A Phase I/II Trial of Radioimmunotherapy (Y-90 cT84.66), Gemcitabine and Hepatic Arterial Infusion of Fudr for Metastatic Colorectal Carcinoma to the Liver
Phase: PHASE1
Conditions: Liver Metastases, Recurrent Colon Cancer, Recurrent Rectal Cancer, Stage IV Colon Cancer, Stage IV Rectal Cancer
Sponsor: City of Hope Medical Center

 
 
CITY OF HOPE NATIONAL MEDICAL CENTER 
1500 E. DUARTE ROAD 
DUARTE, CA 91010 
Division of Radiation Oncology 
 
TITLE: A PHASE I/II TRIAL OF RADIOIMMUNOTHERAPY (Y-90 cT84.66), GEMCITABINE AND HEPATIC 
ARTERIAL INFUSION OF FUDR FOR METASTATIC COLORECTAL CARCINOMA TO THE LIVER 
 
COH PROTOCOL NUMBER/VERSION: IRB PROTOCOL #04122 
VERSION: 10 
 
DATE(S)/OF AMENDMENT(S)/REVISION(S):  Initial Review – Protocol dated 11/29/04  
Version: 00 
Initial Approval – Protocol dated 01/11/05  
Version: 00 
Amendment 01 – Protocol dated 07/20/05  
Version: 01 
Amendment 02 – Protocol dated 10/07/05 
Version 02 
Amendment 03 – Protocol dated 11/22/05 
Version 03 
Amendment 03 – Protocol dated 01/23/06 
Version 03 
Amendment 03 – Protocol dated 03/06/06 
Version 03 
Amendment 04 – Protocol dated 07/11/06 
Version 04 
Amendment 05 – Protocol dated 11/28/06 
Version 05 
Amendment 06 – Protocol dated 06/01/07 
Version 06 
Amendment 07 – Protocol dated 05/19/08 
Version 07 
Amendment 08 – Protocol dated 09/30/09 
Version 08 
Amendment 09 – Title Page dated 10/22/13 
Version 09 
Amendment 10 -  Title Page dated 07/01/14 
Version 10 
 
Site:  Colorectal/Hepatic Metastases 
Stage:  IV 
Modality:  RIT, gemcitabine, fluorodeoxyuridine 
Type:  Phase I/II 
 
Principal Investigators:  
 
   Jeffrey Wong, M.D. 
 
 
Division of Radiation Oncology 
 
Collaborating Investigators:  
   Lucille Leong, M.D. 
 
 
Division of Medical Oncology and Experimental Therapeutics  
 
Participating Clinicians: 
   Joseph Kim, M.D. 
 
 
Division of General and Oncologic Surgery 
   John E. Shively, Ph.D.  
 
Division of Immunology 
   Lawrence E. Williams, Ph.D. 
 
Division of Radiology 
   Sharon Wilzcynski, M.D., Ph.D.  
Division of Pathology 
   David Colcher, Ph. D. 
 
 
Department of Radioimmunotherapy 
 
Investigational Drug Monitors: 
   Oscar Martin, Pharm.D.  
 
Clinical Pharmacy 
   Sharon Denison, