leukemia

Leukemia, Myeloid

Leukemia, Myelogenous, Chronic, BCR-ABL Positive

Neoplasms by Histologic Type

Hematologic Diseases

Myeloproliferative Disorders

Bone Marrow Diseases

Chronic Disease

Disease Attributes

Chronic Graft Versus Host Disease

Myeloid Leukemia

Chronic Myeloid Leukemia

Chronic Myeloproliferative Disorders

All Drugs and Chemicals

Nilotinib

Gianantonio Rosti, Pr.

The GIMEMA CML Working Party promotes a multicentre, observational, prospective study of CML patients treated frontline with NIL. Patients will be followed for 5 years. This study will help the definition of guidelines for the treatment of CML patients in early CP.

The primary objective of the study is to describe the stability of molecular response with NIL as frontline therapy in newly diagnosed, unselected, CP CML patients, in an independent, investigator-initiated observational study. Imatinib mesylate (IM), a protein tyrosine kinase inhibitor (TKI) targeting BCR-ABL, has become in the last decade the standard of care for Chronic Myeloid Leukaemia (CML) in chronic phase (CP)1,2. Nilotinib (NIL) is a second generation TKI, effective in IM-resistant and IM-intolerant patients, which demonstrated superior efficacy to IM in early CP BCR-ABL+ CML patients3. Currently, the most important target of the treatment of CML with TKIs is the major molecular response (MMR), defined as a ≥ 3 log reduction in BCR-ABL/ABL transcript level, marker of better long-term outcome. With imatinib therapy, achieving a MMR correlates with an improved probability of a durable cytogenetic remission30. Results from IRIS suggest that a MMR after 12 months of imatinib therapy may be a marker of stable response. Further on, the IRIS study showed that patients with a MMR after 12 months of therapy had a significantly better probability of disease-free survival compared with those in complete cytogenetic remission, but not in MMR31. Moreover, obtaining an undetectable BCR-ABL transcript level is extremely relevant in order to consider TKIs discontinuation. This condition is known as "Complete Molecular Response" (CMR) and is further defined according to the sensitivity achieved (for the definition see the "Criteria of evaluation" section). As far as treatment discontinuation, two experiences have been published so far, aimed at evaluating the persistence of the CMR after imatinib discontinuation. The first was a pilot study32 where 12 patients were included. These 12 patients discontinued imatinib after at least 2 years of CMR (median duration of negativity, 32 months). Six patients displayed a molecular relapse with a detectable BCR-ABL transcript at 1, 1, 2, 3, 4, and 5 months. Imatinib was then reintroduced and led to a novel molecular response. Six other patients (50%) still have an undetectable level of BCR-ABL transcript after a median follow-up of 18 months (range, 9-24 months). The results of this pilot trial have been confirmed and extended in a second trial, the STIM trial33: 100 patients were enrolled, median follow-up 17 months, 69 patients with at least 12 months follow-up: 42 (61%) of these 69 patients relapsed (40 before 6 months, one patient at month 7, and one at month 19). At 12 months, the probability of persistent CMR for these 69 patients was 41% (95% CI 29-52). All patients who relapsed responded to reintroduction of imatinib. An increase of the CMR rate could possibly translate in a higher proportion of patients candidate to stopping anti-CML treatment, with higher probability of remaining disease-free in the long term. The advantages of this possible future scenario could be: first, the possibility of treatment discontinuation at least in patients with chronic clinical adverse events; second, a potential reduction of the costs of TKI treatment (after the introduction of TKI, the costs of CML treatment is increasing year by year, with the increasing prevalence of CML patients). Standardized molecular monitoring has become widely available in Europe through the efforts of EUTOS cooperation19 and now allows for the generation of comparable data on the residual disease using recalculation on the international scale despite these data being analyzed in many different laboratories. These advances in the standardization of molecular responses and the improvement of targeted therapy have allowed for comparable response assessment across Italian Centres and early treatment optimization of patients.

In summary, 1) monitoring of molecular response and of deep and sustained molecular response, provides a straightforward opportunity to assess patients' response and possible prognosis in the use of targeted therapy. 2) Most data on second generation TKIs are from company-sponsored studies generally implemented in selected referral centres. 3) The detailed description of the kinetic of the molecular response and, particularly, the rate of stable MR4, potentially related in turn with a subsequent treatment discontinuation, within the frame of a long-term post-marketing surveillance observational trial offered to all eligible patients followed at a nation-wide, independent multicentre group is the core distinctive feature of this observational trial.

Front-line Nilotinib Treatment of BCR-ABL+ Chronic Myeloid Leukaemia in Chronic Phase

Front-line Nilotinib Treatment of BCR-ABL+ Chronic Myeloid Leukaemia in Chronic Phase. An Observational Multicentre Study of the GIMEMA CML WP.

(at least three PCR results with MR4 within the last year \[± 2 months\] and no results \> 0.01% during the same period).

(at least three PCR results with MR4.5 within the last year \[± 2 months\] and no results \> 0.0032% during the same period)

(for failure \[defined according to ELN recommendations 2009\], intolerance, and death for any reason; not for patients in ≥ MR4 entering clinical trials exploring nilotinib discontinuation)

Gruppo Italiano Malattie EMatologiche dell'Adulto

Immune System Diseases

Precursor Cell Lymphoblastic Leukemia-Lymphoma

Leukemia, Lymphoid

Philadelphia Chromosome

Lymphoma

Lymphoproliferative Disorders

Lymphatic Diseases

Immunoproliferative Disorders

Acute Lymphoblastic Leukemia

Lymphoblastic Lymphoma

Acute Graft Versus Host Disease

Lymphosarcoma

Antineoplastic Agents

Amino Acids

Imatinib Mesylate

Tyrosine Kinase Inhibitors

Protein Kinase Inhibitors

Enzyme Inhibitors

Tyrosine

Imatinib

Michele Baccarani

This proposal, developed in the framework of the GIMEMA, will permit:

* to evaluate the activity and toxicity of imatinib in the treatment of Ph+ acute lymphoblastic leukemia;
* to evaluate the molecular response to the treatment, and to monitor the molecular status of remission in all cases achieving or not a molecular response.

The GIMEMA has activated a network to centralize all biological samples (bone marrow and peripheral blood) at diagnosis from all new ALL patients. This will permit to identify, in particular, Ph + and/or BCR/ABL + cases within 5 days from diagnosis, thus permitting to treat these patients according to different programs on the basis of the presence of Ph chromosome.

Imatinib shows a specific activity for the ABL protein- tyrosine kinase at the in vitro and in vivo level. The compound exerts a direct inhibition on the proliferation of BCR/ABL+ve cells, in cell lines derived from ALL and CML patients, inducing apoptosis. Induction of apoptosis by imatinib was observed also in primary samples of leukemic cells obtained from Ph+ve ALL patients. Since activated BCR/ABL tyrosine kinase is present in nearly all patients with CML and in 25-30% of those with ALL, these two diseases are the ideal targets to verify the potential therapeutic activity of this ABL specific tyrosine kinase inhibitor. So far only limited experiences on the therapeutic benefit of imatinib in ALL patients have been referred. In one of these studies, all 10 treated patients had received prior chemotherapeutic treatment for their leukemia. Imatinib was administered as daily oral therapy and all patients were treated on outpatient basis. Different dosages were tested: 300, 400, 500 mg/day for 28 days. Some responding patients showed prolonged myelosuppression, but only a minority of these required hospitalization, while other side effects appeared acceptable. Although these results demonstrated that Imatinib, as a single agent, is active in BCR/ABL +ve ALL, being able to induce a high response rate, however these responses appeared to be short. This occurred mainly in patients with advanced leukemia, thus it could be hypothesized that early relapse, in these patients, may due to a pre-existing resistance or developed resistance to Imatinib. In vitro studies as well as limited preclinical experiences are showing enhanced antileukemic effects of Imatinib in combination with cytotoxic drugs, thus further clinical trials should be aimed to ascertain, mainly in previously untreated patients, which are the optimal dosage and the best duration of treatment for maximal therapeutic benefit and to test if this agent, combined with conventional chemotherapy, could really enhance its antileukemic activity.

The Gimema Group will run two distinct studies among the same protocol to verify the antileukemic activity and safety of imatinib in Ph+ve and/or BCR/ABL +ve ALL:

Study A: Imatinib as post-consolidation therapy in adult (\>=18 and \<=60 yrs) ALL patients in 1st CHR; Study B: Imatinib without chemotherapy for remission induction in elderly (\>60 years) ALL patients.

This proposal, developed in the framework of the GIMEMA, will include:

1. centralization of all biological samples (bone marrow and peripheral blood) at diagnosis from all new ALL patients, to identify, in particular, Ph + and/or BCR/ABL + cases;
2. evaluation of the molecular response to the treatment, and monitoring the molecular status during the hematological remission in all cases in CR;
3. treatment of all adult patients with the same induction and consolidation treatment already used in the past by GIMEMA for Ph+ ALL, to have also the possibility of an historical control versus patients treated before the "imatinib era".

Study A: Imatinib in Ph +ve and/or BCR/ABL +ve adult (age \<60 years) ALL patients in first CHR after induction and consolidation treatment.

Aimed to verify the activity and safety of STI 571 administered after the induction and consolidation therapy in Ph+ve and/or Bcr/Abl+ve ALL patients in 1st CHR (+CMR). A cohort of 38 patients will be enrolled. All Gimema Centers can join this study. Quantitative Rt-PCR assay is mandatory before start of Imatinib treatment.

Patients will receive on an out-patients basis Imatinib p.o. at the dosage of 400 mg x 2/daily for 6 months. After completing the 6-months therapy, and in absence of safety concerns, patients may receive additional therapy with Imatinib, provided that, in the opinion of investigator, the patient has benefited from treatment.

Study B: Imatinib as induction treatment in newly diagnosed Ph+ and/or Bcr/Abl+ elderly (age \>60 years) ALL patients.

Aimed to verify the activity and safety of Imatinib combined with steroids during the induction phase in elderly (\>60 years) Ph+ve and/or Bcr/Abl+ve ALL patients. A cohort of 53 patients will be enrolled. All Gimema Centers can join this study. The cytogenetic and/or molecular diagnosis must be obtained within 5 days from diagnosis.

Patients will receive Imatinib p.o at the dosage of 400 mg x 2/daily for 30 days on an out-patients basis. After completing induction therapy patients may receive additional therapy with Imatinib, provided that, in the opinion of investigator, the patient benefited from treatment.

STI 571 (GLIVEC) in the Treatment of Adult Acute Lymphoblastic Leukemia

STI 571 (GLIVEC) in the Treatment of Philadelphia-chromosome Positive and/or BCR/ABL Rearranged Adult Acute Lymphoblastic Leukemia. GIMEMA LAL 0201.

Translocation, Genetic

Chromosome Aberrations

Bosutinib

Part 1, starting dose 400 mg oral, daily dosing in the dose-escalation component.

Part 2, 500 mg oral, continuous, daily dosing.

Pfizer CT.gov Call Center

This is an open-label, continuous daily dosing, two-part safety and efficacy study of SKI-606 (bosutinib) in Philadelphia chromosome positive leukemias (Ph+). Part 1 is a dose-escalation study in chronic phase Chronic Myelogenous Leukemia (CML) subjects to establish the maximum tolerated dose (MTD) in this subject population. Part 2 has begun after the completion of Part 1 and after a dose has been established for the compound in chronic phase subjects. Part 2 is a study of the the efficacy of 500mg daily oral SKI-606 (bosutinib) in patients with all phases of Ph+ CML and Ph+ Acute Lymphocytic Leukemia (ALL). The protocol will test the hypotheses that oral daily dosing of bosutinib at 500 mg will attain (1) Major Cytogenetic Response (MCyR) in chronic phase CML patients and (2) Overall Hematological Response (OHR) in advanced leukemia patients. Each phase of the disease will be evaluated as a separate cohort.

Study Evaluating SKI-606 (Bosutinib) In Philadelphia Chromosome Positive Leukemias

A Phase 1/2 Study Of Bosutinib (Ski-606) In Philadelphia Chromosome Positive Leukemias

DLT was defined as any of the following events occurring during the first 28 days of study medication and considered at least possibly-related to study medication: any grade 3 or 4 clinically-relevant non-hematologic toxicity, any clinically-significant grade 2 non-hematologic toxicity that requires 14 days to resolve (to grade 1).

MTD was defined as highest dose level for which no more than 1 participant in a dose cohort experienced DLT. DLT was defined as any of the following events occurring during the first 28 days of study medication and considered at least possibly-related to study medication: any grade 3 or 4 clinically-relevant non-hematologic toxicity, any clinically-significant grade 2 non-hematologic toxicity that requires 14 days to resolve (to grade 1).

NA = not estimable.

Plasma decay half-life is the time measured for the plasma concentration to decrease by one half.

NA = not estimable.

AUC(0-48)= Area under the plasma concentration versus time curve from time zero (pre-dose) to time of last quantifiable concentration (0-48).

AUC is a measure of the serum concentration of the drug over time. It is used to characterize drug absorption.

NA = not estimable.

Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. Clearance was estimated from population pharmacokinetic (PK) modeling. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood.

NA = not estimable.

Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Apparent volume of distribution after oral dose (Vz/F) is influenced by the fraction absorbed.

Maximum plasma concentration over 24 hours at steady state (ss), on Day 15.

Time to reach maximum observed plasma concentration over 24 hours at steady state (ss), on Day 15.

Plasma decay half-life is the time measured for the plasma concentration to decrease by one half. Plasma decay half-life over 24 hours at steady state (ss), on Day 15 was calculated.

AUC is a measure of the serum concentration of the drug over time. It is used to characterize drug absorption. AUC over 24 hours at steady state (ss), on Day 15 was calculated.

Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. Clearance was estimated from population pharmacokinetic (PK) modeling. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood. Apparent oral clearence over 24 hours at steady state (ss), on Day 15 was calculated.

R=accumulation ratio (AUCss on Day 15/AUC0-24 on Day 1)

CyR is based on the prevalence of Ph+ cells. Major cytogenetic response was categorized as either CCyR or partial CyR (PCyR). CCyR was achieved when there was 0 percent (%) Ph+ cells from at least 20 metaphases from conventional bone marrow cytogenetics or less than (\<) 1% positive cells from at least 200 cells analyzed from fluorescent in situ hybridization (FISH). PCyR was achieved when 1 to 35% Ph+ cells were present.

Cytogenetic response (CyR) is based on the prevalence of Philadelphia positive (Ph+) cells. Major cytogenetic response was categorized as either complete cytogenetic response (CCyR) or partial cytogenetic response (PCyR). CCyR was achieved when there was 0% Ph+ cells from at least 20 metaphases from conventional bone marrow cytogenetics or \<1% positive cells from at least 200 cells analyzed from FISH. PCyR was achieved when 1 to 35% Ph+ cells were present.

bcr-Abl is a protein resulting from the transcription of the Philadelphia chromosome following 9:22 chromosomal translocation, and phosphorylation inhibition of which correlates with inhibition of tumor cell growth.

CrkL is a protein, phosphorylation of which has been shown to correlate with CML cell growth; and conversely inhibition of their phosphorylation correlates with inhibition of tumor cell growth. Phosphorylation of CrkL was monitored in whole blood cells, as well as in the cluster of differentiation 3 (CD3+) (T cell), CD19+ (B cell) and CD34+ (blast cell) compartments by using fluorescent activated cell sorter (FACS) flow cytometry.

CrkL is a protein, phosphorylation of which has been shown to correlate with CML cell growth; and conversely inhibition of their phosphorylation correlates with inhibition of tumor cell growth. Phosphorylation of CrkL was monitored in whole blood cells, as well as in the CD3+ (T cell), CD19+ (B cell) and CD34+ (blast cell) compartments by using FACS flow cytometry.

NA = not estimable.

CyR is based on the prevalence of Ph+ cells. MCyR was categorized as either CCyR or PCyR. CCyR was achieved when there was 0% Ph+ cells from at least 20 metaphases from conventional bone marrow cytogenetics or \<1% positive cells from at least 200 cells analyzed from FISH. PCyR was achieved when 1 to 35% Ph+ cells were present.

MCyR was categorized as either CCyR or PCyR. CCyR was achieved when there was 0% Ph+ cells from at least 20 metaphases from conventional bone marrow cytogenetics or \<1% positive cells from at least 200 cells analyzed from FISH. PCyR was achieved when 1 to 35% Ph+ cells were present. The Kaplan-Meier probability of retaining an attained/maintained MCyR at Year 5 is reported. Median durations were not reached as of the minimum follow-up. Duration of response in weeks =(date of confirmed loss of first attained response or last valid cytogenetic assessment for those censored - date of first attained response)/7.

MCyR was categorized as either CCyR or PCyR. CCyR was achieved when there was 0% Ph+ cells from at least 20 metaphases from conventional bone marrow cytogenetics or \<1% positive cells from at least 200 cells analyzed from FISH. PCyR was achieved when 1 to 35% Ph+ cells were present. Time to MCyR was the interval from the date of first dose of study medication until the first date of achieving a given response.

Time to response in weeks equals (=) (event date minus (-) first dose date plus (+) 1)divided (/)7, where the event date is the non-missing date of the first attained response for responders only.

Hematologic response: if participants met all of the following criteria of CHR: White Blood Cells equal to or less than (≤) institutional upper limit of normal, no peripheral blood blasts or promyelocytes, myelocytes+metamyelocytes \<5% in blood, absolute neutrophil count greater than or equal to (≥) 1.0×10\^9 per liter (/L) , platelets ≥100×10\^9/L \& \<450×10\^9/L, \<20% basophils in blood \& no extramedually involvement (including hepato- or splenomegaly), ≤5% BM blasts (ADV only \& applicable to CP if BM aspirate was performed). The duration of CHR was defined as the interval from the first date of response until the first date of confirmed loss of response. Duration of response in weeks =(date of confirmed loss of attained response or last valid hematologic assessment for those censored - date of first confirmed response)/7. The Kaplan-Meier estimate of maintaining CHR at the end of minimum follow-up is presented (CP2L: Year 5; CP3L \& ADV: Year 4). NA = not estimable.

NA = not estimable.

Hematologic response: if participants met all of the following criteria of CHR: White Blood Cells equal to or less than (≤) institutional upper limit of normal, no peripheral blood blasts or promyelocytes, myelocytes+metamyelocytes less than (\<)5% in blood, absolute neutrophil count greater than or equal to (≥) 1.0×10\^9 per liter (/L) , platelets \<450×10\^9/L, platelets ≥100×10\^9/L, \<20% basophils in blood and no extramedually involvement (including hepato- or splenomegaly), ≤5% BM blasts (required for ADV only and applicable to CP if BM aspirate was performed). The duration of CHR was defined as the interval from the first date of response until the first date of confirmed loss of response. Duration of response in weeks =(date of confirmed loss of attained response or last valid hematologic assessment for those censored - date of first confirmed response)/7.

NA = not estimable.

The time to CHR was measured from the date of first dosing to the first date of response. Time to response in weeks = (event date - first dose date plus 1)/7, where the event date is the non-missing date of the first attained response for responders only.

The cumulative incidence of on-treatment progression or death adjusting for the competing risk of treatment discontinuation without the event. Disease progression was determined by the investigator as the reason for treatment discontinuation and death was due to any cause within 30 days of last dose. Duration in months = (date of PD/death or last valid cytogenetic/hematologic assessment if censored - first dose date)/30.4. 95% confidence intervals were calculated using Gray's method.

NA = not estimable. One year = 12 months.

PFS was based on Kaplan-Meier method. Disease progression was determined by the investigator as the reason for treatment discontinuation and death was due to any cause within 30 days of last dose. Duration in months = (date of PD/death or last valid cytogenetic/hematologic assessment if censored - first dose date)/30.4.

NA = not estimable. One year = 12 months

OS was based on Kaplan-Meier method. Survival was defined as the time period from the date of first dose of bosutinib to the date of death or date of last contact for those censored.

NA = not estimable. One year = 12 months.

Hematologic response: if participants met all of the following criteria of CHR: White Blood Cells ≤ institutional upper limit of normal, no peripheral blood blasts or promyelocytes, myelocytes+metamyelocytes \<5% in blood, absolute neutrophil count ≥ 1.0×10\^9/L , platelets \<450×10\^9/L, platelets ≥100×10\^9/L, \<20% basophils in blood and no extramedually involvement (including hepato- or splenomegaly), ≤5% BM blasts (required for ADV only and applicable to CP if BM aspirate was performed).

OHR included CHR, no evidence of leukemia (≤5% bone marrow blasts, no peripheral blood blasts or promyelocytes, \<5% myelocytes + metamyelocytes in blood, white blood cells ≤ institutional upper limit of normal, 450x10\^9/L \> platelets \> 20x10\^9/L, absolute neutrophil count ≥0.5x10\^9/L, \<20% basophils in blood, no extramedullary involvement \[including liver or spleen\]), minor hematologic response (acute lymphoblastic leukemia \[ALL\] patients only, defined as \<15% blasts in marrow \& blood, \<30% blasts + promyelocytes in marrow \& blood, \<20% basophils in peripheral blood \& no extramedullary disease other than spleen \& liver) or return to chronic phase (AP/BP participants, defined as \<15% blasts in both peripheral blood \&bone marrow, \<30% blasts + promyelocytes in both peripheral blood \& bone marrow, \<20% basophils in both peripheral blood \& bone marrow, no extramedullary Involvement other than liver or spleen). Participants had to meet at least 1 criterion.

An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent are events between first dose of study drug and up to 30 days after last dose that were absent before treatment or that worsened relative to pretreatment state.

An AE was any untoward medical occurrence attributed to study drug in a participant who received study drug. The event did not necessarily have a causal relationship with the treatment. PCI AEs included anemia, alanine aminotranferase (ALT), aspartate aminotransferase (AST), cardiac, diarrhea, edema, effusion, gastrointestinal, hemorrhage, hypersensitivity, hypertension, infection, liver, myelosuppression, nausea, neutropenia, rash, renal, thrombocytopenia, vomiting, and vascular events. Duration of AE was calculated as (stop date minus start date) plus 1 for non-missing and non-partial dates.

NA = not estimable.

Laboratory assessments included urinalysis, complete blood count (CBC), prothrombin time/partial prothromboplastin time (PT/PPT), international normalized ratio (INR), blood chemistry and serum pregnancy test (β-HCG). Parameters of special interest included liver function tests and those related to myelosuppression. Potentially clinically important (PCI) laboratory values were defined as National Cancer Institute Common Terminology Criteria for Adverse Events Version 3.0 (NCI CTCAE v3.0) grade 3 or higher. Maximum CTCAE grade, and only participants who shifted to Grade 3/4 on-treatment, are reported.

Criteria for PCI changes in ECG (12-lead) were defined as: no sinus rhythm; PR interval \>=220 msec and increase of \>=20 msec; QRS interval \>=120 msec; QT interval corrected using the Fridericia formula (QTcF) and QT interval corrected using the Bazett formula (QTcB) \>500 msec or increase of \>60 msec; heart rate \<=45 beats per minute (bpm) or \>=120 bpm or decrease/increase of \>=15 bpm.

Number of participants whose chest X-ray results changed (worsened or improved) from the Baseline.

Number of participants taking any non-study medications which were administered from Study Day 1 to 30 days after last dose of study treatment as a management of an AE are reported.

ECOG-PS measured on-therapy (time between first dose and last dose date with a 30-day lag) assessed participant's performance status on 5 point scale: 0=Fully active/able to carry on all pre-disease activities without restriction;1=restricted in physically strenuous activity, ambulatory/able to carry out light or sedentary work;2=ambulatory (\>50% of waking hrs), capable of all self care, unable to carry out any work activities;3=capable of only limited self care, confined to bed/chair \>50% of waking hrs;4=completely disabled, cannot carry on any self care, totally confined to bed/chair;5=dead.

Percentage of participants with PCI physical examinations and vital signs is reported during therapy and at post therapy. Criteria for PCI change in vital signs: heart rate value of \<40 beats per min and value \>150 beats per min, systolic blood pressure (SBP) of \<80 or \>210 millimeter of mercury (mmHg), diastolic blood pressure (DBP) of \<40 or \>130 mmHg, temperature \<32 or \>40 degree centigrade, respiratory rate (Resp) of \<10 or \>50 breaths/min and criteria for PCI change in physical examination: \>=10% increase or decrease of body weight in kilogram (kg).

Percentage of participants with PCI physical examinations and vital signs is reported during therapy and at post therapy. Criteria for PCI change in vital signs: heart rate value of \<40 beats per min and value \>150 beats per min, SBP of \<80 or \>210 mmHg, DBP of \<40 or \>130 mmHg, temperature \<32 or \>40 degree centigrade, Resp of \<10 or \>50 breaths/min and criteria for PCI change in physical examination: \>=10% increase or decrease of body weight in kg. No Ph+ ALL participants were analyzed post-therapy (N=0). Part 1 safety data were originally presented in 2011 and are included as cumulative data in the Part 2 final safety results.

Pfizer

An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study. Part 1 safety data were originally presented in 2011 and are included as cumulative data in the Part 2 final safety results.

Bosutinib 500 mg was administered orally once-daily in participants with CP2L IM-R CML; who had no prior proto-oncogene tyrosine-protein kinase Src, Abl, or Src-Abl inhibitor exposure other than IM.

Bosutinib 500 mg, CP2L-CML IM-R (Part 2)

Bosutinib 500 mg was administered orally once-daily in participants with CP2L IM-I CML; who had no prior proto-oncogene tyrosine-protein kinase Src, Abl, or Src-Abl inhibitor exposure other than IM.

Bosutinib 500 mg, CP2L-CML IM-I (Part 2)

Bosutinib 500 mg was administered orally once-daily in participants with CP3L IM R/I, D and NI R/I or IM R/I and NI-I CML.

Bosutinib 500 mg, CP3L-CML IM R/I, (D+NI) R/I or NI-I (Part 2)

Bosutinib 500 mg was administered orally once-daily in participants with CP3L IM R/I and D-R CML.

Bosutinib 500 mg, CP3L-CML IM R/I + D-R (Part 2)

Bosutinib 500 mg was administered orally once-daily in participants with CP3L IM R/I and D-I CML.

Bosutinib 500 mg, CP3L-CML IM R/I + D-I (Part 2)

Bosutinib 500 mg was administered orally once-daily in participants with CP3L IM R/I and NI-R CML.

Bosutinib 500 mg, CP3L-CML IM R/I + NI-R (Part 2)

All participants who received bosutinib 500 mg orally once daily in AP CML who were IM R/I or multiple tyrosine kinase inhibitor (Multi-TKI): IM, D and/or NI R/I.

AP-CML Total (Part 2)

All participants who received bosutinib 500 mg orally once daily in blast phase (BP) CML who were IM R/I or Multi-TKI: IM, D and/or NI R/I.

BP-CML Total (Part 2)

Bosutinib 500 mg was administered orally once-daily in participants with Ph+ ALL

Bosutinib 500 mg, Ph+ ALL (Part 2)

Total

<18 years

Between 18 and 44 years

Between 45 and 64 years

>=65 years

Age, Customized

Sex: Female, Male

All-treated population - included all enrolled participants who received at least one dose of bosutinib.

Analyses of progression free survival and overall survival was based on all-treated population, instead of evaluable population which was the primary efficacy population as per planned analyses.

