Conditions: EGFR Exon 19 Deletion Mutation EGFR NP_005219.2:p.L858R Lung Non-Squamous Non-Small Cell Carcinoma Stage IV Lung Non-Small Cell Cancer AJCC v7
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 88
Healthy volunteers: no

Brief summary:
This randomized phase II trial studies how well erlotinib hydrochloride (Tarceva) with or without bevacizumab (Avastin) works in treating patients with stage IV non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations. Erlotinib hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as bevacizumab, may block tumor growth in different ways by targeting certain cells. Bevacizumab may also stop the growth of NSCLC by blocking the growth of new blood vessels necessary for tumor growth. It is not yet known whether erlotinib hydrochloride is more effective when given alone or with bevacizumab in treating patients with NSCLC.

Detailed description:
PRIMARY OBJECTIVE:

I. To determine the progression-free survival of erlotinib (erlotinib hydrochloride) and bevacizumab versus that of erlotinib alone for the purpose of deciding if the combination arm is worth pursuing in a phase III trial.

SECONDARY OBJECTIVES:

I. To investigate the overall survival of erlotinib and bevacizumab versus erlotinib alone.

II. To investigate the response rate of erlotinib and bevacizumab versus erlotinib alone.

III. To investigate the progression-free survival in patients with exon deletion 19 or exon 21 L858R point mutations.

IV. To investigate the toxicity of erlotinib and bevacizumab versus erlotinib alone using Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.

CORRELATIVE RESEARCH OBJECTIVES:

I. To correlate EGFR mutations detected in plasma deoxyribonucleic acid (DNA) with those detected in tumor DNA.

II. To estimate the prevalence of EGFR T790M resistance mutations from pretreatment tumor biopsies using more sensitive mutation detection methods.

III. To investigate progression free survival of EGFR mutant NSCLC patients with and without concurrent EGFR T790M detected from pre-treatment tumor specimen using allele specific quantitative polymerase chain reaction (PCR).

IV. To prospectively evaluate the predictive value of plasma VEGF-A levels on progression free survival in patients treated with erlotinib alone or in combination with bevacizumab.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM A: Patients receive erlotinib hydrochloride orally (PO) once daily (QD) on days 1-21. (erlotinib will no longer be supplied and all patients will be removed from study treatment. No further follow-up by any study participants as of September 1, 2019)

ARM B: Patients receive erlotinib hydrochloride as in Arm A and bevacizumab intravenously (IV) over 30-90 minutes on day 1. (erlotinib will no longer be supplied and all patients will be removed from study treatment. No further follow-up by any study participants as of September 1, 2019)

In both arms, courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3-6 months for 6 years.

Arms:
arm 1: Patients receive erlotinib hydrochloride PO QD on days 1-21. (erlotinib will no longer be supplied and all patients will be removed from study treatment. No further follow-up by any study participants as of September 1, 2019) arm 2: Patients receive erlotinib hydrochloride as in Arm A and bevacizumab IV over 30-90 minutes on day 1. (erlotinib will no longer be supplied and all patients will be removed from study treatment. No further follow-up by any study participants as of September 1, 2019)

Interventions: intervention 1: Bevacizumab intervention 2: Erlotinib intervention 3: Erlotinib Hydrochloride intervention 4: Laboratory Biomarker Analysis
Intervention descriptions: intervention 1: Given IV intervention 2: Given PO intervention 3: Given PO intervention 4: Correlative studies

Protocol document:
Prot_SAP_000.pdf: 
RC1126 
 
Academic and Community Cancer Research United (ACCRU) 
 
A Randomized Phase II Trial of Erlotinib Alone or In Combination with Bevacizumab in Patients with Non-
Small Cell Lung Cancer and Activating Epidermal Growth Factor Receptor Mutations 
 
For any communications regarding this protocol, please contact 
the protocol resource person on the following page. 
 
Study Chairs 
 
Study Chair: 
Thomas E. Stinchcombe, M.D. (Medical Oncology-ACCRU) 
Duke University  
DUMC 3476 
30 Medical Center Circle 
Room 25177 Morris Bldg 
Durham, NC  27710 
507/284-4565 
507/538-0906 (FAX) 
thomas.stinchcombe@duke.edu 
 
 
 
Study Co-chairs:  
 
 
Statistician:  
 
 
  
Drug Availability  
Drug Company Supplied:  Erlotinib (Commercial supply) and Bevacizumab (Commercial supply) 
 
√ Study contributor(s) not responsible for patient care. 
 
Study Participants 
Date Activated 
ACCRU Membership 
March 16, 2012 
 
Research Coordinating Center 
Academic and Community Cancer Research United 
200 First Street Southwest 
Rochester, MN 55905 
FAX# 507-284-5280 
 
February 2, 2012 
Document History 
(effective date) 
Activation ACCRU 
March 16, 2012 
Addendum 1 
July 20, 2012 
Addendum 2 
February 1, 2013 
Addendum 3 
July 26, 2013 
Addendum 4 
August 1, 2014 
Addendum 5 
June 26, 2015 
Addendum 6 
November 6, 2015 
Addendum 7 
July 22, 2016 
Addendum 8 
June 30, 2017 
Addendum 9 
March 9, 2018 
Addendum 10 
July 26, 2019 


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    2 
      Addendum 10 
Index 
 
Schema 
 
  1.0 
Background 
  2.0 
Goals 
  3.0 
Patient Eligibility 
  4.0 
Test Schedule 
  5.0  
Stratification Factors  
  6.0 
Registration/Randomization Procedures 
  7.0 
Protocol Treatment 
  8.0 
Dosage Modification Based on Adverse Events  
  9.0 
Ancillary Treatment/Supportive Care 
10.0 
Adverse Event (AE) Reporting and Monitoring  
11.0 
Treatment Evaluation Using RECIST Guideline 
12.0 
Descriptive Factors 
13.0 
Treatment/Follow-up Decision at Evaluation of Patient  
14.0 
Body Fluid Biospecimens 
15.0 
Drug Information 
16.0 
Statistical Considerations and Methodology 
17.0 
Pathology Considerations/Tissue Biospecimens 
18.0 
Records and Data Collection Procedures 
19.0 
Budget 
20.0 
References 
 
 
 
 
 
 
 
 
 
 


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    3 
      Addendum 10 
Schema 
NOTE: With amendment 10, Erlotinib (Tarceva) will no longer be supplied by Genentech to participants on this 
study. Therefore, all patients currently taking Erlotinib will be removed from study treatment and have the 
option to transition to the commercial product. No further follow-up will be required by any study participants 
after September 1, 2019.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
*Cycle Length = 21 days 
Therapy will be continued until disease progression, unacceptable toxicity, or patient withdraws consent. 
 
 
 
Generic name: Erlotinib 
Brand name(s): Tarceva 
ACCRU Abbreviation: OSI774 
Availability: ACCRU Research Coordinating Center  
Pharmacy 
Generic name: Bevacizumab 
 
Brand name(s): Avastin 
ACCRU Abbreviation: AVASTN 
Availability: ACCRU Research Coordinating Center  
Pharmacy 
 
Randomization 
(Confirmation of EGFR exon 19 
or exon 21L858R mutation 
required prior to enrollment) 
Arm A* 
Erlotinib 150 mg PO daily 
Arm B* 
Erlotinib 150 mg PO daily 
Bevacizumab 15 mg/kg IV every 
21 days 
Observation 
(21-42 days after 
treatment 
discontinuation) 
Event Monitoring 
PD at any time        
Unacceptable adverse  
 
 
 events    
 
Observation
EM** 
Patient refusal 
Investigator’s decision 
 
** EM= Event Monitoring 
 


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    4 
      Addendum 10 
1.0 
Background  
 
Lung cancer is the leading cause of cancer mortality in the United States, and it is estimated in 2010 
more patients died from lung cancer than colon, breast cancer, and prostate cancer combined.[Jemal et 
al., 2010] Eighty-seven percent of patients with lung cancer will have non-small cell lung cancer 
(NSCLC), and the majority of patients will present with locally advanced or metastatic disease.[Yang et 
al., 2005, Govindan et al., 2006] Tobacco use accounts for 90% of the cases of lung cancer in men, and 
75-85% of the cases in women. Approximately 10-15% of cases of lung cancer occur in patients who 
have never smoked in the United States.[Subramanian et al., 2007] Given the prevalence of lung cancer 
in the United States this represents a substantial patient population. Lung cancer in never smokers 
appears to have a different prognosis and response to therapy.[Nordquist et al., 2004, Dibble et al., 
2005, Tsao et al., 2006] A history of a light or never smoking history is associated with a higher 
response to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) therapy (e.g. 
erlotinib or gefitinib), and this patient population has a higher prevalence of activating EGFR mutations. 
[Pao et al., 2004, Thatcher et al., 2005] Other clinical factors associated with a higher prevalence of 
activating EGFR mutations are adenocarcinoma histology, Asian ethnicity, and female gender.[Pao et 
al., 2005, Thatcher et al., 2005] The prevalence of these mutations in the overall patient population in 
Europe and the United States is estimated to be 10-15%.[Sequist et al., 2007] The prevalence among 
patients with a history of never-smoking in Europe or the United States is estimated to be approximately 
35-40%.[Sequist et al., 2007, Rosell et al., 2009] The specific EGFR mutations that are associated with 
response are deletion of exon 19, and an exon 21 L858R point mutation. Retrospective data suggest that 
patients with NSCLC whose tumors have the exon 19 compared to L858R mutations may have a better 
survival with EGFR TKI therapy. [Jackman et al., 2006, Riely et al., 2006] 
 
Several single arm phase II trials have investigated the efficacy of EGFR TKI therapy in patients whose 
tumors have demonstrated the presence of an activating EGFR mutation. [Asahina et al., 2006, Sequist 
et al., 2008, Inoue et al., 2009] A phase III non-inferiority trial with the primary end-point of PFS 
investigated the efficacy of single agent gefitinib in comparison to carboplatin and paclitaxel was 
performed in Asia. [Mok et al., 2009] Patients were required to have an adenocarcinoma histology, a 
never or light smoking history (defined as ≤ 10 pack years and quit smoking ≥ 15 years ago), and a 
performance status of 0 to 2. Treatment with gefitinib demonstrated superiority in PFS compared to 
carboplatin and paclitaxel (HR = 0.74, 95% CI, 0.65 to 0.85; p<0.001). A higher response rate was 
observed among patients who received treatment of the gefitinib arm in comparison to the carboplatin 
and paclitaxel arm (43% vs. 32.2%, respectively; odds ratio (OR) 1.59 (95% CI, 1.25 to 2.01; p<0.001). 
A lower rate of common toxicity criteria (CTC) grade 3 to 4 treatment related adverse events was 
observed of the gefitinib arm compared to the carboplatin and paclitaxel arm (28.7% versus 61%, 
respectively). A statistically significant higher rate of improvement quality of life (Qol) assessment and 
symptom reduction was observed among patients on gefitinib arm compared to patients on carboplatin 
and paclitaxel arm as assessed by the Functional Assessment of Cancer Therapy-Lung (FACT-L) and 
Trial Outcome Index (TOI). 
 
Of the 1217 randomized patients 437 (35.9%) had samples analyzed for activating EGFR mutations and 
the prevalence of mutations in this clinically enriched patient population was 60% (n=261). Of these 
261 samples, 140 (53.6%) had exon 19 deletions, and 111 (42.5%) had a mutation at exon 21. In the 
subset of patients with evidence of an activating EGFR mutation (n=261) patients who received 
gefitinib experienced a statistically significant improvement in PFS in comparison to patients who 
received carboplatin and paclitaxel (HR=0.48, 95% CI, 0.36 to 0.64; p<0.001; median 9.5 vs. 6.3 
months, respectively). The response rate was significantly higher among patients who received gefitinib 
in comparison to carboplatin and paclitaxel as well (71.2% vs. 47.3%, p<0.001). Conversely among 
patients without evidence of an activating EGFR mutation (n=176) the patients who received gefitinib 
experienced a statistically significant inferior PFS in comparison to patients who received carboplatin 
and paclitaxel (HR=2.85, 95% CI, 2.05 to 3.98; p<0.001). The response rate was significantly lower 
among patients who received gefitinib in comparison to patients who received carboplatin and paclitaxel 
(1.1% vs. 23.5%, OR=0.04, 95% CI, 0.01 to 0.27; p=0.001); one patient responded to the gefitinib. Not 
enough events have occurred to assess the secondary end-point of OS. 


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    5 
      Addendum 10 
 
A phase III trial performed in Japan compared treatment with gefitinib to carboplatin and paclitaxel 
among patients with EGFR mutations and the absence of the resistant EGFR mutation 
T790M.[Maemondo et al., 2010] The primary end-point was PFS, and secondary end-points were 
overall survival, response rate and toxicity. After a planned interim analysis the PFS was significant 
longer among patients in the gefitinib arm compared to the chemotherapy arm resulting in early 
termination of the study after 200 patients had been enrolled. Patients in the gefitinib arm experienced a 
significantly longer PFS (HR=0.30, 95% CI, 0.22 to 0.41; p<0.001; median 10.8 and 5.4 months, 
respectively), higher response rate (73.7% vs. 30.7%, p<0.001), and lower rate of grade ≥ 3 toxicity 
(41.2 vs. 71.7, p<0.001). The median OS observed in the gefitinib and chemotherapy treatment arms 
were 30.5 and 23.6 months, respectively. A second phase III trial in Japan compared gefitinib to 
cisplatin and docetaxel among patients with an EGFR mutation.[Mitsudomi et al., 2010] The primary 
end-point was PFS, and enrollment to this trial was stopped after 177 patients had been enrolled when 
the results of other trials[Mok et al., 2009, Maemondo et al., 2010] had revealed a superior PFS with 
gefitinib among patients with an EGFR mutation were publicly presented. Patients in the gefitinib 
treatment arm experienced a significantly longer PFS (HR=0.489, 95% CI 0.336 to 0.710; p<0.0001; 
median PFS 9.2 and 6.3 months, respectively), and higher response rate (62.1% vs. 32.2%, 
respectively). Not enough events have occurred to assess the secondary end-point of OS. 
 
A separate study performed in Europe screened patients for an activating EGFR mutation, and identified 
mutations in 16.6% of patients and among 37.7% of patients with history as having never smoked.13 In 
the 217 patients who received erlotinib the median PFS and OS observed was 14 months (95% CI, 11.3 
to 16.7) and 27.0 months (95% CI, 22.7 to 31.3), respectively. The PFS and OS were similar in patients 
who received erlotinib as first and second-line therapy. However, poor progressive-free survival was 
associated with the presence of the L858R mutation (HR=1.92; 95% CI, 1.19 to 3.10; p=0.02) as well as 
OS (HR=2.98 (95% CI, 1.48 to 6.04); p=0.002), and on a multivariate analysis of OS the L858R 
mutation was associated with poor prognosis. A randomized phase III trial compared erlotinib to four 
cycles of carboplatin and gemcitabine in patients with an EGFR mutation (n=154); the primary end-
point was PFS. [Zhou et al., 2011] The PFS was significantly longer among patients in the erlotinib arm 
compared to the chemotherapy arm (HR=0.16, 95% CI, 0.10-0.26; p<0.0001; median PFS 13.1 and 4.6 
months, respectively) and the overall response rate was higher as well (83% vs. 36%, p<0.0001). 
Patients assigned to the erlotinib compared to the chemotherapy had a significant improvement in their 
quality of life as assessed by the FACT-L and LCS score (p<0.0001).  A second phase III trial compared 
erlotinib to platinum-based therapy in patients with an EGFR mutation; the primary end-point was PFS. 
[Rosell et al., 2011] The patients assigned to the erlotinib arm compared to the chemotherapy arm 
experienced a significantly longer PFS (HR=0.37, 95% CI, 0.25 to 0.54; p<0.0001); median PFS of 9.7 
and 5.4 months, respectively). The overall response rate in the erlotinib and chemotherapy arm was 58 
and 15%, respectively.  
 
In summary these phase III trials have demonstrated the superiority of EGFR TKI therapy in patients 
with evidence of activating EGFR mutation, and the inferiority of EGFR TKI therapy as initial therapy 
in patients who do not have evidence of an activating EGFR mutation in comparison to standard 
chemotherapy. The IPASS trial demonstrated that clinical criteria alone (smoking history, histology, and 
ethnicity) cannot be used alone to select for patients who may benefit from first-line therapy with EGFR 
TKI therapy. The median PFS observed with EGFR TKI therapy in patients with an activating EGFR 
mutation was 9.2 to 13.1 months on these trials. The current American Society of Clinical Oncology and 
National Comprehensive Cancer Network (NCCN) guidelines recommend first-line EGFR TKI therapy 
for patients with an EGFR mutation.[Azzoli et al., 2009, Ettinger et al., 2010] 
 
 
 


RC1126 
    6 
      Addendum 10 
1.1 
Cancer and Leukemia Group B 30406 
 
Four phase III trials have investigated chemotherapy alone versus in combination with EGFR 
TKI therapy in unselected patient populations.[Giaccone et al., 2004, Herbst et al., 2004, Herbst 
et al., 2005, Gatzemeier et al., 2007] On a retrospective analysis of patients with a history of 
never smoking (n=72) who received chemotherapy in combination with erlotinib (n=28) had a 
superior survival to patients who received chemotherapy alone (n=44) (HR=0.49, 95% CI 0.28 
to 0.85; median overall survival of 22.5 vs. 10.1 months).[Herbst et al., 2005] These data led to 
the development of Cancer and Leukemia Group (CALGB) trial 30406, a randomized phase II 
trial of erlotinib alone or in combination with carboplatin and paclitaxel in patients with 
adenocarcinoma and a light or never smoking history.[Janne et al., 2010] The primary end-point 
was PFS, and the trial was not designed to compare the two treatment arms. In the erlotinib 
alone arm (n=81) the PFS and OS observed was 6.7 months (95% CI, 4.0 to 8.3) and 24.3 
months (95% CI, 18.4 to 31.3), respectively. In the chemotherapy and erlotinib arm the PFS and 
OS observed was 6.6 months (95% CI, 5.4 to 8.2) and 19.6 (95% CI, 14.4 to 28.7), respectively. 
Among patients in the erlotinib arm with an EGFR mutation (n=33) the PFS and OS observed 
were 15.7 months (95% CI, 8.6 to 20.4) and 31.3 months (95% CI, 23.8 to 42.8), respectively. 
Patients with an activating EGFR mutation (n=33) compared to EGFR wild-type (n=44) 
experienced a statistically significant longer PFS and OS in the erlotinib alone arm. Among 
patients with an activating EGFR mutation (n=33) in the erlotinib with carboplatin and 
paclitaxel arm the PFS and OS observed were 17.2 months (95% CI, 10.3 to not available (NA)) 
and 39.0 (95% CI, 38.1 to NA), respectively. In the erlotinib and chemotherapy treatment arm 
the patients with activating EGFR mutation (n=33) compared to the EGFR wild-type (n=54) 
experienced a statistically significant longer PFS and OS. Patients in the erlotinib and 
chemotherapy arm experienced a numerically higher rate of hematologic and non-hematologic 
toxicity compared to patients in the erlotinib alone arm.  
 
1.2 
Bevacizumab 
 
In addition to the development of EGFR TKI therapy for advanced NSCLC the development of 
anti-angiogenesis therapy has been an area of active investigation. Two phase III trials have 
been performed comparing standard platinum-based therapy with and without bevacizumab, a 
monoclonal antibody directed against vascular endothelial growth factor (VEGF), in patients 
with chemotherapy naïve advanced NSCLC.[Sandler et al., 2006, Reck et al., 2009; 2010] 
Eastern Oncology Group (ECOG) trial 4599, compared carboplatin and paclitaxel with and 
without bevacizumab, and revealed a statistically significantly superior response rate (35% vs. 
15%, p<0.001) , PFS (HR=0.66, 95% CI, 0.57 to 0.77; p< 0.001; median 6.2 and 4.5 months) 
and OS (HR=0.79, 95% CI, 0.67 to 0.92; p=0.003) with the addition bevacizumab to platinum-
based chemotherapy.[Sandler et al., 2006] A second phase III trial compared cisplatin, 
gemcitabine, and placebo to the cisplatin and gemcitabine with bevacizumab 7.5 mg/kg or 15 
mg/kg every 3 weeks with the primary end-point of PFS, and secondary end-point of OS.[Reck 
et al., 2009; 2010] Patients in cisplatin, gemcitabine, and bevacizumab 7.5 mg/kg treatment arm 
compared to cisplatin, gemcitabine, and placebo arm experienced a superior response rate 
(34.1% vs. 20.1%, p<0.0001) and PFS (HR=0.75, 95% CI, 0.62 to 0.91; p=0.003; median PFS 
6.7 and 6.1 months, respectively), but no improvement in OS (HR=093, 95% CI, 0.78 to 1.11; 
p=0.420; median OS 13.6 and 13.1 respectively). Patients in the cisplatin, gemcitabine, and 
bevacizumab 15 mg/kg compared to the cisplatin, gemcitabine, and placebo arm experienced a 
superior response rate (30.4% vs. 20.1%; p=-.0023), and PFS (HR=0.82, 95% CI, 0.68 to 0.98; 
p=0.03: median PFS 6.5 and 6.1 months, respectively), but no difference is OS (HR=1.03, 95% 
CI, 0.86 to 1.23; p=0.761, median OS 13.4 and 13.1 months, respectively).  
 
 
 


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      Addendum 10 
A single arm phase II trial revealed promising activity of the combination of erlotinib and 
bevacizumab in patients who had progressed after previous chemotherapy.[Herbst et al., 2011] 
A phase III trial compared erlotinib alone or in combination with bevacizumab in patients who 
had progressed on chemotherapy (n=650) with the primary end-point of overall survival. The 
overall survival was not different between the erlotinib and bevacizumab in comparison to 
erlotinib and placebo (HR=0.97, 955 CI, 0.80-1.18; p=0.7583; median OS 9.3 and 9.2 months, 
respectively).Patients who received erlotinib and bevacizumab in comparison to patients who 
received erlotinib experienced a statistically significant higher response (13% vs. 6%, p=0.006), 
and improved PFS (HR=0.62, 95% CI, 0.52 to 0.75; p<0.0001, median PFS 3.4 and 1.7 months. 
respectively). In the subset of patients with a history of never smoking (n=67) the combination 
therapy demonstrated a statistically significantly superior PFS (HR=0.39 (95% CI, 020 to 0.74: 
p=0.0295) and OS (HR=0.44, 95% CI, 0.21 to 0.94; p=0.0295). Of the 636 patients enrolled 
tumor samples were available on 477 patients. In a subset analysis of patients with activating 
EGFR mutation (n=30) the combination of erlotinib and bevacizumab (n=12) demonstrated a 
numerically superior PFS in comparison to erlotinib and placebo (n=18); HR=0.52, 95% CI, 
0.19 to 1.38); median PFS of 17.1 months vs. 9.7 months).[Herbst et al., 2009] The overall 
survival observed in the erlotinib and bevacizumab was numerically superior to erlotinib and 
placebo (HR=0.44, 95% CI, 0.11 to 1.67; median survival time  not reached and 20.2 months, 
respectively).[Herbst et al., 2011]. 
 
A phase II trial investigated erlotinib compared to erlotinib and bevacizumab in patients with an 
EGFR exon 19 deletion or exon 21 L858R mutations [Seto et al 2014]. The primary end-point 
was PFS by independent radiological review and 154 patients were enrolled. Patients assigned 
to the erlotinib and bevacizumab compared to the erlotinib alone arm experienced a statistically 
significant difference in PFS (HR of 0.54, 95% CI, 0.36 to 0.79; p=0.0015: median 16.0 and 9.7 
months).  In a subset analysis, patients with exon 19 deletion mutations (n=80) who received 
erlotinib and bevacizumab compared to erlotinib alone experienced statistically significant 
longer PFS (HR of 0.41, 95% CI, 0.24 to 0.72; p=0.0011; median PFS of 18.0 and 10.3 months, 
respectively). In a subset analysis patients exon 21 L858R mutations (n=72) who received 
erlotinib and bevacizumab compared to erlotinib experienced a numerically longer PFS (HR of 
0.67, 95% CI< 0.38 to 1.18; p=0.01653; median PFS of 13.9 and 7.1 months, respectively). The 
most common grade ≥ 3 adverse events in the erlotinib/bevacizumab and erlotinib arms were 
rash (25% vs. 19%), hypertension (60% vs. 10%), and proteinuria (8% vs.0%). 
 
At the time the trial was written treatment anti-coagulation was a relative contraindication for 
treatment with bevacizumab. Since the initiation of the trial additional data has revealed that the 
treatment of patients on anticoagulation do not experience an increased risk of severe bleeding 
events.  [Leighl et al 2011] Importantly, no episodes of severe pulmonary hemorrhage were 
observed in patients on therapeutic anticoagulation. Several recently completed trials of 
bevacizumab in advanced NSCLC have allowed patients on therapeutic anticoagulation to be 
enrolled or remain on trial if full dose anticoagulation is required. [Reck et al 2009] Additional 
safety data is available from the phase IV Safety of Avastin in Lung cancer study (SAiL) of 
2,212 patients which did not reveal an increased risk of bleeding events with concomitant use of 
bevacizumab and anticoagulation.  [Crino et al 2010]. The current Eastern Cooperative 
Oncology Group trial which is investigating bevacizumab in combination with carboplatin and 
paclitaxel allows for full dose anti-coagulation (NCT01107626). Thus, we are amending the 
trial to allow full dose anti-coagulation. 
 
 
 


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      Addendum 10 
The management of patients with brain metastases receiving bevacizumab has changed since 
the time the protocol was written. The original protocol was based on a phase II trial the 
eligibility criteria were based on bevacizumab starting 4 weeks after completion of radiation 
therapy to brain metastases.[Socinski et al., 2009] A prospective phase II trial demonstrated the 
safety of using bevacizumab with first-line chemotherapy or second-line erlotinib in patients 
with asymptomatic untreated brain metastases.[Besse et al., 2013] In addition to the data from 
treatment of patients with NSCLC and brain metastases there are data several phase III trials 
have investigated the role of bevacizumab in the treatment of glioblastoma. A phase III trial 
initiated bevacizumab week 4 of a 6 week course of radiotherapy in combination with 
temozolomide.[Gilbert et al., 2014] A second phase III trial in glioblastoma initiated 
bevacizumab concurrently with temozolomide and radiation, and continued bevacizumab after 
completion of radiation therapy.[Chinot et al., 2014] In order to be consistent with literature and 
other trials investigating bevacizumab (e.g. Eastern Cooperative Oncology Group 5508, 
NCT01107626) we have amended the trial so that patients with treated brain metastases would 
be eligible if ≥ 2 weeks since completion of any radiotherapy and radiation therapy for 
treatment of brain metastases.  
 
1.3 
Epidermal Growth Factor Tyrosine Kinase Inhibitor Resistance 
 
Despite the significant effects of EGFR TKIs in EGFR mutant NSCLC, all patients eventually 
develop resistance to single agent EGFR TKI treatment. This typically occurs between 8-14 
months from initiating treatment. Two common mechanisms of acquired resistance to gefitinib 
and erlotinib have been identified; secondary mutations in EGFR itself (EGFR T790M) or 
amplification of the MET oncogene.[Kobayashi et al., 2005, Pao et al., 2005, Shih et al., 2005, 
Kosaka et al., 2006, Bean et al., 2007, Engelman et al., 2007] In addition, a recent study 
suggested that EGFR T790M may pre-exist in EGFR mutant caners prior to gefitinib or 
erlotinib treatment [Maheswaran et al., 2008]. Those patients in whom a pre-treatment EGFR 
T790M was detected (n=10) had a shorter time to disease progression than patients without 
detectable EGFR T790M (N=16), 7.7 months and 16.5 months (p<0.001).[Maheswaran et al., 
2008] The detection of the T790M can be difficult because of allelic dilution due to the fact that 
the EGFR gene is amplified but only a few copies of T790M allele are needed to confer 
resistance which may obscure results with conventional sequencing methods.[Janne, 2008] 
 
As resistance occurs in all patients, it is critical to identify effective treatments for EGFR mutant 
NSCLC patients that may overcome acquired resistance or prevent or delay the emergence of 
acquired resistance. Unfortunately, repeat biopsies to detect the mechanisms of EGFR TKI 
resistance frequently are not feasible and/or associated with risk to the patient which may be 
difficult to justify given the poor prognosis associated with advanced stage NSCLC. The issue 
is further complicated by the fact that many biopsies provide insufficient material for molecular 
analysis.  
 
The tumor specimens from this trial will provide a valuable resource in which to perform 
correlative studies on EGFR mutations. These include the ability to correlate plasma detected 
EGFR mutations with tumor EGFR mutations and to study the pre-existence of erlotinib 
resistance mechanisms. This trial can prospectively assess whether patients with pre-existing 
EGFR T790M mutations have a shorter TTP with erlotinib (or erlotinib/bevacizumab) 
treatment. If so, such findings would have significant future therapeutic implications including 
the use of second generation irreversible EGFR inhibitors as initial therapy 
 
 
 


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      Addendum 10 
1.4 
Epidermal Growth Factor Receptor mutation testing 
 
The testing for the EGFR mutation will be performed prior to enrollment on this clinical trial. 
The results of the IPASS and other phase III trials have led to EGFR mutational testing 
becoming more prevalent, particularly in patient populations clinically likely to have a high 
prevalence of activating EGFR mutations. In recent months an increasing percentage of patients 
who present for a second opinion have previously undergone EGFR mutational analysis prior to 
their appointment indicating that this practice has already gained acceptance among community 
oncologists. For enrollment in the trial the EGFR mutation testing must be performed at Clinical 
Laboratory Improvement Amendments (CLIA) certified lab; either institutional or through a 
commercial laboratory (e.g. Genzyme, Response Genetics, etc).  The laboratory reports from 
the commercial laboratories report the specific mutations detected, including the exon 19 and 
exon 21 L858R point mutations.  
 
 
2.0 
Goals 
 
2.1 
Primary  
 
2.11 
To determine the progression-free survival of erlotinib and bevacizumab versus that of 
erlotinib alone for the purpose of deciding if the combination arm is worth pursuing in a 
phase III trial. 
 
2.2 
Secondary 
 
2.21 
To investigate the overall survival of erlotinib and bevacizumab versus erlotinib alone. 
 
2.22 
To investigate the response rate of erlotinib and bevacizumab versus erlotinib alone. 
 
2.23 
To investigate the progression-free survival in patients with exon deletion 19 or exon 21 
L858R point mutations. 
 
2.24 
To investigate the toxicity of erlotinib and bevacizumab versus erlotinib alone using 
CTCAE version 4.0. 
 
2.3 
Correlative Research 
 
2.31 
To correlate EGFR mutations detected in plasma DNA with those detected in tumor 
DNA. 
 
2.32 
To estimate the prevalence of EGFR T790M resistance mutations from pre-treatment 
tumor biopsies using more sensitive mutation detection methods. 
 
2.33 
To investigate progression free survival of EGFR mutant NSCLC patients with and 
without concurrent EGFR T790M detected from pre-treatment tumor specimen using 
allele specific quantitative PCR. 
 
2.34 
To prospectively evaluate the predictive value of plasma VEGF-A levels on progression 
free survival in patients treated with erlotinib alone or in combination with 
bevacizumab. 
 
 
 


RC1126 
    10 
      Addendum 10 
3.0 
Patient Eligibility 
 
3.1 
Inclusion Criteria 
 
3.11 
Age ≥18 years. 
 
3.12 
Histologic documentation of primary lung carcinoma, non-squamous histology with 
activating epidermal growth factor receptor (defined as deletion 19 or exon 21 L858R 
mutation). Note:  EGFR mutation testing must be performed at a Clinical Laboratory 
Improvement Amendments (CLIA) certified lab; either institutional or through a 
commercial laboratory (e.g. Genzyme, Response Genetics, etc). The laboratory report 
from the commercial laboratories report the specific mutations detected, and the method 
of detecting the exon 19 and exon 21 L858R point mutations must be available.  
 
3.13 
Stage IV disease according to the 7th Edition of the American Joint Committee on 
Cancer staging system [Goldstraw et al., 2007] 
 
3.14 
Measureable disease as defined in Section 11.0 [Eisenhauer et al., 2009]. 
 
3.15 
Life expectancy of ≥12 months. 
 
3.16 
ECOG Performance Status (PS) 0 or 1 (See Appendix III). 
 
3.17 
The following laboratory values obtained ≤ 14 days prior to randomization. 
 
• 
ANC ≥ 1, 500 / mm3 
• 
Platelet count, ≥ 100,000 / mm3 
• 
Hemoglobin ≥ 9.0 g / dL 
• 
Total bilirubin ≤ 1.5 x upper limit of normal (ULN) 
• 
SGOT (AST) and SGPT (ALT) ≤2.5 x ULN in patients without liver or bone 
metastases; < 5 x ULN in patients with liver or bone metastases. 
• 
Cockcroft-Gault calculated creatinine clearance of ≥ 45 ml/min* or creatinine ≤1.5 
x ULN 
• 
Urine dipstick proteinuria <2+ or urine protein/creatinine (UPC) ratio ≤1.0 
 
Note: Patients discovered to have ≥2 + proteinuria on dipstick urinalysis at baseline 
should undergo a 24-hour urine collection and must demonstrate ≤ 1 g of protein in 
24 hours. 
 
* Cockcroft-Gault formula: 
 
 
 
Cockcroft-Gault Equation: 
 
Creatinine clearance for males =   
(140 - age)(weight in kg) 
 
 
 
 
 
 
 
 
 
(72)(serum creatinine 
in mg/dL) 
 
Creatinine clearance for females =   
(140 - age)(weight in kg)(0.85) 
 
 
 
 
 
 
(72)(serum creatinine in mg/dL) 


RC1126 
    11 
      Addendum 10 
3.18 
Negative pregnancy test done ≤7 days prior to randomization, for women of 
childbearing potential only. 
 
3.19a 
Provide informed written consent. 
 
3.19b Willing to return to ACCRU enrolling institution for follow-up. 
 
3.19c 
Willing to provide tissue and blood samples for correlative research purposes (see 
Sections 6.0, 14.0 and 17.0)  
 
3.2 
Exclusion Criteria 
 
3.21 
Mixed, non-small cell and small cell tumors or mixed adenosquamous carcinomas with 
a predominant squamous component. 
 
3.22 
Prior chemotherapy or treatment for metastatic non-small cell lung cancer.  
 
3.23 
Any of the following because this study involves an investigational agent whose 
genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are 
unknown  
 
• 
Pregnant women 
• 
Nursing women 
• 
Men or women of childbearing potential who are unwilling to employ adequate 
contraception  
 
3.24 
Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment 
of the investigator, would make the patient inappropriate for entry into this study or 
interfere significantly with the proper assessment of safety and toxicity of the 
prescribed regimens. 
 
3.25 
Immunocompromised patients (other than that related to the use of corticosteroids) 
including patients known to be HIV positive, per MD discretion. 
 
3.26 
Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection, or psychiatric illness/social situations, or any other medical condition that 
would limit compliance with study requirements. 
 
3.27 
Receiving any other investigational agent which would be considered as a treatment for 
the primary neoplasm. 
 
3.28 
Other active malignancy ≤ 3 years prior to randomization.  EXCEPTIONS:  Non-
melanotic skin cancer or carcinoma-in-situ of the cervix.  NOTE:  If there is a history of 
prior malignancy, they must not be receiving other specific treatment (i.e. hormonal 
therapy) for their cancer.  
 
3.29a 
History of myocardial infarction or other evidence of arterial thrombotic disease 
(angina), symptomatic congestive heart failure (New York Heart Association  ≥  grade 
2), unstable angina pectoris, or cardiac arrhythmia . Note:   Allowed only if patient has 
no evidence of active disease for at least 6 months prior to randomization.  
 
 
 


RC1126 
    12 
      Addendum 10 
3.29b History of cerebral vascular accident (CVA) or transient ischemic attack (TIA) ≤6 
months prior to randomization. 
 
 
3.29c 
History of bleeding diathesis or coagulopathy. 
 
3.29d Inadequately controlled hypertension (systolic blood pressure of >150 mmHg or 
diastolic pressure >100 mmHg on anti-hypertensive medications). Note:  History of 
hypertensive crisis or hypertensive encephalopathy not allowed. 
 
3.29e 
Current or recent (≤10 days prior to randomization) use of aspirin (>325 mg/day), 
clopidogrel (> 75 mg/day), or prasugrel (> 10 mg/day).  
 
3.29f 
Serious non-healing wound, ulcer, bone fracture, or have undergone a major surgical 
procedure, open biopsy, or significant traumatic injury ≤ 28 days or core biopsy ≤ 7 
days prior to randomization.  
 
3.29g History of abdominal fistula, gastrointestinal perforation, or intraabdominal abscess ≤6 
months prior to randomization.  
 
3.29h Known hypersensitivity to Chinese hamster ovary cell products or other recombinant 
human antibodies.  
 
3.29i 
History of hemoptysis ≥grade 2 (defined as bright red blood of at least 2.5 mL) 
 ≤ 3 months prior to randomization. 
 
3.29j 
Known CNS disease, except for treated brain metastasis. Note:  Treatment for brain 
metastases may include whole brain radiotherapy (WBRT), radiosurgery (RS); Gamma 
Knife, LINAC, or equivalent) or a combination as deemed appropriate by the treating 
physician.  Patients with CNS metastases treated by neurosurgical resection or brain 
biopsy performed ≤3 months prior to randomization will be excluded. Note: 
Craniotomy or intracranial biopsy site must be adequately healed, free of drainage or 
cellulitis, and the underlying cranioplasty must appear intact at the time of 
randomization. Study treatment should be initiated > 28 days following the last surgical 
procedure (including biopsy, surgical resection, wound revision, or any other major 
surgery involving entry into a body cavity). 
 
3.29k Significant vascular disease (e.g. aortic aneurysm surgical repair or recent peripheral 
arterial thrombosis) ≤6 months prior to randomization. 
 
3.29l 
Radiotherapy to any site for any reason ≤ 14 days prior to randomization. 
 
3.29m Receiving any medications or substances that are strong or moderate inhibitors of 
CYP3A4. 
 
 
 


RC1126 
    13 
      Addendum 10 
Use of the following strong or moderate inhibitors is prohibited < 7 days prior to randomization: 
 
Strong Inhibitors of CYP3A4  
> 5-fold increase in the plasma AUC values or more than 80% decrease in clearance 
Indinavir (Crixivan®) 
Nelfinavir (Viracept®) 
Atazanavir (Reyataz®)  
Ritonavir (Norvir®) 
Clarithromycin (Biaxin®, Biaxin XL®) 
Itraconazole (Sporanox®) 
Ketoconazole (Nizoral®) 
Nefazodone (Serzone®) 
Saquinivir (Fortovase®, Invirase®) 
Telithromycin (Ketek®) 
Moderate Inhibitors of CYP3A4 
> 2-fold increase in the plasma AUC values or 50-80% decrease in clearance 
Aprepitant (Emend®) 
Erythromycin (Erythrocin®, E.E.S. ®, Ery-Tab®, Eryc®, EryPed®, PCE® 
Fluconazole (Diflucan®) 
Grapefruit juice 
Verapamil (Calan®, Calan SR®, Covera-HS®, Isoptin SR®, Verelan®, Verelan PM®) 
Diltiazem (Cardizem®, Cardizem CD®, Cardizem LA®, Cardizem SR®, Cartia XT™, Dilacor 
XR®, Diltia XT®, Taztia XT™, Tiazac®) 
 
3.29n Receiving any medications or substances that are inducers of CYP3A4. 
 
Use of the following inducers are prohibited < 7 days prior to randomization: 
 
Inducers of CYP3A4 
Efavirenz (Sustiva®) 
Nevirapine (Viramune®) 
Carbamazepine (Carbatrol®, Epitol®, Equetro™, Tegretol®, Tegretol-XR®) 
Modafinil (Provigil®) 
Phenobarbital (Luminal®) 
Phenytoin (Dilantin®, Phenytek®) 
Pioglitazone (Actos®) 
Rifabutin (Mycobutin®) 
Rifampin (Rifadin®) 
St. John’s wort 
 
 


RC1126 
                                                       15 
 
 
 
     Addendum 9 
4.0 
Test Schedule 
 
Tests and Procedures 
Active Monitoring Phase 
≤14 days prior 
to 
randomization 
Prior to 
each cycle 
(≤ 7 days) 
Re-staging every 2 
cycles for 18 months 
from randomization, 
then every 4 cycles 
until disease 
progression 
At PD, 
withdrawal, or 
removal12 
Observation4,12 
(21-42 days after treatment 
discontinuation) 
History and exam including weight, blood 
pressure, smoking history 
X 
X5, 8 
 
 
X 
ECOG PS 
X 
X 
 
X 
X 
Adverse event assessment 
X 
X9 
 
 
X 
Urine dipstick proteinuria or urine protein 
creatinine ratio  
X 
X 
 
 
 
Hematology: CBC/ differential, PT/INR6, 
PTT6  
X 
 
X7 
 
 
 
 
 
 
 
Chemistry: SGOT (AST), SGPT (ALT), alk 
phos, T. bili, creatinine, calcium, phosphorus, 
glucose, Na, K 
X 
X6,7 
 
 
 
 
 
 
Tumor measurement (see Section 11.0) 
X11 
 
X3 
X 
X 
MRI or CT scan of brain10 
X 
 
 
 
 
Pregnancy test 
X1 
 
 
 
 
Mandatory blood sample (see Section 14.0)2, R 
X 
 
X 
X 
 
Mandatory tissue sample (see Section 17.3)R 
X 
 
 
 
 
 
 
 


RC1126 
    15 
      Addendum 10 
1. For women of childbearing potential only.  Must be done ≤ 7 days prior to randomization. 
2. See Section 14.241.  Kits are required for this collection. Research blood sample to be drawn prior to treatment. 
3. Patients should undergo imaging for disease progression every 2 cycles for the initial 18 months, then after 18 months every 4 cycles until 
disease progression. Submit relevant radiographic images as a digital image (via CD) with a viewing tool free of marks that may obscure 
the lesions or bias the evaluation of the independent reviewer(s) of tumor response at baseline and tumor response and/or progression. 
Submit CD’s to the A
 
 
4. All patients (including those who have left the study because of progressive disease, unacceptable toxicity, patient refusal, investigator’s 
decision to remove patient, etc) must have a toxicity check at this time point. 
5. Hypertensive medication should be initiated or increased per routine practice. 
 
6. PT/INR, PTT, glucose, calcium, phosphorus, Na, and K at baseline and then only as clinically indicated. 
7. Only SGOT (AST), SGPT (ALT), alk phos, T. bili, and CBC/differential checked on Day 1 of each cycle. 
8. Smoking history collected only at baseline. 
9. Prior to subsequent cycle. 
10. MRI is the preferred test for imaging for brain metastases, CT scan with contrast is acceptable for patients who are unable or intolerant of 
undergoing MRI of the brain. Patients must have either MRI or CT scan prior to randomization. MRI and CT scans should be done < 28 
days prior to randomization. 
11. Tumor measurements should be done < 28 days prior to randomization. 
12. Patients who discontinue study therapy prior to disease progression should be followed until disease progression. The schedule of follow-
up imaging is at the discretion of physician, but an interval of 6 to 12 weeks is recommended.  
R Research funded (see Section 19.0) 


RC1126 
16 
Addendum 10 
5.0 
Stratification Factors  
 
5.1 
Gender: Male vs. female. 
 
 
 
5.2 
Mutation type: Exon 19 vs. Exon 21 L858R. 
 
 
6.0 
Registration/Randomization Procedures 
 
6.1 
Randomization Procedures 
 
6.11 
To register a patient, access the ACCRU web page at 
click on “Training Page” and enter the 
registration/randomization application.  The registration/randomization application is 
available 24 hours a day, 7 days a week.  Back up and/or system support contact 
information is available on the Web site.  If unable to access the Web site, call the 
Academic and Community Cancer Research United (ACCRU) Registration Office at 
 the hours of 8 a.m. and 4:30 p.m. Central Time (Monday through 
Friday). 
 
The instructions for the registration/randomization application are available by using the 
Help button.  Prior to initiation of protocol study intervention, this process must be 
completed in its entirety and a ACCRU subject ID number must be available as noted in the 
instructions.  It is the responsibility of the individual and institution registering the patient to 
confirm the process has been successfully completed prior to release of the study agent.  
Patient registration via the registration/randomization application can be confirmed in any 
of the following ways: 
 
• 
Contact the ACCRU Registration Office 
  If the patient was fully 
registered, the ACCRU Registration Office staff can access the information from 
the centralized database and confirm the registration. 
• 
Refer to “Instructions for Remote Registration” in section “Finding/Displaying 
Information about A Registered Subject.” 
 
6.12 
Correlative Research 
 
A mandatory correlative research component is part of this study, the patient will be 
automatically registered onto this component (see Sections 3.0, 14.0 and 17.0). 
 
6.13 
Documentation of IRB approval must be on file in the Registration Office before 
an investigator may register any patients.  
 
In addition to submitting initial IRB approval documents, ongoing IRB approval 
documentation must be on file (no less than annually) at the Registration Office (fax: 
507-284-0885).  If the necessary documentation is not submitted in advance of 
attempting patient registration, the registration will not be accepted and the patient may 
not be enrolled in the protocol until the situation is resolved. 
 
When the study has been permanently closed to patient enrollment, submission of 
annual IRB approvals to the Registration Office is no longer necessary. 
 
 
 


RC1126 
17 
Addendum 10 
6.14 
Prior to accepting the registration/randomization, the registration/randomization 
application will verify the following: 
 
• 
IRB approval at the registering institution 
• 
Patient eligibility 
• 
Existence of a signed consent form 
• 
Existence of a signed authorization for use and disclosure of protected health 
information   
 
6.15 
At the time of randomization, the following will be recorded: 
 
• 
Patient has/has not given permission to store and use his/her blood for future 
research to learn about, prevent, or treat cancer. 
• 
Patient has/has not given permission to store and use his/her blood for future 
research to learn, prevent, or treat other health problems (for example:  diabetes, 
Alzheimer’s disease, or heart disease). 
• 
Patient has/has not given permission to store and use his/her tissue for future 
research to learn about, prevent, or treat cancer. 
• 
Patient has/has not given permission to store and use his/her tissue for future 
research to learn, prevent, or treat other health problems (for example:  diabetes, 
Alzheimer’s disease, or heart disease). 
• 
Patient has/has not given permission for ACCRU to give his/her sample(s) to 
outside researchers. 
 
6.16 
Treatment cannot begin prior to randomization and must begin ≤14 days after 
randomization. 
 
6.17 
Pretreatment tests/procedures (see Section 4.0) must be completed within the guidelines 
specified on the test schedule. 
 
6.18 
All required baseline symptoms (see Section 10.5) must be documented and graded. 
 
6.19a 
Treatment on this protocol must commence at an ACCRU institution under the 
supervision of a medical oncologist. 
 
6.19b Study drug is available on site.  
 
6.19c 
Blood draw kit is available on site.  
 
6.2 
Randomization Procedures 
 
6.21 
The factors defined in Section 5.0, together with the registering membership, will be 
used as stratification factors. 
 
6.22 
After the patient has been registered into the study, the values of the stratification 
factors will be recorded, and the patient will be assigned to one of the following 
treatment groups using the Pocock and Simon dynamic allocation procedure which 
balances the marginal distributions of the stratification factors between the treatment 
groups (Pocock and Simon 1975. [Pocock et al., 1975] 
 
• 
Arm A: Erlotinib 150 mg daily 
• 
Arm B: Erlotinib 150 mg daily and bevacizumab 15 mg/kg every 21 days 
 
 


RC1126 
18 
Addendum 10 
7.0 
Protocol Treatment 
 
7.1 
Treatment Schedule - Use actual weight or estimated dry weight if fluid retention 
 
Patients will be randomized between arm A (erlotinib alone) and arm B (erlotinib and 
bevacizumab), and will continue treatment until disease progression according to response 
evaluation criteria for solid tumors (RECIST) 1.138or unacceptable toxicity. One cycle will 
considered 21 days on both treatment arms. Patients will be assessed for response using the 
radiological test used at baseline every 2 cycles for the initial 18 months, and then every 4 
cycles until disease progression from time to randomization. 
 
Arm 
Agent 
Dose Level 
Route 
Day 
ReRx 
A 
Erlotinib 
150 mg 
PO 
Daily 
Every 21 
days 
B 
Erlotinib 
150 mg 
PO 
Daily 
Bevacizumab* 
15 mg/kg 
IV 
1 
 
* The first dose will be administered over 90 (+ 10) minutes. If well-tolerated, the second dose 
may be administered over 60 (± 10) minutes. Again, if well-tolerated, subsequent doses may be 
administered over 30 (± 10) minutes. If the patient is pre-medicated for infusion reaction, 
maintain previous infusion rate for first pre-medicated infusion. If well-tolerated with pre-
medication, the subsequent infusion time may then be decreased by 30 minutes, as long as the 
subject continues to be pre-medicated. If the patient experiences infusion associated adverse 
events with the 60-minute infusion, all subsequent infusions should be given over 90 minutes. 
Similarly, if a patient experiences infusion associated adverse events with the 30-minute 
infusion, all subsequent doses should be given over 60 minutes. 
 
7.2 
Erlotinib only: Patients can be instructed in administration techniques and granted treatment 
independence with nursing staff approval. 
 
7.3 
For this protocol, the patient must return to an ACCRU institution for evaluation at least every 
21 days (+/- 7 days). 
 
7.4 
Treatment by a local medical doctor (LMD) is not allowed. 
 
 
8.0 
Dosage Modification Based on Adverse Events  
 
Strictly follow the modifications in this table for the first two cycles, until individual treatment tolerance 
can be ascertained. Thereafter, these modifications should be regarded as guidelines to produce mild-to-
moderate, but not debilitating, side effects. If multiple adverse events are seen, administer dose based on 
greatest reduction required for any single adverse event observed. Reductions or increases apply to 
treatment given in the preceding cycle and are based on adverse events observed since the prior dose. If 
patients discontinue either agent, they will go to observation and event monitoring. 
 
 
ALERT: 
ADR reporting may be required for some adverse events (See Section 10) 
 
 
 
 


RC1126 
19 
Addendum 10 
8.1  
Bevacizumab:  This section applied to adverse events associated with bevacizumab.  For 
Adverse events associated with erlotinib, please refer to Section 8.2. 
  Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0* unless 
otherwise specified   
CTCAE 
System/Organ/Class 
(SOC) 
ADVERSE 
EVENT 
ACTION** 
BASED ON OBSERVED ADVERSE EVENT 
CARDIAC 
DISORDERS 
Left Ventricular 
Systolic 
Dysfunction 
 
Grades 1-2 
No dose modifications 
Grade 3 
Omit bevacizumab until resolution to Grade ≤1. 
Grade 4 
Discontinue bevacizumab, go to observation and event 
monitoring. 
Myocardial 
Infarction 
 
Any Grade 
Discontinue bevacizumab, go to observation and event 
monitoring. 
GASTROINTESTINAL 
DISORDERS 
 
Rectal Perforation 
 
Any Grade 
Discontinue bevacizumab, go to observation and event 
monitoring. 
Small Intestinal 
Perforation 
 
Any Grade 
Discontinue bevacizumab, go to observation and event 
monitoring. 
Colonic Perforation 
 
Any Grade 
Discontinue bevacizumab, go to observation and event 
monitoring. 
Gastric Perforation 
 
Any Grade 
Discontinue bevacizumab, go to observation and event 
monitoring. 
Colonic Obstruction 
 
Grade 1 
Continue patient on study for partial obstruction NOT 
requiring medical intervention. 
Grade 2 
Omit bevacizumab for partial obstruction requiring 
medical intervention. Patient may restart upon complete 
resolution. 
Grade 3-4 
Omit bevacizumab for complete obstruction. If surgery is 
necessary, patient may restart bevacizumab after full 
recovery from surgery, and at investigator’s discretion. 
Small Intestinal 
Obstruction 
 
Grade 1 
Continue patient on study for partial obstruction NOT 
requiring medical intervention. 
Grade 2 
Omit bevacizumab for partial obstruction requiring 
medical intervention. Patient may restart upon complete 
resolution. 
Grade 3-4 
Omit bevacizumab for complete obstruction. If surgery is 
necessary, patient may restart bevacizumab after full 
recovery from surgery, and at investigator’s discretion. 
Anal Hemorrhage 
 


RC1126 
20 
Addendum 10 
Grade 1 or 2 
No dose modifications. 
Grade 3 
Subjects who are also receiving full-dose anticoagulation 
will be discontinued from receiving bevacizumab. 
All other subjects will have bevacizumab omitted until all 
of the following criteria  are met: 
 
• 
The bleeding has resolved and hemoglobin is stable. 
• 
There is no bleeding diathesis that would increase the 
risk of therapy. 
• 
There is no anatomic or pathologic condition that 
significantly increases the risk of hemorrhage 
recurrence. 
 
Subjects who experience a repeat Grade 3 hemorrhagic 
event will be discontinued from receiving bevacizumab, 
go to observation and event monitoring. 
Grade 4 
Discontinue bevacizumab, go to observation and event 
monitoring. 
Colonic 
Hemorrhage 
 
Grade 1 or 2 
No dose modifications. 
Grade 3 
Subjects who are also receiving full-dose anticoagulation 
will be discontinued from receiving bevacizumab. 
All other subjects will have bevacizumab omitted until all 
of the following criteria  are met: 
 
• 
The bleeding has resolved and hemoglobin is stable. 
• 
There is no bleeding diathesis that would increase the 
risk of therapy. 
• 
There is no anatomic or pathologic condition that 
significantly increases the risk of hemorrhage 
recurrence. 
 
Subjects who experience a repeat Grade 3 hemorrhagic 
event will be discontinued from receiving bevacizumab, 
go to observation and event monitoring. 
Grade 4 
Discontinue bevacizumab, go to observation and event 
monitoring. 
Duodenal 
Hemorrhage 
 
Grade 1 or 2 
No dose modifications. 


RC1126 
21 
Addendum 10 
Grade 3 
 
Subjects who are also receiving full-dose anticoagulation 
will be discontinued from receiving bevacizumab. 
All other subjects will have bevacizumab omitted until all 
of the following criteria  are met: 
 
• 
The bleeding has resolved and hemoglobin is stable. 
• 
There is no bleeding diathesis that would increase the 
risk of therapy. 
• 
There is no anatomic or pathologic condition that 
significantly increases the risk of hemorrhage 
recurrence. 
 
Subjects who experience a repeat Grade 3 hemorrhagic 
event will be discontinued from receiving bevacizumab, 
go to observation and event monitoring. 
Grade 4 
 
Discontinue bevacizumab, go to observation and event 
monitoring. 
Rectal Hemorrhage 
 
Grade 1 or 2 
No dose modifications. 
Grade 3 
Subjects who are also receiving full-dose anticoagulation 
will be discontinued from receiving bevacizumab. 
All other subjects will have bevacizumab omitted until all 
of the following criteria  are met: 
 
• 
The bleeding has resolved and hemoglobin is stable. 
• 
There is no bleeding diathesis that would increase the 
risk of therapy. 
• 
There is no anatomic or pathologic condition that 
significantly increases the risk of hemorrhage 
recurrence. 
 
Subjects who experience a repeat Grade 3 hemorrhagic 
event will be discontinued from receiving bevacizumab, 
go to observation and event monitoring. 
Grade 4 
Discontinue bevacizumab, go to observation and event 
monitoring. 
Oral Hemorrhage 
 
Grade 1 or 2 
No dose modifications. 
Grade 3 
Subjects who are also receiving full-dose anticoagulation 
will be discontinued from receiving bevacizumab. 
All other subjects will have bevacizumab omitted until all 
of the following criteria  are met: 
 
• 
The bleeding has resolved and hemoglobin is stable. 
• 
There is no bleeding diathesis that would increase the 
risk of therapy. 
• 
There is no anatomic or pathologic condition that 
significantly increases the risk of hemorrhage 
recurrence. 
 
Subjects who experience a repeat Grade 3 hemorrhagic 
event will be discontinued from receiving bevacizumab, 
go to observation and event monitoring. 


RC1126 
22 
Addendum 10 
Grade 4 
Discontinue bevacizumab, go to observation and event 
monitoring. 
Lower 
Gastrointestinal 
Hemorrhage 
 
Grade 1 or 2 
No dose modifications. 
Grade 3 
Subjects who are also receiving full-dose anticoagulation 
will be discontinued from receiving bevacizumab. 
All other subjects will have bevacizumab omitted until all 
of the following criteria  are met: 
 
• 
The bleeding has resolved and hemoglobin is stable. 
• 
There is no bleeding diathesis that would increase the 
risk of therapy. 
• 
There is no anatomic or pathologic condition that 
significantly increases the risk of hemorrhage 
recurrence. 
 
Subjects who experience a repeat Grade 3 hemorrhagic 
event will be discontinued from receiving bevacizumab, 
go to observation and event monitoring. 
Grade 4 
Discontinue bevacizumab, go to observation and event 
monitoring. 
Jejunal Hemorrhage 
 
Grade 1 or 2 
No dose modifications. 
Grade 3 
 
Subjects who are also receiving full-dose anticoagulation 
will be discontinued from receiving bevacizumab. 
All other subjects will have bevacizumab omitted until all 
of the following criteria  are met: 
 
• 
The bleeding has resolved and hemoglobin is stable. 
• 
There is no bleeding diathesis that would increase the 
risk of therapy. 
• 
There is no anatomic or pathologic condition that 
significantly increases the risk of hemorrhage 
recurrence. 
 
Subjects who experience a repeat Grade 3 hemorrhagic 
event will be discontinued from receiving bevacizumab, 
go to observation and event monitoring. 
Grade 4 
 
Discontinue bevacizumab, go to observation and event 
monitoring. 
Intra-abdominal 
Hemorrhage 
 
Grade 1 or 2 
No dose modifications. 


RC1126 
23 
Addendum 10 
Grade 3 
 
Subjects who are also receiving full-dose anticoagulation 
will be discontinued from receiving bevacizumab. 
All other subjects will have bevacizumab omitted until all 
of the following criteria  are met: 
 
• 
The bleeding has resolved and hemoglobin is stable. 
• 
There is no bleeding diathesis that would increase the 
risk of therapy. 
• 
There is no anatomic or pathologic condition that 
significantly increases the risk of hemorrhage 
recurrence. 
 
Subjects who experience a repeat Grade 3 hemorrhagic 
event will be discontinued from receiving bevacizumab, 
go to observation and event monitoring. 
Grade 4 
Discontinue bevacizumab, go to observation and event 
monitoring. 
Ileal Hemorrhage 
 
Grade 1 or 2 
No dose modifications. 
Grade 3 
 
Subjects who are also receiving full-dose anticoagulation 
will be discontinued from receiving bevacizumab. 
All other subjects will have bevacizumab omitted until all 
of the following criteria  are met: 
 
• 
The bleeding has resolved and hemoglobin is stable. 
• 
There is no bleeding diathesis that would increase the 
risk of therapy. 
• 
There is no anatomic or pathologic condition that 
significantly increases the risk of hemorrhage 
recurrence. 
 
Subjects who experience a repeat Grade 3 hemorrhagic 
event will be discontinued from receiving bevacizumab, 
go to observation and event monitoring. 
Grade 4 
Discontinue bevacizumab, go to observation and event 
monitoring. 
Gastric Hemorrhage 
 
Grade 1 or 2 
No dose modifications. 
Grade 3 
Subjects who are also receiving full-dose anticoagulation 
will be discontinued from receiving bevacizumab. 
All other subjects will have bevacizumab omitted until all 
of the following criteria  are met: 
 
• 
The bleeding has resolved and hemoglobin is stable. 
• 
There is no bleeding diathesis that would increase the 
risk of therapy. 
• 
There is no anatomic or pathologic condition that 
significantly increases the risk of hemorrhage 
recurrence. 
 
Subjects who experience a repeat Grade 3 hemorrhagic 
event will be discontinued from receiving bevacizumab, 
go to observation and event monitoring. 


RC1126 
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Addendum 10 
Grade 4 
Discontinue bevacizumab, go to observation and event 
monitoring. 
Esophageal 
Hemorrhage 
 
Grade 1 or 2 
No dose modifications. 
Grade 3 
Subjects who are also receiving full-dose anticoagulation 
will be discontinued from receiving bevacizumab. 
All other subjects will have bevacizumab omitted until all 
of the following criteria  are met: 
 
• 
The bleeding has resolved and hemoglobin is stable. 
• 
There is no bleeding diathesis that would increase the 
risk of therapy. 
• 
There is no anatomic or pathologic condition that 
significantly increases the risk of hemorrhage 
recurrence. 
 
Subjects who experience a repeat Grade 3 hemorrhagic 
event will be discontinued from receiving bevacizumab, 
go to observation and event monitoring. 
Grade 4 
Discontinue bevacizumab, go to observation and event 
monitoring. 
Upper 
Gastrointestinal 
Hemorrhage 
 
Grade 1 or 2 
No dose modifications. 
Grade 3 
Subjects who are also receiving full-dose anticoagulation 
will be discontinued from receiving bevacizumab. 
All other subjects will have bevacizumab omitted until all 
of the following criteria  are met: 
 
• 
The bleeding has resolved and hemoglobin is stable. 
• 
There is no bleeding diathesis that would increase the 
risk of therapy. 
• 
There is no anatomic or pathologic condition that 
significantly increases the risk of hemorrhage 
recurrence. 
 
Subjects who experience a repeat Grade 3 hemorrhagic 
event will be discontinued from receiving bevacizumab, 
go to observation and event monitoring. 
Grade 4 
 
Discontinue bevacizumab, go to observation and event 
monitoring. 
Retroperitoneal 
Hemorrhage 
 
Grade 1 or 2 
No dose modifications. 


