Clinical trial NCT02045446
Conditions: Stage IV Non-Small Cell Lung Cancer
Sponsor: University of Texas Southwestern Medical Center
Start date: 2014-02-01; Completion date: 2022-05-02
Enrollment: 29 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The core hypothesis to be tested is that the use of consolidative SBRT followed by maintenance chemotherapy in patients with less than or equal to 6 metastatic sites (primary + 5) will improve progression free survival (PFS) compared to maintenance chemotherapy alone.

Detailed description:
This protocol is a randomized phase II trial of maintenance chemotherapy versus consolidative Stereotactic Body Radiation Therapy (SBRT) plus maintenance chemotherapy for patients with Stage IV non-small cell lung cancer (NSCLC).

Prior to accrual on the trial, patients with Stage IV NSCLC will be treated with standard first-line chemotherapy. Patients who achieve a partial response or stable disease by imaging criteria with fewer than or equal to six sites of oligometastatic disease will be randomized to maintenance chemotherapy or consolidative SBRT to all sites of disease (followed by maintenance chemotherapy at the medical oncologist's discretion). Choices of first line and maintenance chemotherapy will be determined by the medical oncologist based on clinical appropriateness.

Arms: arm 1: FDA approved drugs for the study population: Bevacizumab, Docetaxel, Erlotinib, Gemcitabine, Pemetrexed arm 2: consolidative Stereotactic Body Radiation Therapy (SBRT) plus maintenance chemotherapy
Interventions: intervention 1: Stereotactic Body Radiation Therapy intervention 2: Maintenance chemotherapy
Intervention descriptions: intervention 1: None intervention 2: Maintenance chemotherapy

Protocol documents:
Prot_SAP_002.pdf: 
Official Title: Maintenance Chemotherapy Versus Consolidative Stereotactic Body 
Radiation Therapy (SBRT) plus Maintenance Chemotherapy for Stage IV Non-Small 
Cell Lung Cancer (NSCLC): A Randomized Phase II Trial 
 
NCT #: 02045446 
 
Document Date: 05/23/2019 
 
Version: 3 
 


STU 092013-070 
Maintenance Chemotherapy Versus Consolidative Stereotactic Body Radiation 
Therapy (SBRT) plus Maintenance Chemotherapy for Stage IV Non-Small Cell 
Lung Cancer (NSCLC): A Randomized Phase II Trial 
 
 
PRINCIPAL INVESTIGATORS: 
 
 
Puneeth Iyengar, MD, PhD 
 
 
 
David Gerber, MD 
Department of Radiation Oncology      
 
Department of Hematology and Oncology 
Simmons Comprehensive Cancer Center                 Simmons Comprehensive Cancer Center 
UT Southwestern Medical Center                             UT Southwestern Medical Center5801 
5801Forest Park Road, Dallas, Texas 75390           5323 Harry Hines Blvd, Dallas, TX75235                               
puneeth.iyengar@utsouthwestern.edu 
 
david.gerber@utsouthwestern.edu 
 
CO- INVESTIGATORS: 
 
 
 
Robert Timmerman, MD 
Hak Choy, MD 
Department of Radiation Oncology  
 
Department of Radiation Oncology 
Simmons Comprehensive Cancer Center 
 
Simmons Comprehensive Cancer Center 
UT Southwestern Medical Center                              UT Southwestern Medical Center 
5801 Forest Park Road, Dallas, TX 75390            5801 Forest Park Road, Dallas, TX 75390 
robert.timmerman@utsouthwestern.edu 
 
hak.choy@utsouthwestern.edu 
 
Zabi Wardak, MD                                                       Kenneth Westover, MD, PhD 
Department of Radiation Oncology                            Department of Radiation Oncology 
Simmons Comprehensive Cancer Center                 Simmons Comprehensive Cancer Center 
UT Southwestern Medical Center                              UT Southwestern Medical Center 
5801 Forest Park Road, Dallas, TX 75390             5801 Forest Park Road, Dallas, TX 75390                           
zabi.wardak@utsouthwestern.edu                             Kenneth.westover@utsouthwestern.edu 
                                                     
 
Jonathan Dowell, MD                                                Randall Hughes, MD 
Department of Hematology and Oncology                Department of Hematology and Oncology 
Simmons Comprehensive Cancer Center                 Simmons Comprehensive Cancer Center 
UT Southwestern Medical Center                             UT Southwestern Medical Center 
5323 Harry Hines Blvd, Dallas, TX 75235             5323 Harry Hines Blvd, Dallas, TX 75235 
Jonathan.dowell@utsouthwestern.edu                     Randall.hughes@utssouthwestern.edu 
 
Saad Khan, MD                                                        Joan Schiller, MD 
Department of Hematology and Oncology               Department of Hematology and Oncology 
Simmons Comprehensive Cancer Center                Simmons Comprehensive Cancer Center 
UT Southwestern Medical Center                             UT Southwestern Medical Center 
5323 Harry Hines Blvd, Dallas, TX 75235                5323 Harry Hines Blvd, Dallas, TX 75235 
Saad.khan@utsouthwestern.edu                              joan.schiller@utsouthwestern.edu 
 
 
 
 
 


ii 
 
 
 
Biostatistician:  
 
 
Chul Ahn, Ph.D. 
Professor of Biostatistics 
Department of Clinical Sciences & Simmons 
Comprehensive Cancer Center 
UT Southwestern Medical Center 
 
xian-jin.xie@utsouthwestern.edu  
 
Project Manager: 
 
 
Jean Wu  
Clinical Research Manager 
Dept. of Radiation Oncology 
UT-Southwestern School of Medicine 
                                                           5641  Southwestern Medical Avenue, Dallas, TX 
75235 
214-633-1753 
jean.wu@utsouthwestern.edu 
 
Initial version:  
 
 
November 7, 2013 
 
Version 1: 
 
 
            March 28, 2014 
 
 
 
Version 2: 
 
 
            March 02, 2015 
Version 3: 
 
 
 
May 23, 2019 
 


iii 
 
Signature Page 
 
 
The signature below constitutes the approval of this protocol and the attachments, and provides the 
necessary assurances that this trial will be conducted according to all stipulations of the protocol, including 
all statements regarding confidentiality, and according to local legal and regulatory requirements and 
applicable U.S. federal regulations and ICH guidelines. 
 
 
 
Principal Investigator (PI) Name:_____________________________ 
 
 
 
PI Signature: _____________________________ 
 
 
 
Date:____________________ 
 
 
 
 


 
TABLE OF CONTENTS 
 
PROTOCOL SYNOPSIS……………………………………………………………………….1 
 
SCHEMA………………………………………………………………………………………...2 
 
1.  
INTRODUCTION………………………………………………………………………..3 
1.1  
Maintenance Chemotherapy for Non-Small Cell Lung Cancer 
1.2 
Rationale for Stereotactic Body Radiation Therapy (SBRT) 
1.3 
EGFR Mutation/ ALK-Positive Mutation 
1.4 
Study Rationale 
1.5 
Study Design 
 
2.  
OBJECTIVES…………………………………………………………………………..8 
2.1 
Primary 
2.2 
Secondary 
 
3. 
TRIAL POPULATION………………………………………………………………….8 
3.1 
Inclusion criteria 
3.2 
Exclusion criteria 
 
4.  
SBRT DOSE AND TECHNIQUES……………………………………………………9 
4.1 
SBRT Prescription Dose  
4.2 
Planning Constraints and Concerns 
4.3 
Technical Factors 
4.4 
Simulation/Image Guidance 
4.5 
Treatment Planning/Target Volumes 
4.6 
Dosimetry 
4.7 
Normal Tissue Dose Constraints 
4.8 
Radiation Therapy Quality Assurance 
 
5. 
Study Medications……………………………………………………………………16 
5.1 
Erlotinib (Tarceva) 
5.2 
Pemetrexed (Alimta) 
5.3 
Docetaxel (Taxotere) 
5.5 
Gemcitabine (Gemzar) 
5.5 
Bevacizumab (Avastin) 
 
6. 
CLINICAL AND LABORATORY EVALUATIONS………………………………...21 
6.1 
Study Calendar 
6.2 
Follow-up Schedule 
 
7. 
CRITERIA FOR STUDY DISCONTINUATION…………………………………….22 
 
8. 
DATA SAFETY AND MONITORING PLAN………………………………………..22 
 


 
9. 
EVALUATION OF PROGRESSION……………………………………………….26 
 
10. 
STATISTICAL CONSIDERATIONS……………………………………………….26 
 
11. 
DATA COLLECTION AND PATIENT REGISTRATION………………………...28 
 
12. 
RETENTION OF RECORDS……………………………………………………….28 
 
13. 
APPENDICES………………………………………………………………………..29 
 
14. 
REFERENCES……………………………………………………………………….41 
 
 


 
PROTOCOL SYNOPSIS 
 
Summary 
 
This protocol is a randomized phase II trial of maintenance chemotherapy versus consolidative 
Stereotactic Body Radiation Therapy (SBRT) plus maintenance chemotherapy for patients with 
Stage IV non-small cell lung cancer (NSCLC). The core hypothesis to be tested is that the use 
of consolidative SBRT followed by maintenance chemotherapy in patients with less than or 
equal to 6 metastatic sites (primary + 5) will improve progression free survival (PFS) compared 
to maintenance chemotherapy alone. 
 
Prior to accrual on the trial, patients with Stage IV NSCLC will be treated with standard first-line 
chemotherapy.  Patients who achieve a partial response or stable disease by imaging criteria 
with fewer than or equal to six sites of oligometastatic disease will be randomized to 
maintenance chemotherapy or consolidative SBRT to all sites of disease (followed by 
maintenance chemotherapy at the medical oncologist’s discretion). Choices of first line and 
maintenance chemotherapy will be determined by the medical oncologist based on clinical 
appropriateness.  Preliminary data from an earlier phase II single arm study with SBRT plus 
Tarceva demonstrated significant PFS and OS with limited toxicity in patients with limited 
metastatic stage IV NSCLC who progressed through first line platinum doublet chemotherapy 
when compared to historical findings (unpublished data). The goal of the former study was to 
validate the potential role of cytoreduction in promoting progression free survival.   
 
The primary endpoint of the current proposed study is progression free survival. The estimated 
progression free survival is 5 months for patients treated with maintenance chemotherapy alone 
based on historical data from randomized phase III trials. We anticipate an improvement of 
progression free survival to 10 months with the addition of SBRT in patients with stable or partial 
response to first line therapy with oligometastatic disease. This estimate of improved 
progression free survival is in part based on our prior phase II protocol for patients with Stage IV 
NSCLC with progression of disease on first line therapy treated with SBRT and Erlotinib. 
Progression free survival in that study was 10.7 months. Our estimates are also based on the 
experiences of several studies that have examined radiation in consolidative fashion to systemic 
therapy for oligometastatic disease.   
 
A two-sided log-rank test with an overall sample size of 36 patients (18 patients in the 
maintenance chemotherapy arm and 18 patients in the SBRT arm) achieves 80% power at a 
10% significance level to detect a hazard ratio of 0.4000 when the median progression-free 
survival (PFS) times are 4 and 10 months in the maintenance group and SBRT treated group, 
respectively. Patients will be accrued within 24 months with a follow-up period of 12 months 
after the end of the accrual period. 
 
 
 
 
 
 
 
 
 


 
Schema 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
1. 
INTRODUCTION 
 
Lung cancer is a leading cause of cancer-related mortality. An estimated 228,190 new cases of 
lung cancer are expected in 2013 in the United States with an estimate of approximately 
160,000 deaths [1].  While advances in local and systemic therapy have been achieved in 
recent years, there remains a great need for improvement in clinical management. 
Approximately two-thirds of patients present with advanced stage non-small cell lung cancer 
(NSCLC) and often are treated with chemotherapy alone [2]. It remains a poorly controlled and 
fatal disease, with estimates of median survival of 11 months following first line chemotherapy 
with a platinum doublet [3].  
 
The principle of oligometastases was well popularized in 1995 by Hellman and Weichselbaum 
who hypothesized that metastastic disease occurs in a step-wise manner, initially with limited 
metastases followed by progression to widespread disease. Early on, metastases may be 
limited in number and location based on interaction of tumor cells with target organs in a “seed 
and soil” pattern [4,5]. With improvements in imaging, including PET/CT and MRI, identification 
of isolated metastatic deposits is accomplished with higher sensitivity and specificity than ever 
before. A significantly greater proportion of patients may be identified early in the metastatic 
spectrum and offered potentially curative local treatment, creating a new paradigm in the 
management of limited volume metastatic NSCLC. The traditional grouping of all patients with 
metastatic disease may no longer be relevant with potential implications in changing of tumor 
staging. 
 
Support for the benefit provided by treatment of oligometastases was first derived from surgical 
metastectomy. Patients treated with surgical resection of hepatic, pulmonary, or adrenal 
metastases have had improved rates of survival with resection [6-8]. Furthermore, 
advancements in systemic therapy may convert a greater proportion of patients with widely 
metastatic disease to a limited volume metastatic state. With current first line platinum doublet 
chemotherapy, up to 70-80% of patients achieve either a partial response or stable disease [9]. 
In those patients who do show progression of disease, up to 65% progress only at sites present 
prior to the start of first line chemotherapy [10]. This represents a large cohort of patients who 
may be candidates for early treatment of oligometastatic disease.  
 
Systemic maintenance therapy with targeted and cytotoxic agents has now shown statistically 
significant benefits in both progression free and overall survival. By intervening with non-
invasive locally ablative stereotactic therapy prior to maintenance chemotherapy there is the 
potential for further benefits in PFS and/or OS. Stereotactic radiotherapy has the advantage 
over surgical metastectomy in that there is minimal toxicity with quicker recovery and limited 
delay in initiation of maintenance chemotherapy. 
 
1.1 
Maintenance Chemotherapy for Non-Small Cell Lung Cancer   
 
The introduction of maintenance chemotherapy has led to statistically significant, albeit modest, 
gains in progression free survival and overall survival following standard first line platinum 
doublet chemotherapy (Table 1). Drugs used for maintenance chemotherapy can be considered 
either cytotoxic or biologic and include Docetaxel, Pemetrexed, Erlotinib, Gefitinib, Gemcitabine, 
and Bevacizumab. Maintenance chemotherapy can be given as continuation maintenance, 
utilizing one or more first line drugs, or as switch maintenance, utilizing a previously unused 


 
drug. A recent meta-analysis has proven the benefit of switch maintenance over continuation 
maintenance in both overall survival and progression free survival in the stage IV NSCLC 
population [11]. Unfortunately, these drugs alone provide modest gains and oblige patients to 
indefinite chemotherapy with their associated toxicities.   
 
Table 1. 
Study/Author 
Drug 
PFS (months) 
OS (months) 
Ciuleanu et al 
Pemetrexed 
4.3 vs 2.6* 
13.4 vs 10.6* 
 
PARAMOUNT 
Pemetrexed 
4.1 vs 2.8* 
13.9 vs 11.0* 
 
Capuzzo et al 
Erlotinib 
2.8 vs 2.6* 
12 vs 11* 
 
Brodowicz et al 
Gemcitabine 
3.6 vs 2.0* 
13 vs 11 
 
EORTC 08021 
Gefitinib 
4.1 vs 2.9* 
10.9 vs 9.4 
 
Fidias et al 
Docetaxel 
5.7 vs 2.7* 
12.3 vs 9.7 
 
  INFORM 
 
Gefitinib 
4.8 vs 2.6* 
18.7 vs 16.9 
 
AVAPERL 
Pemetrexed + 
Bevacizumb vs 
Pemetrexed 
 
7.4 vs 3.7* 
Pending 
* Statistically significant (p <0.05) 
 
1.2 
Rationale for Stereotactic Body Radiation Therapy (SBRT) 
 
Stereotactic body radiation therapy (SBRT) is an emerging treatment paradigm defined in the 
American Society of Therapeutic Radiology and Oncology guidelines as a “treatment method to 
deliver a high dose of radiation to the target, utilizing either a single dose or a small number of 
fractions with a high degree of precision within the body” [12]. 
 