Pfizer ClinicalTrials.gov Call Center

Single oral dose of bosutinib 400 mg on Day 1 and then bosutinib 400 mg orally once daily continuously from Day 3 up to Week 4. All participants who completed treatment in Part 1 were continued in CP2L-CML Part 2 of the study.

Bosutinib 400 mg (Part 1)

Single oral dose of bosutinib 500 mg on Day 1 and then bosutinib 500 mg orally once daily continuously from Day 3 up to Week 4. All participants who completed treatment in Part 1 were continued in CP2L-CML Part 2 of the study.

Bosutinib 500 mg (Part 1)

Single oral dose of bosutinib 600 mg on Day 1 and then bosutinib 600 mg orally once daily continuously from Day 3 up to Week 4. All participants who completed treatment in Part 1 were continued in CP2L-CML Part 2 of the study. Eleven participants who completed treatment in Part 1 were continued in CP2L-CML Part 2 of the study and 1 participant was continued in AP-CML Part 2 of the study.

Bosutinib 600 mg (Part 1)

Safety population included all participants who received at least 1 dose of study medication.

Number of Participants With Dose Limiting Toxicity (DLT)

Safety population included all participants who received at least 1 dose of study medication

Maximum Tolerated Dose (MTD)

Evaluable population included all enrolled participants who received at least 1 dose of study medication and had an adequate baseline efficacy assessment.

Maximum Observed Plasma Concentration (Cmax) - Part 1

Evaluable population included all enrolled participants who received at least one dose of study medication and had an adequate baseline efficacy assessment.

Time to Reach Maximum Observed Plasma Concentration (Tmax) - Part 1

Evaluable population included all enrolled participants who received at least 1 dose of study medication and had an adequate baseline efficacy assessment. 'N' (number of participants analyzed) signifies number of participants who were evaluable for this measure.

Plasma Decay Half-Life (t1/2) - Part 1

Area Under the Curve From Time Zero to Last Quantifiable Concentration [AUC(0-48)] - Part 1

Area Under the Concentration-Time Curve (AUC) - Part 1

Apparent Oral Clearance (CL/F) - Part 1

Apparent Volume of Distribution (Vz/F) - Part 1

Maximum Observed Plasma Concentration at Steady State (Cmax,ss) - Part 1

Time to Reach Maximum Observed Plasma Concentration at Steady State (Tmax,ss) - Part 1

Plasma Decay Half-Life at Steady State (t1/2,ss) - Part 1

Area Under the Concentration-Time Curve at Steady State (AUCss) - Part 1

Apparent Oral Clearance at Steady State (CL/F,ss) - Part 1

Accumulation Ratio (R)

Cytogenetic evaluable population included all enrolled participants who received at least one dose of study medication and had an adequate baseline cytogenetic assessment.

Percentage of Participants With MCyR at Week 24 in Chronic Phase Second-line Imatinib Resistant CML Population - Part 2

Cytogenetic evaluable population included all enrolled participants who received at least 1 dose of study medication and had an adequate baseline cytogenetic assessment.

Percentage of Participants With Major Cytogenetic Response (MCyR) - Part 1

Data was not summarized since inadequate data included the issue that molecular transcript analyses could not be performed, because of potential sample quality issues due to time required to transport the specimens from the few investigational sites to the central laboratory.

Phosphorylation Inhibition of Breakpoint Cluster Region-Abelson Kinase (Bcr-Abl) - Part 1

Phosphorylation Inhibition of Crk Like (CrkL) Protein at Baseline - Part 1

Day 1: post-dose (n=1, 1, 9)

Day 8: pre-dose (n=1, 1, 9)

Day 8: post-dose (n=1, 1, 9)

Day 15: pre-dose (n=1, 2, 7)

Day 15: post-dose (n=1, 3, 7)

Evaluable population included all enrolled participants who received at least 1 dose of study medication and had an adequate baseline efficacy assessment. 'N' signifies number of participants who were evaluable for this measure. n=number of participants evaluable for this measure at specified time points for each arm group respectively.

Percent Change From Baseline in Phosphorylation Inhibition of Crk Like Protein (CrkL) at Day 1, 8 and 15 - Part 1

Percentage of Participants With Major Cytogenetic Response (MCyR) in Chronic Phase Second-line and Chronic Phase Third-line CML Population - Part 2

Subgroup of participants from evaluable population who had MCyR.

Kaplan-Meier Estimate of Retaining an Attained/Maintained Major Cytogenetic Response (MCyR) at Year 5 in Chronic Phase Second-line CML - Part 2

Time to Achieve Major Cytogenetic Response (MCyR) in Chronic Phase Second-line CML for Responders Only - Part 2

Bosutinib 500 mg was administered orally once-daily in participants with AP IM R/I CML; who had no prior proto-oncogene tyrosine-protein kinase Src, Abl, or Src-Abl inhibitor exposure other than IM.