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25 
Addendum 10 
Grade 3 
Subjects who are also receiving full-dose anticoagulation 
will be discontinued from receiving bevacizumab. 
All other subjects will have bevacizumab omitted until all 
of the following criteria  are met: 
 
• 
The bleeding has resolved and hemoglobin is stable. 
• 
There is no bleeding diathesis that would increase the 
risk of therapy. 
• 
There is no anatomic or pathologic condition that 
significantly increases the risk of hemorrhage 
recurrence. 
 
Subjects who experience a repeat Grade 3 hemorrhagic 
event will be discontinued from receiving bevacizumab, 
go to observation and event monitoring. 
Grade 4 
Discontinue bevacizumab, go to observation and event 
monitoring. 
HEPATOBILIARY 
DISORDERS 
Hepatic 
Hemorrhage 
 
Grade 1 or 2 
No dose modifications. 
Grade 3 
Subjects who are also receiving full-dose anticoagulation 
will be discontinued from receiving bevacizumab. 
All other subjects will have bevacizumab omitted until all 
of the following criteria  are met: 
 
• 
The bleeding has resolved and hemoglobin is stable. 
• 
There is no bleeding diathesis that would increase the 
risk of therapy. 
• 
There is no anatomic or pathologic condition that 
significantly increases the risk of hemorrhage 
recurrence. 
 
Subjects who experience a repeat Grade 3 hemorrhagic 
event will be discontinued from receiving bevacizumab, 
go to observation and event monitoring. 
Grade 4 
Discontinue bevacizumab, go to observation and event 
monitoring. 
INJURY, POISONING 
AND PROCEDURAL 
COMPLICATIONS 
Wound dehiscence 
 
Any Grade  
(requiring medical 
or surgical therapy) 
Discontinue bevacizumab, go to observation and event 
monitoring. 
NERVOUS SYSTEM 
DISORDERS 
Leukoencephalopath
y (confirmed by 
MRI) 
 
Any Grade 
Discontinue bevacizumab, go to observation and event 
monitoring. 
Ischemia 
cerebrovascular 
 
Any Grade 
Discontinue bevacizumab, go to observation and event 
monitoring. 
Intracranial 
hemorrhage 
 


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26 
Addendum 10 
Grade 1 
Subjects who are also receiving full-dose anticoagulation 
will be discontinued from receiving bevacizumab. 
All other subjects will have bevacizumab omitted until all 
of the following criteria  are met: 
 
• 
The bleeding has resolved and hemoglobin is stable. 
• 
There is no bleeding diathesis that would increase the 
risk of therapy. 
 
There is no anatomic or pathologic condition that 
significantly increases the risk of hemorrhage recurrence. 
Grade ≥2 
Discontinue bevacizumab, go to observation and event 
monitoring. 
RENAL AND 
URINARY 
DISORDERS 
Hematuria 
 
Grade 1 or 2 
No dose modifications. 
Grade 3 
Subjects who are also receiving full-dose anticoagulation 
will be discontinued from receiving bevacizumab. 
All other subjects will have bevacizumab omitted until all 
of the following criteria  are met: 
 
• 
The bleeding has resolved and hemoglobin is stable. 
• 
There is no bleeding diathesis that would increase the 
risk of therapy. 
• 
There is no anatomic or pathologic condition that 
significantly increases the risk of hemorrhage 
recurrence. 
 
Subjects who experience a repeat Grade 3 hemorrhagic 
event will be discontinued from receiving bevacizumab, 
go to observation and event monitoring. 
Grade 4 
Discontinue bevacizumab, go to observation and event 
monitoring. 
Proteinuria 
 
Grade 1 defined as 
any of the 
following: 
1. Urine dipstick 1 
2. Urine protein 
level 0.15-1.0g/24 
hrs on 24 hour urine 
collection 
3.Urine protein 
creatinine ratio ≤ 
0.15-1.0)*** 
No dose modifications. 
 


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27 
Addendum 10 
Grade 2 defined as 
any of the 
following: 
1.Urine dipstick 2+   
2.Urine protein level 
>1-3.4g/24 hrs on 
24 hour urine 
collection 
3.Urine protein 
creatinine ratio > 1.0 
to 3.4)*** 
1. Omit bevacizumab for ≥2 grams/24 hrs or urine 
protein creatinine ratio of ≥ 2 and resume when 
proteinuria is <2 grams/24 hr or urine 
protein/creatinine ratio < 2.0 
2. For urine <2 grams/24 hrs or urine protein 
creatinine ratio < 2 may proceed with 
bevacizumab treatment 
3. For 2+ dipstick obtain 24 hour urine or urine 
protein/creatinine ratio prior to treatment with 
bevacizumab  
 
 
Grade 3 defined as 
any of the 
following: 
1. Urine dipstick 3+ 
or 4+  
2. Urine protein 
level >3.5g/24 hrs 
on 24 hour urine 
collection 
3. Urine protein 
creatinine > 3.5)*** 
 
1. Omit bevacizumab for ≥2 grams/24 hrs or urine 
protein creatinine ratio of ≥2 and resume when 
proteinuria is <2 grams/24 hrs or urine 
protein/creatinine ratio < 2.0 
2. For grade 3+ or 4+ omit bevacizumab and obtain a 
24 hour urine or urine protein creatinine ratio.  
Omit bevacizumab for ≥2 grams/24 hrs or urine 
protein creatinine ratio of ≥2 and resume when 
proteinuria is <2 grams/24 hrs or urine 
protein/creatinine ratio < 2.0 
3. For urine <2 grams/24 hrs or urine protein 
creatinine ratio < 2 may proceed with 
bevacizumab treatment 
 
REPRODUCTIVE 
SYSTEM AND 
BREAST DISORDERS 
Vaginal 
Hemorrhage 
 
Grade 1-2 
No dose modifications. 
Grade 3 
Subjects who are also receiving full-dose anticoagulation 
will be discontinued from receiving bevacizumab. 
All other subjects will have bevacizumab omitted until all 
of the following criteria  are met: 
 
• 
The bleeding has resolved and hemoglobin is stable. 
• 
There is no bleeding diathesis that would increase the 
risk of therapy. 
• 
There is no anatomic or pathologic condition that 
significantly increases the risk of hemorrhage 
recurrence. 
 
Subjects who experience a repeat Grade 3 hemorrhagic 
event will be discontinued from receiving bevacizumab, 
go to observation and event monitoring. 
Grade 4 
Discontinue bevacizumab, go to observation and event 
monitoring. 
 
 
 
 
 
 
 


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Addendum 10 
RESPIRATORY, 
THORACIC AND 
MEDIASTINAL 
DISORDERS 
Tracheal fistula 
 
Any Grade 
Discontinue bevacizumab, go to observation and event 
monitoring. 
Fistula 
 
Grade 4 
Discontinue bevacizumab, go to observation and event 
monitoring. 
Bronchopulmonary 
hemorrhage 
 
Grade 1-2 
Subjects who are also receiving full-dose anticoagulation 
will be discontinued from receiving bevacizumab. 
All other subjects will have bevacizumab omitted until all 
of the following criteria  are met: 
 
• 
The bleeding has resolved and hemoglobin is stable. 
• 
There is no bleeding diathesis that would increase the 
risk of therapy. 
 
There is no anatomic or pathologic condition that 
significantly increases the risk of hemorrhage recurrence. 
Grade ≥2 
Discontinue bevacizumab, go to observation and event 
monitoring. 
Pleural hemorrhage 
 
Grade 1 
Subjects who are also receiving full-dose anticoagulation 
will be discontinued from receiving bevacizumab. 
All other subjects will have bevacizumab omitted until all 
of the following criteria  are met: 
 
• 
The bleeding has resolved and hemoglobin is stable. 
• 
There is no bleeding diathesis that would increase the 
risk of therapy. 
 
There is no anatomic or pathologic condition that 
significantly increases the risk of hemorrhage recurrence 
Grade ≥2 
Discontinue bevacizumab, go to observation and event 
monitoring 
VASCULAR 
DISORDERS 
Hypertension 
 
Grades 1-2 
No dose modifications. 
Grade 3 
If not controlled to 150/100 mmHg with medication, 
discontinue bevacizumab, go to observation and event 
monitoring. 
Grade 4 
(including 
hypertensive 
encephalopathy) 
Discontinue bevacizumab, go to observation and event 
monitoring. 
Peripheral Ischemia 
 
Any Grade 
Discontinue bevacizumab, go to observation and event 
monitoring. 
Thromboembolic 
Event 
 
Grade 1-2 
No dose modifications. 


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Addendum 10 
 
 
 
 
 
 
 
**If dose is omitted more than 2 cycles, patient should go off study and go to observation and event 
monitoring. If patient discontinues bevacizumab, they will come off study (i.e. patients cannot continue 
on single agent erlotinib and remain on study). Patients will go to observation and event monitoring. 
 
*** Urine protein creatinine ratio can be reported in several formats. The mg/g approximates the protein 
excretion in mg/24 hours.  
 
 
8.2 
Erlotinib: This section applies to adverse events associated with erlotinib.  For adverse events associated 
with bevacizumab, please refer to Section 8.1. 
 
Dose modification table 
 
Dose level 
Erlotinib dose 
       0 
150 mg daily 
      -1 
100 mg daily  
      -2 
  50 mg daily 
 
 
 
Grade 3-4 
Discontinue bevacizumab, go to observation and event 
monitoring 
OTHER UNSPECIFIED 
ADVERSE EVENTS 
ASSOCIATED WITH 
BEVACIZUMAB 
Grade 3 
Omit until resolved to ≤Grade 1. 
Grade 4 
Discontinue bevacizumab, go to observation and event 
monitoring. 


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Addendum 10 
 
 
  Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0* unless 
otherwise specified   
CTCAE 
System/Organ/Class 
(SOC) 
 
ADVERSE EVENT 
 
ACTION** 
BASED ON OBSERVED ADVERSE EVENT 
GASTROINTESTINAL 
DISORDERS 
Diarrhea 
 
Grades 1-2 
See Section 9.8 for symptom-related control.  Continue 
erlotinib at the same dose level and institute treatment 
for diarrhea.  If Grade 2 persists over 48-72 hours 
despite optimal medical management, decrease 
erlotinib by 1 dose level. 
Grade 3 
See Section 9.8 for symptom-related control.  Omit 
erlotinib and institute treatment for diarrhea.  Once 
diarrhea resolves to ≤Grade 2, resume with one dose 
level reduction. If erlotinib is omitted for >21 days, 
discontinue erlotinib, go to observation and event 
monitoring. 
Grade 4 
Discontinue erlotinib, go to observation and event 
monitoring. 
Small Intestinal 
Perforation 
 
Any Grade 
Discontinue erlotinib, go to observation and event 
monitoring. 
Colonic Perforation 
 
Any Grade 
Discontinue erlotinib, go to observation and event 
monitoring. 
Gastric Perforation 
 
Any Grade 
Discontinue erlotinib, go to observation and event 
monitoring. 
Esophageal Perforation 
 
Any Grade 
Discontinue erlotinib, go to observation and event 
monitoring. 
EYE DISORDERS 
Keratitis 
(corneal inflammation 
/corneal ulceration) 
 
Grade 1 
Continue treatment.  See Section 9.8. 
Grade 2 
Omit in cases of persistent Grade 2 keratitis (>14 days) 
while on therapy.  See Section 9.8. 
Grade 3 
Discontinue, see Section 9.8.  Go to observation and 
event monitoring 
Eye Pain 
 
Grade 3 
Omit until Grade ≤2 then ↓ dose by the dose levels in 
the above table. 
Grade 4 
Discontinue erlotinib, go to observation and event 
monitoring.  See Section 9.8. 
INVESTIGATIONS 
Aspartate 
aminotransferase 
increased 
 
≥Grade 3 
(i.e. >5x   ULN) 
Omit until grade ≤2 then ↓ dose by the following dose 
levels according to current treatment dose (150 mg → 
100 mg →50 mg). 


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Addendum 10 
  Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0* unless 
otherwise specified   
CTCAE 
System/Organ/Class 
(SOC) 
 
ADVERSE EVENT 
 
ACTION** 
BASED ON OBSERVED ADVERSE EVENT 
Blood Bilirubin 
Increased 
 
≥Grade 3 
(i.e. >3x ULN) 
Omit until grade 0-2 then ↓ dose by the following dose 
levels according to current treatment dose (150 mg → 
100 mg →50 mg). 
SKIN AND 
SUBCUTANEOUS 
TISSUE DISORDERS 
Rash Acneiform 
 
Grades 1-2 
Continue at the same dose level and institute treatment 
of rash (See Section 9.8).  If Grade 2 rash persists and 
is intolerable, dose reduction according to the dose 
modification table above should be considered, and 
continuing erlotinib at the reduced dose is an option. 
Alternatively, treatment interruption until rash is 
tolerable and dose reduction according to the dose 
modification is an option.  Maximum interval of 
erlotinib interruption is 21 days.  Once patient requires 
a dose reduction, dose re-escalation is not allowed. 
Grade 3 
See Section 9.8 for symptom-related control.  Continue 
erlotinib at the current dose.  If skin rash is intolerable, 
dose reduction according to the dose modification table 
above and continuing erlotinib at the reduced dose is an 
option.  The preferred option is a treatment interruption 
until rash is tolerable and dose reduction according to 
the dose modification.  Maximum interval of erlotinib 
interruption is 21 days.   Once patient requires a dose 
reduction, dose re-escalation is not allowed. 
Grade 4 
Discontinue erlotinib, go to observation and event 
monitoring. 
OTHER UNSPECIFIED 
ADVERSE EVENTS 
ASSOCIATED WITH 
ERLOTINIB 
Grade 2 
For symptomatic patients, the dose may be omit until 
recovery to grade 0-1, initiate at the same dose. 
≥Grade 3 
Omit drugs until grade ≤2, then ↓ dose by the 
following dose levels according to current treatment 
dose (150 mg → 100 mg →50 mg). 
**Patients who require discontinuation of the erlotinib for greater than 21 consecutive days will go off 
treatment and go to observation and event monitoring. 
 
**Erlotinib should not be restarted in those suspected of having drug-related interstitial lung disease 
(ILD).  
 
NOTE: If the patient experiences a significant adverse event requiring a dose reduction at the start 
of the next cycle, then the dose will remain lowered for all subsequent cycles. 
 
NOTE: Adverse events requiring a dose-reduction step for any or all drugs beyond the two dose-
reduction steps (levels –1 and –2) will be at the discretion of the treating physician, if the decision 
is made for the patient to be kept on treatment. These dose reductions must be clearly recorded in 
reported clinical data. 


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32 
Addendum 10 
 
9.0 
Ancillary Treatment/Supportive Care 
 
9.1 
Antiemetics may be used at the discretion of the attending physician. 
 
9.2 
Blood products and growth factors should be utilized as clinically warranted and following 
institutional policies and recommendations. The use of growth factors should follow published 
guidelines of the Journal of Clinical Oncology, Vol 24, No 19 (July 1), 2006: pp. 3187-3205. 
 
9.3 
Patients should receive full supportive care while on this study. This includes blood product 
support, antibiotic treatment, and treatment of other newly diagnosed or concurrent medical 
conditions. All blood products and concomitant medications such as antidiarrheals, 
analgesics, and/or antiemetics received from the first day of study treatment administration 
until 30 days after the final dose will be recorded in the medical records. 
 
9.4 
Diarrhea: This could be managed conservatively with loperamide. The recommended dose of 
loperamide is 4 mg at first onset, followed by 2 mg every 2-4 hours until diarrhea free 
(maximum 16 mg/day). 
 
In the event of grade 3 or 4 diarrhea, the following supportive measures are allowed: hydration, 
octreotide, and antidiarrheals.   
 
If diarrhea is severe (requiring intravenous rehydration) and/or associated with fever or severe 
neutropenia (grade 3 or 4), broad-spectrum antibiotics must be prescribed. Patients with severe 
diarrhea or any diarrhea associated with severe nausea or vomiting should be hospitalized for 
intravenous hydration and correction of electrolyte imbalances. 
 
9.5 
Hypertension is a known and potentially serious adverse event associated with bevacizumab 
treatment. An increase in blood pressure of >20 mmHg (systolic) and 10 mmHg (diastolic) 
should be reported to the treating physician immediately (see Section 8.0 for hypertension 
management and dose reduction guidelines). 
 
9.6 
Anti-platelet therapy (e.g., ≤ 325 mg/day aspirin) should be considered for the treatment of 
patients at high risk of developing an arterial thromboembolic event unless contraindicated and 
may be continued in patients receiving it at time of entry. Patients developing bleeding on study 
should be evaluated for possible bevacizumab discontinuation as described in the protocol. 
 
9.7 
Patients who experience infusion-associated temperature elevations to ≥ 38.5°C (101.3°F) or 
other infusion-associated symptoms may be treated symptomatically with acetaminophen, 
diphenhydramine, meperidine, or other medications as clinically indicated. 
 
 
 


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Addendum 10 
9.8 
Management of erlotinib-associated adverse events 
 
9.81 
Rash: Patients should be informed that skin toxicity is to be expected during treatment 
with erlotinib. Rash was the most commonly reported adverse event considered related 
to erlotinib therapy in phase III trials. Rash typically develops within 8 to 10 days of 
initiation of treatment but may appear within 1 to 113 days. Although the rash is 
commonly referred to as “acneiform”, it is not acne, but rather a papulopustular 
reaction, and should not be treated as acne. Patients are recommended to wear sun 
screen protection, hat, long sleeves to avoid sun as it can exacerbate skin rash. 
 
Redness and/or a warm sensation of the skin can be an initial indicator in the 
development of erlotinib-related rash. Tender skin and inflammatory pustules and 
papules begin to appear on the face, head, and upper torso as the rash develops, and the 
rash is typically accompanied by pruritis, dry skin, and erythema. Most incidences of 
rash are intermittent and mild to moderate in severity. When accurately managed, rash 
and other erlotinib-related skin toxicities generally do not interfere with a patient’s 
treatment; however, a small proportion of patients may experience a severe rash that 
could lead to significant physical and/or cosmetic discomfort and may require 
discontinuation of therapy at the patient’s request. 
 
In addition to rash, other erlotinib-related skin toxicities include dry, itchy, or flaky skin 
(especially on the scalp); increased growth of facial hair (including eyelashes/brows); 
small skin fissures on the fingertips; brittle and/or loose fingernails; sores around the 
eyes, corners of the mouth, or inside the nose; easily bruised skin; dry, itchy eyes; 
inflammation around the nails (especially thumbs and big toes) sometimes accompanied 
by pain; and decreased hair growth and/or hair loss on the legs, arm, and scalp. 
 
Prophylactic treatment of the skin may prevent or reduce skin toxicity. Patients should 
avoid soap as it is drying and use bath oil with tepid water when bathing. The patient 
should be encouraged to use an alcohol-free, emollient cream applied twice a day to the 
entire body as soon as the patient starts therapy with erlotinib. Creams and ointments 
are recommended because they have a greater ability to retain moisture than lotions.  
Examples of suitable emollient creams include: Neutrogena® Norwegian formula, 
SARNA® Ultra, Vanicream™, Aveeno® (fragrance-free formulation), and Eucerin® 
cream. Other over-the-counter aqueous creams or emulsifying ointments may also 
provide symptomatic benefit. Lotions should be avoided because they often contain 
alcohol, which will dry the skin. Patients should also be encouraged to use a titanium 
dioxide or zinc oxide-based sunscreen product applied to sun-exposed areas twice per 
day. 
 
Patients who develop skin toxicity and are symptomatic should be treated with topical 
therapy such as hydrocortisone cream or clindamycin gel. If needed, oral minocycline 
or oral doxycycline may be combined with the topical therapy. A topical immodulating 
cream such as Elidel could also be considered. For more severe rash, oral 
corticosteroids may be beneficial. Patients who fail to respond to these measures may 
have the dose of erlotinib interrupted or reduced.  See Appendix II for more information 
on skin toxicity management. 
 
Minocycline is known to interfere with anticoagulants and oral contraceptives. Patients 
treated with minocycline who are taking anticoagulants and/or oral contraceptives 
should be monitored accordingly. 
 
 
 


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Addendum 10 
9.82 
Diarrhea: previous trials have shown that the frequency of severity of diarrhea rarely 
hindered administration of erlotinib and could be managed conservatively with 
loperamide. The recommended dose of loperamide is 4 mg at the first onset, followed 
by 2 mg every 2-4 hours (4 mg every four hours can be given at night) until diarrhea 
free for 12 hours.  
 
