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Hsp90 Inhibitor AUY922 and Erlotinib Hydrochloride in Treating Patients With Stage IIIB-IV Non-Small Cell Lung Cancer

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ClinicalTrials.gov Identifier: NCT01259089
Recruitment Status : Completed
First Posted : December 13, 2010
Results First Posted : November 21, 2018
Last Update Posted : September 11, 2019
Sponsor:
Collaborator:
Robert H. Lurie Cancer Center
Information provided by (Responsible Party):
Northwestern University

Tracking Information
First Submitted Date  ICMJE December 10, 2010
First Posted Date  ICMJE December 13, 2010
Results First Submitted Date  ICMJE October 22, 2018
Results First Posted Date  ICMJE November 21, 2018
Last Update Posted Date September 11, 2019
Actual Study Start Date  ICMJE April 27, 2011
Actual Primary Completion Date June 4, 2013   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 27, 2019)
  • Maximally Tolerated Dose (MTD) of AUY922 and Erlotinib Treatment Combination (Phase I) [ Time Frame: During the first 4 weeks of treatment for each patient. ]
    To determine the maximally tolerated dose (MTD), and recommended phase II dose of AUY922 when given in combination with erlotinib for patients with acquired resistance to erlotinib. (Phase I) Escalation of dose will be in a 3+3 design. If no dose limiting toxicities (DLTs) are seen in 3 patients enrolled at that dose level, then dose will be escalated to the next dose level and the next 3 patients will be enrolled at that dose. Alternatively, if 1 DLT is seen in 3 patients at that dose level, 3 more patients will be added at that same dose level. If 1 DLT is seen in 6 patients at that dose level, MTD will be determined to be at that dose. If more than 1 DLT is seen at that dose level, then the prior lower dose level will be the considered the MTD. DLT is defined as any of the following related to the investigational agent: Death and grade 3 and 4 specific hematological and non-hematological toxicities defined in the protocol.
  • Overall Response Rate (ORR), Defined as Complete Response(CR) + Partial Response (PR) Using the Modified RECIST 1.1 Criteria for All Patients Treated at Dose of 70mg/m2 AUG922 [ Time Frame: At 8 weeks from treatment initiation ]
    Overall response rate (ORR) will be measured per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by CT scan or MRI: Complete response (CR) defined as disappearance of all target lesions. Partial Response (PR), defined as >=30% decrease in the sum of the longest diameter of target lesions. Stable Disease (SD) defined as neither sufficient shrinkage to qualify for partial response nor sufficient increase to qualify for progressive disease, taking as reference the smallest sum diameters while on study. Progressive Disease (PD) defined as having at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter recorded since the treatment started or the appearance of one or more new lesions
Original Primary Outcome Measures  ICMJE
 (submitted: December 10, 2010)
  • Maximally tolerated dose (MTD) of AUY922 (Phase I) [ Time Frame: At weeks 1-4 and every 2 weeks thereafter ]
  • Overall response rate (ORR), defined as (CR+PR) using the modified RECIST 1.1 criteria (Phase II) [ Time Frame: At 8 weeks ]
  • Toxicity as assessed by NCI CTCAE version 4.02 (Phase I and II) [ Time Frame: At weeks 1-4 and every 2 weeks thereafter ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: August 27, 2019)
  • Toxicity as Assessed by NCI CTCAE Version 4.00 When AUG922 Administered at Its MTD (Phase I and II) [ Time Frame: At weeks 1 through 4 and then every 2 weeks during treatment and 30 days post last treatment for up to 2 years and half years ]
    To characterize the toxicity profile for the combination of erlotinib and AUY922. Toxicity data will be collected every week for the first 28 day cycle and then every two weeks during treatment and up to 28 days after the last treatment. Adverse events will be graded according to the National Cancer Institute's Common Toxicity Criteria for adverse events version 4.0 (CTCAE v4.0). In general adverse events (AEs) will be graded according to the following: Grade 1 Mild AE Grade 2 Moderate AE Grade 3 Severe AE Grade 4 Life-threatening or disabling AE Grade 5 Death related to AE
  • Incidence of Reported Adverse Events in Phase I [ Time Frame: At weeks 1 through 4 and then every 2 weeks during treatment and 30 days post last treatment, for up to 2 years and half years ]
    Adverse events will be collected weekly for the first 28 day cycle and then every two weeks during treatment and up to 28 days after the last treatment. Adverse events will be graded according to the National Cancer Institute's Common Toxicity Criteria for adverse events version 4.0 (CTCAE v4.0). In general adverse events (AEs) will be graded according to the following: Grade 1 Mild AE Grade 2 Moderate AE Grade 3 Severe AE Grade 4 Life-threatening or disabling AE Grade 5 Death related to AE
  • Progression-free Survival (Phase II) [ Time Frame: From the time of first treatment with AUY922 to disease progression for up to 2 years post treatment ]
    Median Progression Free Survival (PFS) will be calculated from time of treatment initiation until the first documentation of progressive disease. Patients will be considered to have progressive disease when CT scan or MRI show at least a 20% increase in the sum of the 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.
  • Overall Survival (Phase II) [ Time Frame: From the time of first treatment with AUY922 to death, followed up to 2 years post treatment ]
    Overall survival (OS) is defined as the time from treatment initiation until death due to any cause.
  • Overall Survival Among Patients With Acquired Resistance With T790M Mutations (Phase II) [ Time Frame: From the time of first treatment with AUY922 to death, followed for up to 2 years ]
    Overall Survival (OS) will be measured from treatment initiation until death due to any cause for patients with acquired resistance with T790M mutations in the phase II portion of the study.
Original Secondary Outcome Measures  ICMJE
 (submitted: December 10, 2010)
  • Incidence of reported adverse events (Phase I) [ Time Frame: For 28 days following the last dose of study medication ]
  • Progression-free Survival (Phase II) [ Time Frame: From the time of first treatment with AUY922 to disease progression ]
  • Overall Survival (Phase II) [ Time Frame: From the time of first treatment with AUY922 to death ]
  • Overall Survival Among Patients With Acquired Resistance With T790M Mutations (Phase II) [ Time Frame: From the time of first treatment with AUY922 to death ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Hsp90 Inhibitor AUY922 and Erlotinib Hydrochloride in Treating Patients With Stage IIIB-IV Non-Small Cell Lung Cancer
Official Title  ICMJE A Phase I/II Trial of Hsp 90 Inhibitor AUY-922 in Patients With Lung Adenocarcinoma With "Acquired Resistance" to EGFR Tyrosine Kinase Inhibitors
Brief Summary Hsp90 inhibitor AUY922 and erlotinib hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. This phase I/II trial is studying the side effects and best dose of Hsp90 inhibitor AUY922 when given together with erlotinib hydrochloride and to see how well it works in treating patients with stage IIIB-IV non-small cell lung cancer.
Detailed Description This is a phase I, dose-escalation study of Hsp90 inhibitor AUY922 followed by a phase II study. Patients receive Hsp90 inhibitor AUY922 IV over 1 hour once weekly and oral erlotinib hydrochloride once daily. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up periodically.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Adenocarcinoma of the Lung
  • Non-small Cell Lung Cancer
Intervention  ICMJE
  • Drug: erlotinib hydrochloride
    Given orally
    Other Names:
    • CP-358,774
    • erlotinib
    • OSI-774
    • Tarceva
  • Drug: Hsp90 inhibitor AUY922
    Given IV
    Other Name: AUY922
  • Other: laboratory biomarker analysis
    Correlative studies
  • Procedure: needle biopsy
    Undergo image-guided needle biopsy (correlative studies)
    Other Names:
    • aspiration biopsy
    • puncture biopsy
  • Genetic: mutation analysis
    Correlative studies
  • Other: pharmacological study
    Correlative studies
    Other Name: pharmacological studies
Study Arms  ICMJE Experimental: Arm I
Patients receive Hsp90 inhibitor AUY922 IV over 1 hour once weekly and oral erlotinib hydrochloride once daily. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.
Interventions:
  • Drug: erlotinib hydrochloride
  • Drug: Hsp90 inhibitor AUY922
  • Other: laboratory biomarker analysis
  • Procedure: needle biopsy
  • Genetic: mutation analysis
  • Other: pharmacological study
Publications * Johnson ML, Yu HA, Hart EM, Weitner BB, Rademaker AW, Patel JD, Kris MG, Riely GJ. Phase I/II Study of HSP90 Inhibitor AUY922 and Erlotinib for EGFR-Mutant Lung Cancer With Acquired Resistance to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors. J Clin Oncol. 2015 May 20;33(15):1666-73. doi: 10.1200/JCO.2014.59.7328. Epub 2015 Apr 13.

*   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: October 24, 2018)
38
Original Estimated Enrollment  ICMJE
 (submitted: December 10, 2010)
43
Actual Study Completion Date  ICMJE September 29, 2014
Actual Primary Completion Date June 4, 2013   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • All patients must have pathologic evidence of advanced lung adenocarcinoma (stage IIIB or stage IV) confirmed histologically/cytologically at NU, MSKCC, or DFCI and EITHER previous RECIST-defined response (CR or PR) to an EGFR-TKI (erlotinib or gefitinib) or an investigational EGFR TK inhibitor OR a documented mutation in the EGFR gene (G719X, exon 19 deletion, L858R, L861Q)
  • Radiographic progression by RECIST during treatment with erlotinib/gefitinib
  • Received treatment with erlotinib/gefitinib throughout the one month prior to enrollment and at least six months at any time
  • Measurable (RECIST) indicator lesion not previously irradiated
  • Must have undergone a biopsy after the development of acquired resistance
  • Karnofsky Performance Status >= 70% OR ECOG/WHO Performance Status 0-1
  • Signed informed consent
  • Effective contraception and negative serum pregnancy test obtained within two weeks prior to the first administration of AUY922 in all pre-menopausal women (ie., last menstrual period =< 24 months ago) and women < 2 years after onset of menopause; menopause is defined as the time at which fertility ceases, where a woman has had no menstruation for > 24 months
  • Total bilirubin =< 1.5 x Upper Limit of Normal (ULN)
  • AST/SGOT and ALT/SGPT =< 3.0 x ULN, or =< 5.0 x ULN if liver metastasis present
  • Absolute neutrophil count (ANC) >= 1.5 x10^9/L
  • Hemoglobin (Hgb) >= 9g/dL
  • Platelets (plts) >= 100 x 10^9/L
  • Serum creatinine =< 1.5 x ULN or 24 hour clearance >= 50 mL/min

Exclusion Criteria:

  • Symptomatic CNS metastases which are symptomatic and /or requiring escalating doses of steroids
  • Prior treatment with any HSP90 inhibitor compounds
  • Conventional chemotherapy, radiation or monoclonal antibodies within 4 weeks (erlotinib/gefitinib therapy within the past 4 weeks IS allowed)
  • Palliative radiation within 2 weeks
  • Unresolved diarrhea >= CTCAE grade 2
  • Pregnant or lactating women
  • Women of childbearing potential (WCBP) (i.e. women able to become pregnant) not using double-barrier methods of contraception (abstinence, oral contraceptives, intrauterine device or barrier method of contraception in conjunction with spermicidal jelly, or surgically sterile); male patients whose partners are WCBP not using double-barrier methods of contraception
  • Acute or chronic liver or renal disease
  • Other concurrent severe and/or uncontrolled medical conditions that could cause unacceptable safety risks or compromise compliance with the protocol
  • Major surgery =< 2 weeks prior to randomization or who have not recovered from such therapy
  • History (or family history) of long QT syndrome
  • Mean QTc >= 450 msec on baseline ECG
  • History of clinically manifested ischemic heart disease =< 6 months prior to study start
  • History of heart failure or left ventricular (LV) dysfunction (LVEF =< 45%) by MUGA or ECG
  • Clinically significant resting bradycardia (< 50 beats per minute)
  • Clinically significant ECG abnormalities including 1 or more of the following: left bundle branch block (LBBB), right bundle branch block (RBBB) with left anterior hemi-block (LAHB); ST segment elevation or depression > 1mm, or 2nd (Mobitz II), or 3rd degree AV block
  • History ventricular tachycardia
  • Other clinically significant heart disease including congestive heart failure (New York Heart Association class III/IV) or uncontrolled hypertension (> 160/90 despite intensive medical management)
  • Patients who are currently receiving treatment with any medication which has a relative risk of prolonging the QTcF interval and cannot be switched or discontinued to an alternative drug prior to commencing AUY922
  • Known diagnosis of HIV infection (HIV testing is not mandatory)
  • Patients with a history of another primary malignancy that is currently clinically significant or currently requires active intervention
  • Patients who are receiving warfarin (Coumadin®) will be excluded unless =< 2 mg/d, with an INR < 1.5
  • Patients with known disorders due to a deficiency in bilirubin glucuronidation (e.g. Gilbert's syndrome)
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 United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01259089
Other Study ID Numbers  ICMJE NU 10L01
STU00038215 ( Other Identifier: Northwestern University IRB )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Northwestern University
Study Sponsor  ICMJE Northwestern University
Collaborators  ICMJE Robert H. Lurie Cancer Center
Investigators  ICMJE
Principal Investigator: Melissa Johnson Northwestern University
PRS Account Northwestern University
Verification Date October 2018

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