Bosutinib 500 mg, AP-CML IM R/I (Part 2)

Bosutinib 500 mg was administered orally once-daily in participants with AP Multi-TKI: IM, D and/or NI R/I CML.

Bosutinib 500 mg, AP-CML Multi-TKI R/I (Part 2)

Bosutinib 500 mg was administered orally once-daily in participants with BP IM R/I CML ; who had no prior proto-oncogene tyrosine-protein kinase Src, Abl, or Src-Abl inhibitor exposure other than IM.

Bosutinib 500 mg, BP-CML IM R/I (Part 2)

Bosutinib 500 mg was administered orally once-daily in participants with BP Multi-TKI: IM, D and/or NI R/I CML.

Bosutinib 500 mg, BP-CML Multi-TKI R/I (Part 2)

Subgroup of participants from evaluable population who had confirmed CHR.

Kaplan-Meier Estimate of Maintaining Complete Hematologic Response (CHR) at Year 4 (CP3L and ADV) or Year 5 (CP2L) - Part 2

Duration of Complete Hematologic Response (CHR) - Part 2

Hematologic evaluable population included all enrolled participants who received at least one dose of study medication and had an adequate baseline hematologic assessment - responders only.

Time to Achieve Complete Hematologic Response (CHR) for Responders Only - Part 2

Year 1

Year 2

Year 3

Year 4

Year 5

All-treated population included all enrolled participants who received at least one dose of study medication.

Cumulative Incidence of Progression/Death - Part 2

Progression Free Survival (PFS) - Part 2

All-treated population included all enrolled participants who received at least 1 dose of study medication.

Kaplan-Meier Estimate of Overall Survival (OS) - Part 2

Overall Survival (OS) - Part 2

Hematologic evaluable population included all enrolled participants who received at least one dose of study medication and had an adequate baseline hematologic assessment.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Front-line Nilotinib Treatment of BCR-ABL+ Chronic Myeloid Leukaemia in Chronic Phase	NCT01699217	Chronic Phase P... BCR-ABL Positiv... Chronic Myeloid...		18 Years -	Gruppo Italiano Malattie EMatologiche dell'Adulto
STI 571 (GLIVEC) in the Treatment of Adult Acute Lymphoblastic Leukemia	NCT00376467	Acute Lymphobla...	Imatinib	18 Years -	Gruppo Italiano Malattie EMatologiche dell'Adulto
Front-line Nilotinib Treatment of BCR-ABL+ Chronic Myeloid Leukaemia in Chronic Phase	NCT01699217	Chronic Phase P... BCR-ABL Positiv... Chronic Myeloid...		18 Years -	Gruppo Italiano Malattie EMatologiche dell'Adulto
Study Evaluating SKI-606 (Bosutinib) In Philadelphia Chromosome Positive Leukemias	NCT00261846	Chronic Myeloid...	Bosutinib	18 Years -	Pfizer
Nilotinib and LDE225 in the Treatment of Chronic or Accelerated Phase Myeloid Leukemia in Patients Who Developed Resistance to Prior Therapy	NCT01456676	Philadelphia Ch...	Nilotinib + LDE...	18 Years -	Novartis
Nilotinib as First-line Treatment of Ph+ CML in Early Chronic Phase	NCT00481052	Chronic Myeloid...	Nilotinib	18 Years -	Gruppo Italiano Malattie EMatologiche dell'Adulto
Study Evaluating SKI-606 (Bosutinib) In Philadelphia Chromosome Positive Leukemias	NCT00261846	Chronic Myeloid...	Bosutinib	18 Years -	Pfizer
STI 571 (GLIVEC) in the Treatment of Adult Acute Lymphoblastic Leukemia	NCT00376467	Acute Lymphobla...	Imatinib	18 Years -	Gruppo Italiano Malattie EMatologiche dell'Adulto
Efficacy of 400 Mg Versus 800 Mg Imatinib in Chronic Myeloid Leukemia in Chronic Phase Patients - TOPS (Tyrosine Kinase Inhibitor Optimization and Selectivity)	NCT00124748	Leukemia, Myelo...	Imatinib mesyla...	18 Years - 75 Years	Novartis
Phase II Front-line Ponatinib in Adult Philadelphia+/BCR-ABL+ Acute Lymphoblastic Leukemia.	NCT01641107	Philadelphia Po... BCR-ABL Positiv... Acute Lymphobla...	Ponatinib	18 Years -	Incyte Corporation

Spots Global Cancer Trial Database for philadelphia positive