SBRT allows the delivery of ablative treatment doses using highly conformal radiotherapy to an 
increasing number of sites in the body. By providing treatment as a short course of therapy, 
patients are not subjected to prolonged treatment times that may compromise quality of life.  
Treatment is delivered non-invasively and with an increasing body of data supporting its 
tolerability with limited toxicity. 
 
To date, there have been no successful, prospective randomized studies which examine the 
role of locally aggressive therapy in limited volume stage IV NSCLC. The NCCTG initiated a 
randomized phase III trial in patients with stage IV NSCLC, treating 1 to 3 sites of metastatic 
disease following 4-6 cycles of systemic therapy. Stereotactic body radiotherapy was not used. 
Patients were treated with traditional fractionation to 60 Gy in 30 fractions or 45 Gy in 15 
fractions. Unfortunately, this study closed due to poor accrual [13]. A second study from the 
University of Chicago randomized patients with oligometastatic NSCLC to SBRT during the third 
and fourth cycle of docetaxel/cisplatin first line chemotherapy. Unfortunately, this study also had 
difficulty with accrual and closed early [14].  Currently, a single arm phase II trial at Wake Forest 


 
University is the only SBRT study open and accruing patients with limited volume stage IV 
NSCLC [15].   
 
Preliminary data from our earlier phase II single arm study demonstrated statistically significant 
improvements in both PFS and OS in patients with Stage IV NSCLC treated with SBRT plus 
Tarceva. The patient population chosen in this study was unique, with treatment limited to 
patients who progressed through first line platinum doublet chemotherapy and with limited 
metastases. Historically, the outcomes in this population are extremely poor. Nonetheless, in 
this study progression free survival was 10.7 months with median overall survival of 20.8 
months. Furthermore, in patients tested for the EGFR mutation, 0/10 patients were positive. It is 
known that the benefit of Tarceva is most significant in patients who possess the EGFR 
mutation which lends support to the notion that locally ablative radiotherapy proves effective in 
improving progression free and overall survival [16]. 
 
Retrospective data from the University of Chicago is available for patients with oligometastatic 
NSCLC treated with SBRT to 1 to 5 sites of metastatic or primary disease following systemic 
therapy. Patients were treated to all known sites of active disease at a minimum of two weeks 
following first line systemic therapy. The most commonly used fractionation schedule was 50 Gy 
in 10 fractions. A total of 62 lesions were treated in 25 patients with a median of 2 lesions 
treated per patient. The median lesion size was 2.65 cm. Treatment was well tolerated with only 
2 patients suffering Grade 3 toxicity. With a median follow-up of 14 months, the median PFS 
was 7.6 months and median OS was 22.7 months. Progressive disease was identified in 52% of 
patients following initial first-line chemotherapy. Analysis of PFS and OS in patients with 
progressive versus stable/regressive disease following first line chemotherapy showed the 
former population to possess significantly worse PFS and OS relative to the latter. Despite the 
significant number of patients with progressive disease the results of this study show a PFS that 
is higher than those achieved by maintenance chemotherapy alone [17].  
 
Further support for selection of patients with stable or partial response to first-line chemotherapy 
is available from the University of Rochester. Patients with up to five sites of oligometastatic 
disease of any histology were treated to all sites of disease with SBRT. There were 121 patients 
enrolled prospectively with 74% treated to 50 Gy in 5 fractions. Patients who achieved a 
response or stable disease to initial systemic therapy prior to SBRT showed significantly higher 
rates of overall survival and freedom from distant metastases compared to those with 
progressive disease following initial systemic therapy [18]. 
 
A retrospective review of patients treated at the University of Rochester compared outcomes of 
patients with stage III NSCLC treated with curative intent radiotherapy against patients with 
limited volume stage IV NSCLC who received SBRT. Oligometastases was expanded in this 
review to fewer than 8 sites of disease. Patients with stage III NSCLC were treated to an 
average dose of 60 Gy via a 3-D conformal technique with or without chemotherapy. Patients 
with limited volume metastases were treated with SBRT to a dose of 50-60 Gy in 5-10 fractions. 
Patients with limited volume stage IV NSCLC treated with SBRT had higher rates of 5-year 
survival relative to patients with stage III NSCLC treated definitively, 14% vs 7%, respectively. 
The 5-year survival data for Stage III patients was lower than expected in this study, however, 
the survival of patients with limited volume stage IV NSCLC is comparable to historical data of 
patients with stage III NSCLC treated definitively [19]. 
 


 
The most commonly treated sites of metastatic disease with SBRT are sites within the lung and 
liver. A recent multi-institutional Phase I/II trial from the University of Colorado enrolled patients 
with 1-3 pulmonary metastases from a solid tumor, cumulative tumor diameter < 7 cm, and 
adequate pulmonary function (FEV1 > 1.0 L, DLCO > 40%).  The planning target volume (PTV) 
was constructed from the gross tumor volume (GTV)  by expanding 5 mm radially and 10 mm 
craniocaudally, and 7 mm radially and 15 mm craniocaudally, when using active breathing 
control and abdominal compression, respectively. In the initial phase, the SBRT dose was 
escalated from 48 Gy to 60 Gy in 3 fractions. The percent of normal lung receiving more than 15 
Gy (V15) was restricted to less than 35%.  Dose-limiting toxicities (DLT) included acute grade 3 
lung or esophageal toxicity or any acute grade 4 toxicity. Thirty- eight patients were enrolled on 
the study, 9 patients in the Phase I portion and 29 on Phase II, receiving 60 Gy in 3 fractions, for 
a total of 63 lesions treated. With a median follow-up of 15.4 months, the actuarial in-field local 
control at 2 years was 96% with a median overall survival of 19 months. Treatment was well 
tolerated with only 7.9% of the population suffering grade 3 toxicity with no grade 4 or 5 toxicity 
[20]. 
 
A second multi-institutional Phase I/II trial from the University of Colorado enrolled patients with  
1-3 liver metastases from any solid tumor, cumulative maximum tumor diameter < 6 cm, 
adequate liver and kidney function, and no chemotherapy 14 days before or after SBRT.  In the 
phase I portion the SBRT dose was escalated from 36 Gy to 60 Gy in 3 fractions. Thirteen 
patients were treated with a dose of less than 60 Gy and 36 patients treated at 60 Gy, for a total 
of 63 hepatic lesions.  Volume delineation was similar to that in the lung oligometastases trial, 
with the PTV defined as as GTV expanded by 5 mm radially and 10 mm craniocaudally, and 7 
mm radially and 15 mm craniocaudally, with active breathing control and abdominal 
compression, respectively.  At least 700 cc of normal liver had to receive a total dose <15 Gy 
and the sum of the left and right kidney volume receiving 15 Gy had to be less than 35%. With a 
median follow-up of 16 months the 2 year actuarial in-field local control was 92% with a median 
overall survival of 20.5 months. Treatment was well tolerated with 1 patient suffering Grade 3 
soft-tissue toxicity, no grade 4 or 5 toxicity, and no instances of radiation induced liver 
dysfunction (RILD) [21]. 
 
A recent prospective dose escalation study at the University of Chicago enrolled patients with 1 
to 5 oligometastases of any histology to receive SBRT to any site amenable to treatment. The 
starting dose was 24 Gy in 3 fractions. Treatment dose was escalated at 2 Gy per fraction 
intervals with a ceiling of 60 Gy in 3 fractions. A total of 61 patients were evaluated with 113 
treated sites. The final dose cohort with sufficient follow-up and enrollment was 42 Gy. With a 
median follow-up of 20.9 months, the median PFS was 5.1 months. Patients with 1 to 3 
metastases were found to have significantly longer PFS than patients with 4 to 5 metastases. It 
is significant to note in this study that 55% of patients had a limited pattern of progression in 3 or 
fewer sites, which may have been amenable to further SBRT [22].   
 
1.3 EGFR Mutation/ ALK-Positive Mutation 
 
Activating mutations in EGFR, which occur with exon 19 deletions or exon 21 point mutations, 
have been identified in up to 26% of patients with non-small cell lung cancer, most commonly in 
patients of Asian descent [23]. EGFR tyrosine kinase inhibitors with proven efficacy include 
gefitinib and erlotinib.  Four prospective randomized trials in the Asian population and one 
randomized trial in the European population have evaluated first-line treatment with gefitinib or 


 
erlotinib in EGFR-mutant NSCLC. All five trials have shown a significantly improved rate of 
progression free survival in patients compared to chemotherapy [24-28].  
 
Anaplastic lymphoma kinase is aberrantly activated in approximately 4% of NSCLC, due to 
chromosomal rearrangement leading to the oncogenic fusion kinase EML4-ALK. These patients 
present with young age of onset, minimal or absent smoking history, and adenocarcinoma 
histology. Crizotinib is an orally available small-molecule inhibitor of ALK and c-Met receptor 
tyrosine kinase currently in clinical trials. No randomized prospective data yet exists for targeting 
with crizotinib. However, a prospective phase I clinical trial has now shown a 61% objective 
response with median progression free survival of 10 months in ALK positive patients with Stage 
III-IV NSCLC [29]. 
 
1.4 
Study Rationale  
 
SBRT is a rapidly disseminating practice that may be performed with a wide range of dedicated 
equipment.  It is currently under active clinical investigation at numerous institutions worldwide. 
The utilization of maintenance chemotherapy alone following first line chemotherapy including 
novel biologic or cytotoxic agents is now proven to provide modest benefits in progression free 
survival and overall survival. SBRT prior to any potential maintenance chemotherapy may 
provide further benefit over maintenance chemotherapy alone with respect to PFS.   
 
SBRT has an acceptable toxicity profile with an increasing number of sites in the body 
amenable to treatment. It has the added benefit of providing a full course of treatment within a 
few fractions, providing an alternative to a protracted course of therapy with a non-invasive 
technique.  By eradicating gross disease it is believed that progression free survival will be 
improved compared to maintenance chemotherapy.  
 
For patients with oligometastatic disease, there exists limited effective treatment beyond second 
line chemotherapy. By expanding the available treatment options with SBRT while preventing 
progression and potentially prolonging survival, this study will prove practice changing. 
Furthermore, it is anticipated that short course radiotherapy will not compromise the patient’s 
quality of life. We hope to show that the ease of delivery of short course ablative radiotherapy 
will increase the percentage of patients with stage IV NSCLC who receive consolidative therapy 
following first line chemotherapy. 
 
 
1.5 
Study Design  
 
This study is a two-arm randomized phase II trial. All patients enrolled on the trial will have 
received 4-6 cycles of first line chemotherapy. Patients with non-squamous histology may have 
the addition of bevacizumab to first-line therapy at the medical oncologist’s discretion.  Patients 
receiving first-line erlotinib, crizotinib for EGFR mutant-positive or EML4-ALK positive NSCLC 
will be excluded. Patients will be assessed within 42 days following completion of first line 
chemotherapy with repeat diagnostic CT or PET/CT. Patients with stable disease or partial 
response with oligometastatic disease, defined by six or fewer sites amenable to SBRT, will be 
randomized within 21 days of imaging to either maintenance chemotherapy alone or SBRT to all 
gross disease followed by maintenance chemotherapy. SBRT will be given according to 


 
guidelines outlined in Section 4. Maintenance chemotherapy will continue until disease 
progression, intolerable toxicity, or death. 
 
Patients who develop new lesions amenable to SBRT during follow-up imaging and not 
previously treated will be evaluated for additional SBRT at the Radiation Oncologist’s discretion.  
This event will not constitute progression if the lesion is treated by SBRT. However, if the lesion 
is not amenable to SBRT, the patient is either unwilling to pursue further treatment or cannot 
tolerate treatment due to coexisting comorbidities, then progression will be deemed to have 
occurred.  
 
SBRT, in and of itself, can alter the effectiveness of imaging in determining progression vs. 
response. Imaging at 3 months post SBRT will be instituted as a standard on the trial but will 
mostly relate to disease outside the irradiated fields. Imaging at other times may be instituted 
earlier based on clinical need. Because the sites of initial gross disease may still be obfuscated 
by the SBRT at the time of the 3 month assessment, caution will be observed in interpreting any 
lack of evidence of progression relative to non-SBRT treated historical controls. 
 
2. 
OBJECTIVES 
 
2.1 
Primary 
The primary objective of this study is to evaluate the effect of SBRT with or without  
maintenance chemotherapy versus maintenance chemotherapy alone on progression free 
survival 
 
2.2 
Secondary 
Secondary objectives include the following: 
1. To describe the actuarial rate in-field local control and rate of out-of-field disease progression. 
2. To evaluate the safety of SBRT with metastatic NSCLC after prior chemotherapy 
3. To evaluate overall survival after SBRT followed by maintenance chemotherapy in 
comparison to maintenance chemotherapy alone. 
4. To evaluate the duration of maintenance chemotherapy and time to initiation of third line 
systemic agent (chemotherapy or biologic agent) 
 
3. 
TRIAL POPULATION 
 
3.1 
Inclusion Criteria 
Patients must meet all of the following inclusion criteria to be eligible for participation in this 
study: 
1. Patients must have biopsy proven metastatic NSCLC (Stage IV). 
2. Patients must have received first line chemotherapy, from 4-6 cycles, and achieved 
stable disease or a partial response. 
3. Patients receiving first-line erlotinib, crizotinib for EGFR mutant-positive or EML4-ALK 
positive NSCLC will be excluded.  
4. Age ≥ 18 years 
5. Patients must have measurable disease at baseline. 
6. Patients can have up to only 6 discrete active extracranial lesions (≤3 in the liver and ≤3 
in the lung) identified by diagnostic CT or PET/CT scan or MRI within 8 weeks prior to the 
initiation of SBRT. 


 
a) For patients who have received prior radiotherapy to the primary site in the lung, 
residual PET activity is difficult to interpret and will not be considered a site of active 
disease if the CT appearance is stable or improved over an interval of at least three 
months 
b) Patients who previously received radiotherapy to the primary site will be ineligible if 
there is CT evidence of disease progression within the past 3 months. 
c) Patients with previously un-irradiated primary sites will be potentially eligible, but 
special considerations apply (section 4.3.2). 
d) Up to 2 contiguous vertebral metastases will be considered a single site of disease. 
7. Patients must have a KPS >60 
8. AST, ALT & Alkaline phosphates must be ≤ 2.5X the upper limit of normal. Total bilirubin 
 
must be within the limit of normal. 
9. Patients should have adequate bone marrow function as defined by peripheral 
granulocyte count of ≥1500/mm³.  
10. Patients should have adequate renal function (serum creatinine ≤1.5 times the ULN). 
11. Women of child-bearing potential and men must agree to use adequate contraception 
(hormonal or barrier method of birth control; abstinence) prior to study entry, for the 
duration of study participation, and for 90 days following completion of therapy. Should a 
woman become pregnant or suspect she is pregnant while participating in this study, she 
should inform her treating physician immediately. 
 
