Clinical trial NCT01854034
Conditions: Non Small Cell Lung Cancer
Keywords: Advanced disease EGFR mutation
Sponsor: Massachusetts General Hospital
Start date: 2013-07-01; Completion date: 2017-03-01
Enrollment: 29 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This research study is a Phase II clinical trial, which tests the safety and effectiveness of an investigational drug to learn whether the drug works in treating a specific cancer. "Investigational" means that the drug is being studied. It also means that the FDA has not yet approved the drug for your type of cancer or for any use outside of research studies.

It has been found that some people with NSCLC have a change (mutation) in a certain gene called the EGFR gene. This mutated gene helps cancer cells grow. The majority of NSCLC patients with EGFR mutations achieve good outcomes with erlotinib or other EGFR inhibitor therapies, with a high response rate, prolonged progression-free survival and possibly improved overall survival from therapy. However, the 4% of EGFR mutant patients that harbor an exon 20 insertion mutation historically have reaped little benefit from EGFR-directed therapy due to the low affinity of this mutation for direct EGFR inhibitors, especially erlotinib and gefitinib (see Yasuda et al, Lancet Oncol 2011). This group of patients is ideal for studying other targeted therapeutic strategies that could affect the oncogene mutation in EGFR via alternative mechanisms.

AUY922 is an investigational drug that may stop cancer cells from growing abnormally. This drug has been used in other research studies. Information from those other research studies suggests that AUY922 may be effective in killing cancer cells in patients with exon 20 insertion mutations in EGFR.

The purpose of this study is to test the safety of AUY922 and determine how well AUY922 works for participants with advanced NSCLC and exon 20 insertion mutations in EGFR.

Detailed description:
Interested patients will be asked to undergo some screening tests and procedures to confirm that they are eligible. Many of these tests and procedures are likely to be part of regular cancer care and may be done even if it turns out that patients do not take part in the research study. If patients have had some of these tests or procedures recently, they may or may not have to be repeated. These tests and procedures include: a medical history physical exam, performance status, assessment of tumor, EKG, electrocardiogram or multigated acquisition scan, eye exam, blood draw, blood pregnancy test, urine test and collection of a piece of the stored tumor tissue.

The study treatment is given in 21 day cycles. AUY922 is given by IV (into a vein). This is called an infusion. Patients will receive an infusion of AUY922 on days 1, 8 and 15 of each cycle (once per week). The infusion will take about 60 minutes.

A schedule of clinic visits for the study is summarized below.

Cycle 1, Day 1: physical exam, including measurement of vital signs and weight; performance status; EKG; blood draw; routine urine test Cycle 1, Day 2: EKG Cycle 1, Day 3: EKG Cycle 1, Day 8: Vital signs, performance status, EKG, questions about side effects and other medications taken Cycle 1, Day 15: Physical exam, including measurement of vital signs, performance status; EKG; blood draw; questions about side effects and other medications taken Note that in Cycle 1 patients will need to stay at (or return to) the clinic for the last EKG following the Day 1 AUY922 infusion, and come to the clinic on Days 2 and 3 for EKGs.

Cycle 2 and beyond, Day 1: physical exam, including measurement of vital signs and weight; performance status; EKG; blood draw; questions about side effects and other medications taken; routine urine test Cycle 2 and beyond, Day 8: Vital signs; performance status; EKG; questions about side effects and other medications taken Cycle 2 and beyond, Day 15: Physical exam, including measurement of vital signs; performance status; EKG; blood draw; questions about side effects and other medications taken.

Additional EKGs may be done at any time if the study doctor thinks it is necessary. A blood test to measure the amount of cardiac enzymes in the blood may be done whenever abnormal findings are suspected or seen on the EKG.

Additional tests and procedures:

* CT or MRI scans will be done to measure the disease about every 6 weeks.
* A blood pregnancy test, for women who can become pregnant, will be performed every 6 weeks or at any point in which pregnancy is suspected.
* A standard eye exam will be done on Cycle 3, Day 1. Additional eye exams will be done if patients experience any eye-related symptoms, such as changes in vision.

Within 1 week after the last dose of the study drug AUY922, patients will be asked to return to the clinic. At this visit the following will be done: physical examination, performance status, EKG, ECHO or MUGA scan, blood draw, urine test, eye exam, questions about side effects and other medications taken. Patients will be asked to return to the clinic a second time so investigators can follow-up on any ongoing side effects after stopping AUY922.

Arms: arm 1: AUY922 administered once weekly via intravenous, 70 mg/m2
Interventions: intervention 1: AUY922
Intervention descriptions: intervention 1: AUY922 administered intravenously once a week at 70mg/m2

Protocol documents:
Prot_SAP_000.pdf: 




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TABLE OF CONTENTS 
1.
OBJECTIVES .................................................................................................................................................... 4 
1.1 
Study Design............................................................................................................................................... 4 
1.2 
Primary Objectives ..................................................................................................................................... 4 
1.3 
Secondary Objectives ................................................................................................................................. 4 
2.
BACKGROUND ................................................................................................................................................ 4 
2.1 
Study Agent: AUY922 ................................................................................................................................. 4 
2.2 
Study Disease: EGFR mutation-positive NSCLC ..................................................................................... 10 
2.3 
Rationale .................................................................................................................................................. 11 
3.
PARTICIPANT SELECTION ........................................................................................................................ 12 
3.1 
Eligibility Criteria .................................................................................................................................... 12 
3.2 
Exclusion Criteria .................................................................................................................................... 13 
3.3 
Inclusion of Women, Minorities and Other Underrepresented Populations ............................................ 15 
4.
REGISTRATION PROCEDURES ................................................................................................................ 15 
4.1 
General Guidelines for DF/HCC and DF/PCC Institutions ..................................................................... 15 
4.2 
Registration Process for DF/HCC and DF/PCC Institutions ................................................................... 15 
4.3 
General Guidelines for Other Participating Institutions .......................................................................... 16 
4.4 
Registration Process for Other Participating Institutions ........................................................................ 16 
5.
TREATMENT PLAN ...................................................................................................................................... 16 
5.1 
Pre-treatment Criteria .............................................................................................................................. 17 
5.2 
AUY922 Administration............................................................................................................................ 17 
5.3 
Definition of Dose-Limiting Toxicity ........................................................................................................ 19 
5.4 
General Concomitant Medication and Supportive Care Guidelines ........................................................ 19 
5.5 
Duration of Therapy ................................................................................................................................. 20 
5.6 
Duration of Follow Up ............................................................................................................................. 20 
5.7 
Criteria for Removal from Study .............................................................................................................. 20 
6.
EXPECTED TOXICITIES AND DOSING DELAYS/DOSE MODIFICATIONS .................................... 21 
6.1 
Anticipated Toxicities ............................................................................................................................... 21 
6.2 
Surveillance and Management of Specific Toxicities ............................................................................... 22 
6.3 
Dose Modifications/Delays ....................................................................................................................... 26 
7.
CORRELATIVE/SPECIAL STUDIES .......................................................................................................... 31 
7.1 
Pharmacokinetic Studies .......................................................................................................................... 32 
8.
STUDY CALENDAR ...................................................................................................................................... 33 


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9.
MEASUREMENT OF EFFECT..................................................................................................................... 35 
9.1 
Treatment Efficacy .................................................................................................................................... 35 
10.
ADVERSE EVENT REPORTING REQUIREMENTS .......................................................................... 40 
10.1 
Definitions ................................................................................................................................................ 40 
10.2 
Procedures for AE and SAE Recording and Reporting ............................................................................ 42 
10.3 
Reporting Requirements ........................................................................................................................... 42 
10.4 
Reporting to the Study Sponsor ................................................................................................................ 42 
10.5 
Reporting to the Institutional Review Board (IRB) ................................................................................... 43 
10.6 
Reporting to the Food and Drug Administration (FDA) .......................................................................... 43 
10.7 
Reporting to Novartis ............................................................................................................................... 44 
10.8 
Reporting to Hospital Risk Management .................................................................................................. 44 
10.9 
Monitoring of Adverse Events and Period of Observation.......................................................................44 
11.
DATA AND SAFETY MONITORING ..................................................................................................... 45 
11.1 
Data Reporting ......................................................................................................................................... 45 
11.2 
Safety Meetings ......................................................................................................................................... 46 
11.3 
Monitoring................................................................................................................................................ 46 
12.
REGULATORY CONSIDERATIONS ..................................................................................................... 46 
12.1 
Protocol Review and Amendments ........................................................................................................... 46 
12.2 
Informed Consent ..................................................................................................................................... 47 
12.3 
Ethics and Good Clinical Practice (GCP) ............................................................................................... 47 
12.4 
Study Documentation ................................................................................................................................ 48 
12.5 
Records Retention ..................................................................................................................................... 48 
13.
STATISTICAL CONSIDERATIONS ....................................................................................................... 48 
13.1 
Study Design/Endpoints ............................................................................................................................ 48 
13.2 
Sample Size/Accrual Rate ......................................................................................................................... 48 
13.3 
Patient Disposition ................................................................................................................................... 49 
13.4 
Patient Characteristics ............................................................................................................................. 49 
13.5 
Safety of Treatment ................................................................................................................................... 49 
13.6 
Analysis of Response Rate ........................................................................................................................ 50 
13.7 
Analysis of Progression-Free and Overall Survival ................................................................................. 50 
14.
PUBLICATION PLAN ............................................................................................................................... 50 
15.
REFERENCES ............................................................................................................................................ 51 
16.
APPENDICES ............................................................................................................................................. 54 


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1. OBJECTIVES
1.1
Study Design
The primary purpose of this study is to determine the efficacy of AUY922 when administered 
intravenously on a once-weekly schedule at 70 mg/m2 in adult NSCLC patients with advanced 
disease and EGFR exon 20 insertion mutations. The design will be a Simon two-stage phase 2 
study, with 10 patients enrolled to the first stage and an additional 19 patients enrolled to the 
second stage provided we observe at least 1 partial or complete response or stable disease lasting 
 3 months in the first stage. Additional safety and tolerability assessments of AUY922 will be 
evaluated as secondary objectives. Pre- and post-treatment biopsy specimens, if available, will 
also be analyzed to determine which exon 20 EGFR mutations may be most sensitive to Hsp90 
inhibition and explore potential mechanisms of resistance to treatment.  
1.2
Primary Objectives 
To evaluate the overall response rate to AUY922 in patients with advanced NSCLC and exon 20 
insertion mutations in EGFR. 
1.3
Secondary Objectives 
x
To estimate progression-free survival (PFS) and overall survival (OS) in the study
population
x
To determine the safety and tolerability of AUY922
x
To explore variance in clinical outcome between different types of exon 20 EGFR
mutations
2.
BACKGROUND
2.1
Study Agent: AUY922
2.1.1 Heat Shock Proteins 
Heat shock proteins (HSPs) are molecular chaperones, which play a vital role in the maintenance 
of the proteome. HSPs assist in the structural folding and stabilization of a broad range of 
proteins within the cells, which are commonly referred to as “client proteins.” Without active 
HSPs, these client proteins become misfolded and subject to ubiquitination and degradation 
within the proteasome. 
HSP90, an ATP-dependent molecular chaperone, is the most abundant form of HSPs that 
accounts for 1-2% of all proteins within the cell (Welch and Feramisco 1982). There are vast 
majority of client proteins within the cell that is dependent upon HSP90 (Pratt and Toft 2003), 
some summarized in Table 1, and the list keeps growing every year with more than 200 client 
proteins identified up to date (Li, Zhang, and Sun 2009). HSP90 consist of three domains, a 24-
28 kDa NH2-terminal region, 33-44 kDa middle region, and a 11-15 kDa COOH domain (Banerji 
2009). The primary functions of these domains are ATP binding, client protein binding and 
dimerization, respectively (Banerji 2009). HSP90 forms multi-chaperone complex with a variety 


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of other co-chaperones and protein kinases to exert its effect on client protein folding and 
stabilization, a process that is ATP-dependent (Pratt 1998). Pratt and Toft, in their 2003 review 
article, have elegantly suggested a mechanism involving 5 proteins (Pratt and Toft 2003). The 
co-chaperones HSP40 and HSP70 forms a unit which couples with HSP90 through the co-
chaperone HOP. In this conformation the complex is able to bind to the client protein and the 
structure is stabilized by the entry of p23 that binds to HSP90. Recently, it has been discovered 
that HSP90 binding to p23 is possible through the Sgt-1 co-chaperone. HSP90 and Sgt1-CS 
couples through the N-domain of HSP90 and forms a closed complex that later interacts with 
p23/sba1 (Zhang, et al 2008). 
Table 1. Selected Hsp90 Client Proteins 
Cellular process 
Client protein 
Apoptosis 
Apaf-1, P53, RIPK1, AKT, MDM2, Survivin 
Cell proliferation 
CDC2, CDK4, CDK6, CDK9, CDK11, CHEK1, hTERT, PLK1 
Angiogenesis
VEGFR, FLT-3
Oncogenic 
HER2, IGF1R, B-RAF, RAF1, BCR-ABL, c-MET, c-Mos, c-SRC, c-KIT, 
EGFR, NPM-ALK, PIM1, RET, FAK, EML4-ALK 
Signal transduction 
CAMK1, GRK2, GRK3, GRK5, GRK6, KSR, MAP3K1, MAP3K11, PDK1, 
HCK, IKKalpha, IKKbeta, LCK, MEK 
Transcription factors 
AHR, ER, GR, MR, HSF1, HIF1A, RUNX1T1, p53, PPARa, NR1I2, STAT1, 
STAT3, STAT5 
Transporter/ion channel 
CFTR, APOB, CX43, KCNH2, SLC12A2, P2X7, ABCB1 
Chromatin remodeling 
DNMT1, Histones (H1, H2A, H2B, H3, H4) 
Others 
TPMT, TRKB, ACK2 
Most tumors do not depend de novo on a single protein abnormality, but on multiple pathway 
driven processes with redundancies that enable a number of proteins to activate the same 
pathways for proliferation (Erlichmann 2009). Due to the multitude of client proteins that HSP90 
affects, HSP90 inhibitors simultaneously have the potential to disrupt multiple targets in parallel 
signal transduction pathways by inactivating a large number of oncoproteins, with their crucial 
targets varying in different cell types. Thus HSP90 inhibitors are expected to have broad utility 
in oncology. It has been shown that in many tumors HSP90 is either overexpressed and/or 
exclusively complexed into an activated state with its co-chaperones (Kamal, et al 2003). Many 
of the HSP90 client proteins are key regulators in cell proliferation, survival and apoptosis. 
Moreover, oncoproteins are often expressed as mutant forms which depend on HSP90 for proper 
folding and stability more than their wildtype counterparts. Furthermore, cancer cells present an 
environment of cellular stress that requires a high level of intact chaperoning activity. By 
inhibiting HSP90, it is believed, cancer cells will be deprived of key oncogenic proteins for their 
survival, giving potential HSP90 inhibitors a wide range of molecular targets within cancer cells; 
a desired outcome in aggressive tumor types such as advanced non small-cell lung cancer 
(NSCLC). This concept is supported by pre-clinical studies, where HSP90 inhibitors induced cell 
cycle arrest and apoptosis in a variety of hematological and solid malignancies including 
lymphomas, sarcomas and NSCLC cell lines. 


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There are several HSP90 inhibitors currently in development, and 17-AAG (an analogue of 
geldanamycin, which is a naturally occurring antibiotic) has been the most studied. It should also 
be noted that geldanamycin has been the choice of agent to identify HSP90 client proteins in
vitro. Pre-clinical work with 17-AAG has shown activity in a wide range of cancer models. In 
osteosarcoma cell lines 17-AAG significantly down regulated cellular proliferation markers such 
as pAKT, p44Erk, p-mTOR, cyclinD-1 and other proteins (Gazitt, et al 2009). Growth were 
inhibited, and VEGFR expression was suppressed when 17-AAG was applied to a variety of 
neuroblastoma cell lines (Jayanthan, et al 2008). Synergistic effects of 17-AAG has also been 
shown with radiation in esophageal and NSCLC cell lines (Kim 2009, Wu 2009). 
17-AAG has been studied extensively in the clinic. It has shown to prolong stable disease in
patients with melanoma, lung, prostate and renal cancers (Solit and Rosen 2006). Combination
treatment has shown beneficial in some settings, where in a combination study with trastuzumab
a partial response where reported in a HER2 positive breast cancer patient (Modi, et al 2006). In
combination with paclitaxel, a partial response was observed in a lung cancer patient who had
previously responded to erlotinib (Solit and Rosen 2006). Responses has also been reported in
hematological settings where 17-AAG has shown a partial response in one patient in a 14 patient
phase 1 study in multiple myeloma (Mitsiades, et al 2005).
17-DMAG (alvespimycin) is a hydrophobic derivate of 17-AAG that is water soluble with good
bioavailability. 17-DMAG does not have the stability and solubility problems as seen with
17-AAG. In vitro studies have shown DMAG to be potent, especially in combination with
radiotherapy in NSCLC cell lines, NCI-H460 and A549 (Kol, et al 2008). In the clinic, partial
responses has been observed in a hormone refractory prostate cancer patient and in a melanoma
patient in a 25 patient phase 1 study (Pacey, et al 2009). Combination treatment with 17-DMAG
and trastuzumab achieved a partial response in a heavily pretreated HER2 positive metastatic
breast cancer patient in a 21 patient phase 1 study (Miller, et al 2007).
With CNF 1010, an oil-in-water nanoemulsion of 17-AAG, 3 minor responses were observed in 
patients with melanoma, gastric and duodenal cancers (Saif, et al 2006). In a phase I study with 
the novel HSP90 inhibitor IPI-504, decreased uptake of 18F-FDG in PET scans was observed in 7 
out of 18 patients with progressive GIST following imatinib and sunitinib treatment, and 6 
patients experienced stable disease for  4 treatment cycles (Demetri, et al 2007). A recent 
phase 2 study in advanced NSCLC showed prolonged disease stabilization and partial responses 
in patients with EGFR wild type, EGFR activating mutations, and EML4-ALK translocation 
kinase after receiving IPI-504 bi-weekly with a one week rest (Sequist, et al 2010). 
Collectively, all these data confirm that targeting HSP90 in various tumors to have anti-
neoplastic effect. 
2.1.2 AUY922
2.1.2.1 Mechanism of action 
AUY922, an isoxazole derivative, inhibits the ATPase activity of HSP90 by competitively 
binding to the ATP binding pocket of the N-Terminal, which causes the dissociation of client 
proteins, resulting in their ubiquitination and degradation within the proteasome through a 
cascade of events. This translates into an anti-tumor effect in non-clinical in vitro and in vivo 
studies (please see the current AUY922 Investigator’s brochure for details). Binding of AUY922 


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also induces a stress response. When AUY922 binds to HSP90 it locks the ATP pocket in an 
ADP-bound confirmation and prevents the step-wise binding of p23 described above, a process 
that is ATP dependent. This results in the chaperone complex dissociating and the relocation of 
the protein heat shock factor 1 (HSF-1) to the nucleus of the cell where it binds to the promoter 
region of the heat shock genes, named heat shock elements (HSE), and induces the transcription 
of stress-inducible proteins, including HSP70 and HSP27, up to 100 to 1000 fold concentrations 
in comparison to unstressed base-line levels (McCollum, et al 2008). 
2.1.2.2 In vitro pharmacology 
The ATPase activity of AUY922 was measured in a special fluorescence polarization assay and 
the drug was demonstrated to have potent HSP90 binding activity (IC50: 30 nM). 
At the cellular level, AUY922 inhibition of HSP90 induces cell cycle arrest and apoptosis. In 
turn, this inhibits the proliferation of a range of tumor and non-tumor cell lines at low nanomolar 
concentrations. In studies involving the breast cancer cell line BT-474, AUY922 was shown to 
have strong antiproliferative activity (GI50: 2.8 nM). The anticancer activity of AUY922 was also 
evaluated in 46 primary human tumor samples of 11 different human tumor types (bladder 
cancer, colon, liver, NSCLC, small cell lung, mammary, ovary, pancreatic and renal cancer, 
melanoma, pleuramesothelioma) and 3 preparations of hematopoietic stem cells in vitro using a 
clonogenic assay. Recent work completed at UCLA by Dr. Garon and colleagues has shown that 
AUY922 inhibit a wide range of NSCLC cell lines including ones with EGFR mutations and 
KRAS mutations at concentrations below 100 nM (Garon, et al 2009). 
As explained in more detail in the introduction section, a key step in the functioning of HSP90 is 
the formation of a complex with the co-chaperone protein p23. This action is driven by the 
binding of ATP to the complex. In the presence of an ATP competitive inhibitor such as 
17-AAG, the HSP90-p23 complex was shown to dissociate (Georgakis and Younes 2005). In 
BT-474 breast cancer cells, AUY922 was shown to destabilize the HSP90-p23 complex in a 
concentration dependent manner and this mechanistically demonstrated the compound’s ability 
to disrupt HSP90 activity. 
With the inhibition of the HSP90 target, the downstream effects of AUY922 inhibition were 
examined. It was found that a variety of client proteins had been degraded, and a number of 
signaling pathways disrupted. The effect of AUY922 on the cellular content of several client 
proteins were analyzed in BT-474 tumor cell and the compound was shown to affect both ErbB2 
and p-AKT in a dose dependent manner, confirming that inhibition of HSP90 catalytic activity 
induces destabilization of HSP90 client proteins, and leads to their degradation within the 
proteasome. 
2.1.2.3 In vivo pharmacology 
The anti-tumor effect of AUY922 was evaluated in a number of tumor xenograft models. 
AUY922 was administered intravenously (i.v.) on a three times weekly schedule to the NSCLC 
cancer xenograft model NCI-H1975. Efficacy in this experiment was assessed by dividing the 
change in tumor volume with the change in the vehicle group. The experiment demonstrated a 
cytostatic effect at a dose level of 50 mg/kg, reaching a Treatment vs Control (T/C) ratio of 21 
%. In another xenograft model, A549 cell lines, the same dose and treatment schedule was less 
potent but still showed cytostatic effect with a T/C ratio of 45. For more information about 


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AUY922 xenograft studies on other solid tumors please refer to the current AUY922 
Investigators Brochure. 
2.1.2.4 Preclinical safety of AUY922 
The preclinical safety profile of AUY922 was studied in rat and dog toxicology studies. Two 
separate dosing schedules were utilized during toxicology studies. During the 2-week studies in 
rats and dogs, AUY922 was administered i.v. every other day. During the 4-week studies 
AUY922 was administered in a once- weekly i.v. schedule. 
The main significant findings from both set of toxicology studies in both species were cytotoxic 
and inflammatory reactions in the intestine, bone marrow, adrenal glands, and lymphoid tissue. 
A moderate risk of local irritation at the injection site was also noted in rats. All toxicities were 
reversible. However, there is a risk that patients may experience GI toxicities such as diarrhea 
following AUY922 treatment. Hence, patients should be followed closely by the diarrhea 
management plan. No ocular histopathological changes were determined. 
In vitro cardiac safety studies demonstrated a pre-clinical signal for QT prolongation, however 
no effects, such as QTc prolongation or proarrhythmia, were observed in the GLP dog and 
monkey telemetry studies in vivo. Due to potential cardiac toxicity, patients in ongoing clinical 
studies are undergoing extensive cardiac monitoring. These safety parameters will be monitored 
in the current study using an intensive ECG and vital signs monitoring schedule. Due to the 
potential risk of local irritation the infusion site should be monitored carefully during the time of 
infusion, if a peripheral line is used for the infusion of the study drug. 
For a detailed description and results of the pre-clinical safety studies please refer to the current 
AUY922 Investigator’s Brochure. 
2.1.3 Clinical experience 
There are several studies assessing the efficacy, safety and tolerability of AUY922 in both solid 
and hematological malignancies. Detailed information on safety, efficacy, and PK data from 
patients treated at dose levels from 2 to 70 mg/m2 can be found in the current AUY922 
Investigator’s brochure. Below is a brief summary of the relevant clinical experience thus far. 
CAUY922A2101: A Phase I study of AUY922 in patients with advanced solid tumors 
The FIH phase I study [CAUY922A2101] to determine safety and tolerability of AUY922 as a 
single agent in adult patients with solid malignancies, has been completed. A total of 101 
patients were treated with AUY922 at increasing dose levels from 2 mg/m2 to 70 mg/m2. Of the 
patients enrolled in the two highest dosing cohorts (i.e., 54 and 70 mg/m2), 5 DLTs were 
reported. Grade 3 asthenia and grade 3 diarrhea were reported in two patients in the 54 mg/m2 
cohort. In the 70 mg/m2 cohort, two patients reported grade 3 visual symptoms and one patient 
experienced grade 3 diarrhea. Based on the available safety profile, the 70 mg/m2 dose 
administered intravenously once weekly was declared as the recommended phase II dose (RP2D) 
(Samuel 2010). 
The most common adverse events in the highest dosing cohorts, regardless of AUY922 
relationship, included diarrhea, nausea, fatigue, vomiting, decreased appetite, asthenia, 
abdominal pain, anemia, night blindness, dyspnea, pyrexia, constipation, headache, and 
hypokalemia. Most toxicities were associated with either the gastrointestinal or visual system. 


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In the highest dose cohorts of 54 mg/m2 and 70 mg/m2, patients reported grade 1-3 visual 
symptoms including but not limited to: delayed dark to light adaptation, blurred vision, floaters 
and flashes in peripheral vision, dark or black spots, darkening of visual field, reduced night 
vision, decreased peripheral vision, decreased color vision and dry eye syndrome. Per 
investigator follow-up, all visual symptoms suspected to be related to AUY922 resolved after 
discontinuation or dose reduction of AUY922 treatment. 
 
CAUY922A2206: A Phase 2 Study of AUY922 in NSCLC Patients 
 
As of April 2012, 121 patients with NSCLC have been treated on this phase 2 study examining 
the activity of AUY922 in patients with defined molecular subtypes of NSCLC who had received 
prior chemotherapy. The molecular groups included were those with EGFR mutations, those 
with KRAS mutations, those with EML4-ALK rearrangements, and those that were wild-type for 
all 3 driver mutations. Patients were treated at 70mg/m2 and the primary outcome was rate of 
partial response (PR) and prolonged stable disease (SD; >18 weeks) within each molecular 
subgroup. Interestingly, the EGFR mutant subgroup had a 20% response rate and the ALK 
rearranged group had a 29% response rate on this phase II study (Garon, 2012), supporting 
further study of AUY922 in both of these molecularly-defined patients groups. 
 
The most frequent adverse events (AEs, all grades) were visual AEs (77%), diarrhea (74%), and 
nausea (46%). Overall 7% of patients had a grade 3 or 4 AE involving visual symptoms; most 
commonly photopsia (20%), visual impairment (19%), vision blurred (18%), night blindness 
(17%), and visual acuity reduced (17%). These effects were all reversible upon discontinuation 
of drug. 
2.1.4 Pharmacokinetics of AUY922 
As of February 18th, 2010, preliminary PK data are available from 100 patients in the first dose 
escalation clinical trial for AUY922 [CAUY922A2101]. PK profiles of AUY922 and its inactive 
metabolite BJP762 obtained on Days 1, 22, and 29 for dose cohorts of 2, 4, 8, 16, 22, 28, 40, 54, 
and 70 mg/m2 were assessed by noncompartmental analysis. 
As of February 18th, 2010, preliminary PK data are available from 20 patients from the second 
clinical trial at 8, 16, 30, 45, 60 and 70 mg/m2 [CAUY922A2103] and 16 patients from the third 
clinical trial at 8, 16, 22, 28, and 40 mg/m2 (CAUY922A1101). 
Following a weekly i.v. infusion (1 hr duration), AUY922 blood concentration followed a bi-
exponential decline with a fast phase (t1/2 <10 min) and a slow terminal phase (t1/2~80hr). Peak 
concentration Cmax occurred at the end of infusion for both AUY922 and BJP762 (Tmax around 
1 hr). No apparent drug accumulation for either AUY922 or BJP762 was observed following 
weekly dosing. AUY922 blood Cmax increased proportionally with dose, though blood AUC 
was less than dose-proportional. The observed nonlinear blood AUC of AUY922 with dose was 
likely caused by saturable distribution of AUY922 to red blood cells (RBC). The increase in the 
exposure ratio of BJP762/AUY922 reached a maximum at a dose of 28 mg/m2. The dose 
dependent exposure ratio of BJP762 to AUY922 was also observed, possibly due to the 
nonlinear distribution of AUY922 to RBC, and the linear distribution of BJP762 to RBC. Both 
AUY922 blood CL and Vss increased with dose. At 70mg/m2, the Vss value was over 1000 L, 
suggesting extensive distribution of AUY922 to the tissues. The observed dose-dependent 


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increases of CL and Vss were consistent with the nonlinear distribution of AUY922 to RBC. The 
PK results of AUY922 observed thus far are generally consistent between three studies 
[CAUY922A2101], [CAUY922A2103], and CAUY922A1101. 
The absorption, distribution, metabolism and excretion (ADME) of AUY922 was determined in 
an open-label, single-center, phase I study following a single intravenous administration of 30 
mg [14C]AUY922 in healthy male volunteers [CAUY922A2105]. Mass balance was achieved in 
this study with  93.8% of the administered radioactivity being recovered in the excreta of all 
four patients after 13 days. In feces, 73.0 - 78.7% of the dose was recovered while 15.1 - 23.5% 
of the dose was recovered in the urine. The most prominent biotransformation pathways for 
AUY922 in humans was direct glucuronidation at the 2-hydroxy position on the 2,4-dihydroxy-
5-isopropyl-phenyl ring of AUY922 to yield M29.7/BJP762 and conversion of the isoxazole ring
to a dihydro-pyranone ring by isoxazole ring-opening followed by re-cyclization through the 2-
hydroxy group in the adjacent 2,4-dihydroxy-5-isopropyl-phenyl ring to yield M29.1/BGX833.
Unchanged AUY922 in urine and feces accounting for 0.39-1.16% and 4.82-27.5% of dose,
respectively. The higher total radioactivity exposure observed in blood relative to plasma
suggested that the drug-related radioactivity was significantly distributed to blood cells. In
contrast to AUY922, metabolite BJP762 does not distribute to blood cells to any significant
degree.
2.2
Study Disease: EGFR mutation-positive NSCLC 
Non-small cell lung cancer (NSCLC) is the most common cause of cancer mortality in men and 
women in the U.S. Approximately 170,000 Americans will be diagnosed with NSCLC this year 
and approximately half of them will have advanced or metastatic disease at presentation, which 
is not curable. Chemotherapy and biologically targeted agents can extend survival modestly for 
these patients; however, discovery of novel ways to prolong the disease course is a top research 
priority. 
The epidermal growth factor receptor (EGFR) signaling pathway plays a central role in the 
neoplastic transformation of NSCLC and promotes cancer cell survival, metastasis, and 
angiogenesis. The predominance of EGFR signaling in NSCLC makes the pathway an attractive 
candidate for the development of targeted therapeutics. In the last eight years, the FDA has 
approved two drugs in this class for salvage treatment of NSCLC, gefitinib (Iressa ®, formerly 
known as ZD1839) and erlotinib (Tarceva ®, formerly known as OSI-774). Both are small 
molecule orally-bioavailable tyrosine kinase inhibitors (TKIs) of the EGFR TK domain. 
Erlotinib improves survival compared to placebo when administered after failure of first line or 
second line chemotherapy for advanced NSCLC and is currently approved for that indication 
(Shepherd, 2005). Gefitinib received accelerated approval for salvage treatment of NSCLC based 
on response to treatment and symptom improvement in phase II clinical trials, but then a 
randomized placebo-controlled trial failed to demonstrate a survival benefit and gefitinib is no 
longer available in the US. (Thatcher, Lancet 2005). 


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Our group and others described somatic mutations in the EGFR gene that sensitize NSCLC 
tumors to TKIs, present in about 10% of unselected US patients with NSCLC but in up to 50% 
of never-smoking NSCLC patients. (Lynch 2004 and Paez 2004). EGFR mutations confer a state 
of “oncogene addiction” on the molecular biology of the tumor, such that the critical downstream 
signaling pathways are solely controlled by EGFR and are therefore highly susceptible to cell 
death by blockade of EGFR. Multiple randomized trials have now confirmed a progression-free 
survival benefit when patients with EGFR mutations are treated with genotype-directed 
strategies like using first-line gefitinib or erlotinib compared to standard chemotherapy. (Mok 
2009, Mitsudomi 2010, Rosell 2012). This targeted strategy has evolved to being considered 
standard of care for patients with EGFR mutations. (Ettinger 2012). 
 
Though EGFR mutations primarily consist of overlapping deletion mutations in the LREA 
region of exon 19 or the point substitution mutation L858R in exon 21, though there are several 
less common EGFR mutations, for example exon 20 insertion mutations of EGFR. This class of 
EGFR-mutants seems to have an EGFR-addicted biology, but have historically reaped little 
benefit from EGFR-directed therapy due to the low affinity of this mutation for direct EGFR 
inhibitors, especially erlotinib and gefitinib (Yasuda, 2011). Identifying alternative targeted 
therapeutic options for exon 20 EGFR mutation-positive patients is a priority.  
2.3 Rationale
 
EGFR is a client of Hsp90 and there is strong pre-clinical evidence that Hsp90 inhibition may be 
preferentially effective in cancers with EGFR mutations (Shimamura, 2008 and 2012). However, 
other Hsp90 inhibitors have disappointingly failed to show significant activity in EGFR 
mutation-positive NSCLC patients, though most of the patients on these studies were treated 
after acquiring resistance to EGFR tyrosine kinase inhibitors (Sequist, 2010 and Wong, 2011).  
 
As discussed above, in the ongoing phase II [CAUY922A2206] study of AUY922 in NSCLC, 
there has been a 20% response rate among patients with EGFR mutations, the highest response to 
Hsp90 inhibition seen in this patient group to date. At least one of the EGFR-mutant responders 
had an exon 20 insertion mutation, an 80 year-old woman with advanced NSCLC who had been 
treated with first-line erlotinib and had not responded but rather experienced progressive disease 
after about 4 months of therapy. She went on AUY922 as second-line therapy and achieved a 
partial response on her first restaging with a 35% reduction in tumor burden, improving to a 42% 
decrease on her confirmation of response scans 6 weeks later. This type of marked response to 
therapy and clinical benefit in an EGFR exon 20 insertion mutation-positive patient is atypical, 
provocative, and deserving of further study. This is the basis of the current trial. 
 
AUY922 will be administered intravenously at a dose of 70 mg/m2 on a weekly schedule. This 
dose and schedule is the established MTD from study [CAUY922A2101] and has demonstrated 
partial responses across a range of genotypes in NSCLC in the ongoing phase II protocol 
[CAUY922A2206]. 
 
 


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3.
PARTICIPANT SELECTION 
 
3.1 Eligibility Criteria 
Participants must meet the following criteria on screening examination to be eligible to 
participate in the study: 
 
3.1.1 Participants must have histologically or cytologically confirmed stage IV 
or recurrent non-small cell lung cancer with a documented exon 20 
insertion mutation in EGFR (exon 20 insertion/deletion and deletion 
mutations will also be allowed) 
 
3.1.2 Participants must have measurable disease by RECIST 1.1 
 
3.1.3 Patients must have received at least one prior line of therapy for their 
advanced lung cancer but there is no restrictions on the maximum number 
of prior therapies allowed.
 
3.1.4  Age  18 years. 
 
3.1.5 Life expectancy  12 weeks. 
 
3.1.6 ECOG performance status  2 (see Appendix A) 
 
3.1.7 Participants must have normal organ and marrow function as defined 
below: 
Hematologic: 
x Absolute Neutrophil Count (ANC) t1.5x109/L 
x Hemoglobin (Hgb) t 8 g/dl 
x Platelets (plt) t100x109/L 
Biochemistry:  
x Potassium within normal limits or correctable with supplements 
x Magnesium > LLN or correctable with supplements 
x Calcium (after correction for albumin level) >LLN or correctable with 
supplements 
Liver and Kidney Functions 
x AST/SGOT and ALT/SGPT  3.0 x Upper Limit of Normal (ULN) or  
5.0 x Upper Limit of Normal (ULN) if liver metastases are present 
x Serum bilirubin d 1.5 x ULN 
x Serum creatinine d 1.5 x ULN or 24-hour clearance t 50 ml/min 
 


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3.1.8 The effects of AUY922 on the developing human fetus are unknown. For 
this reason women of child-bearing potential and men must agree to use 
adequate contraception (hormonal or barrier method of birth control; 
abstinence) prior to study entry and for the duration of study participation. 
Should a woman become pregnant or suspect she is pregnant while 
participating in this study, she should inform her treating physician 
immediately. In addition, women of child-bearing potential must have a 
documented negative serum pregnancy test. The serum pregnancy test 
must be obtained prior to the first administration of AUY922 ( 72 hours 
prior to dosing) in all pre-menopausal women and women <2 years after 
the onset of menopause. 
 
3.1.9 Ability to understand and the willingness to sign a written informed 
consent document. 
 
3.1.10 Patients must have a normal baseline ophthalmologic examination or have 
only clinically-insignificant abnormalities. Patients with significant 
visual/ocular abnormalities identified during the baseline eye exam may be 
eligible after discussion with the study PI and it is thought that the 
abnormalities pose no increased risk with study therapy. 
 
3.2
Exclusion Criteria 
 
Participants who exhibit any of the following conditions at screening will not be 
eligible for admission into the study. 
 
3.2.1 Participants may not have had other anti-neoplastic therapies within the 
following timelines: 
x Radiation within 2 weeks 
x Cytotoxic chemotherapy or monoclonal antibodies within 2 weeks, if 
all treatment-related toxicites have resolved to < grade 1 prior to 
starting study treatment. 
x EGFR tyrosine kinase inhibitor within 2 weeks 
x Any other small molecule inhibitor within 2 weeks or 5 half-lives of 
the compound, whichever is shorter 
x Experimental treatment of any type within 30 days 
 
3.2.2 Participants may not be currently receiving any other experimental agents. 
 
3.2.3 No prior treatment with any HSP90 or HDAC inhibitor compound is 
allowed 
 
3.2.4 Participants with known and untreated brain metastases are excluded. 
Note: Patients without known prior CNS metastases and without clinical 
signs and symptoms of CNS involvement are not required to have an MRI 
of the brain prior to enrollment. Patients with treated brain metastases 


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that are asymptomatic and clinically stable for two weeks will be 
eligible for protocol participation.  
 
3.2.5 History of allergic reactions attributed to compounds of similar chemical 
or biologic composition to AUY922
 
3.2.6 Unresolved diarrhea  CTCAE version 4, grade 1.
 
3.2.7 Pregnant or lactating women
 
3.2.8 Participants who have undergone any major surgery  2 weeks prior to 
starting study drug or who have not recovered from side effects of such 
therapy
 
3.2.9 Participants with known disorders due to a deficiency in bilirubin 
glucuronidation (e.g. Gilbert’s syndrome).
 
3.2.10 Participants requiring the use of therapeutic doses of warfarin (Coumadin).
 
3.2.11 Participants with any of the following cardiac conditions:
 
x History of long QT syndrome. 
x QTcF  450 ms during screening ECG. 
x History of clinically manifest ischemic heart disease including myocardial 
infarction, stable or unstable angina pectoris, coronary arteriography or cardiac 
stress testing/imaging with findings consistent with infarction or clinically 
significant coronary occlusion  6 months prior to study start. 
x History of heart failure or left ventricular (LV) dysfunction (LVEF  45%) by 
MUGA or ECHO. 
x Clinically significant ECG abnormalities including one or more of the following: 
left bundle branch block (LBBB), right bundle branch block (RBBB) with left 
anterior hemiblock (LAHB). ST segment elevations or depressions > 1mm, or 2nd 
(Mobitz II) or 3rd degree AV block. 
x History and presence of atrial fibrillation, atrial flutter or ventricular arrhythmias 
including ventricular tachycardia or Torsades de Pointes. 
x Other clinically significant heart disease (e.g. congestive heart failure, uncontrolled 
hypertension, history of labile hypertension, or history of poor compliance with an 
hypertensive regimen). 
x Clinically significant resting bradycardia (<50 beats per minute). 
x Patients who are currently receiving treatment with any medication which has a 
relative risk or prolonging the QTc interval or inducing Torsades de Pointes (as 
listed in protocol section 5.4) and cannot be switched or discontinued to an 
alternative drug prior to commencing AUY922 dosing. 
x Patients who are on a cardiac pacemaker.


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3.2.12 Uncontrolled intercurrent illness including, but not limited to ongoing or 
active infection, symptomatic congestive heart failure, unstable angina 
pectoris, cardiac arrhythmia, or psychiatric illness/social situations that 
would limit compliance with study requirements. 
 
3.2.13 Concurrent malignancies or invasive cancers diagnosed within the past 3 
years, except for adequately treated basal cell cancer of the skin or in situ 
cancer of the cervix. 
 
3.2.14 Patients known to be HIV positive, because of the potential for 
pharmacokinetic interactions with AUY922 and increased risk of life-
threatening infections. HIV testing is not required in the absence of 
clinical signs and symptoms suggesting HIV infection. 
 
3.3
Inclusion of Women, Minorities and Other Underrepresented Populations 
Lung cancer affects men and women, and people of all race and socioeconomic class. We do not 
expect the inclusion and exclusion criteria to negatively affect enrollment of underrepresented 
populations. 
 
4.
REGISTRATION PROCEDURES 
 
4.1
General Guidelines for DF/HCC and DF/PCC Institutions 
 
Institutions will register eligible participants with the DF/HCC Quality Assurance 
Office for Clinical Trials (QACT) central registration system. Registration must occur 
prior to the initiation of therapy. Any participant not registered to the protocol before 
treatment begins will be considered ineligible and registration will be denied.  
 
A member of the study team will confirm eligibility criteria and complete the protocol-
specific eligibility checklist. 
 
Following registration, participants may begin protocol treatment. Issues that would 
cause treatment delays should be discussed with the Principal Investigator. If a 
participant does not receive protocol therapy following registration, the participant’s 
protocol status must be changed. Notify the QACT Registrar of participant status 
changes as soon as possible. 
 
4.2
Registration Process for DF/HCC and DF/PCC Institutions 
 
The QACT registration staff is accessible on Monday through Friday, from 8:00 AM to 
5:00 PM Eastern Standard Time. In emergency situations when a participant must begin 
treatment during off-hours or holidays, call the QACT registration line at 
 
and follow the instructions for registering participants after hours. 
 
The registration procedures are as follows: 
 


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1. 
Obtain written informed consent from the participant prior to the performance 
of any study related procedures or assessments. 
 
2. 
Complete the protocol-specific eligibility checklist using the eligibility 
assessment documented in the participant’s medical/research record. To be 
eligible for registration to the study, the participant must meet each 
inclusion and exclusion criteria listed on the eligibility checklist. 
 
Reminder: Confirm eligibility for ancillary studies at the same time as 
eligibility for the treatment study. Registration to both treatment and ancillary 
studies will not be completed if eligibility requirements are not met for all 
studies. 
 
3. 
Fax the eligibility checklist(s) and all pages of the consent form(s) to the 
QACT at 
 
 
Exception: DF/PCC Affiliate sites must fax the entire signed consent form 
including HIPAA Privacy Authorization and the eligibility checklist to the 
Network Affiliate Office. The Network Affiliate Office will register the 
participant with the QACT. 
 
4. 
The QACT Registrar will (a) validate eligibility, (b) register the participant on 
the study, and (c) randomize the participant when applicable. 
 
5. 
The QACT Registrar will send an email confirmation of the registration 
and/or randomization to the person initiating the registration immediately 
following the registration and/or randomization. 
 
4.3
General Guidelines for Other Participating Institutions 
N/A 
 
4.4
Registration Process for Other Participating Institutions 
N/A 
 
5.
TREATMENT PLAN 
 
Treatment will be administered on an outpatient basis. Expected toxicities and potential risks as 
well as dose modifications for AUY922 are described in Section 6 (Expected Toxicities and 
Dosing Delays/Dose Modification). No investigational or commercial agents or therapies other 
than those described below may be administered with the intent to treat the participant’s 
malignancy. 
 
This is a single-arm, open-label, phase II trial of AUY922. All patients will receive the same 
dose and schedule of study medication, which is: 
 


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AUY922 intravenously at 70 mg/m2 once weekly, i.e. days 1, 8 and 15 of every 21-day cycle 
 
Although it is ideal for patients to receive their study medication on the same day of the week 
each week, there is a 2-day plus/minus window allowed to be flexible with holidays, inclement 
weather, transportation difficulties, etc. For patients who are unable to tolerate the protocol-
specified dosing schedule, schedule adjustments are permitted. This includes the ability to skip a 
week of dosing if needed up to once per cycle. 
 
5.1
Pre-treatment Criteria 
 
5.1.1 Cycle 1, Day 1 
 
The patient should continue to meet all eligibility criteria on C1D1, as they did during the 
screening period.  
5.1.2 Subsequent treatment days (weekly) 
x Any grade 3 or higher toxicity should have resolved to grade 1 or baseline prior to 
dosing 
x ECG should be reviewed by a clinician to verify QTcF is not prolonged >500ms 
 
5.2
AUY922 Administration
5.2.1 How AUY922 is supplied 
Novartis supplies AUY922 in individual vials and/oramber-colored, glass ampoules. Vials will 
also be available.  Each vial is 20mL, each containing nominally 50 mg AUY9222 (calculated as 
free base).  The storage conditions for study drug will be described on the medication label. The 
vials/ampoules should be stored safely and separately from other drugs. Please see handling 
instructions. 
Dosage Forms:
Vials: 20 mL vials, each containing nominally 50 mg AUY922 (calculated as free base). 
Glass ampoules: 10 mL amber-colored, glass ampoules, each containing 10 ml of a 5 mg/ml 
active drug substance in 5% aqueous glucose solution. 
 
5.2.2 Preparation and storage for AUY922 
AUY922 is intended for IV infusion and should be diluted to the appropriate concentration 
(according to patient body surface area) in a 500ml infusion bag containing 5% dextrose or 
glucose (with a maximum infusion volume of 500 ml) prior to administration. Note that 
concentrations within the range of 0.006 mg/ml up to 0.28 mg/ml are acceptable.The drug may be 
administered using a central line or via peripheral vein. If a peripheral line is used, the injection 
site should be monitored carefully during the time of infusion and at subsequent follow-up visits. 
Please follow the preparation instruction provided below. 




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5.3  Administration of AUY922 
x AUY922 will be administered to patients through a 0.2 μm in-line filter. 
14. Once the AUY922 Concentrate for Infusion has been compounded in the 
infusion bag, it should be administered immediately. 
15. The infusion set has to be flushed with a carrier solution (5% dextrose) prior 
administration of the infusion solution. 
16. From a microbiological point of view, the aseptic techniques, in-use storage 
time (60 minutes) and conditions prior to use are the responsibility of the person who is 
administering the infusion (e.g. hospital pharmacist / nurse). 
17. From a chemical - and physicochemical point of view, in-use stability of 
AUY922 infusion solution has been demonstrated for a maximum of 6 hours at room 
temperature and at 2-8°C (opening of the Vials until end of infusion). 
18. Carefully inspect the final infusion solution prior to administration. The final 
infusion solution should be a clear solution free from any particles.  
19. The final infusion solution must be administered through an integrated or 
additional 0.2 μm in-line filter. 
. 
 
5.4 Definition of Dose-Limiting Toxicity 
N/A 
 
5.5
General Concomitant Medication and Supportive Care Guidelines 
 
In general, the use of any concomitant medication/therapies deemed necessary for the care of the 
patient is permitted with the following exceptions: 
 
x Therapeutic doses of warfarin sodium (Coumadin®) are not permitted. 
x Preliminary in vitro metabolism studies suggest that AUY922 is a moderate CYP2C9, 
2C8, 2C19, and CYP3A4 inhibitor. Therefore, drugs known to be metabolized by 
CYP3A4, CYP2C8, CYP2C9 or CYP2C19 should be used with caution because of 
the inherent potential risk of either reduced activity or enhanced toxicity of the 
respective concomitant medication and/or AUY922 with preliminary in vitro 
metabolism studies. Patients using concomitant medications known to be metabolized 
by these cytochrome p450 isoenzymes will not be excluded from the study. However, 
the patients must be carefully monitored for potentiation of toxicity due to individual 
concomitant medications. 
x Please refer to a list of known medications that are substrates, inhibitors, and inducers 
of CYP2C9, CYP2C8, 2C19, and 3A4/5 enzymes and avoid co-administration with 
AUY922 in For the most updated information, please also visit the following website: 
medicine.iupui.edu/flockhart/table.htm 


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If, after a patient has been enrolled, he/she requires the concomitant use of any of the 
medications which may cause QT prolongation, then the patient must be discontinued from the 
study. Excluded medications which may cause QTc prolongation are also listed and updated in 
web address: qtdrugs.org/medical-pros/drug-lists/drug-lists.htm. The investigator should 
instruct the patient to notify the study site about any new medications he or she takes after the 
start of the study drug. 
 
5.6
Duration of Therapy 
 
Duration of therapy will depend on individual response, evidence of disease 
progression and tolerance. In the absence of treatment delays due to adverse events, 
treatment may continue until one of the following criteria applies: 
x Disease progression.  
x Intercurrent illness that prevents further administration of treatment, 
x Unacceptable adverse event(s), 
x Participant decides to withdraw from the study, or 
x General or specific changes in the participant's condition render the participant 
unacceptable for further treatment in the opinion of the treating investigator. 
 
Patients may continue to receive AUY922 beyond RECIST-defined progression at the 
discretion of the treating physician if they are continuing to show clinical benefit. 
 
5.7
Duration of Follow Up  
 
Participants will be followed for survival every 3 months after removal from study or 
until death, whichever occurs first. Participants removed from study for unacceptable 
adverse events will be followed until resolution or stabilization of the adverse event. 
 
5.8
Criteria for Removal from Study
 
Participants will be removed from study when any of the criteria listed in 
Section 5.5 applies. The reason for study removal and the date the participant was 
removed must be documented in the study-specific case report form (CRF). 
Alternative care options will be discussed with the participant. 
 
In the event of unusual or life-threatening complications, participating investigators 
must immediately notify the Principal Investigator (or Protocol Chair), Dr. Lecia 
Sequist, at 
 
 


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6.
EXPECTED TOXICITIES AND DOSING DELAYS/DOSE MODIFICATIONS  
 
Dose delays and modifications will be made using the recommendations in this section of the 
protocol. Toxicity assessments will be done using the CTEP Version 4.0 of the NCI Common 
Terminology Criteria for Adverse Events (CTCAE) which is identified and located on the 
CTEP website at: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.  
 
If possible, symptoms should be managed symptomatically. In the case of toxicity, 
appropriate medical treatment should be used (including anti-emetics, anti-diarrheals, etc.). 
 
All adverse events experienced by participants will be collected from the time of the first 
dose of study treatment, through the study and until the final study visit. Participants 
continuing to experience toxicity at the off study visit may be contacted for additional 
assessments until the toxicity has resolved or is deemed irreversible. 
 
6.1
Anticipated Toxicities 
 
The preclinical safety evaluation showed that the toxicity profile of AUY922 is dominated by 
cytotoxic and inflammatory reactions in the intestine, bone marrow and lymphoid tissue, as well 
as a moderate risk of local irritation at the injection site. The observed changes were reversible in 
the animal experiments. Nevertheless, there is a probability that patients may experience diarrhea 
following treatment with AUY922. Safety pharmacology studies revealed no effects on CNS or 
respiratory functions. 
 
Based on in vitro and in vivo data, a potential for cardiovascular toxicity, such as QTc 
prolongation or proarrhythmia could not be completely excluded. In vitro cardiac safety studies 
demonstrated a pre-clinical signal for QT prolongation, however, no effects on QT or QTc were 
observed in the GLP dog and monkey telemetry studies in vivo. Due to potential cardiac toxicity 
patients in ongoing studies are undergoing careful cardiac monitoring. 
 
No potential for genotoxicity (in vitro and in vivo) or phototoxicity (in vitro) was found in the 
preclinical safety studies conducted so far. Patients treated with this medication have had 
reversible ocular toxicities, see below. 
 
In conclusion, main target organs for AUY922 are the intestine, bone marrow and lymphoid 
tissue. There may be a risk of QTc prolongation, of visual changes, and of a local irritative 
effect. 
 
The cardiac safety parameters can be monitored in the clinic using an intensive ECG and vital 
signs monitoring schedule, see Section 6.2.3. Detailed instructions for the observation and 
treatment of diarrhea and visual toxicities are also provided in this study protocol, Sections 6.2 
and 6.3. If a peripheral line is used for the infusion of the study drug, the injection site should be 
monitored carefully during the time of infusion. 
 


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6.2
Surveillance and Management of Specific Toxicities 
 
Dose modification instructions for general adverse events are found in Section 6.3.  
6.2.1 Diarrhea Management 
 
In previous studies, AUY922 was shown to induce gastrointestinal toxicities in some patients 
and therefore there is a substantial risk that patients will develop diarrhea. 
Proactively look for occurrence of diarrhea after start of AUY922 treatment. Call patients at 
home, if necessary, to detect diarrhea early during the first 8 weeks. If no problems occur, 
instruct the patient to call if and when a problem does arise. 
General suggestions: 
x Stop all lactose-containing products, and alcohol 
x Stop laxatives, bulk fiber (i.e Metamucil®, Procter & Gamble), and stool softeners 
(docusate sodium; Colace, Roberts) 
x Drink 8 to 10 large glasses of clear liquids per day (i.e water, Pedialyte® (Ross),Gatorade 
(Quaker), broth) 
x Eat frequent small meals (bananas, rice, applesauce, Ensure®, toast) 
x Stop high-osmolar food supplements such as Ensure Plus and Jevity Plus (with fiber) 
It is recommended that patients be provided loperamide tablets and that patients are instructed on 
the use of loperamide at cycle 1 in order to manage signs or symptoms of diarrhea at home. 
Patients should be instructed to start oral loperamide (initial administration of 4 mg, then 2 mg 
every 4 hours (maximum of 16 mg/day) at the first sign of loose stool or symptoms of abdominal 
pain. At the beginning of each cycle, each patient should be specifically questioned regarding 
any experience of diarrhea or diarrhea related symptoms.  
 
Treatment of diarrhea grade 1 or 2
Diarrhea grade 1 or 2 will be treated with loperamide (initial administration 4 mg, then 2 mg 
every 4 hours (maximum of 16 mg/day) or after each unformed stool). 
 
24 hours after the start of diarrhea, if: 
Diarrhea resolved 
x Continue dietary modifications 
x Gradually add solid foods to diet 
x Discontinue loperamide after 12-hour interval without diarrhea 
x See Section 6.3 for dose modification recommendations upon re-initiation of 
AUY922 
 


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Diarrhea unresolved 
x Addition of opium tincture or dihydrocodeine tartrate tablets/injections 
x Re-assessment for dehydration, sepsis, ileus 
x Medical check and selected work-up to evaluate whether patient does not need 
hospitalization (see below for recommended diarrhea work-up) 
 
48 hours after the start of diarrhea, if:  
 
Diarrhea resolved 
x Continue dietary modifications 
x Gradually add solid foods to diet 
x Discontinue loperamide and/or other agents after 12-hour interval without diarrhea 
x See Section 6.3 for dose modification recommendations upon re-initiation of 
AUY922 
 
Diarrhea unresolved 
x If persistent diarrhea (CTCAE grades 1 or 2) after 2x 24 hours with high dose 
loperamide and opiates, admit to hospital and follow recommendations for grade 
3/4 diarrhea until resolved.  
 
If diarrhea has progressed to CTCAE grades 3 or 4, begin measures outlined below 
 
Treatment of diarrhea grade 3 or 4
Severe diarrhea grade 3 or 4 may be treated with hospitalization, high dose loperamide (initial 
4 mg, then 2 mg every 2 hours) and addition of opium tincture or dihydrocodeine tartrate 
tablets/injections. Additionally, intravenous fluids and antibiotics may be given as needed with 
monitoring of the patient’s condition to rule out other causes for diarrhea. Observe for response. 
 
24 hours after the start of diarrhea, if diarrhea is unresolved: 
x Administer subcutaneous octreotide (100-500 ȝg TID) 
x Consider intravenous fluids and antibiotics as clinically indicated.  
x If grade 3 or 4 diarrhea persists, patients should receive opium tincture or 
dihydrocodeine tartrate by subcutaneous or intra-muscular injection.  
x If grade 3 or 4 diarrhea persists despite opium tincture or dihydrocodeine, 
subcutaneous octreotide (500-1000 ȝg TID) should be administered.  
x See table 5 for dose modifications secondary to diarrhea.  
 


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Diarrhea work-up
x History and physical exam. 
x Examination of stool for occult blood. 
x Examine the stool for fecal leukocytes. 
x Examine the stool for C. difficile toxin if high clinical suspicion. 
x Consider stool cultures for pathogens such as Shigella and pathogenic E. coli. 
x Endoscopic examinations may be considered only if absolutely necessary. The bowel is 
likely to be fragile with evidence of colitis and thus great care and caution must be 
exercised in undertaking these invasive procedures. 
6.2.2 Ocular Toxicity Management 
 
Weekly administration of AUY922 may cause visual symptoms. The visual symptom 
descriptions from ongoing phase studies have included slow dark-light adaptation or 
photophobia, blurred vision, floaters and flashes in peripheral vision, dark or black spots, 
darkening of vision, decreased peripheral vision, color vision disturbances, and dry eye 
syndrome. The visual symptoms were mostly reported the day after the second or third infusion 
and typically resolved within a week or two weeks post dose. All visual symptoms were 
reversible; in some patients the events resolved with omission of a dose or after discontinuation 
of AUY922 treatment. 
 
The standard recommendation for managing visual toxicities with AUY is to hold the drug if 
toxicities are grade 2 or higher. See Section 6.3 for dose reduction guidelines. 
 
Standard ophthalmologic assessments will be required at baseline and follow-up exams will be 
conducted at the time when visual symptom(s) are reported (if any), at the beginning of cycle 3 if 
no visual symptom(s) are reported, and at study discontinuation. 
 
The following standard ophthalmologic assessments are required: 
1. Visual acuity test 
2. Intraocular pressure test 
3. Slit-lamp test 
4. Dilated fundus test 
5. Color-vision (Ishihara-plate) test 
 
Additional assessments or tests may be conducted as clinically indicated. Visual symptoms will 
be graded using NCI CTCAE 4.0. However, for the acuity test (Snellen charts) the following 
grading should be applied. 
 
Table 2. Visual AE Grading for AUY922 Using Snellen Charts 
 
Toxicity 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Decreased 
Acuity 
Baseline-
20/20 despite 
visual 
symptoms 
20/30-20/40 
20/50-20/100 
20/200 or 
below 


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Toxicity 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Note: Refers to the visual acuity when a patient wears his or her best eyeglasses. 
The acuity scores pertains to the better eye.  


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6.2.3 Surveillance for Cardiac Toxicities 
 
In telemetry studies in monkeys, no clear effects on the QTc interval have been observed 
following administration of AUY922. But based upon in vitro and in vivo data, a potential for 
cardiovascular toxicity, such as QTc prolongation or proarrhythmia with AUY922 could not be 
excluded; therefore, cardiovascular monitoring will be conducted throughout the study. 
 
As part of the screening process, patients will be required to undergo either a MUGA or 
transthoracic echocardiogram to assess left ventricular ejection fraction (LVEF). Patients will be 
closely monitored by ECG throughout the study, see schedule below. If cardiac changes are 
observed during monitoring, please refer to Section 6.3 for dose modifications. 
 
Table 3. Schedule for 12-lead ECG Monitoring 
 
Cycle 
Day 
12-lead ECG 
Timing and details 
Baseline 
Baseline 
X 
Three 12-lead ECGs. 
1 
1 
X 
A 12-lead ECG should be obtained prior to the infusion  and 
after infusion. 
2 
X 
A 12-lead ECG should be obtained at approximately 24hrs 
post end of infusion. 
3 
X 
A 12-lead ECG should be obtained at approximately 48 hrs 
post end of infusion. 
8 
X 
A 12-lead ECG should be obtained at pre-infusion (timing is 
not pre-specified) and after infusion.  
15 
X 
A 12-lead ECG should be obtained at pre-infusion (timing is 
not pre-specified) and after infusion.  
All subsequent 
cycles 
1, 8, 15 
X 
A 12-lead ECG should be obtained at pre-infusion (timing is 
not pre-specified) and after infusion.  
 
 
6.3
Dose Modifications/Delays 
 
If the patient experiences unacceptable toxicities, treatment with the study drug should be 
suspended until the toxicities return to  CTCAE grade 1 (or baseline). Dose modification may 
be required upon treatment resumption, see below.  
 
Patients whose treatment is interrupted or permanently discontinued due to an adverse event or 
abnormal laboratory value should be followed at least once a week for 4 weeks, and 
subsequently at 4-week intervals, until resolution or stabilization of the event, whichever comes 
first. If a patient requires a dose delay of >21 days from the intended day of the next scheduled 
dose, then the patient must discontinue the study. All patients will be followed for adverse events 
and serious adverse events for 28 days following the last dose of AUY922. 


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Toxicity will be assessed using the NCI-CTC for Adverse Events, version 4.0 (CTCAE v4.0) 
 
For patients who are unable to tolerate the protocol-specified dosing schedule, schedule 
adjustments are permitted. This includes the ability to skip a week of dosing if needed up to once 
per cycle. 
 
Dose reduction levels are listed in Table 4 and specific instructions for holding drug, reducing 
doses, and managing toxicities are listed in Table 5. Only two dose level reductions are allowed 
per patient. 
 
Table 4. Does Reduction Levels for AUY922 
Dose reduction* 
 
Starting dose level  0 
Dose level – 1 
Dose level – 2 
AUY922 
70 mg/m2 
55 mg/m2 
40 mg/m2 
*Dose reduction should be based on the worst toxicity demonstrated at the last dose. 
Dose may be reduced a maximum of 2 times, no further reduction is permitted. 
 
Table 5. Criteria for Interruption, Dose Reduction and Re-Initiation of AUY922 
 
Recommended Dose Modifications for AUY922 
Worst Toxicity 
CTCAE Grade a. unless otherwise 
specified  
At any time during a cycle of AUY922 
(including intended day of dosing) 
No toxicity 
Maintain dose level 
Diarrhea 
 
Grade 1 (see Section 6.2 for recommended 
treatment algorithm) 
 
Maintain dose level 
Grade 2 
(see Section 6.2 for recommended treatment 
algorithm) 
Omit dose administration until recovery to Grade 1 or 
baseline, then continue AUY922 at: 
- current dose level if grade 2 toxicity persisted ≤ 7 days. 
- one dose level lower if grade 2 toxicity persisted > 7 days  
 
Grade 3 
(see Section 6.2 for recommended treatment 
algorithm) 
 
Omit dose administration until recovery to Grade 1 or baseline 
then decrease the next scheduled dose by 1 dose level. 
Grade 4 
(see Section 6.2 for recommended treatment 
algorithm) 
Omit dose administration until recovery to Grade 1 or baseline 
then: 
- if grade 4 toxicity lasted ≤ 24 hours, may resume AUY922 
but decrease the next scheduled dose by 1 dose level. 
- In the event Grade 4 toxicity lasted >24 hours despite 
maximal medical attention, permanently discontinue 
treatment. 
 
If grade 4 toxicity recurs upon re-exposure, permanently 
discontinue treatment. 
 


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Recommended Dose Modifications for AUY922 
Worst Toxicity 
CTCAE Grade a. unless otherwise 
specified  
At any time during a cycle of AUY922 
(including intended day of dosing) 
Hematological 
Neutropenia (ANC) 
 
Grade 1 (ANC < LLN - 1.5 x 109/L) or 
Grade 2 (ANC < 1.5 - 1.0 x 109/L ) 
 
Maintain dose level 
Grade 3 (ANC < 1.0 - 0.5 x 109/L) 
Omit dose administration until resolved to ≤ grade 1, 
x 
If resolved in ≤ 7 days, then maintain dose level 
x 
If resolved in > 7 days, then decrease by 1 dose level 
 
Grade 4 (ANC < 0.5 x 109/L) 
Omit dose administration until resolved to ≤ grade 1, then 
decrease by 1 dose level 
 
Febrile neutropenia  
Omit dose administration until resolved, then decrease by 1 
dose level 
 
Thrombocytopenia 
 
Grade 1 (PLT < LLN - 75 x 109/L) 
 
Maintain dose level 
Grade 2 (PLT < 75 - 50 x 109/L) or 
Grade 3 (PLT < 50-25 x 109/L) 
Omit administration dose until resolved to ≤ grade 1, then: 
x 
If resolved in ≤ 7 days, then maintain dose level 
x 
If resolved in > 7 days, then decrease by 1 dose level 
 
Grade 4 (PLT < 25 x 109/L) 
Omit administration dose until resolved, then decrease by 1 
dose level 
 
Renal 
Serum creatinine 
 
( < 2 x ULN) 
Maintain dose level 
 
( 2 - 3 x ULN) 
Omit dose administration until resolved to ≤ grade 1, then 
x 
If resolved in ≤ 7 days, then maintain dose level 
x 
If resolved in > 7 days, then decrease by 1 dose level 
 
Grade 3 (>3.0 baseline; > 3.0 - 6.0 x ULN) or 
Grade 4 (> 6.0 x ULN) 
Omit dose administration and permanently discontinue patient 
from study treatment 
 
Hepatic 
Bilirubin 
 
( < 2 x ULN) 
 
Maintain dose level 
(2 - 3 x ULN) 
Omit dose administration until resolved to ≤ grade 1, then 
x 
If resolved in ≤ 7 days, then maintain dose level 
x 
If resolved in > 7 days, then decrease by 1 dose level 
 
Grade 3 (> 3.0 - 10.0 x ULN) 
 
Omit dose administration until resolved to ≤ grade 1, then 
decrease by 1 dose level 
 
Grade 4 (> 10.0 x ULN) 
Omit dose administration and permanently discontinue patient 
from study treatment 
 


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Recommended Dose Modifications for AUY922 
Worst Toxicity 
CTCAE Grade a. unless otherwise 
specified  
At any time during a cycle of AUY922 
(including intended day of dosing) 
AST or ALT 
 
Grade 1 (>ULN - 3.0 x ULN) or 
Grade 2 (Asymptomatic with ALT >3.0 - 5.0 x 
ULN;  >3 x ULN with the appearance of 
worsening of fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness, fever, 
rash, or eosinophilia) 
 
Maintain dose level 
Grade 3 (>5.0 - 20.0 x ULN ) 
Omit dose administration until resolved to ≤ grade 1 (or ≤ 
grade 2 in case of liver metastasis), then 
x 
If resolved in ≤ 7 days, then maintain dose level 
x 
If resolved in > 7 days, then decrease by 1 dose level 
 
Grade 4 (> 20.0 x ULN) 
Omit dose administration until resolved to ≤ grade 1, then 
decrease by 1 dose level 
 
Cardiac - Prolonged QTcF interval 
During cycle 1 
 
Absolute QTcF ≤ 480msec 
 
Maintain dose level and ECG monitoring as per visit schedule. 
Absolute QTcF ≥ 481msec and, ≤ 500 msec 
Maintain dose level. ECG monitoring assessments should be 
performed for 2 additional cycles at the same frequency as in 
cycle 1. After the second additional cycle, ECGs for 
subsequent cycles will be performed as follows: 
x 
If ECG in the additional cycles shows no QTcF absolute 
≥ 481 msec then, for subsequent cycles ECG monitoring 
will be performed as per visit schedule. 
x 
If ECG still abnormal (QTcF absolute ≥ 481 msec and 
≤ 500 msec) then ECG monitoring must continue at the 
same frequency as in cycle 1 for all subsequent cycles. 
 


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Recommended Dose Modifications for AUY922 
Worst Toxicity 
CTCAE Grade a. unless otherwise 
specified  
At any time during a cycle of AUY922 
(including intended day of dosing) 
During any cycle 
Grade 3 or QTcF ≥ 501 msec as identified by 
the investigator on the ECG. 
Omit dose administration. Monitor patient with hourly ECGs 
until the QTcF has returned to ≤ 450 msec. Further monitoring 
as clinically indicated. Exclude other causes of QTcF 
prolongation such has hypokalemia, hypomagnesemia and 
blood oxygenation statusb. 
Once QTcF prolongation has resolved, patients may be re-
treated at one lower dose level at the investigator’s discretion. 
ECG monitoring must continue throughout the treatment 
period as follows: 
x 
ECG monitoring assessments should be performed for 
2 additional cycles at the same frequency as in cycle 1 
x 
If the ECGs obtained in the first and second additional 
cycle (after dose reduction) are without any QTcF 
prolongation, then ECG monitoring in subsequent cycles 
will be continued as per the visit schedule. 
x 
If the patient had an absolute QTcF ≥ 481 msec and ≤500 
msec, then ECG monitoring at the same frequency as in 
cycle 1 will be continued for all subsequent cycles. 
x 
Patients who experience absolute QTcF ≥ 501 msec after 
one dose reduction will be discontinued from study. 
Note: If Torsades de Pointes are observed in a patient, the 
patient will be discontinued from the study. 
 


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Recommended Dose Modifications for AUY922 
Worst Toxicity 
CTCAE Grade a. unless otherwise 
specified  
At any time during a cycle of AUY922 
(including intended day of dosing) 
Other adverse events 
Grade 1 or 2 
Maintain dose level 
 
Grade 3 
Omit dose administration until resolved to ≤ grade 1, then 
decrease by 1 dose level 
 
Grade 4 
Omit dose administration and permanently discontinue patient 
from study 
 
Eye disorders (see section 6.2 for Grading Table) 
Grade 1  
 
Maintain dose level  
Grade 2  
Omit dose administration until resolved to ≤ grade 1 (or 
baseline), then continue treatment with AUY922 at the current 
dose level 
If visual symptoms ≥ Grade 2 recur upon re-exposure to 
AUY922,   omit dose until resolution to ≤ Grade 1, then 
decrease 1 dose level  
 
Grade 3  
Omit dose administration until resolved to ≤ grade 1 (or 
baseline), then decrease 1 dose level  
 
Grade 4 
Omit dose administration and permanently discontinue patient 
from study 
 
All dose modifications should be based on the worst preceding toxicity. 
If a patient requires a treatment interruption of > 21 days from the last dose of AUY922, then the patient must 
be discontinued from the study treatment. Patients who discontinue from the study for a study-related adverse 
event or an abnormal laboratory value must be followed as per protocol. 
- Up to two dose reductions are allowed. In case the patient had clinical benefit and needs more than two dose 
reduction, it will be discussed case by case with the sponsor 
a. Common Terminology Criteria for Adverse Events (CTCAE Version 4.0) 
b. Exclude other causes of QTc prolongation such has hypokalemia, hypomagnesemia and blood oxygenation 
status. Patients who develop hypokalemia or hypomagnesemia during the study should receive electrolyte 
replacement as soon as possible and should not receive further AUY922 dosing until the respective 
electrolytes are documented to be within normal limits. 
 
7. CORRELATIVE/SPECIAL STUDIES  
Patients with available tumor tissue will have EGFR exon 20 analyzed by direct sequencing 
if they have not already had this testing. The purpose of this is to know the exact exon 20 
mutation for all patients on the study, variations in outcome by mutation type can be 
explored. Some of the participating institutions use direct sequencing already as their clinical 
test to identify these patients, while some use a sizing assay that does not provide the exact 
insertion or insertion/deletion mutation. Patients without available tumor tissue will be 
eligible to participate in the study and will not have to undergo a biopsy. 


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September 29, 2016 
 
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7.1
Pharmacokinetic Studies 
 
N/A 


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8.
 STUDY CALENDAR 
Table 6. Required Data 
 
 
Baseline 
Cycle 1 
Cycle 2 
Subsequent 
cycles 
End of 
Treatment 
28 Day Safety 
Visit 
Tumor 
FU 
Survival 
FU 
End of 
Study 
Day of Cycle 
-21 to -1 
1 
2 
3 
8 
15 
1 
8 
15 
1 
8 
15 
≤ 7 days of 
last dose 
28 (±7) days 
of last dose  
N/A 
N/A 
N/A 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Collection of baseline 
required demographic 
and clinical data  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vitals signs and ECOG 
Performance status1 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Physical Exam 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
12-lead ECG2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Cardiac imaging (MUGA 
or ECHO) 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
Hematology and 
biochemistry labs3 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Coagulation labs 
X 
X 
 
 
 
 
X 
 
 
X10 
 
 
X 
 
 
 
 
Urinalysis 
X 
X 
 
 
 
 
X 
 
 
X10 
 
 
X 
 
 
 
 
Eye Exam4 
X4 
 
 
 
 
 
 
 
 
X4 
 
 
X4 
 
 
 
 
AUY922 IV infusion5 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
Concomitant Medications 
X 
Ongoing 
X 
 
 
 
 
Adverse Events 
X 
Ongoing 
X 
X 
 
 
 
Radiological assessment 
of tumor – CT/MRI6 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X7 
 
 
Survival8 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
Tumor sample for 
mutation and 
amplification testing9 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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1. Vital sings – During treatment period, vital signs will be performed pre-dose (including temperature, respiratory rate, blood pressure, pulse, weight and ECOG PS) and 
immediately post-dose infusion (including temperature, respiratory rate, blood pressure and pulse).  
2. ECG- Please refer to Table 3 for detailed schedule of ECGs.  
3. In women of child-bearing potential, a serum pregnancy test must be obtained prior (within 14 days) to the first administration of AUY922. CHEMISTRY: BUN, 
Creatinine, Glucose, Total Protein, Albumin, AST/SGOT, ALT/SGPT, Total Bilirubin, Alkaline Phosphatase, Magnesium, Calcium, Sodium, Potassium, 
Phosphorous. HEMATOLOGY: CBC with differential 
4. Standard ophthalmologic assessments will be required at baseline and follow-up exams will be conducted at the time when visual symptoms are reported (if any), at 
cycle 3 day 1 if no visual symptoms are reported, and at study discontinuation. There is a +/- 7 day window allowed for eye exam at Cycle 3 day 1 
5. One should aim to administer AUY922 on the same day each week, but there is a +/- 2 day window allowed to account for holidays, inclement weather, transportation 
difficulties, etc. For patients who are unable to tolerate the protocol-specified dosing schedule, schedule adjustments are permitted. This includes the ability to skip a 
week of dosing if needed up to once per cycle. Patients who continue treatment beyond progression can skip up to two infusions per cycle if needed after discussion 
between the treating MD and the overall PI of the study. 
6. A CT scan with contrast of the chest, abdomen, and pelvis will be performed on patients at baseline (screening) -30 to -1 days prior to study drug administration. The 
same type of imaging modality (CT with contrast or MRI) used at screening must be used for all subsequent follow-up assessments. Follow-up CT/MRI scans will be 
performed every 6 weeks (±7 days) from registration. 
7. In the event that a patient is discontinued from treatment for any reason other than disease progression, an end of treatment CT/MRI is recommended to be performed 
if the last scan was conducted ≥ 4 weeks previously. Such patients who discontinue study treatment for reasons other than disease progression should be re-staged 
every 12 weeks (±7 days) until start of another anti-cancer treatment. 
8. Patients will be followed for survival every 3 months after discontinuing the trial. Follow-ups may be conducted over the telephone. 
9. If available, tumor samples will be sequenced for EGFR exon 20 mutation. 
10. For patients who miss a D1 visit of any cycle (as allowed per protocol,) any missed day 1 assessments (for example, coagulation studies and urinalysis) will be 
performed at the next clinic visit. 
 
 


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9. MEASUREMENT OF EFFECT
9.1 Treatment Efficacy 
For the purposes of this study, participants should be re-evaluated for response every 
6 weeks. Response and progression will be evaluated in this study using the new 
international criteria proposed by the Response Evaluation Criteria in Solid Tumors 
(RECIST) (Eisenhauer et al., 2009). Changes in the diameter (unidimensional 
measurement) of the tumor lesions are used in the RECIST criteria.
9.1.1 Disease Parameters 
Measurable disease. Measurable disease is the presence of at least one (1) lesion 
that can be accurately measured in at least one dimension with longest diameter 
>20 millimeters (mm) using conventional techniques (CT, MRI, x-ray) or 
>10 mm with spiral CT scan. Measurable lesions must be at least 2 times the 
slice thickness in mm. All tumor measurements must be recorded in millimeters 
(or decimal fractions of centimeters). 
Reminder: A lesion in a previously irradiated area is not eligible for measurable 
disease unless there is objective evidence of progression of the lesion prior to 
study enrollment. Lesions in previously irradiated areas must be clearly 
identified as such. 
  
Malignant lymph nodes. To be considered pathologically enlarged and 
measurable, a lymph node must be  15 mm in short axis when assessed by CT 
scan (CT scan slice thickness recommended to be no greater than 5 mm). At 
baseline and in follow-up, only the short axis will be measured and followed. 
 
Non-measurable disease.
All other lesions (or sites of disease), including small lesions (longest diameter 
<10 mm or pathological lymph nodes with  10 to < 15 mm short axis, are 
considered non-measurable disease. Bone lesions, leptomeningeal disease, ascites, 
pleural/pericardial effusions, lymphangitis cutis/pulmonis, inflammatory breast 
disease, abdominal masses identified by physical exam that are not measurable by 
reproducible imaging techniques, and cystic lesions are all considered non-
measurable. 


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Target lesions. 
All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in 
total, representative of all involved organs, should be identified as target lesions 
and recorded and measured at baseline. Lesions must be accurately measured in 1 
dimension with a minimum size of 10 mm by CT or MRI (slice thickness no 
greater than 5 mm), 20 mm by chest x-ray. Nodes must have a short axis 
 15 mm. The short axis should be included in the sum of the lesions in the 
calculation of response. Nodes that shrink to < 10 mm are considered normal. 
Target lesions should be selected on the basis of their size, be representative of 
all the involved organs, and should be lesions that can be followed with 
reproducible repeated measurements.  
Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue 
components, that can be evaluated by cross sectional imaging techniques such as 
CT or MRI can be considered target lesions if the soft tissue component meets 
the definition of measurability as defined above. Cystic lesions thought to 
represent cystic metastases can be considered as target lesions. However, if non-
cystic lesions are present, these are preferred for selection as target lesions. 
Lesions in previously irradiated areas or areas subject to other loco-regional 
therapy are usually not considered measurable unless there has been 
demonstrated progression of that lesion. 
 
Non-target lesions.
All other lesions, including small lesions < 10 mm or pathological lymph nodes 
measuring  10 mm to < 15 mm in short axis, as well as truly non-measurable 
lesions, which include leptomeningeal disease, ascites, pleural or pericardial 
effusion, inflammatory breast disease, lymphangitic involvement of skin or lung, 
abdominal masses identified by physical exam that are not measurable by 
reproducible imaging techniques.  
9.1.2 Methods for Evaluation of Measurable Disease 
The same method of assessment (CT or MRI) and the same technique should be 
used to characterize each identified and reported lesion at baseline and during 
follow-up. Spiral CT should be performed using a 5 mm contiguous 
reconstruction algorithm. 
9.1.3 Response Criteria  
9.1.3.1 Evaluation of Target Lesions 
 
Complete Response (CR):
Disappearance of all target lesions. Any pathological lymph node must 
have reduction in short axis to < 10 mm. 


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Partial Response (PR):
At least a 30% decrease in the sum of the diameters of target lesions, 
taking as reference the baseline sum diameters. 
 
Progressive Disease (PD):
 
At least a 20% increase in the sum of the diameters of target lesions, 
taking as reference the smallest sum on study with at least a 5 mm 
absolute increase in the sum of all lesions. The appearance of one or 
more new lesions* denotes disease progression. 
 
Stable Disease (SD): 
 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on 
study. 
Unknown (UN): Assessment of target lesions cannot be made due to 
insufficient or unevaluable data. In this case, a concise explanation must 
be given. 
Note: If tumor response data is missing for target lesions, the overall 
assessment must be UN unless there is new disease that would result in 
an overall assessment of PD. However, if there is missing or unevaluable 
data for non-target lesions, but data is available for all target lesions, the 
overall response for that time point will be assigned based on the sum 
LD of all target lesions. Additionally, the assessment of CR cannot be 
made if there is missing or unevaluable data for non-target lesions. In 
this case, the overall assessment would be PR. 
*Definition of New Lesion: The finding of a new lesion should be unequivocal 
(i.e. not due to difference in scanning technique, imaging modality, or findings 
thought to represent something other than tumor (ex: new bone lesions may be 
healing or flare of pre-existing lesions). However, a lesion identified on a follow-
up scan in an anatomical location that was not scanned at baseline is considered 
new and will indicate PD. If a new lesion is equivocal (because of small size, 
etc.), follow-up evaluation will clarify if it truly represents new disease and if PD 
is confirmed, progression should be declared using the date of the initial scan on 
which the lesion was discovered. 
9.1.3.2 Evaluation of Non-Target Lesions 
Complete Response (CR): Disappearance of all non-target lesions. All 
lymph nodes must be non-pathological in size ( < 10 mm short axis).  
Incomplete Response/Stable Disease (SD): Persistence of one or 
more non-target lesions. 


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Progressive Disease (PD): Appearance of one or more new 
lesions* (new lesions must be > slice thickness) and/or 
unequivocal progression of existing non-target lesions and /or 
overall level of substantial worsening that merits discontinuation 
of therapy. A useful test that can be applied when assessing non-
targets for unequivocal progression is to consider if the increase in 
overall disease burden based on the change in non-measurable 
disease is comparable in magnitude to the increase that would be 
required to declare PD for measurable disease. 
Unknown (UN): Assessment of non-target lesions cannot be made due 
to insufficient or unevaluable data. In this case, a concise explanation 
must be given. 
 
*Definition of New Lesion: The finding of a new lesion should be unequivocal 
(i.e. not due to difference in scanning technique, imaging modality, or findings 
thought to represent something other than tumor (ex: new bone lesions may be 
healing or flare of pre-existing lesions). However, a lesion identified on a follow-
up scan in an anatomical location that was not scanned at baseline is considered 
new and will indicate PD. If a new lesion is equivocal (because of small size, 
etc.), follow-up evaluation will clarify if it truly represents new disease and if PD 
is confirmed, progression should be declared using the date of the initial scan on 
which the lesion was discovered. 
 
9.1.3.3 Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of 
the treatment until disease progression/recurrence (taking as reference 
for progressive disease the smallest measurements recorded since the 
treatment started). The participant's best response assignment will 
depend on the achievement of both measurement and confirmation 
criteria. 
 
 


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Table 7. Evaluation of Best Overall Response 
 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response for 
when Confirmation is 
Required: 
CR 
CR 
No 
CR 
>4 wks confirmation 
CR 
Non-CR/Non-PD
No 
PR 
>4 wks confirmation 
CR 
Not evaluated
No
PR
PR 
Non-CR/Non-
PD/Not 
evaluated 
No 
PR 
SD 
Non-CR/Non-
PD/Not 
evaluated
No 
SD 
Documented at least once 
>4 wks from baseline 
PD 
Any
Yes or No
PD
No prior SD, PR or CR 
Any 
PD*
Yes or No
PD
Any 
Any
Yes
PD
* 
In exceptional circumstances, unequivocal progression in non-target lesions may be 
accepted as disease progression. 
 
Note:   Participants with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
reported as "symptomatic deterioration". Every effort should be made to document the 
objective progression even after discontinuation of treatment. 
 
9.1.4 Duration of Response 
Duration of overall response: The duration of overall response is measured from 
the time measurement criteria are met for CR or PR (whichever is first recorded) 
until the first date that recurrence or PD is objectively documented, taking as 
reference for PD the smallest measurements recorded since the treatment started. 
Duration of overall complete response: The duration of overall CR is measured 
from the time measurement criteria are first met for CR until the first date that 
recurrent disease is objectively documented. 
Duration of stable disease: Stable disease is measured from the start of the 
treatment until the criteria for progression are met, taking as reference the 
smallest measurements recorded since the treatment started. 
 
9.1.5 Progression-Free Survival 
Progression-Free Survival (PFS) is defined as the duration of time from start of 
treatment to time of objective disease progression.  


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9.1.6 Response Review 
Restaging imaging will be assessed at the DF/HCC Tumor Imaging Metrics Core to 
provide unbiased formal RECIST measurements 
 
10. ADVERSE EVENT REPORTING REQUIREMENTS 
 
10.1 Definitions
10.1.1 Adverse Event (AE)
 
An adverse event (AE) is any undesirable sign, symptom or medical condition or 
experience that develops or worsens in severity after starting the first dose of 
study treatment or any procedure specified in the protocol, even if the event is not 
considered to be related to the study. 
 
Abnormal laboratory values or diagnostic test results constitute adverse events 
only if they induce clinical signs or symptoms or require treatment or further 
diagnostic tests. 
10.1.2 Serious adverse event (SAE)
 
A serious adverse event (SAE) is any adverse event, occurring at any dose and 
regardless of causality that:  
x Results in death 
x Is life-threatening. Life-threatening means that the person was at 
immediate risk of death from the reaction as it occurred, i.e., it does not 
include a reaction which hypothetically might have caused death had it 
occurred in a more sever form. 
x Requires or prolongs inpatient hospitalization (i.e., the event required at 
least a 24-hour hospitalization or prolonged a hospitalization beyond the 
expected length of stay). Hospitalization admissions and/or surgical 
operations scheduled to occur during the study period, but planned prior to 
study entry are not considered SAEs if the illness or disease existed before 
the person was enrolled in the trial, provided that it did not deteriorate in 
an unexpected manner during the trial (e.g., surgery performed earlier than 
planned). 
x Results in persistent or significant disability/incapacity. Disability is 
defined as a substantial disruption of a person’s ability to conduct normal 
life functions. 
x Is a congenital anomaly or birth defect; or 


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x Is an important medical event when, based upon appropriate medical 
judgment, it may jeopardize the participant and require medical or surgical 
intervention to prevent one of the outcomes listed above. Examples of 
such medical events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home; blood dyscrasias or 
convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse. 
 
Events not considered to be serious adverse events are hospitalizations for: 
x routine treatment or monitoring of the studied indication, not associated 
with any deterioration in condition, or for elective procedures 
x elective or pre-planned treatment for a pre-existing condition that did not 
worsen 
x emergency outpatient treatment for an event not fulfilling the serious 
criteria outlined above and not resulting in inpatient admission 
x respite care 
 
10.1.3 Expectedness 
 
Adverse events can be 'Expected' or 'Unexpected.' 
 
10.1.3.1 
Expected adverse event
 
Expected adverse events are those that have been previously identified as 
resulting from administration of the agent. For the purposes of this study, 
an adverse event is considered expected when it appears in the 
Investigator’s Brochure or is included in the informed consent document 
as a potential risk. 
 
10.1.3.2 
Unexpected adverse event
 
For the purposes of this study, an adverse event is considered unexpected when it 
varies in nature, intensity or frequency from information provided in the 
Investigator’s Brochure or when it is not included in the informed consent 
document as a potential risk. 
10.1.4 Attribution 
 
Attribution is the relationship between an adverse event or serious adverse event 
and the study treatment. Attribution will be assigned as follows: 
 
x Related – The AE is clearly or may possibly be related to the study 
treatment. 


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x Unrelated – The AE is unlikely or clearly not related to the study 
treatment. 
10.2 Procedures for AE and SAE Recording and Reporting 
 
Reporting Participating investigators will assess the occurrence of AEs and SAEs at all 
participant evaluation time points during the study.  
 
All AEs and SAEs whether reported by the participant, discovered during questioning, 
directly observed, or detected by physical examination, laboratory test or other means, 
will be recorded in the participant’s medical record and on the appropriate study-
specific case report forms. 
 
The descriptions and grading scales found in the CTEP NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for AE reporting, and 
can be found on the CTEP website at: 
http://ctep.cancer.gov/protocolDevelopment/electronic applications/ctc.htm.  
 
10.3 Reporting Requirements 
 
Each participating investigator is required to abide by the reporting requirements set by 
the DF/HCC. The study must be conducted in compliance with FDA regulations, local 
safety reporting requirements, and reporting requirements of the principal investigator.  
10.4 Reporting to the Study Sponsor 
10.4.1 Serious Adverse Event Reporting 
 
All serious adverse events that occur after the initial dose of study treatment, 
during treatment, or within 30 days of the last dose of treatment must be reported 
to the DF/HCC Overall Principal Investigator Dr. Sequist (who is the Study 
Sponsor) on the local institutional SAE form. This includes events meeting the 
criteria outlined in Section 10.1.2, as well as the following: 
 
x Grade 2 (moderate) and Grade 3 (severe) events that are unexpected and at 
least possibly related/associated with the intervention. 
 
x All Grade 4 (life-threatening or disabling) events that are unexpected or 
not specifically listed in the protocol as not requiring reporting. 
 
x All Grade 5 (fatal) events while the participant is enrolled and actively 
participating in the trial OR when the event occurs within 30 days of the 
last study intervention. 
 




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serious, unexpected and reasonably related (i.e., possible, probable, definite) to the 
study treatment.
 
Unexpected fatal or life-threatening experiences associated with the use of the study 
treatment will be reported to FDA as soon as possible but in no event later than 7 
calendar days after initial receipt of the information. 
 
All other serious unexpected experiences associated with the use of the study treatment 
will be reported to FDA as soon as possible but in no event later than 15 calendar days 
after initial receipt of the information. 
 
Events will be reported to the FDA by telephone (1-800-FDA-1088) or by fax (1-800-
FDA-0178) using Form FDA 3500A (Mandatory Reporting Form for investigational 
agents) or FDA Form 3500 (Voluntary Reporting Form for commercial agents). Forms 
are available at http://www.fda.gov/medwatch/getforms.htm.  
10.7 Reporting to Novartis 
 
All SAEs should be reported, by FAX 
, to Novartis Pharmaceuticals 
Integrated Medical Safety Department within 24 hours of learning of its occurrence. 
This includes serious, related, labeled (expected) and serious, related, unlabeled 
(unexpected) adverse experiences. All deaths during treatment or within 30 days 
following completion of active protocol therapy must be reported within 1 working 
day. 
 
10.8 Reporting to Hospital Risk Management 
 
Participating investigators will report to their local Risk Management office any subject 
safety reports or sentinel events that require reporting according to institutional policy. 
10.9 Monitoring of Adverse Events and Period of Observation 
 
All adverse events, both serious and non-serious, and deaths that are encountered from 
initiation of study intervention, throughout the study, and within 30 days of the last 
study intervention should be followed to their resolution, or until the participating 
investigator assesses them as stable, or the participating investigator determines the 
event to be irreversible, or the participant is lost to follow-up. The presence and 
resolution of AEs and SAEs (with dates) should be documented on the appropriate case 
report form and recorded in the participant’s medical record to facilitate source data 
verification. 
 
For some SAEs, the study sponsor or designee may follow-up by telephone, fax, and/or 
monitoring visit to obtain additional case details deemed necessary to appropriately 
evaluate the SAE report (e.g., hospital discharge summary, consultant report, or 
autopsy report). 


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Participants should be instructed to report any serious post-study event(s) that might 
reasonably be related to participation in this study. Participating investigators should 
notify the DF/HCC Overall Principal Investigator and their respective IRB of any 
unanticipated death or adverse event occurring after a participant has discontinued or 
terminated study participation that may reasonably be related to the study.  
 
11. DATA AND SAFETY MONITORING 
 
11.1 Data Reporting 
11.1.1 Method  
The QACT will collect, manage, and monitor data for this study. Electronic 
case report forms (eCRFs) will be used. 
11.1.2 Data Submission  
Table 8. Schedule for completion and submission of eCRFs to the QACT  
 
Form 
Submission Timeline 
Eligibility Checklist 
Complete prior to registration with QACT 
On Study Form 
Within 14 days of registration 
Baseline Assessment Form 
Within 14 days of registration 
Treatment Form 
Within 10 days of the last day of the cycle 
Adverse Event Report Form 
Within 10 days of the last day of the cycle 
Response Assessment Form 
Within 10 days of the completion of the cycle 
required for response evaluation 
Off Treatment/Off Study Form 
Within 14 days of completing treatment or 
being taken off study for any reason 
Follow up/Survival Form 
Within 14 days of the protocol defined follow 
up visit date or call 
 


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11.2 Safety Meetings 
 
The DF/HCC Data and Safety Monitoring Committee (DSMC) will review and monitor 
toxicity and accrual data from this trial. The committee is composed of clinical 
specialists with experience in oncology and who have no direct relationship with the 
study. Information that raises any questions about participant safety will be addressed 
with the Principal Investigator and study team. 
 
The DSMC will meet quarterly and/or more often if required to review toxicity and 
accrual data. Information to be provided to the committee may include:  up-to-date 
participant accrual; current dose level information; DLT information; all grade 2 or 
higher unexpected adverse events that have been reported; summary of all deaths 
occurring within 30 days for Phase I or II protocols; for gene transfer protocols, 
summary of all deaths while being treated and during active follow-up; any response 
information; audit results, and a summary provided by the study team. Other 
information (e.g. scans, laboratory values) will be provided upon request. 
11.3 Monitoring
 
Involvement in this study as a participating investigator implies acceptance of potential 
audits or inspections, including source data verification, by representatives designated 
by the DF/HCC Overall Principal Investigator (or Protocol Chair) or DF/HCC. The 
purpose of these audits or inspections is to examine study-related activities and 
documents to determine whether these activities were conducted and data were 
recorded, analyzed, and accurately reported in accordance with the protocol, 
institutional policy, Good Clinical Practice (GCP), and any applicable regulatory 
requirements. 
 
All data will be monitored for timeliness of submission, completeness, and adherence 
to protocol requirements. Monitoring will begin at the time of participant registration 
and will continue during protocol performance and completion. 
 
12. REGULATORY CONSIDERATIONS
12.1 Protocol Review and Amendments 
This protocol, the proposed informed consent and all forms of participant information 
related to the study (e.g., advertisements used to recruit participants) and any other 
necessary documents must be submitted, reviewed and approved by a properly 
constituted IRB governing each study location.  
Any changes made to the protocol must be submitted as amendments and must be 
approved by the IRB and by Novartis prior to implementation. Any changes in study 
conduct must be reported to the IRB. The DF/HCC Overall Principal Investigator will 
disseminate protocol amendment information to all participating investigators.  
All decisions of the IRB concerning the conduct of the study must be made in writing. 


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12.2 Informed Consent 
 
All participants must be provided a consent form describing this study and providing 
sufficient information for participants to make an informed decision about their 
participation in this study. The formal consent of a participant, using the IRB approved 
consent form, must be obtained before the participant is involved in any study-related 
procedure. The consent form must be signed and dated by the participant or the 
participant’s legally authorized representative, and by the person obtaining the consent. 
The participant must be given a copy of the signed and dated consent document. The 
original signed copy of the consent document must be retained in the medical record or 
research file. 
12.3 Ethics and Good Clinical Practice (GCP) 
This study is to be conducted according to the following considerations, which 
represent good and sound research practice: 
x 
E6 Good Clinical Practice: Consolidated Guidance 
www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM129515.pdf  
x 
US Code of Federal Regulations (CFR) governing clinical study conduct and 
ethical principles that have their origin in the Declaration of Helsinki 
o Title 21 Part 11 – Electronic Records; Electronic Signatures 
www.access.gpo.gov/nara/cfr/waisidx 02/21cfr11 02.html 
o Title 21 Part 50 – Protection of Human Subjects 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr50_02.html 
o Title 21 Part 54 – Financial Disclosure by Clinical Investigators 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr54_02.html 
o Title 21 Part 56 – Institutional Review Boards 
www.access.gpo.gov/nara/cfr/waisidx 02/21cfr56 02.html 
o Title 21 Part 312 – Investigational New Drug Application 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr312_02.html 
x 
State laws 
x 
DF/HCC research policies and procedures 
http://www.dfhcc.harvard.edu/clinical-research-support/clinical-research-unit-
cru/policies-and-procedures/  
 
It is understood that deviations from the protocol should be avoided, except when 
necessary to eliminate an immediate hazard to a research participant. In such case, the 
deviation must be reported to the IRB according to the local reporting policy. 


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12.4 Study Documentation 
 
The investigator must prepare and maintain adequate and accurate case histories 
designed to record all observations and other data pertinent to the study for each 
research participant. This information enables the study to be fully documented and the 
study data to be subsequently verified. 
 
Original source documents supporting entries in the case report forms include but are 
not limited to hospital records, clinical charts, laboratory and pharmacy records, 
recorded data from automated instruments, microfiches, photographic negatives, 
microfilm or magnetic media, and/or x-rays. 
12.5 Records Retention 
 
All study-related documents must be retained for the maximum period required by 
applicable federal regulations and guidelines or institutional policies. 
13. STATISTICAL CONSIDERATIONS 
 
13.1 Study Design/Endpoints 
 
The primary purpose of this study is to determine the efficacy of AUY922 when administered 
intravenously on a once-weekly schedule at 70 mg/m2 in adult NSCLC patients with advanced 
disease and EGFR exon 20 insertion mutations. The design will be a Simon two-stage phase 2 
study, with 10 patients enrolled to the first stage and an additional 19 patients enrolled to the 
second stage provided we observe at least 1 partial or complete response or stable disease lasting 
 3 months in the first stage. 
 
The Primary Objective is: 
x To evaluate the overall response rate to AUY922 in patients with advanced NSCLC and 
exon 20 insertion mutations in EGFR. 
 
Secondary Objectives include: 
x To estimate progression-free survival (PFS) and overall survival (OS) in the study 
population 
x To determine the safety and tolerability of AUY922 
x To explore variance in clinical outcome between different types of exon 20 EGFR 
mutations 
 
13.2 Sample Size/Accrual Rate 
 
A Simon two-stage design will be used. In this design we will consider a rate of response 
plus SD lasting  3 months that is no greater than 5% as evidence that AUY922 is ineffective 
as a monotherapy in patients with exon 20 insertion mutations in EGFR, and 20% will be the 
target rate of effectiveness. In other words, Ho=0.05 and Ha=0.20. 


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This design requires that 10 patients will be initially enrolled (the first stage of the Simon 
design). If there are no responses or patients with SD lasting  3 months in these 10 patients 
then AUY922 will be considered ineffective in EGFR exon 20 insertion mutation patients. If 
at least 1 PR or SD lasting  3 months is noted, then an additional 19 patients will be enrolled 
(the second stage of the Simon design). 
If the total number of responses plus SD lasting  3 months in the entire set of 29 patients is 
4 or more, then AUY922 will be considered for further evaluation, likely in a randomized 
setting. If the number of responses of PR or SD lasting  3 months is 3 or fewer in the entire 
set of 29 patients, then AUY922 will be considered potentially ineffective and further 
investigation may be unwarranted. 
Using this design, if AUY922 is actually not effective, there is a 0.047 probability of 
concluding that it is (the target for this value was 0.050, the D-level). If the drug is actually 
effective, there is a 0.199 probability of concluding that it is not (the target for this value was 
0.200, the beta-level [80% power]). The power and D-level are slightly different from the 
nominal values due to the discrete nature of the binomial distribution of response. 
Among the three participating clinics (MGH, DFCI and BIDMC), we expect to enroll 
approximately 1.5 patients per month. Therefore, assuming full enrollment to 29 patients, 
accrual should be complete within 20 months. 
13.3 Patient Disposition 
A detailed description of patient disposition will be provided. It will include: 
x
A definition of patient enrollment
x
A summary of data regarding patient discontinuation of study treatment
x
A summary of data regarding patient inclusion and exclusion in efficacy and safety
analyses
13.4 Patient Characteristics 
Patient characteristics will include a summary of the following: 
x Patient demographics
x Baseline disease characteristics
x Baseline tumor molecular characteristics
x Significant medical history and co-morbidities
x Concomitant therapies
x Other characteristics as appropriate
13.5 Safety of Treatment 
A summary of the adverse events and their attributed relatedness to treatment will be provided. 
All patients will be included in the safety analyses 


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13.6 Analysis of Response Rate 
Response rate will be assessed as per RECIST, see Section 9.1. Results will be reported with 
95% confidence intervals. All patients will be evaluable for response rate. 
13.7 Analysis of Progression-Free and Overall Survival 
Progression-Free Survival (PFS) will be defined as the duration of time from start of treatment 
to time of objective disease progression or death. Overall survival (OS) will be defined as the 
duration of time from start of treatment until death. Analysis will be performed using the 
Kaplan-Meier method. All patients will be evaluable for survival endpoints. 
14. PUBLICATION PLAN
At the end of the study, the results will be analyzed and a manuscript submitted for peer review 
within 24 months of the end of data collection.


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16. APPENDICES
Appendix A: Performance Status Criteria 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade
Description
Percent
Description
0 
Normal activity. Fully active, able to 
carry on all pre-disease performance 
without restriction. 
100 
Normal, no complaints, no 
evidence of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of 
disease. 
1 
Symptoms, but ambulatory. 
Restricted in physically strenuous 
activity, but ambulatory and able to 
carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active 
work. 
2 
In bed < 50% of the time. 
Ambulatory and capable of all self-
care, but unable to carry out any 
work activities. Up and about more 
than 50% of waking hours. 
60 
Requires occasional assistance, 
but is able to care for most of 
his/her needs. 
50 
Requires considerable assistance 
and frequent medical care. 
3 
In bed >50% of the time. Capable of 
only limited self-care, confined to 
bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care 
and assistance. 
30 
Severely disabled, hospitalization 
indicated. Death not imminent. 
4 
100% bedridden. Completely 
disabled. Cannot carry on any self-
care. Totally confined to bed or 
chair. 
20 
Very sick, hospitalization 
indicated. Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly.  
5 
Dead. 
0 
Dead.