9.83 
Keratitis: Preservative-free artificial tears, ointments, and/or other therapies as clinically 
indicated, with a follow-up examination within 2 weeks. Any symptoms of keratitis 
(corneal inflammation/corneal ulceration) should prompt an ophthalmologic evaluation 
as soon as possible 
 
 
10.0 
Adverse Event (AE) Reporting and Monitoring 
 
10.1 
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 for AE reporting.  All appropriate treatment areas should have access to a copy of the 
CTCAE version 4.0.  A copy of the CTCAE version 4.0 can be downloaded from the CTEP 
web site: (http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm)     
 
10.11 Adverse event monitoring and reporting is a routine part of every clinical trial. First, 
identify and grade the severity of the event using the CTCAE version 4.0. Next, 
determine whether the event is expected or unexpected (see Section 10.2) and if the 
adverse event is related to the medical treatment or procedure (see Section 10.3). With 
this information, determine whether the event must be reported as an expedited report 
(see Section 10.4). Important: Expedited adverse event reporting requires submission of 
a Med Watch report(s). Expedited reports are to be completed within the timeframes 
and via the mechanisms specified in Section 10.4. All AEs reported via expedited 
mechanisms must also be reported via the routine data reporting mechanisms defined by 
the protocol (see Sections 10.5 and 18.0). 
 
10.12 Each CTCAE term in the current version is a unique representation of a specific event 
used for medical documentation and scientific analysis and is a single MedDRA Lowest 
Level Term (LLT). 
 
• 
NOTE: A severe AE, as defined by the above grading scale, is NOT the same as 
serious AE which is defined in the table in Section 10.4. 
 
10.2 
Expected vs. Unexpected Events  
 
• 
The determination of whether an AE is expected is based on agent-specific 
information provided in Section 15.0 of the protocol. 
• 
Unexpected AEs are those not listed in the agent-specific information provided in 
Section 15.0 of the protocol. 
 
NOTE: “Unexpected adverse experiences” means any adverse experience that is neither 
identified in nature, severity, or frequency of risk in the information provided for IRB review 
nor mentioned in the consent form.  
 
 
 


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35 
Addendum 10 
10.3 
Assessment of Attribution 
 
When assessing whether an adverse event is related to a medical treatment or procedure, the 
following attribution categories are utilized: 
 
Definite - The adverse event is clearly related to the agent(s). 
Probable - The adverse event is likely related to the agent(s). 
Possible - The adverse event may be related to the agent(s). 
Unlikely - The adverse event is doubtfully related to the agent(s). 
Unrelated - The adverse event is clearly NOT related to the agent(s). 
 
Events determined to be possibly, probably or definitely attributed to a medical 
treatment suggest there is evidence to indicate a causal relationship between the 
drug and the adverse event.  
 
10.31 Special Situations for Expedited Reporting 
 
Exceptions to Expedited Reporting: EXPECTED Serious Adverse Events 
 
An expedited report may not be required for specific Grade 1, 2 and 3 Serious Adverse Events 
where the AE is listed in Section 15.0 of the protocol as EXPECTED. Any protocol specific 
reporting procedures MUST BE SPECIFIED BELOW and will supersede the standard 
Expedited Adverse Event Reporting Requirements: (Note: These adverse events must still be 
reported through the routine reporting mechanism [i.e. Nadir/adverse events form]; see footnote 
1):  
  
System Organ Class 
(SOC) 
Adverse event/ 
Symptoms 
CTCAE Grade at 
which the event 
will not be 
expediently 
reported. 
Gastrointestinal 
Disorders 
Diarrhea 
Grade 3 
Renal and Urinary 
Disorders 
Proteinuria 
Grade 3 
Skin and Subcutaneous 
Tissue Disorders 
Rash Acneiform 
Grade 3 
Vascular Disorders 
Hypertension 
Grade 3 
1. These exceptions only apply if the adverse event does not result in hospitalization. If the 
adverse event results in hospitalization, then the standard expedited adverse events 
reporting requirements must be followed. 
 
Specific protocol exceptions to expedited reporting should be reported expeditiously by 
investigators ONLY if they exceed the expected grade of the event. 
 
10.311 
Persistent or Significant Disabilities/Incapacities 
Any AE that results in persistent or significant incapacity or substantial disruption of 
the ability to conduct normal life functions (formerly referred to as disabilities), 
congenital abnormities or birth defects, must be reported immediately if they occur 
at any time following treatment with an agent under an IND/IDE since they are 
considered to be a serious AE and must be reported to the sponsor as specified in 21 
CFR 312.64(b). 
 


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36 
Addendum 10 
10.312 
Death 
• 
Any death occurring within 30 days of the last dose, regardless of 
attribution to an agent/intervention under an IND/IDE requires 
expedited reporting within 24-hours. 
• 
Any death occurring greater than 30 days with an attribution of 
possible, probable, or definite to an agent/intervention under an 
NCI IND/IDE requires expedited reporting within 24-hours. 
 
• 
Reportable categories of Death  
• 
Death attributable to a CTCAE term. 
• 
Death Neonatal:  A disorder characterized by cessation of 
life during the first 28 days of life. 
• 
Death NOS: A cessation of life that cannot be attributed to a 
CTCAE term associated with Grade 5. 
• 
Sudden death NOS: A sudden (defined as instant or within 
one hour of the onset of symptoms) or an unobserved 
cessation of life that cannot be attributed to a CTCAE term 
associated with Grade 5. 
• 
Death due to progressive disease should be reported as Grade 
5 “Neoplasms benign, malignant and unspecified (incl 
cysts and polyps) – Other (Progressive Disease)” under the 
system organ class (SOC) of the same name. 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. 
 
10.313 
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. 
• 
All secondary malignancies that occur following treatment with an agent 
under an IND/IDE to be reported. Three options are available to describe 
the event: 
o Leukemia secondary to oncology chemotherapy (e.g., Acute 
Myeloctyic Leukemia [AML]) 
o Myelodysplastic syndrome (MDS) 
o 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. 
 
10.314 
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 reporting. 
 
 
 


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37 
Addendum 10 
10.4 
Expedited Reporting Requirements for Studies using Commercial Agent(s) ONLY: 
 
Expedited Reporting Requirements for Adverse Events that Occur in a Non-IND/IDE trial within 
30 Days of the Last Administration of a Commercial Agent 1, 2 
 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE: Investigators MUST immediately report to the sponsor 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 sponsor within 
the timeframes detailed in the table below. 
Hospitalization 
Grade 1 
Timeframes 
Grade 2 
Timeframes 
Grade 3 Timeframes 
Grade 4 & 5 
Timeframes 
Resulting in 
Hospitalization  
≥ 24 hrs 
7 Calendar Days 
24-Hour 3 
Calendar Days 
Not resulting in 
Hospitalization  
≥ 24 hrs 
Not required 
7 Calendar Days 
NOTE:  Protocol specific exceptions to expedited reporting of serious adverse events are found in section 
10.31 of the protocol. 
Expedited AE reporting timelines are defined as: 
o 
“24-Hour; 3 Calendar Days” - The AE must initially be reported via MedWatch within 24 hours of 
learning of the AE, followed by a complete expedited report within 3 calendar days of the initial 24-
hour report. 
o “7 Calendar Days” - A complete expedited report on the AE must be submitted within 7 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 3 calendar days for: 
• 
All Grade 4, and Grade 5 AEs 
Expedited 7 calendar day reports for: 
• 
Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization  
• 
Grade 3 adverse events 
2 For 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 
 
 
 
 


RC1126 
38 
Addendum 10 
Additional Instructions: 
1. An increased incidence of an expected adverse event (AE) is based on the patients treated for this 
study at their site. A list of known/expected AEs is reported in the package insert or the literature, 
including AEs resulting from a drug overdose. 
2. If FDA Form 3500A (MedWatch) was completed, Grade 4 or 5 Non-AER Reportable 
Events/Hospitalization Form need not be completed. 
3. Submit form to the FDA, MedWatch, 5600 Fishers Lane, Rockville, MD 20852-9787, by fax at 1-
800-332-0178 or online at http://www.fda.gov/Safety/MedWatch/HowToReport/default.htm. 
 
Mayo Clinic Cancer Center (MCCC) Institutions: Provide copies, along with the UPIRTSO 
cover sheet, by fax 
 the MCCC Regulatory Affairs Unit (RAU) Risk 
Information Specialist who will determine and complete IRB reporting. The RAU will submit 
to the ACCRU SAE Coordinator. 
  
Non-MCCC Institutions: Provide copies by fax 
 to the ACCRU SAE 
Coordinator. 
 
The ACCRU SAE Coordinator will forward a copy of the expedited reports using the 
Genentech Fax Coversheet to: 
 
• 
Genentech Drug Safety  at 
 
 
4. Pregnancy - Any reports of pregnancy following the start of administration with the Erlotinib & 
Bevacizumab will be transmitted to Genentech within thirty (30) calendar days of the Awareness 
Date.  Follow-up to obtain the outcome of the pregnancy should also occur. Abortion, whether 
accidental, therapeutic, or spontaneous, should always be classified as serious, and expeditiously 
reported as an SAE. Similarly, any congenital anomaly/birth defect in a child born to a female 
subject exposed to the Erlotinib or Bevacizumab should be reported as an SAE. 
 
 
EVENT TYPE 
REPORTING PROCEDURE 
Other Grade 4 or 5 Events 
and/or Any Hospitalizations 
During Treatment Not 
Otherwise Warranting an 
Expedited Report 
Notification form: Grade 4 or 5 Non-AER Reportable Events/ 
Hospitalization Form to MCCRC within 5 working days2 
 
 
 
 


RC1126 
39 
Addendum 10 
10.5 
Other Required Reporting 
 
10.51 Adverse events to be graded at each evaluation and pretreatment symptoms/conditions to be 
evaluated at baseline per the CTCAE v4.0 grading unless otherwise stated in the table below: 
 
System Organ Class (SOC) 
Adverse event/Symptoms 
Baseline 
Each 
evaluation 
Hepatobiliary Disorders 
Hepatic Hemorrhage 
X 
X 
Gastrointestinal Disorders 
Diarrhea 
# stools per day 
X 
Anal Hemorrhage 
X 
X 
Colonic Hemorrhage 
X 
X 
Duodenal Hemorrhage 
X 
X 
Rectal Hemorrhage 
X 
X 
Oral Hemorrhage 
X 
X 
Lower Gastrointestinal 
Hemorrhage 
X 
X 
Jejunal Hemorrhage 
X 
X 
Intra-Abdominal Hemorrhage 
X 
X 
Ileal Hemorrhage 
X 
X 
Gastric Hemorrhage 
X 
X 
Esophageal Hemorrhage 
X 
X 
Upper Gastrointestinal 
Hemorrhage 
X 
X 
Retroperitoneal Hemorrhage 
X 
X 
Renal and Urinary 
Disorders 
Hematuria 
X 
X 
Proteinuria 
X 
X 
Reproductive System and 
Breast Disorders 
Vaginal Hemorrhage 
X 
X 
Respiratory, Thoracic and 
Mediastinal Disorders 
Bronchopulmonary Hemorrhage 
X 
X 
Pleural Hemorrhage 
X 
X 
Skin and Subcutaneous 
Tissue Disorders 
Rash Acneiform 
X 
X 
Vascular Disorders 
Hypertension 
X 
X 
 
10.51 Submit via appropriate Academic and Community Cancer Research United (ACCRU) 
Case Report Forms (i.e., paper or electronic, as applicable) the following AEs 
experienced by a patient and not specified in Section 10.5: 
 
10.511 
Grade 2 AEs deemed possibly, probably, or definitely related to the study 
treatment or procedure. 
 
10.512 
Grade 3 and 4 AEs regardless of attribution to the study treatment or 
procedure. 
 
 
 


RC1126 
40 
Addendum 10 
10.513 
Grade 5 AEs (Deaths) 
 
10.5131 
Any death within 30 days of the patient’s last study treatment or 
procedure regardless of attribution to the study treatment or 
procedure. 
 
10.5132 
Any death more than 30 days after the patient’s last study 
treatment or procedure that is felt to be at least possibly treatment 
related must also be submitted as a Grade 5 AE, with a CTCAE 
type and attribution assigned. 
 
10.52 Refer to the instructions in the Forms Packet (or electronic data entry screens, as 
applicable) regarding the submission of late occurring AEs following completion of the 
Active Monitoring Phase (i.e., compliance with Test Schedule in Section 4.0). 
 
10.53 All non-serious adverse events originating from the study will be forwarded by ACCRU 
in a quarterly report to Genentech. 
 
10.54 Study Close-Out- Any study report submitted to the FDA by the Sponsor-Investigator 
should be copied to Genentech. This includes all Clinical Study Reports (final study 
report). Additionally, any literature articles that are a result of the study should be sent 
to Genentech. Copies of such reports should be mailed to the assigned Clinical 
Operations contact for the study.   
 
 
11.0 
Treatment Evaluation Using RECIST Guideline 
 
NOTE: This study uses protocol RECIST v1.1 template dated 2/16/2011.  See the footnote for the table 
regarding measureable disease in Section 11.44, as it pertains to data collection and analysis. 
 
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) guidelines (version 1.1) 
(Eisenhauer et al 2009). Changes in the largest diameter (unidimensional measurement) of the tumor 
lesions and the short axis measurements in the case of lymph nodes are used in the RECIST guideline. 
 
11.1 
Schedule of Evaluations: For the purposes of this study, patients should be reevaluated every 6 
weeks for 18 months then every 3 months until disease progression, unacceptable toxicity, or 
withdraw of consent.  
 
Patients who discontinue study therapy prior to disease progression should be followed until 
disease progression. The schedule of follow-up imaging is at the discretion of physician, but an 
interval of 6 to 12 weeks is recommended. 
 
11.2 
Definitions of Measurable and Non-Measurable Disease 
 
11.21 Measurable Disease 
 
11.211 
A non-nodal lesion is considered measurable if its longest diameter can be 
accurately measured as ≥2.0 cm with chest x-ray, or as ≥1.0 cm with CT scan, 
CT component of a PET/CT, or MRI.  
 
11.212 
A superficial non-nodal lesion is measurable if its longest diameter is ≥ 1.0 cm 
in diameter as assessed using calipers (e.g. skin nodules) or imaging. In the 
case of skin lesions, documentation by color photography, including a ruler to 
estimate the size of the lesion, is recommended. 
 


RC1126 
41 
Addendum 10 
11.213 
A malignant lymph node is considered measurable if its short axis is >1.5 cm 
when assessed by CT scan (CT scan slice thickness recommended to be no 
greater than 5 mm).   
 
NOTE: Tumor lesions in a previously irradiated area are not considered 
measurable disease.   
 
11.22 Non-Measurable Disease 
 
11.221 
All other lesions (or sites of disease) are considered non-measurable disease, 
including pathological nodes (those with a short axis ≥1.0 to <1.5 cm). Bone 
lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, 
lymphangitis cutis/pulmonis, inflammatory breast disease, and abdominal 
masses (not followed by CT or MRI), are considered as non-measurable as 
well. 
 
Note: ‘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.  In addition, lymph nodes that have a short axis <1.0 cm are 
considered non- pathological (i.e., normal) and should not be recorded or followed. 
 
11.3 
Guidelines for Evaluation of Measurable Disease 
 
11.31 Measurement Methods:   
 
• 
All measurements should be recorded in metric notation (i.e., decimal fractions of 
centimeters) using a ruler or calipers. 
• 
The same method of assessment and the same technique must be used to characterize 
each identified and reported lesion at baseline and during follow-up. For patients 
having only lesions measuring at least 1 cm to less than 2 cm must use CT imaging 
for both pre- and post-treatment tumor assessments.   
• 
Imaging-based evaluation is preferred to evaluation by clinical examination when 
both methods have been used at the same evaluation to assess the antitumor effect of 
a treatment.  
 
11.32 Acceptable Modalities for Measurable Disease: 
 
• 
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 or less. If CT scans 
have slice thickness greater than 5 mm, the minimum size for a measurable lesion 
should be twice the slice thickness. 
• 
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. The lesions should be measured on the same pulse sequence. 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: 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. 


RC1126 
42 
Addendum 10 
• 
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 scans are 
preferable. 
• 
Physical Examination: For superficial non-nodal lesions, physical examination is 
acceptable, but imaging is preferable, if both can be done. In the case of skin lesions, 
documentation by color photography, including a ruler to estimate the size of the 
lesion, is recommended. 
• 
FDG-PET: FDG-PET scanning is allowed to complement CT scanning in 
assessment of progressive disease [PD] and particularly possible 'new' disease. A 
‘positive’ FDG-PET scanned lesion is defined as one which is FDG avid with an 
update greater than twice that of the surrounding tissue on the attenuation corrected 
image; otherwise, an FDG-PET scanned lesion is considered ‘negative.’ 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: 
 
i. 
If the positive FDG-PET at follow-up corresponds to a new site of disease 
confirmed by CT, this is PD. 
ii. If the positive FDG-PET at follow-up is not confirmed as a new site of 
disease on CT at the same evaluation, additional follow-up CT scans (i.e., 
additional follow-up scans at least 4 weeks later) are needed to determine if 
there is truly progression occurring at that site. In this situation, the date of 
PD will be the date of the initial abnormal PDG-PET scan. 
iii 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, it 
is not classified as PD. 
 
11.33 Measurement at Follow-up Evaluation: 
 
• 
In the case of stable disease (SD), follow-up measurements must have met the SD 
criteria at least once after study entry at a minimum interval of 6 weeks (see Section 
11.44). 
• 
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. 
• 
Cytologic and histologic techniques can be used to differentiate between PR and CR 
in rare cases (e.g., residual lesions in tumor types such as germ cell tumors, where 
known residual benign tumors can remain.) 
 
11.4 
Measurement of Effect 
 
11.41 Target Lesions & Target Lymph Nodes 
 
• 
Measurable lesions (as defined in Section 11.21) up to a maximum of 5 lesions, 
representative of all involved organs, should be identified as “Target Lesions” and 
recorded and measured at baseline. These lesions can be non-nodal or nodal (as 
defined in 11.21), where no more than 2 lesions are from the same organ and no 
more than 2 malignant nodal lesions are selected.  
 


RC1126 
43 
Addendum 10 
Note: If fewer than 5 target lesions and target lymph nodes are identified (as there 
often will be), there is no reason to perform additional studies beyond those specified 
in the protocol to discover new lesions. 
 
• 
Target lesions and target lymph nodes should be selected on the basis of their size, 
be representative of all involved sites of disease, but in addition should be those that 
lend themselves to reproducible repeated measurements. It may be the case that, on 
occasion, the largest lesion (or malignant lymph node) does not lend itself to 
reproducible measurements in which circumstance the next largest lesion (or 
malignant lymph node) which can be measured reproducibly should be selected.   
 
• 
Baseline Sum of Dimensions (BSD): A sum of the longest diameter for all target 
lesions plus the sum of the short axis of all the target lymph nodes will be calculated 
and reported as the baseline sum of dimensions (BSD). The BSD will be used as 
reference to further characterize any objective tumor response in the measurable 
dimension of the disease.   
 
• 
Post-Baseline Sum of the Dimensions (PBSD): A sum of the longest diameter for all 
target lesions plus the sum of the short axis of all the target lymph nodes will be 
calculated and reported as the post-baseline sum of dimensions (PBSD). If the 
radiologist is able to provide an actual measure for the target lesion (or target lymph 
node), that should be recorded, even if it is below 0.5 cm. If the target lesion (or 
target lymph node) is believed to be present and is faintly seen but too small to 
measure, a default value of 0.5 cm should be assigned. If it is the opinion of the 
radiologist that the target lesion or target lymph node has likely disappeared, the 
measurement should be recorded as 0 cm. 
 
• 
The minimum sum of the dimensions (MSD) is the minimum of the BSD and the 
PBSD. 
 
11.42 Non-Target Lesions & Non-Target Lymph Nodes 
 
Non-measurable sites of disease (Section 11.22) are classified as non- target lesions or 
non-target lymph nodes and should also be recorded at baseline. These lesions and 
lymph nodes should be followed in accord with 11.433. 
 
11.43 Response Criteria 
 
11.431 
All target lesions and target lymph nodes followed by CT/MRI/PET-
CT/Chest X-ray/physical examination must be measured on re-evaluation at 
evaluation times specified in Section 11.1. Specifically, a change in objective 
status to either a PR or CR cannot be done without re-measuring target 
lesions and target lymph nodes.  
 
Note: Non-target lesions and non-target lymph nodes should be evaluated at 
each assessment, especially in the case of first response or confirmation of 
response. In selected circumstances, certain non-target organs may be 
evaluated less frequently. For example, bone scans may need to be repeated 
only when complete response is identified in target disease or when 
progression in bone is suspected. 
 
 
 


RC1126 
44 
Addendum 10 
11.432 
Evaluation of Target Lesions 
 
Complete Response (CR): All of the following must be true: 
 
a. Disappearance of all target lesions. 
 
b. Each target lymph node must have reduction 
in short axis to <1.0 cm. 
 
Partial Response (PR): 
At least a 30% decrease in PBSD (sum of the 
longest diameter for all target lesions plus the 
sum of the short axis of all the target lymph 
nodes at current evaluation) taking as reference 
the BSD (see Section 11.41). 
 
Progression (PD): 
At least one of the following must be true: 
 
a. At least one new malignant lesion, which 
also includes any lymph node that was 
normal at baseline (< 1.0 cm short axis) and 
increased to ≥ 1.0 cm short axis during 
follow-up.  
 
b. At least a 20% increase in PBSD (sum of the 
longest diameter for all target lesions plus 
the sum of the short axis of all the target 
lymph nodes at current evaluation) taking as 
reference the MSD (Section 11.41).  In 
addition, the PBSD must also demonstrate an 
absolute increase of at least 0.5 cm from the 
MSD.  
 
c. See Section 11.32 for details in regards to 
the requirements for PD via FDG-PET 
imaging. 
  
Stable Disease (SD): 
Neither sufficient shrinkage to qualify for PR, 
nor sufficient increase to qualify for PD taking as 
reference the MSD. 
 
11.433 
Evaluation of Non-Target Lesions & Non-target Lymph Nodes 
 
Complete Response (CR): 
All of the following must be true: 
 
 
a. Disappearance of all non-target lesions.  
 
b. Each non-target lymph node must have a 
reduction in short axis to <1.0 cm. 
 
Non-CR/Non-PD: 
Persistence of one or more non-target lesions or 
non-target lymph nodes. 
 
 
 


RC1126 
45 
Addendum 10 
Progression (PD): 
At least one of the following must be true: 
 
a. At least one new malignant lesion, which 
also includes any lymph node that was 
normal at baseline (< 1.0 cm short axis) and 
increased to ≥ 1.0 cm short axis during 
 
follow-up.   
 
b. Unequivocal progression of existing non-
target lesions and non-target lymph nodes.  
(NOTE:  Unequivocal progression should 
not normally trump target lesion and target 
lymph node status.  It must be representative 
of overall disease status change.)  
 
c. See Section 11.32 for details in regards to 
the requirements for PD via FDG-PET 
imaging. 
 
11.44 Overall Objective Status 
 
The overall objective status for an evaluation is determined by combining the patient’s 
status on target lesions, target lymph nodes, non-target lesions, non-target lymph nodes, 
and new disease as defined in the following tables:  
 
For Patients with Measurable Disease  
 
Target Lesions & 
Target Lymph Nodes 
Non-Target Lesions & 
Non-Target Lymph 
Nodes 
New Sites of 
Disease 
Overall Objective 
Status 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
PR 
CR 
Non-CR/Non-PD 
No 
PR 
CR/PR 
Not All Evaluated* 
No 
PR** 
SD 
CR 
Non-CR/Non-PD 
Not All Evaluated* 
No 
SD 
Not all Evaluated 
CR 
Non-CR/Non-PD 
Not All Evaluated* 
No 
Not Evaluated 
(NE) 
PD 
Unequivocal PD 
CR 
Non-CR/Non-PD 
Not All Evaluated* 
Yes or No 
PD 
CR/PR/SD/PD/Not all 
Evaluated 
Unequivocal PD 
Yes or No 
PD 
CR/PR/SD/PD/Not all 
Evaluated 
CR 
Non-CR/Non-PD 
Not All Evaluated* 
Yes 
PD 
*See Section 11.431 
** NOTE: This study uses the protocol RECIST v1.1 template dated 2/16/2011. For data collection and 
analysis purposes the objective status changed from SD to PR in the ACCRU protocol RECIST v1.1 
template as of 2/16/2011 and to match RECIST v1.1 requirements. 


RC1126 
46 
Addendum 10 
 
11.45 Symptomatic Deterioration: Patients with global deterioration of health status requiring 
discontinuation of treatment without objective evidence of disease progression at that 
time, and not either related to study treatment or other medical conditions, should be 
reported as PD due to “symptomatic deterioration.” Every effort should be made to 
document the objective progression even after discontinuation of treatment due to 
symptomatic deterioration. A patient is classified as having PD due to “symptomatic 
deterioration” if any of the following occur that are not either related to study treatment 
or other medical conditions: 
• 
Weight loss >10% of body weight. 
• 
Worsening of tumor-related symptoms. 
• 
Decline in performance status of >1 level on ECOG scale. 
 
 
12.0 
Descriptive Factors 
 
12.1 
Smoking Status:  Never smoker (less than 100 cigarettes in a lifetime) vs. light smoker (under 
10 pack years and quit at least 15 years ago) vs. former smoker (quit greater than 1 year ago and 
less than 15 years or greater than 10 pack years) vs. current smoker. 
 
12.2 
Weight loss ≤3 months: <10% vs. ≥10%. 
 
 
13.0 
Treatment/Follow–up Decision at Evaluation of Patient   
 
13.1 
Patients who are CR, PR, or SD will continue treatment per protocol. 
 
13.2 
Patients who develop PD while receiving therapy will go to the event-monitoring phase. 
Complete the Event Monitoring Form at the time of PD. Patient will then be observed 21-42 
days following discontinuation of treatment and will then go to event monitoring (see Section 
18.0). 
 
13.3 
Patients will continue treatment until PD, unacceptable toxicity, investigator’s decision remove 
patient from the study, patient refusal to continue, or alternate treatment. Treatment will then be 
discontinued. Patients will be observed 21-42 days following discontinuation of treatment and 
will then go to event monitoring (see Section 18.0). 
 
13.4 
Patients who go off protocol treatment for reasons other than PD will go to observation per 
Section 4.0 (day 21-42 days after treatment discontinuation), and then to the event-monitoring 
phase per Section 18.0. 
 
13.5 
Patients who develop PD in the CNS only should receive appropriate treatment for brain 
metastases and should be considered as having progressive disease. 
 
13.6 
Patients who develop non-CNS PD at any time should go to event monitoring. Complete the 
Event Monitoring Form at the time of PD. Patient will then be observed 21-42 days following 
discontinuation of treatment and will then go to event monitoring (see Section 18.0). These 
patients should be treated with alternative chemotherapy if their clinical status is good enough 
to allow further therapy.   
 
13.7 
Patients who have an ongoing bevacizumab-related Grade 4 or serious adverse event at the time 
of discontinuation from study treatment will continue to be followed until resolution of the 
event or until the event is considered irreversible (see Section 8.0). 
 
 
 


RC1126 
47 
Addendum 10 
13.8 
A patient is deemed ineligible if after registration, it is determined that at the time of 
registration, the patient did not satisfy each and every eligibility criteria for study entry. The 
patient may continue treatment off-protocol at the discretion of the physician as long as there 
are no safety concerns, and the patient was properly registered. The patient will go directly to 
the event-monitoring phase of the study (or off study, if applicable).  
• 
If the patient received treatment, all data up until the point of confirmation of ineligibility 
must be submitted.  Event monitoring will be required per Section 18.0 of the protocol.  
• 
If the patient never received treatment, on-study material must be submitted. Event 
monitoring will be required per Section 18.0 of the protocol.  
 
13.9a 
A patient is deemed a major violation, if protocol requirements regarding treatment in cycle 1 of 
the initial therapy are severely violated that evaluability for primary end point is questionable. 
All data up until the point of confirmation of a major violation must be submitted. The patient 
will go directly to the event-monitoring phase of the study. The patient may continue treatment 
off-protocol at the discretion of the physician as long as there are no safety concerns, and the 
patient was properly registered. Event monitoring will be required per Section 18.0 of the 
protocol. 
 
13.9b A patient is deemed a cancel if he/she is removed from the study for any reason before any 
study treatment is given. On-study material and the End of Active Treatment/Cancel 
Notification Form must be submitted. The patient will go directly to the event-monitoring phase 
of the study, and event monitoring will be required per Section 18.0 of the protocol. 
 
 
14.0 
Body Fluid Biospecimens   
 
14.1 
Body Fluid Biospecimen Submission  
 
 
14.11 Summary Table of Body Fluid Biospecimens for This Protocol 
Type of 
biospecimen to 
submit 
Mandatory 
or optional 
When to submit 
Reason for submission 
(background/methodology 
section) 
Where to 
find specific 
details for 
specimen 
submission 
Blood/blood 
products (no 
additive whole 
blood) 
Mandatory 
Multiple draws 
(see Section 14.24 
for schedule) 
Defined translational 
studies (Section 14.4) 
Section 14.2 
 
14.2 
Blood/Blood Products Handling  
 
14.21 Kits are required for this study. 
 
14.211 
The kit contains supplies and instructions for collecting, processing, and 
shipping specimens. 
 
14.212 
Participating institutions may obtain kits by completing and faxing the 
Supply Order Form (found in the Forms Packet) to the number listed on the 
form. Fill out the site address to where the kits will be shipped on the Fax 
Supply form. Because we are now being charged for all outgoing kits, a 
small, but sufficient, supply of the specimen collection kits should be ordered 
prior to patient entry. Do not send the unused kits back to Biospecimen 
Accessioning and Processing (BAP) Receiving or the BAP Shared Resource. 


RC1126 
48 
Addendum 10 
 
14.213 
Kits will be sent via FedEx® Ground at no additional cost to the participating 
institutions. Allow at least two weeks to receive the kits. Kits will arrive 
inside the shipping boxes.   
 
14.214 
Kits will not be sent via rush delivery service unless the participating 
institution provides their own FedEx® account number or alternate billing 
number for express service. ACCRU will not cover the cost for rush 
delivery of kits. 
 
14.22 All Samples must be collected Monday – Friday. 
 
14.23 Label specimen tube(s) with protocol number, ACCRU patient ID number, and time 
and date blood is drawn. 
 
14.24 Collect and process all blood/blood products according to specific kit instructions and 
table below. 
 
14.241 
Summary Table of Research Blood/Blood Products to Be Collected for This 
Protocol  
 
Indicate if 
specimen is 
mandatory 
or optional 
Collection 
tube 
description 
and/or 
additive 
(color of 
tube top) 
Volume 
to collect 
per tube 
(number 
of tubes 
to be 
collected) 
Blood 
product 
being 
processed 
and 
submitted by 
participating 
site 
Baseline 
Every 2 cycles 
until 18 
months from 
randomization 
Every 4 
cycles after 
18 months 
until 
progression 
At 
Progression, 
withdrawal, 
removal 
Additional 
processing 
required 
at site 
after blood 
draw? 
Storage 
/shipping 
conditions1 
Mandatory 
None 
(red) 
10 ml (1) 
Serum 
X 
X 
X 
X 
Yes 
Freeze/dry 
ice 
Mandatory 
Purple 
10 ml (1) 
Plasma  
EGFR 
mutation 
X 
X 
X 
X 
Yes 
Freeze/dry 
ice 
Mandatory 
Purple 
10 ml (1) 
Platelet Poor 
Plasma 
VEGF-A 
X 
 
 
 
Yes 
Freeze/dry 
ice 
1. After all samples have been processed according to kit instructions, ship all specimens according to 
shipping instructions (see Section 14.25 for detailed shipping instructions). 
 
14.25 Shipping 
 
14.251 
Verify ALL sections of the Research Blood Submission Form (see Forms 
Packet), BAP Requisition Form (provided in kit) and specimen collection 
labels are completed and filled in correctly. Enter information from the Blood 
Specimen Submission Form into the remote data entry system ≤1 day after 
specimen collection (see Forms Packet). 
 
14.252 
Specimens should be shipped the same day they are drawn unless drawn on a 
Friday.  Then specimens should be stored frozen at -80◦C and shipped on the 
following Monday or Tuesday if Monday is a Federal Holiday. 
 
14.253    Ship all serum and plasma via Priority Overnight service on dry ice. 
14.254     Ship specimens via Priority Overnight service, Monday – Thursday ONLY,       
to BAP Receiving according to kit instructions.  Do not send samples on                            
weekends or just prior to federal holidays. 
 


RC1126 
49 
Addendum 10 
14.255 
BAP kits will include a smart shipper label (3x5 white barcoded label) 
affixed to the shipping boxes.  The smart shipper label is a pre-addressed 
return label which replaces the need for a paper air bill.  Shipping costs will 
be covered by ACCRU if the shipping box is used for shipping specimens to 
BAP Freezer. 
 
14.256 
BAP Freezer will receive the samples and immediately forward specimens to 
the ACCRU Research Coordinating Center BAP Shared Resource, Hilton 
SL-21, Attention: BAP Supervisor. 
 
14.257 
BAP Shared Resource will store specimens according to internal instructions.  
 
14.3 
Other Body Fluids Handling: None 
 
14.4 
Study Methodology and Storage Information 
 
14.41 Blood/blood product samples will be collected for the following research 
 
Plasma EGFR detection: There has been great interest in developing non-invasive 
methods for EGFR genotyping. This would provide a means of non-invasively 
evaluating whether a patient’s tumor harbors an EGFR mutation if such information 
cannot be obtained from their diagnostic tumor biopsy. In addition such a method 
would have the ability to query any changes in EGFR mutations over time and in 
response to treatment. Most studies have found a concordance of ~70% with the tumor 
EGFR mutation.[Bai et al., 2009, Kuang et al., 2009, Rosell et al., 2009] However, very 
few if any studies have performed such analyses prospectively and from treatment naïve 
advanced NSCLC patients that are undergoing treatment with EGFR inhibitors. 
Furthermore, the ability to detect mutations non-invasively will likely increase over 
time with the advent of new and novel technology. As patients need to have a known 
EGFR mutation at study entry, the current trial provides an ideal study in which to 
query the correlation of plasma and tumor EGFR mutations. The correlation with the 
EGFR activating mutation will be performed from the baseline (pre-treatment 
specimen) as all patients will be treatment naïve. 
 
EGFR T790M: EGFR T790M is the common mechanism of drug resistance to erlotinib 
and is detected in up to 60% of EGFR mutant NSCLC patients that develop acquired 
resistance to EGFR kinase inhibitors including erlotinib.[Kobayashi et al., 2005, Pao et 
al., 2005, Oxnard et al., 2011]  In addition to being a drug resistance mutation, this 
mutation is associated with a unique biology. Prior studies have demonstrated that 
patients that develop this mechanism of drug resistance appear to have more indolent 
disease and a better overall survival.[Oxnard et al., 2011] The evolution of this 
mutation during the course of erlotinib therapy has not been prospectively assessed 
from patients undergoing therapy. It will be interesting to determine at which point 
during the course of a patient’s treatment can EGFR T790M be detected from plasma 
DNA and the relationship to clinical progression as defined by RECIST criteria. EGFR 
T790M will be assayed from plasma DNA at baseline and during each radiographic 
assessment and at the time of progression.  
 
 
 


RC1126 
50 
Addendum 10 
Plasma VEGF-A levels: Despite multiple efforts no biomarker has emerged that can 
predict the efficacy of bevacizumab. The only potential exception is pre-bevacizumab 
treatment plasma VEGF-A levels. Plasma VEGF-A level will be evaluated from pre-
treatment plasma levels in both arms of the study and correlated with outcome. The 
goal is to prospectively validate the significance of plasma VEGF-A levels in patients 
treated with erlotinib alone or in combination with bevacizumab.  
 
14.411 
A portion of the serum/plasma will initially be analyzed for the presence of 
EGFR mutation and VEGF-1 in Dr. Pasi Janne’s laboratory, Lowe Center for 
Thoracic Oncology, Dana Farber Cancer Institute, 450 Brookline Ave, 
HIM223, Boston, MA 02215 using standard laboratory protocols. According 
to patient consent information (see Section 6.15), remaining serum/plasma 
will be stored frozen at -70ºC by BAP, until specific analyses are identified.  
As protocols are developed, they will be presented for ACCRU and IRB 
review and approval. (This collection is part of a general strategy of 
investigation for the majority of ACCRU studies.) 
 
14.412 
As part of ongoing ACCRU research, we will collect serum/plasma/platelet 
poor plasma for future research studies, according to patient consent 
information (see Section 6.15), on molecular determinants of efficacy and 
tolerability. Samples will be stored frozen at -70ºC by BAP until specific 
analyses are identified. As protocols are developed, they will be presented for 
ACCRU and IRB review and approval.   
 
14.5 
Return of Genetic Testing Research Results 
 
No genetic specimens will be collected from non-solid tissue (body fluid) biospecimens for this 
study. If future genetic testing is being requested for stored specimens, patient reconsent is 
required. 
 
 
15.0 
Drug Information 
 
Investigator brochures: Investigator brochures for both agents are available on the ACCRU web site 
under study RC1126. 
 
15.1 
Bevacizumab (Avastin)  
 
15.11 Background: Bevacizumab is classified as an Anti-VEGF Monoclonal Antibody and a 
Vascular Endothelial Growth Factor (VEGF) Inhibitor. Bevacizumab is a recombinant, 
humanized monoclonal immunoglobulin G1 (IgG1) antibody which binds to, and 
neutralizes, vascular endothelial growth factor (VEGF), preventing its association with 
endothelial receptors, Flt-1 and KDR. VEGF binding initiates angiogenesis (endothelial 
proliferation and the formation of new blood vessels). The inhibition of microvascular 
growth is believed to retard the growth of all tissues (including metastatic tissue).  
 
15.12 Formulation: Bevacizumab is manufactured by recombinant DNA technology, using a 
genetically engineered Chinese hamster ovary (CHO) cell line. The protein is purified 
from the cell culture medium by routine methods of column chromatography and 
filtration. The final product is tested for quality, identity, safety, purity, potency, 
strength, and excipient/chemical composition according to International Conference on 
Harmonisation (ICH) guidelines. The purity of bevacizumab is > 95%. 
 
 
 


RC1126 
51 
Addendum 10 
Bevacizumab is supplied in 100 mg (4 mL) and 400 mg (16 mL) glass vials, each with a 
concentration of 25 mg/mL. Vials contain bevacizumab with phosphate, trehalose, 
polysorbate 20, and sterile water for injection (SWFI), USP. Vials contain no 
preservative and are suitable for single use only. 
 
15.13 Preparation and storage: Bevacizumab vials should be stored in a refrigerator at 2°C-
8°C. Keep vial in the outer carton due to light sensitivity. DO NOT FREEZE. DO 
NOT SHAKE. 
 
Chemical and physical in-use stability has been demonstrated for 48 hours at 2°C-30°C 
in 0.9% sodium chloride solution. Do not administer or mix with dextrose solution.  
From a microbiological point of view, the product should be used immediately. If not 
used immediately, in-use storage times and conditions are the responsibility of the user 
and would normally not be longer than 24 hours at 2°C to 8°C, unless dilution has taken 
place in controlled and validated aseptic conditions. 
 
Withdraw the necessary amount of bevacizumab and dilute to the required 
administration volume with 0.9% sodium chloride solution. The concentration of the 
final bevacizumab solution should be kept within the range of 1.4 - 16.5 mg/mL. 
Discard any unused portion left in a vial, as the product contains no preservatives. 
Parenteral drug products should be inspected visually for particulate matter and 
discoloration prior to administration. 
 
15.14 Administration: Do not administer as an intravenous push or bolus. Administer only as 
an intravenous (IV) infusion. Do not initiate bevacizumab for 28 days following major 
surgery and until surgical wound is fully healed.    
 
Refer to Section 7 for protocol-specific administration instructions. Guidelines 
recommended by the manufacturer are included for reference. 
 
First infusion: Administer infusion over 90 minutes. Subsequent infusions: Administer 
second infusion over 60 minutes if first infusion is tolerated; administer all subsequent 
infusions over 30 minutes if infusion over 60 minutes is tolerated.  
 
15.15 Pharmacokinetic information: 
Distribution: Vd: 3.28 L  
Half-life elimination: 3-4 weeks 
Clearance: 0.22 L/day. A low serum albumin and high tumor burden increase 
clearance by 30% and 7% respectively.  Clearance increases with increasing 
body weight, and is 15% slower in women than men. 
Time to steady state: 100 days 
 
15.16 Potential Drug Interactions:   
No clnically relevant pharmacokinetic interaction of co-administered chemotherapy on 
bevacizumab pharmacokinetics has been observed based on the results of a population 
PK analysis. There was neither statistical significance nor clinically relevant difference 
in clearance of bevacizumab in patients receiving bevacizumab monotherapy compared 
with patients receiving bevacizumab in combincation with Interferon alpha 2a or other 
chemotherapies (IFL, 5-FU/LV, carboplatin/paclitaxel, capecitabine, doxorubicin or 
cisplatin/gemcitabine).  
 


RC1126 
52 
Addendum 10 
No clinically relevant interactions of bevazizumab was observed on the 
pharmacokinetics of co-administered interferon alpha 2a, erlotinib (and its active 
metabolite OSI-420), or the chemotherapies irinotecan (and its active metabolite 
SN38), capecitabine, oxaliplatin (as determined by measurement of free and total 
platinum), and cisplatin. Conclusions on the impact of bevacizumab on 
gemcitabine pharmacokinetics cannot be drawn. 
 
Combination of bevacizumab and sunitinib malate: In two clinical studies of 
metastatic renal cell carcinoma, microangiopathic hemolytic anemia (MAHA) 
was reported in 7 of 19 patients treated with bevacizumab (10 mg/kg every two 
weeks) and sunitinib malate (50 mg daily) combination. MAHA is a hemolytic 
disorder which can present with red cell fragmentation, anemia, and 
thrombocytopenia. In addition, hypertension (including hypertensive crisis), 
elevated creatinine, and neurological symptoms were observed in some of these 
patients. All of these findings were reversible upon discontinuation of 
bevacizumab and sunitinib malate. 
 
15.17 Known potential adverse events: Consult the investigator’s brochure and 
package insert for the most current and complete information. U.S. Boxed 
Warnings report that  severe or fatal hemorrhage, including hemoptysis, 
gastrointestinal bleeding, hematemesis, central nervous system hemorrhage, 
epistaxis, and vaginal bleeding, occurs up to 5-fold more frequently in patients 
receiving bevacizumab products. Do not administer bevacizumab products to 
patients with a recent history of hemoptysis. Discontinue in patients who develop 
grade 3 to 4 hemorrhage. Percentages reported as Monotherapy and as part of 
combination chemotherapy regimens. 
 
Very Common (≥ 1/10) 
Infections and infestations: paronychia 
Blood and lymphatic system disorders: febrile neutropenia, leucopenia, 
neutropenia, thrombocytopenia 
Metabolism and nutrition disorders: anorexia, hypomagnesemia, hyponatremia 
Nervous system disorders: peripheral sensory neuropathy, dysgeusia, headache, 
dysarthria 
Eye disorders: eye disorder, increased lacrimation 
Vascular disorders: hypertension 
Respiratory, thoracic and mediastinal disorders: dyspnea, epistaxis, rhinitis, 
cough 
Gastrointestinal disorders: diarrhea, nausea, vomiting, abdominal pain, 
constipation, stomatitis, rectal hemorrhage 
Endocrine disorders: ovarian failure 
Skin and subcutaneous tissue disorders: exfoliative dermatitis, dry skin, skin 
discoloration 
Musculoskeletal, connective tissue, and bone disorders: arthralgia 
Renal and urinary disorders: proteinuria 
General disorders and administration site conditions: asthenia, fatigue, pyrexia, 
pain, mucosal inflammation 
Investigations: weight decreased 
 
Common (≥ 1/100 to < 1/10) 
Infections and infestations: sepsis, abscess, cellulitis, infection 
Blood and lymphatic system disorders: anemia, lymphopenia 
Metabolism and nutrition disorders: dehydration 
Cardiac disorders: cardiac failure congestive, supraventricular tachycardia  
Vascular disorders: arterial thromboembolism, deep vein thrombosis, 


RC1126 
53 
Addendum 10 
hemorrhage 
Respiratory, thoracic and mediastinal disorders: pulmonary embolism, hypoxia 
Gastrointestinal disorders: intestinal perforation, ileus, intestinal obstruction, 
recto-vaginal fistula, gastrointestinal disorder, proctalgia 
Skin and subcutaneous tissue disorders: palmar-plantar erythrodysesthesia 
syndrome 
Musculoskeletal, connective tissue, and bone disorders: muscular weakness, 
myalgia, arthralgia, back pain 
Renal and urinary disorders: urinary tract infection 
General disorders and administration site conditions: lethargy 
Reproductive system and breast: pelvic pain 
 
Rare (≥ 1/10,000 to < 1/1,000) 
Infections and infestations: necrotizing fasciitis 
Nervous system disorders: posterior reversible encephalopathy syndrome 
 
15.18 Drug procurement: 
Investigational bevacizumab is provided free of charge to patients by Genentech. Each 
participating ACCRU membership will order a starter supply of bevacizumab from the 
appropriate distribution source.  Fax the appropriate ACCRU Clinical Drug 
Order/Return Form to: 
 
ACCRU Site 
Distribution Source 
Clinical Drug Order / Return Form 
• 
Duke University 
Medical Center 
• 
University of North 
Carolina at Chapel Hill 
Biologics, Inc. 
Attn. Clinical Research 
Services 
FAX: 
 
 
 
(Located in protocol-specific Forms folder) 
All other ACCRU sites 
Medical Oncology 
Pharmacist 
Mayo Clinic 
 
 
 
  
(Located in Non-protocol Specific Forms) 
 
 
Each participating ACCRU membership will be responsible for monitoring the supply 
of bevacizumab and will use the appropriate ACCRU Clinical Drug Order/Return Form 
to order additional supplies as needed.  
 
Outdated or remaining drug is to be destroyed on-site as per procedures in place at 
each institution. 
 
 
 
15.19 Nursing guidelines:  
 
15.191 
Monitor patients closely for infusion type reactions, including fever, chills, 
myalgias, rigors, or other allergic reactions. While this is less likely given that 
bevacizumab is a humanized antibody, there still exists the potential for 
severe allergic reactions. If these signs or symptoms occur stop the infusion 
immediately and contact MD. Have emergency equipment nearby and be 


RC1126 
54 
Addendum 10 
prepared to administer emergency treatment as ordered by MD. 
 
15.192 
Monitor urine dipstick or UPC as required by the test schedule. 
 
15.193 
Evaluate IV site regularly for signs of infiltration. 
 
15.194 
Bleeding in the absence of thrombocytopenia is a dose limiting toxicity. 
Monitor patient closely for hemorrhagic events, including CNS hemorrhage, 
epistaxis, hematemesis and hemoptysis. Most cases of bleeding have occurred 
at the tumor site. Advise patient about the potential for bleeding or 
thrombosis. 
 
15.195 
In patients receiving treatment for lung cancer, hemoptysis and pulmonary 
hemorrhage occurred in up to 10% of patients in one study. Monitor these 
patients especially closely.  
 
15.196 
Patient may experience Grade 1-2 nausea, however vomiting is uncommon. 
Medicate as ordered and monitor for effectiveness.  
 
15.197 
Monitor for skin rash, instruct patient to report to MD. 
 
15.198 
Monitor blood pressure. Administer antihypertensives as ordered by MD. 
 
15.199a 
Monitor for signs and symptoms of deep vein thrombosis (DVT) or 
pulmonary embolism (PE), or myocardial infarction (MI) including new or 
worsening angina. These have been reported with therapy. Instruct patient to 
report any calf pain, chest pain or shortness of breath to MD immediately.  
 
15.199b Asthenia and headache were reported commonly during therapy (in up to 
70% and 50% of patients respectively). Administer acetaminophen as needed. 
Monitor for its effectiveness. Avoid the use of aspirin, or ibuprofen as this 
may interfere with the coagulation cascade and further add to the risk of 
bleeding. 
 
15.199c Monitor CBC, including platelets. Instruct patient to report signs and 
symptoms of infection, unusual bruising or bleeding to the MD. 
  
15.199d Patients receiving warfarin therapy for thrombosis should have their PT or 
INR monitored weekly until two stable therapeutic levels are attained. For 
patients on warfarin for venous access prophylaxis, routine monitoring is 
satisfactory. 
 
15.199e A rare but serious complication of bevacizumab is wound dehiscence. 
Patients who have had recent surgery or have other open wounds should be 
monitored carefully. 
 
15.199f Gastrointestinal perforation with or without abdominal abscess is rare but 
possible. This may present itself as vague abdominal pain associated with 
constipation and vomiting. Instruct patient to report abdominal pain to the 
MD.  
 
15.199g Reversible Posterior Leukoencephalopathy Syndrome (RPLS) is a rare (<1%) 
but serious condition. Presenting symptoms may include changes in mental 
status, visual disturbance, seizure, or other CNS changes. Patients with this 
syndrome generally had HTN as well, therefore BP monitoring is important. 


RC1126 
55 
Addendum 10 
Instruct patient to report any mental status changes, visual changes, seizures, 
or other CNS changes to the MD immediately. These may be a sign of RPLS 
or more serious condition, such as hemorrhagic event in the CNS.  
 
15.199h Warn female patients of the possibility of ovarian failure and subsequent 
infertility. Vaginal hemorrhage is also possible. Instruct patients to report any 
heavy or unusual vaginal bleeding to health care team. 
 
15.199i 
Warn female patients of the risk of rectovaginal fistula. 
 
15.199j 
Agent may cause increased cardiotoxic effects of anthracyclines as well as 
toxic effects of irinotecan, sorafenib, and sunitinib.  Patients who are on dual 
therapy with these agents should be monitored closely. 
 
15.2 
Erlotinib (OSI-774, Tarceva) 
 
15.21 Background: Epidermal growth factor receptor (EGFR) is expressed on the cell surface 
of both normal and cancer cells. In some tumor cells signaling through this receptor 
plays a role in tumor cell survival and proliferation irrespective of EGFR mutation 
status. Erlotinib reversibly inhibits the kinase activity of EGFR, preventing 
autophosphorylation of tyrosine residues associated with the receptor and thereby 
inhibiting further downstream signaling. Erlotinib binding affinity for EGFR exon 19 
deletion or exon 21 L858R mutations is higher than its affinity for the wild type 
receptor. Erlotinib inhibition of other tyrosine kinase receptors has not been fully 
characterized. 
 
15.22 Formulation: Erlotinib is currently formulated as conventional, immediate-release 
tablets in 25 mg, 100 mg, and 150 mg strengths. The tablets are film-coated, round, 
white, and bi-convex. The tablets contain lactose monohydrate, microcrystalline 
cellulose, sodium starch glycolate, sodium lauryl sulfate, hypromellose, hydroxypropyl 
cellulose, titanium dioxide, and magnesium stearate as inactive ingredients. The film 
coating includes Opadry® White. Erlotinib tablets are supplied for clinical trials in 
either bottles or blister packs. 
 
15.23 Preparation and storage: Erlotinib tablets should be stored at 25° C (77°F), with 
excursions permitted to 15°-30° C (59°-86°F). 
 
15.24 Administration: Erlotinib should be taken orally once daily in the morning with water 
at least one hour before or two hours after the ingestion of food. Missed doses should 
not be made up. Avoid grapefruit and grapefruit juice while taking erlotinib. Patients 
should report any change in smoking status while taking erlotinib. 
 
15.25 Pharmacokinetic information: 
a) Absorption – The bioavailability of erlotinib following a single oral Food may 
increase bioavailability.  
b) Distribution – Erlotinib is highly protein bound (92 to 95%) in humans. 
c) Metabolism – Erlotinib is metabolized in humans in the liver by the hepatic 
cytochromes (primarily CYP3A4 and CYP3A5, and to a lesser extent CYP1A2), 
and the pulmonary isoform CYP1A1. 
d) Excretion – Erlotinib and its metabolites are excreted predominately via the feces 
(> 90%), with a small amount recovered in urine. 
 
15.26 Potential Drug Interactions: 
A potential for drug-drug interaction exists when erlotinib is co-administered with 
drugs that are highly protein bound (92% to 95%) or that are potent CYP3A4 


RC1126 
56 
Addendum 10 
inhibitors/inducers. Potent inducers of CYP3A4 activity (eg. rifampicin) increase 
erlotinib metabolism and significantly decrease erlotinib plasma concentrations, while 
potent CYP3A4 inhibitors (eg, ketoconazole) result in increased exposure to erlotinib. It 
has also been shown that co-administration of erlotinib with proton pump inhibitors 
(e.g., omeprazole) decreases the bioavailability of erlotinib and hence the exposure to 
erlotinib and its metabolites.  Co-administration of drugs reducing gastric acid 
production with erlotinib should be avoided where possible. If patients need to be 
treated with such drugs, then an H2-receptor antagonist such as ranitidine should be 
considered and used in a staggered manner.  Erlotinib must be taken at least 2 hours 
before or 10 hours after the H2-receptor antagonist dosing. Erlotinib exposure was 
moderately increased when coadministered with ciprofloxacin, a CYP3A4 and 
CYP1A2 inhibitor.  
 
The combination of erlotinib and a statin may increase the potial for statin-induced 
myopathy, including rhabdomyolysis, which was observed rarely. 
 
Cigarette smoking (a moderate CYP1A2 inducer) has been shown to reduce erlotinib 
exposure by 50% to 60% (Studies OSI-774-103 and OSI-774-107). Smokers should be 
advised to stop smoking. Concomitant use of Tarceva with moderate CYP1A2 inducers 
should be avoided.  
Interaction with coumarin-derived anticoagulants, including warfarin, leading to 
increased INR and bleeding events, which in some cases were fatal, have been reported 
in patients receiving erlotinib. Patients taking coumarin-derived anticoagulants should 
be monitored regulatrly for any changes in prothrombin time or INR.  
 
15.27 Known potential toxicities:  
Adverse Drug Reactions to be Considered Expected in Erlotinib-treated Patients are the 
following: 
Eye Disorders:  Keratitis, ulcerative keratitis, corneal perforation, dry eye, uveitis, 
growth of eyelashes, and conjunctivitis.  
Gastrointestinal Disorders:  Abdominal pain, gastrointestinal hemorrhage, 
gastrointestinal perforation, stomatitis, diarrhea, vomiting, nausea, flatulence, and 
dyspepsia. 
General Disorders and Administration Site Conditions:  Fatigue, chills, and pyrexia. 
Hepatobiliary Disorders:  Hepatitis, hepatic function abnormal, and hepatic failure. 
Infections and Infestations:  Paronychia, sepsis, cellulitis, folliculitis, pneumonia, and 
infection. 
Injury, Poisoning and Procedural Complications:  Radiation pneumonitis. 
Investigations:  Weight decreased 
Metabolism and Nutrition Disorders:  Decreased appetite, hypokalemia, and 
electrolyte imbalance. 
Miscellaneous:  Hair injury or hair color changes. 
Nervous System Disorders:  Peripheral neuropathy and headache. 
Psychiatric Disorders:  Depression 
Renal and Urinary Disorders:  Renal failure 
Respiratory, Thoracic and Mediastinal Disorders:  Acute interstitial pneumonitis, 
cough, lung infiltration, dyspnea, acute respiratory distress syndrome, epistaxis, 
alveolitis, interstitial lung disease, pneumonitis, obliterative bronchiolitis, pulmonary 
fibrosis, and alveolitis allergic. 
Skin and Subcutaneous Tissue Disorders:  Acne, Stevens-Johnson syndrome, rash 
pustular/rash maculo-papular, toxic epidermal necrolysis, dermatitis acneiform, 
dermatitis bullous, dry skin, skin hyperpigmentation, skin exfoliation, hirsutism, 
pruritus, onychoclasis, rash, nail disorder, rash erythematous, alopecia, and skin 
fissures. 
 


RC1126 
57 
Addendum 10 
 
For a complete list of reported erlotinib risks, please see the Consent Form, or the 
current version of the Investigator’s Brochure. 
 
15.28 Drug procurement:  Genentech will supply erlotinib to the ACCRU Research 
Coordinating Center pharmacy.  Each participating ACCRU membership will order a 
starter supply of erlotinib from the appropriate distribution source.  Fax the appropriate 
ACCRU Clinical Drug Order/Return Form to: 
 
ACCRU Site 
Distribution Source 
Clinical Drug Order / Return Form 
• 
Duke University 
Medical Center 
• 
University of North 
Carolina at Chapel Hill 
Biologics, Inc. 
Attn. Clinical Research 
Services 
 
 
 
(Located in protocol-specific Forms folder) 
All other ACCRU sites 
Medical Oncology 
Pharmacist 
Mayo Clinic 
 
 
 
  
(Located in Non-protocol Specific Forms) 
 
 
Each participating ACCRU membership will be responsible for monitoring the supply 
of erlotinib and will use the appropriate ACCRU Clinical Drug Order/Return Form to 
order additional supplies as needed.  
 
Outdated or remaining drug is to be destroyed on-site as per procedures in place at 
each institution. 
 
15.29 Nursing Guidelines:  
 
15.291 Erlotinib should be taken orally once daily in the morning with water at least 
one hour before or two hours after food. Missed doses should not be made up. 
 
15.292 Advise patient of possible rash, pruritus, scaling and peeling of skin. Dose 
reduction may be necessary. Advise patient to cover skin while in the sun, to 
wear sunscreen, and to moisturize skin daily. Instruct patient to report the above 
symptoms immediately to health care team for initiation of treatment. See 
Section 9.9 for treatment recommendations.  Rarely Steven’s Johnson 
Syndrome and toxic epidermal necrolysis are reported. Instruct patient to report 
any oral lesions and or fever immediately. 
 
15.293 Administer antidiarrheals as indicated. Loperamide has been helpful. See 
Section 9.0 for treatment recommendations. 
 
15.294 Caution patients against doubling up on missed doses. If the patient vomits 
after taking the tablets, the dose may be replaced ONLY if the tablets can 
actually be seen and counted in the emesis. 
 
15.295 If patient complains of a dry mouth, advise the use of sugar free candies, ice 
chips, increasing fluid intake, or they may try Xero-Lube, an artificial saliva. 


RC1126 
58 
Addendum 10 
 
15.296 If patient complains of dry eyes, suggest artificial tears. If patient normally 
wears contact lenses, advise against their use.  Additionally patients should 
report any dry eyes, eye pain, or visual changes to the study team. 
 
15.297 Work with the patient that is experiencing weakness and fatigue. Advise 
frequent rest periods.  Instruct patient in energy-saving lifestyle. 
 
15.298 Patients should report any change in smoking status to the study team. 
 
15.299a Although the causal agent is unknown, severe pneumonitis has been diagnosed 
in patients receiving erlotinib. Therefore the physician should be alerted if any 
patients develop new onset or worsening dyspnea, cough, and/or fever. The 
patient should be thoroughly evaluated for possible interstitial pneumonitis. 
 
15.299b Nausea and vomiting are common. Premedicate with antiemetics and evaluate 
for their effectiveness. 
 
15.299c Stomatitis may occur. Encourage proper oral care. 
 
15.299d Instruct patient that they cannot eat grapefruit or drink grapefruit juice while on 
erlotinib. 
 
15.299e Instruct patient that if they smoke they should refrain from smoking while on 
erlotinib as smoking is known to induce CYP1A1 and CYP1A2 and has been 
shown to reduce erlotinib exposure by 50 to 60%. 
 
15.299fMonitor LFT’s.  Instruct patients to report any jaundice or dark colored urine to 
the study team. 
 
16.0 
Statistical Considerations and Methodology  
 
16.1 
Study Design 
 
The goal of this randomized phase II trial is to compare the efficacy of erlotinib / bevacizumab 
(arm B) to erlotinib alone (arm A) in untreated advanced non-small cell lung cancer patients 
who have activating EGFR mutations, for the purpose of screening whether the combination 
regimen (arm B) is worthy of further investigation. Since this phase II trial is not a confirmatory 
study to compare survival benefits between the two treatment regimens, we use a slightly 
inflated Type I error to calculate sample size. The primary endpoint is the progression free 
survival (PFS), which is the time from the date of randomization of eligible patients with 
activating EGFR mutations to the date of disease progression or death of any cause, whichever 
comes first. 
 
For untreated advanced NSCLC patients, the prevalence rate for EGFR mutants are about 15%. 
Patients meeting eligibility criteria will be screened for EGFR mutation; a total of 112 eligible 
patients with EGFR mutations will be randomized with 1:1 allocation to arm A and arm B. 
Randomization will be done using the Pocock and Simon dynamic allocation procedure with 
stratification on gender (male vs. female), and mutation type (exon 19 deletion vs. exon 21 
L858R).  
 
As of Addendum 5, the study size was amended to randomize 86 eligible patients with 1:1 
allocation to Arm A and Arm B.  
 
16.2 
Sample Size, Accrual Time and Study Duration  


RC1126 
59 
Addendum 10 
  
A total of 118 patients with EGFR mutants are expected to register to the study. Taking 5% 
these patients early withdraw before randomization, a total of 112 EGFR patients will be 
randomized. At a randomization rate of 2 patients per months, it will take about 4.7 years to 
reach accrual target. All patients will be followed to the time of final analysis, approximately 12 
months after the last enrollment.  
 
According to current prospective first line trials of EGFR TKI therapy in patients with evidence 
of an activating EGFR mutation, the median PFS for erlotinib only is approximately 13 
months.[Rosell et al., 2009] Investigators look for a 5.6-month increase (43%) in median PFS, 
or a median PFS of 18.6 months for erlotinib/bevacizumab. The following assumptions are 
made while determining the statistical power: (i) the median PFS is 13 months for patients on 
erlotinib only (arm A) and 18.6 months for erlotinib/bevacizumab (arm B), a 43% increase in 
median PFS and a hazard ratio λB/λA = 0.70 under constant hazards; (ii) 112 eligible patients (56 
per arm) with EGFR mutations will be randomized with 1:1 allocation; (iii) an accrual period of 
56 months (4.7 years); and (iv) an additional follow-up of 12 months after the enrollment of the 
last patient. Using a stratified log rank test at a one-sided significance level of 0.20, the study 
has approximately 80% power to reject the null hypothesis λB/λA = 1 and accept the alternative 
hypothesis λB/λA < 1 when the true λB/λA = 0.70. At the time of analysis, or approximately 5.7 
years after the first enrollment, a total of 88 events (47 on arm A and 41 on arm B) are 
anticipated under the alternative hypothesis.  
 
As of March 6, 2015, a total of 38 patients have been randomized. Based on the positive results 
from Seto et al (2014), we amended the sample size of this trial by reducing the hazard ratio 
λB/λA from 0.70 in the original design to 0.667. In particular, we assume that (i) the median PFS 
is 10 months for patients on erlotinib only (arm A) and 15 months for erlotinib/bevacizumab 
(arm B), a 60% increase in median PFS and a hazard ratio λB/λA = 0.667 under constant hazards; 
(ii) 86 eligible patients (43 per arm) with EGFR mutations will be randomized with 1:1 
allocation; (iii) an accrual period of 43 months (3.6 years); and (iv) an additional follow-up of 
12 months after the enrollment of the last patient. Using a stratified log rank test at a one-sided 
significance level of 0.20, the study has approximately 81% power to reject the null hypothesis 
λB/λA = 1 and accept the alternative hypothesis λB/λA < 1 when the true λB/λA = 0.667. At the 
time of analysis, or approximately 4.6 years after the first enrollment, a total of 69 events (37 on 
arm A and 32 on arm B) are anticipated under the alternative hypothesis.  
 
The time of analysis (after first patient enrolled), at which 69 events occur, is estimated to be 53 
months (95% CI=47-55 months). The analysis will be conducted when 69 events have occurred. 
The power of the study design under this timing criterion is approximately 79%. 
 
16.3 
Primary Endpoint and Analysis 
 
The primary endpoint is progression-free survival (PFS). The primary hypothesis is that 
erlotinib / bevacizumab (arm B) will improve PFS relative to erlotinib alone (arm A) in 
untreated advanced non-small cell lung cancer patients who have activating EGFR mutations. 
The relative efficacy in term of PFS in favor of erlotinib / bevacizumab warrants further 
investigator of the experimental regimen in a future phase III trial. The primary analysis will 
include all randomized patients, regardless of the treatment received. Progression free survival 
(PFS) is defined as the time from randomization to disease progression and death of any cause, 
whichever comes first. The primary analysis will be carried out after 88 events have been 
observed. The Kaplan and Meier product limit estimator[Kaplan et al., 1958] will be used to 
graphically describe progression free survival for patients randomized to each treatment arm. 
From these product limit estimates, median survival and 12-month progression free survival rate 
and their 95% confidence intervals by treatment arms will be derived. Comparisons of PFS 
between arms will be conducted using a stratified log rank test.[Mantel, 1966]. The association 
of baseline prognostic factors with PFS, such as performance status, gender and mutation type, 


RC1126 
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Addendum 10 
will be evaluated one by one in univariate analysis. Cox proportional hazards model[Cox, 1972] 
will be used to estimate the adjusted hazard ratios and their 95% confidence intervals of arm B 
relative arm A with adjusting for significant baseline prognostic factors. Interactions between 
treatment and the significant prognostic factors will be tested in a Cox proportional hazards 
model with treatment, prognostic factors and the interaction terms as possible predictors. 
Hazard ratio for treatment effect will be estimated for each subgroup of patients that has 
significant interaction with treatment. The robustness of treatment effects in different patient 
subgroups will examined in Forest plots.  
 
16.4 
Interim Analysis Design for Primary Endpoint 
 
No interim analysis is planned for the primary endpoint. 
 
16.5 
Supplementary Analysis Plans  
 
To address secondary objective 2.21, we will carry out the same set of analyses described in 
section 16.3 for overall survival (OS), which is defined as the time from randomization to death 
of any causes. 
 
To address secondary objective 2.22, we will estimate the proportion of patients who respond 
(completely or partially) to each treatment as well as their 95% confidence intervals. Response 
rates will be tested using Fisher’s exact test and multivariately using a logistic regression model 
with performance status, gender and genetic mutation type and other significant prognostic 
factors.[Cox et al., 1989] 
 
To address secondary objective 2.23, we will estimate the progression free survival of patients 
with different mutation types (exon deletion 19 vs. exon 21 L858R), and test survival difference 
of these subgroups using Cox proportional hazard model after adjusting for treatment effect. 
The robustness of treatment effect in different subgroups will be examined in a Forest plot. 
 
To address secondary objective 2.24, we will tabulate the types and the frequency of treatment-
related adverse events for erlotinib and bevacizumab and erlotinib using CTCAE version 4.0. 
 
To address correlative objective 2.31, we will evaluate the agreement of EGFR mutations 
detected in plasma DNA with those detected in tumor DNA. Since only those patients with 
tumor EGFR mutation will have plasma EGFR mutation determined, we are able to estimate the 
true positive rate (sensitivity) but not the false positive rate (1-specificity).  
 
To address correlative objective 2.32, we will estimate the prevalence of EGFR T790M 
resistance mutations from pre-treatment tumor. 
 
To address correlative objective 2.33, we will investigate the effect of EGFR T790M on 
progression-free survival using similar methods for 2.23.  
 
To address correlative objective 2.34, we will use time-dependent ROC curve and AUC to 
evaluate the predictive value of plasma VEGF-A levels on progression free survival in patients 
treated with erlotinib alone or erlotinib/bevacizumab. 
 
16.6 
Adverse Event Stopping Rule  
 
Overall, if 5 or more of the first 20 patients in the erlotinib and bevacizumab arm (or 25% of all 
patients after 20 are accrued) experience grade 4/5 non-hematologic adverse events (excluding 
diarrhea and rash) that are probably, possibly, or definitely related to study treatment, OR if the 
rate of treatment-related deaths within the first 60 days exceeds 4 or more in either arm among 
the first 20 patients (or >20% after the first 20 patients in either arm) at any time, accrual to the 


RC1126 
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Addendum 10 
study will be suspended to allow for investigation. After consideration by the study team (study 
chair[s], statistician, etc.) and the primary IRB, a decision will be made as to whether accrual 
can be resumed, potentially with modifications to entry criteria and/or study conduct.  In 
addition, all toxicity patterns will be monitored by an independent Mayo Clinic Data Safety 
Monitoring Board on a bi-annual basis. 
 
16.7 
Accrual Monitoring Stopping Rule  
The accrual will be monitored closely by the study team. If the trial is not terminated for 
adverse events or other unexpected reasons, accrual will continue until the target accrual is met, 
approximately 4.7 years after the first enrollment. 
 
As of Addendum 5, the sample size is reduced and the accrual time is shortened to 
approximately 3.6 years.  
 
16.8 
Study Monitoring (reports)  
This study will be monitored by the Mayo Clinic Data Safety Monitoring Board (DSMB).  
Reports containing patient characteristics, toxicity, and administrative information will be 
provided to the DSMB every six months, with the first report due at the first reporting period 
after study initiation. 
 
16.9a 
Missing Data  
Missing and incomplete data will be identified through a review of the tables and listings of 
summarizing available data. Identified missing and incomplete data will be resolved by 
inquiries from data coordinators. In general, unresolvable missing data will be treated as 
missing in all analyses. The secondary endpoints, such as response rate, patients without an 
assessment of disease response will be treated as non-responder. 
 
16.9b Primary Endpoint Completion Time Estimation  
 
It will take additional l2 months of follow-up after the last enrollment to have the primary 
endpoint completion, or equivalently about 5.7 years after the first enrollment.  
 
As of Addendum 5, the sample size is reduced and the time for primary endpoint completion is 
now estimated 4.6 years after the first enrollment.  
 
The time of analysis (after first patient enrolled), at which 69 events occur, is estimated to be 53 
months (95% CI=47-55 months).  The analysis will be conducted after  69 events have 
occurred. 
 
 
 
 


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Addendum 10 
17.0 
Pathology Considerations/Tissue Biospecimens  
 
17.1 
Tissue Biospecimen  
 
 
17.11 Summary Table of Tissue Biospecimens for This Protocol 
Type of tissue 
biospecimen to submit 
Mandatory or 
optional 
When to submit 
Reason for submission 
(background/methodology 
section) 
Where to find 
specific details for  
biospecimen 
submission 
Formalin-fixed paraffin-
embedded (FFPE) tissue 
blocks with 
corresponding H&E 
(OR 15 5-micron 
unstained slides with 2 
corresponding H&E) 
Mandatory 
≤30 days after 
registration 
Correlative Studies 
Assessment of pre-
treatment EGFR T790M 
Section 17.3 
Formalin-fixed paraffin-
embedded (FFPE) tissue 
blocks (OR 5 10-micron 
unstained slides) 
Mandatory 
≤30 days after 
registration 
Correlative studies  
Assessment of tumor status 
performed centrally  
(Section 17.5) 
Section 17.3 
 
Note: If an institution is not able to provide the tissue, it does not cause the patient to be ineligible; however, the 
collection of these tissues is strongly recommended. 
 
17.2 
Diagnostic Slides from Original Tissue: None.  
 
17.3 
Paraffin Embedded Tissue Blocks/Slides  
 
17.31 Submit one formalin fixed paraffin-embedded (FFPE) tumor tissue block with largest 
amount of invasive tumor (at least 1 cm of tumor for cases of surgical resection) from 
original surgery for NSCLC.  A corresponding H&E slide for each submitted block 
must be provided to permit quality assessment of each tissue block.   
 
17.32 The FFPE tissue block is preferred; however, if an institution is unable to provide a 
tissue block, cut 17 five micron sections (labeled 1-17) and mount on charged glass 
slides AND cut 5 ten micron sections (labeled 18-22) and mount on uncharged glass 
slides. Label the slides with ACCRU patient ID number, accession number, order 
of sections (i.e., 1-22) and thickness of section (i.e., 5 or 10 micron). H&E stain every 
10th slide (i.e., slides labeled 1, 11). These H&E slides will be reviewed centrally under 
the research base’s protocol for assessing tissue quality. The remaining unstained slides 
will be processed as described in 17.5. Ideally, each slide must have a minimum of 75% 
tumor tissue on the slide to be deemed adequate for study. Do not bake or place covers 
slips on the slides. 
 
17.33 The following materials below are mandatory (unless indicated otherwise) and required 
for shipment: 
• 
Paraffin embedded tissue blocks with corresponding H&E slide (OR unstained 
slides with corresponding H&E(s) per table in Section 17.11 above). 
• 
Research Tissue Submission Form 
• 
Surgical Pathology Report 
• 
Operative Report (optional) 
 
Note: Please include the ACCRU patient ID number on all materials listed above. 
 


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Addendum 10 
 
17.34 The block/slides must be appropriately packed to prevent damage (e.g., slides should be 
placed in appropriate slide container) and placed in an individual plastic bag. Label the 
bag with the protocol number, ACCRU patient ID number, and patient initials. 
 
17.35 Tissue specimens must be shipped ≤30 days after registration. 
 
17.36 Verify that the appropriate sections of the Research Tissue Specimen Submission Form 
are completed and filled in correctly. Enter information from the Research Tissue 
Specimen Submission Form into the remote data entry system on the same day the 
specimen is submitted (see Forms Packet). 
 
17.37 Ship all block/slide tissue specimens and accompanying materials to the ACCRU 
Research Base: 
 
ACCRU Operations Office 
 
 
 
17.38 If a corresponding H&E wasn’t submitted with the block/slides, the ACCRU 
Operations Office will request a slide to be processed (i.e., cut and H&E stained) from 
the tumor tissue block and forwarded the cytotechnologist, Hilton 10, to be reviewed 
under the research base’s protocol for assessing tissue quality for the proposed 
correlative studies, unless the tumor size is too small.  If the tumor tissue is too small, 
assessment of tissue quality will occur at the time the translational studies are 
performed. 
 
17.39a After the pathologist assesses the tissue quality, the block and appropriate paperwork 
will be returned to the ACCRU Operations Office. 
 
17.39b When an appropriate request is submitted, the ACCRU Operations Office will forward 
the blocks/slides to the Dana Farber Cancer Institute Translational Research Laboratory 
 for processing as outlined in Section 
17.5. 
 
17.4 
Frozen Tumor Tissue :None 
 
17.5 
Study Methodology and Storage Information 
 
17.51 A secondary goal of this study is to determine whether the pre-existence of the EGFR 
T790M drug resistance mutation predicts for a worse clinical outcome with EGFR 
inhibitor therapy. EGFR T790M was first identified in 2004 as a co-mutation with 
L858R in a pretreatment lung cancer specimen, one of 111 EGFR-mutant tumors 
studied.[Kosaka et al., 2004] In 2006, it was shown that with more sensitive testing 
methods (mutant-enriched PCR) T790M could be found in 4% of pretreatment EGFR-
mutant lung cancers,[Inukai et al., 2006] and these cases were found to not respond to 
TKI. More recently, both Maheswaran et al and Rosell et al found that, with multiple 
cycles of DNA amplification, highly sensitive assays could detect a T790M co-mutation 
in as many as 38% of baseline specimens,[Maheswaran et al., 2008, Rosell et al., 2011] 
making it a potential biomarker of poorer outcome on TKI. However, these studies 
were both performed with techniques that can be associated with false positive results 
thus obscuring the potential clinical relevance of this mutation if detected from a pre-
treatment tumor specimen.  


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Addendum 10 
 
In the current study we will evaluate EGFR T790M from pre-treatment specimens using 
techniques that are optimized to prevent false positive amplifications of T790M. These 
include the use of a locked nucleic acid (LNA) to block amplification of wild-type 
DNA allows identification of T790M in as little as 0.1% of DNA (Arcila, CCR, 2011). 
A new T790M assay developed at DFCI and by Transgenomic Inc. and uses 
coamplification at a lower denaturation temperature (COLD)-PCR.[Li et al., 2009] By 
further blocking amplification of wild-type DNA, this technique could prevent the 
appearance of false peaks and reduce the risk of false positive results. 
 
We will evaluate the prevalence of EGFR T790M from pre-treatment tumor specimens. 
In addition, we will correlate the outcome of patients (as measured by progression free 
survival) with and without evidence of pre-treatment T790M in each arm of the study.  
The ability to perform these studies will be dependent on the pre-treatment prevalence 
of EGFR T790M in patients enrolling in this clinical trial.  
 
Submitted tissue samples will be analyzed as follows:  
 
17.52 FFPE tumor tissue blocks/slides will be collected in order to assess the prevalence of 
baseline EGFR T790M and to correlate the findings with progression free survival in 
each of the treatment arms. The H&E slides will be reviewed by a cytotechnologist to 
assess tumor content of the specimen. Appropriately identified tumor sections will then 
be used to isolate DNA. The analyses for EGFR T790M will be performed in Dr. 
Jänne’s laboratory at the Dana Farber Cancer Institute. They will be performed in a 
blinded fashion without knowledge of patient outcome or treatment arm of the study.  
 
17.53 At the completion of the study, any unused/remaining material will be stored in the 
ACCRU Central Operations Office (attn: Pathology Coordinator) for future research 
according to the patient consent permission (see Section 6.16). Potential future research 
may include immunohistochemistry (IHC) analyses, DNA extraction, and/or tissue 
microarray (TMA) construction to analyze predictive biomarkers, changes in expression 
pattern with therapy, and correlation with response and/or adverse events. For TMAs, 
the donor block remains intact except for 6 small (0.6mm) holes where the cores were 
taken. This process has minimal impact on the utility of the block for future clinical 
diagnostic needs. When a protocol is developed, it will be presented for IRB review and 
approval. 
 
17.54 Banking of tumor tissue, according to the patient consent permission (see Section 6.5), 
is for future research. As protocols are developed, they will be presented for ACCRU 
and IRB review and approval. (This collection is part of a general strategy of 
investigation for Mayo Clinic Cancer Center lung studies.) 
 
17.55 The institutional pathologist will be notified by the ACCRU Operations Office 
(Pathology Coordinator) if the block may be depleted. 
 
17.56 Blocks requested to accommodate individual patient management will be returned 
promptly upon request. 
 
 
 


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Addendum 10 
17.6 
Return of Genetic Testing Research Results  
Because the results generated by the genetic testing included in this section are not currently 
anticipated to have clinical relevance to the patient or their family members, the genetic results 
will not be disclosed to the patients or their physicians. 
 
 
If, at any time, genetic results are obtained that may have clinical relevance, IRB review and 
approval will be sough regarding the most appropriate manner of disclosure and whether or not 
validation in a CLIA certified setting will be required. Sharing of research data with individual 
patients should only occur when data have been validated by multiple studies and testing has 
been done in CLIA-approved laboratories. 
 
 
18.0 
Records and Data Collection Procedures 
 
18.1 
Submission Timetable 
 
Initial Material(s) -  
CRF 
Active-Monitoring Phase 
(Compliance with Test Schedule Section 4.0) 
On-Study Form 
 
 
 
 
≤2 weeks after registration 
Baseline Adverse Event Form 
Pretreatment RECIST Measurement Form 
Baseline Research Blood Submission Form 
(see Section 14.0)2 
Baseline Research Tissue Submission Form 
(see Section 17.0) 
OP and Path Reports (see Section 17.0)1  
CD Submission Form3 
End of Active Treatment/Cancel Notification 
Form 
Submit ≤2 weeks after registration if withdrawal/refusal 
occurs prior to beginning protocol therapy 
 
1. Submit copy to the ACCRU Ops Office, Attn. QAS for RC1126. This is in addition to the pathology 
material requirements for tissue submission (Section 17.0). 
2. Submit ≤1 day after specimen collection. 
3. Submit relevant radiographic images as a digital image (via CD) with a viewing tool free of marks 
that may obscure the lesions or bias the evaluation of the independent reviewer(s) of tumor response 
at baseline and tumor response and/or progression. Submit CD’s labeled with study number 
(RC1126), ACCRU patient ID, patient initials, and visit date to the
 
 
 
 
 
 


RC1126 
66 
Addendum 10 
Test Schedule Material(s) -  
CRF 
Active-Monitoring Phase 
(Compliance with Test Schedule Section 4.0) 
 
At each evaluation 
during treatment 
At end of 
treatment 
 
Observation 
(All Patients) 
Evaluation/Treatment Form 
X3 
X 
 
Evaluation/Observation Form 
 
 
X2 
Adverse Event Form 
X 
X 
X 
RECIST Measurement Form 
X1,4 
X1,4 
X1,4 
 
Research Blood Submission Form 
X (see Section 14.0) 
 
 
CD Submission Form5 
At each occurrence5 
 
 
End of Active Treatment/Cancel Notification 
Form 
 
X 
 
Notification Form – Grade 4 or 5 Non-AER 
Reportable Events/Hospitalization Form 
At each occurrence 
(see Section 10.0) 
 
 
ADR/AER 
At each occurrence 
(see Section 10.0) 
 
 
1. Submit copy of documentation of response or progression to the 
 
2. Complete at each evaluation during Observation (see Section 4.0). 
3. Complete at each evaluation during Active Treatment (see Section 4.0). 
4. Patients should undergo imaging for disease progression every 2 cycles for the initial 18 months, 
then after 18 months every 4 cycles until disease progression. 
5. Submit relevant radiographic images as a digital image (via CD) with a viewing tool free of marks 
that may obscure the lesions or bias the evaluation of the independent reviewer(s) of tumor response 
at baseline and tumor response and/or progression. Submit CD’s labeled with study number 
(RC1126), ACCRU patient ID, patient initials, and visit date to the
 
 
 
Follow-up Material(s) -  
CRF 
Event Monitoring Phase1 
 
 
q. 3 
months 
until PD 
 
 
 
At PD 
 
After 
PD q. 6 
mos. 
 
 
 
Death 
 
 
 
New Primary 
Event Monitoring Form3 
X2 
X2 
X 
X 
At each occurrence 
1. If a patient is still alive 6 years after randomization, no further follow-up is required. 
2. Submit copy of documentation of response or progression to the ACCRU Operations Office, 
Attention:
 
3. If patient discontinues treatment due to PD, complete the Event Monitoring Form at the time of PD 
and then complete Observation (21-42 days after treatment discontinuation) phase and continue on 
the Event Monitoring Phase. 
 
 
 
 


RC1126 
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Addendum 10 
19.0 
Budget 
 
19.1 
Costs charged to patient: Each site should review the test schedule (Section 4.0),  taking into 
account local and regional coverage policies, to determine which items are standard of care and 
which are research at their site. Refer to the payment synopsis for funding provided per accrual 
for covering study costs, as well as any additional invoiceables that may be allowed. 
 
19.2 
Tests to be research funded: Research blood kits/collection and tissue collection. 
 
19.3 
Other budget concerns: Bevacizumab and erlotinib will be provided free of charge by 
Genentech.   
 
 
 


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Addendum 10 
20.0 
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Addendum 10 
and Resistance of Non-Small-Cell Lung Cancer to Gefitinib. N Engl J Med 352: 786-792. 
 
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Appendix I 
Addendum 10 
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Appendix II 
Addendum 10 
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Appendix III 
Addendum 10 
Page 1 of 1