11.1 A female of child-bearing potential is any woman (regardless of sexual 
orientation, having undergone a tubal ligation, or remaining celibate by 
choice) who meets the following criteria: 
 
 Has not undergone a hysterectomy or bilateral oophorectomy; or 
 Has not been naturally postmenopausal for at least 12 
consecutive months (i.e., has had menses at any time in the 
preceding 12 consecutive months). 
12. Patients who would be receiving SBRT for lung tumors who are known or suspected by 
the treating radiation oncologist to have compromised lung function must have a 
documented forced expiratory volume in 1 second (FEV1) ≥ 1L. 
13. Patients must provide verbal and written informed consent to participate in the study. 
 
3.2 
Exclusion Criteria 
Patients who meet any of the following exclusion criteria are not to be enrolled in this study. 
1. Patients who previously received radiotherapy to the primary site with CT evidence of 
disease progression at the primary site within 3 months following the initial radiotherapy. 
2. Patients with untreated brain metastases Patients with serious, uncontrolled, concurrent 
infection(s). 
3. Significant weight loss (>10%) in the prior 3 months. 
4. Because the tolerance dose of SBRT to the gastrointestinal tract is not established, 
patients with metastatic disease invading the esophagus, stomach, intestines, or 
mesenteric lymph nodes will not be eligible. 
5. Patients with cutaneous metastasis of NSCLC. 
6. Patients with more than 6 discrete extra-cranial lesions. 
7. Participation in any investigational drug study within 4 weeks preceding the start of study 
treatment. 


 
8. Unwillingness to participate or inability to comply with the protocol for the duration of the 
study. 
9. Patients who are pregnant. Patients with reproductive capability will need to use 
adequate contraception during the time of participation in the study. 
 
4. 
SBRT DOSE AND TECHNIQUES 
 
SBRT will begin within 3 weeks after randomization to the SBRT arm. 
 
Stereotactic treatment is the targeting, planning, and directing of treatment fields guided to a 
target based on known 3-D coordinates related to reliable fiducial markers. This differs from 
conventional radiation therapy in which treatment is guided by skin or bony landmarks assumed 
to correlate to the target volume based on the initial simulation.  Stereotactic Body Radiation 
Therapy (SBRT) in this study will be delivered with an ablative range of dose per fraction. 
Treatment will account for inter/intra-fractional errors with careful dosimetry that delivers an 
ablative dose to the metastatic lesion(s) while respecting normal tissue constraints. 
 
4.1    SBRT Prescription 
Patients randomized to the SBRT arm will be evaluated by the treating Radiation Oncologist. 
Based on location of the metastatic lesion(s), dose fractionation will be determined by clinical 
appropriateness that balances ablation of the lesion(s) while respecting normal tissue 
constraints.  
 
Prescription Dose 
  
Total Cumulative Dose Encompassing 95% of Planning Target Volume  
Number of 
Fractions 
Protocol Compliant 
Variation Acceptable 
Deviation Unacceptable 
1 
21-27 Gy 
<21 Gy but ≥16 Gy  
<16 Gy or >27 Gy  
3 
26.5-33 Gy 
<26.5 Gy but ≥24.5 Gy 
<24.5 Gy or >33 Gy,  
5 
30-37.5 Gy 
≥28 Gy, <30 Gy 
<28 Gy  or >37.5 Gy,  
 
Treatment may be delivered on consecutive days with 18 hours between fraction or every other 
day as deemed appropriate by the treating Radiation Oncologist. 
 
If the radiation oncology physician believes that the fractionation schemes listed above for any 
lesion (primarily bulky mediastinal/hilar disease) is not achievable with normal tissue constraints, 
they can treat that site to 45 Gy in 15 fractions.  This decision will be discussed with the PI of the 
study.  Each treatment may be given once a day for 3 weeks excluding weekends/holidays, 
using standard tissue constraints and PTV coverages for traditional IMRT techniques.  
 
 
4.2  
Planning Constraints and Concerns  
The tolerance dose of SBRT to the gastrointestinal tract is not established, and patients with 
metastatic disease involving the esophagus, stomach, intestines, or mesenteric lymph nodes 
will not be eligible. Patients with renal or adrenal metastases are potentially eligible if normal 
tissue constraints are otherwise met.  
 
Cutaneous metastases are an uncommon manifestation of non-small cell lung cancer that are 
typically associated with poor prognosis [12-14]. Patients with cutaneous metastases will be 


 
ineligible. As this may represent a group of patients with particularly poor prognosis, again this 
will be considered within any comparison with historical controls. 
 
It is well established that for palliative effect for a painful bone metastasis, a single dose of 8 Gy 
is usually as effective as 30 Gy [15]. Long term survival after bone metastasectomy has been 
reported [17].  Irradiation of non-spinal skeletal sites does not generally require specialized 
techniques of treatment. Metastases in major lower extremity weight-bearing bones should 
undergo surgical stabilization if there is plain film evidence of cortical erosion. 
 
Corticosteroid premedication will not be mandated, although it can be used at the discretion of 
the treating oncologist (in which case, its use needs to be reported). Analgesic premedication to 
avoid general discomfort during long treatment durations is recommended when appropriate. 
 
4.3  
Technical Factors 
 
4.3.1 Physical Factors 
Only photon (x-ray) beams produced by linear accelerators with photon energies of 4-15 MV will 
be allowed. Cobalt-60 and charged particle beams (including electrons, protons, and heavier 
ions) are not allowed. Restriction of photon beam energies > 10 MV but less than 15 MV will be 
based on clinical appropriateness taking into account distance the beam must travel to the 
target. 
 
4.3.2 Dose Verification at Treatment 
In-vivo dosimeter measurements (e.g., diode, TLD) may be obtained for surface dose 
verification for accessible beams. This information is not required by the protocol. 
 
4.3.3 Treatment Platforms 
The trial allows most commercially available photon producing treatment units except the 
exclusion of units described in Section 4.3.1 (e.g., cobalt units and charge particle 
accelerators). Conventional linear accelerators and specialized linear accelerators with 
image guidance (e.g., Novalis, Trilogy, Synergy, Artiste) are allowed. These units can be used 
with conformal dose delivery or IMRT. Other specialized accelerators (e.g., the CyberKnife® 
or Tomotherapy) are allowed as long as they meet the technical specifications of the protocol. 
 
4.4 
Simulation/Image Guidance 
 
4.4.1  Patient Positioning 
Patients will be positioned in a stable position that allows accurate reproducibility of the target 
between treatments.  Positions uncomfortable for the patient should be avoided so as to prevent 
uncontrolled movement during treatments.  A variety of immobilization systems may be utilized 
including stereotactic frames that surround the patient on three sides and large rigid pillows 
(conforming to patients external contours) with reference to the stereotactic coordinate system.  
Patient immobilization must be reliable enough to insure that the Gross Tumor Volume (GTV) 
does not deviate beyond the confines of the Planning Treatment Volume (PTV) with any 
significant probability (i.e., < 5%). 
 
At the time of simulation for patients who will receive SBRT to the lung and/or liver, the 
movement of the dome of the diaphragm (superior portion of the liver) is to be observed under 
fluoroscopy or other acceptable means to estimate respiratory movement during treatment if no 
breathing control device is used.  Patients will be assessed for suitability for tolerance of a 


 
respiratory control device using a breath-hold technique, respiratory gating, or abdominal 
compression to limit diaphragmatic excursion during respiration. Patients with severe lung 
disease and patients who cannot tolerate diaphragmatic or breathing control devices for other 
reasons will be treated without them. A larger margin to account for breathing related intra-
fractional organ movement is required. 
 
4.4.2 Image Guidance 
Isocenter or reference point port localization images should be obtained on the treatment unit 
immediately before treatment to ensure proper alignment of the geometric center (i.e., 
isocenter) of the simulated fields. These IGRT images can be obtained with planar kV imaging 
devices or cone-beam CT equipment. For treatment systems that use kV imaging but also allow 
EPID imaging using the treatment beam, orthogonal images verifying the isocenter also should 
be obtained.  
 
4.5 
Treatment Planning/Target volumes 
 
4.5.1 Image Acquisition 
Computed tomography will be the primary image platform for targeting and treatment planning. 
The planning CT scans must allow simultaneous view of the patient anatomy and fiducial 
system for stereotactic targeting. CT scan with IV contrast is recommended unless the patient 
has allergy to contrast or renal insufficiency.  Oral GI contrast to highlight the stomach and 
duodenum is recommended for patients with medial liver lesions or lesions of the caudate lobe. 
Axial acquisitions will be required with spacing ≤ 3.0 mm between scans. Images will be 
transferred to the treatment planning computers.  
 
4.5.2 Target Volumes 
The target lesion will be outlined by an appropriately trained physician and designated the gross 
tumor volume (GTV). The target will generally be drawn using appropriate windowing based on 
location of the metastatic lesion(s). 4-dimensional CT image guided GTV delineation to take 
tumor motion into consideration will be allowed.  
 
For treatment to the lung, the target will generally be drawn using CT pulmonary windows; 
however, soft tissue windows with contrast may be used to avoid inclusion of adjacent vessels, 
atelectasis, or mediastinal or chest wall structures within the GTV. This target will not be 
enlarged whatsoever for prophylactic treatment (including no “margin” for presumed microscopic 
extension); rather, include only abnormal CT signal consistent with gross tumor (i.e., the GTV 
and the clinical target volume [CTV] are identical). An additional 0.5 cm in the axial plane and 
1.0 cm in the longitudinal plane (craniocaudal) will be added to the GTV to constitute the PTV.  
 
For treatment to the liver, the following structures are contoured: entire liver, each individual liver 
gross tumor volume (GTV), each kidney, and the spinal cord. The planning target volume (PTV) 
is constructed to account for the positional uncertainty of the GTV during treatment. The PTV for 
each contoured GTV should be at least 5mm larger than the GTV in the axial plane and 1.0 cm 
larger than the GTV in the craniocaudal plane. Larger margins may be used in cases where 
greater motion of the hemidiaphragm is observed in simulation despite standard maneuvers to 
diminish motion.   
 
Treatment to skeletal and paraspinous lesions may be accomplished with any 3D conformal 
radiotherapy or intensity-modulated radiotherapy technique suitable for this application with 
performance specifications adequate to provide proper tumor dose distribution and normal 
tissue sparing. 
 


 
4.6 
Dosimetry 
 
4.6.1 3D-Conformal Planning 
Three-dimensional coplanar or non-coplanar beam arrangements will be custom designed for 
each case to deliver highly conformal prescription dose distributions. Non-opposing, non-
coplanar beams are preferable. Generally, more beams are used for larger lesion sizes. For this 
protocol, the isocenter is defined as the common point of gantry and couch rotation for the 
treatment unit. Prescription lines covering the PTV will typically be the 60-90% line (rather than 
95-100%); however, higher isodoses (hotspots) must be manipulated to occur within the target 
and not in adjacent normal tissue. The isocenter in stereotactic coordinates will be determined 
from system fiducials (or directly from the tumor in the case of volumetric imaging) and 
translated to the treatment record.  
 
The treatment dose plan will be made up of multiple static beams or arcs as described 
above. The plan should be normalized to a defined point corresponding closely to the 
center of mass of the PTV (COMPTV). Typically, this point will be the isocenter of the beam 
rotation; however, it is not a protocol requirement for this point to be the isocenter. 
Regardless, the point identified as COMPTV must have defined stereotactic coordinates and 
receive 100% of the normalized dose. Because the beam apertures coincide nearly directly with 
the edge of the PTV (little or no added margin), the external border of the PTV will be covered 
by a lower isodose surface than usually used in conventional radiotherapy planning typically 
around 80% but ranging from 60-90%. The prescription dose will be delivered to the margin of 
the PTV. As such, a “hotspot” will exist within the PTV centrally at the COMPTV with a 
magnitude of prescribed dose times the reciprocal of the chosen prescription isodose line (i.e., 
60-90%). 
 
4.6.2 Intensity Modulated Radiation Therapy (IMRT) 
IMRT is allowed in this study. The use of IMRT in this study is at the discretion of the treating 
physician. However, IMRT should be considered only when target coverage, OAR dose limits, 
or dose spillage are not achievable with 3D conformal planning. In addition, IMRT plans should 
follow the same planning principles as discussed above for 3D conformal planning. The number 
of segments (control points) and the area of each segment should be optimized to ensure 
deliverability and avoid complex beam fluences. Ideally, the number of segments should be 
minimized (2-3 segments per beam should be adequate), and the area of each segment 
should be maximized (the aperture of one segment from each beam should correspond to 
the projection of the PTV along a beam’s eye view). 
 
4.6.3  Dose Calculations 
For purposes of dose planning and calculation of monitor units for actual treatment, this 
protocol will require tissue density heterogeneity correction.  
 
Successful treatment planning will require accomplishment of all of the following criteria: 
1. Maximum dose: The treatment plan should be created such that 100% corresponds to 
the maximum dose delivered to the patient. This point must exist within the PTV. 
2. Prescription isodose: The prescription isodose surface must be ≥ 60% and < 90% of 
the maximum dose. 
3. Prescription Isodose Surface Coverage: The prescription isodose surface will be 
chosen such that 95% of the target volume (PTV) is conformally covered by the 
prescription isodose surface (PTV V95%RX = 100%) and 99% of the target volume 
(PTV) receives a minimum of 90% of the prescription dose (PTV V90%RX > 99%). 
 


 
 
4.7 
Normal Tissue Dose Constraints 
In accordance with the prior Phase I studies [7, 8], certain normal tissue dose constraints must 
be respected.  
 
The possibility that SBRT-induced fibrosis might cause occlusion of large central airways, thus 
impeding ventilation distal to the occlusion has been well considered. [22] An adjustment to the 
fractionation scheme may be made if, in the opinion of the treating radiation oncologist, the 
following conditions apply: (1) the location of a lung lesion is close enough to a large proximal 
bronchial airway such that occlusion might occur, and (2) compromised ventilation to the 
segment(s) of lung potentially affected would cause clinically significant adverse consequences.  
 
The same special condition applies in the setting of a patient whose primary lung disease has 
not been irradiated previously but is present as a PET-positive site of disease, often in proximity 
to mediastinal structures which is a dose-limiting concern.  These patients will be considered by 
the PI on a case-by-case basis.   
 
The following table lists the specific organ and dose fractionation constraints on normal tissues. 
 
One Fraction 
 
 
 
 
 
 
 
 
Serial Tissue 
Volume 
Volume Max (Gy) 
Max Point Dose 
(Gy)** 
Endpoint (≥Grade 3) 
Spinal Cord and medulla 
<0.35 cc 
<1.2 cc 
10 Gy 
8 Gy 
14 Gy 
myelitis 
Spinal Cord Subvolume (5-
6 mm above and below 
level treated per Ryu) 
<10% of 
subvolume 
10 Gy 
14 Gy 
myelitis 
Cauda Equina 
<5 cc 
14 Gy 
16 Gy 
neuritis 
Sacral Plexus 
<5 cc 
14.4 Gy 
16 Gy 
neuropathy 
Esophagus* 
<5 cc 
11.9 Gy 
15.4 Gy 
stenosis/fistula 
Brachial Plexus 
<3 cc 
13.6 Gy 
16.4  Gy 
neuropathy 
Heart/Pericardium 
<15 cc 
16 Gy 
22 Gy 
pericarditis 
Great vessels 
<10 cc 
31 Gy 
37 Gy 
aneurysm 
Trachea and Large 
Bronchus* 
<4 cc 
17.4 Gy 
20.2 Gy 
stenosis/fistula 
Bronchus- smaller airways 
<0.5 cc 
12.4 Gy 
13.3 Gy 
stenosis with atelectasis 
Rib 
<5 cc 
28 Gy 
33 Gy 
Pain or fracture 
Skin 
<10 cc 
25.5 Gy 
27.5 Gy 
ulceration 
Stomach 
<5 cc 
17.4 Gy 
22 Gy 
ulceration/fistula 
Bile duct 
 
 
30 Gy 
stenosis 
Duodenum* 
<5 cc 
<10 cc 
11.2 Gy 
9 Gy 
17 Gy 
ulceration 
Jejunum/Ileum* 
<30 cc 
12.5 Gy 
22 Gy 
enteritis/obstruction 
Colon* 
<20 cc 
18 Gy 
29.2 Gy 
colitis/fistula 
Rectum* 
<3.5 cc 
<20 cc 
39 Gy 
22 Gy 
44.2 Gy 
proctitis/fistula 
Ureter 
 
 
35 Gy 
stenosis 
Bladder wall 
<15 cc 
12 Gy 
25 Gy 
cystitis/fistula 
Penile bulb 
<3 cc 
16 Gy 
 
impotence 
Femoral Heads  
<10 cc 
15 Gy 
 
necrosis 
Renal hilum/vascular trunk 
15 cc 
14 Gy 
 
malignant hypertension 
 
 
 
 
 


 
Parallel Tissue 
Critical 
Volume (cc) 
Critical Volume 
Dose Max (Gy) 
 
Endpoint (≥Grade 3) 
Lung (Right & Left) 
1500 cc 
7 Gy 
 
Basic Lung Function 
Lung (Right & Left) 
1000 cc 
7.6 Gy 
V-8Gy <37% 
Pneumonitis 
Liver 
700 cc 
11 Gy 
 
Basic Liver Function 
Renal cortex (Right & Left) 
200 cc 
9.5 Gy 
 
Basic renal function 
*Avoid circumferential irradiation 
** “point” defined as 0.035cc or less 
 
Three Fractions  
 
 
 
 
 
 
 
 
Serial Tissue 
Volume 
Volume Max (Gy) 
Max Point Dose 
(Gy)** 
Endpoint (≥Grade 3) 
Spinal Cord and medulla 
<0.35 cc 
<1.2 cc 
15.9 Gy 
13 Gy 
22.5 Gy 
myelitis 
Spinal Cord Subvolume (5-
6 mm above and below 
level treated per Ryu) 
<10% of 
subvolume 
18 Gy 
22.5 Gy 
myelitis 
Cauda Equina 
<5 cc 
21.9 Gy  
25.5 Gy 
neuritis 
Sacral Plexus 
<5 cc 
22.5 Gy 
24 Gy 
neuropathy 
Esophagus* 
<5 cc 
17.7 Gy 
25.2 Gy 
stenosis/fistula 
Brachial Plexus 
<3 cc 
22 Gy 
26  Gy 
neuropathy 
Heart/Pericardium 
<15 cc 
24 Gy 
30 Gy 
pericarditis 
Great vessels 
<10 cc 
39 Gy 
45 Gy 
aneurysm 
Trachea and Large 
Bronchus* 
<5 cc 
25.8 Gy 
30 Gy 
stenosis/fistula 
Bronchus- smaller airways 
<0.5 cc 
18.9 Gy 
23.1 Gy 
stenosis with atelectasis 
Rib 
<5 cc 
40 Gy 
50 Gy 
Pain or fracture 
Skin 
<10 cc 
31 Gy 
33 Gy 
ulceration 
Stomach 
<5 cc 
22.5 Gy 
30 Gy 
ulceration/fistula 
Bile duct 
 
 
36 Gy 
stenosis 
Duodenum* 
<5 cc 
<10 cc 
15.6 Gy 
12.9 Gy 
22.2 Gy 
ulceration 
Jejunum/Ileum* 
<30 cc 
17.4 Gy 
27 Gy 
enteritis/obstruction 
Colon* 
<20 cc 
24 Gy 
34.5 Gy 
colitis/fistula 
Rectum* 
<3.5 cc 
<20 cc 
45 Gy 
27.5 Gy 
49.5 Gy 
proctitis/fistula 
Ureter 
 
 
40 Gy 
stenosis 
Bladder wall 
<15 cc 
17 Gy 
33 Gy 
cystitis/fistula 
Penile bulb 
<3 cc 
25 Gy 
 
impotence 
Femoral Heads  
<10 cc 
24 Gy 
 
necrosis 
Renal hilum/vascular trunk 
15 cc 
19.5 Gy 
 
malignant hypertension 
 
 
 
 
 
Parallel Tissue 
Critical 
Volume (cc) 
Critical Volume 
Dose Max (Gy) 
 
Endpoint (≥Grade 3) 
Lung (Right & Left) 
1500 cc 
10.5 Gy 
 
Basic Lung Function 
Lung (Right & Left) 
1000 cc 
11.4 Gy 
V-11Gy<37% 
Pneumonitis 
Liver 
700 cc 
17.1 Gy 
 
Basic Liver Function 
Renal cortex (Right & Left) 
200 cc 
15 Gy 
 
Basic renal function 
*Avoid circumferential irradiation 
** “point” defined as 0.035cc or less 
 
Five Fractions 
 
 
 
 
 
 
 
 
 
Serial Tissue 
Volume 
Volume Max (Gy) 
Max Point Dose 
(Gy)** 
Endpoint (≥Grade 3) 
Spinal Cord and medulla 
<0.35 cc 
<1.2 cc 
22 Gy 
15.6 Gy 
28 Gy 
myelitis 


 
Spinal Cord Subvolume (5-
6 mm above and below 
level treated per Ryu) 
<10% of 
subvolume 
22 Gy 
28 Gy 
myelitis 
Cauda Equina 
<5 cc 
30 Gy 
31.5 Gy 
neuritis 
Sacral Plexus 
<5 cc 
30 Gy 
32 Gy 
neuropathy 
Esophagus* 
<5 cc 
19.5 Gy 
35 Gy 
stenosis/fistula 
Brachial Plexus 
<3 cc 
27 Gy 
32.5 Gy 
neuropathy 
Heart/Pericardium 
<15 cc 
32 Gy 
38 Gy 
pericarditis 
Great vessels 
<10 cc 
47 Gy 
53 Gy 
aneurysm 
Trachea and Large 
Bronchus* 
<5 cc 
32 Gy 
40 Gy 
stenosis/fistula 
Bronchus- smaller airways 
<0.5 cc 
21 Gy 
33 Gy 
stenosis with atelectasis 
Rib 
<5 cc 
45 Gy 
57 Gy 
Pain or fracture 
Skin 
<10 cc 
36.5 Gy 
38.5 Gy 
ulceration 
Stomach 
<5cc 
26.5 Gy 
35 Gy 
ulceration/fistula 
Bile duct 
 
 
41 Gy 
stenosis 
Duodenum* 
<5 cc 
<10 cc 
18.5 Gy 
14.5 Gy 
26 Gy 
ulceration 
Jejunum/Ileum* 
<30 cc 
20 Gy 
32 Gy 
enteritis/obstruction 
Colon* 
<20 cc 
28.5 Gy 
40 Gy 
colitis/fistula 
Rectum* 
<3.5 cc 
<20 cc 
50 Gy 
32.5 Gy 
55 Gy 
proctitis/fistula 
Ureter 
 
 
45 Gy 
stenosis 
Bladder wall 
<15 cc 
20 Gy 
38 Gy 
cystitis/fistula 
Penile Bulb 
<3 cc 
30 Gy 
 
impotence 
Femoral Heads  
<10 cc 
30 Gy 
 
necrosis 
Renal hilum/vascular trunk 
15 cc 
23 Gy  
 
malignant hypertension 
 
 
 
 
 
Parallel Tissue 
Critical 
Volume (cc) 
Critical Volume 
Dose Max (Gy) 
 
Endpoint (≥Grade 3) 
Lung (Right & Left) 
1500 cc 
12.5 Gy 
 
Basic Lung Function 
Lung (Right & Left) 
1000 cc 
13.5 Gy 
V-13.5Gy<37% 
Pneumonitis 
Liver 
700 cc 
21 Gy 
 
Basic Liver Function 
Renal cortex (Right & Left) 
200 cc 
18 Gy 
 
Basic renal function 
*Avoid circumferential irradiation 
** “point” defined as 0.035cc or less 
 
Exceeding these dose tolerances by more than 2.5% constitutes a minor protocol violation.  
Exceeding these dose tolerances by more than 5% constitutes a major protocol violation. 
 
4.8 
Radiation Therapy Quality Assurance 
 
Dr. Iyengar will perform an RT Quality Assurance Review after complete data for the first 18 
cases enrolled at the University of Texas Southwestern Medical Center. Dr.  Iyengar will perform 
the final review after complete data for the subsequent 18 cases at the University of Texas 
Southwestern Medical Center are completed. These cases will be reviewed within 3 months 
after this study has reached the target accrual or as soon as complete data for all cases enrolled 
has been received, whichever occurs first. 
 
5. 
STUDY MEDICATIONS 
 


 
Currently accepted drugs used for maintenance chemotherapy include Erlotinib, Pemetrexed, 
Docetaxel, Gemcitabine, and Bevacizumab.  These drugs are standard of care and are 
commercially available.   
 
5.1 
Erlotinib (Tarceva®)  
 
5.1.1 Formulation 
 
The pharmaceutical preparations of Tarceva® are formulations containing the hydrochloride salt.  
Tarceva® is supplied as tablets containing erlotinib hydrochloride equivalent to 150 mg, 100 mg, 
and 25 mg of erlotinib.  All tablets are round, white, film-coated, bi-convex tablets without 
markings.  Additional information regarding Tarceva® can be found in the Package Insert. 
Tarceva® tablets are supplied in blue-white, high-density polyethylene (HDPE) bottles of 30 
tablets each.   
 
5.1.2 Storage and Handling 
 
Tarceva® tablets should be stored between 15°C and 30°C (59°F and 86°F). 
 
5.1.3 Administration 
 
Tarceva® tablets should be taken at approximately the same time of day.  Each Tarceva® dose 
is to be taken with up to 200 mL (~ 1 cup or 8 oz) of water, and should be taken 1 hour before or 
2 hours after meals or medications, including grapefruit juice, vitamins, and iron supplements.  
The entire dose must be taken at one time.  If the patient vomits after taking the tablet(s), the 
dose is replaced only if the tablet(s) can actually be seen and counted.  
 
5.1.4 Potential Drug-Drug Interactions   
 
Erlotinib is both protein bound (92% to 95% in humans) and metabolized in the liver by CYP3A4 
and, to a lesser extent, CYP1A2, and in the lungs by CYP1A1.  A potential for drug-drug 
interaction exists when erlotinib is co-administered with drugs that are highly protein bound or 
that are CYP3A4 and CYP1A2 inhibitors/inducers.   
 
For patients who are being concomitantly treated with a potent CYP3A4 inhibitor, a dose 
reduction should be considered in the presence of severe adverse events.  For patients who are 
being concomitantly treated with a potent CYP3A4 inducer, alternative treatments that lack 
potent CYP3A4-inducing properties should be considered. 
 
Common CYP3A4 inhibitors include but are not limited to Amiodarone, Cannabinoids 
Miconazole, Erythromycin, Fluconazole, Norfloxacin, Fluoxetine, Omeprazole (slight), Quinine, 
Ritonavir, Indinavir, Ketoconazole, and Metronidazole. Common CYP3A4 inducers include but 
are not limited to Carbamazepine, Dexamethasone, Rifabutin, Ethosuximide, Rifampin, 
Phenobarbital, and Phenytoin. 
 
In addition, altered coagulation parameters and bleeding have been reported in patients 
receiving erlotinib alone and in combination with other chemotherapeutic agents and 
concomitant warfarin-derivative anticoagulants.  The mechanism for these alterations is still 
unknown.  When warfarin is coadministered with erlotinib (anytime after Day 5), international 


 
normalized ratio (INR) and prothrombin time should be closely monitored and the anticoagulant 
dose should be adjusted as clinically indicated. 
 
5.2 
Pemetrexed (ALIMTA) 
 
5.2.1 Formulation 
 
ALIMTA is a white to either light-yellow or green-yellow lyophilized powder available in sterile 
single-use vials containing 100 mg or 500 mg pemetrexed. Each 500-mg vial of ALIMTA 
contains pemetrexed disodium equivalent to 500 mg pemetrexed and 500 mg of mannitol. 
Hydrochloric acid and/or sodium hydroxide may have been added to adjust pH. 
 
5.2.2 Storage and Handling 
 
ALIMTA, pemetrexed for injection, should be stored at 25°C (77°F); excursions permitted to 15-
30°C (59-86°F). 
 
5.2.3 Administration 
 
The recommended dose of ALIMTA is 500 mg/m2 administered as an intravenous infusion over 
10 minutes on Day 1 of each 21-day cycle. To reduce toxicity, patients treated with ALIMTA 
must be instructed to take a low-dose oral folic acid preparation or multivitamin with folic acid on 
a daily basis. At least 5 daily doses of folic acid must be taken during the 7-day period preceding 
the first dose of ALIMTA; and dosing should continue during the full course of therapy and for 21 
days after the last dose of ALIMTA. Patients must also receive one (1) intramuscular injection of 
vitamin B12 during the week preceding the first dose of ALIMTA and every 3 cycles thereafter. 
Subsequent vitamin B12 injections may be given the same day as ALIMTA. In clinical trials, the 
dose of folic acid studied ranged from 350 to 1000 mcg, and the dose of vitamin B12 was 1000 
mcg. The most commonly used dose of oral folic acid in clinical trials was 400 mcg  
 
5.2.4 Potential Drug-Drug Interactions   
 
ALIMTA is primarily eliminated unchanged renally as a result of glomerular filtration and  tubular 
secretion. Concomitant administration of nephrotoxic drugs could result in delayed  clearance of 
ALIMTA. Concomitant administration of substances that are also tubularly secreted   (e.g., 
probenecid) could potentially result in delayed clearance of ALIMTA.  Although ibuprofen (400 
mg qid) can be administered with ALIMTA in patients with normal  renal function (creatinine 
clearance ≥80 mL/min), caution should be used when administering  ibuprofen concurrently with 
ALIMTA to patients with mild to moderate renal insufficiency (creatinine clearance from 45 to 79 
mL/min). Patients with mild to moderate renal insufficiency  should avoid taking NSAIDs with 
short elimination half-lives for a period of 2 days before, the day of, and 2 days following 
administration of ALIMTA. In the absence of data regarding potential interaction between 
ALIMTA and NSAIDs longer half-lives, all patients taking these NSAIDs should interrupt dosing 
for at least 5 days before, the day of, and 2 days following ALIMTA administration. If 
concomitant administration of an NSAID is necessary, patients should be monitored closely for 
toxicity, especially myelosuppression, renal, and gastrointestinal toxicity.  
 


 
5.3 
Docetaxel  
 
5.3.1 Formulation 
 
TAXOTERE (docetaxel) Injection Concentrate is a clear yellow to brownish-yellow viscous 
solution. TAXOTERE is sterile, non-pyrogenic, and is available in single-dose vials containing 
20 mg (0.5 mL) or 80 mg (2 mL) docetaxel (anhydrous). Each mL contains 40 mg docetaxel 
(anhydrous) and 1040 mg polysorbate 80. TAXOTERE Injection Concentrate is supplied in a 
single-dose vial as a sterile, pyrogen-free, non-aqueous, viscous solution with an accompanying 
sterile, non-pyrogenic, Diluent (13% ethanol in water for injection) vial. 
 
5.3.2 Storage and Handling 
Store between 2°C and 25°C (36°F and 77°F). Retain in the original package to protect from 
bright light. Freezing does not adversely affect the product. 
After initial puncture, Docetaxel Injection multiple dose vials are stable for 28 days when stored 
between 2oC to 8oC and at room temperature, with or without protection from light. 
 
5.3.3 Administration 
 
Docetaxel should be administered when the neutrophil count is ≥1,500 cells/mm3. In patients 
who experienced either febrile neutropenia, neutrophil < 500 cells /mm3 for more than one 
week, severe or cumulative cutaneous reactions or severe peripheral neuropathy during 
docetaxeltherapy, the dose of docetaxel should be reduced from 100mg/m2 to 75mg/m2 and/or 
from 75 to 60mg/m2. If the patient continues to experience these reactions at 60mg/m2, the 
treatment should be discontinued. 
 
5.3.4 Potential Drug-Drug Interactions   
 
Docetaxel is a CYP3A4 substrate. In vitro studies have shown that the metabolism of docetaxel 
may be modified by the concomitant administration of compounds that induce, inhibit, or are 
metabolized by cytochrome P450 3A4.  In vivo studies showed that the exposure of docetaxel 
increased 2.2-fold when it was coadministered with ketoconazole, a potent inhibitor of CYP3A4. 
Protease inhibitors, particularly ritonavir, may increase the exposure of docetaxel. Concomitant 
use of Docetaxel Injection and drugs that inhibit CYP3A4 may increase exposure to docetaxel 
and should be avoided. In patients receiving treatment with Docetaxel Injection, close 
monitoring for toxicity and a Docetaxel Injection dose reduction could be considered if systemic 
administration of a potent CYP3A4 inhibitor cannot be avoided  
 
5.4 
Gemcitabine  
 
5.4.1 Formulation 
 
Gemzar (gemcitabine for injection, USP) is a white to off-white lyophilized powder available in 
sterile single-use vials containing 200 mg or 1 g gemcitabine. Gemzar (gemcitabine for injection, 
USP), is available in sterile single-use vials individually packaged in a carton containing: 200 mg 
white to off-white, lyophilized powder in a 10-mL size sterile single-use vial - 1 g white to off-
white, lyophilized powder in a 50-mL size sterile single-use vial . 
 
5.4.2 Storage and Handling 


 
 
Unopened vials of Gemzar are stable until the expiration date indicated on the package when 
stored at controlled room temperature 20° to 25°C (68° to 77°F) and that allows for excursions 
between 15° and 30°C (59° and 86°F). 
 
5.4.3 Administration 
 
Two schedules have been investigated and the optimum schedule has not been determined 
(see Clinical Studies (14.3)) Withthe 4-week schedule, Gemzar should be administered 
intravenously at 1000 mg/m2 over 30 minutes on Days 1, 8, and 15 of each 28-day cycle. With 
the 3-week schedule, Gemzar should be administered intravenously at 1250 mg/m2 over 30 
minutes on Days 1 and 8 of each 21-day cycle.  
 
5.4.4 Potential Drug-Drug Interactions   
 
No specific drug interaction studies have been conducted. 
 
5.5 
Bevacizumab 
 
5.5.1 Formulation 
 
Bevacizumab is available in 100 mg/4 mL single use vial (3)  and 400 mg/16 mL, single use 
vials. 
 
5.5.2. Storage and Handling 
 
Avastin vials must be refrigerated at 2°C–8°C (36°F–46°F). Avastin vials should be protected 
from light. Store in the original carton until time of use. DO NOT FREEZE. DO NOT SHAKE. 
Diluted Avastin solutions for infusion may be stored at 2°C–8°C (36°F–46°F) for up to 8 hours 
 
5.5.3 Administration 
 
Avastin should be diluted for infusion using aseptic technique. Withdraw the necessary amount 
of Avastin to obtain the required dose and dilute in a total volume of 100 mL of 0.9% Sodium 
Chloride Injection, USP. Discard any unused portion left in a vial, as the product contains no 
preservatives. Inspect visually for particulate matter and discoloration prior to administration. 
Avastin infusions should not be administered or mixed with dextrose solution. DO NOT 
ADMINISTER AS AN IV PUSH OR BOLUS. ADMINISTER ONLY AS AN IV SOLUTION. Stop 
infusion if a severe adverse reaction occurs and administer appropriate medical therapy 
 
5.5.4 Potential Drug-Drug Interactions   
If used along with chemotherapy drugs known as anthracyclines, such as doxorubicin 
(Adriamycin), daunorubicin (Cerubidine, Daunomycin), epirubicin (Ellence), or mitoxantrone 
(Novantrone), this drug may increase the risk of congestive heart failure. Bevacizumab may 
cause irinotecan (Camptosar) to stay in the body longer, and may raise your risk of severe 
diarrhea. Bevacizumab given with carboplatin (Paraplatin) and paclitaxel (Taxol) may cause less 
paclitaxel to stay in the body. This may keep paclitaxel from working as it should. Any drugs or 
supplements that interfere with blood clotting can raise the risk of bleeding during treatment with 
bevacizumab. 


 
 
 
 


 
6. 
CLINICAL AND LABORATORY EVALUATIONS 
 
6.1 
Study Calendar 
 
Study 
Details 
Pre-
registration 
During 
treatment 
1 month 
follow-up6 
3 month 
follow-up6 
6 month 
follow-
up6 
Every 3, 6, 
or 12 
months7 
History, 
Physical 
Examination 
and Other 
Evaluations 
 Medical history 
 Smoking 
history 
 Physical 
exam (PE) 
 Height 
 Weight 
 Vital signs 
 ECOG 
Performance 
status (PS) 
All1 
    X8 
 
 PE 
 Weight 
 Vital 
signs 
 PS 
 PE 
 Weight 
 Vital 
signs 
 PS 
 PE 
 Weight 
 Vital 
signs 
 PS 
 PE 
 Weight 
 
Vital 
signs 
 PS 
Hematology 
Complete blood 
count, platelets 
X1 
X8 
 
 
X 
X 
X4 
Liver function 
tests 
 Total bilirubin 
 AST 
 ALT 
 Alkaline 
phosphatase 
X1 
X8 
 
 
X 
X 
X4 
Toxicities 
assessment 
Graded per NCI 
CTCAE, v4.0 
X2 
X 
 X 
X 
X 
X 
Radiology 
 CT scan of 
chest 
,abdomen, 
and/or pelvis 
as clinically 
indicated 
  
 
   X3 
 
 
X 
X 
X4 
 Whole body 
PET/CT or  
 MRI 
X3 
 
 
X4  
 X4  
 X4 
Maintenance 
chemotherapy 
usage 
 
 
X 
X5 
X5 
X5 
X5 
1. Within 21 days prior to registration. 
2. Baseline evaluation should document any residual toxicity from previous therapy (SBRT-related Toxicities) . 
3. Baseline studies within 90 days of registration; additional radiographic images of extra-hepatic, extra-
pulmonary sites as clinically indicated. Imaging sufficient for inclusion in trial at time of enrollment  includes 
diagnostic CT or PET/CT or MRI which demonstrates extent of metastatic disease. 
4. Additional studies as clinically indicated. 
5. If maintenance chemotherapy has been discontinued, date of stopping and reason (toxicity or disease 
progression) recorded. 
6. Time from commencement of SBRT. 
7.   Every 3 months for year 1, every 6 months for years 2-3, and every 12 months for years 4-5. 
       8.   Per standard of care for Maintenance chemotherapy 


 
 
6.2  
Follow-Up Schedule 
 
All patients should be followed for study endpoints a minimum of 6 months.  After 6 months, 
patients without progression should be followed according to Follow-Up table below.  Clinical 
and laboratory evaluations will be performed according the Study Calendar in Section 6.1. 
 
Clinical follow up will commence from the start of SBRT or maintenance chemotherapy. 
 
Disease Status 
Follow-up Schedule 
Progression Free 
 
Every 3 mos. for year 1 
Every 6 mos. for years 2 -3 
Every 12 mos. for years 4-5 
Progression 
Every 3 mos. for year 1 
Every 6 mos. for years 2 -3 
 
 
7. 
CRITERIA FOR STUDY DISCONTINUATION 
 
 
Patients should be discontinued from the study in the following instances: 
a. Inability to tolerate maintenance chemotherapy at prescribed dosing. 
b. Disease Progression on maintenance chemotherapy. If the patient develops only a 
limited number of new discrete lesions potentially suitable for eradication with SBRT, 
the decision to continue maintenance chemotherapy or not would be made by the 
treating physicians based on whether the patient was otherwise clinically stable, 
tolerating maintenance chemotherapy without unacceptable toxicity, and wished to 
continue maintenance chemotherapy rather than either discontinue it or switch to 
another systemic agent. In such cases the PI should be notified, and documentation 
will be placed in the research chart that the new sites will be aggressively treated with 
additional SBRT 
c. Other medical or ethical reasons, or noncompliance 
d. Patient request 
 
8. 
 DATA AND SAFETY MONITORING 
 
8.1 
Data and Safety Monitoring Plan 
 
8.1.1 
Data Management and Monitoring/Auditing 
 
Trial monitoring will be conducted no less than annually and refers to a regular interval review of 
trial related activity and documentation performed by the DOT and/or the CRO Multi-Center IIT 
Monitor. This review includes but is not limited to accuracy of case report forms, protocol 
compliance, timeless and accuracy of Velos entries and AE/SAE management and reporting. 
Documentation of trial monitoring will be maintained along with other protocol related documents 
and will be reviewed during internal audit.   
 
For further information, refer to the UTSW SCCC IIT Management Manual. 
 


 
 
Toxicity and dose escalation reviews will be performed annually.  These reviews will be 
documented by written report and distributed to the study team. 
 
The UTSW Simmons Comprehensive Cancer Center (SCCC) Data Safety Monitoring Committee 
(DSMC) is responsible for monitoring data quality and patient safety for all UTSW SCCC clinical 
trials.  As part of that responsibility, the DSMC reviews all local serious adverse events and 
UPIRSOs in real time as they are reported and reviews adverse events on a quarterly basis.  The 
quality assurance activity for the Clinical Research Office provides for periodic auditing of clinical 
research documents to ensure data integrity and regulatory compliance.  A copy of the DSMC plan 
is available upon request. 
 
The SCCC DSMC meets quarterly and conducts annual comprehensive reviews of ongoing clinical 
trials, for which it serves as the DSMC of record. The QAC works as part of the DSMC to conduct 
regular audits based on the level of risk. Audit findings are reviewed at the next available DSMC 
meeting.  In this way, frequency of DSMC monitoring is dependent upon the level of risk.  Risk level 
is determined by the DSMC Chairman and a number of factors such as the phase of the study; the 
type of investigational agent, device or intervention being studied; and monitoring required to 
ensure the safety of study subjects based on the associated risks of the study. Protocol-specific 
DSMC plans must be consistent with these principles.  
 
Adherence to the Protocol 
 
 
Except for an emergency situation, in which proper care for the protection, safety, and well-being of 
the study subject requires alternative treatment, the study shall be conducted exactly as described 
in the approved protocol.  
 
Exceptions (also called single-subject exceptions or single-subject waivers): include any departure 
from IRB-approved research that is not due to an emergency and is: 
 intentional on part of the investigator; or 
 in the investigator’s control; or 
 not intended as a systemic change (e.g., single-subject exceptions to eligibility 
[inclusion/exclusion] criteria) 
 Reporting requirement: Exceptions are non-emergency deviations that require prospective IRB 
approval before being implemented. Call the IRB if your request is urgent. If IRB 
approval is not obtained beforehand, this constitutes a major deviation. 
 
Emergency Deviations: include any departure from IRB-approved research that is necessary to:  
 avoid immediate apparent harm, or 
 protect the life or physical well-being of subjects or others 
 Reporting requirement: Emergency deviations must be promptly reported 
to the IRB within 5 working days of occurrence. 
 
 
Major Deviations (also called violations): include any departure from IRB-approved research that: 
 
Harmed or placed subject(s) or others at risk of harm (i.e., did or has the potential to 
negatively affect the safety, rights, or welfare of subjects or others), or 
 
Affect data quality (e.g., the completeness, accuracy, reliability, or validity of the data) or 
the science of the research (e.g., the primary outcome/endpoint of the study) 
 Reporting requirement: Major deviations must be promptly reported to  
the IRB within 5 working days of PI awareness. 
 


 
 
Minor Deviations: include any departure from IRB-approved research that: 
 
Did not harm or place subject(s) or others at risk of harm (i.e., did not or did not have 
the potential to negatively affect the safety, rights, or welfare of subjects or others), or 
 
Did not affect data quality (e.g., the completeness, accuracy, reliability, or validity of the 
data) or the science of the research (e.g., the primary outcome/endpoint of the study) 
 Reporting requirement: Minor deviations should be tracked and summarized in the progress report at 
the next IRB continuing review. 
 
8.1.2 Internal Data and Safety Monitoring Committee 
 
The Radiation Oncology Clinical Research Office (CRO) reports serious adverse events 
(SAEs) to Radiation Oncology Data Safety Monitoring Committee (DSMC) monthly. 
These SAEs are also reported to the University of Texas Southwestern Medical Center 
(UTSW) IRB per IRB guidelines and SCC DSMC.   
 
All clinical trials are reviewed on monthly basis for enrollment. These trials are assessed 
for safety on a continual basis throughout the life of the trial.  For investigator-initiated 
trials, all SAEs are monitored – both local and at affiliated institutions.   
 
A data safety monitoring committee including radiation oncologists not participating in this 
trial will be formed to review toxicity endpoints and efficacy data. In particular, this 
committee will scrutinize the grading of adverse events and the attribution to therapy 
previously assigned by the investigators.  This panel will have access to basic patient 
information so as to have the ability to critically review toxicity events.  This study will use 
this committee to perform ongoing safety assessment at regular defined intervals defined 
in the statistics section of this protocol.  Unexpected toxicities occurring between defined 
interim analyses points will be reported to the treating center’s IRB and also to the 
University of Texas Southwestern Institutional Review Board. 
 
8.2 
Adverse Events: Definitions and Reporting 
Adverse Events will be reported as indicated by the appropriate following table (see below).   
 
8.2.1 
An adverse event is defined as any untoward or unfavorable medical occurrence in a 
human research study participant, including any abnormal sign (for example, abnormal physical 
exam, imaging finding or clinically significant laboratory finding), symptom, clinical event, or 
disease, temporarily associated with the subject’s participation in the research, whether or not it is 
considered related to the subject’s participation in the research. 
Adverse events encompass clinical, physical and psychological harms. Adverse events occur most 
commonly in the context of biomedical research, although on occasion, they can occur in the 
context of social and behavioral research. Adverse events may be expected or unexpected. 
Acute Adverse Events  
Adverse events occurring in the time period from the signing of the informed consent, through 30 
days post treatment will be considered acute adverse events 
Late Adverse Events (as applicable) 
Adverse events occurring in the time period from the end of acute monitoring, to 5 years post 
treatment, will be defined as late adverse events. Radiation Oncology and Hematologic Oncology 
office notes will be reviewed for adverse events. 


 
Severity  
Adverse events will be graded by a numerical score according to the defined NCI Common 
Terminology Criteria for Adverse Events (NCI CTCAE) Version 5.0. Adverse events not specifically 
defined in the NCI CTCAE will be scored on the Adverse Event log according to the general 
guidelines provided by the NCI CTCAE and as outlined below.   
 
Grade 1: Mild  
 
Grade 2: Moderate 
 
Grade 3: Severe or medically significant but not immediately life threatening 
 
Grade 4: Life threatening consequences 
 
Grade 5: Death related to the adverse event 
 
Serious Adverse Events  
ICH Guideline E2A and the UTSW IRB define serious adverse events as those events, occurring at 
any dose, which meets any of the following criteria:  
 
Results in death   
 
Immediately life-threatening  
 
Results in inpatient hospitalization1,2 or prolongation of existing hospitalization  
 
Results in persistent or significant disability/incapacity  
 
Results in a congenital anomaly/birth defect  
 
Based upon appropriate medical judgment, may jeopardize the subject’s health and may 
require medical or surgical intervention to prevent one of the other outcomes listed in this 
definition. 
Note: A “Serious adverse event” is by definition an event that meets any of the above criteria. 
Serious adverse events may or may not be related to the research project. A serious adverse event 
determination does not require the event to be related to the research. That is, both events 
completely unrelated to the condition under study and events that are expected in the context of 
the condition under study may be serious adverse events, independent of relatedness to the study 
itself. As examples, a car accident requiring >24 hour inpatient admission to the hospital would be 
a serious adverse event for any research participant; likewise, in a study investigating end-stage 
cancer care, any hospitalization or death which occurs during the protocol-specified period of 
monitoring for adverse and serious adverse events would be a serious adverse event, even if the 
event observed is a primary clinical endpoint of the study. 
1Pre-planned hospitalizations or elective surgeries are not considered SAEs. Note: If events occur 
during a pre-planned hospitalization or surgery, that prolong the existing hospitalization, those 
events should be evaluated and/or reported as SAEs.   
2 NCI defines hospitalization for expedited AE reporting purposes as an inpatient hospital stay equal to or 
greater than 24 hours. Hospitalization is used as an indicator of the seriousness of the adverse event and 
should only be used for situations where the AE truly fits this definition and NOT for hospitalizations 
associated with less serious events. For example: a hospital visit where a patient is admitted for 
observation or minor treatment (e.g. hydration) and released in less than 24 hours. Furthermore, 
hospitalization for pharmacokinetic sampling is not an AE and therefore is not to be reported either as a 
routine AE or in an expedited report. 
8.2.2 
Unanticipated Problems Involving Risks to Subjects or Others (UPIRSOs): 
Adverse event data collection and reporting, which are required as part of every clinical trial, are done to 
ensure the safety of subjects enrolled in the studies as well as those who will enroll in future studies. 
Adverse events are reported in a routine manner at scheduled times during a trial. Additionally, certain 
adverse events must be reported in an expedited manner to allow for optimal monitoring of subject safety 
and care.  
 
All subjects experiencing an adverse event, regardless of its relationship to study therapy, will be 
monitored until:  


 
 the adverse event resolves or the symptoms or signs that constitute the adverse event 
return to baseline or is stable in the opinion of the investigator;  
 there is a satisfactory explanation other than the study therapy for the changes observed; 
or 
 death. 
The phrase “unanticipated problems involving risks to subjects or others” is found, but not defined 
in the HHS regulations at 45 CFR 46, and the FDA regulations at 21 CFR 56.108(b)(1) and 21 CFR 
312.66. For device studies, part 812 uses the term unanticipated adverse device effect, which is 
defined in 21 CFR 812.3(s). Guidance from the regulatory agencies considers unanticipated 
problems to include any incident, experience, or outcome that meets ALL three (3) of the following 
criteria: 
• 
Unexpected in terms of nature, severity or frequency given (a) the research procedures that are 
described in the protocol-related documents, such as the IRB-approved research protocol and 
informed consent document; and (b) the characteristics of the subject population being studied;  
 
 
 
 
AND 
• 
Related or possibly related to participation in the research (possibly related means there is a 
reasonable possibility that the incident, experience, or outcome may have been caused by the 
procedures involved in the research); 
 
AND  
• 
Suggests that the research places subjects or others at greater risk of harm (including physical, 
psychological, economic, or social harm) than was previously known or recognized. Note: 
According to OHRP, if the adverse event is serious, it would always suggest a greater risk of harm. 
 
Follow-up  
All adverse events will be followed up according to good medical practices.  
  
8.2.3 
 
Steps to Determine If a Serious Adverse Event Requires Expedited Reporting to the SCCC DSMC and/or 
HRPP 
Step 1: Identify the type of adverse event using the NCI Common Terminology Criteria for Adverse 
Events (CTCAE v5).  
 
Step 2: Grade the adverse event using the NCI CTCAE v5. 
 
Step 3: Determine whether the adverse event is related to the protocol therapy.  
Attribution categories are as follows: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE may NOT be related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
Note: This includes all events that occur to the end of the acute adverse events reporting period as 
defined in section 8.2.1. Any event that occurs during the late adverse event period as defined in 
section 8.2.1 and is attributed (possibly, probably, or definitely) to the agent(s) must also be 
reported as indicated in the sections below. 
 
Step 4: Determine the prior experience of the adverse event. Expected events are those that have 
been previously identified as resulting from administration of the treatment. An adverse event is 
considered unexpected, for expedited reporting purposes only, when either the type of event or the 
severity of the event is not listed in: 
 
the current known adverse events listed in the Agent Information Section of this protocol (if 
applicable); 
 
the drug package insert (if applicable); 


 
 
the current Investigator’s Brochure (if applicable) 
the Study Agent(s)/Therapy(ies) Background and Associated Known Toxicities section of this protocol 
 
8.2.4 
Reporting SAEs and UPIRSOs to the Simmons Comprehensive Cancer Center (SCCC) Data Safety 
Monitoring Committee (DSMC) 
 
All SAE/UPIRSOs at all sites, which occur in research subjects on protocols for which the SCCC is 
the DSMC of record require reporting to the DSMC regardless of whether IRB reporting is required. 
All SAEs/UPIRSOs occurring during the protocol-specified monitoring period should be submitted 
to the SCCC DSMC within 5 business days of the PI or delegated study team members awareness 
of the event(s). In addition, for participating centers other than UTSW, local IRB guidance should 
be followed for local reporting of serious adverse events. 
 
The UTSW study team is responsible for submitting SAEs/UPIRSOs to the SCCC DSMC 
Coordinator.  Hardcopies or electronic versions of the eIRB Reportable Event report; FDA Form 
#3500A forms, or other sponsor forms, if applicable; and/or any other supporting documentation 
available should be submitted to the DSMC Coordinator.  The DSMC Coordinator forwards the 
information onto the DSMC Chairman who determines if immediate action is required.  Follow-up 
eIRB reports, and all subsequent SAE/UPIRSO documentation that is available are also submitted 
to the DSMC Chair who determines if further action is required. (See Appendix III of the SCCC DSMC 
Plan for a template Serious Adverse Event Form which may be utilized when a sponsor form is 
unavailable and SAE submission to the eIRB is not required). 
  
 
If the event occurs on a multi-institutional clinical trial coordinated by the UTSW Simmons 
Comprehensive Cancer Center, the DOT Manager or lead coordinator ensures that all participating 
sites are notified of the event and resulting action, according to FDA guidance for expedited 
reporting. DSMC Chairperson reviews all SAEs/UPIRSOs upon receipt from the DSMC 
Coordinator.  The DSMC Chairperson determines whether action is required and either takes 
action immediately, convenes a special DSMC session (physical or electronic), or defers the action 
until a regularly scheduled DSMC meeting.  
 
 
Written reports to: 
 
UTSW Radiation Oncology Clinical Research Manager 
Email: sarmistha.sen@utsouthwestern.edu 
Fax: 214-645-0780 
 
UTSW Institutional Review Board (IRB) 
Submit a Reportable Event via eIRB with a copy of the final sponsor report as attached 
supporting documentation 
 
Reporting Unanticipated Problems Involving Risks to Subjects or Others (UPIRSOs) to the UTSW 
HRPP/IRB 
 
UTSW reportable event guidance applies to all research conducted by or on behalf of UT 
Southwestern, its affiliates, and investigators, sites, or institutions relying on the UT Southwestern 
IRB. Additional reporting requirements apply for research relying on a non-UT Southwestern IRB. 
 
According to UTSW HRPP/IRB policy, UPIRSOs are incidents, experiences, outcomes, etc. that 
meet ALL three (3) of the following criteria: 
1. Unexpected in nature, frequency, or severity (i.e., generally not expected in a subject’s 
underlying condition or not expected as a risk of the study; therefore, not included in the 
investigator’s brochure, protocol, or informed consent document),AND 
2. Probably or definitely related to participation in the research, AND 
3. Suggests that the research places subjects or others at a greater risk of harm (including 
 


 
physical, psychological, economic, or social harm) than was previously known or recognized.  
Note: According to OHRP, if the adverse event is serious, it would always suggest a greater 
risk of harm. 
 
For purposes of this policy, UPIRSOs include unanticipated adverse device effects (UADEs) and 
death or serious injury related to a humanitarian use device (HUD).  
 
UPIRSOs must be promptly reported to the UTSW IRB within 5 working days of 
PI awareness. 
 
For research relying on a non-UT Southwestern IRB (external, central, or single IRB): 
 
Investigators relying on an external IRB who are conducting research on behalf of UT 
Southwestern or its affiliates are responsible for submitting LOCAL UPIRSOs to the UT 
Southwestern IRB within 5 working days of PI awareness. Investigators must report to their relying 
IRB according to the relying IRB’s policy. In addition, the external IRB’s responses or 
determinations on these local events must be submitted to the UT Southwestern IRB within 10 
working days of receipt. 
 
Events NOT meeting UPIRSO criteria: 
 
Events that do NOT meet UPIRSO criteria should be tracked, evaluated, summarized, and 
submitted to the UTSW HRPP/IRB at continuing review. 
 
For more information on UTSW HRPP/IRB reportable event policy, see 
https://www.utsouthwestern.edu/research/research-administration/irb/assets/policies-combined.pdf. 
  
 
 
9. 
EVALUATION OF PROGRESSION 
 
 
Patients with evidence of new lesions amenable to SBRT during follow-up imaging not 
previously treated will be treated at the Radiation Oncologist’s discretion.  This will not constitute 
an event if the lesion is both amenable to SBRT and subsequently treated. However, if the 
lesion is not amenable to SBRT, the patient is either unwilling to pursue further treatment or 
cannot tolerate treatment due to coexisting comorbidities, then progression will be deemed to 
have occurred.  
 
For liver lesions treated with SBRT, RECIST (Response Evaluation Criteria in Solid Tumors) 
criteria will be used for evaluation of progression. Evaluation of liver lesions within 3 months 
after SBRT is problematic and the appearance of non-enhancing hypodensity on follow-up CT 
scanning should not be mistaken for disease progression. For this reason a 6-month follow-up 
interval result is more reliable to evaluate progression. Measurable liver lesions are defined 
lesions that can be accurately measured in at least one dimension with longest diameter 20 
mm using conventional techniques or 10 mm with spiral CT scan. Complete response (CR) is 
the disappearance of the measurable target lesions on relevant imaging studies. Partial 
response (PR) is at least a 30% decrease in the sum of the longest diameter (LD) of 
measurable target lesions taking as reference the baseline sum LD. Progression (PD) is at least 
a 20% increase in the sum of LD of target lesions taking as reference the smallest sum LD 
recorded since the treatment started or the appearance of one or more new lesions. 
 
Evaluation of lung lesions at any time after SBRT is difficult in view of the expected fibrotic 
reaction. Bone lesions seen only on PET are also not well scored by RECIST criteria and will 


 
not be evaluated in that manner. For these reasons certain study-specific definitions of response 
and local control will apply. For lung lesions a complete response (CR) will be defined as the 
absence of abnormal metabolic activity on PET scan; a partial response (PR) will be defined as 
residual metabolic activity on PET scan in the absence of progressive disease. Fibrosis within 
the lung volume that receives a dose on the order of 18 Gy or more (typically 2-3 cm outside the 
PTV) has been commonly observed. The characteristic pattern is a gradual dissolution of a 
discrete mass and formation of a scar that recapitulates the shape of the radiation dose 
distribution. In this study progressive disease (PD) will be defined as residual increased 
metabolic PET scan in combination with expanded parenchymal opacity that retains mass-like 
discrete borders and extends outside the volume of lung that received at least 18 Gy. 
 
All types of lesions will be scored at the six month time point for local control (LC) versus PD. LC 
for lung and liver lesions will be either CR or PR as described above. Progressive disease (PD) 
for bone lesions will be residual or increased metabolic activity on PET scan relative to baseline 
imaging with complementary CT or MRI that indicates residual solid tumor distinct from and lack 
of biopsy-proven pathologic fracture in the interim. 
 
10. 
STATISTICAL CONSIDERATIONS 
 
10.1 Study Endpoints 
 
10.1.1 Primary Endpoint: Progression-free survival (PFS) 
 
10.1.2 Secondary endpoints: 
 
10.1.2.1 Rate in-field local control and rate of out-of-field disease progression. 
10.1.2.2 Safety of SBRT with locally advanced or metastatic NSCLC after prior chemotherapy 
10.1.2.3 Overall survival 
10.1.2.4 Duration of maintenance of chemotherapy and time to initiation of third line systemic 
agent (chemotherapy or biologic agent) 
 
10.2 Sample Size Determination 
The sample size calculation is based on the primary endpoint, progression-free survival, and the 
assumption that patients are randomized until the end of accrual. The sample size is calculated 
with the 2-sided significance level of 0.1 and 80% statistical power using a two-sample log rank 
test. We assume that the progression-free survival function follows an exponential distribution 
for each arm. Accrual to the study is assumed to be uniformly distributed. The null hypothesis is 
that the there are no difference in median survival rates between two arms.  We assume that 
patients will be accrued for 2 years with a 1-year follow-up. We hypothesize that the patients 
randomly assigned to the SBRT arm and maintenance chemotherapy arm have median PFS 
times of 10 months and 4 months, respectively, which is translated to the hazard ratio of 0.400. 
The total sample size of 36 patients (18 in the SBRT arm and 18 in the maintenance therapy 
arm) will be accrued to achieve the desired 80% statistical power and 2-sided significance level 
of 0.10. Sample size was estimated using the sample size software PASS 2008.  
 
10.3 Patient Accrual 
Patient accrual is projected to be 2 patients per month. This trial should complete the accrual 
phase in 24 months  
 


 
10.4 Randomization Scheme 
Patients will be allocated to the treatment using a randomized permuted block. There will be no 
stratification factor in randomization. 
 
10.5 Analysis Plans 
All eligible patients who are randomized to the study will be included in the comparison of 
treatment arms, regardless of treatment compliance (intent-to-treat analysis). 
Progression-free survival time will be estimated using the Kaplan-Meier approach. The log-rank 
test will be used to test for a statistically significant difference in survival distributions. The null 
and alternative hypotheses are H0: S1(t) = S2 (t) vs. HA: S1 (t) ≠ S2 (t), where Si (t) is the 
distribution of progression-free survival times for patients in arm i. The Cox proportional hazard 
regression model will be used to determine hazard ratios and 95% confidence intervals for the 
treatment difference in progression-free survival. Unadjusted ratios and ratios adjusted for 
covariates of interest will be computed. 
 
Overall survival will be analyzed in the same way as progression-free survival. In-field local 
control and rate of out-of-field disease progression will be estimated using the Kaplan-Meier 
approach.  
 
For safety of SBRT, only adverse events assessed to be definitely, probably, or possibly related 
to protocol treatment will be considered. The rates of all Grade 3-5 adverse events and death 
during or within 30 days of discontinuation of protocol treatment will be computed. Descriptive 
statistics will be computed for the duration of maintenance of chemotherapy, and time to 
initiation of third line systemic agent. 
 
10.5.1 Stopping Rule 
There will be an early stopping rule for unexpected toxicity. If at any point during the study more 
than 1/6 of patients treated to date experience study treatment-related grade 4-5 toxicity of any 
kind, study enrollment will be suspended. Depending on the nature of the toxicity and whether it 
is believed to be related maintenance chemotherapy or SBRT, the dose of one or the other 
might be modified by amendment to the protocol, which would require review and re-approval of 
the amended protocol by the IRBs of all participating institutions. 
 
Please also see section 6.2 for clarification of start of primary endpoint. 
 
 11.     DATA COLLECTION AND PATIENT REGISTRATION 
 
The coordinating center for this trial will be UT-Southwestern. Patients can be registered only 
after eligibility criteria are met and approved by UTSW. For patients who pass screening, a 
completed patient registration form, which can be found in your forms binder, will need to be 
faxed with the provided cover sheet to: Radiation Oncology Clinical Research, UT 
Southwestern, fax 214-648-5923. UTSW will review the eligibility criteria to ensure eligibility 
and will fax back page 2 of the form which will contain PI signature and patient study number. If 
a patient is ineligible or if a waiver is granted, the enrolling institution will be notified of such 
decision which will include a brief explanation. Any waiver granted for patient eligibility is at the 
discretion of the Principal Investigator, Puneeth Iyengar, MD, PhD. Once patient has been 
deemed eligible by UTSW, the patient must be entered into the web database by the 
participating institution. 
 


 
All subsequent data will be collected and entered into the web database as well. Supporting 
source documents for all data will be faxed to the following: Radiation Oncology Clinical 
Research, UT Southwestern, fax 214-648-5923.  A training manual as well as onsite training 
will be provided for all participating institutions utilizing the web database. For patients enrolled 
at participating institutions, data will be collected and stored according to their institutional 
policies.  The data will be kept in a secure location in accordance with prevailing HIPAA 
regulations. Adverse events will be reviewed and discussed at the monthly UTSW Department 
of Radiation Oncology Clinical Research monthly meetings in accordance with UTSW cancer 
center guidelines and meeting minutes will be made available to participating institutions.  
 
12. 
RETENTION OF RECORDS 
 
Documentation of adverse events, records of study drug receipt and dispensation, and all IRB 
correspondence should be retained for at least 2 years after the investigation is completed. 
 
 
 
 
 
 
 
 
 


 
13. 
APPENDICES 
APPENDIX I: Smoker Status Case Report Form 
 
XXXX ASSESSMENTS 
CIGARETTE SMOKING HISTORY AT REGISTRATION 
 
 Date of evaluation:   _____________________ 
 
          DD     MMM     YYYY 
1.  Please indicate one of the following: 
 
 Subject never smoked cigarettes. 
 Subject has smoked < 100 cigarettes in a lifetime and stopped.  
 
Indicate when stopped:  < 1 month 
 1 month-1 year 
 > 1 year  
 Subject has smoked > 100 cigarettes in a lifetime and stopped. 
 
Indicate when stopped:  < 1 month 
 1 month-1 year 
 > 1 year 
 
Average number of cigarettes smoked per day:  _____   Number of years smoked: _____ 
 
  Subject is currently smoking cigarettes. 
 
Average number of cigarettes smoked per day:  _____   Number of years smoked: _____ 
OTHER TOBACCO/NICOTINE HISTORY AT REGISTRATION 
1.  Please indicate one of the following: 
 Subject never used other tobacco or nicotine products.  Do not complete question 2. 
 Subject currently or in the past has used other tobacco or nicotine products.  Complete question 2. 
2.  If a user of tobacco/nicotine products, indicate frequency used and/or how long ago product use stopped. 
 
Cigars/Pipes      Not Applicable 
 
Frequency used:  at least once daily  at least once weekly  at least once monthly 
 
Product stopped:  current  
 < 1 month 
 1 month-1 year 
 > 1 year 
 
 
Oral Tobacco Products      Not Applicable 
 
Frequency used:  at least once daily  at least once weekly  at least once monthly 
 
Product stopped:  current 
 < 1 month 
 1 month-1 year 
 > 1 year 
 
 
Nicotine Replacement Therapy      Not Applicable 
 
Frequency used:  at least once daily  at least once weekly  at least once monthly 
 
Product stopped:  current 
 < 1 month 
 1 month-1 year 
 > 1 year 
 
 
Other, please specify:  
 
 
 
      Not Applicable 
 
Frequency used:  at least once daily  at least once weekly  at least once monthly 
 
Product stopped:  current 
 < 1 month 
 1 month-1 year 
 > 1 year 


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APPENDIX II: Known Risks of Medications 
 
II.I 
Tarceva 
Respiratory 
Respiratory side effects have included reports of serious interstitial lung disease, including 
fatalities in the treatment of non-small cell lung cancer or other advanced solid tumors. Dyspnea 
(41%) and cough (33%) have also been reported. 
Dermatologic 
Dermatologic side effects including rash (75%), pruritus (13%), dry skin (12%), alopecia, 
hirsutism, eyelash/eyebrow changes, paronychia, and brittle and loose nails have been 
reported. Bullous, blistering and exfoliative skin conditions have been reported including cases 
suggestive of Stevens-Johnson syndrome/toxic epidermal necrolysis, which in some cases were 
fatal. Cases of rosacea-like folliculitis and Malassezia sympodialis have also been reported. 
Treatment should be interrupted or discontinued if the patient develops severe bullous, blistering, or 
exfoliating conditions. 
 
The appearance of a rash in cancer patients treated with erlotinib is strongly associated with longer 
survival, according to researchers from the drug's developer, OSI Pharmaceuticals, Inc. 
 
Rash resulted in study discontinuation in 1.2% patients. Dose reduction or interruption for rash 
was needed in 5.1% of patients. In erlotinib-treated patients who developed rash, the onset was 
within two weeks in 66% and within one month in 81%. 
Gastrointestinal 
The median time to onset of diarrhea was 12 days. Diarrhea resulted in study discontinuation in 0.5% of 
patients. Dose reduction or interruption for diarrhea was needed in 2.8% of patients. 
 
Patients receiving concomitant antiangiogenic agents, corticosteroids, NSAIDs, and/or taxane-
based chemotherapy, or who have prior history of peptic ulceration or diverticular disease are at 
an increased risk for gastrointestinal perforation. Erlotinib (the active ingredient contained in 
Tarceva) should be permanently discontinued in patients who develop gastrointestinal 
perforation. 
Gastrointestinal side effects including diarrhea (54%), nausea (33%), vomiting (23%), stomatitis 
(17%), and abdominal pain (11%) have been reported. Gastrointestinal perforation has been 
reported in patients receiving erlotinib, including fatalities. Gastrointestinal bleeding has been 
reported infrequently. 
Hepatic 
Hepatic side effects including hepatic failure, hepatorenal syndrome, and liver function test 
abnormalities such as elevated alanine aminotransferase (ALT), aspartate aminotransferase 
(AST), and bilirubin have been reported. A case of hepatitis has also been reported. 
These elevations were mostly transient or associated with liver metastases. 
 


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A pharmacokinetic study in patients with advanced solid tumors and moderate hepatic impairment 
according to the Child-Pugh criteria has been reported. In this study, 10 of the 15 patients died on 
treatment or within 30 days of the last erlotinib dose. Eight of these patients died from progressive 
disease, one patient died from hepatorenal syndrome, and one patient died from rapidly progressing liver 
failure. Six out of the 10 patients who died had baseline total bilirubin greater than 3 times the upper limit 
of normal suggesting severe, rather than moderate, hepatic impairment. All patients had hepatic 
impairment due to advanced cancer with liver involvement such as hepatocellular carcinoma, 
cholangiocarcinoma, or liver metastases. 
 
Patients with hepatic impairment should be monitored closely during therapy with erlotinib, and dosing 
should be interrupted or discontinued if changes in liver function are severe. 
 
Liver function test abnormalities (including elevated alanine aminotransferase (ALT), aspartate 
aminotransferase (AST) and bilirubin) were observed in patients receiving single-agent erlotinib 
150 mg in the Maintenance study. Grade 2 (>2.5 - 5 x ULN) ALT elevations occurred in 2% and 
1%, and Grade 3 (>5 - 20 x ULN) ALT elevations were observed in 1% and 0% of erlotinib and 
placebo treated patients, respectively. The erlotinib treatment group had Grade 2 (>1.5-3 x 
ULN) bilirubin elevations in 4% and Grade 3 (>3-10 x ULN) in <1% compared with <1% for both 
Grades 2 and 3 in the placebo group. 
General 
General side effects including anorexia (52%) and fatigue (52%) have been reported. 
Immunologic 
Immunologic side effects including infection (24%) have been reported. 
Ocular 
Ocular disorders including abnormal eyelash growth, keratoconjunctivitis sicca, or keratitis are known 
risk factors for corneal ulceration/perforation. 
 
Erlotinib (the active ingredient contained in Tarceva) therapy should be interrupted or 
discontinued if patients present with acute/worsening ocular disorders such as eye pain. 
Ocular side effects including conjunctivitis (12%), keratoconjunctivitis sicca (12%), corneal 
perforation and ulceration, abnormal eyelash growth, and keratitis have been reported. 
Renal 
Renal side effects including cases of hepatorenal syndrome, acute renal failure or renal 
insufficiency (some with fatalities) have been reported. 
Other 
Other side effects including a case of bilateral eardrum perforation have been reported. 
 
 
 
 


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II.II 
Pemetrexed 
Gastrointestinal 
Gastrointestinal side effects including nausea (84%), vomiting (58%), constipation (44%), 
anorexia (35%), stomatitis/pharyngitis (28%), diarrhea without colostomy (26%), dehydration 
(7%), and dysphagia/esophagitis/odynophagia (6%) have been reported. Colitis has been 
reported rarely. 
General 
General side effects including fatigue (80%), chest pain (40%), fever (17%), other constitutional 
symptoms (11%), and edema have been reported. 
Respiratory 
Respiratory side effects including dyspnea (66%) and interstitial pneumonitis have been 
reported. 
Hematologic 
Hematologic side effects including neutropenia (58%), leukopenia (55%), anemia (33%), and 
thrombocytopenia (27%) have been reported. 
Dermatologic 
Dermatologic side effects including rash/desquamation (22%) and asteatotic eczema have been 
reported. 
Nervous system 
Nervous system side effects including neuropathy/sensory effects (17%) have been reported. 
Renal 
Renal side effects including creatinine elevation (16%), and renal failure (2%) have been 
reported. 
Psychiatric 
Psychiatric side effects including mood alterations/depression (14%) have been reported. 
Cardiovascular 
Cardiovascular side effects including thrombosis/embolism (7%) have been reported. 
Immunologic 
Immunologic side effects including infection without neutropenia (1%), infection with grade 3 or 
grade 4 neutropenia (6%), infection/febrile neutropenia-other (3%), and febrile neutropenia (1%) 
have been reported. 


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Hypersensitivity 
Hypersensitivity side effects including allergic reactions (2%) have been reported. 
Other 
Side effects below show the incidence of CTC grade 3/4 toxicities in patients who received both 
pemetrexed and cisplatin along with vitamin supplementation including daily folic acid and 
vitamin B12. Other side effects including radiation recall have been reported in patients who 
have previously received radiotherapy. 
II.III 
Docetaxel 
Hematologic 
Hematologic side effects including bone marrow suppression have been the major dose-limiting 
toxicity. A reversible and not cumulative neutropenia has also been reported. A median of 8 
days to nadir and median duration of severe neutropenia (less than 500 cells/mm3) of 7 days 
has been reported. A fatal gastrointestinal hemorrhage associated with thrombocytopenia has 
been reported in one patient. Three patients with severe liver dysfunction developed fatal 
gastrointestinal bleeding associated with severe drug-induced thrombocytopenia. Disseminated 
intravascular coagulation (DIC), often in association with sepsis or multiorgan failure, has been 
reported during postmarketing experience. 
Patients carrying the GSTP1 A/B and 3435TT genotypes may have excessive hematologic toxicity. 
 
In a summary of 37 clinical trials (n = 1,495), neutropenia (less than 2,000 cells/mm3) has been reported 
in 96.3% of patients with normal LFTs at baseline and 96% of patients with elevated LFTs. Neutropenia 
(less than 500 cells/mm3) has been reported in 76% of patients with normal LFTs at baseline and 86% of 
patients with elevated LFTs. 
 
Leukopenia (less than 4,000 cells/mm3) has been reported in 96.5% of patients with normal LFTs at 
baseline and 98.1% of patients with elevated LFTs. Leukopenia (less than 1,000 cells/mm3) has been 
reported in 31% of patients with normal LFTs at baseline and 44.2% of patients with elevated LFTs. 
Thrombocytopenia (less than 100,000 cells/mm3) has been reported in 7.5% of patients with normal LFTs 
at baseline and 27.3% of patients with elevated LFTs. 
 
Anemia (less than 11 g/dL) has been reported in 89.5% of patients with normal LFTs at baseline and 
92.7% of patients with elevated LFTs. Anemia (less than 8 g/dL) has been reported in 8.4% of patients 
with normal LFTs and 30.9% of patients with elevated LFTs. 
 
Febrile neutropenia has been reported in 11.8% of patients with normal LFTs at baseline and 
26.4% of patients with elevated LFTs. 
Hypersensitivity 
In one institution's experience with 623 courses of docetaxel therapy (n = 168), hypersensitivity 
reactions decreased from 50% to 5% once patients began receiving systemic prophylaxis 
including corticosteroids and antihistamines. 
Hypersensitivity side effects may occur within a few minutes following initiation of a docetaxel 
infusion. Severe hypersensitivity reactions characterized by hypotension and/or bronchospasm, 


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or generalized rash/erythema occurred in 0.9% of patients who received the recommended 
dexamethasone premedication. Hypersensitivity reactions requiring discontinuation of therapy 
have been reported in 5 of 1260 patients who did not receive premedication. Minor events, 
including flushing, rash with or without pruritus, chest tightness, back pain, dyspnea, drug fever 
or chills have also been reported and resolved after discontinuation of the infusion and initiation 
of appropriate therapy. Bullous eruption including erythema multiforme, Stevens-Johnson 
syndrome, and toxic epidermal necrolysis have been reported rarely. Rare cases of 
anaphylactic shock have been reported during postmarketing experience. Very rarely, these 
cases resulted in a fatal outcome in patients who received premedication. 
General 
General side effects including diffuse pain, chest pain, and radiation recall phenomenon have been 
reported. 
 
Severe adverse events have been reported in 49% of patients treated with docetaxel 60 mg/m2 compared 
to 55.3% and 65.9% treated with 75 mg/m2 and 100 mg/m2 respectively. Discontinuation due to 
adverse events was reported in 5.3% of patients treated with 60 mg/m2 versus 6.9% and 16.5% 
for patients treated at 75 mg/m2 and 100 mg/m2 respectively. Deaths within 30 days of last 
treatment occurred at a rate of 4.0% in patients treated with 60 mg/m2 compared to 5.3% and 
1.6% for patients treated at 75 mg/m2 and 100 mg/m2 respectively. 
Cardiovascular 
Cardiovascular side effects including hypotension have been reported in 3.6% of patients (3.4% required 
treatment). Heart failure, sinus tachycardia, atrial fibrillation, atrial flutter, dysrhythmia, unstable 
angina, pulmonary edema, deep vein thrombosis, ECG abnormalities, thrombophlebitis, 
pulmonary embolism, syncope, myocardial infarction, and hypertension have also been 
reported. 
Renal 
Renal side effects including severe fluid retention (generally renal in origin and generally after 
four to five courses of therapy) have been reported in patients using a five day dexamethasone 
premedication regimen. The fluid retention was characterized by one or more of the following 
events; poorly tolerated peripheral edema, generalized edema, pleural effusion requiring urgent 
drainage, dyspnea at rest, cardiac tamponade, or pronounced abdominal distention (due to 
ascites). Renal insufficiency has been reported during postmarketing experience with the 
majority of these cases associated with concomitant nephrotoxic drugs. 
Moderate fluid retention (17.4%), severe fluid retention (6%) and discontinuation (1.7%) have 
been reported among 229 patients with normal liver function using a five day dexamethasone 
premedication regimen. Fluid retention was completely, but sometimes slowly reversible 
resolving in a median of 29 weeks following discontinuation. The median cumulative dose to the 
onset of moderate or severe fluid retention was 705 mg/m2 (in patients receiving 
premedication). In a summary of 37 clinical trials (n = 1,495), fluid retention was reported in 
48.5% of patients with normal LFTs at baseline and 66.7% of patients with elevated LFTs. In the 
same trials, severe fluid retention was reported in 5.2% of patients with normal LFTs at baseline 
and 33.3% of patients with elevated LFTs. Patients developing peripheral edema may be 
treated with standard measures including salt restriction, diuretics (e.g. spironolactone), etc. 


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Nervous system 
Spontaneous reversal of symptoms occurred in a median of 9 weeks from onset. Approximately 
3.8% of the 134 patients required discontinuation of therapy due to neurotoxicity. In a summary 
of 37 clinical trials (n = 1,495), neurosensory symptoms were reported in 53.7% of patients with 
normal LFTs at baseline and 41.8% of patients with elevated LFTs. In the same trials, severe 
neurosensory symptoms were reported in 3.9% of patients with normal LFTs at baseline and 
none of the patients with elevated LFTs. In a study (n = 46) of 209 cycles, peripheral 
neurotoxicity was reported in 30% of patients. In another study (n = 186), 11% of patients 
developed mild to moderate sensory neuropathy at cumulative doses ranging from 50 to 750 
mg/m2 and doses of 10 to 115 mg/m2. 
Nervous system side effects including paresthesia, dysesthesia, and pain (7%) have been 
reported in one study (n = 134). Confusion and rare cases of seizures or transient loss of 
consciousness have been reported, sometimes appearing during the infusion of the drug. 
Hepatic 
Hepatic side effects including various increases in blood levels have been reported. In patients 
with normal LFTs at baseline, bilirubin values greater than the upper limit of normal (ULN) 
occurred in 8.9% of patients. Increases in SGOT or SGPT greater than 1.5 times the ULN, or 
alkaline phosphatase greater than 2.5 times the ULN were observed in 18.1% and 7.6% of 
patients, respectively. Increases in SGOT and/or SGPT greater than 1.5 times the ULN 
concomitant with alkaline phosphatase greater than 2.5 times the ULN occurred in 4.5% of 
patients with normal LFTs at baseline. Rare cases of hepatitis have been reported during 
postmarketing experience. 
Gastrointestinal 
In a summary of 37 clinical trials (n = 1,495), nausea has been reported in 40.4% of patients with normal 
LFTs at baseline and 40% of patients with elevated LFTs. Diarrhea has been reported in 40.4% of patients 
with normal LFTs at baseline and 32.7% of patients with elevated LFTs. Vomiting has been reported in 
24% of patients with normal LFTs at baseline and 25.5% of patients with elevated LFTs. Severe GI 
reactions were reported in 8.2% of patients. 
 
Stomatitis has been reported in 42.3% of patients with normal LFTs at baseline and 47.3% of 
patients with elevated LFTs. Severe stomatitis has been reported in 5.3% of patients with 
normal LFTs at baseline and 14.5% of patients with elevated LFTs. Stomatitis appears to be 
dose dependent. 
Gastrointestinal (GI) side effects including nausea, vomiting, diarrhea, stomatitis abdominal 
pain, anorexia, constipation, duodenal ulcer, esophagitis, GI hemorrhage, GI perforation, 
ischemic colitis, colitis, intestinal obstruction, ileus, neutropenic enterocolitis, ischemic colitis, 
and dehydration as a consequence to GI events have been reported. 
Dermatologic 
Dermatologic side effects including reversible cutaneous reactions characterized by a rash 
including localized eruptions, mainly on the feet and/or hands, but also on the arms, face or 
thorax (and usually associated with pruritus) have been reported. Severe hand and foot 
syndrome has been reported. Severe nail disorders (2.6%), alopecia, and localized erythema of 


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the extremities with edema followed by desquamation have also been reported. Very rare cases 
of cutaneous lupus erythematosus have been reported. Scleroderma-like changes usually 
preceded by peripheral lymphedema have been reported. One case of supravenous 
discoloration of the skin due to docetaxel treatment has been reported. 
Eruptions generally occurred within one week after dosage administration and were not disabling. 
Recovery generally occurred before the next infusion. 
 
In a summary of 37 clinical trials (n = 1,495), cutaneous adverse events have been reported in 58.5% of 
patients with normal LFTs at baseline and 61.8% of patients with elevated LFTs. In the same trials, severe 
cutaneous adverse events have been reported in 5.6% of patients with normal LFTs at baseline and 10.9% 
of patients with elevated LFTs. The discontinuation rate due to skin toxicity was 1.7%. Alopecia has been 
reported in 80% of patients with normal LFTs at baseline and 61.8% of patients with elevated LFTs. In 
one study (n = 46) of 209 cycles, alopecia was reported in 91% of patients. In one institution's experience 
with 623 courses of docetaxel therapy (n = 168), dermatologic toxicity decreased from 53% to 14% once 
patients began receiving systemic prophylaxis including corticosteroids and antihistamines. 
 
Severe nail disorder were characterized by hypo- or hyperpigmentation and occasionally by 
onycholysis (0.8%) and pain. 
Local 
Local side effects consisting of infusion site reactions have been reported. These reactions were 
generally mild and consisted of hyperpigmentation, inflammation, redness or dryness of the 
skin, phlebitis, extravasation or swelling of the vein. Rare cases of transient visual disturbances 
(flashes, flashing lights, scotomata) typically occurring during drug infusion and in association 
with hypersensitivity reactions have been reported during postmarketing experience. These 
were reversible upon discontinuation of the infusion. 
Other 
In a summary of 37 clinical trials (n = 1,495), asthenia has been reported in 61.5% of patients with normal 
LFTs at baseline and 54.5% of patients with elevated LFTs. In the same trials, severe asthenia has been 
reported in 11.1% of patients with normal LFTs at baseline and 23.6% of patients with elevated LFTs. 
In a study (n = 46) of 209 cycles, malaise was reported in 52% of patients. 
Other side effects have included asthenia (11.1% to 61.5%) and malaise (52%). Fatigue and 
weakness have been reported to have lasted a few days to several weeks and were 
occasionally associated with deterioration of performance status in patients with progressive 
disease. Rare cases of ototoxicity, hearing disorders and/or hearing loss have been reported, 
including cases associated with other ototoxic drugs. A case of docetaxel-induced recall 
dermatitis on previous laser treatment sites has also been reported. 
Ocular 
Ocular side effects including conjunctivitis and lacrimation have been reported. Canalicular and 
nasolacrimal duct obstruction has been a common side effect of weekly docetaxel therapy and 
has even been reported to occur when docetaxel is used in the neoadjuvant setting according to 
one study. Excessive tearing which may be attributable to lacrimal duct obstruction has also 
been reported. 


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Respiratory 
Respiratory side effects including dyspnea, acute pulmonary edema, acute respiratory distress 
syndrome, and interstitial pneumonia have been reported. Pulmonary fibrosis has been rarely 
reported. 
 
II.IV 
Gemcitabine 
Hematologic 
Myelosuppression is the major dose-limiting factor associated with gemcitabine therapy. 
 
Dosage adjustments for hematologic toxicity are frequently necessary. Less than 1% of patients have had 
to discontinue therapy for either anemia, leukopenia, or thrombocytopenia. Grade 3/4 thrombocytopenia 
was more common in the elderly, especially older women. 
 
The risk for thrombotic thrombocytopenic purpura increases as the cumulative dose of 
gemcitabine approaches 20,000 mg/m2. 
Hematologic side effects including anemia (68%), leukopenia (62%), neutropenia (63%), 
thrombocytopenia (24%), petechiae (16%), thrombotic thrombocytopenic purpura (0.015% to 
1.4%), and sepsis (less than 1%) have been reported. Red blood cell transfusions were required 
by 19% of patients. 
Gastrointestinal 
Gastrointestinal side effects including nausea and vomiting (69%), diarrhea (19%) and stomatitis 
(11%) have been reported. A case of severe anal pruritus has also been reported. 
If the patient is not vomiting due to their disease state, nausea can generally be prevented by 
administration of prochlorperazine or low-dose oral serotonin antagonists and glucocorticoid 
therapy. One study of 790 patients found the rate of WHO grade 3 nausea and vomiting at a 
frequency of 22% in patients under 65 years of age, and 12% in patients 65 years of age or 
older. 
Hepatic 
No evidence of increased hepatic toxicity has been reported with longer duration or greater total 
cumulative dose. 
Hepatic side effects including transient elevations in ALT (68%), AST (67%), alkaline 
phosphatase (55%), bilirubin (13%), and GGT have been reported. Serious hepatotoxicity 
including liver failure and death have been reported very rarely. 
Renal 
Renal side effects including proteinuria (45%), hematuria (35%), renal failure, hemolytic-uremic 
syndrome (0.25%), and nephrotoxicity have been reported. 
Renal failure may not be reversible, even upon discontinuation of therapy. 


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Other 
The flu-like symptoms usually take place a few hours after drug administration. The symptoms are 
usually self-limiting and recovery is generally within 24 to 48 hours. Less than 1% of patients 
discontinued use due to flu-like symptoms. Some patients get relief from nonsteroidal anti-inflammatory 
drugs or acetaminophen. 
 
Out of the five reported cases of distal ischemic changes, four of those case related to 
combination chemotherapy with cisplatin and gemcitabine, while one case was of gemcitabine 
as a single agent in first-line therapy. 
Other side effects including fever (41%), frequently associated with other flu-like symptoms, has been 
reported. There was a 16% incidence of infection among the patients with fever. Both fever and asthenia 
have frequently been reported as isolated effects. Flu syndrome (19%), including fever, asthenia, 
anorexia, headache, cough, chills, and myalgia has been reported. Insomnia, rhinitis, sweating, and 
malaise have been reported infrequently. Vasculitis and gangrene have been reported very rarely. Five 
cases of distal ischemic changes have been reported. 
 
A pattern of tissue injury typically associated with radiation toxicity has also been reported in 
association with the use of gemcitabine. 
Dermatologic 
Rash was generally a macular or finely granular maculopapular pruritic eruption, mild to 
moderate in severity, involving the trunk and extremities. Alopecia is usually minimal. 
Dermatologic side effects including rash (30%), alopecia (15%), pruritus (13%), and radiation 
recall have been reported. Cellulitis has been reported rarely. Severe skin reactions including 
desquamation and bullous skin eruptions have been reported very rarely. Two cases of 
pseudocellulitis have been reported. A case of linear immunoglobulin A bullous dermatosis has 
also been reported. 
Respiratory 
Some of the dyspnea reported may have been due to underlying disease. Forty percent of the study 
population consisted of lung cancer patients, while some of the other study patients had pulmonary 
manifestations of other malignancies. 
 
Different patterns of lung injury may be related to gemcitabine. A rapid response following the 
administration of corticosteroids would mean the respiratory problem was probably due to a 
hypersensitivity reaction. 
Respiratory side effects including dyspnea (23%), sometimes accompanied by bronchospasm (<2%) 
have been reported. Parenchymal toxicity, including interstitial pneumonitis, pulmonary fibrosis, 
pulmonary edema, and adult respiratory distress syndrome has been reported rarely. 
Respiratory failure and death have been reported very rarely (in some patients, despite the 
discontinuation of therapy). 
Nervous system 
Less than 1% of the paresthesias have been severe. 


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Nervous system side effects including paresthesias (10%) have been reported. 
Local 
Local side effects including "injection-site-related events" (4%) have been reported by the 
manufacturer. 
Hypersensitivity 
Hypersensitivity side effects including anaphylactoid reactions have been reported rarely. 
Cardiovascular 
Many of the patients that suffered cardiovascular effects had a prior history of cardiovascular 
disease. Two percent of patients discontinued therapy due to these effects. Less than 1% of 
patients discontinued due to edema. 
Cardiovascular side effects including peripheral edema (20%), edema (13%), cerebrovascular 
accident, hypotension, hypertension, and generalized edema (less than 1%) have been 
reported. Atrial fibrillation has been reported rarely. Congestive heart failure, myocardial 
infarction, and arrhythmias (predominantly supraventricular in nature) have been reported very 
rarely. 
Immunologic 
Immunologic side effects including a scleroderma-like reaction have been reported. 
Oncologic 
Long term animal studies to evaluate carcinogenic potential have not been conducted. 
Oncologic side effects have been reported in animal studies. Gemcitabine induced forward 
mutations in vitro in a mouse lymphoma assay and was clastogenic in an in vivo micronucleus 
assay. 
 
II. V   
Bevacizumab 
 
Gastrointestinal 
 
Non-Gastrointestinal Fistula Formation: Discontinue Avastin if fistula formation occurs  
Renal 
 
Proteinuria: Monitor urine protein. Discontinue for nephrotic syndrome. Temporarily suspend 
Avastin for moderate proteinuria.  
Other 
 
Ovarian Failure: Inform females of reproductive potential of the risk of ovarian failure with 
Avastin  


STU092013-070, Iyengar, FormA-ResearchProtocol, Mod_31, 10-10-19 (1) 
 
Nervous system 
 
Reversible Posterior Leukoencephalopathy Syndrome (RPLS). Discontinue Avastin.  
Cardiovascular 
 
Hypertension: Monitor blood pressure and treat hypertension. Temporarily suspend Avastin if 
not medically controlled. Discontinue Avastin for hypertensive crisis or hypertensive 
encephalopathy. Arterial Thromboembolic Events (e.g., myocardial infarction, cerebral  
infarction): Discontinue Avastin for severe ATE.  
 
 
 
 
 
 
 
 
 
 


STU092013-070, Iyengar, FormA-ResearchProtocol, Mod_31, 10-10-19 (1) 
 
 
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