Conditions: Recurrent Lung Non-Small Cell Carcinoma Stage IV Lung Non-Small Cell Cancer AJCC v7
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 11
Healthy volunteers: no

Brief summary:
This phase I/II trial studies the side effects and best dose of onalespib lactate when given together with erlotinib hydrochloride and to see how well they work in treating patients with EGFR-mutant non-small cell lung cancer that has come back (recurrent) or has spread to other places in the body (metastatic). Erlotinib hydrochloride and onalespib lactate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Detailed description:
PRIMARY OBJECTIVES:

I. To determine the safety and tolerability of erlotinib hydrochloride (erlotinib) and onalespib lactate (onalespib) in patients with EGFR-mutant non-small cell lung cancer (NSCLC). (PHASE I) II. To preliminarily assess efficacy of combination erlotinib and onalespib at the recommended phase II dose (RP2D) determined in the phase I portion of the study in EGFR-mutant NSCLC patients who have not had a complete or partial response by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 to frontline erlotinib after a minimum of 12 weeks on erlotinib. (PHASE II, COHORT A) III. To preliminarily assess efficacy of combination erlotinib and onalespib at the RP2D in NSCLC patients whose tumor harbors an EGFR exon 20 insertion (an EGFR mutation not typically responsive to single agent erlotinib). (PHASE II, COHORT B)

SECONDARY OBJECTIVES:

I. To observe and record anti-tumor activity (primary aim phase II, secondary aim phase I).

II. To evaluate in a preliminary manner the progression-free survival (PFS) and disease control rate (DCR) of patients treated with erlotinib/onalespib.

III. To characterize the pharmacokinetics of the above drug combinations at the recommended phase II dose (RP2D).

TERTIARY OBJECTIVES:

I. To explore plasma EGFR-mutant deoxyribonucleic acid (DNA) as a biomarker by detecting changes in plasma EGFR-mutant DNA levels (including plasma EGFR-T790M) and new mutations that may represent resistance to treatment.

II. To demonstrate knockdown of Hsp90 client oncoproteins via treatment with erlotinib and onalespib by multiplexed immunofluorescence in serial tumor biopsies.

III. To establish patient derived xenotransplant models in EGFR-mutated NSCLC with a focus on tumors that lack response to single agent erlotinib and in patients with tumors harboring EGFR exon 20 insertions.

OUTLINE: This is a phase I, dose-escalation study of onalespib lactate followed by a phase II study.

Patients receive erlotinib hydrochloride orally (PO) daily and onalespib lactate intravenously (IV) over 1 hour on days 1, 8, and 15. Treatment repeats every 28 days for at least 3 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 12 weeks for 1 year and then annually thereafter.

Arms:
arm 1: Patients receive erlotinib hydrochloride PO daily and onalespib lactate IV over 1 hour on days 1, 8, and 15. Treatment repeats every 28 days for at least 3 courses in the absence of disease progression or unacceptable toxicity.

Interventions: intervention 1: Erlotinib Hydrochloride intervention 2: Laboratory Biomarker Analysis intervention 3: Onalespib Lactate intervention 4: Pharmacological Study
Intervention descriptions: intervention 1: Given PO intervention 2: Correlative studies intervention 3: Given IV intervention 4: Correlative studies

Protocol document:
Prot_SAP_000.pdf: 
NCI Protocol #:9878 
Version Date: March 9, 2018 
 
i 
SUMMARY OF CHANGES 
 
Date: 
March 9, 2018 
Document: 
NCI Protocol #9878, PhI-80: “A Phase 1/2 Trial of Erlotinib and 
Onalespib lactate in EGFR-Mutant Non-Small Cell Lung Cancer.” 
Note: 
The following is a Summary of Changes between the 11.29.17 and 3.9.18 
versions of the protocol 
 
Section 
Description of Change  
Face Page 
Updated protocol version in header and added new version date March 9, 2018 to 
protocol history. 
Updated California Cancer Consortium email address. 
TOC 
Updated page numbers. 
5.2 and 7 
Updated to CTCAE 5.0.   
 
 
Recommendations from last amendment: 
Section 
Description of Change  
4.3.3 
The helpdesk number listed below is incorrect.  Please update as per the below 
information:  
OPEN/IWRS Questions? 
Further instructional information on OPEN is provided on the OPEN tab of the 
CTSU website at https://www.ctsu.org or at https://open.ctsu.org. For any 
additional questions contact the CTSU Help Desk at 1-888-823-5923 or 
ctsucontact@westat.com. Theradex has developed a Slot Reservations and Cohort 
Management User Guide, which is available on the Theradex website: 
http://www.theradex.com/clinicalTechnologies/?National-Cancer-Institute-NCI-
11. This link to the Theradex website is also on the CTSU website OPEN tab. For 
questions about the use of IWRS for slot reservations, contact the Theradex 
Helpdesk: 609-619-7802 or 609-619-7862 or 
Theradex main number 609-799-7580; CTMSSupport@theradex.com. 
PI Response:  DONE 
4.1 
Please revise as shown below: 
Additional information can be found on the CTEP website at 
<https://ctep.cancer.gov/investigatorResources/default.htm TBD>. For questions, 
please contact the RCR Help Desk by email at < RCRHelpDesk@nih.gov >. 
PI Response: DONE 


NCI Protocol #:9878 
Version Date: March 9, 2018 
 
1 
NCI Protocol #: 
9878 
 
Local Protocol #: 
PhI-80 
 
ClinicalTrials.gov Identifier:  NCT02535338 
 
TITLE:  A Phase 1/2 Trial of Erlotinib and Onalespib lactate in EGFR-Mutant Non-Small Cell 
Lung Cancer 
 
Corresponding Organization: LAO-CA043 / City of Hope Comprehensive Cancer Center 
LAO 
 
 
1500 E. Duarte Road, Duarte 
 
 
California 91010 
 
 
Phone:  626-256-HOPE(4673), extension 65928 
 
 
Fax:      626-256-8654 
 
Email:  ccc@coh.org 
 
Principal Investigator: 
Jonathan Riess, MD, MS 
UC Davis Comprehensive Cancer Center  
4501 X Street, Suite 3016  
Sacramento, CA 95817  
Phone: (916) 734-3772  
Fax: (916) 734-7946 
 
Email:  jwriess@ucdavis.edu 
 
Participating Organizations: 
 
LAO-11030 / University Health Network Princess Margaret Cancer Center LAO 
LAO-CA043 / City of Hope Comprehensive Cancer Center LAO 
LAO-CT018 / Yale University Cancer Center LAO 
LAO-MA036 / Dana-Farber - Harvard Cancer Center LAO 
LAO-MD017 / JHU Sidney Kimmel Comprehensive Cancer Center LAO 
LAO-MN026 / Mayo Clinic Cancer Center LAO 
LAO-NC010 / Duke University - Duke Cancer Institute LAO 
LAO-NJ066 / Rutgers University - Cancer Institute of New Jersey LAO 
LAO-OH007 / Ohio State University Comprehensive Cancer Center LAO 
LAO-PA015 / University of Pittsburgh Cancer Institute LAO 
LAO-TX035 / University of Texas MD Anderson Cancer Center LAO 
LAO-NCI / National Cancer Institute LAO 
 
 


NCI Protocol #:9878 
Version Date: March 9, 2018 
 
2 
Statistician: 
Jeffrey Longmate, PhD  
City of Hope 
1500 E. Duarte Road 
Duarte, CA 91010 
Telephone:  626-256-8654 
E-mail:  jlongmate@coh.org  
 
 
 
 
 
NCI-Supplied Agent(s): 
OSI-774 (erlotinib, NSC 718781) 
 
Onalespib (onalespib lactate, AT13387, NSC 749712) 
 
Other Agent(s):   
N/A 
 
IND #: 
 
 
 
IND Sponsor:   
DCTD, NCI  
 
Protocol Type / Version # / Version Date: 
July 29, 2015  
Initial Protocol 
 
 
 
 
August 26, 2015 Consensus Review 
 
 
 
 
November 6, 2015 
Amendment 
 
 
 
 
December 4, 2015  
Amendment 
 
 
 
 
February 25, 2016  
Amendment 
 
 
 
 
August 15, 2016  
RRA Amendment 
 
 
 
 
March 2, 2017  
 
Amendment 
 
 
 
 
June 2, 2017   
 
RRA Amendment 
 
 
 
 
July 18, 2017  
 
RRA Amendment 
 
 
 
 
August 7, 2017 
 
Amendment  
 
 
 
 
November 29, 2017 Amendment 
 
 
 
 
March 9, 2018  
 
Amendment 
 
 
 


NCI Protocol #:9878 
Version Date: March 9, 2018 
 
3 
SCHEMA 
 
 
 
 
Dose Level 
Erlotinib (Oral, Daily) 
ONALESPIB (IV, weekly D1, D8, 
D15) 
-1 
150 mg 
120 mg/m2 
0 (Starting) 
150 mg 
150 mg/m2 
+1 
150 mg 
180 mg/m2 
+2 
150 mg 
220 mg/m2 
Phase 1 Dose Escalation of Erlotinib and 
AT13387 to determine the RP2D  
(Each cycle is 28 days) 
Stage IV NSCLC harboring an EGFR 
activating mutation with progressive 
disease by RECIST 1.1 on EGFR-TKI or 
EGFR-Exon 20 insertion with progressive 
disease on platinum containing 
chemotherapy. 
Phase 2 Cohort A (Closed as of 
10/11/17) 
 
Patients with Stage IV or 
recurrent/metastatic NSCLC that 
harbor an EGFR activating mutation 
(Exon 21 L858R, Exon 19 deletion, 
Exon 18 G719X, Exon 21 L861Q), 
age ≥18, without a complete or partial 
response on erlotinib as defined by 
RECIST 1.1 criteria after a minimum 
of 12 weeks on erlotinib; patients 
must be enrolled within 6 months of 
initiation of erlotinib
Phase 2 Cohort B (Open as of 
10/11/17 and open to all ETCTN 
sites) 
 
Patients with Stage IV or 
metastatic/recurrent NSCLC that 
harbor an EGFR exon 20 insertion 
and have progressive disease on or 
after platinum based chemotherapy.  
Each Phase 2 cohort will be evaluated using Simon’s two-stage minimax design, to 
detect a 25% RECIST response rate against an assumed background of 5%, with 10% 
type I and II error rates.  The initial stage will enroll 13 subjects, continuing if one or 
more respond, with three or more out of 20 regarded as encouraging for further 
development.   


NCI Protocol #:9878 
Version Date: March 9, 2018 
 
4 
 
TABLE OF CONTENTS 
 
SCHEMA .........................................................................................................................................3 
1. 
OBJECTIVES ......................................................................................................................6 
1.1 
Primary Objectives...................................................................................................6 
1.2 
Secondary Objectives...............................................................................................6 
1.3 
Exploratory Objectives ............................................................................................6 
2. 
BACKGROUND .................................................................................................................7 
2.1 
Non-Small Cell Lung Cancer...................................................................................7 
2.2 
CTEP IND AGENTS ...............................................................................................7 
2.3 
Rationale for Trial ..................................................................................................14 
2.4 
Correlative Studies Background ............................................................................18 
3. 
PATIENT SELECTION ....................................................................................................24 
3.1 
Eligibility Criteria ..................................................................................................24 
3.2 
Exclusion Criteria ..................................................................................................26 
3.3 
Inclusion of Women and Minorities ......................................................................27 
4. 
REGISTRATION PROCEDURES ...................................................................................27 
4.1 
Investigator and Research Associate Registration with CTEP ..............................27 
4.2 
Site Registration .....................................................................................................28 
4.3 
Patient Registration ................................................................................................31 
4.4 
General Guidelines.................................................................................................32 
5. 
TREATMENT PLAN ........................................................................................................32 
5.1 
Agent Administration.............................................................................................32 
5.2 
Definition of Dose-Limiting Toxicity ....................................................................34 
5.3 
Dose Escalation Guidelines ...................................................................................35 
5.4 
General Concomitant Medication and Supportive Care Guidelines ......................35 
5.5 
Duration of Therapy ...............................................................................................36 
5.6 
Duration of Follow Up ...........................................................................................37 
5.7 
Criteria for Removal from Study ...........................................................................37 
6. 
DOSING DELAYS/DOSE MODIFICATIONS ...............................................................37 
7. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................43 
7.1 
Comprehensive Adverse Events and Potential Risks List(s) (CAEPRs) ...............43 
7.2 
Adverse Event Characteristics ...............................................................................52 
7.3 
Expedited Adverse Event Reporting ......................................................................52 
7.4 
Routine Adverse Event Reporting .........................................................................54 
7.5 
Secondary Malignancy...........................................................................................54 
7.6 
Second Malignancy ................................................................................................55 


NCI Protocol #:9878 
Version Date: March 9, 2018 
 
5 
8. 
PHARMACEUTICAL INFORMATION ..........................................................................55 
8.1 
CTEP IND Agent(s) ...............................................................................................55 
9. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ........................................64 
9.1 
Integrated Correlative Studies................................................................................65 
9.2 
Exploratory/Ancillary Correlative Studies ............................................................68 
10. 
STUDY CALENDAR .......................................................................................................72 
11. 
MEASUREMENT OF EFFECT........................................................................................74 
12. 
STUDY OVERSIGHT AND DATA REPORTING / REGULATORY 
REQUIREMENTS .............................................................................................................80 
12.1 
Study Oversight .....................................................................................................80 
12.2 
Data Reporting .......................................................................................................81 
12.3 
CTEP Multicenter Guidelines ................................................................................83 
12.4 
Collaborative Agreements Language .....................................................................83 
13. 
STATISTICAL CONSIDERATIONS...............................................................................84 
13.1 
Study Design/Endpoints.........................................................................................84 
13.2 
Sample Size/Accrual Rate ......................................................................................85 
13.3 
Stratification Factors ..............................................................................................86 
13.4 
Analysis of Secondary Endpoints ..........................................................................86 
13.5 
Reporting and Exclusions ......................................................................................87 
14. 
CCC POLICIES FOR MONITORING CONSORTIUM TRIALS ...................................88 
14.1 
Oversight ................................................................................................................89 
REFERENCES ..............................................................................................................................90 
APPENDIX A 
PERFORMANCE STATUS CRITERIA ..................................................92 
APPENDIX B 
PATIENT DRUG INFORMATION HANDOUT AND WALLET CARD93 
APPENDIX C 
PATIENT’S MEDICATION DIARY .......................................................96 
APPENDIX D 
 DRUGS WITH KNOWN RISK OF TORSADES DE POINTES............97 
APPENDIX E 
 FRIDERICIA’S CRITERIA FOR QTC CALCULATION ....................101 
APPENDIX F 
 SPECIMEN COLLECTION FOR PHARMACOKINETIC STUDIES 
FOR PHI-80 (NCI# 9878) ...............................................................................................102 
 
 
 


NCI Protocol #:9878 
Version Date: March 9, 2018 
 
6 
1. OBJECTIVES 
 
1.1 
Primary Objectives 
 
 The primary objective of the phase 1 portion of this study is to determine the safety and 
tolerability of erlotinib and onalespib in patients with EGFR-mutant NSCLC. 
 
 The primary objective of the phase 2 Cohort A is to preliminarily assess efficacy of 
combination erlotinib and onalespib at the RP2D determined in the phase 1 portion of the 
study in EGFR-mutant NSCLC patients who have not had a complete or partial response 
by RECIST 1.1 to frontline erlotinib after a minimum of 12 weeks on erlotinib. Patients 
must be enrolled within 6 months of initiation of erlotinib.  
 
 The primary objective of the phase 2 cohort B is to preliminarily assess efficacy of 
combination erlotinib and onalespib at the RP2D in NSCLC patients whose tumor 
harbors an EGFR Exon 20 Insertion (an EGFR mutation not typically responsive to 
single agent erlotinib). 
 
1.2 
Secondary Objectives 
 
1.2.1 To observe and record anti-tumor activity (primary aim phase 2, secondary aim phase 1).  
Although the clinical benefit of these drugs has not yet been established, the intent of 
offering this treatment is to provide a possible therapeutic benefit, and thus the patient 
will be carefully monitored for tumor response and symptom relief in addition to safety 
and tolerability. 
 
1.2.2 To evaluate in a preliminary manner the progression-free survival (PFS) and disease 
control rate (DCR) of patients treated with erlotinib/ onalespib. 
 
1.2.3 To characterize the pharmacokinetics of the above drug combinations at the 
recommended phase 2 dose (RP2D). 
 
1.3 
Exploratory Objectives 
 
 
1.3.1 To explore plasma EGFR-mutant DNA as a biomarker by detecting changes in plasma 
EGFR-mutant DNA levels (including plasma EGFR-T790M) and new mutations that 
may represent resistance to treatment.  
 
1.3.2 To demonstrate knockdown of Hsp90 client oncoproteins via treatment with erlotinib and 
onalespib by multiplexed immunofluorescence in serial tumor biopsies. 
 
 


NCI Protocol #:9878 
Version Date: March 9, 2018 
 
7 
1.3.3 To establish patient derived xenotransplant models in EGFR-mutated NSCLC with a 
focus on tumors that lack response to single agent erlotinib and in patients with tumors 
harboring EGFR exon 20 insertions. 
 
2. BACKGROUND 
 
2.1 
Non-Small Cell Lung Cancer 
 
Lung cancer is the leading cause of cancer deaths worldwide due to the majority of patients 
presenting with metastatic disease for which there is no cure.  In recent years, advances in the 
systemic treatment of non-small cell lung cancer (NSCLC) have increased survival by several 
months and subsets of patients enjoy prolonged survival beyond two years including patients 
with metastatic EGFR-mutant NSCLC[1].  More efficacious therapies have been a direct result 
of our increased understanding and exploitation of the molecular basis of lung cancer. 
 
Platinum doublet chemotherapy has been the mainstay of NSCLC treatment with median OS of 
about 12 months. The discovery and targeting of oncogene driven subsets of NSCLC including 
EGFR-mutant NSCLC, which comprises about 15% of NSCLC has revolutionized treatment of 
lung cancer.  NSCLC tumors with EGFR-activating mutations are exquisitely sensitive to EGFR 
tyrosine kinase inhibitors (EGFR-TKIs) with overall response rates (ORR) of approximately 60-
70%. However, resistance to currently approved EGFR-TKIs (afatinib, gefitinib, erlotinib) 
invariably develop with a median PFS of approximately 9-11 months. Broad mechanisms of 
resistance include target alterations such as EGFR T790M (~50-60%), which is the most 
common mechanism of acquired resistance to EGFR-TKIs and prevents the TKI from fastening 
to the ATP binding domain of EGFR, bypass tract generation such as PIK3CA mutations, MET 
amplification and Her2 amplification (~20%) as well as target amplification of EGFR (~10%)[2, 
3].  
 
2.2 
CTEP IND AGENTS 
 
2.2.1 OSI-774 (Erlotinib) 
 
Background 
 
 
OSI-774 (erlotinib, Tarceva®) is an orally active, potent, selective inhibitor of the epidermal 
growth factor receptor (EGFR) tyrosine kinase [4]. OSI-774 inhibits the human EGFR tyrosine 
kinase with a 50% inhibitory concentration (IC50) of 2 nM (0.786 ng/mL) in an in vitro enzyme 
assay and reduces EGFR autophosphorylation in intact tumor cells with an IC50 of 20 nM 
(7.86 ng/mL).  OSI-774 inhibits EGF-dependent proliferation of cells at submicromolar 
concentrations and blocks cell-cycle progression in the G1 phase.  
 
OSI-774 appears to bind specifically to EGFR.  In a study of OSI-774 binding specificity, 
affinity of OSI-774 for 67 cellular receptors was examined [4].  OSI-774 was shown to bind with 
low affinity to peripheral benzodiazepine (IC50=2.5 µM [980 ng/ml]), adenosine A1 (IC50=6.8 
µM [2700 ng/ml]), and µ-opiate (IC50=7.0 µM [2800 ng/ml]) receptors.  Binding affinities were 


NCI Protocol #:9878 
Version Date: March 9, 2018 
 
8 
1250-fold higher than the IC50 concentration needed to inhibit purified EGFR tyrosine kinase (2 
nM [0.79 ng/ml]).  When tested at concentrations up to 1 µM (390 ng/ml), no significant 
inhibition of ligand binding to 64 other neurotransmitter receptors, regulatory binding sites, 
calcium channels, opioid receptors, or neurotransmitter uptake sites were observed. 
 
Nonclinical Studies 
 
In mice, daily oral administration of OSI-774 for 20 days inhibited subcutaneous (SC) growth of 
the HN5 human head and neck carcinoma in a dose-dependent manner as compared to vehicle-
treated mice, with an estimated effective dose for 50% inhibition (ED50) of 9.2 mg/kg/day [4].  
Treatment with 11 mg/kg/day of OSI-774 immediately halted growth or slightly decreased the 
size of HN5 tumors >1 cm in diameter.  The tumor stasis profile appeared to extend beyond the 
treatment period such that the tumor size for OSI-774-treated animals did not exceed 
pretreatment levels until at least 33 days post-treatment. Similar results were observed in A431 
squamous cell carcinoma xenografts at a dose of 11 mg/kg/day OSI-774 over 20 days.   
 
OSI-774 (10 mg/kg/day) has been studied in combination with cisplatin, doxorubicin, 5-
fluorouracil, paclitaxel, vinorelbine tartrate, and gemcitabine [4].  No antagonism of therapeutic 
efficacy was observed, and additive effects were observed with cisplatin (10 mg/kg intravenous 
[IV] daily × 1), doxorubicin (15 mg/kg IV daily × 1), paclitaxel (10 mg/kg intraperitoneal [IP] 
daily × 5), and gemcitabine (100 mg/kg IP three times daily × 4).    
 
Nonclinical toxicology studies in rats and dogs have included acute and long-term general 
toxicology, genetic toxicology, reproductive toxicology, and local tissue tolerance of OSI-774.  
Clinical signs of toxicity in rats and/or dogs following a single dose of OSI-774 were dose 
dependent and included transient emesis, ataxia, papillary dilation, increased heart rate, 
decreased blood pressure, decreased activity, irregular respiration, convulsions, rapid chewing, 
salivation, and death.  Following chronic administration in rats and dogs, the following toxicities 
were observed in at least one species:  effects on the cornea (atrophy and ulceration); effects on 
the skin (follicular degeneration and inflammation, redness, and alopecia); atrophy of the ovary, 
lacrimal glands, and salivary glands; necrosis of the liver; papillary necrosis and tubular 
dilatation of the kidney; inflammation in the mandibular lymph nodes; hematopoiesis; delayed 
gastric emptying; and diarrhea.  Increases in alanine aminotransferase, aspartate 
aminotransferase, and bilirubin were observed. 
 
OSI-774 causes maternal toxicity with associated embryo-fetal lethality and abortion in rabbits at 
doses 3 times those in humans (AUC at 150 mg daily dose).  However, when administered 
during organogenesis at plasma concentrations approximately equal to humans, no increase in 
embryo-fetal lethality or abortion in rats or rabbits was observed.  Female rats treated with doses 
0.3 to 0.7 times the human dose prior to mating and during the first week of gestation had an 
increase in early resorptions.  No teratogenic effects were observed in rats or rabbits. 
 
Pharmacokinetics 
 
The total clearance of OSI-774 decreased with increasing dose, resulting in supraproportional 
increases in exposure (AUC) over the dose range of 1-2 mg/kg IV in rats and 0.5-7 mg/kg IV in 


NCI Protocol #:9878 
Version Date: March 9, 2018 
 
9 
dogs [4].  In vitro, OSI-774 is slowly oxidized by liver microsomes.  The majority of the 
absorbed dose is extensively metabolized in rats and dogs, and only a small amount is excreted 
as unchanged drug in urine, bile, and feces.  The oral bioavailability of an aqueous suspension is 
77% in rats and ~88% in dogs.  Plasma protein binding of OSI-774 ranges from 92% to 95% in 
man, monkey, rat, and mouse, and is 85% in the dog.  Corrected for protein binding of 95%, at 
the average plasma concentration responsible for 50% inhibition of tumor growth (oral dose of 
9.2 mg/kg/day in the murine/human tumor xenograft model), the unbound concentration of drug 
in the plasma is estimated to be 86 nM (34 ng/mL).  The estimated unbound concentration of 
OSI-774 in plasma is consistent (4-fold higher) with the IC50 for the in vitro cellular 
phosphotyrosine reduction assay and is 43-fold higher than the IC50 for the in vitro (isolated 
enzyme) tyrosine kinase assay.  Finally, OSI-774 plasma protein binding depends on the levels 
of -1-acid glycoprotein (AAG).  Thus, AAG might be a significant determinant of 
pharmacokinetic and possibly pharmacokinetic–pharmacodynamic relationships in patients. 
 
Pharmacokinetic Data 
 
OSI-774 pharmacokinetics were examined in patients with advanced solid tumors who were 
treated daily for 21 days. Plasma samples were collected on Days 1, 3, and 21 for analysis.  The 
following table lists the pharmacokinetic data for these patients:  
 
 
 
Abbreviations:  AUC0-24, Area under the time-concentration curve from 0 to 24 hours; Cavg, daily average plasma 
concentration; Cmax, maximum serum/plasma concentration; CV, coefficient of variance; R, accumulation ratio 
*Accumulation ratio = AUCDay 3 or 21/AUCDay 1 
aOnly 3 patients day 3, 3 subjects day 21 
bOnly 2 patients day 3, 3 subjects day 21 
cOnly 6 patients day 21 
 
Mean (%CV) OSI-774 Pharmacokinetic Parameters following Daily Dosing 
Dose 
(mg) 
N 
AUC0-24 
(ng•h/ml) 
R* 
Cavg 
(ng/ml) 
Cmax 
(ng/ml) 
Day 
1 
Day 
3 
Day 
21 
Day 
3 
Day 
21 
Day 
1 
Day 
3 
Day 
21 
Day 
1 
Day 
3 
Day 
21 
25 
3 
1580 
(40) 
2180 
(49) 
 
1.38 
(11) 
 
66 
91 
 
208 
(38) 
310 
(40) 
 
50 
6
a 
5650 
(54) 
5790 
(57) 
14900 
(69) 
1.59 
(31) 
1.83 
(30) 
235 
241 
621 
508 
(34) 
716 
(55) 
682 
(59) 
100 
8
b 
9210 
(92) 
9080 
(49) 
32200 
(148) 
1.75 
(35) 
3.21 
(56) 
384 
378 
1340 
765 
(69) 
1140 
(49) 
1740 
(85) 
150 
7
c 
1420
0 
(71) 
2060
0 
(22) 
45800 
(99) 
1.74 
(6.7 
2.57 
(47) 
670 
859 
1910 
1040 
(70) 
2040 
(21) 
1730 
(82) 
200 
7 
3600
0 
(34) 
 
74200 
(29) 
 
2.01 
(42) 
1360 
 
3200 
1420 
(47) 
 
2910 
(29) 
 


NCI Protocol #:9878 
Version Date: March 9, 2018 
 
10 
After oral ingestion, the OSI-774 Cmax values (Tmax) were achieved at a median of 3 hours (range, 2 to 
12 hours). Both Cmax and AUC0-24 values were roughly proportional to the OSI-774 dose in the range of 
25 to 200 mg/d (R2 = 0.33 and 0.46, respectively, on Day 1).  Inter-subject variability was moderate at 
the 150-mg/d dose level, as indicated by coefficient of variation values of 64% for Day 1 AUC0-24 and 
Cmax. 
 
Dose Rationale 
 
Dosing of erlotinib will be at the FDA approved dose of 150 mg daily. 
 
2.2.2 ONALESPIB (Onalespib lactate) 
 
Background 
 
Onalespib (AT13387) is a synthetic non-ansamycin small molecule that acts as an inhibitor of 
heat shock protein 90 (HSP90). HSP90 inhibitors are thought to affect multiple aberrant 
signaling pathways and may therefore be of clinical benefit in the treatment of a wide range of 
cancers. 
 
Nonclinical Studies 
 
Onalespib potently inhibits HSP90 in human tumor cell lines and demonstrates antitumor activity 
against human tumor cell line xenografts in mice. In vivo studies suggest that onalespib leads to 
a prolonged inhibition of HSP90 in tumors. In cancer xenograft models in mice (NSCLC driven 
by mutated EGFR or translocated ALK; vemurafenib-sensitive and -resistant melanoma), 
onalespib inhibited tumor growth and was best tolerated weekly or twice weekly. In upfront 
combination with kinase inhibitors, onalespib was able to delay the emergence of resistance in 
melanoma and NSCLC xenograft models. 
 
The onset of onalespib toxicity was characterized by adverse clinical signs, reduced food 
consumption, hematologic and clinical chemistry effects. Data were obtained in an acute pilot 
study (clinical observations and necropsy), DRF studies (clinical observations and clinical 
pathology and necropsy), and definitive studies (full toxicologic investigations). Results from 
these studies provide a clear picture of the safety and toxicity of onalespib given by a 1-hour 
infusion. 
 
The toxicity profile of onalespib was similar in rats and dogs. Both species exhibited decreased 
body weight and food consumption, and decreases in white blood counts, as well as clinical 
pathology changes. The overall effects observed in surviving rats and dogs were transient and 
reversible, with the exception of the testicular lesions observed in dogs at high doses which had 
not reversed during 14 days recovery. 
 
TK data showed good characterization of onalespib concentration-time profiles achieved for 1 
hour IV infusion and plasma concentration-time profiles were consistent with this mode of 
administration. Exposure was confirmed in all test article dosed groups on Study Days sampled 


NCI Protocol #:9878 
Version Date: March 9, 2018 
 
11 
and increased an approximately dose-related manner. No onalespib was detected in any control 
vehicle-dosed animal samples. There were no consistent gender differences. There was no 
significant accumulation or decrease in exposure upon repeat IV administration. Onalespib was 
essentially completely cleared from plasma by 24 hours. 
 
In rats, onalespib was administered over 1 hour, either through the tail vein or a femoral vein 
cannula, as a single dose or repeated. Both methods of administration were problematic in rats, 
as tail vein administration led to severe toxicity and femoral vein administration led to thrombus 
formation. In the definitive rat study, a surgically implanted femoral vein cannula was associated 
with thrombus formation and occasional early deaths, as confirmed by histopathologic 
investigations.  
 
The main results from these studies were as follows: 
• Clinical pathology changes suggestive of adverse effects in various organs including bone 
marrow, kidney and liver were observed at doses ≥50 mg/kg, but histopathology was not 
examined 
• No unambiguous target organs of toxicity were identified, and the NOAEL was estimated to be 
50 mg/kg/dose given twice weekly for 3 weeks 
• Consequently a dose severely toxic to 10% of rodents (STD10) could not be confidently 
determined in rats although safety was established in this species 
In dogs, a clear dose-effect relationship was established for onalespib (administration through a 
peripheral vein). Dogs were more sensitive than rats on a dose basis (mg/kg and mg/m2) and an 
exposure basis (Cmax and AUC). Histopathology in dogs revealed changes in the bone marrow, 
thymus, testes, gall bladder, and kidney at 3, 10/7, and 12.5/10/7 mg/kg. The nominal HNSTD 
was 3 mg/kg/dose given twice weekly for 3 weeks. The NOAEL was taken to be 1mg/kg/dose on 
the same schedule. 
 
A subsequent repeat-dose study of two new onalespib formulations to assess potential acute 
toxicity and local infusion site irritation in rabbits revealed that higher pH (less acidic) 
phosphate-buffered formulation caused less infusion-site irritation. However, exposures in 
rabbits at the 25 mg/kg dose were more than 2-fold higher than in humans (at the MTD dose of 
260 mg/m2) and as a consequence, the repeat-dose regimen was not tolerated in rabbits, as 
mortalities occurred in all groups. Due to adverse findings secondary to cannulation in rats, as 
well as no detection of unambiguous target organs of toxicity in rats, an STD10 could not be 
confidently determined in the rat. A clear dose-related toxicity was established in dogs, including 
identification of target organs of toxicity; the NOAEL was 1 mg/kg/dose given 2QW×3 and the 
nominal HNSTD was 3 mg/kg/dose given 2QW×3. The dog was found to be more sensitive than 
the rat on a mg/kg and mg/m2 basis, as well as in exposure terms (Cmax and AUC). The human 
clinical start dose was calculated on a mg/m2 basis using accepted body surface area conversion 
factors (FDA 2005). Given its high sensitivity to onalespib, the dog was deemed an appropriate 
species for this purpose; therefore, the start dose was estimated as one-sixth of the nominal dog 
HNSTD (HNSTD = 3 mg/kg = 60 mg/m2), giving a human start dose of 10 mg/m2/dose given 
2QW×3. The human start dose calculated from the dog HNSTD is 3-fold lower than would be 
derived from the rat NOAEL (start dose based on one tenth of the rat NOAEL on a body surface 
area basis = 30 mg/m2/dose). 
 


NCI Protocol #:9878 
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12 
Pharmacokinetics 
 
• After intravenous (IV) administration to mice, rats, and dogs and intraperitoneal (IP) 
administration to mice, onalespib displayed a short plasma half-life in mice and rats (1-3 hours) 
and a moderate half-life in dogs (11 hours) despite high plasma clearance. Volume of 
distribution was greater than total body water indicating distribution of onalespib into tissues. PK 
studies demonstrated that onalespib is highly distributed into xenograft tumors and is cleared 
slowly from tumors. 
 
 • The in vitro intrinsic clearance of onalespib determined in isolated intact hepatocytes was high 
across all the species tested (mouse, rat, dog and human; scaled values ranged from 35 
mL/min/kg in human to 184 mL/min/kg in rat). 
 
 • Binding of onalespib to plasma proteins was moderate and comparable across all species 
tested, ranging from 77.2% in dog plasma to 90.1% in mouse plasma. 
 
 • Blood:plasma distribution in mouse, rat, dog and human whole blood ranged from 0.8, 
indicating approximately equal distribution between the plasma and cellular fraction, to 5.0, 
showing that onalespib favored partitioning into the red blood cells, depending on concentration 
and species. 
 
 • The potential for onalespib to inhibit cytochromes P450 (CYP) 1A2, 3A4, 2D6, 2C9, and 
2C19 was assessed, and results indicated a concentration giving half-maximal inhibition (IC50) 
>10μM, suggesting a low potential for clinically significant drug-drug interactions mediated by 
these enzymes. 
 
• Onalespib is a substrate for P-gp, a modest inhibitor of BCRP and P-gp, and strong inhibitor of 
MATE1 and MATE2-K. 
 
 • Glucuronidation, sulphation and N-oxidation appear to be routes of metabolism for onalespib 
based on in vitro studies of cryopreserved hepatocytes as well as metabolites detected in samples 
in vivo. 
 
 • In a radiolabeled mass balance study in dogs, a mean maximum measured concentration 
(Cmax) of 793 ng-Eq/g occurred at the end of infusion. Area under the curve concentration-time 
curve from time 0 to the last data point (AUC0-t) values were 5924 hr•ng-Eq/g and 7590 hr•ng-
Eq/g for male and female dogs, respectively, with halflife (t1/2) values of 21.3 and 20.5 hour, 
respectively. The majority (~83% in the male and ~72% in the female) of [14C]onalespib-
derived radioactivity was excreted via feces, with less found in urine (~15% in the male and 
~22% in the female). 
 
• The PK of onalespib showed dose-dependent increase in AUC0-t and Cmax from 10 to 310 
mg/m2/dose with relatively low inter-individual variability. Elimination half-life (t1/2 el) was 
dose-independent with mean cohort values ranging from 6.6 to 11.5 hours. Maximum t1/2 
observed was 14 hours. There was no notable accumulation or reduction in exposures between 
Day 1 and Day 18 (twice weekly) or Day 1 and Day 15 (once weekly) of Cycle 1. 


NCI Protocol #:9878 
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13 
 
 • The onalespib PK profile and exposures were similar across several studies, whether as a 
single agent (ONALESPIB-01) or in combination with imatinib (ONALESPIB-02), abiraterone 
acetate (ONALESPIB-04), or crizotinib (ONALESPIB-05), at comparable dose levels, indicating 
no potential for interactions affecting onalespib PK by these agents. 
 
 • Plasma increases in HSP70 were detected at all dose levels in Study ONALESPIB-01. HSP70 
induction is a pharmacodynamic marker of target engagement, but has not been demonstrated to 
be predictive of clinical response. 
 
Clinical Studies 
 
• ONALESPIB-01, Phase 1 study in adults with metastatic solid tumors who receive onalespib 
monotherapy. 
 
• ONALESPIB-02, Phase 2 study in adults with gastrointestinal stromal tumor (GIST) who 
receive onalespib in combination with imatinib. Disease control at 4 months occurred in 5 
(19.2%) subjects. 
 
• ONALESPIB-03 (CTEP 8828), Phase 1 study sponsored by the National Cancer Institute 
(NCI) in adults with refractory solid tumors who receive onalespib monotherapy. 
 
• ONALESPIB-04, 2-part, Phase 1-2 open-label, parallel-group, randomized study in subjects 
with castration resistant prostate cancer (CRPC) who are no longer responding to treatment with 
abiraterone acetate and steroids. 
 
• ONALESPIB-05, 3-part Phase 1-2 study in subjects with ALK+ or other potentially crizotinib-
sensitive NSCLC. 4 PRs have been reported during the dose-escalation part of the study (Part A). 
 
• ONALESPIB-EP-01 (CTEP 9557), Phase 1 study sponsored by the National Cancer Institute 
(NCI) in adults with BRAF-inhibitor resistant patients with BRAF-mutant melanoma who 
receive onalespib in combination with dabrafenib and trametinib. 
 
• In Study ONALESPIB-01 (monotherapy), the best response to treatment was 1 partial response 
(PR) in a subject with GIST and stable disease persisting for ≥6 months in 4 subjects (2 with 
GIST, 1 with adenoid cystic carcinoma of the right parotid, 1 with metastatic uveal melanoma). 
 
Clinical Toxicities 
 
Limited information on the metabolism, elimination, and safety of onalespib is currently 
available. Onalespib appears to be metabolized by the liver and both parent compound and 
metabolites eliminated by the kidneys. 
 
Until further information is available, subjects with the following organ impairment or 
abnormalities should be excluded (according to the specific criteria defined in the clinical study 
protocol): 


NCI Protocol #:9878 
Version Date: March 9, 2018 
 
14 
• Clinically significant abnormal liver function as demonstrated by serum bilirubin >1.5 times 
the upper limit of normal (ULN) or ALT or AST >2.5 times the ULN (or >5 times the ULN in 
the presence of liver metastases). 
• Impaired renal function as demonstrated by serum creatinine >1.25 ULN or creatinine 
clearance <50 mL/min. 
• Left ventricular ejection fraction <50% on echocardiography or multigated acquisition 
(ECHO/MUGA) scan. 
 
QTc >450 ms, or as specified in the individual clinical study protocol. Any clinically significant 
electrolyte imbalance, particularly hypokalemia and hypomagnesemia, should be corrected 
before treatment. Cumulative safety data from the ongoing trials may result in relaxing some of 
the above recommendations in later-stage clinical studies. 
 
The most common SAEs by System Organ Class (SOC; subjects counted once per SOC), 
regardless of relationship, through the cut-off date of 30 December 2014, were categorized under 
Respiratory, Thoracic, and Mediastinal Disorders (23/237; 10%); Gastrointestinal Disorders 
(17/237; 7%); and General Disorders and Administration Site Conditions (12/237; 5%).  
Individual event terms reported for >3 subjects were 8/237 (3.4%) for dyspnea (6 resolved, 1 
decreased in severity, and 1 not resolved); 6/237 (2.5%) for diarrhea (5 resolved and 1 not 
resolved); 5/237 (2.1%) each for dehydration (4 resolved and 1 resolved with sequelae) and 
pulmonary embolism (4 resolved and 1 not resolved); and 4/237 (1.7%) each for back pain (all 
resolved), muscular weakness (1 resolved, 1 decreased in severity, and 2 not resolved), and 
pneumonia (2 resolved and 2 fatal). 
 
Dose Rationale 
 
Dedicated drug-drug interaction studies have not been conducted. However, The potential for 
onalespib to inhibit cytochromes P450 (CYP) 1A2, 3A4, 2D6, 2C9, and 2C19 was assessed, and 
results indicated a concentration giving half-maximal inhibition (IC50) >10μM, suggesting a low 
potential for clinically significant drug-drug interactions mediated by these enzymes. Olanespib 
PK does not appear to be affected when coadministered with imatinib (ONALESPIB-02), 
abiraterone acetate (ONALESPIB-04), or crizotinib (ONALESPIB-05). PK studies of 
ONALESPIB and assessment of drug-drug interactions with erlotinib will be conducted in this 
study. Erlotinib is primarily metabolized by CYP3A4 and CYP3A5 in liver and intestine, and to 
a lesser extent, by CYP1A2 and CYP2C8. While caution is recommended when erlotinib is co-
administered with either strong inducers or inhibitors of CYP3A4/5, there is no evidence that 
onalespib will impact the metabolic clearance of erlotinib. 
 
 
This phase 1 trial dose escalates onalespib to the recommended Phase 2 dose (RP2D) to a 
maximum of 220 mg/m2 once weekly, which is the MTD and/or RP2D for other combination 
studies of onalespib (combination with imatinib, crizotinib in ALK rearranged NSCLC, or 
abiraterone acetate+ steroid). 
 
2.3 
Rationale for Trial 
 


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15 
EGFR-tyrosine kinase inhibitors (EGFR-TKIs) such as erlotinib have revolutionized treatment of 
advanced NSCLC patients whose tumors harbor EGFR activating mutations (EGFR+). 
Unfortunately, on average 30-40% of these patients do not respond to EGFR inhibitors and 
resistance invariably develops with a median PFS of 9-10 months[5, 6]. Mechanisms of 
resistance to erlotinib include: EGFR T790M mutations (~50%), MET, EGFR and Her2 
amplification (~30%), EMT and small cell transformation (~10%) and acquired PIK3CA 
mutations (~10%)[2, 3].  
 
There is an unmet clinical need for new active therapies for patients that circumvent resistance to 
EGFR-TKIs and improve clinical outcomes in EGFR-mutant NSCLC. 
 
Current approaches to address this unmet need include second generation EGFR-TKIs such as 
afatinib (recently approved in the first line setting for treatment of metastatic EGFR-mutant 
NSCLC[7]) though it has not been directly shown to be superior to 1st generation EGFR-TKIs 
such as erlotinib or gefitinib in the first line setting and single agent response rates to afatinib in 
patients who have progressed on 1st generation EGFR-TKIs are low (~7%).[8] Third generation 
EGFR-TKIs such as AZD9291 and CO-1686 have shown promise in patients who have 
progressed on 1st generation EGFR-TKIs with high response rates (50-60%) in patients whose 
tumors harbor the EGFR-T790M resistance mutation, though they are mainly specific for EGFR-
T790M with less selectivity and much lower response rates in patients with EGFR-mutant 
NSCLC lacking EGFR-T790M[9, 10].  
 
Hsp90 is a molecular chaperone that participates in stabilizing and activating hundreds of client 
proteins. In cancer cells, Hsp90 preferentially protects mutated and overexpressed oncoproteins 
from misfolding and degradation[11]. The Hsp90 inhibitor onalespib potently inhibits Hsp90 
chaperone activity and promotes degradation of numerous client proteins including many 
oncoproteins that mediate resistance to erlotinib. Maintaining prolonged knockdown of Hsp90 
client proteins with Hsp90 inhibitors has been a challenge in the development of this class of 
drugs in NSCLC[12]. Oncoprotein knockdown by onalespib is prolonged in NSCLC cell lines 
and xenotransplants, offering a potential advantage of onalespib over other Hsp90 inhibitors in 
development[13]. onalespib has single agent activity and is synergistic with erlotinib in EGFR+ 
NSCLC cell lines and xenotransplants[14, 15]. Since Hsp90 inhibitors preferentially degrade 
several overexpressed oncoproteins known to mediate resistance to erlotinib (including EGFR 
T790M, Her2, PIK3CA, MET) and multiple mechanisms of EGFR-TKI resistance can exist 
within the same tumor[16], we hypothesize that onalespib added to erlotinib can circumvent or 
delay EGFR-TKI resistance in a broad population of EGFR-mutant NSCLC and target multiple 
mechanisms of EGFR-TKI resistance that may exist within the same patient[16].  
 


NCI Protocol #:9878 
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16 
 
 
 
Figure 1: EGFR-mutant NSCLC is sensitive to Hsp90 inhibition with onalespib including erlotinib resistant cell lines (from 
Wallis, N. et al. WCLC 2014). 
 
 
Figure 2: Onalespib inhibits growth of EGFR-mutant tumor xenografts irrespective of sensitivity to erlotinib (from Wallis, N. et 
al. WCLC 2014). 
 
   
 
Figure 3: Combination onalespib and Erlotinib inhibits growth of EGFR-mutant tumor xerografts irrespective of sensitivity to 
erlotinib (HCC827 – EGFR E19del Left, NCI-H1650 - EGFR E19del and PTEN del right) (From Smyth, T. et al. AACR 2014).  
 


NCI Protocol #:9878 
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17 
 
 
Figure 4: Combination erlotinib and onalespib delays resistance in an EGFR-mutant xenograft model (HCC827). Only the 
erlotinib alone treated xenografts had relapsed disease (confidential from Astex – Presented at AACR 2015). 
 
Compared to the two classic EGFR mutations (EGFR Exon 19 deletions and EGFR L858R) 
EGFR exon 20 insertions are less common EGFR mutations that are not typically responsive to 
EGFR-TKIs with reported response rates <10%[17]. Hsp90 inhibitors have pre-clinical activity 
in EGFR Exon 20 insertions with cell line evidence showing Exon 20 insertions with interaction 
and dependence on Hsp90[18]. Generating in vivo models of exon 20 insertions as we proposed 
with the creation of patient derived xenografts is critical to developing new treatments for this 
uncommon EGFR-mutation. Clinical activity of Hsp90 inhibition has been recently described 
with the Hsp90 inhibitor AUY922 in NSCLC patients with EGFR-Exon 20 Insertions (Z. 
Piotrowska et al, ASCO 2015). However, night blindness and other toxicities may inhibit further 
development of this HSP90 inhibitor. This trial combines onalespib with erlotinib in a dedicated 
phase 2 study because select EGFR Exon 20 insertions may be sensitive to EGFR-TKIs, albeit 
with a low single agent EGFR-TKI response rate (RR 5-10%)[17]. 
 
W e e k
R e la tive  T u m ou r V o lu m e
0
10
20
30
40
50
0
50
100
150
200
E rlo tin ib
E rlo tin ib  +  A T 1 3 3 8 7


NCI Protocol #:9878 
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18 
  
Figure 5: Exon 20 insertion mutations in EGFR confer interaction with and dependence on Hsp90. (A) Epidermal growth factor 
receptor exon 20 insertion mutants display 17-AAG-sensitive association with Hsp90. COS7 cells were transfected with wild 
type or mutant EGFR constructs as described in Materials and Methods. One day after transfection, cells were treated 
with/without 0.5μm 17-AAG for 1h, and Hsp90 association with EGFR was monitored by coimmunoprecipitation analysis. 
Membranes were probed sequentially for Hsp90 and EGFR as shown. (B) Stability, autophosphorylation, and downstream 
signaling of EGFR exon 20 insertion mutants are inhibited by 17-AAG. Two days after transfection, COS7 cells were treated 
with 0.5μm 17-AAG, 0.1μm gefitinib, or a combination of the two drugs for 5h. Cells were lysed and processed as described in 
Materials and Methods. Individual membranes were probed as indicated. The EGFR phosphorylation sites examined form 
docking sites linking the activated receptor to various downstream effectors: EGFR/pY1068 associates with Grb2, Stat3/5, and 
Gab1; EGFR/pY1173 associates with Shp1 and Ptp1; EGFR/pY992 associates with PLCγ and Shc; and EGFR/pY1045 associates 
with Cbl. (C) A549 cells, expressing wild-type EGFR, were treated with 17-AAG as shown. Cells were lysed and processed as 
described in Materials and Methods, and Western blots were probed as in (B) above. (From Xu et al, British Journal of Cancer 
2007). 
 
In the more classic EGFR-activating mutations, based on the promising preclinical data and 
mechanism of action of onalespib, we propose a phase 1/2 trial of erlotinib and onalespib to 
determine safety and tolerability and then assess preliminary efficacy by seeing if we can induce 
responses with the combination in patients with EGFR-activating mutations who have not 
responded to frontline single-agent erlotinib. 
 
2.4 
Correlative Studies Background 
 
EGFR-mutation Testing (Integrated Biomarker) 
 
This trial will accept EGFR-mutation testing by any CLIA-certified laboratory for patient 
enrollment and treatment as EGFR-mutation testing is standard of care. Response Genetics is a 
CLIA certified laboratory that will perform EGFR-mutation testing by Sanger Sequencing as 
central confirmation of EGFR-mutation status and determination of EGFR-T790M. Response 
Genetics is also the vendor for EGFR-mutation testing for the adjuvant erlotinib ALCHEMIST 
study in NSCLC sponsored by NCI.  


NCI Protocol #:9878 
Version Date: March 9, 2018 
 
19 
 
Plasma cfDNA (Guardant 360) (Integrated Biomarker) 
 
Description of the Assay 
 
Guardant360 is a cell-free circulating tumor DNA (ctDNA) targeted next-generation sequencing 
(NGS) panel that is indicated for the prevention of a repeat invasive biopsy when the initial 
biopsy is QNS or unavailable/unobtainable as well as when cancer has progressed or recurred 
despite treatment. It is an advanced diagnostic laboratory test (ADLT) offered by a sole source 
Clinical Laboratory Improvement Amendments (CLIA)-certified and College of American 
Pathology (CAP)-accredited laboratory. This solid tumor profiling panel sequences 68 clinically 
actionable genes for single nucleotide variants and copy number variations in 16 genes with a 
simple blood test [1]. The genes are selected because mutations in these genes have FDA-
approved matched therapies or are eligible for late phase clinical trials. The panel also includes 
genomic markers of acquired resistance that may require a change in pharmacotherapy. 
 
Advantages of the Guardant360 cell-free DNA (cfDNA) NGS methodology versus solid tumor 
tissue-based NGS are: 
1. An invasive needle or surgical biopsy is avoided with cfDNA, reducing costs and 
complications. 
2. CfDNA provides a quantitative measure (concentration or mutant allele frequency) of 
mutations present whereas solid tumor biopsy typically provides a qualitative result 
(mutation either present or not detected). The quantitative result may be followed over 
time to monitor response to treatment and evolution of acquired resistance. 
3. CfDNA sequencing identifies both germline and somatic mutations. 
4. The assay failure rate is for cfDNA is essentially null (0.5% in the first 2,000+ samples) 
compared to 15%-25% failure rates of tissue-based NGS related to insufficient quantity 
of tissue (QNS). 
The key differentiator of the Guardant360 cfDNA NGS panel compared to other ctDNA panels 
is that the latter are limited to hotspot or “hot exon” analysis due to the high false positive rates 
related to longer sequencing regions at the low concentrations encountered with ctDNA. The 
high rates of false positives with current NGS assays when tumor DNA is in very low 
concentrations has limited the majority of methods for circulating tumor DNA (ctDNA) to 
hotspot analyses, amplicon sequencing approaches and/or typically involve patients where the 
ctDNA fraction is greater than 1-5% of total circulating cfDNA. To overcome these limitations, 
Guardant360 utilizes algorithmic methods to encode and ultimately decode inputs and outputs 
from massively parallel deep sequencing analysis. By leveraging signal transduction processing 
technology where voice or image data is digitally encoded before transmission and then decoded 
post-transmission, this NGS method, known as Digital SequencingTM, enables signal 
interference to be reduced by two orders of magnitude or more [2]. With high enough sensitivity 
and specificity to robustly quantitate ctDNA from blood, this approach has the potential to 
evaluate the multiple genomic targets required in NCCN guidelines, to act as a “summary” of the 
different tumor clones in patients with intra-tumor and inter-tumor heterogeneity [3], and to 
prevent the time delays, costs and complications inherent in invasive biopsies. The analytical and 
clinical validation of Guardant360 is conducted in conformance with evidentiary standards 
established by the Standards for Reporting of Diagnostic Accuracy (STARD), REporting of 


NCI Protocol #:9878 
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20 
tumor MARKer Studies (REMARK), Evaluation of Genomic Applications in Practice and 
Prevention (EGAPP), and the recent Next-generation Sequencing: Standardization of Clinical 
Testing (Nex-StoCT) biomarker guidelines [4–7].  
 
Methodology 
 
The Guardant360 ctDNA next generation sequencing assay identifies single nucleotide variants 
(SNVs) in 68 genes and includes complete exon coverage of 29 genes and coverage of partial 
exons (“hot exons”) in 39 genes, including copy number variants in 16 genes (see figure at end 
of this report). 
 
The gene list was selected to focus on those genomic alterations that are currently actionable 
defined as being targets of sensitivity or resistance to an FDA-approved matched therapy and/or 
a targeted therapy in clinical trials. The test simultaneously sequences the 68 cancer-related 
genes to an average depth of coverage of greater than 10,000X. To summarize, cell-free DNA is 
extracted from plasma and genomic alterations are analyzed by massively parallel paired end 
synthesis-by-sequencing of amplified target genes utilizing an Illumina Hi-Seq 2500 platform 
complemented by systematic end-to-end process optimization including conversion of cell-free 
DNA fragments into digital sequences, improvements in the Illumina next generation sequencing 
process itself, followed by bioinformatics algorithms which enable ctDNA to be measured as a 
quantitative percentage of total cell-free DNA.  
 
Two 10mls of whole blood are collected in Streck Cell-Free DNA Blood Collection (Streck) 
tubes, which contain a proprietary formaldehyde-free preservative in that stabilizes white blood 
cells, preventing the release of genomic DNA and allowing shipping and stability for seven days 
without need for refrigeration, cold bricks or preliminary centrifugation prior to shipping.  
 
After digital libraries are produced, the sample is sequenced and post-sequencing data is 
processed using bioinformatics algorithms to quantify the absolute number of unique DNA 
fragments at a given nucleotide position. This proprietary process is referred to as Digital 
SequencingTM and enables reporting of the fractional concentration (mutant allele frequency) of a 
given SNV. Circulating cell-free DNA is mostly derived from leukocyte lysis (germline) and 
generally a much smaller amount of tumor DNA is derived from cancer cell apoptosis/necrosis. 
All of the cell-free DNA fragments, including leukocyte-derived and tumor-derived, are 
simultaneously sequenced with up to single molecule sensitivity. In other words, both tumor 
DNA and “normal”/germline DNA are sequenced and measured in the same sequencing assay. 
The fractional concentration or mutant allele frequency for a given mutation is calculated as the 
fraction of circulating tumor DNA harboring that mutation in a background of wild-type cell-free 
DNA fragments. The analytic sensitivity reaches detection of 1-2 single mutant fragments from a 
10 ml blood sample.  
 
Leveraging the ability of Digital Sequencing™ to absolutely quantify the number of unique 
DNA fragments in a sequenced sample, the copy number of a given gene in plasma may be 
ascertained. To determine the copy number variant (CNV) or amplification of a given gene, we 
first measure the total number of unique fragments covering each gene. The mode of the 
normalized number of fragments covering each gene is calculated to estimate the fragment 


N CI Pr ot oc ol #: 9 8 7 8 
Versi o n D ate: M arc h 9, 2 0 1 8 
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S M A D 4  
S M O  
S R C 
S T K 1 1  
T E R T** 
T P 5 3
V H L 
7 
A M P LI FI C A TI O N S  
A R
B R A F
C C N E 1
C D K 4
C D K 8
E G F R
E R B B 2
F G F R 1
F G F R 2
KIT
K R A S
M ET
M Y C
P D G F R A
PI K 3 C A
R A F 1
F U SI O N S 
A L K
R ET
R O S 1
NT R K 1
I N D E L S 
E G F R e x o n 1 9 d el eti o ns
E G F R e x o n 2 0 i ns erti o ns
* C o m pl et e e x o n c o v er a g e f or g e n e s i n b ol d 
**I n cl u d e s T E R T pr o m ot er r e gi o n 
C o m pl et e * or Criti c al Ex o n C o v er a g e i n 6 8 G e n e s


NCI Protocol #:9878 
Version Date: March 9, 2018 
 
22 
The Guardant 360 assay is already incorporated into other NCI sponsored clinical trials such as 
the SWOG study of Afatinib and Cetuximab as frontline treatment of EGFR-mutant NSCLC, in 
pancreatobiliary cancer and in clinical trials of the 3rd generation EGFR-TKI rocilitinib where it 
is used to select for EGFR-TKI (OA Zill, Cancer Discovery 2015). 
 
Pharmacokinetics (Integrated biomarker) 
 
There are no expected interactions between onalespib and erlotinib. As this combination has not 
been explored before we will send a subset of samples for pharmacokinetic analysis conducted 
by a third party bioanalytical laboratory selected by Astex. 
 
Multiplex Immunofluorescence Assay (MIFA) of Hsp90 Target Genes (Exploratory 
Biomarker) 
 
Maintaining prolonged knockdown of Hsp90 client proteins with Hsp90 inhibitors has been a 
challenge in the development of this class of drugs [9]. A critical component of successful drug 
development of Hsp90 inhibitors is demonstrating pharmacodynamic (PD) knockdown of client 
oncoproteins related to erlotinib resistance in patients. A major obstacle to lung cancer research 
is the paucity of diagnostic tissue available for biomarker analysis – often limited to a single core 
needle biopsy. Our approach minimizes usage of precious clinical specimens by analyzing 
multiple markers on a single slide and detects co-expression of key resistance factors in a single 
tumor cell. In contrast to traditional fluorescent imaging, bright-field conversion allows 
assessment by trained pathologists concurrent with quantitative measurements of expression. 
 
This technique will be used to simultaneously assess tumor expression of EGFR exon 19 del, 
EGFR L858R, EGFR wild-type, MET and HER2 in biopsied specimens using a Nuance 2 
Multispectral Imaging System Model (Perkin Elmer) attached to an Olympus fluorescent 
microscope and inForm advanced image analysis software. 
 
The Mack laboratory at UC Davis has extensive experience in the MIFA assay including 
incorporation into NCI sponsored studies such as SWOG 0931 Everest study of the mTOR 
inhibitor everolimus as adjuvant therapy in Renal Cell Carcinoma and FGF/FGFR. 
 
We are currently optimizing the assay to deploy in this clinical trial with optional biopsies at 
baseline and on treatment shortly after receiving onalespib. Demonstrating in vivo on-target 
activity of Hsp90 inhibition in this disease will help elucidate the mechanisms underlying 
potential clinical benefit of the treatment combination; demonstrate proof-of-principle for 
prolonged Hsp90 client oncoprotein knockdown in patients with EGFR-mutant NSCLC treated 
with erlotinib and onalespib and aid in the identification of subsets of patients with EGFR-
mutant NSCLC who may preferentially benefit from this combination. 
 
Using MIFA, we hypothesize that we can detect changes in Hsp90, Hsp70 and client 
oncoproteins that may mediate resistance to EGFR-TKI (MET, Her2, EGFR overexpression) in 
pre-treatment and on-treatment biopsies with erlotinib and onalespib.   
 
 


NCI Protocol #:9878 
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23 
Oncopanel (Next Generation Sequencing) (Exploratory Biomarker) 
 
EGFR-tyrosine kinase inhibitors (EGFR-TKIs) such as erlotinib have revolutionized treatment of 
advanced NSCLC patients whose tumors harbor EGFR activating mutations (EGFR+). 
Unfortunately, resistance to EGFR-TKIs invariably develops, with a median PFS of 9-11 
months[5, 6]. Acquired EGFR T790M mutations that prevent the EGFR-TKI from fastening to 
the ATP-binding domain via steric hindrance is the most common mechanism of resistance (~50-
60%). Other mechanisms of resistance include: BRAF mutations, NF1 loss, MET, EGFR and 
Her2 amplification (~30%), EMT, small cell transformation (~10%) and acquired PIK3CA 
mutations (~10%)[2, 3]. Mechanisms of resistance to erlotinib in combination with Hsp90 
inhibition are unknown. In addition to the most common EGFR-TKI resistance mechanism 
(EGFR T790M), we plan an exploratory analysis via next generation sequencing to 
comprehensively explore mechanisms of resistance prior to initiation of onalespib and erlotinib 
and at progression on this trial to further define mechanisms of resistance to the combination.  
 
Patient Derived Xenografts (PDXs) (Exploratory Biomarker) 
 
Patient-derived xenografts (PDXs) recapitulate the molecular, histological and treatment 
response profile of the original patient tumor. This enables the efficacy of modified or alternative 
therapies to be tested in a controlled, laboratory setting to identify regimens with enhanced 
activity and ability to overcome patient-specific resistance mechanisms emergent in the study 
population. Co-investigators at The Jackson Laboratory and UC Davis Comprehensive Cancer 
Center have a wealth of experience in establishing, maintaining and testing PDX models derived 
from NSCLC[20]. 
 
We plan to establish patient-derived xenografts from fresh tumor samples collected at the time 
initiation and acquired resistance to study therapy.  
 
Establishment of cell cultures and/or patient-derived xenografts from fresh samples collected at 
resistance (Jackson Laboratory). Tumor material will be used to establish PDX models from 
patients enrolled on this study including those with EGFR Exon 20 insertions a subset of EGFR-
mutant NSCLC where PDX models do not exist. At select institutions, fresh tumor specimens 
from biopsies before initiation of treatment with erlotinib and onalespib and at time of 
progression on this treatment will be viably shipped overnight to the JAX-West facilities in 
Sacramento for implantation as per the established protocol. 
 
 


NCI Protocol #:9878 
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24 
3. PATIENT SELECTION 
 
3.1 
Eligibility Criteria  
 
3.1.1 Phase 1: Patients must have metastatic/recurrent, histologically confirmed NSCLC that 
harbors an EGFR activating mutation (Exon 21 L858R, Exon 19 deletion, Exon 18 
G719X, Exon 21 L861Q) with progressive disease by RECIST 1.1 on a previous EGFR-
TKI. 
 
OR 
 
Patients must have metastatic/recurrent histologically confirmed NSCLC that harbors an 
EGFR Exon 20 insertion with progressive disease on platinum containing chemotherapy. 
 
3.1.2 Phase 2 Cohort A:  
 
Patients must have metastatic/recurrent histologically confirmed NSCLC that harbors an 
EGFR activating mutation (Exon 21 L858R, Exon 19 deletion, Exon 18 G719X, Exon 21 
L861Q) with stable disease by RECIST 1.1 as best response on erlotinib compared to 
pre-treatment erlotinib imaging by RECIST 1.1 or progressive disease compared to pre-
treatment imaging by RECIST 1.1 after a minimum duration of treatment on erlotinib of 
12-weeks. Patients must be enrolled within 6 months of initiation of erlotinib.  
 
3.1.3 Phase 2 Cohort B:  
 
Patients must have metastatic/recurrent histologically confirmed NSCLC that harbors an 
EGFR Exon 20 insertion with progressive disease on or after platinum doublet 
chemotherapy. 
 
3.1.4  
 
 For phase 1: if patient is on erlotinib at the time of signed consent, the patient does NOT 
need to be discontinued prior to initiation of erlotinib and onalespib. Other EGFR-TKIs 
must be discontinued at least 7 days prior to initiation of erlotinib and onalespib. 
 
 For Phase 2 Cohort A: If patient is on erlotinib at the time of signed consent, erlotinib 
does NOT need to be discontinued prior to receiving treatment erlotinib and onalespib. 
Last dose of erlotinib must be less than 28 days from when patient signs consent. 
 
 For Phase 2 Cohort B:  (EGFR Exon 20 Insertions): Prior EGFR-TKIs including erlotinib 
is allowed. If patient is on erlotinib at the time of signed consent, erlotinib does NOT 
need to be discontinued prior to initiation of erlotinib and onalespib. 
 
3.1.5 Local testing for EGFR-mutations for this study is acceptable provided it was performed 
in a CLIA certified lab.  
 


NCI Protocol #:9878 
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25 
3.1.6 Patients with a prior history of brain metastases are eligible provided: 
a. The brain metastases have been treated 
b. The patient is asymptomatic from the brain metastases 
c. Corticosteroids prescribed for the management of brain metastases have been 
discontinued at least 7 days prior to registration 
3.1.7 Patients must have completed last chemotherapy ≥ 3 weeks or radiotherapy ≥ 2 weeks 
prior to receiving study drugs. 
  
3.1.8 Patients must have recovered from adverse events attributable to previous treatment to ≤ 
grade 1, except for alopecia and sensory neuropathy  grade 2. 
 
3.1.9 Measurable disease by RECIST 1.1  
 
3.1.9.1 Age ≥18 years. Lung cancer is exceedingly rare in children.  Because no dosing or 
adverse event data are currently available on the use onalespib in combination with 
erlotinib in patients <18 years of age, children are excluded from this study, but will 
be eligible for future pediatric trials. 
 
3.1.10 
ECOG performance status ≤2 (Karnofsky ≥60%, see Appendix A). 
 
3.1.11 
Life expectancy of greater than 3 months. 
 
3.1.12 
Patients must have normal organ and marrow function as defined below: 
 
 
leukocytes 
 
≥3,000/mcL 
 
absolute neutrophil count  
≥1,500/mcL 
 
platelets 
 
≥100,000/mcL 
 
total bilirubin 
 
 
within normal institutional limits 
 
AST(SGOT)/ALT(SGPT) 
≤2.5 x UNL of   normal 
 
creatinine 
 
within normal institutional limits 
OR 
 
creatinine clearance 
 
≥60 mL/min/1.73 m2 for patients with creatinine  
 
 
 
 
 
 
 
levels above institutional normal. 
- 
PT/INR and PTT  
 
< 1.3 ULN 
 
3.1.13 
The effects of erlotinib and onalespib on the developing human fetus are unknown.  
For this reason and because onalespib and erlotinib may be teratogenic, 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 she or her 
partner is participating in this study, she should inform her treating physician immediately.  
Men treated or enrolled on this protocol must also agree to use adequate contraception prior to 
the study, for the duration of study participation, and 4 months after completion of erlotinib 
and/or onalespib administration. 
 


NCI Protocol #:9878 
Version Date: March 9, 2018 
 
26 
3.1.14 
Ability to understand and the willingness to sign a written informed consent 
document. 
 
3.2 
Exclusion Criteria 
 
3.2.1 Patients who are receiving any other investigational agents. 
 
3.2.2 History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to erlotinib and/or onalespib 
 
3.2.3 History of pneumonitis attributed to an EGFR inhibitor. History of radiation pneumonitis 
is allowed provided steroid administration for pneumonitis was not required. 
 
3.2.4 Mean resting corrected QT interval (QTc using Fredericia’s formula (QTcF)) > 470 msec 
(See Appendix E for Fridericia’s formula). 
 
3.2.5 Left ventricular ejection fraction ≤ 50% as demonstrated by echocardiogram or MUGA. 
 
3.2.6 Drugs that are known to increase torsades de pointes should be avoided. Patients must 
discontinue these medications prior to enrollment on study. Please see Appendix D for 
current list of drugs to avoid. Selection of alternate concomitant medications with no or 
minimal torsades de pointes potential is recommended. Because the lists of these agents 
are constantly changing, it is important to regularly consult a frequently-updated list such 
as medical reference texts with crediblemeds.org as an example.  
  
3.2.7 Strong CYP3A4 inducers and inhibitors should be avoided. Selection of alternate 
concomitant medications with no or minimal CYP3A4 enzyme inhibition potential is 
recommended. Because the lists of these agents are constantly changing, it is important to 
regularly consult a frequently-updated list such as medical reference texts such as the 
Physicians’ Desk Reference may also provide this information.  As part of the 
enrollment/informed consent procedures, the patient will be counseled on the risk of 
interactions with other agents, and what to do if new medications need to be prescribed or 
if the patient is considering a new over-the-counter medicine or herbal product.   
 
3.2.8 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. 
 
3.2.9 Pregnant women are excluded from this study because erlotinib and onalespib has the 
potential for teratogenic or abortifacient effects.  Because there is an unknown but 
potential risk for adverse events in nursing infants secondary to treatment of the mother 
with erlotinib and onalespib, breastfeeding should be discontinued if the mother is treated 
with erlotinib and onalespib. 
 


NCI Protocol #:9878 
Version Date: March 9, 2018 
 
27 
3.2.10 HIV-positive patients on combination antiretroviral therapy are ineligible because of the 
potential for pharmacokinetic interactions with erlotinib and/or onalespib.  In addition, 
these patients are at increased risk of lethal infections when treated with marrow-
suppressive therapy.  Appropriate studies will be undertaken in patients receiving 
combination antiretroviral therapy when indicated. 
 
3.2.11 Prior treatment with a Hsp90 inhibitor. 
 
3.2.12 Treatment with proton pump inhibitors within 3 days prior to study entry. 
• 
If treatment with an H2-receptor antagonist such as ranitidine is required, Erlotinib 
must be taken 10 hours after the H2-receptor antagonist dosing and at least 2 hours before 
the next dose of the H2-receptor antagonist. 
• 
Although the effect of antacids on erlotinib pharmacokinetics has not been evaluated, 
the antacid dose and the erlotinib dose should be separated by several hours, if an antacid 
is necessary. 
 
 
3.2.13 Abnormalities of the cornea based on history (e.g., dry eye syndrome, Sjogren’s 
syndrome), congenital abnormality (e.g., Fuch’s dystrophy), abnormal slit-lamp 
examination using a vital dye (e.g., fluorescein, Bengal Rose), and/or an abnormal 
corneal sensitivity test (Schirmer test or similar tear production test). 
 
3.3 
Inclusion of Women and Minorities 
 
NIH policy requires that women and members of minority groups and their subpopulations be 
included in all NIH-supported biomedical and behavioral research projects involving NIH-
defined clinical research unless a clear and compelling rationale and justification establishes to 
the satisfaction of the funding Institute & Center (IC) Director that inclusion is inappropriate 
with respect to the health of the subjects or the purpose of the research.  Exclusion under other 
circumstances must be designated by the Director, NIH, upon the recommendation of an IC 
Director based on a compelling rationale and justification.  Cost is not an acceptable reason for 
exclusion except when the study would duplicate data from other sources.  Women of 
childbearing potential should not be routinely excluded from participation in clinical research.  
Please see http://grants.nih.gov/grants/funding/phs398/phs398.pdf. 
 
4. REGISTRATION PROCEDURES 
 
4.1 
Investigator and Research Associate Registration with CTEP 
 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) policy 
require all individuals contributing to NCI-sponsored trials to register and to renew their 
registration annually.  To register, all individuals must obtain a Cancer Therapy Evaluation 
Program 
(CTEP) 
Identity 
and 
Access 
Management 
(IAM) 
account 
(https://ctepcore.nci.nih.gov/iam).  In addition, persons with a registration type of Investigator 
(IVR), Non-Physician Investigator (NPIVR), or Associate Plus (AP) (i.e., clinical site staff 


NCI Protocol #:9878 
Version Date: March 9, 2018 
 
28 
requiring write access to OPEN or RAVE or acting as a primary site contact) must complete their 
annual registration using CTEP’s web-based Registration and Credential Repository (RCR) 
(https://ctepcore.nci.nih.gov/rcr).  Documentation requirements per registration type are outlined 
in the table below. 
 
Documentation Required 
IVR 
NPIVR AP 
A 
FDA Form 1572 
 
 
Financial Disclosure Form 
 
 
 
NCI Biosketch (education, training, employment, 
license, and certification) 
 
 
 
HSP/GCP training 
 
 
 
Agent Shipment Form (if applicable) 
 
CV (optional) 
 
 
 
 
An active CTEP-IAM user account and appropriate RCR registration is required to access all 
CTEP and CTSU (Cancer Trials Support Unit) websites and applications.  In addition, IVRs and 
NPIVRs must list all clinical practice sites and IRBs covering their practice sites on the FDA 
Form 1572 in RCR to allow the following: 
 Added to a site roster 
 Assigned the treating, credit, consenting, or drug shipment (IVR only) tasks in OPEN 
 Act as the site-protocol PI on the IRB approval 
 Assigned the Clinical Investigator (CI) role on the Delegation of Tasks Log (DTL).     
 
Additional 
information 
can 
be 
found 
on 
the 
CTEP 
website 
at 
<https://ctep.cancer.gov/investigatorResources/default.htm>.  For questions, please contact the 
RCR Help Desk by email at < RCRHelpDesk@nih.gov >. 
 
 
 
4.2 
Site Registration 
 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
 


NCI Protocol #:9878 
Version Date: March 9, 2018 
 
29 
 Each investigator or group of investigators at a clinical site must obtain IRB approval for 
this protocol and submit IRB approval and supporting documentation to the CTSU 
Regulatory Office before they can be approved to enroll patients.  Assignment of site 
registration status in the CTSU Regulatory Support System (RSS) uses extensive data to 
make a determination of whether a site has fulfilled all regulatory criteria including but 
not limited to the following:  An active Federal Wide Assurance (FWA) number 
 An active roster affiliation with the Lead Network or a participating organization 
 A valid IRB approval 
 Compliance with all protocol specific requirements 
 
In addition, the site-protocol Principal Investigator (PI) must meet the following criteria: 
 Active registration status 
 The IRB number of the site IRB of record listed on their Form FDA 1572 
An active status on a participating roster at the registering site 
 
Sites participating on the NCI CIRB initiative that are approved by the CIRB for this study are 
not required to submit IRB approval documentation to the CTSU Regulatory Office. For sites 
using the CIRB, IRB approval information is received from the CIRB and applied to the RSS in 
an automated process.  Signatory Institutions must submit a Study Specific Worksheet for Local 
Context (SSW) to the CIRB via IRBManager to indicate their intent to open the study locally.  
The CIRB’s approval of the SSW is then communicated to the CTSU Regulatory Office.  In 
order for the SSW approval to be processed, the Signatory Institution must inform the CTSU 
which CIRB-approved institutions aligned with the Signatory Institution are participating in the 
study. 
 
4.2.1 Downloading Regulatory Documents 
 
Site registration forms may be downloaded from the 9878 protocol page located on the 
CTSU Web site.  Permission to view and download this protocol is restricted and is based 
on person and site roster data housed in the CTSU RSS.  To participate, Investigators and 
Associates must be associated with the Corresponding or Participating protocol 
organization in the RSS.  
 
 Go to https://www.ctsu.org and log in using your CTEP IAM username and 
password. 
 Click on the Protocols tab in the upper left of your screen.  
 Either enter the protocol # in the search field at the top of the protocol tree, or 
 Click on the By Lead Organization folder to expand, then select LAO-CA043, 
and protocol #9878. 
 Click on LPO Documents, select the Site Registration documents link, and 
download and complete the forms provided.  (Note: For sites under the CIRB 
initiative, IRB data will load to RSS as described above.) 
 
4.2.2 Requirements For 9878 Site Registration: 
 


NCI Protocol #:9878 
Version Date: March 9, 2018 
 
30 
 IRB approval (For sites not participating via the NCI CIRB; local IRB documentation, an 
IRB-signed CTSU IRB Certification Form, Protocol of Human Subjects Assurance 
Identification/IRB Certification/Declaration of Exemption Form, or combination is 
accepted ) 
 
4.2.3 Submitting Regulatory Documents 
 
Submit required forms and documents to the CTSU Regulatory Office, where they will 
be entered and tracked in the CTSU RSS. 
Regulatory Submission Portal: www.ctsu.org (members’ section)  Regulatory Tab  
Regulatory Submission Portal 
 
When applicable, original documents should be mailed to: 
CTSU Regulatory Office 
1818 Market Street, Suite 1100 
Philadelphia, PA 19103 
 
Institutions with patients waiting that are unable to use the Portal should alert the CTSU 
Regulatory Office immediately at 1-866-651-2878 in order to receive further instruction 
and support. 
 
4.2.4 Checking Site Registration Status 
 
You can verify your site registration status on the members’ section of the CTSU 
website.   
 Go to https://www.ctsu.org and log in to the members’ area using your CTEP-IAM 
username and password 
 Click on the Regulatory tab at the top of your screen 
 Click on the Site Registration tab 
 Enter your 5-character CTEP Institution Code and click on Go 
 
Note: The status given only reflects compliance with IRB documentation and institutional 
compliance with protocol-specific requirements as outlined by the Lead Network. It does 
not reflect compliance with protocol requirements for individuals participating on the 
protocol or the enrolling investigator’s status with the NCI or their affiliated networks. 
 
 
 
 
 
 
 


NCI Protocol #:9878 
Version Date: March 9, 2018 
 
31 
 
 
 
4.3 
Patient Registration 
 
4.3.1 OPEN / IWRS 
 
Patient enrollment will be facilitated using the Oncology Patient Enrollment Network 
(OPEN).  OPEN is a web-based registration system available to users on a 24/7 basis.  It 
is integrated with the CTSU Enterprise System for regulatory and roster data interchange 
and with the Theradex Interactive Web Response System (IWRS) for retrieval of patient 
registration/randomization assignment.  Patient enrollment data entered by Registrars in 
OPEN / IWRS will automatically transfer to the NCI’s clinical data management system, 
Medidata Rave. 
 
For trials with slot reservation requirements, OPEN will connect to IWRS at enrollment 
initiation to check slot availability.  Registration staff should ensure that a slot is 
available and secured for the patient before completing an enrollment. 
 
• 
Site 
staff 
with 
the 
appropriate 
roles 
will 
reserve 
slots 
using 
IWRS 
(https://open.ctsu.org/).  
• City of Hope Cancer Center will receive notification via the IWRS when a slot has been 
reserved. An email will be sent from the City of Hope Cancer Center to the site 
requesting further information such as: the patient initials, tumor type and potential start 
date. The spot will show as ‘pending approval’ in the system until the site sends a 
REGISTRATION FORM/ELIGIBILITY CHECKLIST accompanied with the signed 
consent, baseline labs, pathology report, CT/x-ray reports to the City of Hope Cancer 
Center at ccc@coh.org for review and confirmation of eligibility.  
• Once the Registration has been reviewed, the City of Hope Cancer Center will either 
approve or disapprove the request depending on confirmation of patient eligibility. If 
approved, the City of Hope Cancer Centre will update the spot to ‘reserved’ in IWRS.  
• The site can now enroll the patient into the study in OPEN. 
 
The OPEN system will provide the site with a printable confirmation of registration and 
treatment information.  Please print this confirmation for your records.  
 
4.3.2 OPEN/IWRS User Requirements 
 
OPEN/IWRS users must meet the following requirements: 
 Have a valid CTEP-IAM account (i.e., CTEP username and password). 
 To enroll patients or request slot reservations:  Be on an ETCTN Corresponding 
or Participating Organization roster with the role of Registrar.  Registrars must 
hold a minimum of an AP registration type.  If a DTL is required for the study, 
the registrar(s) must also be assigned the OPEN Registrar task on the DTL (Note: 
A DTL is NOT required for this study).   


NCI Protocol #:9878 
Version Date: March 9, 2018 
 
32 
 To approve slot reservations or access cohort management:  Be identified to 
Theradex as the “Client Admin” for the study.  
 Have regulatory approval for the conduct of the study at their site. 
 
Prior to accessing OPEN/IWRS, site staff should verify the following: 
 All eligibility criteria have been met within the protocol stated timeframes. Site 
staff should use the registration forms provided on the CTSU web site as a tool to 
verify eligibility. 
 If applicable, all patients have signed an appropriate consent form and HIPAA 
authorization form. 
 
4.3.3 OPEN/IWRS Questions? 
 
Further instructional information on OPEN is provided on the OPEN tab of the CTSU 
website at https://www.ctsu.org or at https://open.ctsu.org.  For any additional questions 
contact the CTSU Help Desk at 1-888-823-5923 or ctsucontact@westat.com.  
 
Theradex has developed a Slot Reservations and Cohort Management User Guide, which 
is 
available 
on 
the 
Theradex 
website:  
http://www.theradex.com/clinicalTechnologies/?National-Cancer-Institute-NCI-11. This 
link to the Theradex website is also on the CTSU website OPEN tab. For questions about 
the use of IWRS for slot reservations, contact the Theradex Helpdesk: 609-619-7862 or 
Theradex main number 609-799-7580; CTMSSupport@theradex.com. 
 
4.4 
General Guidelines 
 
Following registration, patients should begin protocol treatment within 5 days.  Issues that would 
cause treatment delays should be discussed with the Principal Investigator.  If a patient does not 
receive protocol therapy following registration, the patient’s registration on the study may be 
canceled.  The Study Coordinator should be notified of cancellations as soon as possible. 
 
5. TREATMENT PLAN 
 
5.1 
Agent Administration 
 
Treatment will be administered on an outpatient basis.  Reported adverse events and potential 
risks are described in Section 7.  Appropriate dose modifications are described in Section 6.  No 
investigational or commercial agents or therapies other than those described below may be 
administered with the intent to treat the patient's malignancy. 
This trial has two stages. Stage 1 (Phase 1) is dose escalation using a 3+3 design and stage 2 
(phase 2) will be opened at MTD dose. See Section 13.1 for further details. 
 
Dose Level 
Erlotinib (Oral, Daily) 
Onalespib (IV, weekly D1, D8, D15) 
-1 
150 mg 
120 mg/m2 


NCI Protocol #:9878 
Version Date: March 9, 2018 
 
33 
0 (Starting) 
150 mg 
150 mg/m2 
+1 
150 mg 
180 mg/m2 
+2 
150 mg 
220 mg/m2 
 
 
Regimen Description 
Agent 
Premedications; 
Precautions 
Dose 
Route 
Schedule 
Cycle 
Length 
Onalespib 
Premedicate 
with 
dexamethasone  
and/ or 
antihistamine 
ONLY if 
previous 
infusion reaction 
occurs. 
 
**  in 250 
cc D5W or 
normal 
saline 
IV over 1 hour, 
after erlotinib 
Days 1, 8, 
15. 
28 days  
(4 weeks) 
 
 
 
Erlotinib 
 
150 mg  
tablet 
PO in the a.m. 1 
hour before or 2 
hours after a 
meal.  
Daily 
**Doses as appropriate for assigned dose level. 
 
The patient will be requested to maintain a medication diary of erlotinib (Appendix C).  The 
medication diary will be returned to clinic staff at the end of each course. 
 
Erlotinib Administration 
 
 Tablets should be taken once daily preferably in the morning with up to 200 mL of water 
1 hour before or 2 hours after food. 
 
 If the patient vomits after taking the tablets, the dose is replaced only if the tablets can 
actually be seen and counted. 
 
 Patients should log in their daily dose onto a “Pill Diary,” including missed, skipped, or 
vomited doses. 
 
 Patients should wear sunscreen protection, hat, and long sleeves to avoid sun as it can 
exacerbate skin rash. 
 


NCI Protocol #:9878 
Version Date: March 9, 2018 
 
34 
 On the day of the PK studies, i.e., C1D8, erlotinib is to be administered 30 minutes 
before the administration of Onalespib IV. Please see Section 9.1.3 for additional 
information. 
 
5.2 
Definition of Dose-Limiting Toxicity 
 
All toxicities will be graded using National Cancer Institute (NCI) CTCAE Version 5.0. The 
occurrence of any of the following toxicities during Cycle 1 will be considered a DLT, if judged 
by the Investigator to be possibly, probably or definitely related to study drug administration: 
 
   ≥ Grade 3 non-hematologic toxicity 
 
 Except nausea, vomiting or diarrhea that can be controlled by appropriate medical 
intervention or prophylaxis and that resolves to ≤ grade 1 within 48 hours with medical 
intervention 
 
 Except electrolyte toxicities that can be corrected to ≤ grade 1 or baseline within 48 hours 
 
 Grade 3 rash attributed to the combination will be considered a DLT if grade 3 despite 
maximal medical management (including oral antibiotic, topical or oral steroids) for > 72 
hours 
 
 Febrile neutropenia; grade 4 neutropenia for >7 days 
 
 Thrombocytopenia <25,000/mm3 (grade 4) if associated with: 
• 
A bleeding event which does not result in hemodynamic instability but requires an 
elective platelet transfusion, or 
• 
A life-threatening bleeding event which results in urgent intervention and admission 
to an Intensive Care Unit 
• 
Grade 5 toxicity (i.e., death) 
 
 Pneumonitis ≥ grade 3 
 
 Delay in starting cycle 2 of ≥ 14 days due to toxicity related to one or more protocol 
drugs 
 
 Infusion related reactions such as hypersensitivity reaction from onalespib will not be 
assessed as a DLT regardless of grade. 
 
Dose intensity in cycles beyond cycle 1 will be considered in the assessment of the 
recommended phase 2 dose. To be evaluable for a DLT, 75% of dose must have been 
administered in cycle 1 unless a DLT occurred. 
 
Management and dose modifications associated with the above adverse events are outlined in 
Section 5 and Section 6. 


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35 
 
5.3 
Dose Escalation Guidelines 
 
Dose escalation will proceed within each cohort according to the following scheme.  Dose-
limiting toxicity (DLT) is defined above.  Patients will be considered to have received an 
informative course of therapy for the purpose of dose escalation rules if: (a) after any amount of 
study drug, the patient suffers a DLT, or the course is curtailed to prevent an impending DLT; or 
(b) the patient receives all three planned infusions of Onalespib and at least 75% of the planned 
dose of erlotinib.   The patient will be considered fully followed for their initial course if either a 
DLT is reported, or the adverse event form indicates that reporting is complete for the course.  
Patients who have not received an informative and fully followed first course of therapy will be 
replaced to obtain the necessary denominator for the dose-escalation rules. 
 
Number of Patients with DLT at a 
Given Dose Level 
Escalation Decision Rule 
0 out of 3 
Enter 3 patients at the next dose level. 
≥2 
Dose escalation will be stopped.  This dose level will be 
declared the maximally administered dose (highest dose 
administered).  Three (3) additional patients will be 
entered at the next lowest dose level if only 3 patients 
were treated previously at that dose. 
1 out of 3 
Enter at least 3 more patients at this dose level. 
 If 0 of these 3 patients experience DLT, proceed to 
the next dose level. 
 If 1 or more of this group suffer DLT, then dose 
escalation is stopped, and this dose is declared the 
maximally administered dose.  Three (3) additional 
patients will be entered at the next lowest dose level 
if only 3 patients were treated previously at that dose. 
≤1 out of 6 at highest dose level 
below the maximally administered 
dose 
This is generally the recommended phase 2 dose. At 
least 6 patients must be entered at the recommended 
phase 2 dose. 
 
 
 
 
 
5.4 
General Concomitant Medication and Supportive Care Guidelines 
 
Because there is a potential for interaction of erlotinib and onalespib with other concomitantly 
administered drugs, the case report form must capture the concurrent use of all other drugs, over-
the-counter medications, or alternative therapies.  The Principal Investigator should be alerted if 
the patient is taking any agent known to affect or with the potential for drug interactions. The 


NCI Protocol #:9878 
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36 
potential targets for drug interaction can involve, but are not limited to CYP450, glucuronidation, 
P-glycoprotein, protein binding, or reduced absorption from proton-pump inhibitors.  Drugs that 
are known to increase torsades de pointes should be avoided. Check the study agent 
Investigator’s Brochure for potential sources of drug interactions.  The study team should check 
a frequently-updated medical reference for a list of drugs to avoid or minimize use of.  Appendix 
B (Patient Drug Information Handout and Wallet Card) should be provided to patients if 
available. 
 
Erlotinib 
 
Rash: In some patients, rash appeared to be treatable with standard acne therapies, including 
topical and oral antibiotics used to treat acne. Anecdotal reports of improvement have occurred 
with any of the following: minocycline, topical tetracycline, topical clindamycin, topical silver 
sulfadiazine, diphenhydramine, or oral prednisone (short course).  
 
Diarrhea: Previous trials have shown that the frequency and severity of diarrhea rarely hindered 
administration of Erlotinib (OSI-774) and could be managed with loperamide. The recommended 
dose is loperamide 4 mg at first onset, followed by 2 mg every 2–4 hours until diarrhea-free for 
12 hours. 
 
Drugs affecting gastric pH 
 Avoid concomitant use of Erlotinib (OSI-774) with proton pump inhibitors if possible.  
Separation of doses may not eliminate the interaction since proton pump inhibitors affect 
the pH of the upper gastrointestinal (GI) tract for an extended period. 
 If treatment with an H2-receptor antagonist such as ranitidine is required, Erlotinib (OSI-
774) must be taken 10 hours after the H2-receptor antagonist dosing and at least 2 hours 
before the next dose of the H2-receptor antagonist. 
 Although the effect of antacids on Erlotinib (OSI-774) pharmacokinetics has not been 
evaluated, the antacid dose and the Erlotinib (OSI-774) dose should be separated by 
several hours, if an antacid is necessary. 
 
Onalespib Infusion Reaction 
Local infusion-related irritation and systemic infusion reactions may occur during or shortly after 
the administration of onalespib.  The local infusion adverse events are formulation-related (pH of 
current formulation is ~ 4.0). Systemic adverse events (e.g.; flushing, itching, rigors, chills, nausea, 
tachycardia/bradycardia, dizziness) are reversible.  If that occurs, slow the infusion rate and/or 
hydrate with D5W.  Premedication with dexamethasone, antihistamine and 5HT3 antagonists can 
also be given. 
 
 
5.5 
Duration of Therapy 
 
In the absence of treatment delays due to adverse event(s), treatment may continue until one of 
the following criteria applies: 
 


NCI Protocol #:9878 
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37 
 
Disease progression, 
 
 
Intercurrent illness that prevents further administration of treatment, 
 
 
Unacceptable adverse event(s), 
 
 
Patient decides to withdraw from the study, or 
 
 
General or specific changes in the patient's condition render the patient unacceptable 
for further treatment in the judgment of the investigator. 
 
5.6 
Duration of Follow Up 
 
Patients will be followed every 12 weeks for one year and then annually after removal from 
study or until death, whichever occurs first. Patients removed from study for unacceptable 
adverse event(s) will be followed until resolution or stabilization of the adverse event. 
 
5.7 
Criteria for Removal from Study 
 
Patients 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 patient was removed must be documented in the Case 
Report Form. 
 
 
6. DOSING DELAYS/DOSE MODIFICATIONS 
 
Dose modification criteria 
 
If an adverse event that qualifies as a DLT (including those that occur beyond Cycle 1) is 
observed in any subject, the dose should be withheld until there is sufficient recovery that 
satisfies the study eligibility criteria in terms of organ function. Dosing may be resumed in that 
subject, after recovery, but at a reduced dose 1 level below the dose at which the DLT occurred. 
If the toxicity recurs, another dose level reduction should be performed or treatment 
discontinued. A subject’s dose may be reduced for a ≥ Grade 2 toxicity, if the Investigator deems 
it necessary.  
 
Interstitial Lung Disease (Pneumonitis) 
 
Careful assessment of all patients with an acute onset and/or unexplained worsening of 
pulmonary symptoms (dyspnea, cough, fever) should be performed to exclude interstitial lung 
disease (ILD). Study drugs should be interrupted pending investigation of these symptoms. If 
interstitial lung disease is determined to be related to study drugs, study drugs must be 
permanently discontinued and appropriate treatment instituted as necessary.  
Dose Modifications for Erlotinib 
 


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38 
All dose levels for erlotinib are at the FDA approved starting dose of erlotinib 150 mg PO daily. 
 
 
Table 1. Erlotinib (OSI-774) Dose Level Reductions 
Starting Dose 
Dose (-1) 
Dose (-2) 
150 mg/day 
100 mg/day 
50 mg/day 
 
 
After dose -2 (50 mg/day) of erlotinib, no further dose reduction levels are permitted. The patient 
must then discontinue erlotinib. If the investigator determines the patient is deriving clinical 
benefit from onalespib, onalespib may be continued as a single agent at the investigators 
discretion. 
 
Dose Modification and Management of Adverse Events Consistent with Erlotinib Use 
 
Toxicity 
Grade 
Erlotinib (OSI-774) dosage 
modification* 
Guideline for management 
Keratitis 
1 
None 
No intervention 
2 (if <14 
days) 
None 
Preservative-free artificial tears, 
ointments, and/or other therapies as 
clinically indicated, with a follow-
up examination within 2 weeks 
2 (if >14 
days) 
Hold until recovery to < 
grade 1 
And then 
Reduce 1 dose level 
>3 
Hold until recovery to < 
grade 1 
And then 
Reduce 1 dose level* 
>3 
Hold until recovery to < 
grade 1 
And then 
Reduce 1 dose level 
Bilirubin 
 
(for patients 
without pre-
existing liver 
dysfunction) 
 
>3 x ULN 
Withhold OSI-774. 
Discontinue if levels do not 
improve significantly or 
resolve within three weeks. 
 
(for patients 
with pre-
existing liver 
dysfunction) 
 
≥2 x baseline  
 


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39 
Toxicity 
Grade 
Erlotinib (OSI-774) dosage 
modification* 
Guideline for management 
Liver 
trans-
aminase 
(for patients 
without pre-
existing liver 
dysfunction) 
 
>5 x ULN 
Withhold OSI-774. 
Discontinue if levels do not 
improve significantly or 
resolve within three weeks. 
 
(for patients 
with pre-
existing liver 
dysfunction) 
 
≥3 x baseline 
 
Signs and symptoms of 
interstitial pneumonitis 
Hold pending diagnosis 
Permanently discontinue if 
diagnosis is confirmed and 
considered possibly related to 
Erlotinbi (OSI-774 
Patient should be thoroughly 
evaluated, closely monitored, and 
supported as clinically indicated 
Other 
toxicity 
>2 prolonged 
clinically 
significant 
toxicity 
Hold until recovery to < 
grade 1 
And then 
Reduce 1 dose level* 
Treatment as appropriate 
*if dose has been previously held for grade 2 rash or diarrhea, and grade 2 symptoms recur, OR 
if the patient finds the symptoms unacceptable, hold dose until recovery to < grade 1 and then 
reduce dose one level  
 
Discontinue Erlotinib (OSI-774) for:  
 Severe hepatic toxicity that does not improve significantly or resolve within three weeks. 
 Gastrointestinal perforation. 
 Severe bullous, blistering or exfoliating skin conditions. 
 Corneal perforation or severe ulceration. 
  
Withhold Erlotinib (OSI-774):  
 For severe (grade 3 to 4) renal toxicity, and consider discontinuation of OSI-774. 
 For acute/worsening ocular disorders such as eye pain, and consider discontinuation of 
OSI-774. 
 
 
Reduce Erlotinib (OSI-774) by 50 mg decrements: 
 When restarting therapy following withholding treatment for a dose-limiting toxicity that 
has resolved to baseline or grade ≤1.  
 
Dose Modifications for Onalespib 
 


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40 
The dose levels for this study are as follows:  
 
• Starting dose: 150 mg/m
2 weekly for 3 weeks in a 4-week cycle,  
• Escalation to dose levels of 180 mg/m
2 then to 220 mg/m
2 weekly for 3 weeks in a 4-week 
cycle, and  
• Dose reduction to 120 mg/m
2 weekly for 3 weeks in a 4-week cycle.  
 
If dose reduction of onalespib is required or deemed necessary by the investigator, onalespib 
should be reduced to the doses outlined in the following table.  
 
onalespib IV  
(Day 1, Day 8, Day 15) 
Reduce Dose of onalespib IV 
(Day 1, Day 8, Day 15) 
220 mg/m
2 
180 mg/m
2 
180 mg/m
2 
150 mg/m
2 
150 mg/m
2 
120 mg/m
2 
 
No further dose reduction levels are permitted beyond 120 mg/m
2. The patient must then discontinue 
onalespib. If the investigator determines the patient is deriving clinical benefit from erlotinib, 
erlotinib may be continued as a single agent at the investigators discretion. 
 
Specific dose reduction schemes for erlotinib and onalespib for diarrhea and skin toxicity are 
outlined below. 
 
Diarrhea Management on Erlotinib and Onalespib 
 
Patients should be instructed to use loperamide for the prevention of diarrhea and initiate upon 
the first loose stool (4 mg at first onset, followed by 2mg every 2-4 hours until diarrhea resolves 
for 12 hours). Patients should notify their physician immediately at the first signs of poorly 
formed or loose stool or an increased frequency of bowel movements. Administration of 
antidiarrheal agents is recommended at the first sign of diarrhea as initial management. 
Loperamide is recommended as standard first line therapy. Alternatively, diphenoxylate/atropine 
can be used. Additional agents to consider in subjects with diarrhea that is refractory to the above 
include deodorized tincture of opium and octreotide (Benson, Ajani et al. 2004). Some subjects 
may require concomitant therapy with loperamide, diphenoxylate/atropine, and deodorized 
tincture of opium to control diarrhea. The dose modification guidance the tables below should be 
followed. In addition, general supportive measures should be implemented including continuous 
oral hydration, correction of fluid and electrolyte abnormalities, small frequent meals, and 
stopping lactose-containing products, high fat meals and alcohol. 
 
Dose Modification and Management of Diarrhea 
 


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41 
Toxicity, NCI-CTCAE 
Grade 
Action To Be Taken 
With Erlotinib 
Action To Be Taken 
With Onalespib 
Recommended 
Guidelines For 
Management 
Diarrhea 
Grade 1 
No change in dosage 
No change in dosage 
Administration of 
antidiarrheal agents is 
recommended at the 
first sign of diarrhea. 
Loperamide is 
recommended as 
standard first line 
therapy  
Alternatively, 
diphenoxylate can be 
used. 
Additional agents to 
consider in subjects 
with diarrhea that is 
refractory to the above 
include tincture of 
opium and octreotide 
(Benson et al. 2004). 
Some subjects may 
require concomitant 
therapy with 
loperamide, 
diphenoxylate, and 
tincture of opium for 
optimal management of 
diarrhea. 
Grade 2 
No change in dosage. 
Reduce dose of erlotinib 
if necessary (at 
investigators discretion) 
if diarrhea persists over 
72 hours despite optimal 
medical management 
No change in dosage. 
Reduce dose of 
onalespib if diarrhea 
persists over 72 hours 
despite optimal medical 
management after 
erlotinib dose has been 
reduced. 
 
Grade 3 (despite 
optimal management) 
Hold erlotinib. Restart 
erlotinib at reduced 
dose when diarrhea 
resolves to Grade ≤ 1. 
Hold onalespib 
initially. Restart 
onalespib with no dose 
change when diarrhea 
resolves to Grade ≤ 1. 
Reduce dose of 
onalespib if Grade 3 
diarrhea recurs despite 
optimal medical 
management after 
erlotinib dose has been 
reduced. 
Grade 4 
Discontinue erlotinib 
Hold onalespib initially. 
Restart onalespib at a 
reduced dose when 
diarrhea resolves to 
Grade ≤ 1. Discontinue 
onalespib if Grade 4 
diarrhea recurs despite 
optimal medical 
management. 
 
 
Dose Modification and Management of Rash Consistent with Erlotinib Use 
 


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42 
Toxicity, 
NCI-CTCAE 
Grade 
Action To Be Taken 
With Erlotinib 
Action To Be Taken With Onalespib 
Recommended 
Guidelines For 
Management 
Rash Consistent with the Use of Erlotinib 
Grade 1 
No change in dosage. 
No change in dosage 
Any of the following: 
minocycline or 
doxycycline, topical 
tetracycline, topical 
clindamycin, topical 
hydrocortisone, topical 
pimecrolimus, topical 
silver sulfadiazine, or 
diphenhydramine at 
discretion of investigator 
Grade 2 
No change in dosage. 
Reduce dose of erlotinib 
if necessary if rash 
persists or worsens over 
10-14 days despite 
optimal medical 
management 
No change in dosage. 
Manage as described 
above 
Grade 3 
Hold erlotinib. Restart 
erlotinib at reduced  
dose when rash is Grade 
≤ 2. 
Hold onalespib initially. Restart onalespib 
with no dose change when rash resolves to 
Grade ≤ 2. . Reduce dose of onalespib if 
Grade 3 rash recurs (or if rash does not 
resolve to Grade ≤ 2 within 2 weeks) after 
erlotinib dose has been reduced. 
Manage as described 
above 


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43 
Grade 4 
Discontinue erlotinib 
Hold onalespib initially. Restart onalespib 
with no dose change when rash resolves 
to Grade ≤ 2. Discontinue onalespib if 
Grade 4 rash recurs. 
Manage as described 
above 
 
 
7. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS  
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The 
following list of AEs (Section 7.1) and the characteristics of an observed AE (Section 7.2) will 
determine whether the event requires expedited reporting via the CTEP Adverse Event Reporting 
System (CTEP-AERS) in addition to routine reporting. 
 
7.1 
Comprehensive Adverse Events and Potential Risks List(s) (CAEPRs) 
 
The Comprehensive Adverse Event and Potential Risks list (CAEPR) provides a single list of 
reported and/or potential adverse events (AE) associated with an agent using a uniform 
presentation of events by body system.  In addition to the comprehensive list, a subset of AEs, 
the Specific Protocol Exceptions to Expedited Reporting (SPEER), appears in a separate column 
and is identified with bold and italicized text.  The SPEER is a list of events that are protocol-
specific exceptions to expedited reporting to NCI (except as noted below).  Refer to the 'CTEP, 
NCI 
Guidelines: 
Adverse 
Event 
Reporting 
Requirements' 
http://ctep.cancer.gov/protocolDevelopment/adverse_effects.htm for further clarification.  
 
NOTE:  The highest grade currently reported is noted in parentheses next to the AE in the 
SPEER.  Report ONLY AEs higher than this grade expeditiously.  If this CAEPR is part of a 
combination protocol using multiple investigational agents and has an AE listed on different 
SPEERs, use the lower of the grades to determine if expedited reporting is required. 
 
7.1.1 CAEPRs for CTEP IND Agent(s) 
 
7.1.1.1 
CAEPR for OSI-774 (Erlotinib, NSC 718781) 
 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of 
reported and/or potential adverse events (AE) associated with an agent using a uniform 
presentation of events by body system. In addition to the comprehensive list, a subset, the 
Specific Protocol Exceptions to Expedited (SPEER), appears in a separate column and is 
identified with bold and italicized text. This subset of AEs (SPEER) is a list of events that are 
protocol specific exceptions to expedited reporting to NCI (except as noted below).  Refer to the 
'CTEP, 
NCI 
Guidelines: 
Adverse 
Event 
Reporting 
Requirements' 


NCI Protocol #:9878 
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44 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf 
for 
further clarification.  Frequency is provided based on 3622 patients.  Below is the CAEPR for 
OSI-774 (erlotinib). 
 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses 
next to the AE in the SPEER.  If this CAEPR is part of a combination protocol using multiple 
investigational agents and has an AE listed on different SPEERs, use the lower of the grades 
to determine if expedited reporting is required. 
 
 
 
 
 
Version 2.6, June 20, 20171 
 
 Adverse Events with Possible  
 Relationship to Erlotinib (Tarceva) 
 (CTCAE 4.0 Term) 
[n= 3622] 
 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
 
 
Disseminated 
intravascular coagulation2   
 
 
Hemolytic uremic 
syndrome2 
  
 
 
Thrombotic 
thrombocytopenic 
purpura2 
  
CARDIAC DISORDERS 
  
 
 
Myocardial infarction2 
  
EYE DISORDERS 
  
 
Conjunctivitis 
 
 Conjunctivitis (Gr 2) 
 
Dry eye 
 
 Dry eye (Gr 2) 
 
 
Eye disorders - Other 
(corneal perforation) 
  
 
Eye disorders - Other 
(eyelash in-growth and/or 
thickening) 
 
  
 
 
Keratitis 
  
GASTROINTESTINAL DISORDERS 
  
 
Abdominal pain 
 
 Abdominal pain (Gr 3) 
Diarrhea 
 
 
 Diarrhea (Gr 3) 


NCI Protocol #:9878 
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45 
 
 Adverse Events with Possible  
 Relationship to Erlotinib (Tarceva) 
 (CTCAE 4.0 Term) 
[n= 3622] 
 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
 
 
Dry mouth 
 
 Dry mouth (Gr 2) 
 
Dyspepsia 
 
 Dyspepsia (Gr 2) 
 
Gastrointestinal 
hemorrhage3 
 
  
 
 
Gastrointestinal 
perforation4 
  
 
Mucositis oral 
 
 Mucositis oral (Gr 3) 
 
Nausea 
 
 Nausea (Gr 3) 
Vomiting 
 
 
 Vomiting (Gr 3) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
Fatigue 
 
 
 Fatigue (Gr 3) 
HEPATOBILIARY DISORDERS 
  
 
 
Hepatic failure 
  
INFECTIONS AND INFESTATIONS 
  
 
Infection5 
 
 Infection5 (Gr 3) 
INVESTIGATIONS 
  
 
Alanine aminotransferase 
increased 
 
 Alanine 
aminotransferase 
increased (Gr 3) 
 
Alkaline phosphatase 
increased 
 
  
 
Aspartate aminotransferase 
increased 
 
 Aspartate 
aminotransferase 
increased (Gr 3) 
 
Blood bilirubin increased  
 Blood bilirubin increased 
(Gr 3) 
 
 
INR increased (in patients 
taking Coumadin) 
  
METABOLISM AND NUTRITION DISORDERS 
  
Anorexia 
 
 
 Anorexia (Gr 3) 
 
Dehydration 
 
 Dehydration (Gr 3) 
NERVOUS SYSTEM DISORDERS 
  
 
Dysgeusia 
 
 Dysgeusia (Gr 2) 
 
Headache 
 
 Headache (Gr 2) 
 
 
Intracranial hemorrhage 
  
 
 
Ischemia cerebrovascular2   
RENAL AND URINARY DISORDERS 
  


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46 
 
 Adverse Events with Possible  
 Relationship to Erlotinib (Tarceva) 
 (CTCAE 4.0 Term) 
[n= 3622] 
 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
 
 
 
Acute kidney injury 
  
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Cough 
 
 Cough (Gr 2) 
 
Dyspnea 
 
 Dyspnea (Gr 3) 
 
Epistaxis 
 
  
 
Pneumonitis 
 
 Pneumonitis (Gr 4) 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
Alopecia 
 
 Alopecia (Gr 2) 
 
Dry skin 
 
 Dry skin (Gr 2) 
 
 
Erythema multiforme 
  
 
Nail loss 
 
 Nail loss (Gr 2) 
 
 
Palmar-plantar 
erythrodysesthesia 
syndrome 
  
 
Pruritus 
 
 Pruritus (Gr 2) 
 
Rash acneiform 
 
 Rash acneiform (Gr 2) 
Rash maculo-papular 
 
 
 Rash maculo-papular 
(Gr 3) 
 
 
Stevens-Johnson 
syndrome 
  
 
 
Toxic epidermal 
necrolysis 
  
 
1This table will be updated as the toxicity profile of the agent is revised.  Updates will be 
distributed to all Principal Investigators at the time of revision.  The current version can be 
obtained by contacting PIO@CTEP.NCI.NIH.GOV.  Your name, the name of the investigator, 
the protocol and the agent should be included in the e-mail. 
 
2The risk of myocardial infarction, cerebrovascular accident, and microangiopathic hemolytic 
anemia is increased in patients with pancreatic cancer who were treated concomitantly with 
gemcitabine. 
 
3Gastrointestinal hemorrhage includes Anal hemorrhage, Cecal hemorrhage, Colonic 
hemorrhage, Duodenal hemorrhage, Esophageal hemorrhage, Esophageal varices hemorrhage, 
Gastric hemorrhage, Hemorrhoidal hemorrhage, Ileal hemorrhage, Intra-abdominal hemorrhage, 
Jejunal hemorrhage, Lower gastrointestinal hemorrhage, Oral hemorrhage, Pancreatic 
hemorrhage, Rectal hemorrhage, Retroperitoneal hemorrhage, and Upper gastrointestinal 
hemorrhage under the GASTROINTESTINAL DISORDERS SOC. 


NCI Protocol #:9878 
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47 
 
4Gastrointestinal perforation includes Colonic perforation, Duodenal perforation, Esophageal 
perforation, Gastric perforation, Ileal perforation, Jejunal perforation, Rectal perforation, and 
Small intestinal perforation under the GASTROINTESTINAL DISORDERS SOC. 
 
5Infection includes all 75 sites of infection under the INFECTIONS AND INFESTATIONS 
SOC. 
 
 
Adverse events reported on erlotinib (Tarceva) trials, but for which there is insufficient 
evidence to suggest that there was a reasonable possibility that erlotinib (Tarceva) caused 
the adverse event: 
 
EYE DISORDERS - Blurred vision; Eye disorders - Other (orbital cellulitis); Uveitis; Watering 
eyes 
GASTROINTESTINAL DISORDERS - Colitis; Constipation; Duodenal ulcer; Dysphagia; 
Esophagitis; Gastric ulcer; Gastritis; Gastrointestinal disorders - Other (pneumatosis intestinalis); 
Pancreatitis 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Edema limbs 
HEPATOBILIARY DISORDERS - Cholecystitis 
INVESTIGATIONS - Creatinine increased; Lymphocyte count decreased; Platelet count 
decreased 
METABOLISM AND NUTRITION DISORDERS - Hyperglycemia; Hyperkalemia; 
Hypocalcemia; Hypokalemia; Hypomagnesemia; Hyponatremia; Hypophosphatemia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Generalized muscle 
weakness 
NERVOUS SYSTEM DISORDERS - Dizziness; Peripheral sensory neuropathy 
PSYCHIATRIC DISORDERS - Confusion 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Adult respiratory 
distress syndrome; Pharyngolaryngeal pain 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Urticaria 
VASCULAR DISORDERS - Thromboembolic event 
 
Note: Erlotinib (Tarceva) in combination with other agents could cause an exacerbation of any 
adverse event currently known to be caused by the other agent, or the combination may result in 
events never previously associated with either agent. 
 
Note:  Erlotinib (Tarceva®)-induced diarrhea and/or vomiting has been associated with 
dehydration, hyperkalemia; hypocalcemia; hypokalemia; hypomagnesemia; hyponatremia; 
hypophosphatemia, increased creatinine, and renal failure. 
 
Note:  Cases of hepatic failure and hepatorenal syndrome (including fatalities) have been 
reported during use of erlotinib (Tarceva®) in patients with or without baseline hepatic 
impairment.  
 
 


NCI Protocol #:9878 
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48 
 
 
7.1.1.2 
CAEPR for Onalespib (AT13387) (NSC 749712) 
 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of 
reported and/or potential adverse events (AE) associated with an agent using a uniform 
presentation of events by body system. In addition to the comprehensive list, a subset, the 
Specific Protocol Exceptions to Expedited Reporting (SPEER), appears in a separate column and 
is identified with bold and italicized text. This subset of AEs (SPEER) is a list of events that are 
protocol specific exceptions to expedited reporting to NCI (except as noted below).  Refer to the 
'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf for 
further clarification. Frequency is provided based on 119 patients. Below is the CAEPR for 
AT13387 (Onalespib). 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses 
next to the AE in the SPEER.  If this CAEPR is part of a combination protocol using multiple 
investigational agents and has an AE listed on different SPEERs, use the lower of the grades 
to determine if expedited reporting is required. 
 
Version 2.0, April 6, 20171 
 
 Adverse Events with Possible  
 Relationship to AT13387 (Onalespib) 
 (CTCAE 4.0 Term) 
[n= 119] 
 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious 
(<3%) 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
Anemia 
 
 
 Anemia (Gr 2) 
EYE DISORDERS 
  
 
Blurred vision 
 
  
 
Eye disorders - Other 
(visual impairment) 
 
 Eye disorders - Other (visual 
impairment) (Gr 2) 
GASTROINTESTINAL DISORDERS 
  
 
Abdominal pain 
 
 Abdominal pain (Gr 2) 
 
Constipation 
 
 Constipation (Gr 2) 
Diarrhea 
 
 
 Diarrhea (Gr 2) 
 
Dry mouth 
 
 Dry mouth (Gr 2) 
 
Dyspepsia 
 
 Dyspepsia (Gr 2) 
 
Flatulence 
 
 Flatulence (Gr 2) 
 
Gastrointestinal 
hemorrhage2 
 
  
 
Hemorrhoids  
 
 Hemorrhoids (Gr 2) 


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 Adverse Events with Possible  
 Relationship to AT13387 (Onalespib) 
 (CTCAE 4.0 Term) 
[n= 119] 
 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious 
(<3%) 
 
Nausea 
 
 
 Nausea (Gr 2) 
 
Vomiting 
 
 Vomiting (Gr 2) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
 
Edema limbs 
 
  
Fatigue 
 
 
 Fatigue (Gr 2) 
 
Fever3 
 
 Fever3 (Gr 2) 
 
Infusion related reaction3  
 Infusion related reaction3 
(Gr 2) 
Injection site reaction4 
 
 
 Injection site reaction4 (Gr 
2) 
 
Malaise 
 
 Malaise (Gr 2) 
INFECTIONS AND INFESTATIONS 
  
 
Infection5 
 
 Infection5 (Gr 2) 
INVESTIGATIONS 
  
 
Alanine aminotransferase 
increased 
 
 Alanine aminotransferase 
increased (Gr 2) 
 
Alkaline phosphatase 
increased 
 
 Alkaline phosphatase 
increased (Gr 2) 
 
Aspartate 
aminotransferase 
increased 
 
 Aspartate aminotransferase 
increased (Gr 2) 
 
CPK increased 
 
 CPK increased (Gr 2) 
 
Electrocardiogram QT 
corrected interval 
prolonged 
 
  
 
Lymphocyte count 
decreased 
 
 Lymphocyte count decreased 
(Gr 2) 
 
Platelet count decreased 
 
 Platelet count decreased (Gr 
2) 
 
Weight loss 
 
 Weight loss (Gr 2) 
 
White blood cell 
decreased 
 
  
METABOLISM AND NUTRITION DISORDERS 
  
 
Anorexia 
 
 Anorexia (Gr 2) 
 
Dehydration 
 
 Dehydration (Gr 2) 
 
Hypocalcemia 
 
 Hypocalcemia (Gr 2) 


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 Adverse Events with Possible  
 Relationship to AT13387 (Onalespib) 
 (CTCAE 4.0 Term) 
[n= 119] 
 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious 
(<3%) 
 
 
Hypokalemia 
 
  
 
Hypomagnesemia 
 
  
 
Hyponatremia 
 
 Hyponatremia (Gr 2) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Musculoskeletal and 
connective tissue disorder 
- Other (muscle spasms) 
 
 Musculoskeletal and 
connective tissue disorder - 
Other (muscle spasms) (Gr 
2) 
 
Myalgia 
 
 Myalgia (Gr 2) 
NERVOUS SYSTEM DISORDERS 
  
 
Dizziness 
 
 Dizziness (Gr 2) 
 
Dysgeusia 
 
  
 
Headache 
 
 Headache (Gr 2) 
PSYCHIATRIC DISORDERS 
  
 
Insomnia 
 
 Insomnia (Gr 2) 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Cough 
 
 Cough (Gr 2) 
 
Dyspnea 
 
 Dyspnea (Gr 2) 
 
Hiccups 
 
 Hiccups (Gr 2) 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
Dry skin 
 
 Dry skin (Gr 2) 
 
Hyperhidrosis3 
 
 Hyperhidrosis3 (Gr 2) 
 
Rash acneiform 
 
  
 
Rash maculo-papular 
 
 Rash maculo-papular (Gr 2) 
VASCULAR DISORDERS 
  
 
Flushing 
 
 Flushing (Gr 2) 
 
1This table will be updated as the toxicity profile of the agent is revised.  Updates will be 
distributed to all Principal Investigators at the time of revision.  The current version can be 
obtained by contacting PIO@CTEP.NCI.NIH.GOV.  Your name, the name of the investigator, 
the protocol and the agent should be included in the e-mail. 
 
2Gastrointestinal hemorrhage includes Anal hemorrhage, Cecal hemorrhage, Colonic 
hemorrhage, Duodenal hemorrhage, Esophageal hemorrhage, Esophageal varices hemorrhage, 
Gastric hemorrhage, Hemorrhoidal hemorrhage, Ileal hemorrhage, Intra-abdominal hemorrhage, 
Jejunal hemorrhage, Lower gastrointestinal hemorrhage, Oral hemorrhage, Pancreatic 


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51 
hemorrhage, Rectal hemorrhage, Retroperitoneal hemorrhage, and Upper gastrointestinal 
hemorrhage under the GASTROINTESTINAL DISORDERS SOC. 
 
3Infusion-related reactions may include, tachycardia/bradycardia, hypotension/hypertension, 
flushing, chills, fever, hyperhidrosis, itching, rigors, and abdominal cramps. 
 
4Injection site reaction may include injection site irritation, injection site pain, injection site 
inflammation or redness, or erythema. 
 
5Infection may include all 75 sites of infection under the INFECTIONS AND INFESTATIONS 
SOC. 
 
 
Adverse events reported on AT13387 (Onalespib) trials, but for which there is insufficient 
evidence to suggest that there was a reasonable possibility that AT13387 (Onalespib) 
caused the adverse event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Febrile neutropenia 
CARDIAC DISORDERS - Cardiac disorders - Other (atrioventricular block NOS); Left 
ventricular systolic dysfunction; Palpitations 
EYE DISORDERS - Dry eye; Eye disorders - Other (color distortion); Eye disorders - Other 
(diplopia); Eye disorders - Other (halos); Eye disorders - Other (loss of visual acuity during 
changes in ambient light levels); Eye disorders - Other (tunnel vision); Eye disorders - Other 
(visual color darkening); Eye disorders - Other (visual disturbances); Eye pain; Flashing lights; 
Floaters; Keratitis; Night blindness; Papilledema; Photophobia; Retinopathy 
GASTROINTESTINAL DISORDERS - Colitis; Mucositis oral; Oral dysesthesia; Oral pain; 
Salivary duct inflammation 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Chills3; Flu 
like symptoms 
HEPATOBILIARY DISORDERS - Hepatic hemorrhage 
INVESTIGATIONS - Activated partial thromboplastin time prolonged; Blood bilirubin 
increased; Creatinine increased; Ejection fraction decreased; Neutrophil count decreased 
METABOLISM AND NUTRITION DISORDERS - Hyperglycemia; Hypoalbuminemia; 
Hypophosphatemia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Back pain; Bone 
pain; Generalized muscle weakness 
NERVOUS SYSTEM DISORDERS - Seizure; Syncope; Tremor 
PSYCHIATRIC DISORDERS - Anxiety 
RENAL AND URINARY DISORDERS - Acute kidney injury; Proteinuria 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Pneumonitis 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Palmar-plantar erythrodysesthesia 
syndrome; Pruritus; Skin hyperpigmentation 
VASCULAR DISORDERS - Hypertension3 
 
Note: AT13387 (Onalespib) in combination with other agents could cause an exacerbation of 
any adverse event currently known to be caused by the other agent, or the combination may 


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52 
result in events never previously associated with either agent. 
 
Note: Onalespib dose should be based on the most current weight available and recalculated 
based on weight and BSA at least at the beginning of each cycle and for a threshold change in 
weight of  > 10%. 
 
7.2 
Adverse Event Characteristics  
 
 CTCAE term (AE description) and grade:  The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
4.0 will be utilized until March 31, 2018 for AE reporting.  CTCAE version 5.0 will be 
utilized for AE reporting beginning April 1, 2018.  All appropriate treatment areas should 
have access to a copy of the CTCAE version 5.0.  A copy of the CTCAE version 5.0 can 
be 
downloaded 
from 
the 
CTEP 
web 
site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
 For expedited reporting purposes only:   
- 
AEs for the agent that are bold and italicized in the CAEPR (i.e., those listed in the 
SPEER column, Section 7.1.1) should be reported through CTEP-AERS only if the 
grade is above the grade provided in the SPEER. 
 
 Attribution of the AE: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE is doubtfully related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
7.3 
Expedited Adverse Event Reporting 
 
7.3.1 Expedited AE reporting for this study must use CTEP-AERS (CTEP Adverse Event 
Reporting 
System), 
accessed 
via 
the 
CTEP 
Web 
site 
(https://eapps-
ctep.nci.nih.gov/ctepaers).  The reporting procedures to be followed are presented in the 
“NCI Guidelines for Investigators: Adverse Event Reporting Requirements for DCTD 
(CTEP and CIP) and DCP INDs and IDEs” which can be downloaded from the CTEP 
Web 
site 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm
).  These requirements are briefly outlined in the tables below (Section 7.3.3). 
 
In the rare occurrence when Internet connectivity is lost, a 24-hour notification is to be 
made to CTEP by telephone at 301-897-7497.  Once Internet connectivity is restored, the 
24-hour notification phoned in must be entered electronically into CTEP-AERS by the 
original submitter at the site. 
 
7.3.2 Distribution of Adverse Event Reports 
 


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53 
CTEP-AERS is programmed for automatic electronic distribution of reports to the 
following individuals:  Principal Investigator and Adverse Event Coordinator(s) (if 
applicable) of the Corresponding Organization or Lead Organization, the local treating 
physician, and the Reporter and Submitter.  CTEP-AERS provides a copy feature for 
other e-mail recipients.  
 
7.3.3 Expedited Reporting Guidelines 
 
Use the NCI protocol number and the protocol-specific patient ID assigned during trial 
registration on all reports. 
 
Note:  A death on study requires both routine and expedited reporting, regardless of 
causality.  Attribution to treatment or other cause must be provided. 
 
Death due to progressive disease should be reported as Grade 5 “Disease Progression” 
in the system organ class (SOC) “General disorders and administration site conditions.”  
Evidence that the death was a manifestation of underlying disease (e.g., radiological 
changes suggesting tumor growth or progression: clinical deterioration associated with a 
disease process) should be submitted.  
 
Phase 1 and Early Phase 2 Studies:  Expedited Reporting Requirements for Adverse 
Events that Occur on Studies under an IND/IDE within 30 Days of the Last Administration 
of the Investigational Agent/Intervention 1, 2 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether or not 
they are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
An adverse event is considered serious if it results in ANY of the following outcomes:   
1) 
Death 
2) 
A life-threatening adverse event  
3) 
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 
hours  
4) 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions  
5) 
A congenital anomaly/birth defect.  
6) 
Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization 
may be considered serious when, based upon medical judgment, they may jeopardize the patient or 
subject and may require medical or surgical intervention to prevent one of the outcomes listed in this 
definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via electronic 
submission within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 and Grade 2 Timeframes 
Grade 3-5 
Timeframes 
Resulting in 
Hospitalization  
≥ 24 hrs 
10 Calendar Days 
24-Hour 5 Calendar 
Days 
Not resulting in 
Hospitalization  
≥ 24 hrs 
Not required 


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54 
NOTE:  Protocol specific exceptions to expedited reporting of serious adverse events are found in the Specific 
Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR. 
Expedited AE reporting timelines are defined as: 
o 
“24-Hour; 5 Calendar Days” - The AE must initially be submitted electronically within 24 hours of learning 
of the AE, followed by a complete expedited report within 5 calendar days of the initial 24-hour report. 
o 
“10 Calendar Days” - A complete expedited report on the AE must be submitted electronically within 10 
calendar days of learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
 
All Grade 3, 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
 
Grade 2 AEs resulting in hospitalization or prolongation of hospitalization 
2For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, 
rounded UP to the nearest whole day, after the agent/intervention was last administered.  Footnote “1” above 
applies after this reporting period. 
Effective Date:  May 5, 2011 
 
7.4 
Routine Adverse Event Reporting 
 
All Adverse Events must be reported in routine study data submissions.  AEs reported 
expeditiously through CTEP-AERS must also be reported in routine study data 
submissions. 
 
Adverse event data collection and reporting, which are required as part of every clinical trial, are 
done to ensure the safety of patients enrolled in the studies as well as those who will enroll in 
future studies using similar agents.  AEs are reported in a routine manner at scheduled times 
during the trial using Medidata Rave.  For this trial the Adverse Event CRF is used for routine 
AE reporting in Rave. 
 
7.5 
Secondary Malignancy 
 
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., 
treatment with investigational agent/intervention, radiation or chemotherapy). A secondary 
malignancy is not considered a metastasis of the initial neoplasm. 
 
CTEP requires all secondary malignancies that occur following treatment with an agent under an 
NCI IND/IDE be reported expeditiously via CTEP-AERS.  Three options are available to 
describe the event:  
 
 Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia 
[AML])  
 Myelodysplastic syndrome (MDS)  
 Treatment-related secondary malignancy  
 
Any malignancy possibly related to cancer treatment (including AML/MDS) should also be 
reported via the routine reporting mechanisms outlined in each protocol.  


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55 
 
7.6 
Second Malignancy 
 
A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT a 
metastasis from the initial malignancy).  Second malignancies require ONLY routine AE 
reporting unless otherwise specified. 
 
 
8. PHARMACEUTICAL INFORMATION 
 
A list of the adverse events and potential risks associated with the investigational agents 
administered in this study can be found in Section 7.1. 
 
8.1 
CTEP IND Agent(s) 
 
8.1.1 Erlotinib (OSI-774) (NSC 718781) 
 
Chemical Name: 
N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine, 
monohydrochloride 
 
Other Names: 
  
Erlotinib hydrochloride, Tarceva™ 
 
Classification: 
 
Tyrosine kinase Inhibitor (EGFR) 
 
Molecular Formula: C22H23N3O4 HCl 
 
 
M.W.: 
393.4 (free base) 
429.9 (hydrochloride salt) 
 
Mode of Action: 
Direct inhibition of EGFR tyrosine kinase 
 
How Supplied: Erlotinib tablets are provided by Astellas Pharma and distributed by the 
Pharmaceutical Management Branch, DCTD/NCI as 25 mg, 100 mg, and 150 mg white film-coated 
immediate-release tablets packaged in high-density polyethylene (HDPE) bottles.  Each bottle 
contains 30 tablets.  
 
The tablets are round and convex without markings.  The 25 mg tablets are 1/4 inches (6 mm); 
the 100 mg tablets are 11/32 inches (9 mm); and the 150 mg tablets are 13/32 inches (10 mm). 
Erlotinib excipients include lactose monohydrate, hypromellose, hydroxypropyl cellulose, 
magnesium stearate, microcrystalline cellulose, sodium starch glycolate, sodium lauryl sulfate 
and titanium dioxide. The tablets also contain trace amounts of color additives, including FD&C 
Yellow No. 6 (25 mg only) for product identification. 
 
In 2017 there will be a transition to Erlotinib tablets with a different finished appearance.  The 
new Erlotinib tablets are manufactured to the same specifications, and are packaged in 60 mL 
HDPE bottles.  The tablets are round, with a biconvex face, straight sides, and white film-coated.  
Each strength will be plain on one side, with print on the opposite side: 


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56 
 25 mg – “T” and “25” in orange print 
 100 mg – “T” and “100” in gray print 
 150 mg – “T” and “150” in maroon print 
 
Storage:  Store at 25°C (77°F); excursions permitted to 15° – 30°C (59° – 86°F). 
 
Route of Administration:  Oral. 
  
Method of Administration:  
 
 Tablets should be taken once daily preferably in the morning with up to 200 mL of water one 
hour before or two hours after food. 
 
 Administration through G-tube: Dissolve the dose in 100 mL of sterile water, and shake it 
vigorously to form a uniform suspension.  Draw suspension into a syringe and administer 
through the G-tube port.  Repeat the transfer until the entire volume has been administered.  
Add small volume (40 mL) of sterile water to the container used to dissolve the tablets.  
Shake the residual suspension, aspirate it into a syringe, and administer.  Repeat this last step 
to ensure the entire dose is administered.  The total volume of delivery/rinse is ~180 mL.  
 
Potential Drug Interaction: Erlotinib is highly protein bound (92% to 95% in humans).  Erlotinib 
is metabolized primarily via CYP3A4 and to a lesser extent by CYP1A2, and the pulmonary 
isoform CYP1A1.  Dose Erlotinib cautiously with agents that are highly protein bound or are 
metabolized by, or are inhibitors or inducers of these enzymes. 
 
Significant interactions with the clearance of other CYP3A4 substrates are unlikely. 
 
CYP Iso-Enzymes Inhibitors/Inducers: 
o Potent CYP3A4 or combined CYP3A4/CYP1A2 Inhibitors:  Use alternative drug.  
Alternatively, reduce Erlotinib dose in the event of drug interaction (if permitted by the 
protocol).  
o Potent CYP3A4 inducers:  Use alternative drug.  If an alternative treatment is 
contraindicated, consider increasing the Erlotinib dose (if permitted by the protocol).   
o Potent and moderate CYP1A2 inducers:  concomitant use with Erlotinib should be avoided. 
 
Food-drug interaction:  Avoid grapefruit /grapefruit juice (potent CYP3A4) while taking Erlotinib. 
 
Smoking:  Advise smokers to stop smoking while Erlotinib.  Smoking induces CYP1A2 enzymes 
and has been shown to reduce Erlotinib exposure by 50% to 60%. 
 
Anticoagulant:  Concomitant NSAIDs, warfarin or warfarin-derivatives may increase bleeding and 
PT /INR. Dose adjustment may be needed.  
 
Proton Pump Inhibitor:  Erlotinib’s solubility decreases as the pH increases. Co-administration of 
omeprazole with Erlotinib will increase the AUC and Cmax by 46% and 61%, respectively.  
 


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57 
H2-antagonist: Avoid concomitant use of Erlotinib with gastric acid reducing agents if possible.  
When ranitidine 300 mg is given with Erlotinib, Erlotinib AUC and Cmax  decrease by 33% and 
54%, respectively.  Increasing the dose of Erlotinib will not compensate the loss of exposure.  
However, if an H2-antagonist receptor is needed, take Erlotinib at least 2 hours before or 10 
hours following the H2-antagonist administration.  Dosing such, Erlotinib loss of exposure is 
minimized to AUC of 15% and Cmax   of 17%.   
 
Statins:  The combination of erlotinib and a statin may increase the potential for statin-induced 
myopathy, including rhabdomyolysis, which was observed rarely. 
 
Patient Care Implications: If patient vomits after taking the tablets, readminister the dose only if 
the tablets can actually be seen and counted. 
 
Recommend patients to use sunscreen protection, and wear hat and long sleeve shirts as sunlight 
can exacerbate skin reactions. 
 
Women of childbearing potential must use effective contraception during treatment and for one 
month after the last dose of Erlotinib. 
 
Availability 
 
Erlotinib is an investigational agent supplied to investigators by the Division of Cancer 
Treatment and Diagnosis (DCTD), National Cancer Institute (NCI). 
 
Erlotinib is provided to the NCI under a Clinical Trials Agreement (CTA) between Astellas 
Pharma and the DCTD, NCI. 
 
SAFETY PROFILE 
 
Adverse Events (AEs) Associated with Erlotinib 
 
A comprehensive list of AEs possibly related to Erlotinib is provided in the CAEPR.  Additional 
information can also be found in the Investigator’s Brochure.  A few common or serious AEs are 
described below. 
 
Interstitial lung disease (ILD): Cases of ILD-like events, including fatalities, have been 
reported uncommonly in patients receiving OSI-774 for treatment of non-small cell lung cancer 
(NSCLC), pancreatic cancer, or other advanced solid tumors.  In pivotal study BR 21, in 
NSCLC, the incidence of serious ILD-like events was 0.8% in each of the placebo and OSI-774 
arms.  In the pancreatic cancer study in combination with gemcitabine, the incidence of ILD-like 
events was 2.5% in the OSI-774 plus gemcitabine group versus 0.4% in the placebo plus 
gemcitabine-treated group.  The overall incidence in patients treated with OSI-774 from all 
studies (including uncontrolled studies and studies with concurrent chemotherapy) is 
approximately 0.6%.  Some examples of reported diagnoses in patients suspected of having ILD-
like events include pneumonitis, radiation pneumonitis, hypersensitivity pneumonitis, interstitial 
pneumonia, interstitial lung disease, obliterative bronchiolitis, pulmonary fibrosis, acute 


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58 
respiratory distress syndrome, lung infiltration and alveolitis.  These ILD-like events started from 
a few days to several months after initiating OSI-774 therapy.  Most of the cases were associated 
with confounding or contributing factors such as concomitant or prior chemotherapy, prior 
radiotherapy, pre-existing parenchymal lung disease, metastatic lung disease, or pulmonary 
infections.  In patients who develop acute onset of new and/or progressive unexplained 
pulmonary symptoms, such as dyspnea, cough and fever, OSI-774 therapy should be interrupted 
pending diagnostic evaluation.  If ILD is diagnosed, OSI-774 should be discontinued and 
appropriate treatment initiated as necessary. 
 
Rash or dermatosis: Rash or dermatosis (grades 1-3) has been reported in many subjects 
(~50%) during the first several days of treatment, although severity diminishes after 4 weeks of 
therapy.  The use of topical agents (i.e., diphenhydramine, corticosteroids) and oral antibiotics 
(tetracycline) has been instituted in some patients with variable results.  In patients with severe 
rash, treatment has been discontinued or the study drug dose reduced.  The etiology of the rash is 
still unknown, but may be related to the mechanism of action of OSI-774.  
 
Diarrhea, dehydration, and electrolyte imbalance: Diarrhea has occurred in patients on OSI-
774, and moderate or severe diarrhea should be treated with loperamide.  In some cases, dose 
reduction may be necessary.  In the event of severe or persistent diarrhea, nausea, anorexia, or 
vomiting associated with dehydration, OSI-774 therapy should be interrupted and appropriate 
measures should be taken to treat the dehydration.  There have been rare reports of hypokalemia 
and renal failure (including fatalities).  Some reports of renal failure were secondary to severe 
dehydration due to diarrhea, vomiting and/or anorexia while others were confounded by 
concomitant chemotherapy.  In more severe or persistent cases of diarrhea, or cases leading to 
dehydration, particularly in groups of patients with aggravating risk factors (concomitant 
medications, symptoms or diseases or other predisposing conditions including advanced age), 
OSI-774 therapy should be interrupted and appropriate measures should be taken to intensively 
rehydrate the patients intravenously.  In addition, renal function and serum electrolytes including 
potassium should be monitored in patients at risk of dehydration. 
 
Hepatotoxicity with or without hepatic impairment: Hepatic failure and hepatorenal 
syndrome (including fatal cases) can occur with OSI-774 treatment in patients with normal 
hepatic function; the risk of hepatic toxicity is increased in patients with baseline hepatic 
impairment.  Perform periodic liver testing (transaminases, bilirubin, and alkaline phosphatase) 
during treatment with OSI-774.  Increased frequency of monitoring of liver function is required 
for patients with pre-existing hepatic impairment or biliary obstruction.  Withhold OSI-774 in 
patients without pre-existing hepatic impairment for total bilirubin levels >3 x institutional upper 
limit of normal (ULN) or transaminases >5 x ULN.  Withhold OSI-774 in patients with pre-
existing hepatic impairment or biliary obstruction for doubling of bilirubin or tripling of 
transaminases values over baseline.  Discontinue OSI-774 in patients whose abnormal liver tests 
meeting the above criteria do not improve significantly or resolve within three weeks. 
 
Renal insufficiencies: Cases of hepatorenal syndrome, acute renal failure (including fatalities), 
and renal insufficiency have been reported.  Some were secondary to baseline hepatic 
impairment while others were associated with severe dehydration due to diarrhea, vomiting, 
and/or anorexia, or concurrent chemotherapy use.  In the event of dehydration, particularly in 


NCI Protocol #:9878 
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59 
patients with contributing risk factors for renal failure (e.g., pre-existing renal disease, medical 
conditions or medications that may lead to renal disease, or other predisposing conditions 
including advanced age), OSI-774 therapy should be interrupted and appropriate measures 
should be taken to intensively rehydrate the patient.  Withhold OSI-774 in patients developing 
severe renal impairment until renal toxicity is resolved.  Perform periodic monitoring of renal 
function and serum electrolytes during OSI-774 treatment. 
 
Gastrointestinal perforation: Gastrointestinal perforation (including fatal cases) can occur with 
OSI-774 treatment.  Patients receiving concomitant anti-angiogenic agents, corticosteroids, 
NSAIDs, or taxane-based chemotherapy, or who have prior history of peptic ulceration or 
diverticular disease may be at increased risk of perforation.  Permanently discontinue OSI-774 in 
patients who develop gastrointestinal perforation. 
 
Bullous and exfoliative skin disorders: Bullous, blistering, and exfoliative skin conditions, 
including cases suggestive of Stevens-Johnson syndrome/toxic epidermal necrolysis, which in 
some cases were fatal, can occur with OSI-774 treatment.  Discontinue OSI-774 treatment if the 
patient 
develops 
severe 
bullous, 
blistering 
or 
exfoliating 
conditions. 
 
Myocardial infarction/ischemia: In the pancreatic carcinoma trial, six patients (incidence of 
2.1%) in the OSI-774/gemcitabine group developed myocardial infarction/ischemia.  One of 
these patients died due to myocardial infarction.  In comparison, three patients in the 
placebo/gemcitabine group developed myocardial infarction (incidence 1.1%), and one died due 
to myocardial infarction.  The pooled incidence of myocardial infarction/ischemia in the three 
monotherapy lung cancer studies was 0.2% in the OSI-774 arms and 0.4% in the control arms. 
 
Cerebrovascular accident: In the pancreatic carcinoma trial, seven patients in the OSI-
774/gemcitabine group developed cerebrovascular accidents (incidence: 2.5%).  One of these 
was hemorrhagic and was the only fatal event.  In comparison, in the placebo/gemcitabine group 
there were no cerebrovascular accidents.  The pooled incidence of cerebrovascular accident in 
the three monotherapy lung cancer studies was 0.6% in the OSI-774 arms and 0.9% in the 
control arms. 
 
Microangiopathic hemolytic anemia with thrombocytopenia: The pooled incidence of 
microangiopathic hemolytic anemia with thrombocytopenia in the three monotherapy lung 
cancer studies was 0% in the OSI-774 arms and 0.1% in the control arms.  The incidence of 
microangiopathic hemolytic anemia with thrombocytopenia in the pancreatic cancer study was 
1.4% in the OSI-774 plus gemcitabine arm and 0% in the control arm. 
 
Ocular disorders: Corneal perforation or ulceration can occur with OSI-774 treatment.  Other 
ocular disorders including abnormal eyelash growth, keratoconjunctivitis sicca or keratitis have 
been observed with OSI-774 treatment and are known risk factors for corneal 
ulceration/perforation.  Interrupt or discontinue OSI-774 therapy if patients present with 
acute/worsening ocular disorders such as eye pain. 
 
Embryo-fetal toxicity: Based on its mechanism of action, OSI-774 can cause fetal harm when 
administered to a pregnant woman.  When given during organogenesis, OSI-774 administration 


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60 
resulted in embryo-fetal lethality and abortion in rabbits at doses approximately 3 times the 
recommended human daily dose of 150 mg.  If OSI-774 is used during pregnancy, or if the 
patient becomes pregnant while taking this drug, the patient should be apprised of the potential 
hazard to a fetus.  Advise females of reproductive potential to use highly effective contraception 
during therapy, and for at least 2 weeks after the last dose of OSI-774.  Advise patients to contact 
their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking 
OSI-774. 
 
8.1.2 ONALESPIB (AT13387) (NSC 749712) 
 
Chemical 
Name: 
(2,4-dihydroxy-5-isopropyl-phenyl)-[5-(4-methyl-piperazin-1-ylmethyl)-1,3- 
dihydro-isoindol-2-yl]-methanone, L-lactic acid salt 
 
Other Name: 
AT13387AU, Onalespib 
 
Classification:   
   Heat shock protein 90 (HSP90) inhibitor 
 
Molecular Formula:   C24H31N3O3.C3H6O3  
 
M.W.:  499.61 
 
Mode of Action:  AT13387 is a synthetic non-ansamycin small molecule that inhibits heat shock 
protein 90 (HSP90.  HSP90 seems to affect multiple aberrant signaling pathways and therefore 
may be of clinical benefit in several cancer treatments.  
  
How Supplied:  AT13387 is supplied by Astex Pharmaceuticals Inc. and distributed by CTEP, 
NCI as a 265 mg free base equivalent (L-lactic acid salt) vial, containing white to off-white 
lyophilized powder.  The agent is formulated in pH 5.0 (red cap). 
 
Preparation:  Reconstitute the 265-mg lyophilized powder with 10 mL of Sterile Water for 
Injection (SWFI) resulting in 25.7 mg/mL concentration (10.3 mL total volume).  A sticky mass 
will be formed. Vigorously shake the vial. Agitate until the contents are fully dissolved (about 5 
minutes).  Leave the diluted vial at ambient temperature for 15-30 minutes to allow any foam to 
dissipate. If not used immediately, store the reconstituted vial(s) at 20 to 80 C not to exceed 8 
hours. 
 
Withdraw the calculated dose of AT13387 and further dilute it in 250 mL of D5W or 0.9% NS. 
The prepared IV solution is compatible in PVC or non-PVC infusion bags.   
 
Store the prepared IV solution at 20 to 80 C not to exceed 8 hours if not used immediately.  When 
removed from the refrigerator, allows the prepared IV solution to sit at room temperature 
between 15 to 30 minutes before administering to patients. The prepared IV solution must be 
used within 8 hours -i.e., from the time the drug vial is diluted to the time the IV administration 
is complete. Protection from light during the infusion period is not required.   
 
Storage:     Store the intact vials at 150 to 25ºC (59 to 77ºF).  Protect from light. 
 
If a storage temperature excursion is identified, promptly return AT13387 to 150 to 25ºC (59 to 


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61 
77ºF) and quarantine the supplies.  Provide a detailed report of the excursion (including 
documentation of temperature monitoring and duration of the excursion) to 
PMBAfterHours@mail.nih.gov for determination of suitability. 
 
Stability:     Shelf life surveillance of the intact vials is ongoing.  
Route of Administration:     Intravenous 
 
Method of Administration:  Infuse over 1 hour through a central line or a well-defined peripheral 
vein (Note: an in-line filter is NOT required).  If use a peripheral line, be sure to aspirate venous 
blood prior to starting the infusion.  Check the infusion site every 15 minutes. Change infusion site 
should evidence of swelling or discoloration is observed.   
 
Potential Drug Interactions:   AT13387 is a substrate of UGT with a relatively low affinity for 
UGT isoforms. In vitro data demonstrate that AT13387 is a weak inhibitor of UGT1A1, UGT1A3 
and UGT1A9.   AT13387 is also a weak inhibitor of CYP1A2, -3A4, -2D6, -2C9 and -2C19.  
AT13387 appears to metabolize via the glucuronidation, sulphation and N-oxidation. 
 
Pre-clinical studies suggest that AT13387 is a substrate of P-gp, the efflux ratios was above 2 
(ranging from 3.4 to 4.6); a moderate inhibitor of BCRP (35.9% +/- 2%, p=0.0001) and P-gp 
(31.3% +/- 1.2%, p= 0.0009), and a strong inhibitor of MATE1 (94.6% +/- 0.2%, p=0.0001) and 
MATE2-K (91.2% +/- 1.2%, p= 0.0002). 
 
Patient Care Implications:  There are no genotoxicity, carcinogenicity, developmental and 
reproductive studies conducted with AT13387.  Women of childbearing potential should not 
become pregnant or breastfeed and men should not father a child during the study.  All subjects 
must use acceptable contraceptive measures during the treatment of AT13387 and 3 months after 
the last dose of the investigational drug. 
 
Systemic infusion reactions (e.g., vomiting, itching skin, or swelling), slow the infusion and/or 
administer NS or D5W through a “Y” connector in parallel to AT13387 IV infusion.  Pre-
medication (e.g., dexamethasone, H-1 and H-2 antagonist) may be given before subsequent 
infusions and/or administer additional volume of 500 mL over 1 hour if medically appropriate.   
 
Avoid extravasation. For local irritation, apply cold compress or topical pain medication.  
 
8.1.3 Agent Ordering and Agent Accountability 
 


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62 
8.1.3.1 
NCI-supplied agents may be requested by the Principal Investigator (or their 
authorized designee) at each participating institution.  Pharmaceutical Management 
Branch (PMB) policy requires that agent be shipped directly to the institution where 
the patient is to be treated.  PMB does not permit the transfer of agents between 
institutions (unless prior approval from PMB is obtained).  The CTEP-assigned 
protocol number must be used for ordering all CTEP-supplied investigational agents.  
The responsible investigator at each participating institution must be registered with 
CTEP, DCTD through an annual submission of FDA Form 1572 (Statement of 
Investigator), Curriculum Vitae, Supplemental Investigator Data Form (IDF), and 
Financial Disclosure Form (FDF).  If there are several participating investigators at 
one institution, CTEP-supplied investigational agents for the study should be ordered 
under the name of one lead investigator at that institution. 
 
Confirmation of the subject’s enrolment onto the study is required for agent initial supplies. 
Active CTEP-registered investigators and investigator-designated shipping designees 
and ordering designees can submit agent requests through the PMB Online Agent 
Order Processing (OAOP) application.  Access to OAOP requires the establishment 
of a CTEP Identity and Access Management (IAM) account and the maintenance of 
an “active” account status and a “current” password.  For questions about drug orders, 
transfers, returns, or accountability, call or email PMB any time.  Refer to the PMB’s 
website for specific policies and guidelines related to agent management.   
 
 
8.1.3.2 
Agent Inventory Records – The investigator, or a responsible party designated by the 
investigator, must maintain a careful record of the receipt, dispensing and final 
disposition of all agents received from the PMB using the appropriate NCI 
Investigational Agent (Drug) Accountability Record (DARF) available on the CTEP 
forms page.  Store and maintain separate NCI Investigational Agent Accountability 
Records for each agent, strength, formulation and ordering investigator on this 
protocol. 
 
8.1.3.3 
Investigator Brochures - The current versions of the IBs for the agents will be 
accessible to site investigators and research staff through the PMB Online Agent 
Order Processing (OAOP) application.  Access to OAOP requires the establishment 
of a CTEP Identity and Access Management (IAM) account and the maintenance of 
an “active” account status and a “current” password.  Questions about IB access may 
be directed to the PMB IB coordinator via email. 
 
8.1.3.4 
Useful Links and Contacts 
 CTEP Forms, Templates, Documents:  http://ctep.cancer.gov/forms/ 
 NCI CTEP Investigator Registration:  PMBRegPend@ctep.nci.nih.gov 
 PMB 
policies 
and 
guidelines: 
http://ctep.cancer.gov/branches/pmb/agent_management.htm  
 PMB Online Agent Order Processing (OAOP) application: https://eapps-
ctep.nci.nih.gov/OAOP/pages/login.jspx  
 CTEP Identity and Access Management (IAM) account: https://eapps-


NCI Protocol #:9878 
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63 
ctep.nci.nih.gov/iam/ 
 CTEP 
Associate 
Registration 
and 
IAM 
account 
help:  
ctepreghelp@ctep.nci.nih.gov  
 PMB email:  PMBAfterHours@mail.nih.gov 
 PMB phone and hours of service: (240) 276-6575 Monday through Friday 
between 8:30 am and 4:30 pm (ET) 
 IB Coordinator: IBCoordinator@mail.nih.gov  
 
 


NCI Protocol #:9878 
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64 
 
9. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
 
Correlative Studies include an optional core biopsy before treatment with erlotinib and 
onalespib, 48-72 hours after cycle 2, day 15 and at progression for the correlates outlined below. 
Plasma for cfDNA and pharmacokinetic studies will also be performed. Optional core biopsies 
should only be performed in patients where tissue can be accessed safely and feasibly. 
  
 
 
Figure: Timing of correlative tissue and plasma studies. Note: Biopsies are optional for patients 
in study. Optional biopsies will be obtained prior to initiation of erlotinib and onalespib, 48-72 
hours after cycle 2 D15 onalespib administration and at progression. The order priority for 
biopsies is presented below. 
 
 
Table: Tissue Correlative Studies Summary (Priority for Baseline and post-progression Biopsy) 
C2D15 biopsy will be sent solely for Multiplex Immunofluorescence. 
 
Order Prioritya 
Tissue Correlative Study 
Slidesc 
Cell Blocksb 
Institution 
1 
EGFR Mutation Testing 
5 
1 
Response 
Genetics 
2 
Multiplex 
10 
1 
Mack Lab UC 


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65 
Immunofluorescence for 
Hsp90 Client Oncoprotein 
Davis 
3 
Oncopanel 
15c 
2 
Brigham & 
Women’s 
Hospital 
Center for 
Advanced 
Molecular 
Diagnostics 
4 
PDXd 
Fresh Tissue  
N/A 
Jackson 
Laboratory 
West 
Please send remaining FFPE tissue block, or 15 unstained slides if block is unavailable to the 
California Cancer Consortium Biobank at UC Davis for future research. 
 
a. Prioritization of tissue use and correlates in order from #1 to #4 for baseline biopsy. Biopsy on 
or around C2D15 will be sent for Multiplex Immunofluorescence for Hsp90 Client Oncoprotein 
only. Biopsy at progression will be sent for Oncopanel only. 
b. Paraffin embedded cell block(s) may be substituted for slides. The sample must contain a 
minimum of 20% tumor tissue.   
c. Unstained slides total cut from FFPE blocks at 5 microns thickness. The sample must contain a 
minimum of 20% tumor tissue.   
d. At select institutions that are affiliated with Jackson Laboratories for creation of PDX 
 
Please see the relevant correlative study sections below for further details regarding proper 
collection, shipping and handling of specimens. 
 
 
9.1 
Integrated Correlative Studies 
 
9.1.1 EGFR Mutation Analysis (Response Genetics) 
 
9.1.1.1 
Collection of Specimen(s) 
 
Tissue samples will be sent to Response Genetics for EGFR-mutation testing. This is a 
confirmatory central test. 
 
One cell block or 5 unstained slides should be sent to Response Genetics 
 
9.1.1.2 
Handling of Specimens(s) 
 
PREPARATION OF TISSUE SLIDES 
If the tissue block is unavailable, prepare tissue slides. 
• The number of slides to be submitted is five (5) 10-micron sections plus three (3) 5- 
micron sections. 
• Positively charged frosted ended slides must be used. 


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66 
• Section a single section containing tissue onto each slide. 
• Sections must be from the same tissue block. 
• Subject identifier, and block number must be written legibly in pencil on the frosted end 
of the slide. 
• Slides must not be baked or melted. 
• Cover slips must not be used. 
• Sections must not be stained. 
• Place slides in slide box. 
 
9.1.1.3 
Shipping of Specimen(s) 
 
Shipping Address: 
 
Response Genetics 
Pharmaceutical Services 
1640 Marengo Street 
Suite 410 
Los Angeles, CA 90033 
 
9.1.1.4 
Site(s) Performing Correlative Study   
 
Response Genetics 
 
9.1.2 Guardant 360 cfDNA Assay 
 
9.1.2.1 
Collection of Specimen(s) 
 
Collect two 10mls of whole blood are collected in Streck Cell-Free DNA Blood Collection 
(Streck) tubes, which contain a proprietary formaldehyde-free preservative in that stabilizes 
white blood cells, preventing the release of genomic DNA and allowing shipping and stability 
for seven days without need for refrigeration, cold bricks or preliminary centrifugation prior to 
shipping. 
 
9.1.2.2 
Handling of Specimens(s) 
 
Mix by gentle inversion 8 to 10 times. Complete the provided barcode label with patient’s name, 
DOB and collection date. Place a barcode label on each tube with barcode in the vertical 
position. Place blood tubes into foam packaging. Place foam with tubes into specimen bag, close 
securely and put into the provided shipping box on top of one of the gel packs. (Do not freeze gel 
packs, use at room temperature). Place test requisition form into outer pocket of the specimen 
bag. Place the second gel pack on top of the specimen bag and close the shipping box. Place the 
completed specimen kit into a pre-printed FedEx Clinical Pak and call FedEx for a pick-up. The 
kit should be kept at room temperature during preparation, while awaiting shipping pick-up and 
during transit. 
 


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67 
9.1.2.3 
Shipping of Specimen(s) 
 
The shipping is pre-paid by Guardant Health and shipping label is pre-printed for Overnight 
Delivery. 
 
9.1.2.4 
Site  Performing Correlative Study 
 
Guardant Health 
 
9.1.3 Pharmacokinetics of onalespib 
 
9.1.3.1 
Collection of Specimen(s) 
 
Blood specimens (3 mL whole blood collected in heparinized tubes (Li) sufficient to provide a 
minimum of 1 mL of plasma) for PK will be collected from patients on day C1D8 of onalespib 
administration. The timing of start of onalespib infusion should be within 30 min of erlotinib 
intake on that day (timing of both erlotinib intake and start of onalespib infusion should be 
recorded). Blood samples for PK should be drawn at time 0 (immediately prior to start of 
onalespib infusion), then at 0.5 hr (± 5 min), 1 hr (to coincide with immediately at the end of 
onalespib infusion ±2 min), 2 hr (±5 min), 3 hr (± 5 min), 4 (± 5 min), 6 (± 5 min), 8-9 hr, and 24 
hours (this sample falls on the next day) hours post start of onalespib infusion. 
 
Pharmacokinetic Sample Collection Schedule 
Sample Number 
Day of Collection 
Planned Collection Time 
Relative to onalespib 
Infusion* (hours) 
1 
C1D8 
0 (Pre onalespib infusion) 
2 
0.5 
3 
1 (Immediately at the end 
of onalespib  infusion) 
4 
2 
5 
3 
6 
4 
7 
6 
8 
8-9 
9 
C1D9 
24 (post start of onalespib 
infusion) 
* Infusion should start within 30 min of erlotinib intake for that day. Time for erlotinib intake 
and start of onalespib infusion should be recorded. 
 
9.1.3.2 
Handling of Specimens(s) 
 
1. Obtain at least 3 mL of blood into Lithium Heparin (Green Top) Vacutainer tube. 
Allow enough time for the tube to fill sufficiently. 
2. Gently invert the tube for 30 seconds to ensure proper mixing.  
3. Place tube on a standard blood roller for a minimum of 5 minutes. If a blood roller 


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68 
is not available continue to invert the tube further 8-10 times.  
4. Centrifuge the tube at 1100 - 1500g for 10-15 minutes at 4-8°C within 1 hour of 
sample collection.  
5. Pipette off the plasma layer (using the pipette provided with the kit)  
6. Introduce roughly equal proportions of the plasma into the 2 (primary and 
secondary) cryovial tubes (size 2 mL).  
7. Discard the Lithium Heparin tube per your local policy. 
8. Freeze the 2 aliquots of plasma at -70°C or less until shipment to the bioanalytical 
lab (instructed by Astex).   
 
9.1.3.3 
Shipping of Specimen(s) 
 
BASi  
2701 Kent Avenue 
West Lafayette, IN  
47906 
 
Send an electronic manifest to samples@basinc.com along with the tracking information. 
 
9.1.3.4 
Site(s) Performing Correlative Study  
 
Astex Pharmaceuticals / BASi 
 
9.2 
Exploratory/Ancillary Correlative Studies 
 
9.2.1 Tumor Molecular Characterization (Oncopanel) 
 
This targeted cancer next generation sequencing assay (Oncopanel) detects somatic mutations, 
copy number variations and structural variants in tumor DNA extracted from fresh, frozen or 
formalin-fixed paraffin-embedded samples. This clinically validated assay surveys exonic DNA 
sequences of 300 cancer genes and 113 introns across 35 genes for rearrangement detection. 
DNA is isolated from tissue containing at least 20% tumor nuclei and analyzed by massively 
parallel sequencing using a solution-phase Agilent SureSelect hybrid capture kit and an Illumina 
HiSeq 2500 sequencer.  Sequencing results are analyzed and filtered using an in-house 
developed bioinformatics pipeline and variant calls are further reviewed by a laboratory scientist 
and molecular pathologist for technical quality and biologic relevance.  Results are reported in a 
tiered format reflecting clinical actionability.  Overall, the assay provides an average of 187 fold 
read depth and is successful in >96% of samples run.  In general, this assay is sensitive to 10% 
mutant allelic fraction (AF) but can detect mutant AF down to 3%; low AF calls are made at the 
discretion of the reviewing scientists and pathologists.  
 
9.2.1.1 
Collection of Specimen(s) 
 
Completion of both assays requires a total of 15 unstained slides cut from FFPE blocks at 5 
microns thickness. Hematoxylin and eosin staining will be performed on one slide upon receipt 
at BWH.   


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69 
 
9.2.1.2 
Handling of Specimens(s) 
 
The sample must contain a minimum of 20% tumor tissue. Tumor material must be reviewed by 
a local pathologist to ensure sufficient tumor cells are present in the sample.  
 
Specimens will be identified with the NCI Protocol number (P9898), Patient Accession ID, 
Specimen Name (e.g., tissue), Specimen Number, Date, and Time and alphanumeric identifier 
for serial samples (e.g., T0, T1, T2 …). 
 
9.2.1.3 
Shipping of Specimen(s) 
 
Brigham & Women’s Hospital 
Center for Advanced Molecular Diagnostics 
Shapiro 5054 
75 Francis Street 
Boston, MA 02115 
 
9.2.1.4 
Site(s) Performing Correlative Study 
 
Brigham & Women’s Hospital 
Center for Advanced Molecular Diagnostics 
 
 
9.2.2 Patient Derived Xenotransplants (Institutions with agreements with Jackson Laboratory 
assuring collaborator rights). 
 
9.2.2.1 
Collection of Specimen(s) 
 
Tissue for PDX should only be obtained at procedures performed on a Monday, Tuesday, 
Wednesday, or Thursday. The fresh specimen will be submitted directly and immediately to The 
Jackson Laboratory using the following procedures.  
 
a. The physician should obtain the maximum amount of tumor that is prudent at the time of 
biopsy or resection. Minimum sample size is a core measuring 8mm x3mm. Please 
approximate these dimensions. 
 
b. The specimen should be collected following Institution Universal precautions SOPs for 
maintaining tissue integrity. Please remind all personnel that are involved in processing 
the sample that it will be implanted in profoundly immune deficient mice, which is why it 
is imperative that extra care be taken in sample collection to minimize the risk of 
transferring human bacteria to the mice. 
 
9.2.2.2 
Handling of Specimens(s) 
 
The tumor sample should be placed in a 50 ml screw cap conical tube containing 40 ml RPMI 


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70 
buffer (without fetal calf serum); preferably within 30 minutes of tumor removal. Seal cap tightly 
with Parafilm. Sample should be refrigerated at 4°C until packed for shipping on the same day as 
procurement. 
 
9.2.2.3 
Shipping of Specimen(s) 
 
The sealed conical tube containing RPMI & the tumor specimen must be wrapped in absorbent 
material (i.e. paper towels) and placed in an airtight plastic bag (i.e. a ziplock bag). Pack the 
specimen into an insulated Styrofoam shipper with a refrigerated (4° C) cool pack (not frozen) to 
protect specimen from temperature fluctuations. All paperwork pertaining to the patient should 
be placed in a plastic bag, sealed tightly, and packed with the tissue shipment. Include the 
Jackson Laboratory Sample Submission Form. 
 
Ship by Fed Ex for overnight delivery to:  
 
The Jackson Laboratory 
In Vivo Services 
c/o Margaret Bundy or James Keck 1650 Santa Ana Ave. 
Sacramento, CA 95838 
 
Prior to shipping, contact for sample coordination:  Margaret Bundy 916-469-2609. 
 
9.2.2.4 
Site(s) Performing Correlative Study   
 
The Jackson Laboratory 
 
9.2.3 Banking of FFPE tissue for future correlative studies 
 
9.2.3.1 
Collection of Specimen(s) 
 
Any remaining FFPE tumor tissue from archival and/or pre-treatment biopsy, and progression 
biopsy (if available) should be submitted to the California Cancer Consortium Biobank at UC 
Davis to be accessioned and stored for future research. All submissions must be accompanied by 
a completed CCC specimen submission form (to be obtained on the CTSU website) and a copy 
of the corresponding pathology report. 
   
9.2.3.2 
Handling of Specimens(s) 
 
Ideally, 1-2 paraffin-embedded tissue blocks containing formalin-fixed tumor, processed 
according to standard institutional protocols, will be submitted.  If blocks are unavailable, 15 
unstained slides will be accepted as an alternative.  Tissue should be cute at 5 microns and 
mounted on positively charged (+) slides. 
 
9.2.3.3 
Shipping of Specimen(s) 
 
All FFPE tissue for banking should be sent at ambient temperature.  For summer shipments, 


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71 
please include a room temperature cool pack to insulate the specimen and protect paraffin from 
melting.  Specimens should be shipped to the following address: 
 
Dr. Philip Mack/ Anthony Martinez 
UC Davis Comprehensive Cancer Center 
4501 X Street, Suite 1009 
Sacramento, CA 95817 
Phone: 916-734-6447 
Email: axmartinez@ucdavis.edu or pcmack@ucdavis.edu 
 
Please notify the bank at the time of shipping via email (axmartinez@ucdavis.edu) 
 
 
 


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72 
10. STUDY CALENDAR 
 
Baseline evaluations are to be conducted within 7 days prior to start of protocol therapy.  Scans 
and x-rays must be done <4 weeks prior to the start of therapy.  In the event that the patient’s 
condition is deteriorating, laboratory evaluations should be repeated within 48 hours prior to 
initiation of the first cycle of therapy.  For subsequent cycles, laboratory evaluations should be 
conducted within 72 hours prior to initiation of therapy. 
 
 
Cycle 1 
Cycle 2 
Cycle 3 (and  subsequent 
cycles) 
 
 
Pre- 
Study 
Wk 
1 
Wk 
2 
Wk 
3 
Wk 
4 
Wk 
5 
Wk 
6 
Wk 
7 
Wk 
8 
Wk 
9 
Wk 
10 
Wk 
11 
Wk 
12 
Off Studyc 
Erlotinib 
 
X--------------------------------------------------------------------------------------------------X 
 
onalespib n 
 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concurrent meds 
X 
X---------------------------------------------------------------------------------------------X 
 
History and Physical exam 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Vital signs 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Performance status 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
CBC w/diff, plts m 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum chemistrya, m 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PTT/INRk 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
EKG (and as indicated l) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Echocardiogram or MUGA 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse event evaluation 
 
X---------------------------------------------------------------------------------------------X 
X 
Tumor measurements 
X 
Tumor measurements are repeated every 2 cycles (8 weeks).  Documentation 
(radiologic) must be provided for patients removed from study for progressive 
disease. 
X 
Radiologic evaluation 
X 
Radiologic measurements should be performed every 8 weeks (+/- 7 days) (~2 
cycles). 
X 
Brain Imaging h 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
B-HCG 
Xb 
 
 
 
 
 
 
 
 
 
 
 
 
 
EGFR Mutation Testing 
Xd 
 
 
 
 
 
 
 
 
 
 
 
 
 
Oncopanel (NGS) g 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Pharmacokinetic Studies 
 
 
Xe 
 
 
 
 
 
 
 
 
 
 
 
Plasma cfDNA 
Xf 
 
 
 
 
 
 
 
 
Xf 
 
 
 
Xf 
Multiplex 
Immunofluorescence of Hsp90 
Client Oncoproteinsi 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
Tissue for PDXj 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 


NCI Protocol #:9878 
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73 
A: 
Erlotinib:  Dose as assigned; PO daily continuous. Each cycle is 28 days in length. 
B: 
Onalespib:  Dose as assigned; IV every Day 1, 8, 15. Each cycle is 28 days in length. 
a: 
Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, magnesium, phosphorus, 
potassium, total protein, SGOT [AST], SGPT [ALT], sodium. 
b: 
Serum pregnancy test (women of childbearing potential). 
c: 
Off-study evaluation.  Patients will then be followed every 12 weeks for 1 year then annually. Please see Section 5.6 for further details.. 
d:      Optional biopsy for EGFR mutation. See section 9 of protocol for further details. 
e:       Blood samples for PK analysis will be obtained at C1D8. See section 9 of protocol for further details. 
f:       Collect  blood for cfDNA prior to treatment and every 2 cycles. Draw venous blood into two (2) 10 mL Streck tubes and immediately  
          gently invert the tubes 8-10 times. See section 9 of protocol for further details. 
g:        Optional studies on biopsied tissue before initiation of erlotinib and onalespib obtained by fresh biopsy. 
h.        Brain imaging required prior to treatment. Untreated brain metastases are not allowed per protocol, but patients with treated brain   
            metastases are allowed. MRI brain or CT head is acceptable. Contrast enhanced scans are suggested unless contraindicated. 
i.         Optional biopsy prior to treatment and 48-72 hours after administration of onalespib cycle 2 day 15 (cycle 2 day 17, and within 4 weeks     
        of demonstration of progressive disease. 
j.         Only at institutions with affiliation with Jackson Laboratories for creation of PDX. 
k.        Patients taking warfarin or other coumarin-derivative anticoagulants should have more frequent INR/PT determinations on study (once a  
           week for the first month on treatment and then as clinically indicated not less than once per cycle (28 days) and then once a week for a  
           minimum of 2 weeks following discontinuation of Erlotinib). 
l.        Mean resting corrected QT interval on 3 separate EKGs (QTc using Fredericia’s formula (QTcF)) > 470 msec (See Appendix E for  
          Fridericia’s formula). Additional EKGs on study not required but may be performed at the treating investigators discretion. 
m.    Window for laboratories after initiation of treatment is within 72 hours of subsequent treatment. 
n.     Window of 48 hours permitted for onalespib dosing. 
 
 
 
 


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74 
11. MEASUREMENT OF EFFECT 
 
Although the clinical benefit of these drugs in combination has not yet been established in the 
patient population being studies, the intent of offering this treatment is to provide a possible 
therapeutic benefit, and thus the patient will be carefully monitored for tumor response and 
symptom relief in addition to safety and tolerability.  Patients with measurable disease will be 
assessed by standard criteria.  For the purposes of this study, patients should be re-evaluated 
every 8 weeks.  
 
Antitumor Effect – Solid Tumors 
 
For the purposes of this study, patients should be re-evaluated for response every 8 weeks. 
 
Response and progression will be evaluated in this study using the new international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline 
(version 1.1) [Eur J Ca 45:228-247, 2009].  Changes in the largest diameter (unidimensional 
measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph 
nodes are used in the RECIST criteria. 
 
11.1.1 Definitions 
 
Evaluable for toxicity.  All patients will be evaluable for toxicity from the time of their 
first treatment with erlotinib and onalespib. 
 
Evaluable for objective response.  Patients who have received at least one cycle of 
therapy, and have had their disease re-evaluated will be considered evaluable for 
response.  All patients are required to have measurable disease at baseline. These patients 
will have their response classified according to the definitions stated below.  (Note:  
Patients who exhibit objective disease progression prior to the end of cycle 1 will also be 
considered evaluable.) 
 
Evaluable Non-Target Disease Response.  Patients who have lesions present at baseline 
that are evaluable but do not meet the definitions of measurable disease, have received at 
least one cycle of therapy, and have had their disease re-evaluated will be considered 
evaluable for non-target disease.  The response assessment is based on the presence, 
absence, or unequivocal progression of the lesions.  
 
11.1.2 Disease Parameters 
 
Measurable disease.  Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) as ≥20 mm (≥2 cm) 
by chest x-ray or as ≥10 mm (≥1 cm) with CT scan, MRI, or calipers by clinical exam.  
All tumor measurements must be recorded in millimeters (or decimal fractions of 
centimeters). 
 
Note:  Tumor lesions that are situated in a previously irradiated area might or might not 


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be considered measurable.   
 
Malignant lymph nodes.  To be considered pathologically enlarged and measurable, a 
lymph node must be ≥15 mm (≥1.5 cm) in short axis when assessed by CT scan (CT scan 
slice thickness recommended to be no greater than 5 mm [0.5 cm]).  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 [<1 cm] or pathological lymph nodes with ≥10 to <15 mm [≥1 
to <1.5 cm] short axis), are considered non-measurable disease.  Bone lesions, 
leptomeningeal 
disease, 
ascites, 
pleural/pericardial 
effusions, 
lymphangitis 
cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not followed by 
CT or MRI), are considered as non-measurable. 
 
Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts 
should not be considered as malignant lesions (neither measurable nor non-measurable) 
since they are, by definition, simple cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non-
cystic lesions are present in the same patient, these are preferred for selection as target 
lesions. 
 
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.  Target lesions should be selected on the 
basis of their size (lesions with the longest diameter), be representative of all involved 
organs, but in addition should be those that lend themselves to reproducible repeated 
measurements.  It may be the case that, on occasion, the largest lesion does not lend itself 
to reproducible measurement in which circumstance the next largest lesion which can be 
measured reproducibly should be selected.  A sum of the diameters (longest for non-
nodal lesions, short axis for nodal lesions) for all target lesions will be calculated and 
reported as the baseline sum diameters.  If lymph nodes are to be included in the sum, 
then only the short axis is added into the sum.  The baseline sum diameters will be used 
as reference to further characterize any objective tumor regression in the measurable 
dimension of the disease. 
 
Non-target lesions.  All other lesions (or sites of disease) including any measurable 
lesions over and above the 5 target lesions should be identified as non-target lesions and 
should also be recorded at baseline.  Measurements of these lesions are not required, but 
the presence, absence, or in rare cases unequivocal progression of each should be noted 
throughout follow-up.  
 
11.1.3 Methods for Evaluation of Measurable Disease 
 
All measurements should be taken and recorded in metric notation using a ruler or 


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calipers.  All baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than 4 weeks before the beginning of the 
treatment. 
 
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up. Imaging-based 
evaluation is preferred to evaluation by clinical examination unless the lesion(s) being 
followed cannot be imaged but are assessable by clinical exam. 
 
Clinical lesions  Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and ≥10 mm (≥1 cm) diameter 
as assessed using calipers (e.g., skin nodules).  In the case of skin lesions, documentation 
by color photography, including a ruler to estimate the size of the lesion, is 
recommended.  
 
Chest x-ray  Lesions on chest x-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung.  However, CT is preferable.  
 
Conventional CT and MRI  This guideline has defined measurability of lesions on CT 
scan based on the assumption that CT slice thickness is 5 mm (0.5 cm) or less.  If CT 
scans have slice thickness greater than 5 mm (0.5 cm), the minimum size for a 
measurable lesion should be twice the slice thickness.  MRI is also acceptable in certain 
situations (e.g. for body scans).   
 
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which 
greatly impact image quality, lesion conspicuity, and measurement.  Furthermore, the 
availability of MRI is variable globally.  As with CT, if an MRI is performed, the 
technical specifications of the scanning sequences used should be optimized for the 
evaluation of the type and site of disease.  Furthermore, as with CT, the modality used at 
follow-up should be the same as was used at baseline and the lesions should be 
measured/assessed on the same pulse sequence.  It is beyond the scope of the RECIST 
guidelines to prescribe specific MRI pulse sequence parameters for all scanners, body 
parts, and diseases.  Ideally, the same type of scanner should be used and the image 
acquisition protocol should be followed as closely as possible to prior scans.  Body scans 
should be performed with breath-hold scanning techniques, if possible. 
 
PET-CT  At present, the low dose or attenuation correction CT portion of a combined 
PET-CT is not always of optimal diagnostic CT quality for use with RECIST 
measurements.  However, if the site can document that the CT performed as part of a 
PET-CT is of identical diagnostic quality to a diagnostic CT (with IV and oral contrast), 
then the CT portion of the PET-CT can be used for RECIST measurements and can be 
used interchangeably with conventional CT in accurately measuring cancer lesions over 
time.  Note, however, that the PET portion of the CT introduces additional data which 
may bias an investigator if it is not routinely or serially performed.   
 


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77 
Ultrasound  Ultrasound is not useful in assessment of lesion size and should not be used 
as a method of measurement.  Ultrasound examinations cannot be reproduced in their 
entirety for independent review at a later date and, because they are operator dependent, it 
cannot be guaranteed that the same technique and measurements will be taken from one 
assessment to the next.  If new lesions are identified by ultrasound in the course of the 
study, confirmation by CT or MRI is advised.  If there is concern about radiation 
exposure at CT, MRI may be used instead of CT in selected instances. 
 
Endoscopy, Laparoscopy  The utilization of these techniques for objective tumor 
evaluation is not advised.  However, such techniques may be useful to confirm complete 
pathological response when biopsies are obtained or to determine relapse in trials where 
recurrence following complete response (CR) or surgical resection is an endpoint. 
 
Tumor markers  Tumor markers alone cannot be used to assess response.  If markers are 
initially above the upper normal limit, they must normalize for a patient to be considered 
in complete clinical response.  Specific guidelines for both CA-125 response (in recurrent 
ovarian cancer) and PSA response (in recurrent prostate cancer) have been published 
[JNCI 96:487-488, 2004; J Clin Oncol 17, 3461-3467, 1999; J Clin Oncol 26:1148-1159, 
2008].  In addition, the Gynecologic Cancer Intergroup has developed CA-125 
progression criteria which are to be integrated with objective tumor assessment for use in 
first-line trials in ovarian cancer [JNCI 92:1534-1535, 2000]. 
 
Cytology, Histology  These techniques can be used to differentiate between partial 
responses (PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor 
types, such as germ cell tumors, where known residual benign tumors can remain). 
 
The cytological confirmation of the neoplastic origin of any effusion that appears or 
worsens during treatment when the measurable tumor has met criteria for response or 
stable disease is mandatory to differentiate between response or stable disease (an 
effusion may be a side effect of the treatment) and progressive disease. 
 
FDG-PET  While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in 
assessment of progression (particularly possible 'new' disease).  New lesions on the basis 
of FDG-PET imaging can be identified according to the following algorithm:  
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of 
PD based on a new lesion. 
b. No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the positive FDG-
PET at follow-up corresponds to a new site of disease confirmed by CT, this is PD.  If 
the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT  scans are needed to determine if there is truly progression 
occurring at that site (if so, the date of PD will be the date of the initial abnormal 
FDG-PET scan).  If the positive FDG-PET at follow-up corresponds to a pre-existing 
site of disease on CT that is not progressing on the basis of the anatomic images, this 
is not PD. 
c. FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy 


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in cases where a residual radiographic abnormality is thought to represent fibrosis or 
scarring.  The use of FDG-PET in this circumstance should be prospectively 
described in the protocol and supported by disease-specific medical literature for the 
indication.  However, it must be acknowledged that both approaches may lead to false 
positive CR due to limitations of FDG-PET and biopsy resolution/sensitivity. 
 
Note:  A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake 
greater than twice that of the surrounding tissue on the attenuation corrected image. 
 
11.1.4 Response Criteria 
 
11.1.4.1 
Evaluation of Target Lesions 
 
Complete Response (CR):  Disappearance of all target lesions.  Any pathological 
lymph nodes (whether target or non-target) must have reduction in short axis to <10 
mm (<1 cm). 
 
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 (this includes the 
baseline sum if that is the smallest on study).  In addition to the relative increase of 
20%, the sum must also demonstrate an absolute increase of at least 5 mm (0.5 cm).  
(Note:  the appearance of one or more new lesions is also considered progressions). 
 
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. 
 
11.1.4.2 
Evaluation of Non-Target Lesions 
 
Complete Response (CR):  Disappearance of all non-target lesions and normalization 
of tumor marker level.  All lymph nodes must be non-pathological in size (<10 mm 
[<1 cm] short axis). 
 
Note:  If tumor markers are initially above the upper normal limit, they must 
normalize for a patient to be considered in complete clinical response. 
 
Non-CR/Non-PD:  Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal limits. 
 
Progressive Disease (PD):  Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions.  Unequivocal progression 
should not normally trump target lesion status.  It must be representative of overall 
disease status change, not a single lesion increase. 


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79 
 
Although a clear progression of “non-target” lesions only is exceptional, the opinion 
of the treating physician should prevail in such circumstances, and the progression 
status should be confirmed at a later time by the review panel (or Principal 
Investigator). 
 
11.1.4.3 
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 patient's best 
response assignment will depend on the achievement of both measurement and 
confirmation criteria. 
 
For Patients with Measurable Disease (i.e., Target Disease) 
 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response 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 
 
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
**    Only for non-randomized trials with response as primary endpoint. 
***  In exceptional circumstances, unequivocal progression in non-target lesions may be 
accepted as disease progression. 
 
Note:  Patients 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. 
 
For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 


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Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
 
‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly used as an endpoint for assessment of efficacy in some trials so to assign this 
category when no lesions can be measured is not advised 
 
11.1.5 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 recurrent or progressive disease is objectively documented (taking as reference 
for progressive disease the smallest measurements recorded since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are first met 
for CR until the first date that progressive 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, including the baseline measurements.  
 
11.1.6 Progression-Free Survival 
 
PFS (not otherwise specified) is defined as the duration of time from start of treatment to 
time of progression or death, whichever occurs first.  Because Phase 2 Cohort A will 
include patients who have failed to respond to Erlotinib after up to 6 months on Erlotinib 
alone, the study will also collect the date of first Erlotinib therapy prior to enrollment.  
 
 
12. STUDY OVERSIGHT AND DATA REPORTING / REGULATORY 
REQUIREMENTS 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.0 
(Adverse Events: List and Reporting Requirements). 
 
12.1 
Study Oversight 
 
See also Section 14 ‘CCCP POLICIES FOR MONITORING CONSORTIUM TRIALS,’ 
Subsection 14.1 ‘Oversight.’ 
 
This protocol is monitored at several levels, as described in this section.  The Protocol Principal 
Investigator is responsible for monitoring the conduct and progress of the clinical trial, including 
the ongoing review of accrual, patient-specific clinical and laboratory data, and routine and 
serious adverse events; reporting of expedited adverse events; and accumulation of reported 
adverse events from other trials testing the same drug(s).  The Protocol Principal Investigator and 


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statistician have access to the data at all times through the CTMS web-based reporting portal.   
 
For the Phase 1 portion of this study, all decisions regarding dose escalation/expansion/de-
escalation require sign-off by the Protocol Principal Investigator through the CTMS/IWRS.  In 
addition, for the Phase 1 portion, the Protocol Principal Investigator will have at least monthly, 
or more frequently, conference calls with the Study Investigators and the CTEP Medical 
Officer(s) to review accrual, progress, and adverse events and unanticipated problems.   
 
During the Phase 2 portion of the study, the Protocol Principal Investigator will have, at a 
minimum, quarterly conference calls with the Study Investigators and the CTEP Medical 
Officer(s) to review accrual, progress, and pharmacovigilance.  Decisions to proceed to the 
second stage of a Phase 2 trial will require sign-off by the Protocol Principal Investigator and the 
Protocol Statistician. 
 
All Study Investigators at participating sites who register/enroll patients on a given protocol are 
responsible for timely submission of data via Medidata Rave and timely reporting of adverse 
events for that particular study.  This includes timely review of data collected on the electronic 
CRFs submitted via Medidata Rave. 
 
All studies are also reviewed in accordance with the enrolling institution’s data safety monitoring 
plan. 
 
12.2 
Data Reporting 
 
Data collection for this study will be done exclusively through Medidata Rave.  Access to the 
trial in Rave is granted through the iMedidata application to all persons with the appropriate 
roles assigned in the Regulatory Support System (RSS).  To access Rave via iMedidata, the site 
user must have an active CTEP IAM account (check at < https://ctepcore.nci.nih.gov/iam  >) and 
the appropriate Rave role (Rave CRA, Read-Only, CRA (Lab Admin, SLA or Site Investigator) 
on either the LPO or participating organization roster at the enrolling site. To the hold Rave CRA 
role or CRA Lab Admin role, the user must hold a minimum of an AP registration type.  To hold 
the Rave Site Investigator role, the individual must be registered as an NPIVR or IVR.  
Associates can hold read-only roles in Rave.  If the study has a DTL, individuals requiring write 
access to Rave must also be assigned the appropriate Rave tasks on the DTL (Note:  A DTL is 
not required for this study). 
 
Upon initial site registration approval for the study in RSS, all persons with Rave roles assigned 
on the appropriate roster will be sent a study invitation e-mail from iMedidata.  To accept the 
invitation, site users must log into the Select Login (https://login.imedidata.com/selectlogin) 
using their CTEP-IAM user name and password, and click on the “accept” link in the upper 
right-corner of the iMedidata page.  Please note, site users will not be able to access the study in 
Rave until all required Medidata and study specific trainings are completed.  Trainings will be in 
the form of electronic learnings (eLearnings), and can be accessed by clicking on the link in the 
upper right pane of the iMedidata screen.   
 
Users that have not previously activated their iMedidata/Rave account at the time of initial site 


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registration approval for the study in RSS will also receive a separate invitation from iMedidata 
to activate their account. Account activation instructions are located on the CTSU website, Rave 
tab under the Rave resource materials (Medidata Account Activation and Study Invitation 
Acceptance).  Additional information on iMedidata/Rave is available on the CTSU members’ 
website under the Rave tab or by contacting the CTSU Help Desk at 1-888-823-5923 or by e-
mail at ctsucontact@westat.com. 
 
12.2.1 Method 
 
This study will be monitored by the Clinical Trials Monitoring Service (CTMS).  Data 
will be submitted to CTMS at least once every two weeks via Medidata Rave (or other 
modality if approved by CTEP).  Information on CTMS reporting is available at:  
http://www.theradex.com/clinicalTechnologies/?National-Cancer-Institute-NCI-11.  On-
site audits will be conducted on an 18-36 month basis as part of routine cancer center site 
visits. More frequent audits may be conducted if warranted by accrual or due to concerns 
regarding data quality or timely submission.  For CTMS monitored studies, after users 
have activated their accounts, please contact the Theradex Help Desk at (609) 799-7580 
or by email at CTMSSupport@theradex.com for additional support with Rave and 
completion of CRFs. 
 
12.2.2 Responsibility for Data Submission 
 
For ETCTN trials, it is the responsibility of the PI(s) at the site to ensure that all 
investigators at the ETCTN Sites understand the procedures for data submission for each 
ETCTN protocol and that protocol specified data are submitted accurately and in a timely 
manner to the CTMS via the electronic data capture system, Medidata Rave.   
 
Data are to be submitted via Medidata Rave to CTMS on a real-time basis, but no less 
than once every 2 weeks.  The timeliness of data submissions and timeliness in resolving 
data queries will be tracked by CTMS.  Metrics for timeliness will be followed and 
assessed on a quarterly basis.  For the purpose of Institutional Performance Monitoring, 
data will be considered delinquent if it is greater than 4 weeks past due. 
 
Data from Medidata Rave and CTEP-AERS is reviewed by the CTMS on an ongoing 
basis as data is received.  Queries will be issued by CTMS directly within Rave.  The 
queries will appear on the Task Summary Tab within Rave for the CRA at the ETCTN to 
resolve.  Monthly web-based reports are posted for review by the Drug Monitors in the 
IDB, CTEP.  Onsite audits will be conducted by the CTMS to ensure compliance with 
regulatory requirements, GCP, and NCI policies and procedures with the overarching 
goal of ensuring the integrity of data generated from NCI-sponsored clinical trials, as 
described in the ETCTN Program Guidelines, which may be found on the CTEP 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm
)  and CTSU websites. 
 
An End of Study CRF is to be completed by the PI, and is to include a summary of study 
endpoints not otherwise captured in the database, such as (for phase 1 trials) the 


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recommended phase 2 dose (RP2D), and a description of any dose-limiting toxicities 
(DLTs).  CTMS will utilize a core set of eCRFs that are Cancer Data Standards Registry 
and Repository (caDSR) compliant (http://cbiit.nci.nih.gov/ncip/biomedical-informatics-
resources/interoperability-and-semantics/metadata-and-models).  Customized eCRFs will 
be included when appropriate to meet unique study requirements.  The PI is encouraged 
to review the eCRFs, working closely with CTMS to ensure prospectively that all 
required items are appropriately captured in the eCRFs prior to study activation.  CTMS 
will prepare the eCRFs with built-in edit checks to the extent possible to promote data 
integrity. 
12.3 
CTEP Multicenter Guidelines 
 
N/A 
 
12.4 
Collaborative Agreements Language 
 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the NCI 
under a Collaborative Agreement (CRADA, CTA, CSA) between the Pharmaceutical 
Company(ies) (hereinafter referred to as “Collaborator(s)”) and the NCI Division of Cancer 
Treatment and Diagnosis.  Therefore, the following obligations/guidelines, in addition to the 
provisions in the “Intellectual Property Option to Collaborator”  
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) contained within the 
terms of award, apply to the use of the Agent(s) in this study: 
 
1. Agent(s) may not be used for any purpose outside the scope of this protocol, nor can 
Agent(s) be transferred or licensed to any party not participating in the clinical study.  
Collaborator(s) data for Agent(s) are confidential and proprietary to Collaborator(s) and shall 
be maintained as such by the investigators.  The protocol documents for studies utilizing 
Agents contain confidential information and should not be shared or distributed without the 
permission of the NCI.  If a copy of this protocol is requested by a patient or patient’s family 
member participating on the study, the individual should sign a confidentiality agreement.  A 
suitable model agreement can be downloaded from: http://ctep.cancer.gov. 
 
2. For a clinical protocol where there is an investigational Agent used in combination with 
(an)other Agent(s), each the subject of different Collaborative Agreements, the access to and 
use of data by each Collaborator shall be as follows (data pertaining to such combination use 
shall hereinafter be referred to as "Multi-Party Data”): 
 
a. NCI will provide all Collaborators with prior written notice regarding the existence and 
nature of any agreements governing their collaboration with NCI, the design of the 
proposed combination protocol, and the existence of any obligations that would tend to 
restrict NCI's participation in the proposed combination protocol. 
 
b. Each Collaborator shall agree to permit use of the Multi-Party Data from the clinical trial 
by any other Collaborator solely to the extent necessary to allow said other Collaborator 
to develop, obtain regulatory approval or commercialize its own Agent. 


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84 
 
c. Any Collaborator having the right to use the Multi-Party Data from these trials must 
agree in writing prior to the commencement of the trials that it will use the Multi-Party 
Data solely for development, regulatory approval, and commercialization of its own 
Agent. 
 
3. Clinical Trial Data and Results and Raw Data developed under a Collaborative Agreement 
will be made available to Collaborator(s), the NCI, and the FDA, as appropriate and unless 
additional disclosure is required by law or court order as described in the IP Option to 
Collaborator 
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm).  
Additionally, all Clinical Data and Results and Raw Data will be collected, used and 
disclosed consistent with all applicable federal statutes and regulations for the protection of 
human subjects, including, if applicable, the Standards for Privacy of Individually 
Identifiable Health Information set forth in 45 C.F.R. Part 164. 
 
4. When a Collaborator wishes to initiate a data request, the request should first be sent to the 
NCI, who will then notify the appropriate investigators (Group Chair for Cooperative Group 
studies, or PI for other studies) of Collaborator's wish to contact them. 
 
5. Any data provided to Collaborator(s) for Phase 3 studies must be in accordance with the 
guidelines and policies of the responsible Data Monitoring Committee (DMC), if there is a 
DMC for this clinical trial. 
 
6. Any manuscripts reporting the results of this clinical trial must be provided to CTEP by the 
Group office for Cooperative Group studies or by the principal investigator for non-
Cooperative Group studies for immediate delivery to Collaborator(s) for advisory review and 
comment prior to submission for publication.  Collaborator(s) will have 30 days from the 
date of receipt for review.  Collaborator shall have the right to request that publication be 
delayed for up to an additional 30 days in order to ensure that Collaborator’s confidential and 
proprietary data, in addition to Collaborator(s)’s intellectual property rights, are protected.  
Copies of abstracts must be provided to CTEP for forwarding to Collaborator(s) for courtesy 
review as soon as possible and preferably at least three (3) days prior to submission, but in 
any case, prior to presentation at the meeting or publication in the proceedings.  Press 
releases and other media presentations must also be forwarded to CTEP prior to release.  
Copies of any manuscript, abstract and/or press release/ media presentation should be sent to: 
 
Email:  ncicteppubs@mail.nih.gov 
 
The Regulatory Affairs Branch will then distribute them to Collaborator(s).  No publication, 
manuscript or other form of public disclosure shall contain any of Collaborator’s confidential/ 
proprietary information. 
 
13. STATISTICAL CONSIDERATIONS 
 
13.1 
Study Design/Endpoints 
 


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85 
This is a phase 1/2 trial of Onalespib in combination with erlotinib.  The initial segment of the 
trial will attempt to escalate the starting dose of onalespib, in two steps, when given in 
combination with a fixed dose of erlotinib.  The primary endpoint during dose escalation is dose-
limiting toxicity (DLT), as defined in Section 5.2.  Dose escalation will follow a 3+3 design, 
motivated by the desire to limit the incidence of dose-limiting toxicity to the lowest feasible 
levels.  Dose escalation rules are defined in Section 5.3. All patients who receive any amount of 
study drug will be evaluable for toxicity and reported, but patients must either receive an 
informative treatment (as defined in Sections 5.2 and 5.3) or experience DLT to be informative 
about dose escalation decisions.   
 
When the phase 2 dose has been established, recruitment into Phase 2 cohorts A and B will begin 
simultaneously.  Cohort A will enroll patients with EGFR activating mutations (specified above) 
who have begun erlotinib within the previous 6 months (180 days), and have been evaluated, but 
without achieving a partial or complete response as defined by RECIST criteria by imaging 
performed not less than 12 weeks after starting erlotinib.  Cohort B will enroll patients with 
metastatic or recurrent NSCLC that harbor an EGFR exon 20 insertion and have progressive 
disease on platinum-based chemotherapy.  The primary endpoint for the phase 2 segment is best 
response by RECIST criteria, and each cohort will be independently governed by Simon’s two-
stage minimax design, implemented to distinguish a 25% response rate from an assumed 
background rate of 5%, with 10% type I and type II error rates.  For each phase 2 cohort, the 
initial stage will enroll 13 subjects, continuing if one or more respond.  The target total accrual in 
each cohort will be 20 subjects, with 3 responses considered encouraging for further 
development in the relevant class of patients.    
 
13.2 
Sample Size/Accrual Rate 
 
The phase 1 segment of the trial is expected to enroll between 12 and 18 subjects, with a worst-
case scenario requiring 24 informative subjects.  The Phase 2 segment is expected to require 40 
subjects (20 per cohort) but could stop for futility with 26 total subjects.  The target sample size 
is thus 46, allowing for 6 subjects from phase 1 at the RP2D to be included in one or the other 
Phase 2 cohort.   The likely range of sample size is from 32 to 52.   
 
PLANNED ENROLLMENT REPORT 
Racial Categories 
Ethnic Categories 
Total 
Not Hispanic or Latino 
Hispanic or Latino 
 
Female 
Male 
Female 
Male 
 
American Indian/ Alaska 
Native 
0 
0 
0 
0 
0 
Asian 
4 
3 
0 
0 
7 
Native Hawaiian or 
Other Pacific Islander 
0 
0 
0 
0 
0 


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86 
Racial Categories 
Ethnic Categories 
Total 
Not Hispanic or Latino 
Hispanic or Latino 
 
Female 
Male 
Female 
Male 
 
Black or African 
American 
2 
1 
0 
0 
3 
White 
16 
14 
4 
2 
36 
More Than One Race 
0 
0 
0 
0 
0 
Total 
22 
18 
4 
2 
46 
PHS 398 / PHS 2590 (Rev. 08/12 Approved Through 8/31/2015)  
OMB No. 0925-0001/0002 
 
 
13.3 
Stratification Factors 
 
Eligible patients will be classified in one of two possible strata: (A) patients with EGFR 
activating mutations who have been treated with erlotinib; or (B) patients will metastatic or 
recurrent NSCLC that harbor an EGFR exon 20 insertion and have progressive disease on 
platinum-based chemotherapy.  The strata are pooled during the dose-escalation segment, but 
eligible stratum A patients will have progressed on erlotinib.  In phase 2, the strata are enrolled 
as separate cohorts, and stratum A patients are eligible if they have not responded to erlotinib. 
 
 
13.4 
Analysis of Secondary Endpoints 
 
Tumor response is the primary endpoint for phase 2, but secondary for phase 1.  The phase 2 
results will be reported with respect to the Simon’s two-stage design, including any relevant 
patients from phase 1, of the same stratum, treated at the RP2D.  If there is a response at a lower 
dose, the report will be supplemented with isotonic regression estimates.  Because stratum A 
includes subjects who have progressed on erlotinib, as well as subjects who have neither 
progressed nor responded after at least 12 weeks on erlotinib, results for these two groups will be 
reported separately as a secondary data summary.  A significant difference (two-sided 0.10 level) 
in response rates is not expected, but it would imply a significant number of responses in at least 
one sub-group, and any response after progression on erlotinib would be an interesting finding. 
 
PFS is a secondary endpoint, and will be summarized for stratum B as time from first protocol 
treatment, using the product-limit (Kaplan-Meier) estimator.   For stratum A, the product-limit 
estimate of PFS will be calculated separately for second-line patients, who have progressed on 
erlotinib.  For patients in stratum A who have not yet progressed on erlotinib, the time on pre-
protocol erlotinib and PFS on protocol therapy will be displayed as event time-lines, and any 
Kaplan-Meyer plot using the combined data for stratum A will use left truncation, to avoid 


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87 
crediting the combination with the progression-free time required to enter the study. 
 
13.5 
Reporting and Exclusions 
 
13.5.1 Evaluation of Toxicity 
 
Adverse events from all patients will be reported  from the time of their first treatment 
with protocol agents.  . Replacement of patients for dose escalation decisions is described 
in Section 5.3. 
 
13.5.2 Evaluation of Response 
 
All patients included in the study must be assessed for response to treatment, even if there 
are major protocol treatment deviations or if they are ineligible.  Each patient will be 
assigned one of the following categories:  1) complete response, 2) partial response, 3) 
stable disease, 4) progressive disease, 5) early death from malignant disease, 6) early 
death from toxicity, 7) early death because of other cause, or 8) unknown (not assessable, 
insufficient data).   
 
All of the patients who met the eligibility criteria and received no study medication will 
be included in the main analysis of the response rate.  Patients in response categories 4-8  
will be considered to have a treatment failure (analyzed as if disease progression).  Thus, 
an incorrect treatment schedule or drug administration does not result in exclusion from 
the analysis of the response rate.  
 
Phase 2 conclusions will be based on all eligible patients treated at the RP2D.  
Subanalyses may then be performed on the basis of a subset of patients, excluding those 
for whom major protocol deviations have been identified (e.g., early death due to other 
reasons, early discontinuation of treatment, major protocol violations, etc.).  However, 
these subanalyses may not serve as the basis for drawing conclusions concerning 
treatment efficacy, and the reasons for excluding patients from the analysis should be 
clearly reported.  The 95% confidence intervals should also be provided.  
 
Analysis of tissue and plasma biomarkers are exploratory in nature, constrained by the 
sample size requirements of a phase 1/2 trial, and availability of biopsies.  For circulating 
DNA, the Guardant panel will provide an opportunity to observe loss of stratum-defining 
markers after treatment.   Such loss-of-signal events will be cross-classified with best 
response and summarized with changes in tumor measurements.  Strong association 
between loss of marker signal (including plasma EGFR-T790M) and response may 
provide preliminary indication of potential as a predictive marker.  Emergent markers 
will be similarly evaluated as potential predictors of treatment resistance, and the 
mutation profile of responding patients will be examined informally for repeating 
patterns.  Multiplexed immunofluorescence in paired tumor biopsies will be used to 
demonstrate the knockdown of Hsp90 client oncoproteins.  Analysis will similarly 
involve association of knockdown and tumor response or measurements.  Biopsies are 
optional. Because any observation of target knock-down is an informative observation, 


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88 
biopsies will continue to be sought, even if the initial rate of consent to biopsies is low. If 
zero out of 6 on-treatment biopsies show target knock-down, the upper 80% confidence 
bound would be below 25%, and hence inconsistent with the target response rate under 
assumed mechanisms. We thus regard 6 biopsies as a minimum, if negative. When 
available, 
the 
first 
6-paired 
biopsies 
will 
be 
examined 
for 
multiplexed 
immunofluorescence. Failure to observe target knock-down in the first zero out of 6 
biopsies will prompt a re-evaluation of performing on-target biopsies in additional 
patients enrolled on trial. 
 
14. CCC POLICIES FOR MONITORING CONSORTIUM TRIALS 
 
This protocol is monitored at several levels, as described in this section.  To summarize:  The 
trial PI has access to the data at all times.  The CCC Data Coordinating Center reviews accrual 
and toxicities monthly.  An external, independent DSMC reviews the study progress twice 
yearly.  In addition, for the Phase 1 portion, the study PI will have monthly - and as needed - 
conference calls with study investigators to review accrual, progress, and any unforeseen 
issues.  Dose escalation/expansion/de-escalation decisions require sign-off by the study PI (or his 
or her designee) and study statistician (or his or her designee).  During the Phase 2 portion, the 
study PI will have quarterly - and as needed - conference calls with study investigators to review 
accrual, progress, and any unforeseen issues.  Decisions to proceed to the second stage of the 
Phase 2 trial will require sign-off by the study PI and (the trial statistician). 
 
The protocol principal investigator (PI) is responsible for monitoring the conduct and progress of 
this Phase 2 trial, including the ongoing review of accrual, data and toxicities, as well as the 
accumulation of reported adverse events from other trials testing the same drug(s).  The 
participating clinicians and their designees are responsible for timely submission of adverse 
event reports (see Section 7.0) and electronic case report forms.  The Data Coordinating Center 
for the CCC Consortium is responsible for providing the PI with access to the submitted case 
report form data in summary and detail in a timely fashion.   Although the PI is responsible for 
evaluating the cumulative reported adverse events and the impact that these have on the 
continued conduct of the trial, it is the Data Coordinating Center of the CCC that distributes all 
submitted SAE reports to the appropriate individuals, including the local protocol principal 
investigators, at each of the participating institutions.   
 
The Data Coordinating Center posts a summary (accrual, toxicities, and responses) of each CCC 
initiated trial on the CCC website.  In this way, each PI has access to up-to-date information on 
the status of his or her trial.  In consultation with the collaborating statistician, the PI is 
responsible for review of: 
 
(a) 
for Phase 1 trials, all dose limiting toxicities and decisions regarding dose escalation, 
expansion, as well as decisions to terminate escalation, and  
(b) 
for Phase 2 trials, the toxicities and therapeutic endpoints referred to in the statistical 
plan. 
 
The Data Coordinating Committee meets monthly to review data management and data quality 
issues – completeness of data submissions as well as accuracy in terms of built-in, computerized 


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89 
logic checks.  Any issues identified and the corrective plans are presented to the Internal 
Committee and at the next CCC teleconference meeting for review and approval. 
 
14.1 
Oversight 
 
Oversight of the conduct of CCC trials occurs at several levels: 
 
1. 
The Data Coordinating Center for the CCC flags all trials that are approaching a decision 
in terms of toxicity (for both Phase 1 and Phase 2 trials) or responses (for Phase 2 trials).  
Decisions are made by the PI with input from the statistician and discussion with the 
principal investigator of the funding mechanism or his or her designee, and are 
communicated to the participating centers by the CCC Data Coordinating Center. At the 
monthly teleconferences, the accrual of each open protocol is reviewed. 
 
2. 
For CTEP sponsored Phase 1 trials, data are reported to the NCI-designated clinical trials 
monitoring service (CTMS) which will audit patients’ records on each protocol – at each 
CCC institution; this audit is initiated by CTEP.   
 
3. 
An independent CCC DSMC will review CCC trials every 6 months. This DSMC will 
consist of 6 voting members (3 medical oncologists or hematologists involved in Phase 
1/2 cancer clinical trials but not participating in CCC studies, a patient representative and 
a statistician) and a non-voting CCC statistician.   
 
a. 
DSMC meetings will take place twice a year.  Additional meetings will be convened if 
necessary.  
b. 
This DSMC will review each CCC trial in terms of accrual, toxicity/safety, and 
adherence to trial design, audit results, and likelihood of successful completion.   
c. 
The DSMC will report to the CCC leadership. 
 


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90 
REFERENCES 
 
1. 
Wu, Y.L., et al., Intercalated combination of chemotherapy and erlotinib for patients 
with advanced stage non-small-cell lung cancer (FASTACT-2): a randomised, double-
blind trial. The lancet oncology, 2013. 14(8): p. 777-86. 
2. 
Sequist, L.V., et al., Genotypic and histological evolution of lung cancers acquiring 
resistance to EGFR inhibitors. Science translational medicine, 2011. 3(75): p. 75ra26. 
3. 
Takezawa, K., et al., HER2 amplification: a potential mechanism of acquired resistance 
to EGFR inhibition in EGFR-mutant lung cancers that lack the second-site EGFRT790M 
mutation. Cancer discovery, 2012. 2(10): p. 922-33. 
4. 
Erlotinib Investigator's Brochure, OSI Pharmaceuticals, Inc., Genentech, Inc., and F. 
Hoffman-La Roche Ltd. 13th Edition. 2009. 
5. 
Mok, T.S., et al., Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. The 
New England journal of medicine, 2009. 361(10): p. 947-57. 
6. 
Rosell, R., et al., Erlotinib versus standard chemotherapy as first-line treatment for 
European patients with advanced EGFR mutation-positive non-small-cell lung cancer 
(EURTAC): a multicentre, open-label, randomised phase 3 trial. The lancet oncology, 
2012. 13(3): p. 239-246. 
7. 
Sequist, L.V., et al., Phase III study of afatinib or cisplatin plus pemetrexed in patients 
with metastatic lung adenocarcinoma with EGFR mutations. Journal of clinical oncology 
: official journal of the American Society of Clinical Oncology, 2013. 31(27): p. 3327-34. 
8. 
Miller, V.A., et al., Afatinib versus placebo for patients with advanced, metastatic non-
small-cell lung cancer after failure of erlotinib, gefitinib, or both, and one or two lines of 
chemotherapy (LUX-Lung 1): a phase 2b/3 randomised trial. The lancet oncology, 2012. 
13(5): p. 528-38. 
9. 
Lecia V. Sequist, J.-C.S., Shirish M. Gadgeel, Heather A. Wakelee, D. Ross Camidge, 
Andrea Varga, Benjamin J. Solomon, Vassiliki Papadimitrakopoulou, Sarah S. Jaw-Tsai, 
Lisa Caunt, Paramjit Kaur, Lindsey Rolfe, Andrew R. Allen, Jonathan Wade Goldman, 
First-in-human evaluation of CO-1686, an irreversible, highly selective tyrosine kinase 
inhibitor of mutations of EGFR (activating and T790M). Journal of clinical oncology : 
official journal of the American Society of Clinical Oncology, 2014. 32(5s): p. suppl; 
abstr 8010. 
10. 
Pasi A. Janne, S.S.R., James Chih-Hsin Yang, Myung-Ju Ahn, Dong-Wan Kim, Sang-We 
Kim, David Planchard, Yuichiro Ohe, Enriqueta Felip, Claire Watkins, Mireille 
Cantarini, Serban Ghiorghiu, Malcolm Ranson, Clinical activity of the mutant-selective 
EGFR inhibitor AZD9291 in patients (pts) with EGFR inhibitor–resistant non-small cell 
lung cancer (NSCLC). Journal of clinical oncology : official journal of the American 
Society of Clinical Oncology, 2014. 32(5s): p. suppl; abstr 8009. 
11. 
Trepel, J., et al., Targeting the dynamic HSP90 complex in cancer. Nature reviews. 
Cancer, 2010. 10(8): p. 537-49. 
12. 
Shimamura, T., et al., Hsp90 inhibition suppresses mutant EGFR-T790M signaling and 
overcomes kinase inhibitor resistance. Cancer research, 2008. 68(14): p. 5827-38. 
13. 
Graham, B., et al., The heat shock protein 90 inhibitor, AT13387, displays a long 
duration of action in vitro and in vivo in non-small cell lung cancer. Cancer science, 
2012. 103(3): p. 522-7. 
14. 
Keisha Hearn, T.S., Jon Lewis, Vanessa Martins, Neil Thompson, Mohammad Azab, 


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John Lyons, Nicola G. Wallis, The HSP90 inhibitor, AT13387, displays single agent 
activity in erlotinib-sensitive and -resistant models of EGFR-activated NSCLC. World 
Congress on Lung Cancer, 2013: p. P1.05-012. 
15. 
Tomoko Smyth, J.L., Keisha Hearn, Neil Thompson, John Lyons, Nicola G. Wallis, The 
HSP90 inhibitor, AT13387, combined with erlotinib improves response in EGFR-driven 
xenograft models of NSCLC. AACR Annual Meeting, 2014: p. 1794. 
16. 
Bean, J., et al., MET amplification occurs with or without T790M mutations in EGFR 
mutant lung tumors with acquired resistance to gefitinib or erlotinib. Proceedings of the 
National Academy of Sciences of the United States of America, 2007. 104(52): p. 20932-
7. 
17. 
Yasuda, H., S. Kobayashi, and D.B. Costa, EGFR exon 20 insertion mutations in non-
small-cell lung cancer: preclinical data and clinical implications. The lancet oncology, 
2012. 13(1): p. e23-31. 
18. 
Xu, W., et al., Sensitivity of epidermal growth factor receptor and ErbB2 exon 20 
insertion mutants to Hsp90 inhibition. British journal of cancer, 2007. 97(6): p. 741-4. 
19. 
Chen, Z., et al., A murine lung cancer co-clinical trial identifies genetic modifiers of 
therapeutic response. Nature, 2012. 483(7391): p. 613-7. 
20. 
Gandara, D.R., et al., Bridging tumor genomics to patient outcomes through an 
integrated patient-derived xenograft platform. Clinical lung cancer, 2015. 16(3): p. 165-
72. 
 
 
 


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92 
APPENDIX A 
PERFORMANCE STATUS CRITERIA 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
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. 
 
 
 


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93 
APPENDIX B 
PATIENT DRUG INFORMATION HANDOUT AND WALLET 
CARD 
 
Information for Patients, Their Caregivers, and Non-Study Healthcare Team on Possible 
Interactions with Other Drugs and Herbal Supplements  
 
The patient ____________________________ is enrolled on a clinical trial using the 
experimental study drugs AT13887 and Erlotinib.  This clinical trial is sponsored by the National 
Cancer Institute.  This form is addressed to the patient, but includes important information for 
others who care for this patient.  
 
These are the things that you as a healthcare provider need to know: 
  
Erlotinib interacts with a certain specific enzyme in your liver.  
 
 The enzyme in question is CYP3A4 and erlotinib is broken down by this enzyme and may 
be affected by other drugs that inhibit or induce this enzyme. 
 
To the patient: Take this paper with you to your medical appointments and keep the 
attached information card in your wallet.   
 
Erlotinib and/or onalespib may interact with other drugs which can cause side effects. For this 
reason, it is very important to tell your study doctors of any medicines you are taking before you 
enroll onto this clinical trial.  It is also very important to tell your doctors if you stop taking any 
regular medicines, or if you start taking a new medicine while you take part in this study.  When 
you talk about your current medications with your doctors, include medicine you buy without a 
prescription (over-the-counter remedy), or any herbal supplements such as St. John’s Wort.  It is 
helpful to bring your medication bottles or an updated medication list with you. 
 
Many health care providers can write prescriptions.  You must tell all of your health care 
providers (doctors, physician assistants, nurse practitioners, pharmacists) you are taking part in a 
clinical trial.  
 
These are the things that you and they need to know:  
 
Erlotinib must be used very carefully with other medicines that use certain CYP3A4 to be 
effective or to be cleared from your system. Before you enroll onto the clinical trial, your study 
doctor will work with your regular health care providers  to review any medicines and herbal 
supplements  that are considered strong inducers of CYP3A4. 
 
 Please be very careful!  Over-the-counter drugs (including herbal supplements) may 
contain ingredients that could interact with your study drug.  Speak to your doctors or 
pharmacist to determine if there could be any side effects.  
 If you take acetaminophen regularly: You should not take more than 4 grams a day if you 
are an adult or 2.4 grams a day if you are older than 65 years of age. Read labels 
carefully! Acetaminophen is an ingredient in many medicines for pain, flu, and cold. 


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94 
 Your 
prescribers 
should 
look 
at 
this 
web 
site 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugIn
teractionsLabeling/ucm093664.htm or consult a medical reference to see if any medicine 
they want to prescribe is on a list of drugs to avoid. 
 If you drink grapefruit juice or eat grapefruit or Seville oranges: Avoid these until the study 
is over.  
 Do not take omeprazole (also known as Prilosec) for heartburn or for stomach reflux.  Talk 
to your doctor or pharmacist before taking it. 
 If use ranitidine, cimetidine, or famotidine for heartburn, erlotinib must be taken 10 hours 
after these drugs and at least 2 hours before the next dose of ranitidine, cimetidine, or 
famotidine.  Talk to your doctor or pharmacist. 
 If use antacids, take the antacid dose several hours from erlotinib dose.   
 
 If you take herbal medicine regularly: You should not take St. John’s wort while you are 
taking erlotinib and onalespib.  
 Your regular health care provider should check a frequently updated medical reference or 
call your study doctor before prescribing any new medicine or discontinuing any 
medicine.  Your study doctor’s name is __________________________________ and he 
or she can be contacted at _____________________________________. 
 


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95 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
STUDY DRUG INFORMATION WALLET CARD   
You are enrolled on a clinical trial using the experimental study  
drugs erlotinib and AT13387 (Onalespib lactate). This clinical trial is 
sponsored by the NCI.  Erlotinib and AT13387 (Onalespib lactate).may 
interact with drugs that are processed by your liver.  Because of this, 
it is very important to: 
 Tell your doctors if you stop taking any medicines or if you start 
taking any new medicines. 
 Tell all of your health care providers (doctors, physician assistants, 
nurse practitioners, or pharmacists) that you are taking part in a 
clinical trial. 
 Check with your doctor or pharmacist whenever you need to use 
an over-the-counter medicine or herbal supplement. 
 
Erlotinib interacts with a specific liver enzyme called CYP3A4 and 
must be used very carefully with other medicines that interact with 
CYP3A4.  
 Before you enroll onto the clinical trial, your study doctor will 
work with your regular health care providers to review any 
medicines  and herbal supplements that are considered strong 
inducers/inhibitors of CYP3A4. 
 Before prescribing new medicines, your regular health care 
providers should go to a frequently-updated medical reference for 
a list of drugs to avoid, or contact your study doctor.   
 Your study doctor’s name is _____________________________ 
and can be contacted at _________________________________.  


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96 
APPENDIX C 
PATIENT’S MEDICATION DIARY 
 
Today’s date _____________________           Cycle Number: __________           Agent:  Erlotinib 
Patient Name_____________________(initials acceptable)            Patient Study ID ______________________ 
INSTRUCTIONS TO THE PATIENT: 
1. 
Complete one form for each cycle of treatment. 
2. 
You will take Erlotinib tablets by mouth once a day (in the morning).  You should take the tablets on an empty stomach at 1 hour 
before food or 2 hours after a meal.  Take with 1 cup (200 mL) of water.  Tablets should be swallowed whole, do not chew or crush 
If you have a G-tube, your study doctor will provide you with specific instructions for administration of erlotinib. If you miss a dose 
and do not take it within 6 hours of the usual time of your morning dose, skip the dose and resume taking Erlotinib the next 
morning. Please contact your doctor if you have any questions. 
         Dose:  take _____ x __________ mg tablet(s).   
3. 
Record the date, the number of tablets of each size of tablet that you took, and when you took them.   
4. 
If you have any comments or notice any side effects, please record them in the Comments column.   
5. 
Please bring this form and your bottles of Erlotinib tablets when you return for each appointment. 
 
Day 
 
Date 
 
Time of dose 
Erlotinib # of 
tablets taken 
Comments 
_____ mg 
 
1 
 
 
 
 
2 
 
 
 
 
3 
 
 
 
 
4 
 
 
 
 
5 
 
 
 
 
6 
 
 
 
 
7 
 
 
 
 
8 
 
 
 
 
9 
 
 
 
 
10 
 
 
 
 
11 
 
 
 
 
12 
 
 
 
 
13 
 
 
 
 
14 
 
 
 
 
15 
 
 
 
 
16 
 
 
 
 
17 
 
 
 
 
18 
 
 
 
 
19 
 
 
 
 
20 
 
 
 
 
21 
 
 
 
 
22 
 
 
 
 
23 
 
 
 
 
24 
 
 
 
 
25 
 
 
 
 
26 
 
 
 
 
27 
 
 
 
 
28 
 
 
 
 
 
 
Patient Signature: _______________________________________________________________ 
Physician’s Office will complete this section: 
1. Date patient started protocol treatment______________      
2. Date patient was removed from study_______________ 
3. Patient’s planned total daily dose ___________________________________________________________________  
3. Total number of tablets taken this month Erlotinib_________________ ___________________________________  
4. Physician/Nurse/Data Manager’s Signature  __________________________________________________________  
 
CTEP-assigned Protocol # 9987 
Consortium Protocol PhI-80 
Local Protocol # ___________________ 


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97 
 
APPENDIX D 
 
DRUGS WITH KNOWN RISK OF TORSADES DE 
POINTES 
 
Generic Name 
Brand Names 
(Partial List) 
Drug Class 
Therapeutic Use 
Amiodarone 
Cordarone®, 
Pacerone®, 
Nexterone® 
Antiarrhythmic 
Abnormal heart 
rhythm 
Anagrelide 
Agrylin®, Xagrid® 
Phosphodiesterase 3 
inhibitor 
Thrombocythemia 
Arsenic trioxide 
Trisenox® 
Anticancer 
Cancer (leukemia) 
Astemizole 
(Removed from US 
Market) 
Hismanal® 
Antihistamine 
Allergic rhinitis 
Azithromycin 
Zithromax®, 
Zmax® 
Antibiotic 
Bacterial infection 
Bepridil (Removed 
from US Market) 
Vascor® 
Antianginal 
Angina Pectoris 
(heart pain) 
Chloroquine 
Aralen® 
Antimalarial 
Malaria 
Chlorpromazine 
Thorazine®, 
Largactil®, 
Megaphen® 
Antipsychotic / 
Antiemetic 
Schizophrenia, 
nausea, many others 
Cilostazol 
Pletal® 
Phosphodiesterase 3 
inhibitor 
Intermittent 
claudication 
Ciprofloxacin 
Cipro®, Cipro-
XR®, Neofloxin® 
Antibiotic 
Bacterial infection 
Cisapride (Removed 
from US Market) 
Propulsid® 
GI stimulant 
Increase GI motility 
Citalopram 
Celexa®, 
Cipramil® 
Antidepressant, 
SSRI 
Depression 
Clarithromycin 
Biaxin®, Prevpac® 
Antibiotic 
Bacterial infection 
Cocaine 
Cocaine 
Local anesthetic 
Anesthesia (topical) 
Disopyramide 
Norpace® 
Antiarrhythmic 
Abnormal heart 
rhythm 
Dofetilide 
Tikosyn® 
Antiarrhythmic 
Abnormal heart 
rhythm 
Domperidone (On 
non US Market) 
Motilium®, 
Motillium®, 
Motinorm Costi®, 
Nomit® 
Antinausea 
Nausea, vomiting 
Donepezil 
Aricept® 
Cholinesterase 
inhibitor 
Dementia 
(Alzheimer's Disease) 
Dronedarone 
Multaq® 
Antiarrhythmic 
Abnormal heart 
rhythm 


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98 
Droperidol 
Inapsine®, 
Droleptan®, 
Dridol®, Xomolix® 
Antipsychotic / 
Antiemetic 
Anesthesia (adjunct), 
nausea 
Erythromycin 
E.E.S.®, 
Robimycin®, 
EMycin®, 
Erymax®, Ery-
Tab®, Eryc 
Ranbaxy®, 
Erypar®, Eryped®, 
Erythrocin Stearate 
Filmtab®, 
Erythrocot®, E-
Base®, 
Erythroped®, 
Ilosone®,  MY-E®, 
Pediamycin®, 
Zineryt®, 
Abboticin®, 
Abboticin-ES®, 
Erycin®, PCE 
Dispertab®, 
Stiemycine®, 
Acnasol®, 
Tiloryth® 
Antibiotic 
Bacterial infection, 
increase GI motility 
Escitalopram 
Cipralex®, 
Lexapro®, Nexito®, 
Anxiset-E® (India), 
Exodus® (Brazil), 
Esto® (Israel), 
Seroplex®, Elicea®, 
Lexamil®, 
Lexam®, Entact® 
(Greece), Losita® 
(Bangladesh), 
Reposil® (Chile), 
Animaxen® 
(Colombia), 
Esitalo® 
(Australia), 
Lexamil® (South 
Africa) 
Antidepressant, 
SSRI 
Depression (major), 
anxiety disorders 
Flecainide 
Tambocor®, 
Almarytm®, 
Apocard®, 
Ecrinal®, Flécaine® Antiarrhythmic 
Abnormal heart 
rhythm 


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Version Date: March 9, 2018 
 
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Fluconazole 
Diflucan®, Trican® 
Antifungal 
Fungal infection 
Gatifloxacin 
(Removed from US 
Market) 
Tequin® 
Antibiotic 
Bacterial infection 
Grepafloxacin (Off 
market worldwide) 
Raxar® 
Antibiotic 
Bacterial infection 
Halofantrine 
Halfan® 
Antimalarial 
Malaria 
Haloperidol 
Haldol® (US & 
UK), Aloperidin®, 
Bioperidolo®, 
Brotopon®, 
Dozic®, 
Duraperidol® 
(Germany), Einalon 
S®, Eukystol®, 
Halosten®, 
Keselan®, Linton®, 
Peluces®, 
Serenace®, 
Serenase®, 
Sigaperidol® 
Antipsychotic 
Schizophrenia, 
agitation 
Ibutilide 
Corvert® 
Antiarrhythmic 
Abnormal heart 
rhythm 
Levofloxacin 
Levaquin®, 
Tavanic® 
Antibiotic 
Bacterial infection 
Levomethadyl 
(Removed from US 
Market) 
Orlaam® 
Opioid agonist 
Narcotic dependence 
Mesoridazine 
(Removed from US 
Market) 
Serentil® 
Antipsychotic 
Schizophrenia 
Methadone 
Dolophine®, 
Symoron®, 
Amidone®, 
Methadose®, 
Physeptone®, 
Heptadon® 
Opioid agonist 
Narcotic dependence, 
pain 
Moxifloxacin 
Avelox®, Avalox®, 
Avelon® 
Antibiotic 
Bacterial infection 
Ondansetron 
Zofran®, Anset®, 
Ondemet®, 
Zuplenz®, 
Emetron®, 
Ondavell®, 
Emeset®, 
Ondisolv®, 
Antiemetic 
Nausea, vomiting 


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100 
Setronax® 
Pentamidine 
Pentam® 
Antifungal 
Fungal infection 
(Pneumocystis 
pneumonia) 
Pimozide 
Orap® 
Antipsychotic 
Tourette's Disorder 
Probucol (Removed 
from US Market) 
Lorelco® 
Antilipemic 
Hypercholesterolemia 
Procainamide (Oral 
off US mkt) 
Pronestyl®, 
Procan® 
Antiarrhythmic 
Abnormal heart 
rhythm 
Propofol 
Diprivan®,  
Propoven® 
Anesthetic, general 
Anesthesia 
Quinidine 
Quinaglute®, 
Duraquin®, 
Quinact®, 
Quinidex®, Cin-
Quin®, Quinora® 
Antiarrhythmic 
Abnormal heart 
rhythm 
Sevoflurane 
Ulane®, Sojourn® 
Anesthetic, general 
Anesthesia 
Sotalol 
Betapace®, 
Sotalex®, Sotacor® 
Antiarrhythmic 
Abnormal heart 
rhythm 
Sparfloxacin 
(Removed from US 
Market) 
Zagam® 
Antibiotic 
Bacterial infection 
Sulpiride (On non 
US Market) 
Dogmatil®, 
Dolmatil®, 
Eglonyl®, 
Espiride®, Modal®, 
Sulpor® 
Antipsychotic, 
atypical 
Schizophrenia 
Terfenadine 
(Removed from US 
Market) 
Seldane® 
Antihistamine 
Allergic rhinitis 
Thioridazine 
Mellaril®, 
Novoridazine®, 
Thioril® 
Antipsychotic 
Schizophrenia 
Vandetanib 
Caprelsa® 
Anticancer 
Cancer (thyroid) 
 
 
 
 
 
 
 


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Version Date: March 9, 2018 
 
101 
APPENDIX E 
 
FRIDERICIA’S CRITERIA FOR QTC CALCULATION  
 
Fridericia’s formula QTcF = (QT/RR^0.33). RR is the time from the interval of 1 QRS complex 
to the next measured in seconds and is commonly calculated as (60/HR) (Hosmane et al, Journal 
of Applied Research 2006). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


NCI Protocol #:9878 
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102 
APPENDIX F 
 
SPECIMEN COLLECTION FOR PHARMACOKINETIC 
STUDIES FOR PHI-80 (NCI# 9878) 
 
Title: A Phase 1/2 Trial of Erlotinib and Onalespib lactate in EGFR-Mutant Non-Small Cell 
Lung Cancer 
 
At each protocol specified time, draw and collect 3 ml blood in heparinized (green top) tube. Start 
prior to Onalespib dosing on cycle 1, day 8. Blood specimens (3 mL whole blood collected in 
heparinized tubes (Li) sufficient to provide a minimum of 1 mL of plasma) for PK will be 
collected from patients on day C1D8 of Onalespib administration. The timing of start of onalespib 
infusion should be within 30 min of erlotinib intake on that day (timing of both erlotinib intake 
and start of Onalespib infusion should be recorded). 
 
Handling of Specimen 
1. Obtain at least 3 mL of blood into Lithium Heparin (Green Top) Vacutainer tube. Allow 
enough time for the tube to fill sufficiently. 
2. Gently invert the tube for 30 seconds to ensure proper mixing.  
3. Place tube on a standard blood roller for a minimum of 5 minutes. If a blood roller is not 
available continue to invert the tube further 8-10 times.  
4. Centrifuge the tube at 1100 - 1500g for 10-15 minutes at 4-8°C within 1 hour of sample 
collection.  
5. Pipette off the plasma layer (using the pipette provided with the kit)  
6. Introduce roughly equal proportions of the plasma into the 2 (primary and secondary) cryovial 
tubes (size 2 mL).  
7. Discard the Lithium Heparin tube per your local policy. 
8. Freeze the 2 aliquots of plasma at -70°C or less until shipment to the bioanalytical lab 
(instructed by Astex).   
  
 
 
 
 


NCI Protocol #:9878 
Version Date: March 9, 2018 
 
103 
Pharmacokinetic Sample Collection Schedule 
 
Title: A Phase 1/2 Trial of Erlotinib and Onalespib lactate in EGFR-Mutant Non-Small Cell Lung Cancer 
 
Patient's Initials _______________   _____________________         Patient ID #  ______ _____ 
                                          (first)                                        (last) 
 
Study Site _____________     Height ________ cm    Weight:  ____ . ____ kg    BSA ____ . ____ ____ m2 
Erlotinib Dose   __________ mg    Start Date/time   __________________________ 
 
Onalespib (AT13387) Dose                              mg/m2 IV infusion  
 
Infusion Start Date/time   __________________         Infusion End time _______________________ 
 
Blood samples (at least 3 mL) for PK should be drawn into lithium heparin containing tubes at time 0 (immediately prior 
to start of onalespib infusion), then at 0.5 hr (± 5 min), 1 hr (to coincide with immediately at the end of onalespib 
infusion ±2 min), 2 hr (±5 min), 3 hr (± 5 min), 4 (± 5 min), 6 (± 5 min), 8-9 hr, and 24 hours (this sample falls on the 
next day) hours post start of onalespib infusion. 
 
*Infusion should start within 30 min of erlotinib intake for that day. Time for erlotinib intake and start of onalespib 
infusion should be recorded. 
 
** 24 hour sample should be taken prior to C1D9 dosing of erlotinib. 
Sample 
 Name 
Matrix 
Planned Collection 
Time Relative to 
onalespib Infusion* 
(hours) 
Sample Date 
(mm:dd:yy) 
Expected Time 
(hh:mm) 
Actual Time 
(hh:mm) 
Drawn By 
(initials) 
Comments 
P1 
Plasma 
Pre-ONALESPIB 
infusion 
 
 
 
 
 
P2 
Plasma 
 
0.5 hr (± 5 min) after 
ONALESPIB 
 
 
 
 
 
P3 
   Plasma 
1 hr (± 2 min) 
after ONALESPIB 
(immediately at end 
of infusion) 
 
 
 
 
 
P4 
Plasma 
 
2 hr (± 5 min) 
after ONALESPIB 
 
 
 
 
 
P5 
Plasma 
 
3 hr (± 5 min) 
after ONALESPIB 
 
 
 
 
 
P6 
Plasma 
 
4 hr (± 5 min) 
after ONALESPIB 
 
 
 
 
 
P7 
Plasma 
 
6 hr (± 5 min) 
after ONALESPIB 
 
 
 
 
 
P8 
Plasma 
 
8-9 hr after 
ONALESPIB 
 
 
 
 
 
P9 
Plasma 
 
24 hr** 
(post-start of 
ONALESPIB infusion)