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A Clinical Trial Testing The Efficacy Of Crizotinib Versus Standard Chemotherapy Pemetrexed Plus Cisplatin Or Carboplatin In Patients With ALK Positive Non Squamous Cancer Of The Lung (PROFILE 1014)

This study has been completed.
Sponsor:
ClinicalTrials.gov Identifier:
NCT01154140
First Posted: June 30, 2010
Last Update Posted: November 6, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Information provided by (Responsible Party):
Pfizer
  Purpose
This study will evaluate the anti-cancer effects of crizotinib when compared with standard chemotherapy in patients with ALK positive lung cancer.

Condition Intervention Phase
Non Squamous Lung Cancer Drug: treatment Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase 3, Randomized, Open-label Study Of The Efficacy And Safety Of Crizotinib Versus Pemetrexed/Cisplatin Or Pemetrexed/Carboplatin In Previously Untreated Patients With Non-squamous Carcinoma Of The Lung Harboring A Translocation Or Inversion Event Involving The Anaplastic Lymphoma Kinase (Alk) Gene Locus.

Resource links provided by NLM:


Further study details as provided by Pfizer:

Primary Outcome Measures:
  • Progression-Free Survival (PFS) Based on IRR [ Time Frame: Randomization to objective progression, death or last tumor assessment without progression before any additional anti-cancer therapy (up to 35 months) ]
    PFS was defined as the time from the date of randomization in study until the date of first documented objective tumor progression (according to RECIST v1.1 as determined by IRR) or death (due to any cause), whichever occurred first. PFS (in months) was calculated as (first event date − randomization date +1)/30.44. Objective progression was defined as a 20 percent (%) increase in the sum of the diameters of target measurable lesions taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study), with a minimum absolute increase of 5 millimeter (mm) or clear progression of pre-existing non-target lesions, or the appearance of any new clear lesions.


Secondary Outcome Measures:
  • Overall Survival (OS) [ Time Frame: From randomization to death or last date known alive for those not known to have died (up to 72 months) ]
    OS (in months) was defined as the duration from start of study treatment to date of death due to any cause. OS = (date of death minus the date of randomization of study medication plus 1) divided by 30.4. For participants who were alive, overall survival was censored on last date the participants were known to be alive.

  • Overall Survival Probability at Month 12 and 18 [ Time Frame: Month 12, 18 ]
    Overall survival probability at Month 12 and 18 was defined as the probability of overall survival at 12 and 18 months respectively, where the OS was defined as the duration from date of randomization to date of death due to any cause. The survival probability was estimated using the Kaplan-Meier method.

  • Objective Response Rate (ORR): Percentage of Participants With Objective Response as Assessed by IRR [ Time Frame: Randomization to objective progression, death or last tumor assessment without progression before any additional anti-cancer therapy (up to 35 months) ]
    ORR was defined as percentage of participants with complete response (CR) or partial response (PR) according to RECIST v1.1 determined by IRR. CR was defined as complete disappearance of all target lesions and non-target disease. All nodes, both target and non-target, must decrease to normal (short axis <10 mm). No new lesions and disappearance of all non-target lesions. PR was defined as greater than or equal to (>=) 30% decrease taking as reference the baseline sum of lesion dimensions. The short axis was used in the sum for target nodes, while the longest diameter was used in the sum for all other target lesions. No clear progression of non-target disease. No new lesions.

  • Duration of Response (DR) Based on IRR [ Time Frame: From objective response to date of progression, death or last tumor assessment without progression before any additional anti-cancer therapy (up to 35 months) ]
    DR: time from first documentation of objective tumor response (CR or PR) to first documentation of PD or death due to any cause, whichever occurred first as per RECIST v1.1 determined by IRR. CR: complete disappearance of all target and non-target disease. All nodes, both target and non-target, must decrease to normal (short axis <10 mm). No new lesions, disappearance of all non-target lesions. PR: >=30% decrease taking as reference the baseline sum of lesion dimensions. Short axis was used in sum for target nodes, while longest diameter was used in sum for all or target lesions. No clear progression of non-target disease. No new lesions. c) PD: 20 % increase in the sum of the diameters of target measurable lesions taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study), with a minimum absolute increase of 5 mm or clear progression of pre-existing non-target lesions, or the appearance of any new clear lesions.

  • Time to Tumor Response (TTR) Based on IRR [ Time Frame: Randomization to first documentation of objective tumor response (up to 35 months) ]
    TTR was defined as the time from randomization to first documentation of objective tumor response (CR or PR) according to RECIST v1.1 determined by IRR. CR: complete disappearance of all target lesions and non-target disease. All nodes, both target and non-target, must decrease to normal (short axis <10 mm). No new lesions and disappearance of all non-target lesions. PR: >=30% decrease taking as reference the baseline sum of lesion dimensions. Short axis was used in sum for target nodes, while longest diameter was used in sum for all or target lesions. No clear progression of non-target disease. No new lesions.

  • Percentage of Participants With Disease Control at Week 12 Based on IRR [ Time Frame: Week 12 ]
    Disease control rate at week 12 is defined as the percent of participants with CR, PR, or stable disease (SD) at week 12 according to RECIST v1.1 determined by IRR. The best response of SD would be assigned if SD criteria was met at least once after randomization at a minimum interval of 6 weeks. CR: complete disappearance of all target lesions and non-target disease, with exception of nodal disease. All nodes, both target and non-target, must decrease to normal (short axis <10 mm). No new lesions and disappearance of all non-target lesions. PR: >=30% decrease taking as reference the baseline sum of lesion dimensions. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters. Short axis was used in sum for target nodes, while longest diameter was used in sum for all or target lesions. No clear progression of non-target disease. No new lesions.

  • Time to Progression (TTP) Based on IRR [ Time Frame: Randomization to objective progression or last tumor assessment without progression before any additional anti-cancer therapy (up to 35 months) ]
    TTP was defined as the time from the date of randomization to the date of the first documentation of objective tumor progression according to RECIST v1.1 determined by IRR. Objective tumor progression was defined as 20% increase in the sum of the diameters of target measurable lesions taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study), with a minimum absolute increase of 5 mm or clear progression of pre-existing non-target lesions, or the appearance of any new clear lesions. If tumor progression data included more than 1 date, the first date was used. TTP (in months) was calculated as (first event date − randomization date +1)/30.44.

  • Time to Intracranial Progression (IC-TTP) Based on IRR [ Time Frame: Randomization to objective intracranial progression or last tumor assessment without progression before any additional anti-cancer therapy (up to 35 months) ]
    IC-TTP was defined similarly to TTP, but only considering intracranial disease (excluding extracranial disease) and the progression was determined based on either new brain metastases or progression of existing brain metastases. TTP was defined as the time from the date of randomization to the date of the first documentation of objective tumor progression according to RECIST v1.1 determined by IRR. Objective tumor progression was defined as 20% increase in the sum of the diameters of target measurable lesions taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study), with a minimum absolute increase of 5 mm or clear progression of pre-existing non-target lesions, or the appearance of any new clear lesions.

  • Time to Extracranial Progression (EC-TTP) Based on IRR [ Time Frame: Randomization to objective extracranial progression or last tumor assessment without progression before any additional anti-cancer therapy (up to 35 months) ]
    EC-TTP was defined similarly to TTP, but only considering extracranial disease (excluding intracranial disease) and the progression was determined based on either new extracranial lesions or progression of existing extracranial lesions. TTP was defined as the time from the date of randomization to the date of the first documentation of objective tumor progression according to RECIST v1.1 determined by IRR. Objective tumor progression was defined as 20% increase in the sum of the diameters of target measurable lesions taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study), with a minimum absolute increase of 5 mm or clear progression of pre-existing non-target lesions, or the appearance of any new clear lesions.

  • Percentage of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: Baseline up to follow up period (up to 72 months) ]
    An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. 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 28 days after last dose of study drug that were absent before treatment or that worsened relative to pretreatment state. AEs included both SAEs and non-SAEs.

  • Percentage of Participants With Treatment Emergent Treatment-Related Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: Baseline up to follow up period (up to 72 months) ]
    Treatment-related AE was any untoward medical occurrence attributed to study drug in a participant who received study drug. 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 28 days after last dose of study drug that were absent before treatment or that worsened relative to pre-treatment state. Relatedness to study drug was assessed by the investigator.

  • Percentage of Participants With Adverse Events (AEs) According to Maximum Severity [ Time Frame: Baseline up to follow up period (up to 72 months) ]
    An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. AE was assessed according to maximum severity grading based on National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0. Grade 1 =mild; Grade 2 =moderate; within normal limits, Grade 3 =severe or medically significant but not immediately life-threatening; Grade 4 =life-threatening or disabling; urgent intervention indicated; Grade 5 =death.

  • Plasma Predose Concentration (Ctrough) of Crizotinib and Its Metabolite PF-06260182 [ Time Frame: Predose at Day 1 of Cycle 2, 3 and 5 ]
    Ctrough is the concentration prior to study drug administration on Day 1 of Cycle 2 onwards. PF-06260182 is the metabolite of Crizotinib.

  • Percentage of Participants For Each Anaplastic Lymphoma Kinase (ALK) Gene Fusion Variants [ Time Frame: 28 days prior to day 1 of study treatment ]
    The Response Genetics, Inc. Echinoderm Microtubule Associated Protein Like 4 (EML4) ALK reverse transcriptase polymerase chain reaction (RT PCR) gene fusion test was used for the analysis of tissue samples for the ALK gene fusion variants (either no rearrangement, or 1 of 9 results reflecting 8 specific rearrangements [V1, V2, V3a, V3b,V3a/b, V4, V5a, V6, V7]). Percentage of participants who tested positive for ALK gene fusion variants were reported in this outcome measure.

  • Objective Response Rate (ORR) of Anaplastic Lymphoma Kinase (ALK) Variant Groups Based on IRR [ Time Frame: Randomization to objective progression, death or last tumor assessment without progression before any additional anti-cancer therapy (up to 35 months) ]
    The Response Genetics, Inc. EML4 ALK reverse transcriptase polymerase chain reaction (RT PCR) gene fusion test was used for the analysis of tissue samples for the ALK gene fusion variants (either no rearrangement, or 1 of 9 results reflecting 8 specific rearrangements [V1, V2, V3a, V3b,V3a/b, V4, V5a, V6, V7]). Percentage of participants with confirmed CR or PR according to RECIST v1.1 determined by IRR, by type of ALK gene fusion variant were reported in this outcome measure. CR: complete disappearance of all target lesions and non-target disease. All nodes, both target and non-target, must decrease to normal (short axis <10 mm). No new lesions and disappearance of all non-target lesions. PR: >=30% decrease decrease taking as reference the baseline sum of lesion dimensions. Short axis was used in sum for target nodes, while longest diameter was used in sum for all or target lesions. No clear progression of non-target disease. No new lesions.

  • Time to Deterioration (TTD) in Chest Pain, Dyspnea or Cough [ Time Frame: From randomization of treatment up to deterioration while on study treatment (up to 35 months) ]
    TTD in pain in chest, dyspnea, or cough from the Quality of Life Questionnaire Core 30 (QLQ-LC13) was a composite endpoint defined as the time from randomization to the earliest time the participant's scale scores showed a 10 point or greater increase after baseline in any of the 3 symptoms. For those who had not shown deterioration, the data was censored at the last date when the participants completed an assessment (QLQ-LC13) for pain, dyspnea, or cough or at last visit date prior to crossover for participants randomized to chemotherapy who subsequently crossed over to crizotinib. A 10-point or higher change in the score was perceived by participants as clinically significant. The transformed score of pain, dyspnea, and cough symptom scales of EORTC QLQ-LC13 (European Organization for the Research and Treatment of Cancer) range from 0 to 100, where higher scores indicate greater symptom severity.

  • Change From Baseline in Functioning and Global Quality of Life (QOL) as Assessed by the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC-QLQ-C30) [ Time Frame: Baseline, From Cycle 1 Day 1 up to end of study treatment or crossover to crizotinib arm (up to 35 months) ]
    EORTC QLQ-C30: included 5 functional scales (physical, role, cognitive, emotional and social), global health status/global quality of life scale, 3 symptom scales (fatigue, pain, nausea and vomiting), 6 single items that assess the additional symptoms (dyspnea, appetite loss, sleep disturbance, constipation, diarrhea) and financial difficulties. All scales and single-item measures range from 0 to 100. A high score for a functional scale represents a high/healthy level of functioning, for the global health status/QoL represents a high QoL (better participant state), and for a symptom scale/item represents a high level of symptoms/problems (worse participant state).

  • Change From Baseline Scores in QLQ-C30 Symptoms as Assessed by the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC-QLQ-C30) [ Time Frame: Baseline, From Cycle 1 Day 1 up to end of study treatment or crossover to crizotinib arm (up to 35 months) ]
    EORTC QLQ-C30: included 5 functional scales (physical, role, cognitive, emotional and social), global health status/global quality of life scale, 3 symptom scales (fatigue, pain, nausea and vomiting), 6 single items that assess the additional symptoms (dyspnea, appetite loss, sleep disturbance, constipation, diarrhea) and financial difficulties. All scales and single-item measures range from 0 to 100. A high score for a functional scale represents a high/healthy level of functioning, for the global health status/QoL represents a high QoL (better participant state), and for a symptom scale/item represents a high level of symptoms/problems (worse participant state).

  • Change From Baseline in Lung Cancer Symptom Scores as Assessed by the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire-Lung Cancer 13 (QLQ- LC13) [ Time Frame: Baseline, From Cycle 1 Day 1 up to end of study treatment or crossover to crizotinib arm (up to 35 months) ]
    QLQ-LC13 consists of 1 multi-item scale and 9 single items that assess the specific symptoms (dyspnea, cough, hemoptysis, and site-specific pain), side effects (sore mouth, dysphagia, neuropathy, and alopecia), and pain medication use of patients with lung cancer receiving chemotherapy. All multi-item scales and single-item measures range from 0 to 100, where higher score indicates greater degree of symptom severity.

  • Change From Baseline in General Health Status as Assessed by EuroQol 5D (EQ-5D)- Visual Analog Scale (VAS) [ Time Frame: Baseline, From Cycle 1 Day 1 up to end of study treatment or crossover to crizotinib arm (up to 35 months) ]
    EQ-5D: participant rated questionnaire to assess health-related quality of life in terms of a single index value. VAS component: participants rated their current health state on a scale from 0 (worst imaginable health state) to 100 (best imaginable health state); higher scores indicate a better health.

  • Percentage of Participants With Hospital Admissions-Healthcare Resource Utilization (HCRU) [ Time Frame: Baseline up to follow up period (up to 72 months) ]
    Healthcare resource utilization was to be evaluated using the assessment of the following: date and duration of index admission, duration of hospitalization and date of discharge.

  • Percentage of Participants With Laboratory Test Abnormalities By Maximum Severity: National Cancer Institute Common Terminology Criteria for Adverse Event (Version 4.0) Grade 1 to 4 Hematological Test Abnormalities [ Time Frame: Baseline up to follow up period (up to 72 months) ]
    Anemia(grade[g]1:Less than[<] Lower limit of normal[LLN] to 10gram per[/] deciliter[g/dL],g2:<10 to 8g/dL,g3:<8g/dL,g4:lifethreatening);platelet (g1:<LLN to 75*10^3/millimeter[mm]^3,g2:<75*10^3/mm^3 to 50*10^3/mm^3,g3:<50*10^3/mm^3 to 25*10^3/mm^3,g4:<25*10^3/mm^3);lymphopenia(g1:<LLN to 8*10^2/mm^3,g2:<8*10^2 to 5*10^2/mm^3,g3:<5*10^2 to 2*10^2/mm^3,g4:<2*10^2/mm^3);neutrophil (Absolute)(g1:<LLN to 15*10^2/mm^3,g2:<15*10^2 to 10*10^2/mm^3,g3:<10*10^2 to 5*10^2/mm^3,g4:<5*10^2/mm^3);white blood cell count(g1:<LLN to 3*10^3/mm^3,g2:<3*10^3 to 2*10^3/mm^3,g3:<2*10^3 to 1*10^3/mm^3,g4:<1*10^3/mm^3);hemoglobin(g1:increase in hemoglobin level>0 to 2 g/dL above ULN or above baseline if baseline is above ULN,g2:increase in hemoglobin level>2 to 4g/dL above ULN or above baseline if baseline is above ULN,g3:increase in hemoglobin level>4 g/dL above ULN or above baseline if baseline is above ULN). Only categories with atleast 1 participant with abnormality are reported in this outcome measure.

  • Percentage of Participants With Laboratory Test Abnormalities By Maximum Severity: National Cancer Institute Common Terminology Criteria for Adverse Event (Version 4.0) Grade 1 to 4 Chemistry Test Abnormalities [ Time Frame: Baseline up to follow up period (up to 72 months) ]
    ALT/AST (Grade[g]1:>ULN-3*ULN,g2:>3-5*ULN,g3:>5-20*ULN,g4:>20*ULN);Alkaline Phosphatase (g1:>ULN-2.5*ULN,g2:>2.5-5*ULN,g3:>5-20*ULN,g4:>20*ULN);Creatinine (g1:>ULN-1.5*ULN,g2:>1.5-3*ULN,g3:>3-6*ULN,g4:>6*ULN);hyperglycemia (g1:>ULN-160,g2:>160-250,g3:>250-500,g4:>500mg/dL);bilirubin(total) (g1:>ULN-1.5*ULN,g2:>1.5-3*ULN,g3:>3-10*ULN,g4:>10*ULN);hypoglycaemia (g1:<LLN-55,g2:<55-40,g3:<40-30,g4:<30mg/dL);hyperkalemia (g1:>ULN-5.5,g2:>5.5-6,g3:>6-7,g4:>7mmol/L);hypokalemia (g1:<LLN-3,g2:<LLN-3,g3:<3-2.5,g4:<2.5mmol/L);hypermagnesemia (g1:>ULN-3,g3:>3-8,g4:>8mg/dL);hypocalcemia (g1:<LLN-8,g2:<8-7,g3:<7-6,g4:<6mg/dL); hypercalcemia (g1:>ULN-11.5,g2:>11.5-12.5,g3:>12.5-13.5,g4:>13.5mg/dL);hypomagnesemia (g1:<LLN-1.2,g2:<1.2-0.9,g3:<0.9-0.7,g4:<0.7mg/dL);hyponatremia (g1:<LLN-130,g3:<130-120,g4:<120mmol/L);hypoalbuminemia (g1:<LLN-3,g2:<3-2,g3:<2,g4:lifethreatening);hypophosphatemia (g1:<LLN-2.5,g2:<2.5-2,g3:<2-1,g4:<1mg/dL). Participant>=1 abnormality given.


Enrollment: 343
Actual Study Start Date: January 13, 2011
Study Completion Date: November 30, 2016
Primary Completion Date: November 30, 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: A Drug: treatment
crizotinib 250mg orally continuous twice daily dosing
Active Comparator: B Drug: treatment
pemetrexed 500mg/m2 IV day 1 plus cisplatin 75mg/m2 IV day 1 every 21 days OR pemetrexed 500mg/m2 IV day 1 plus carboplatin AUC 5 or 6 day 1 every 21 days investigator's choice

  Eligibility

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Proven diagnosis of locally advanced not suitable for local treatment, recurrent and metastatic non-squamous cell carcinoma of the lung
  • Positive for translocation or inversion events involving the ALK gene locus
  • No prior systemic treatment for locally advanced or metastatic disease; Patients with brain metastases only if treated and neurologically stable with no ongoing requirement for corticosteroids
  • Evidence of a personally signed and dated informed consent document and willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures including completion of patient reported outcome [PRO] measures.
  • 18 years of age or older with the exception of India which has an upper age limit of 65 years old

Exclusion Criteria:

  • Current treatment on another therapeutic clinical trial.
  • Prior therapy directly targeting ALK.
  • Any of the following within the 3 months prior to starting study treatment: myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass graft, congestive heart failure, or cerebrovascular accident including transient ischemic attack. - - Appropriate treatment with anticoagulants is permitted.
  • Ongoing cardiac dysrhythmias of NCI CTCAE Grade >=2, uncontrolled atrial fibrillation of any grade, or QTc interval >470 msec.
  • Pregnancy or breastfeeding.
  • Use of drugs or foods that are known potent CYP3A4 inducers/inhibitors Concurrent use of drugs that are CYP3A4 substrates with narrow therapeutic indices.
  • Known HIV infection
  • Known interstitial lung disease or interstitial fibrosis
  • Other severe acute or chronic medical conditions (including severe gastrointestinal conditions such as diarrhea or ulcer) or psychiatric conditions, or laboratory abnormalities that would impart, in the judgment of the investigator and/or sponsor, excess risk associated with study participation or study drug administration, and which would, therefore, make the patient inappropriate for entry into this study
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01154140


  Show 249 Study Locations
Sponsors and Collaborators
Pfizer
Investigators
Study Director: Pfizer CT.gov Call Center Pfizer
  More Information

Additional Information:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Pfizer
ClinicalTrials.gov Identifier: NCT01154140     History of Changes
Other Study ID Numbers: A8081014
2010-021336-33 ( EudraCT Number )
XALCORI ( Other Identifier: Alias Study Number )
First Submitted: June 29, 2010
First Posted: June 30, 2010
Results First Submitted: November 26, 2014
Results First Posted: January 5, 2015
Last Update Posted: November 6, 2017
Last Verified: September 2017

Keywords provided by Pfizer:
open label
randomized Phase 3
first line treatment
non squamous lung cancer
ALK translocation event positive

Additional relevant MeSH terms:
Cisplatin
Carboplatin
Pemetrexed
Crizotinib
Antineoplastic Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Folic Acid Antagonists
Nucleic Acid Synthesis Inhibitors
Protein Kinase Inhibitors