Conditions: Oligometastases
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 38
Healthy volunteers: no

Brief summary:
Patients with metastatic lesions of the lung, liver, or bone will be candidates for treatment. Within three weeks of the initial treatment planning, a 15 Gy dose (per lesion site) of SBRT will be administered. Prior to SBRT, patients will initiate Nelfinavir oral therapy twice daily for 7 days. Once SBRT is completed, the patient will repeat the same Nelfinavir therapy for an additional 7 days for a total of 14 days of treatment.

Detailed description:
The use of radiation therapy to treat metastatic tumors is well established and promising data are emerging with the use of SBRT for metastatic disease. However, the use of a single large fraction concurrent with a radiosensitizer as is being proposed is not of proven benefit. This investigation aims to confirm the safety and efficacy for SBRT used concurrently with a radiosensitizer in the setting of oligometastatic disease. The dose selected has been chosen with the belief that it is safe and effective based on prior experience with SBRT of lung cancer, pancreatic cancer and brain radiosurgery. All patients will be treated with a single fraction (per lesion site), targeted to the lesion concurrently with the radiosensitizer Nelfinavir.

On the basis of this preclinical evidence, we propose a phase II study of Nelfinavir combined with SBRT in patients with oligometastatic disease. Because the standard dose of Nelfinavir for HIV patients is known to be safe and does inhibit the phosphorylation of Akt and decrease tumor hypoxia, we propose to study this in conjunction with a 15 Gy dose of SBRT. Experience with single-fraction pulmonary and pancreas SBRT provides a useful dose for this trial. With published data establishing the relative safety of large single-fraction SBRT to the lungs and pancreas, we have decided to proceed to determine the safety of 15 Gy SBRT concurrently with the radiosensitizer Nelfinavir. Once this is established, we propose to continue to enroll more patients to the study at this dose to determine the efficacy of this type of therapy.

The proposed study represents an informed estimate based on current knowledge of SBRT doses and those administered in currently approved image-guided protocols (brain, base of skull, cervico-thoracic spine, pancreas and liver). This study will refine the current understanding of single fraction radiation tolerance for normal tissues, thereby making it possible to treat future patients more safely and aggressively.

Arms:
arm 1: Patients with metastatic lesions of the lung, liver, or bone will be candidates for treatment. Within three weeks of the initial treatment planning, a 15 Gy dose (per lesion site) of SBRT will be administered. Prior to SBRT, patients will initiate Nelfinavir oral therapy twice daily for 7 days. Once SBRT is completed, the patient will repeat the same Nelfinavir therapy for an additional 7 days for a total of 14 days of treatment.

Interventions: intervention 1: Nelfinavir intervention 2: Stereotactic Body Radiation (SBRT)
Intervention descriptions: intervention 1: Commercially available nelfinavir (1250 mg) will be administered orally twice daily for 14 days. intervention 2: 15 Gy dose (per lesion site) of SBRT will be administered

Protocol document:
Prot_SAP_000.pdf: 
SBRT and Nelfinavir 
Protocol Chair:  Phuoc Tran, MD  
J12137 (NA_00069585) - May 19, 2020 
 
 
1 
 
Single-Arm Phase II Study of Stereotactic Body Radiation Therapy Concurrent with 
Nelfinavir for Oligometastases 
 
Protocol Number 
 
J12137 (NA_00069585) 
IND Number 
 
 
Exempt 
 
Principal Investigator  
Phuoc tran, MD, M.D. 
Sidney Kimmel Comprehensive Cancer Center 
Johns Hopkins University 
Weinberg Building 
401 N. Broadway, Suite 1440 
Baltimore, MD 21231 
Phone:  410-614-3880 
Fax:  410-502-1419 
Email: tranp@jhmi.edu  
 
Co-Investigators 
Russell Hales, M.D. 
Lawrence Kleinberg, M.D. 
Danny Song, M.D. 
Michael Lim, M.D. 
Fariba Asrari, M.D. 
Shirl DiPasquale, RN 
 
Statistician 
Hao Wang 
 
Research Managers: 
Dana Kaplin 
Terry Caldwell 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
NCT01728779


SBRT and Nelfinavir 
Protocol Chair:  Phuoc Tran, MD  
J12137 (NA_00069585) - May 19, 2020 
 
 
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Table of Contents 
 
SCHEMA ...................................................................................................................................................................... 4 
1. 
PROTOCOL SYNOPSIS .................................................................................................................................. 5 
2. 
ABBREVIATIONS AND DEFINITIONS OF TERMS .................................................................................. 6 
3. 
OBJECTIVES .................................................................................................................................................... 7 
3.1 
PRIMARY OBJECTIVE .................................................................................................................................... 7 
3.2 
SECONDARY OBJECTIVES .............................................................................................................................. 7 
4. 
BACKGROUND ................................................................................................................................................ 7 
4.1 
OLIGOMETASTATIC DISEASE......................................................................................................................... 7 
4.2 
STEREOTACTIC BODY RADIATION THERAPY (SBRT) ................................................................................... 8 
4.3 
TUMOR HYPOXIA .......................................................................................................................................... 8 
4.4 
NELFINAVIR .................................................................................................................................................. 8 
4.5 
RATIONALE FOR USE IN PULMONARY METASTASIS ...................................................................................... 9 
4.6 
RATIONALE FOR USE IN LIVER METASTASIS ............................................................................................... 10 
4.7 
CONCURRENT SBRT AND NELFINAVIR ....................................................................................................... 11 
5. 
PARTICIPANT SELECTION AND ENROLLMENT PROCEDURES .................................................... 12 
5.1 
INCLUSION CRITERIA .................................................................................................................................. 13 
5.2 
EXCLUSION CRITERIA ................................................................................................................................. 13 
6. 
TREATMENT PLAN ...................................................................................................................................... 14 
6.1 
DIAGNOSTIC PROCEDURES .......................................................................................................................... 14 
6.2 
THERAPEUTIC PROCEDURES ....................................................................................................................... 14 
6.3 
FOLLOW-UP PROCEDURES .......................................................................................................................... 16 
6.4 
DURATION OF THERAPY .............................................................................................................................. 16 
6.5 
DURATION OF FOLLOW-UP ......................................................................................................................... 17 
6.6 
CRITERIA FOR PATIENT REMOVAL .............................................................................................................. 17 
6.7 
ALTERNATIVES ........................................................................................................................................... 17 
6.8 
COSTS ......................................................................................................................................................... 17 
6.9 
COMPENSATION .......................................................................................................................................... 17 
6.10 
WITHDRAWAL FROM STUDY ....................................................................................................................... 18 
7. 
INVESTIGATIONAL AGENT/DEVICE/PROCEDURE INFORMATION ............................................. 18 
7.1 
INVESTIGATIONAL AGENT .......................................................................................................................... 18 
7.2 
AVAILABILITY ............................................................................................................................................ 18 
7.3 
AGENT ACCOUNTABILITY ........................................................................................................................... 18 
8. 
DOSING DELAYS/DOSE MODIFICATIONS ............................................................................................ 18 
9. 
CORRELATIVE/SPECIAL STUDIES .......................................................................................................... 18 
9.1 
ASSESSMENT OF PHOSPHO-AKT .................................................................................................................. 18 
10. 
STUDY CALENDAR ...................................................................................................................................... 19 
11. 
MEASUREMENT OF EFFECT..................................................................................................................... 21 
11.1 
ANTITUMOR EFFECT-SOLID TUMORS.......................................................................................................... 21 
11.2 
DEFINITIONS ............................................................................................................................................... 21 
11.3 
DISEASE PARAMETERS ................................................................................................................................ 21 
11.4 
METHODS FOR EVALUATION OF MEASURABLE DISEASE ............................................................................ 22 
11.5 
RESPONSE CRITERIA (VIA RECIST 1.1) ...................................................................................................... 22 


SBRT and Nelfinavir 
Protocol Chair:  Phuoc Tran, MD  
J12137 (NA_00069585) - May 19, 2020 
 
 
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12. 
ADVERSE EVENT REPORTING REQUIREMENTS ............................................................................... 23 
12.1 
GENERAL .................................................................................................................................................... 23 
12.2 
DEFINITIONS ............................................................................................................................................... 24 
12.3 
POTENTIAL ADVERSE EVENTS .................................................................................................................... 25 
12.4 
STEREOTACTIC BODY RADIATION TREATMENT .......................................................................................... 25 
12.5 
NELFINAVIR ................................................................................................................................................ 26 
12.6 
FIDUCIAL IMPLANTATION ........................................................................................................................... 27 
12.7 
REPORTING PROCEDURES ........................................................................................................................... 27 
13. 
DATA AND SAFETY MONITORING PLAN .............................................................................................. 28 
14. 
REGULATORY CONSIDERATIONS .......................................................................................................... 28 
14.1 
PROTOCOL REVIEW AND AMENDMENTS ..................................................................................................... 28 
14.2 
INFORMED CONSENT ................................................................................................................................... 28 
14.3 
ETHICS AND GCP ........................................................................................................................................ 29 
15. 
STATISTICAL CONSIDERATIONS ............................................................................................................ 29 
15.1 
ENDPOINTS ................................................................................................................................................. 29 
15.2 
SAMPLE SIZE/ACCRUAL RATE .................................................................................................................... 29 
15.3 
SAFETY RUN-IN PHASE ............................................................................................................................... 30 
15.4 
EARLY STOPPING GUIDELINES: ................................................................................................................... 30 
15.5 
ANALYSIS OF PRIMARY OBJECTIVE ............................................................................................................ 31 
15.6 
ANALYSIS OF SECONDARY OBJECTIVES ...................................................................................................... 31 
15.7 
EVALUATION OF TOXICITY ......................................................................................................................... 31 
15.8 
EVALUATION OF RESPONSE ........................................................................................................................ 32 
REFERENCES: ......................................................................................................................................................... 33 
APPENDIX I: BRIEF PAIN INVENTORY FORM ......................................................................................................... 37 
APPENDIX II: SKCCC DSMP ............................................................................................................................... 39 
APPENDIX III: PERFORMANCE STATUS CRITERIA ................................................................................................. 40 
 


SBRT and Nelfinavir 
Protocol Chair:  Phuoc Tran, MD  
J12137 (NA_00069585) - May 19, 2020 
 
 
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SCHEMA 
 
Radiation Oncology Consultation 
 
 
 
Research Participant Informed Consent and Privacy Authorization Form 
 
 
 
Eligibility Evaluation & Subsequent Enrollment 
 
 
 
Pre-Study Requirements* 
{ie. Coagulation Profile, Assay, CT or MRI, PET-CT (optional), etc.} 
 
 
 
Cycle #1 of Nelfinavir 
(1250mg BID/7 days) 
 
 
 
Stereotactic Body Radiation Therapy 
 
 
 
Cycle #2 of Nelfinavir 
(1250mg BID/7 days) 
 
 
 
Follow-Up Schedule 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
*Pre-Study Requirements are specific to each patient 
* If scheduling or safety prevents all lesions from being irradiated within one day, participants will complete Cycle #2 of 
Nelfinavir then undergo a minimum of 7 days “clear out”. Following this break participants will repeat Cycle #1 of Nelfinavir 
then receive radiation to the remaining lesions followed by a repeat Cycle #2 of Nelfinavir. This process may not exceed three 
“rounds” of treatment (NFV1, SBRT, NFV2) and may include repeat imaging and/or blood work. 


SBRT and Nelfinavir 
Protocol Chair:  Phuoc Tran, MD  
J12137 (NA_00069585) - May 19, 2020 
 
 
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1. PROTOCOL SYNOPSIS 
TITLE 
Single-Arm Phase II Study of Stereotactic Body Radiation 
Therapy Concurrent with Nelfinavir for Oligometastases 
STUDY PHASE 
Phase II 
INDICATION 
Patients presenting with oligometastatic disease, where 
metastases are limited in number and location. 
PRIMARY OBJECTVES 
 To determine the 6-month  freedom from local 
progression rate of the radiosensitizer Nelfinavir used 
concurrently with 15 Gy of stereotactic body 
radiation therapy (SBRT) delivered in 1 fraction (per 
lesion) in patients with oligometastatic disease 
SECONDARY OBJECTIVES 
 To assess the toxicity of the radiosensitizer Nelfinavir 
used concurrently with 15 Gy of stereotactic body 
radiation therapy (SBRT) delivered in 1 fraction(per 
lesion) in patients with oligometastatic disease 
 To determine local control at 6 months after SBRT 
delivered to a dose of 15 Gy in 1 fraction (per lesion) 
combined with Nelfinavir in patients with 
oligometastatic disease  
 To assess long-term clinical outcomes of this patient 
population after completion of SBRT in combination 
with Nelfinavir 
 To assess quality of life following completion of 
SBRT in combination with Nelfinavir  
 To determine the correlation between phospho-Akt 
levels and lesion response rate 
HYPOTHESES 
Concurrent SBRT and Nelfinavir will achieve greater than  
70% freedom from local progression  6 months.  
STUDY DESIGN 
Patients with metastatic lesions of the lung, liver, or bone 
will be candidates for treatment. Within three weeks of the 
initial treatment planning, a 15 Gy dose (per lesion) of SBRT 
will be administered.  Prior to SBRT, patients will initiate 
Nelfinavir oral therapy twice daily for 7 days.  Once SBRT is 
completed, the patient will repeat the same Nelfinavir 
therapy for an additional 7 days for a total of 14 days of 
treatment. 
SAMPLE SIZE BY 
TREATMENT GROUP 
42 patients total   
SUMMARY OF SUBJECT 
ELIGIBILITY CRITERIA 
1. Metastasis at one or more of the following sites: bone, 
liver, and/or lung. No more than 5 lesions will be treated. 
2. Tumor(s) to be treated is(are)  ≤ 5.0 cm or ≤250 cm3. 
3. Age > 18 years. 
4. ECOG perfomance status ≤ 2. 
5. Histologic confirmation of malignancy (primary or 
metastatic tumor). 


SBRT and Nelfinavir 
Protocol Chair:  Phuoc Tran, MD  
J12137 (NA_00069585) - May 19, 2020 
 
 
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INVESTIGATIONAL 
PRODUCTS DOSAGE AND 
ADMINISTRATION 
Commercially available Nelfinavir (1250 mg) will be 
administered orally twice daily for 14 days. 
CONTROL GROUP 
N/A 
PROCEDURES 
1. Physical exam 
2. Blood draw 
4. CT or MRI of Involved Site 
5. PET-CT (all are optional) 
6. SBRT + oral Nelfinavir administration 
 
2. ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
ADL 
Activities of daily living 
AE 
Adverse event 
BID 
Twice daily 
BSA 
Body surface area 
CBC 
Complete blood count 
CI 
Confidence interval 
CMAX 
Maximum concentration of drug 
CNS 
Central nervous system 
CRF 
Case report/Record form 
CR 
Complete response 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLT 
Dose Limiting Toxicity 
DSMB 
Data Safety Monitoring Board 
ECG 
Electrocardiogram 
GI 
Gastrointestinal 
Hgb 
Hemoglobin 
HIV 
Human Immunodeficiency Virus 
HPF 
High-power field  
HTN 
Hypertensions 
IRB 
Institutional Review Board 
IV 
Intravenous 
LLN 
Lower limit of normal  
MTD 
Maximum tolerated dose 
OS 
Overall survival  
PLT 
Platelet 
PD 
Progressive diseased 
PFS 
Progression free survival  
PR 
Partial response 
QD 
Once daily 
RECIST 
Response evaluation criteria in solid tumors 
RR 
Response rate 
SAE 
Serious adverse event 


SBRT and Nelfinavir 
Protocol Chair:  Phuoc Tran, MD  
J12137 (NA_00069585) - May 19, 2020 
 
 
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Abbreviation 
Definition 
SBRT 
Stereotactic body radiation therapy 
SD 
Stable disease 
TTP 
Time to progression 
ULN 
Upper limit of normal 
UNK 
Unknown 
WBC 
White blood cell 
WHO 
World Health Organization 
 
3. OBJECTIVES 
3.1 
Primary Objective 
To determine the 6-month freedom from local progression rate of the radiosensitizer 
Nelfinavir used concurrently with 15 Gy of stereotactic body radiation therapy (SBRT) 
delivered in 1 fraction (per lesion) in patients with oligometastatic disease. 
3.2 
Secondary Objectives 
To assess the toxicity of the radiosensitizer Nelfinavir used concurrently with 15 Gy of 
stereotactic body radiation therapy (SBRT) delivered in 1 fraction (per lesion) in patients 
with oligometastatic disease. 
 
To determine local control at 6 months after SBRT delivered to a dose of 15 Gy in 1 
fraction (per lesion) combined with Nelfinavir patients with oligometastatic disease. 
 
To assess long-term clinical outcomes of this patient population after completion of SBRT 
in combination with Nelfinavir. 
 
To assess quality of life following completion of SBRT in combination with Nelfinavir. 
 
To determine the correlation between Phospho-Akt levels and lesion response rate. 
4. BACKGROUND 
4.1 
Oligometastatic Disease 
Cancer is the second leading cause of death in the United States, chiefly from an inability 
to control metastatic disease. Systemic therapy alone is not curative for patients with most 
metastatic solid tumors.(1) The metastatic capacity of cancers behaves along a spectrum of 
disease progression, such that some tumors have spread widely before clinical detectability 
and others never metastasize. Contained within this spectrum, is an oligometastatic state 
where metastases are limited in number and location. The presence of an oligometastatic 
state was originally proposed by Hellman who suggested that these oligometastatic patients 
would benefit from effective local therapy in addition to systemic therapy.(1) In agreement 
with this hypothesis, surgery and chemotherapy for isolated pulmonary metastases can 
result in long term disease-free periods. (2) Additionally, some 25% of patients following 


SBRT and Nelfinavir 
Protocol Chair:  Phuoc Tran, MD  
J12137 (NA_00069585) - May 19, 2020 
 
 
8 
 
resection and chemotherapy for colorectal cancer and isolated liver metastases can 
similarly have long-term disease free survival.(3)(4)(5) 
 
The treatment of metastases depends on multiple factors including 1) the location of the 
primary tumor, 2) the presence or absence of other metastatic foci, 3) the size, number and 
location of metastases, 4) the effectiveness of various forms of therapy (such as surgery, 
radiation and chemotherapy), and 5) patient’s functional status. Extracranial metastatic 
tumors most often referred for local therapy in the form of resection include colon cancer, 
sarcomas, germ cell tumors, and melanoma metastatic to the lung. For the more common 
primary tumors such as those of breast and lung, metastases are rarely referred for resection 
as chemotherapy (or hormonal manipulation) is generally considered to be the primary 
mode of treatment. 
4.2 
Stereotactic Body Radiation Therapy (SBRT) 
Conventional moderate dose radiation for metastatic disease is given primarily for 
palliation. Recent advancements in radiation delivery now make it possible to image and 
treat precisely within any anatomical region of the body.(6, 7) As a result, the capacity to 
deliver tumor killing radiation doses in a single or few (1-5) outpatient radiation treatments 
is now possible.(8-12) In addition, by minimizing the irradiation of surrounding healthy 
tissue, it should also be possible to decrease the rate of complications. Intracranial 
stereotactic body radiation therapy (SBRT) has been shown to be a highly effective 
treatment for brain metastases.(13) This suggests that selective small extracranial tumors 
(either primary or metastatic tumors) may be effectively controlled by similar focal high-
dose SBRT. There is an increasing experience with extracranial SBRT as effective local 
therapy for metastatic lesions. Local control in excess of 75% has been reported for 
metastatic tumors of the spine, lung and liver, which is significantly higher than standard 
conventional moderate dose radiation.(9, 11, 12, 14)(15) Toxicity has been minimal in 
multiple U.S., European and Japanese trials of extracranial stereotactic radiotherapy to the 
lung, liver, spine, pelvis and abdomen despite the use of very high biological equivalent 
doses for patients with both organ confined and metastatic cancer.  
4.3 
Tumor Hypoxia 
Another factor potentially limiting the efficacy of SBRT or hypofractationated regimens is 
intratumoral hypoxia. Tumor hypoxia is a well substantiated poor prognostic factor for 
multiple tumor types and increases tumor cell radioresistance. A several week course of 
fractionated radiation therapy can partially mitigate tumor hypoxia because death of well 
oxygenated tumor cells allows for reoxygenation of more hypoxic clonogens in a tumor. 
The efficacy of SBRT or hypofractionated regimens are suscetible to tumor hypoxia 
because treatment is delivered in an abbreviated course not allowing for tumor 
reoxygenation. A normoxic and hypoxic tumor selective radiosensitizer in combination 
with SBRT would hypothetically overcome barriers to intratumoral hypoxia. 
4.4 
Nelfinavir 
A compound ideally situated to meet the requirements as a normoxic and hypoxic tumor 
selective radiosensitizer is the HIV protease inhibitor Nelfinavir. The first report of an 
antitumoral activity of an HIV protease inhibitor (HPI) was published in 1999 as a case 


SBRT and Nelfinavir 
Protocol Chair:  Phuoc Tran, MD  
J12137 (NA_00069585) - May 19, 2020 
 
 
9 
 
report. The normoxic radiosensitizing effect of Nelfinavir has been well characterized in 
vitro and in vivo and has been linked to the inhibition of phospho-Akt which is 
overexpressed in many different types of solid tumors, but not normal tissues. Nelfinavir 
can radiosensitize hypoxic cells within a tumor by decreasing HIF-1α expression and 
vascular endothelial growth factor (VEGF) release resulting in angiogenesis inhibition and 
improved tumor oxygenation. Nelfinavir also sensitizes endothelial cells to radiation-
induced death. Finally, utilization of Nelfinavir (Viracept; F. Hoffmann-La Roche Ltd, 
Basel, Switzerland) as an anticancer agent would have the advantage that the drug has 
already been used for more than a decade in the clinic and its safety profile is well defined. 
Retrospective data from HIV positive patients taking routine doses of HPIs concurrently 
during conventional radiation therapy suggests no increased normal tissue toxicity. (37, 
38) 
4.5 
Rationale for Use in Pulmonary Metastasis 
Pulmonary tissue represents a fertile area for metastatic seeding from epithelial 
malignancies. Aggressive management with surgical resection has resulted in good 
outcomes. For example, in the International Registry of Lung Metastases, over 5000 cases 
of lung metastasectomy are recorded.  
 
Multiple series have shown local control for primary lung tumors of >90% using 
stereotactic body radiotherapy in medically inoperable patients.(16-19)(20) A related series 
compared outcomes of wedge resection versus SBRT in primary lung cancer and found 
improved local control with SBRT.(21) These studies report acceptable toxicity profiles 
with a low risk of grade III or greater toxicity. Consequently, two randomized trials are 
investigating the role of SBRT versus surgery in medically fit patients. This includes the 
Dutch ROSEL trial which randomizes operable stage T1N0 patients to surgery versus 
SBRT as well as the STARS trial which randomizes operable stage 1 (<4cm) patients to 
surgery versus SBRT.  
 
Taken together, less invasive techniques such as SBRT are now being applied in place of 
metastasectomy in oligometastatic disease to target pulmonary metastasis. Multiple 
institutions have reported favorable outcomes using either single or multi-fraction SBRT 
for oligometastatic sites within the lung. Wulf et al. prescribed 26 Gy in single fraction and 
reported a 90% local control at 9 months.(22) Hof and colleagues report 63% progression 
free survival at 3 years using 12-30 Gy prescribed to the isocenter.(23)  Le treated primary 
early stage and metastatic lung tumors with SBRT using doses of 15-30 Gy and report a 
local control of 91% for doses greater than 20 Gy and 54% for doses less than 20 Gy.(11) 
 
Single dose fraction of 15 Gy with SBRT to the lung is used to allow for acceptable toxicity 
and to meet dose constraints when multiple pulmonary targets are treated.  Single dose 
SBRT is limited by treatment toxicity at higher doses. Le and colleagues report a 12.5% 
rate of grade 2 to 3 pneumonitis and a 9.4% rate of possible treatment related death when 
single SBRT doses of greater than 25 Gy were given. However, toxicity was rare when 
doses of less than 25 Gy were given.(11) The potential for multiple targets in the 
oligometastatic setting results in difficulty in achieving pulmonary tissue constraints when 


SBRT and Nelfinavir 
Protocol Chair:  Phuoc Tran, MD  
J12137 (NA_00069585) - May 19, 2020 
 
 
10 
 
doses of >25 Gy are applied to each target. An attractive alternative is to dose reduce 
radiation while giving a radiation sensitizer.   
 
A dose of 15 Gy will allow for safe targeting of multiple pulmonary metastases.  
Radiosensitizing effects of Nelfinavir may improve local control to mirror those results 
with higher dose radiation while providing acceptable toxicity. To date, there is no 
literature to suggest an increased rate of pneumonitis or other pulmonary toxicity with 
concurrent administration of Nelfinavir and radiation. 
 
Reports of SBRT in pulmonary metastasis are heterogeneous. Most reports of metastatic 
lung tumors include medically inoperable patients with a primary lung malignancy. While 
some groups report equivalent outcomes, others reports decreased local control with 
metastatic versus primary lung cancer. For example, Le et al., report a 1 year freedom from 
local relapse of 92% for primary NSCLC compared with 44% for metastatic lesions with 
doses >20 Gy are given.(11) Additionally, series report a heterogeneous dose of radiation 
given, making direct comparisons by dose difficult. However, early reports of control do 
provide a basic framework from which to compare the efficacy of Nelfinavir with SBRT 
compared to those treated with higher doses of RT alone.  
4.6 
Rationale for Use in Liver Metastasis 
The primary management of unresectable metastatic disease to the liver is systemic 
chemotherapy. Some uncontrolled trials have investigated liver-directed therapies such as 
transarterial embolization (TACE), radioembolization, stereotactic body radiation therapy 
(SBRT), chemoradiation (CRT), radiofrequency ablation, and cryotherapy in the palliative 
or, in rare cases, neoadjuvant setting(15, 24-27). Liver metastases are a common source of 
cancer morbidity and mortality and are often the only site of metastases. Major 
advancements in radiation treatment planning and delivery have resulted in resurgence in 
the use of radiation therapy (RT) as a treatment for liver tumors. With the development of 
3-dimensional conformal radiation treatment (CRT), partial liver irradiation became 
possible. Stereotactic body radiation therapy (SBRT) is defined as highly focused, 
stereotactic localized, high-dose RT delivered in a hypofractionated course. In selected 
patients, very high local control rates have been observed, with minimal toxicity. Patients 
most likely to benefit from RT are those with liver confined disease, focal distribution of 
metastases, and metastases more than 1.5 cm from luminal gastrointestinal organs.  
 
Chemotherapy and molecular-targeted agents rarely eradicate metastases permanently. For 
colorectal carcinoma liver metastases, selected resection series have yielded 5-year 
survival rates of approximately 50% showing that local therapy has the potential to cure 
“oligo” or isolated liver metastases (5, 9, 28-31). Patients are not suitable for resection 
because of medical or surgical reasons. The benefit of local therapy in non-colorectal liver 
metastases is less clearly defined, but long-term survival has been reported after the 
resection of liver metastases from sarcoma, breast cancer, and other tumor sites (32). 
 
The dose-limiting toxicity from whole-liver RT is radiation-induced liver disease (classic 
RILD), initially called radiation hepatitis (33-35)and characterized pathologically by 
central vein occlusion as described by Reed and Cox.(36)With the advent of 3-dimensional 


SBRT and Nelfinavir 
Protocol Chair:  Phuoc Tran, MD  
J12137 (NA_00069585) - May 19, 2020 
 
 
11 
 
conformal radiation treatment (CRT) planning and delivery technology that allows for 
partial liver irradiation, and that higher tumor doses could be delivered safely as long as 
the mean dose to the liver was kept to less than safely tolerated whole-liver doses. At the 
University of Michigan, no cases of RILD after CRT for colorectal liver metastases were 
seen when the mean liver dose was <31 Gy in 1.5 Gy twice a day. This group also found 
the Lyman normal tissue complication probability model useful as a means of relating 
dose-volume histogram data to risk of liver toxicity (35). In recent years, the application of 
stereotactic body radiation therapy (SBRT) has allowed even more intensive tumor dose 
escalation in a hypofractionated schedule with increased conformality that limit the dose 
to the liver usually well below the threshold above which severe RILD is observed(15). 
 
It is now recognized that some patients with “oligo,” or few sites of metastases, may have 
isolated sites of metastases that can be potentially cured with local therapy. The term 
“oligometastases” was coined to refer to this stage of distant metastases. Typically, the 
entire burden of disease can be recognized as a finite number of discreet lesions. Although 
there is no strict definition of oligometastases, it is commonly interpreted to be no more 
than 5 or 6 metastatic sites. Milano et al. (9)from the University of Rochester have also 
shown that the net tumor burden for patients with 5 or fewer sites of macrometastatic 
disease, treated on 2 prospective SBRT protocols, was an independent predictor of overall 
outcome. Whether SBRT, as an adjunct to systemic therapy, to selected macroscopic 
metastases can influence overall survival by keeping the burden of disease below such a 
“lethal threshold” is being investigated. 
 
Goodman et al.(15) reported a phase I dose-escalation single-fraction trial for patients with 
liver metastases or intrahepatic cholangiocarcinoma. Doses were escalated in 4-Gy cohorts 
from 18 Gy up to 30 Gy in 1 fraction. Twenty-six patients with 40 lesions were treated. 
There was no dose-limiting toxicity. The median follow-up was 17 months, and this 
corresponded to a 12-month local control rate of 77%. The 2-year actuarial survival rate 
was 50.4%.  
 
Based on data above, in this study we will evaluate whether a Nelfinavir plus a single 
fraction of SBRT can be combined with Nelfinavir to control liver metastases with up to 5 
liver metastases. Patients will be closely monitored for grade 3 or above liver toxicity 
including RILD. 
4.7 
Concurrent SBRT and Nelfinavir 
The use of radiation therapy to treat metastatic tumors is well established and promising 
data are emerging with the use of SBRT for metastatic disease. However, the use of a single 
large fraction concurrent with a radiosensitizer as is being proposed is not of proven 
benefit. This investigation aims to confirm the safety and efficacy for SBRT used 
concurrently with a radiosensitizer in the setting of oligometastatic disease. The dose 
selected has been chosen with the belief that it is safe and effective based on prior 
experience with SBRT of lung cancer, pancreatic cancer and brain radiosurgery. All 
patients will be treated with a single fraction, targeted to the lesion concurrently with the 
radiosensitizer Nelfinavir. 
 


SBRT and Nelfinavir 
Protocol Chair:  Phuoc Tran, MD  
J12137 (NA_00069585) - May 19, 2020 
 
 
12 
 
On the basis of this preclinical evidence, we propose a phase I-II study of Nelfinavir 
combined with SBRT in patients with oligometastatic disease. Because the standard dose 
of Nelfinavir for HIV patients is known to be safe and does inhibit the phosphorylation of 
Akt and decrease tumor hypoxia, we propose to study this in conjunction with a 15 Gy 
dose of SBRT. Experience with single-fraction pulmonary and pancreas SBRT provides a 
useful dose for this trial. With published data establishing the relative safety of large single-
fraction SBRT to the lungs and pancreas, we have decided to proceed to determine the 
safety of 15 Gy SBRT concurrently with the radiosensitizer Nelfinavir. Once this is 
established, we propose to continue to enroll more patients to the study at this dose to 
determine the efficacy of this type of therapy. 
 
In general metastatic disease carries an extremely high mortality rate. Current therapies 
provide only partial palliation of symptoms and mild to moderate prolongation of survival. 
Patients are rarely cured of this disease; consequently, better treatment is clearly needed. 
The proposed treatment represents a logical extension of the current state-of-the-art 
radiation therapy. It has the potential to translate into more effective palliation and longer 
patient survival. Another advantage to the patient is that several weeks of radiation therapy 
can be accomplished in a single day, which is not inconsequential for patients with a limited 
life expectancy. 
 
The proposed study represents an informed estimate based on current knowledge of SBRT 
doses and those administered in currently approved image-guided protocols (brain, base of 
skull, cervico-thoracic spine, pancreas and liver). This study will refine the current 
understanding of single fraction radiation tolerance for normal tissues, thereby making it 
possible to treat future patients more safely and aggressively. 
 
5. PARTICIPANT SELECTION AND ENROLLMENT PROCEDURES 
 
All patients will be eligible to receive chemotherapy alone or conventional chemo-radiotherapy at 
the time of clinical or radiographic disease progression or at 4 weeks post-treatment.   
 


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13 
 
5.1 
Inclusion Criteria  
5.1.1 Patient’s tumor(s) to be treated is(are) ≤ 5.0 cm or ≤250 cm3 
5.1.2 Patient must have metastasis at one or more of the following sites: bone, liver, lymph 
node and/or lung. No more than five lesions will be treated. 
5.1.3 Histological confirmation of malignancy (primary or metastatic tumor). 
5.1.4 Patient may have any prior therapy allowed aside from having had prior radiotherapy 
to the treatment site (see exclusion criteria 5.2.3). 
5.1.5 Patient must be ≥ 18 years of age. 
5.1.6 Patient must have a life expectancy ≥ 9 months.  
5.1.7 Patient must have an ECOG performance status ≤ 2.  
5.1.8 Patient must have normal organ and marrow function as defined as: 
Leukocytes 
>2,000/μL 
Absolute Neutrophil Count 
>1,000/μL 
Platelets  
>50,000/μL 
5.1.9 Patient must have the ability to understand and the willingness to sign a written 
informed consent document. 
5.2 
Exclusion Criteria 
5.2.1 Patient has had chemotherapy or radiotherapy within 2 weeks (6 weeks for 
nitrosoureas, anti-angiogenic agents, or mitomycin C) prior to entering the study or 
those who have not recovered from adverse events due to agents administered more 
than 4 weeks earlier. 
5.2.2 Patient receiving any other investigational agents. 
5.2.3 Patient who has had any prior radiotherapy to the treatment site(s). As in, definitive 
therapy for lesion of interest. Field overlap from previous treatment is permitted at the 
discretion of the treating investigator. 
5.2.4 Patient is taking concurrent drugs that are contraindicated with Nelfinavir, including 
any of the following: 
Alfuzosin 
Cisapride 
Sildenafil (Revatio®) 
Amiodarone 
Quinidine 
Rifampin 
Dihydroergotamine 


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Protocol Chair:  Phuoc Tran, MD  
J12137 (NA_00069585) - May 19, 2020 
 
 
14 
 
Ergonovine 
Ergotamine 
Methylergonovine 
Hypericum perforatum (St. John's wort) 
Lovastatin 
Simvastatin 
Pimozide 
Midazolam 
 Triazolam 
Oral Midazolam 
5.2.5 Patient refuses to take a pregnancy test prior to treatment if the patient is a woman 
with child bearing potential.  
5.2.6 Patient is participating in a concurrent treatment protocol.  
5.2.7 Patient is a pregnant woman (pregnant women are excluded from this study because 
radiation treatment has known potential for teratogenic or abortifacient effects). 
5.2.8 Patient refusesto sign informed consent. 
5.2.9 Patient has poor liver function (>2.5 times normal of ALT/AST/Alk phos) suggestive 
of cirrhosis or steatohepatitis. 
5.2.10 Patient has been treated with Nelfinavir within 3 months of entry into this trial. 
5.2.11 Patient is receieving Warfarin (Coumadin). 
 
6. TREATMENT PLAN 
6.1 
Diagnostic Procedures 
A CT scan or MRI will be performed for tumor localization using rigid immobilization 
appropriate for stereotactic treatment. A separate PET-CT may be performed (all are 
optional)  for diagnostic purposes and can be used for treatment planning with fusion -- 
this study would be done identically if the patient were having standard moderate dose 
radiation. 
 
6.2 
Therapeutic Procedures 
Upon confirmation of eligibility and enrollment in the study, the following will be 
completed: 
1) Demographics review, medical history and clinical exam 
2) Review of concurrent medications 
3) Vital signs, height and weight 
4) CBC, chemistry panel and coagulation profile 


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Protocol Chair:  Phuoc Tran, MD  
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15 
 
5) Peripheral blood mononuclear cells will be collected and subsequently assayed for 
phospho-Akt before administration of Nelfinavir, on the day of SBRT, and optionally 
at the 1MFU. 
6) CT or MRI of the involved site(s) (if not previously conducted within 1 month of start 
of Nelfinavir). 
7) Positron Emission Tomography scan (optional) (if not previously conducted within 1 
month of start of Nelfinavir). 
 
Upon entry into the protocol, all patients will be seen by at least one of the Co-Investigator 
Radiation Oncologists. CT simulation will be performed with fabrication of a radiation 
therapy immobilization device (such as the Alpha Cradle) which will be custom made for 
each patient. The treating radiation oncologist will identify the location of the tumor. Gross 
tumor volume (GTV) delineation will be performed with a diagnostic radiologist on 
sequential axial computed tomography images. A radiosurgical treatment plan will be 
developed based on tumor geometry and location. The dose will be prescribed to the 
minimal isodose line that completely covers the GTV plus a 5 mm margin. Adjacent normal 
structures including but not limited to the heart, esophagus, aorta, spinal cord, kidneys, 
rectum, bowel, liver, and stomach within 5 cm of the GTV will be identified for the purpose 
of limiting incidental radiation to these structures. 
 
In addition, prior to treatment delivery, a four-dimensional cone beam CT study will be 
performed on individual patients to assess respiration in these patients and to determine 
tumor targeting accuracy for those tumors that may be subject to respiratory motion such 
as those in the lung or liver. If tumor motion is greater than 5 mm, the planning target 
volume (PTV) will be expanded to account for respiration. 
 
Within three weeks of the initial treatment planning imaging study, SBRT will be 
administered using image-guidance. An Alpha Cradle (or equivalent immobilization 
device) will be used to minimize movement of the chest, spine, and abdomen during 
treatment. During treatment, real time cone beam CT images of the patient’s body site of 
interest will be obtained. Cone beam CT scan will be obtained immediately prior to 
treatment and will be repeated until the treatment shift, required to align the CT planning 
scan and the cone beam CT scan performed on the day of treatment cone beam CT, is 
within tolerance for the body site.  
 
The patient will begin on 1250 mg oral Nelfinavir twice a day for seven days prior to 
starting SBRT. Once having completed the Nelfinavir, the patient will begin SBRT. 
Afterwards, the patient will again take Nelfinavir for 7 days. If scheduling or safety 
prevents all lesions from being irradiated within one day, participants will complete Cycle 
#2 of Nelfinavir then undergo a minimum of 7 days “clear out”. Following this break 
participants will repeat Cycle #1 of Nelfinavir then receive radiation to the remaining 
lesions followed by a repeat Cycle #2 of Nelfinavir. This process may not exceed three 
“rounds” of treatment (NFV1, SBRT, NFV2) and may include repeat imaging and/or blood 
work.. This dose of Nelfinavir has been shown to reliably inhibit Akt phosphorylation. 


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Protocol Chair:  Phuoc Tran, MD  
J12137 (NA_00069585) - May 19, 2020 
 
 
16 
 
 
Patients will be evaluated for adverse events/toxicities during their treatment. 
6.2.1 The dose limits for surrounding critical structures are as follows: 
 Spinal Cord: maximal allowable dose should be = 1000 cGy in 1 fraction  
 Lung: 2/3 of the lung volume should be kept under 500 cGy. 
 Heart: 50 % of the heart volume should be kept under 1000 cGy. 
 Esophagus: 50 % of the esophagus volume should be kept under 1000 cGy and 
no single point dose in the esophagus should exceed 2000 cGy. 
 Brachial Plexus: maximal allowable point dose = 1000 cGy 
 Liver: One third of the uninvolved liver or approximately 700 cc <15 Gy.  
 Kidneys: 75% of volume of each kidney <5 Gy. 
 Small Bowel: <5% of bowel limited to <20 Gy. 
6.3 
Follow-Up Procedures 
Subsequent to SBRT, patients will be followed clinically for toxicity and interval history 
at Months 1, 2, 3 6, 12, and every 6 months thereafter until 3 years post SBRT. A detailed 
medical and physical examination will be performed at 4 weeks, 3 months, 6 months and 
1 year post SBRT. The following procedures are optional at Months 1, 3, 6 and every 6 
months through 3 years post SBRT: 
 A complete blood count (CBC) and comprehensive chemistry panel  
 CT scan or MRI including the treated site  (Note: this is required at Months 3 and 
6 for the reason noted below) 
 Physicial Exam and ECOG Performance Status 
 
PET-CT will be recommended at 3 months, 6 months, and annually thereafter however all 
are optional.  
 
CT scans at 3 and 6 months will be used to determine radiographic response based on 
RECIST 1.1 criteria.  
All follow-ups may be conducted by telephone for patient convenience.  Study staff will 
request any of the optional procedures noted above that were performed by local phsicians 
to be forwarded for study records. 
6.4 
Duration of Therapy 
The patient will initiate Nelfinavir oral therapy twice daily seven days prior to SBRT. 
Within three weeks of the initial treatment planning imaging study, SBRT will be 
administered in a single dose to each treated lesion. After completion of SBRT a second 
seven day cycle of Nelfinavir will occur. 
 
If scheduling or safety prevents all lesions from being irradiated within one day, 
participants will complete Cycle #2 of Nelfinavir then undergo a minimum of 7 days “clear 
out”. Following this break participants will repeat Cycle #1 of Nelfinavir then receive 
radiation to the remaining lesions followed by a repeat Cycle #2 of Nelfinavir. This process 


SBRT and Nelfinavir 
Protocol Chair:  Phuoc Tran, MD  
J12137 (NA_00069585) - May 19, 2020 
 
 
17 
 
may not exceed three “rounds” of treatment (NFV1, SBRT, NFV2) and may include repeat 
imaging and/or blood work.. 
6.5 
Duration of Follow-Up 
It is anticipated that this study will last 3 years.  
6.6 
Criteria for Patient Removal 
Unacceptable adverse events grade IV or greater with an attribution of possibly related 
while on Nelfinavir before SBRT.  
6.7 
Alternatives 
The study has been designed (see above) to minimize potential risks to participants. This 
is primarily through designation of a dose shown to be safe in previous SBRT trials and 
careful patient monitoring. The risk of Nelfinavir is minimal as has been documented for 
greater than a decade following FDA approval in post-market surveillance. Risks to 
confidentiality will be minimized by having access to study records avaialble only to the 
investigators with the exception of the standard clinical records (lab values, dictations, 
operative notes, etc) which are maintained through the Weinberg Comprehensive Cancer 
Center. 
 
Standard therapies for metastatic disease include conventional radiotherapy, 
chemotherapy, or observation. Such treatment may or may not be applicable for patients 
enrolled in this study. Regardless, patients will be expected to forgo standard chemotherapy 
or radiotherapy until there is evidence of clinical or radiographic disease progression or 
until completion of a 4-week post-treatment evaluation. 
 
The amount of radiation administered via protocol therapy will be considered in 
determining how much additional radiation can be given using conventional external beam 
fractionation. 
6.8 
Costs 
Patients and/or their insurance companies will be responsible for the cost of all procedures 
and treatments under this protocol except the study drug nelfinavir. Nelfinavir will be 
supplied to the participant at no cost. 
6.9 
Compensation 
Patients and/or their insurance companies will be responsible for the cost of all procedures 
and treatments under this protocol. 


SBRT and Nelfinavir 
Protocol Chair:  Phuoc Tran, MD  
J12137 (NA_00069585) - May 19, 2020 
 
 
18 
 
6.10 Withdrawal from Study 
The reasons for withdrawal from the study include: 
 Subject withdraws consent for follow-up. 
 Subject is lost to follow-up. 
 Study is terminated for any reason. 
 
If participants withdraw from the study, they will be followed for survival data. 
7. 
INVESTIGATIONAL AGENT/DEVICE/PROCEDURE INFORMATION 
7.1 
Investigational Agent 
Nelfinavir is the commercially available agent being used in this study. 
7.2 
Availability 
Nelfinavir will be ordered and obtained from the Johns Hopkins Pharmacy. 
7.3 
Agent Accountability 
Only subjects enrolled in the study may receive Nelfinavir, in accordance with all 
applicable regulatory requirements. Subjects enrolled on the study will self-administer 
nelfinavir and keep track of their dosing intake via a study drug administration record. 
Nelfinavir will only be dispensed to the patient when the treating physician involved in the 
study provided a written order. 
8. 
DOSING DELAYS/DOSE MODIFICATIONS 
There will be no dose modifications. 
9. 
CORRELATIVE/SPECIAL STUDIES 
9.1 
Assessment of Phospho-Akt 
9.1.1 A blood sample (plasma and serum) will be obtained by venipuncture into a vacutainer 
coated with 3.2% sodium citrate anticoagulant before Nelfinavir administration, on the 
day of SBRT treatment, and optionally at the 1MFU. The samples will be centrifuged 
within 30 minutes of collection and processed in preparation for phosphor-akt assay 
then stored at -80°C for future analysis. 
9.1.2 The study coordinator will transport the specimen to the laboratory of Phuoc T. Tran, 
M.D., PhD for storage and processing. 
9.1.3 Specimen will be labeled by patient case ID to protect patient privacy


SBRT and Nelfinavir 
Protocol Chair:  Phuoc Tran, MD  
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19 
 
10. STUDY CALENDAR 
Parameter 
Pre-
Study 
NFV^ 
Cycle #1 
SBRT
~ 
NFV^  
Cycle #2 
Follow-Up% 
1M 
(+/- 5 
days) 
2M 
(+/- 7 days) 
3Mi 
(+/- 7 
days) 
6M@, h, i 
12M@,i 
18M@,i 
24M@,i 
30M@,i 
36M@,i 
Informed 
Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Med HX & 
Medication Rev  
X 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
Physical Exam 
X 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
Vital Signs 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
Weight 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
Perf Status 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CBC w/ Diffa 
Xf 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
Serum Chemb 
Xf 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
Coagulation 
Profile 
Xf 
 
 
 
 
 
 
 
 
 
 
 
 
Blood Draw for 
Phospho-Akt 
Xf 
 
X 
 
X* 
 
 
 
 
 
 
 
 
CT or MRIh 
(of Involved Site(s)c) 
Xf 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
PET-CT* 
Xf 
 
 
 
 
 
X 
X 
 
X 
 
X 
 
CT-Guided 
Fiducial 
Placement* 
X 
 
 
 
 
 
 
 
 
 
 
 
 
AE Evaluationg 
X 
Xd 
 
Xd 
X 
X 
X 
X 
X 
X 
X 
X 
X 
B-HCGe 
X 
 
 
 
 
 
 
 
 
 
 
 
 
^ Nelfinavir (NFV): to be administered in two cycles (1250 mg BID (orally) for 7 days/cycle). Cycle #1 will conclude the day prior to SBRT. Cycle #2 will initiate the day after completion of SBRT.  
~ SBRT: to be administered in one day. However, if scheduling or safety prevents all lesions from being irradiated within one day, participants will complete Cycle #2 of Nelfinavir then undergo a 
minimum of 7 days “clear out”. Following this break participants will repeat Cycle #1 of Nelfinavir then receive radiation to the remaining lesions followed by a repeat Cycle #2 of Nelfinavir. This 
process may not exceed three “rounds” of treatment (NFV1, SBRT, NFV2) and may include repeat imaging and/or blood work. Accordingly, the study calendar will be affected.  
% Follow-up appointments will be scheduled based on date of SBRT completion. 
* indicates optional  
@ +/- 30 days 
a. Including platelets. 
b. Albumin, Alkaline Phosphatase, Total Bilirubin, Bicarbonate, BUN, Calcium, Chloride, Creatinine, Glucose, Potassium, Total Protein, SGOT [AST], SPGT [ALT], Sodium. 
c. Tumor measurements are to be calculated after all radiographic tests. 
d. Will occur on the last day of Nelfinavir Cycle #1 or on date of SBRT administration and the last day of Nelfinavir Cycle #2. May be conducted via phone. 
e. Serum pregnancy test (women of childbearing potential). 
f. Should occur within 30 days of start of Nelfinavir. 


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Protocol Chair:  Phuoc Tran, MD  
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20 
 
g. Follow up AE evaluations may be conducted via phone. 
h. Required at 3 and 6 months  
i. May be conducted via telephone.  All procedures are optional, EXCEPT for interval history and AE evaluations.  Study staff will remind subjects of upcoming optional procedures at each telephone 
or follow-up visit.  If obtained locally, staff will request that the results be forwarded for study records. 


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Protocol Chair:  Phuoc Tran, MD  
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11. 
MEASUREMENT OF EFFECT 
11.1 Antitumor Effect-Solid Tumors 
For the purposes of this study, patients should be re-evaluated for response 4 weeks after 
the initial treatment, 12 weeks after treatment, 24 weeks after treatment, and every 24 
weeks thereafter.  
 
Response and progression will be evaluated in this study using the new international 
criteria proposed by the Response Evaluation Criteria in Solid Tumors (RECIST 1.1) 
Committee (30). Changes in only the largest diameter (unidimensional measurement) of 
the tumor lesions are used in the RECIST criteria. 
11.2 Definitions 
Evaluable Population: will consist of all patients who have received 28 doses of Nelfinavir 
treatment preceding SBRT. 
Safety Population: Will consist of all subjects who were enrolled and have taken at least 
one dose of the study medication. This will be used to assess the clinical safety and 
tolerability of the study. 
 
Evaluable for Objective Response: Only those patients who have measurable disease 
present at baseline, have completed all fractions of SBRT, and have had their disease re-
evaluated will be considered evaluable for response. These patients will have their response 
classified according to the definitions stated below.  
11.3 Disease Parameters 
Measurable Disease: Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) as >10 mm with 
diagnostic techniques (CT, PET/CT (all are optional), or MRI). All tumor measurements 
must be recorded in millimeters (or decimal fractions of centimeters). 
 
Non-Measurable Disease: All other lesions (or sites of disease), including small lesions 
(longest diameter <10 mm with diagnostic techniques), are considered non-measurable 
disease. Bone lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, 
lymphangitis, inflammatory breast disease, abdominal masses (not followed by CT or 
MRI), and cystic lesions are all non-measurable. 
 
Target Lesions: Target lesions in this study will be considered oligometastatic sites up to 
a maximum of 5 lesions per patient. They should be recorded and measured at baseline. 
Target lesions should be equal to or larger than 10 mm in the smallest cross-sectional 
diameter on CT or MRI and/or any lesion that shows increase metabolic uptake on PET/CT 
scans. A sum of the longest diameter (LD) for all target lesions will be calculated and 
reported as the baseline sum LD. The baseline sum LD will be used as reference by which 
to characterize the objective tumor response. 
 


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Protocol Chair:  Phuoc Tran, MD  
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Non-Target Lesions: N/A 
11.4 Methods for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation using a ruler or calipers. 
All baseline evaluations should be performed as closely as possible to the beginning of 
treatment and never more than 4 weeks before the beginning of the treatment. 
 
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up. Imaging-based 
evaluation is preferred to evaluation by clinical examination when both methods have been 
used to assess the antitumor effect of a treatment. 
 
Conventional CT, PET/CT (all are optional), and MRI These techniques should be 
performed with cuts of 10 mm or less in slice thickness contiguously. Spiral CT should be 
performed using a 5 mm contiguous reconstruction algorithm. This applies to tumors of 
the chest, abdomen, and pelvis. Head and neck tumors and those of extremities usually 
require specific protocols. 
11.5 Response Criteria (via RECIST 1.1) 
11.5.1 Evaluation of Target Lesions  
Complete Response (CR): 
 
Disappearance of all target lesions 
 
Partial Response (PR): 
 
 
 At least a 30% decrease in the sum of the longest diameter 
(LD) of target lesions, taking as reference the baseline sum 
LD 
 
Progressive Disease (PD): 
 
 At least a 20% increase in the sum of the 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 
 
Stable Disease (SD):  
 
 
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest 
sum LD since the treatment started 
11.5.2 Evaluation of Non-Target Lesions 
N/A 
11.5.3 Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the treatment 
until disease progression/recurrence (taking as reference for progressive disease the 
smallest measurements recorded since the treatment started). Best overall response will 
be based on the overall response of the target lesions. 


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11.5.4 Duration of Response 
Response will be defined as evidence of CR, PR, or stable disease. The duration of 
response will be measured from the start of treatment until the criteria for progression 
are met.  
 
Duration of CR or PR: The duration of CR or PR will be recorded from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first 
date that current or progressive disease is objectively documented (taking as reference 
for progressive disease the smallest measurements recorded since the treatment 
started). 
 
Duration of Stable Disease: Stable disease is measured from the start of the treatment 
until the criteria for progression are met, taking as reference the smallest measurements 
recorded since the treatment started.  
11.5.5 Clinical Response Parameters 
 
Time to Local Progression (TTLP) is defined as the elapsed time from the start of 
treatment to the date of documented local progression or death, whichever happens 
earliest.  
Progression-Free Survival (PFS) is defined is the time from starting treatment to the 
time of first documented tumor progression or death due to any cause, whichever 
occurs first. Death is considered as an event here. For subjects whose disease does not 
progress or who do not die, PFS will be censored at the time of the last visit. 
Time to Progression (TTP) is defined as the time from starting treatment to the time 
of first documented tumor progression. Subjects who do not progress will be censored 
at the time of the last contact. In addition, death from any cause will also be censored.  
Overall Survival (OS) is defined as the time from starting treatment until death due to 
any cause. For subjects who do not die, time to death will be censored at the time of 
last contact. 
 
 Locoregional Control (LRC) is defined as the time from starting treatment until local 
and/or regional relapse is documented 
11.5.6 Response Review 
All responses will be reviewed by the study co-investigator radiologist. 
12. 
ADVERSE EVENT REPORTING REQUIREMENTS 
12.1 General 
Adverse event collection and reporting is a routine part of every clinical trial. This study 
will use the descriptions and grading scales found in the NCI Common Terminology 
Criteria for Adverse Events version 4.0 (CTCAE v 4.0) that is available at 
http://ctep.cancer.gov/reporting//ctc.html.  


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Information on all adverse events, whether reported by the participant, directly observed, 
or detected by physical examination, laboratory test or other means, will be collected, 
recorded, followed and reported as described in the following sections.  
 
Participants should be instructed to report any serious post-study event(s) that might 
reasonably be related to participation in this study. The investigator should notify the IRB 
and any other applicable regulatory agency of any unanticipated death or adverse event 
occurring after a participant has discontinued or terminated study participation that may 
reasonably be related to the study.  
12.2 Definitions 
12.2.1 
Adverse Event (AE) 
An adverse event is any undesirable sign, symptom or medical condition or experience 
that develops or worsens in severity after starting the first dose of study treatment or 
any procedure specified in the protocol, even if the event is not considered to be related 
to the study.  
 
Abnormal laboratory values or diagnostic test results constitute adverse events only if 
they induce clinical signs or symptoms or require treatment or further diagnostic tests.  
12.2.2 
Serious adverse event (SAE) 
A serious adverse event is an undesirable sign, symptom, or medical condition which: 
 
 
is fatal or life-threatening; 
 
requires or prolongs inpatient hospitalization; 
 
results in persistent or significant disability/incapacity; 
 
constitutes a congenital anomaly or birth defect; or 
 
jeopardizes the participant and requires medical or surgical intervention to prevent 
one of the outcomes listed above.  
 
Events not considered to be serious adverse events are hospitalizations for: 
 
routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition, or for elective procedures 
 
elective or pre-planned treatment for a pre-existing condition that did not worsen 
 
emergency outpatient treatment for an event not fulfilling the serious criteria 
outlined above and not resulting in inpatient admission 
 
respite care 
12.2.3 
Expectedness  
 
Expected: Expected adverse events are those that have been previously identified 
as resulting from administration of the agent. For the purposes of this study, an 
adverse event is considered expected when it appears in the current adverse event 
list, the Investigator’s Brochure, the package insert or is included in the informed 
consent document as a potential risk. 


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 
Unexpected: An adverse event is considered unexpected when it varies in nature, 
intensity or frequency from information provided in the current adverse event list, 
the Investigator’s Brochure, the package insert or when it is not included in the 
informed consent document as a potential risk 
12.2.4 
Attribution  
Attribution is the relationship between an adverse event or serious adverse event and 
the study treatment. Attribution will be assigned 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 is doubtfully related to the study treatment. 
 
Unrelated - The AE is clearly NOT related to the study treatment. 
12.3 Potential Adverse Events 
Signs and symptoms of disease progression are not considered AEs. The development of a 
new cancer should be regarded as an AE. New cancers are those that are not the primary 
reason for administration of study treatment and have been identified after inclusion of the 
patient into the clinical study. 
 
Because patients are receiving standard treatments, which are not part of this study, their 
treating physician will be counseling them on the risk of their treatments, including the risk 
of surgery, radiation therapy, and/or chemotherapy, whichever is appropriate for the type 
and the stage of their cancer. The procedures related to the study are phlebotomy, PET 
imaging (all are optional), SBRT, and Nelfinavir administration. 
 
Phlebotomy can cause pain, bleeding, and rare needle site infection. PET imaging results 
in low dose radiation exposure (see Investigator’s Brochure for details of dosimetry), which 
has an extremely small risk of causing a secondary cancer.  
12.4 Stereotactic Body Radiation Treatment 
It is difficult at this time to predict with confidence the complication rate from the proposed 
SBRT; however, it is reasonable to extrapolate from the current experience with SBRT to 
the lung and pancreas. One significant toxicity is radiation pneumonitis, which can be 
manifested as fever, increased excertional dypsnea, pleuritic chest pain, and peritumoral 
infiltrate on chest imaging. It generally occurs between 1 to 3 months of completion of 
radiotherapy. The risk of grade 2-4 radiation pneumonitis is aproximately 10-15% in 
patients treated with standard fractionated large field radiotherapy and higher in patients 
treated with combined chemoradiotherapy. It is highly dependent on the volume of the lung 
treated to high dose and the mean lung dose. At this point, the incidence of RT pneumonitis 
from stereotactic radiosurgery for small pulmonary tumors is unknown. However, if the 
treated tumor volume is kept ≤ 65 cc, the risk should be < 10-15% with the proposed dose 
level. 
 


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Other toxicities commonly associated with such treatment includes dysphagia, 
odynophagia, nausea, vomiting, anorexia, and weight loss. Some of these symptoms can 
also be due to tumor progression. Clinical and radiographic assessments will be performed 
as indicated to identify all adverse effects, ascertain their etiology, and provide the most 
appropriate palliative measures. Complications orther than radiation pneumonitis, if any, 
will be graded according to the Common Toxicity Criteria, National Cancer Institute, 
version 4.0. 
12.5 Nelfinavir 
12.5.1 The safety of VIRACEPT (Nelfinavir mesylate) was studied in over 5000 patients who 
received drug either alone or in combination with nucleoside analogues. The majority 
of adverse events were of mild intensity. The most frequently reported adverse event 
among patients receiving VIRACEPT was diarrhea, which was generally of mild to 
moderate intensity. The frequency of Nelfinavir-associated diarrha may be increased 
in patients receiving the 625 mg tablet because of the increased bioavailability of this 
formulation. 
 
Adverse events occurring in patients receiving VIRACEPT in all phase II/III clinical 
trials and considered at least possibly related or of unknown relationship to treatment 
and of at least moderate severity are listed below: 
Body as a Whole: abdominal pain, accidental injury, allergic reaction, asthenia, back 
pain, fever, headache, malaise, pain, and redistribution/accumulation of body fat. 
Digestive System: anorexia, nausea dyspepsia, epigastric pain, gastrointestinal 
bleeding, hepatitis, mouth ulceration, pancreatitis and vomiting. 
Hemic/Lymphatic System: anemia, neutropenia, leukopenia and thrombocytopenia. 
Metabolic/Nutritional System: increases in alkaline phosphatase, amylase, creatinine, 
phosphokinase, lactic dehydrogenase, SGOT, SGPT and gamma glutamyl 
transpeptidase; hyperlipemia, hyperuricemia, hyperglycemia, hypoglycemia, new 
onset or exacerbation of diabetes mellitus, dehydration, hepatitis, jaundice, and liver 
function tests abnormal. 
Musculoskeletal System: arthralgia, arthritis, cramps, myalgia, myasthenia and 
myopathy. 
Nervous System: anxiety, depression, dizziness, emotional lability, hyperkinesia, 
insomnia, migraine, paresthesia, seizures, sleep disorder, somnolence and suicide 
ideation. 
Respiratory System: dyspnea, pharyngitis, rhinitis, and sinusitis. 
Skin/Appendages: dermatitis, folliculitis, fungal dermatitis, maculopapular rash, 
pruritus, sweating, and urticaria. 
Special Senses: acute iritis and eye disorder. 
Urogenital System: kidney calculus, sexual dysfunction and urine abnormality. 
12.5.2 The following additional adverse experiences have been reported from post marketing 
surveillance as at least possibly related or of unknown relationship to VIRACEPT: 
Body as a Whole: hypersensitivity reactions (including bronchospasm, moderate to 
severe rash, fever and edema). 


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Cardiovascular System: QTc prolongation, torsades de pointes. 
Digestive System: jaundice. 
Metabolic/Nutritional System: bilirubinemia, metabolic acidosis. 
12.5.3 Human experience of acute overdose with VIRACEPT is limited. There is no specific 
antidote for overdose with VIRACEPT. If indicated, elimination of unabsorbed drug 
should be achieved by emesis or gastric lavage. Administration of activated charcoal 
may also be used to aid removal of unabsorbed drug. Since Nelfinavir is highly protein 
bound, dialysis is unlikely to significantly remove drug from blood. 
12.6 Fiducial Implantation 
The risk associated with implantation of fiducials is primarily related to the small risk of 
pneumothorax associated with percutaneous placement of a needle within the lung. The 
procedure is analogous to percutaneous needle biopsy, a commonly performed procedure 
which is associated with a pneumothorax risk ranging from 16-40%. Of patients who 
develop a pneumothorax, most are managed by observation alone, with only 5-7% of 
patients requiring intervention such as chest tube placement. Another rare risk of fiducial 
placement is exacerbation of chronic obstructive lung disease, which may require medical 
interventions, including rare hospitalization. Other potential complications of fiducial 
implantation is embolization. In the literature, there is little data regarding this potential 
complication, but if one were to extrapolate from patients suffering gun-shot wounds to the 
chest, either with pellets or bullets, standard surgical teaching is not to removal of the small 
foreign bodies as they rarely cause harm. To further avoid the potential risk of 
embolization, every effort will be made to place the fiducials in the substance of te tumor 
rather than in the adjacent lung parenchyma. Theoretically, fiducials implanted elsewhere 
in the body could embolize to the lungs; to date this has not been reported. 
12.7 Reporting Procedures 
12.7.1 
General 
Adverse events will be recorded at each visit. If an adverse event requiring medical 
attention occurs between visits, this will be recorded as well. The variables to be 
recorded for each adverse event include, but are not limited to, onset, resolution, 
intensity, action taken, outcome, causality rating and whether it constitutes an SAE or 
not. The intensity of the adverse event should be captured using CTCAE criteria, 
version 4.0, when possible.  
 
Pregnancy should be excluded before enrollment. Pregnancy in itself is not reported as 
an AE unless there is a suspicion that an investigational product may have interfered 
with the effectiveness of a contraceptive medication.  
 
All adverse events will be captured on the appropriate study-specific case report forms 
(CRFs).  


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12.7.2 
Institutional Review Board 
All adverse events and serious adverse events will be reported to the IRB per current 
institutional standards. If an adverse event requires modification of the informed 
consent, these modifications will be provided to the IRB with the report of the adverse 
event. If an adverse event requires modification to the study protocol, these 
modifications will be provided to the IRB as soon as is possible. 
13. 
DATA AND SAFETY MONITORING PLAN  
This is a DSMP Level I study under the SKCCC Monitoring Plan (see Appendix II). A Level I study 
requires both internal and external data monitoring. The Principal Investigator is responsible for 
internal monitoring for both safety and data quality. External data monitoring will be performed by 
the SKCCC at Johns Hopkins Clinical Research Office Quality Assurance Program (CRO QA).  
 
Data and safety monitoring oversight will be conducted by the SKCCC at Johns Hopkins Safety 
Monitoring Committee. Per the SKCCC at Johns Hopkins Safety Monitoring plan, the CRO AQ will 
forward summaries of all monitoring reports to the Safety Monitoring Committee for review. All 
reportable anticipated and unanticipated protocol events/problems and amendments that are 
submitted to the IRB will also be reviewed by the Safety Monitoring Committee Chair (or designee) 
and QA manager. 
 
14. 
REGULATORY CONSIDERATIONS 
14.1 Protocol Review and Amendments 
 
Information regarding study conduct and progress will be reported to the Institutional 
Review Board (IRB) per the current institutional standards. 
 
Any changes to the protocol will be made in the form of an amendment and must be 
approved by the IRB prior to implementation.  
 
14.2 Informed Consent 
The investigator (or his/her designee) will explain to each subject the nature of the study, 
its purpose, the procedures involved, the expected duration, the potential risks and benefits 
involved and any discomfort it may entail. Each subject will be informed that participation 
in the study is voluntary, that she may withdraw from the study at any time, and that 
withdrawal of consent will not affect her subsequent medical treatment or relationship with 
the treating physician(s) or institution. The informed consent will be given by means of a 
standard written statement, written in non-technical language, which will be IRB approved. 
The subject should read and consider the statement before signing and dating it, and will 
be given a copy of the document. No subject will enter the study or have study-specific 
procedures done before his/her informed consent has been obtained. 
 
In accordance with the Health Information Portability and Accountability Act (HIPAA), 
the written informed consent document (or a separate document to be given in conjunction 


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with the consent document) will include a subject authorization to release medical 
information to the study sponsor and supporting agencies and/or allow these bodies, a 
regulatory authority, or Institutional Review Board access to subjects’ medical information 
that includes all hospital records relevant to the study, including subjects’ medical history. 
 
14.3 Ethics and GCP 
This study will be carried out in compliance with the protocol and Good Clinical Practice, 
as described in: 
 
1. ICH Harmonized Tripartite Guidelines for Good Clinical Practice 1996. 
2. US 21 Code of Federal Regulations dealing with clinical studies (including parts 50 
and 56 concerning informed consent and IRB regulations). 
3. Declaration of Helsinki, concerning medical research in humans (Recommendations 
Guiding Physicians in Biomedical Research Involving Human Subjects, Helsinki 1964, 
amended Tokyo 1975, Venice 1983, Hong Kong 1989, Somerset West 1996). 
 
The investigator agrees to adhere to the instructions and procedures described in it and 
thereby to adhere to the principles of Good Clinical Practice that it conforms to.  
15. 
STATISTICAL CONSIDERATIONS  
15.1 Endpoints 
15.1.1 Primary Objective 
To determine the 6-month freedom from local progression of the radiosensitizer 
Nelfinavir used concurrently with 15 Gy of stereotactic body radiation therapy (SBRT) 
delivered in 1 fraction (per lesion site) in patients with oligometastatic disease. 
15.1.2 Secondary Objectives 
o To describe the toxicity of SBRT combined with Nelfinavir delivered for the 
population enrolled using grading with CTCAE v. 4.0 
o To determine the local control at 6 months after SBRT is delivered to a dose of 15 
Gy in 1 fraction (per lesion rate) combined with Nelfinavir in patients with 
oligometastatic disease. 
o To assess long-term clinical outcomes of this patient population after completion 
of SBRT and Nelfinavir by measuring progression-free survival and overall 
survival. Progression-free survival will be measured from time of enrollment to 
date of disease progression or death. Patients who are lost to follow-up will be 
censored for determination of progression-free survival on the date of their last 
evaluation. Overall survival is defined as time from enrollment to death due to any 
cause.  
o To assess quality of life following completion of SBRT and Nelfinavir using pre- 
and post-SBRT completion of the Brief Pain Inventory form which will be filled 
out by the patient at the treatment response intervals outlined above.  
 
15.2 Sample Size/Accrual Rate 
The primary endpoint will be freedom from local progression at 6 months. The treatment 
regimen would be considered of insufficient activity for further study in this population 


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if the 6-month FFLP rate is 70% or less, and the minimum required level of efficacy that 
would warrant further study with the proposed regimen is a 90% FFLP at 6 months. The 
accrual rate is 3 patients per month, and the patients will be followed for up to 3 years. 
A total of 42 patients will be entered in the study accounting for a 15% dropout rate. This 
study would have 90% power to detect an improved 6-month FFLP from 70% to 90% 
using a two-sided test at significance level 0.05. Alternatively, this corresponds to the 
power to detect a reduction of hazard rate from 0.06 to 0.02, a reduction of 70% in hazard 
rate. 
There will be no interim analysis for futility, since the progression endpoint will not have 
been reached by a meaningful number of patients before full accrual. 
15.3 Safety Run-In Phase 
There is no previous experience with SBRT used concurrently with Nelfinavir in this 
study population. Therefore, to ensure that the combination is safe, the first six patients 
will be treated and observed for toxicity for 30 days after radiation before continuing with 
further accrual. 6 patients will be enrolled at the proposed dose of Nelfinavir and SBRT.If 
≤ 2 toxicity events occur in the first 6 patients within 30 days of therapy, we proceed with 
additional accrual with this regimen to complete a total of 42 patients. If ≥ 3 toxicity events 
occur among the first 6 patients, we will suspend the study pending data review. 
 
Toxicity Event: ≥grade 3 adverse event (CTCAE v 4.0) with an attribution of possible, 
probable, or definite. 
15.4 Early Stopping Guidelines: 
This study will monitor site-specific grade 4/5 toxicity. If it becomes evident that the 
proportion of grade 4/5 toxicity at specific sites convincingly exceeds 20%, the study will 
be halted for a safety consultation. Specifically, we will apply a Bayesian toxicity 
monitoring rule that suspends the enrollment if the posterior probability of toxicity being 
larger than 20% threshold is 75% or higher. The monitoring rule uses Beta (0.5, 5.5) as 
prior distribution. This means that our prior guess of the proportion of toxicity is 8.3%, 
and there is 90% chance that this proportion is 0.04%-30.6%. The monitoring will start 
from the 7th patient, and the decision rule for safety stopping is as follows: 
 
Stop if: 
 
# grade 4/5 toxicities ≥  
4 
5 
6 
7 
8 
9 
10 
Out of # patients 
7 - 10 
11 - 14 
15 - 18 
19 - 23 
24 - 27 
28 - 32 
33 - 36 
# grade 4/5 toxicities ≥  
11 
12 
 
 
 
 
 
Out of # patients 
37 - 41 
42 
 
 
 
 
 
 
The operating characteristics of the stopping rule are shown below and are based on 5000 
simulations: 


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True AE rate 
% simulated trials 
declaring unsafe 
Average sample size 
(out of 42) 
0.10 
2.1 
41.4 
0.15 
11.3 
39.2 
0.2 
32.7 
34.3 
0.25 
59.5 
27.7 
0.3 
81.9 
21.2 
0.35 
93.6 
16.1 
0.4 
98.3 
12.7 
 
15.5 Analysis of Primary Objective 
The primary efficacy analysis will estimate 6-month freedom from local. Freedom from 
local progression (FFLP) is defined as the elapsed time from the start date of treatment to 
the date of documented local. Patients who die without local progression will be censored 
at the time of death. We will plot the Kaplan-Meier curve for FFLP and estimate 6-month 
FFLP and its 95% confidence interval based on KM estimate and Greenwood’s formula. 
The analysis population includes all registered subjects who have received at least one 
fraction of SBRT. Patients that develop distant metastasis before local progression will 
remain on study. 
 
15.6 Analysis of Secondary Objectives 
o For safety analysis, adverse events will be summarized by type and grade. 
o Hazard rate estimates and 95% confidence intervals as well as Kaplan-Meier (KM) 
estimates will be used to summarize survival (OS), progression free survival (PFS), 
time to locoregional progression (TTLP) and time to distant progression (TTDP), 
duration of response functions over time. The median OS, PFS, TTLP and TTDP will 
be reported.  
o The efficacy of SBRT combined with Nelfinavir with oligometastatic disease will also 
be determined by measuring local control of each lesion at 6 month. Each metastatic 
lesion will be considered a target lesion and independently evaluated for response using 
RECIST 1.1. The lesion will be coded as being locally controlled if it is considered 
stable radiographic disease or if there is evidence of a partial or complete response. 
Local control assessment will start at one month following completion of protocol 
treatment and continuous assessment will be pursued during the follow-up period. The 
proportion of the lesions that have a stable or better response will be estimated using 
generalized estimating equation. The above analyses will also be performed by 
metastases site (bone, liver and lung). 
 
o Quality of life will be assessed using the Brief Pain Inventory form. An overall score 
will be calculated pre-treatment and at the time of the 2nd radiologic reassessment. The 
change in score will be evaluated with a paired t-test.  
o The analysis for the correlative study will be done by Western blot. The change of 
phospho-Akt levels will be correlated to progression-free survival outcome.  
15.7 Evaluation of Toxicity 
All patients will be evaluable for toxicity from the time of their first treatment for SBRT. 


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15.8 Evaluation of Response 
All patients included in the study must be assessed for response to treatment, even if there 
are major protocol treatment deviations or if they are ineligible. Each patient will be 
assigned one of the following categories: 1) complete response, 2) partial response, 3) 
stable disease, 4) progressive disease, 5) early death from malignant disease, 6) early death 
from toxicity, 7) early death because of other cause, or 9) unknown (not assessable, 
insufficient data). [Note: By arbitrary convention, category 9 usually designates the 
“unknown” status of any type of data in a clinical database.] 
 
All of the patients who met the eligibility criteria (with the possible exception of those who 
received no study medication) should be included in the main analysis of the response rate. 
Patients in response categories 4-9 should be considered to have a treatment failure (disease 
progression).  
 
All conclusions should be based on all eligible patients. Sub-analyses may then be 
performed on the basis of a subset of patients, excluding those for whom major protocol 
deviations have been identified (e.g., early death due to other reasons, early discontinuation 
of treatment, major protocol violations, etc.). However, these sub-analyses may not serve 
as the basis for drawing conclusions concerning treatment efficacy, and the reasons for 
excluding patients from the analysis should be clearly reported. The reason for performing 
subset analyses would be to generate hypotheses for future prospective clinical trials. 
 


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34. Dawson LA, Ten Haken RK. Partial volume tolerance of the liver to radiation. Semin Radiat 
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APPENDIX I: Brief Pain Inventory Form 
 


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38 
 
 


SBRT and Nelfinavir 
Protocol Chair:  Phuoc Tran, MD  
J12137 (NA_00069585) - May 19, 2020 
 
 
39 
 
APPENDIX II: SKCCC DSMP 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


SBRT and Nelfinavir 
Protocol Chair:  Phuoc Tran, MD  
J12137 (NA_00069585) - May 19, 2020 
 
 
40 
 
APPENDIX III: Performance Status Criteria 
 
 
 
 
 
 
 
 
ECOG Performance Status Scale 
 
 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead.