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A Phase II, Open Label, Multiple Arm Study of AUY922, BYL719, INC280, LDK378 and MEK162 in Chinese Patients With Advanced Non-small Cell Lung Cancer

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ClinicalTrials.gov Identifier: NCT02276027
Recruitment Status : Completed
First Posted : October 27, 2014
Results First Posted : December 16, 2020
Last Update Posted : December 16, 2020
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Tracking Information
First Submitted Date  ICMJE October 9, 2014
First Posted Date  ICMJE October 27, 2014
Results First Submitted Date  ICMJE October 14, 2020
Results First Posted Date  ICMJE December 16, 2020
Last Update Posted Date December 16, 2020
Actual Study Start Date  ICMJE January 20, 2015
Actual Primary Completion Date October 15, 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: November 20, 2020)
Overall Response Rate (ORR) [ Time Frame: Up to 231 weeks ]
Overall response rate is the proportion of patients with a best overall response of complete response (CR) or partial response (PR) according to Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 criteria (Overall Response (OR) = CR + PR). Complete Response (CR): Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to < 10 mm Partial Response (PR): At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters.
Original Primary Outcome Measures  ICMJE
 (submitted: October 23, 2014)
Overall Response Rate (ORR) [ Time Frame: from the date of treatment until disease progression, up to 1 year ]
ORR (Overall response rate ) of non-small cell lung cancer (NSCLC) patients. Overall response rate is the proportion of patients with a best overall response of complete response (CR) or partial response (PR) according to RECIST 1.1 criteria
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: November 20, 2020)
  • Median Overall Survival (OS) [ Time Frame: Up to 231 weeks ]
    OS is defined as the time from date of randomization/start of treatment to date of death due to any cause.
  • Number of Participants With Progression-free Survival (PFS) [ Time Frame: Up to 231 weeks ]
    PFS event is defined as the first documented progression or death due to any cause according to RECIST 1.1 criteria
  • Disease Control Rate (DCR) [ Time Frame: Up to 231 weeks ]
    DCR is the percentage of patients with a best overall response of complete response (CR) or partial response (PR) or Stable Disease (SD) according to RECIST 1.1 criteria (DCR: CR+PR+SD) Complete Response (CR): Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to < 10 mm Partial Response (PR): At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for PD
  • Median Duration of Overall Response (DOR) [ Time Frame: Up to 231 weeks ]
    Duration of overall response (DOR) is defined as the time from the first documented CR or PR (confirmed by the subsequent assessment) to the date of the first documented progression or death due to underlying cancer.
  • Number of Participants With Adverse Events [ Time Frame: up to 235 weeks ]
    Adverse events were assessed according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. If CTCAE grading does not exist for an adverse event, the severity of mild, moderate, severe, and life-threatening, corresponding to grades 1 - 4, was used.
  • Pharmacokinetics Profile, AUCtau and AUClast [ Time Frame: Day 1 (pre-dose, 0.5, 1, 2, 4, 6, 8 and 24 hours) and Day 15 (pre dose, 0.5, 1, 2, 4, 6, 8 hours post dose and only for BYL719 350 mg QD and LDK378 750 mg QD arms also at 24 hours post dose) ]
    PK parameters are estimated from each individual plasma concentration-time profile using non-compartmental analysis (Phoenix software version 6.2 and above). AUCtau is the AUC calculated to the end of a dosing interval (tau) (amount x time x volume-1) AUClast is the AUC from time zero to the last measurable concentration sampling time (tlast) (mass x time x volume-1) On Cycle 1 Day 1, PK parameters for only BYL719 350 mg QD arm were analyzed
  • Pharmacokinetics Profile, Cmax [ Time Frame: Day 1 (pre-dose, 0.5, 1, 2, 4, 6, 8 and 24 hours) and Day 15 (pre dose, 0.5, 1, 2, 4, 6, 8 hours post dose and only for BYL719 350 mg QD and LDK378 750 mg QD arms also at 24 hours post dose) ]
    PK parameters are estimated from each individual plasma concentration-time profile using non-compartmental analysis (Phoenix software version 6.2 and above). Cmax is the maximum (peak) observed plasma concentration (mass x volume-1) On Cycle 1 Day 1, PK parameters for only BYL719 350 mg QD arm were analyzed
  • Pharmacokinetics Profile, Tmax [ Time Frame: Day 1 (pre-dose, 0.5, 1, 2, 4, 6, 8 and 24 hours) and Day 15 (pre dose, 0.5, 1, 2, 4, 6, 8 hours post dose and only for BYL719 350 mg QD and LDK378 750 mg QD arms also at 24 hours post dose) ]
    PK parameters are estimated from each individual plasma concentration-time profile using non-compartmental analysis (Phoenix software version 6.2 and above). Tmax is the time to reach maximum (peak) plasma concentration (time) On Cycle 1 Day 1, PK parameters for only BYL719 350 mg QD arm were analyzed
Original Secondary Outcome Measures  ICMJE
 (submitted: October 23, 2014)
  • Overall survival of NSCLC patients [ Time Frame: from the date of treatment until death, up to 2 year ]
    Overall survival (OS) of non-small cell lung cancer (NSCLC) patients. OS is defined as the time from date of randomization/start of treatment to date of death due to any cause.
  • Progression-free survival of NSCLC patients [ Time Frame: from the date of treatment until disease progression, up to 1 year ]
    Progression-free survival (PFS) of non-small cell lung cancer (NSCLC) patients. PFS is the time from date of randomization/start of treatment to the date of event defined as the first documented progression or death due to any cause according to RECIST 1.1 criteria
  • Disease control rate of NSCLC patients [ Time Frame: from the date of treatment until disease progression, up to 1 year ]
    Disease control rate (DCR) of non-small cell lung cancer (NSCLC) patients treated with first or second line therapies. DCR is the proportion of patients with a best overall response of CR or PR or SD according to RECIST 1.1 criteria
  • Duration of overall response of NSCLC patients [ Time Frame: from the date of treatment until disease progression, up to 1 year ]
    Duration of overall response (CR or PR) of non-small cell lung cancer (NSCLC) patients. For patients with a CR or PR (which may have to be confirmed the start date is the date of first documented response (CR or PR) and the end date and censoring is defined the same as that for time to progression according to RECIST 1.1 criteria
  • Frequency/severity of adverse events (AEs) [ Time Frame: 30 days post treatment ]
    As a measure of safety and tolerability.
  • Pharmacokinetics profile of AUY922 [ Time Frame: Day 15, Day 16, Day 17 and Day 22 of cycle 1; Day 1 of Cycle 2 and Cycle3, 1 cycle is 28 days ]
    Pharmacokinetics parameters including but not limited to area under the curve (AUC0-t), Maximum plasma concentration after a single dose (Cmax), Peak plasma concentration (Tmax), Median terminal elimination half-life (T1/2), The median accumulation ratio (Racc), Clearance (CL/F) and volume of distribution.
  • Pharmacokinetics profile of BYL719 [ Time Frame: Day 1, Day 2, Day 15 and Day 16 of cycle 1; Day 1 of Cycle 2 and Cycle3, 1 cycle is 28 days ]
    Pharmacokinetics parameters including but not limited to area under the curve (AUC0-t), Maximum plasma concentration after a single dose (Cmax), Peak plasma concentration (Tmax), Median terminal elimination half-life (T1/2), The median accumulation ratio (Racc), Clearance (CL/F) and volume of distribution.
  • Pharmacokinetics profile of INC280 [ Time Frame: Day 15 and Day 16 of cycle 1; Day 1 of Cycle 2 and Cycle3, 1 cycle is 28 days ]
    Pharmacokinetics parameters including but not limited to area under the curve (AUC0-t), Maximum plasma concentration after a single dose (Cmax), Peak plasma concentration (Tmax), Median terminal elimination half-life (T1/2), The median accumulation ratio (Racc), Clearance (CL/F) and volume of distribution.
  • Pharmacokinetics profile of LDK378 [ Time Frame: Day 15 and Day 16 of cycle 1; Day 1 of Cycle 2 and Cycle3, 1 cycle is 28 days ]
    Pharmacokinetics parameters including but not limited to area under the curve (AUC0-t), Maximum plasma concentration after a single dose (Cmax), Peak plasma concentration (Tmax), Median terminal elimination half-life (T1/2), The median accumulation ratio (Racc), Clearance (CL/F) and volume of distribution.
  • Pharmacokinetics profile of MEK162 [ Time Frame: Day 15 and Day 16 of cycle 1; Day 1 of Cycle 2 and Cycle3, 1 cycle is 28 days ]
    Pharmacokinetics parameters including but not limited to area under the curve (AUC0-t), Maximum plasma concentration after a single dose (Cmax), Peak plasma concentration (Tmax), Median terminal elimination half-life (T1/2), The median accumulation ratio (Racc), Clearance (CL/F) and volume of distribution.
  • Frequency/severity of serious adverse events (SAEs) [ Time Frame: 30 days post treatment ]
    As a measure of safety and tolerability.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Phase II, Open Label, Multiple Arm Study of AUY922, BYL719, INC280, LDK378 and MEK162 in Chinese Patients With Advanced Non-small Cell Lung Cancer
Official Title  ICMJE A Phase II, Open Label, Multiple Arm Study of Single Agent AUY922, BYL719, INC280, LDK378 and MEK162 in Chinese Patients With Advanced Non-small Cell Lung Cancer (NSCLC)
Brief Summary

The purpose of this study was to evaluate the anti-tumor activity of single agent BYL719, INC280, LDK378 and MEK162 in advanced NSCLC patients carrying specific molecular alterations.

There is a great unmet medical need in NSCLC patients with advanced or metastatic disease. Novel approaches using targeted therapeutic agents for these patient populations with molecular characterization could potentially identify subsets of advanced NSCLC patients who would benefit from targeted kinase inhibition. Study treatments, BYL719, INC280, LDK378 and MEK162, which target PIK3CA, c-MET, ALK/ROS1 and MEK respectively, have shown promising data in either preclinical or clinical lung cancer settings.

Detailed Description

To enter the screening phase of the study, the subjects' molecular alterations were determined using locally validated methodologies from a newly obtained tumor sample (preferred) or the most recent archival tumor sample available. Based on the molecular alterations of the tumor, subjects were assigned to one of the treatment arms. Subjects with multiple molecular alterations in epidermal growth factor receptor (EGFR) and the relevant pathways were excluded, except under the conditions described in Inclusion criteria.

The treatment period began on Cycle 1 Day 1 and continued in 28-day cycles until disease progression, unacceptable toxicity, withdrawal of informed consent, death or the subject transferred to another Novartis study that could continue to provide the study drug.

All subjects were required to be followed up for 30 days for safety after receiving the last dose of study treatment. Subjects who discontinued study treatment for any reason other than disease progression were followed up for progression of disease. All subjects were required to be followed for survival. For subjects transferred to another Novartis study, an end of treatment visit (EOT) was required to be performed and the subject would not enter the follow-up period.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Adenocarcinoma Lung Cancer; Squamous Cell Lung Carcinoma
Intervention  ICMJE
  • Drug: BYL719
    BYL719 was dosed as 350 mg once daily. On the first day of each cycle, patient received a prescription of adequate drug supply for self-administration at home. The investigator must emphasized compliance and instructed the patient to take BYL719 exactly as prescribed.
  • Drug: INC280
    INC280 was dosed as 600 mg (tablet) or 400mg(Capsule) twice daily. On the first day of each cycle, patient received a prescription of adequate drug supply for self-administration at home. The investigator must emphasized compliance and instructed the patient to takeINC280 exactly as prescribed.
  • Drug: LDK378
    LDK378 was dosed as 750 mg once daily. On the first day of each cycle, patient received a prescription of adequate drug supply for self-administration at home. The investigator must emphasized compliance and instructed the patient to take LDK378 exactly as prescribed.
  • Drug: MEK162
    MEK162 was dosed as 45 mg twice daily. On the first day of each cycle, patient received a prescription of adequate drug supply for self-administration at home. The investigator must emphasized compliance and instructed the patient to take MEK162 exactly as prescribed.
Study Arms  ICMJE
  • Experimental: BYL719 350 mg QD
    Patient's tumor must have molecular alteration of the PIK3CA gene.
    Intervention: Drug: BYL719
  • Experimental: INC280 400 mg BID tab/600 mg BID cap
    Patient's tumor must have molecular alteration of the c-MET gene.
    Intervention: Drug: INC280
  • Experimental: LDK378 750 mg QD
    Patient's tumor must have ALK or ROS1 gene rearrangement.
    Intervention: Drug: LDK378
  • Experimental: MEK162 45 mg BID
    Patient's tumor must have KRAS, NRAS or BRAF mutation.
    Intervention: Drug: MEK162
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: January 17, 2020)
66
Original Estimated Enrollment  ICMJE
 (submitted: October 23, 2014)
115
Actual Study Completion Date  ICMJE October 15, 2019
Actual Primary Completion Date October 15, 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Advanced (stage IIIB or stage IV) NSCLC
  • Must have specific molecular alterations

Exclusion Criteria:

  • Symptomatic central nervous system (CNS) metastases which are neurologically unstable or requiring increasing doses of steroids within the 4 weeks prior to study entry to control their CNS disease
  • Radiation therapy within ≤ 4 weeks prior to study entry, with the exception of limited field palliative radiotherapy for bone pain relief.
  • Any other malignancies within the last 5 years before study entry
  • Major surgery ≤ 2 weeks prior to study entry or who have not recovered from side effects of such therapy
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE China
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02276027
Other Study ID Numbers  ICMJE CINC280X2205
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description:

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

Responsible Party Novartis ( Novartis Pharmaceuticals )
Study Sponsor  ICMJE Novartis Pharmaceuticals
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
PRS Account Novartis
Verification Date November 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP