Neoplasms

Respiratory Tract (Lung and Bronchial) Diseases

All Conditions

Symptoms and General Pathology

Lung Neoplasms

Carcinoma, Non-Small-Cell Lung

Recurrence

Carcinoma

Respiratory Tract Neoplasms

Thoracic Neoplasms

Lung Diseases

Respiratory Tract Diseases

Carcinoma, Bronchogenic

Bronchial Neoplasms

Antineoplastic Agents

All Drugs and Chemicals

Micronutrients

Hematinics

Vitamins

Pemetrexed

Enzyme Inhibitors

Folic Acid

Vitamin B Complex

Folic Acid Antagonists

Folinic Acid

Folate

Vitamin B9

Patients receive Hsp90 inhibitor AUY922 IV over 60 minutes weekly and pemetrexed disodium IV over 15 minutes every 3 weeks. Courses repeat every 21 days for 6 months in the absence of disease progression or unacceptable toxicity.

Hsp90 inhibitor AUY922

pemetrexed disodium

pharmacological study

laboratory biomarker analysis

Edward Garon

This phase I trial studies the side effects and the best dose of Hsp90 inhibitor AUY922 when given together with pemetrexed disodium in treating patients with previously treated stage IV non-small cell lung cancer. Hsp90 inhibitor AUY922 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as pemetrexed disodium, work in different ways to stop the growth of tumor cell, either by killing the cells or stopping them from dividing. Giving Hsp90 inhibitor AUY922 together with pemetrexed disodium may kill more tumor cells

PRIMARY OBJECTIVES:

I. Evaluate the safety and tolerability of escalating doses of AUY922 (Hsp90 inhibitor AUY922) when given with pemetrexed (pemetrexed disodium) 500 mg/m\^2 in participants with previously-treated stage IV non-squamous, non-small cell lung cancer (NSCLC).

SECONDARY OBJECTIVES:

I. Determine the objective tumor response rate as defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria in participants with previously treated non-squamous NSCLC treated with pemetrexed and AUY922.

II. Evaluate the pharmacokinetic profile of pemetrexed and AUY922. III. Evaluate toxicity, including visual toxicity, in participants treated with AUY922 and pemetrexed.

IV. Analyze tumor-tissue biomarkers for potential correlation with response.

OUTLINE: This is a dose-escalation study of Hsp90 inhibitor AUY922.

Patients receive Hsp90 inhibitor AUY922 intravenously (IV) over 60 minutes weekly and pemetrexed disodium IV over 15 minutes every 3 weeks. Courses repeat every 21 days for 6 months in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days.

Pemetrexed Disodium and Hsp90 Inhibitor AUY922 in Treating Patients With Previously Treated Stage IV Non-Small Cell Lung Cancer

A Phase IB Dose-Escalation Study of Pemetrexed and AUY922 in Previously-Treated Patients With Metastatic Non-Squamous, Non-Small Cell Lung Cancer

Safety will be assessed through tabulation, grading and attribution of serious adverse events (SAEs) and AEs.

The proportion of ever achieving a clinical response will be estimated and constructed with an exact one-sided 90% confidence interval to identify the likely range for the underlying tumor response rate. Clinical response will be correlated with biomarkers using a variety of analytic techniques.

Translational Research in Oncology

Novartis

Jonsson Comprehensive Cancer Center

Rare Diseases

Adenocarcinoma

Adenocarcinoma of Lung

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Lung Adenocarcinoma

Amino Acids

Tyrosine Kinase Inhibitors

Erlotinib Hydrochloride

Protein Kinase Inhibitors

Tyrosine

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.

erlotinib hydrochloride

Undergo image-guided needle biopsy (correlative studies)

needle biopsy

mutation analysis

Melissa Johnson

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.

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.

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

A Phase I/II Trial of Hsp 90 Inhibitor AUY-922 in Patients With Lung Adenocarcinoma With "Acquired Resistance" to EGFR Tyrosine Kinase Inhibitors

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) 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

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

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

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 (OS) is defined as the time from treatment initiation until death due to any cause.

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.

Robert H. Lurie Cancer Center

Northwestern University

Only highest grade lab AEs were collected for each patient. All other AEs were collected as defined by clinicaltrials.gov. Phase I+II data collected together as toxicity objectives for the study were looking at AEs in relation to this combination of treatment rather than treatment dose.

Patients receive Hsp90 inhibitor AUY922 IV over 1 hour once weekly and 75mg oral erlotinib hydrochloride once daily. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.

erlotinib hydrochloride: Given orally

Hsp90 inhibitor AUY922: Given IV

laboratory biomarker analysis: Correlative studies

needle biopsy: Undergo image-guided needle biopsy (correlative studies)

mutation analysis: Correlative studies

pharmacological study: Correlative studies

Cohort 1 - 25 mg/m2 AUY922+75 mg Daily Erlotinib

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.

erlotinib hydrochloride: Given orally

Hsp90 inhibitor AUY922: Given IV

laboratory biomarker analysis: Correlative studies

needle biopsy: Undergo image-guided needle biopsy (correlative studies)

mutation analysis: Correlative studies

pharmacological study: Correlative studies

Cohort 2 - 25 mg/m2AUY922+150 mg Daily Erlotinib

Cohort 3 - 37.5 mg/m2 AUY922+150 mg Daily Erlotinib

Cohort 4 - 55 mg/m2 AUY922+150 mg Daily Erlotinib

Cohort 5 - 70 mg/m2 AUY922+150 mg Daily Erlotinib

Phase II- 70 mg/m2 AUY922+150 mg Daily Erlotinib

Arm I

Age, Categorical

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

Data was collected up until September 30 2014 when study was closed permanently and no further data was collected for patients survival due to IND withdrawal.

Clinical Trials Office

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

All patients that were treated at the MTD dose of 70mg/m2 AUG922 IV were evaluable for this outcome measure (This includes patients treated in cohort 5 of phase I and all patients treated in phase II of the study)

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

Diarrhea

Skin rash

Hyperglycemia

Night blindness

Hypoalbuminemia

Fatigue

Elevated AST

Nausea

Hyponatremia

Elevated bilirubin

Elevated ALT

Myalgias/arthralgias

Visual complaints

Vomiting

Elevated APL

Decreased leukocytes

Hypokalemia

Pruritis/dry skin

Hypocalcemia

Anemia

Mucositis

Decreased lymphocytes

Decreased platelets

Hypomagnesemia

Decreased neutrophils

Toxicity collected from all patients treated at the MTD of 70mg/m2 AUY922. 6 patients in phase I and 19 patients in phase II were treated at this dose.

Toxicity as Assessed by NCI CTCAE Version 4.00 When AUG922 Administered at Its MTD (Phase I and II)

Elevated ALP

hypokalemia

anemia

Most frequent adverse events for patients treated with 25 to 55mg/m2 dose of AUY9222.

Incidence of Reported Adverse Events in Phase I

25 of the patients were treated at the MTD and were evaluable for progression free survival. Data was collected up until September 30 2014 when study was closed permanently and no further data was collected for patients survival due to IND withdrawal.

Progression-free Survival (Phase II)

Overall Survival (Phase II)

No data was collected or analyzed for this outcome measure. There is no data to report. IND was withdrawn before the studies anticipated termination date.

Overall Survival Among Patients With Acquired Resistance With T790M Mutations (Phase II)

Reached First Response at 4 Weeks

Confirmed Response at 8 Weeks

Continued Treatment After 8 Weeks

Survival Follow up for Two Years

Capecitabine

Antimetabolites

Hsp90 Inhibitor AUY922: 22mg/m2 IV days 1, 8, and 15 of 21-day cycles Capecitabine: 1000mg/m2 PO BID d 1-14 of 21-day cycles

Hsp90 Inhibitor AUY922: 28mg/m2 IV days 1, 8, and 15 of 21-day cycles Capecitabine: 1000mg/m2 PO BID d 1-14 of 21-day cycles

Hsp90 Inhibitor AUY922: 40mg/m2 IV days 1, 8, and 15 of 21-day cycles Capecitabine: 1000mg/m2 PO BID d 1-14 of 21-day cycles

Hsp90 Inhibitor AUY922: 55mg/m2 IV days 1, 8, and 15 of 21-day cycles Capecitabine: 1000mg/m2 PO BID d 1-14 of 21-day cycles

Hsp90 Inhibitor AUY922: 70mg/m2 IV days 1, 8, and 15 of 21-day cycles Capecitabine: 1000mg/m2 PO BID d 1-14 of 21-day cycles

Hsp90 Inhibitor AUY922: 70mg/m2 IV days 1, 8, and 15 of 21-day cycles Capecitabine: 1250mg/m2 PO BID d 1-14 of 21-day cycles

Taken orally twice daily on Days 1 through 14 of 21 day cycle.

IV infusion over 60 minutes on Days 1, 8, and 15 of each 21 day cycle

Hsp90 Inhibitor AUY 922

Johanna C Bendell, MD

The investigators propose this Phase I trial of the combination of AUY922 and capecitabine to determine the maximum tolerated dose (MTD) in patients with advanced solid tumors. This combination treatment has potential applicability in tumor types where capecitabine or fluorouracil is a treatment option, including colorectal and breast cancer.

A Study of the Hsp90 Inhibitor AUY922 Plus Capecitabine for the Treatment of Patients With Advanced Solid Tumors

A Phase I Study of the Hsp90 Inhibitor AUY922 Plus Capecitabine for the Treatment of Patients With Advanced Solid Tumors

To determine the maximum tolerated dose (MTD) of AUY922 plus capecitabine in patients with advanced solid tumors.

To evaluate the drug related toxicities associated with different doses of the drugs used in this regimen.

Response Rate (RR) is defined as the total number of patients with Complete Response (CR) or Partial Response (PR) as defined in RECIST v2. CR is defined as the dissappearance of all target lesions, disappearance of all non-target lesions and normalization of tumor markers. PR is defined as at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD.

Novartis Pharmaceuticals

SCRI Development Innovations, LLC

Hsp90 Inhibitor AUY922: 22mg/m2 IV days 1, 8, and 15 of 21-day cycles Capecitabine: 1000mg/m2 PO BID d 1-14 of 21-day cycles

Capecitabine: Taken orally twice daily on Days 1 through 14 of 21 day cycle.

Hsp90 Inhibitor AUY 922: IV infusion over 60 minutes on Days 1, 8, and 15 of each 21 day cycle

Dose Level 1

Hsp90 Inhibitor AUY922: 28mg/m2 IV days 1, 8, and 15 of 21-day cycles Capecitabine: 1000mg/m2 PO BID d 1-14 of 21-day cycles

Capecitabine: Taken orally twice daily on Days 1 through 14 of 21 day cycle.

Hsp90 Inhibitor AUY 922: IV infusion over 60 minutes on Days 1, 8, and 15 of each 21 day cycle

Dose Level 2

Hsp90 Inhibitor AUY922: 40mg/m2 IV days 1, 8, and 15 of 21-day cycles Capecitabine: 1000mg/m2 PO BID d 1-14 of 21-day cycles

Capecitabine: Taken orally twice daily on Days 1 through 14 of 21 day cycle.

Hsp90 Inhibitor AUY 922: IV infusion over 60 minutes on Days 1, 8, and 15 of each 21 day cycle

Dose Level 3

Hsp90 Inhibitor AUY922: 55mg/m2 IV days 1, 8, and 15 of 21-day cycles Capecitabine: 1000mg/m2 PO BID d 1-14 of 21-day cycles

Capecitabine: Taken orally twice daily on Days 1 through 14 of 21 day cycle.

Hsp90 Inhibitor AUY 922: IV infusion over 60 minutes on Days 1, 8, and 15 of each 21 day cycle

Dose Level 4

Hsp90 Inhibitor AUY922: 70mg/m2 IV days 1, 8, and 15 of 21-day cycles Capecitabine: 1000mg/m2 PO BID d 1-14 of 21-day cycles

Capecitabine: Taken orally twice daily on Days 1 through 14 of 21 day cycle.

Hsp90 Inhibitor AUY 922: IV infusion over 60 minutes on Days 1, 8, and 15 of each 21 day cycle

Dose Level 5

Hsp90 Inhibitor AUY922: 70mg/m2 IV days 1, 8, and 15 of 21-day cycles Capecitabine: 1250mg/m2 PO BID d 1-14 of 21-day cycles

Capecitabine: Taken orally twice daily on Days 1 through 14 of 21 day cycle.

Hsp90 Inhibitor AUY 922: IV infusion over 60 minutes on Days 1, 8, and 15 of each 21 day cycle

Dose Level 6

Total

Age, Continuous

John D Hainsworth, MD

AUY922 dose

Capecitabine dose

The Maximum Tolerated Dose (MTD) is determined for all patients

All Patients

Dose Determination

Vision changes

Hand-foot syndrome

Anorexia

Drug Related Toxicities

Includes all patients evaluable for response. 4 patients were not evaluable: dose level 2 (1 pt), dose level 4 (2 pts), dose level 6 (1 pt).

Preliminary Efficacy Assessment: Response Rate (RR)

Overall Study

Patients receive Hsp90 inhibitor AUY922 IV over 1 hour on days 1, 8, 15, and 22. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Dale Shepard

This phase I trial studies the side effects and best dose of Hsp90 inhibitor AUY922 in treating older patients with advanced solid malignancies. Hsp90 inhibitor AUY922 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth

PRIMARY OBJECTIVES:

I. The primary objective is to determine the maximally tolerated dose (MTD) of AUY922 (Hsp90 inhibitor AUY922) as a single agent when administered intravenously (IV) on a once-weekly schedule to adult patients 75 years of age or older with advanced solid tumors whose disease has progressed despite standard therapy or for whom no standard therapy exists.

SECONDARY OBJECTIVES:

I. To characterize the safety and tolerability of treatment with AUY922. II. To characterize the pharmacokinetic profiles of AUY922, including the parent drug and any potential metabolites.

III. To determine the efficacy of AUY922 in elderly patients with measurable disease.

IV. To evaluate of effect of geriatric-focused assessment of comorbidity and functional status on the toxicity and response to AUY922.

V. To assess the ethical constraints to enrollment of elderly patients in phase I trials.

TERTIARY OBJECTIVES:

I. Determine the effect of therapy with AUY922 on the number of circulating tumor cells (CTC).

II. To assess changes HSP70 induction as a measure of pharmacodynamic effect in pre- and post-AUY922 samples in peripheral blood mononuclear cell (PBMCs) to explore age-related differences in HSP90 inhibition by AUY922 compared with the previous phase I trial.

III. To assess changes in cellular response markers of apoptosis in pre- and post-AUY922 dosing in peripheral blood including measurement of M30 and M65 to explore age-related differences in pharmacodynamics compared to patients enrolled in the previous phase I trial.

IV. To determine associations between pharmacokinetic (PK) and pharmacodynamic (PD) parameters.

V. To determine the relationship between geriatric-focused assessment of comorbidity and functional ability and toxicity and response.

OUTLINE: This is a dose-escalation study.

Patients receive Hsp90 inhibitor AUY922 IV over 1 hour on days 1, 8, 15, and 22. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 28 days.

Hsp90 Inhibitor AUY922 in Treating Older Patients With Advanced Solid Malignancies

A Phase I Dose Escalation, Single Center, Open-Label Study of AUY922 Administered IV on a Once-Weekly Schedule in Adult Patients 75 Years of Age or Older With Advanced Solid Malignancies

A dose-limiting toxicity (DLT) is defined as an adverse event or abnormal laboratory value assessed as clinically relevant, and occurs \< 28 days following the first dose of AUY922. Toxicity will be measured by CTCAE criteria (Version 4.02). The MTD will be determined using a standard design.

Prior to 1st infusion; 30 minutes after start infusion; end infusion; 5, 30 minutes post-infusion; 1, 2, 4, 5, 24, 48 hours post-infusion course 1 days 8 (pretreatment) and 15 (pretreatment/end infusion); and course 2 day 1 (pretreatment/end infusion)

Imaging with CT or MRI will be obtained at baseline (within 21 days of study Day 1) and every other cycle commencing at the end of cycle 2 (beginning of cycle 3). These scans should be schedule within 7 days of the start of the cycle. Imaging will be obtained at the end of the study.

This trial will incorporate geriatric assessment to determine the relationship between functional ability or comorbidity and treatment response or toxicity. Patients will be have a geriatric assessment which will included a range of assessments, such as mini mental status, up and go test, and the geriatric depression scale, at baseline and after every 2 cycles of therapy.

Blood will be collected for measurement of CTCs on Cycle 1 Day 1 pre-infusion, Cycle 2 Day 1 pre-infusion, Cycle 3 Day 1, pre-infusion, then Day 1 of every other cycle until the end of the study.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Pemetrexed Disodium and Hsp90 Inhibitor AUY922 in Treating Patients With Previously Treated Stage IV Non-Small Cell Lung Cancer	NCT01784640	Recurrent Non-s... Squamous Cell L... Stage IV Non-sm...	Hsp90 inhibitor... pemetrexed diso... pharmacological... laboratory biom...	18 Years -	Jonsson Comprehensive Cancer Center
Hsp90 Inhibitor AUY922 and Erlotinib Hydrochloride in Treating Patients With Stage IIIB-IV Non-Small Cell Lung Cancer	NCT01259089	Adenocarcinoma ... Non-small Cell ...	erlotinib hydro... Hsp90 inhibitor... laboratory biom... needle biopsy mutation analys... pharmacological...	18 Years -	Northwestern University
A Study of the Hsp90 Inhibitor AUY922 Plus Capecitabine for the Treatment of Patients With Advanced Solid Tumors	NCT01226732	Metastatic or U...	Capecitabine Hsp90 Inhibitor...	18 Years -	SCRI Development Innovations, LLC
Hsp90 Inhibitor AUY922 and Erlotinib Hydrochloride in Treating Patients With Stage IIIB-IV Non-Small Cell Lung Cancer	NCT01259089	Adenocarcinoma ... Non-small Cell ...	erlotinib hydro... Hsp90 inhibitor... laboratory biom... needle biopsy mutation analys... pharmacological...	18 Years -	Northwestern University
Pemetrexed Disodium and Hsp90 Inhibitor AUY922 in Treating Patients With Previously Treated Stage IV Non-Small Cell Lung Cancer	NCT01784640	Recurrent Non-s... Squamous Cell L... Stage IV Non-sm...	Hsp90 inhibitor... pemetrexed diso... pharmacological... laboratory biom...	18 Years -	Jonsson Comprehensive Cancer Center
Hsp90 Inhibitor AUY922 in Treating Older Patients With Advanced Solid Malignancies	NCT01602627	Unspecified Adu...	Hsp90 inhibitor... pharmacological... laboratory biom...	75 Years -	Case Comprehensive Cancer Center

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