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

Phase 1

Completed

• Conditions: Adenocarcinoma of the Lung; Non-small Cell Lung Cancer
• Interventions: Drug: erlotinib hydrochloride; Drug: Hsp90 inhibitor AUY922; Other: laboratory biomarker analysis; Procedure: needle biopsy; Genetic: mutation analysis; Other: pharmacological study

• Registration Number: NCT01259089
• Lead Sponsor: Northwestern University

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.

Basic Information
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Recruitment & Eligibility
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Study & Design
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Trial Locations

Study Timeline

• Study First Submitted: 2010-12-10
• Study First Submitted QC: 2010-12-10
• Study First Posted: 2010-12-13
• Study Start: 2011-04-27
• Primary Completion: 2013-06-04
• Study Completion: 2014-09-29
• Status Verified: 2018-10
• Results First Submitted: 2018-10-22
• Results First Submitted QC: 2018-10-24
• Results First Posted: 2018-11-21
• Last Update Submitted: 2019-08-27
• Last Update Posted: 2019-09-11

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 38

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

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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)

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Arm I	laboratory biomarker analysis	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.
Arm I	Hsp90 inhibitor AUY922	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.
Arm I	needle biopsy	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.
Arm I	mutation analysis	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.
Arm I	erlotinib hydrochloride	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.
Arm I	pharmacological 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.

Primary Outcome Measures

Name	Time	Method
Maximally Tolerated Dose (MTD) of AUY922 and Erlotinib Treatment Combination (Phase I)	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	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

Secondary Outcome Measures

Name	Time	Method
Progression-free Survival (Phase II)	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.
Toxicity as Assessed by NCI CTCAE Version 4.00 When AUG922 Administered at Its MTD (Phase I and II)	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
Overall Survival (Phase II)	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.
Incidence of Reported Adverse Events in Phase I	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
Overall Survival Among Patients With Acquired Resistance With T790M Mutations (Phase II)	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.

Trial Locations

Locations (2)

Memorial Sloan-Kettering Cancer Center; 🇺🇸 New York, New York, United States

Northwestern University; 🇺🇸 Chicago, Illinois, United States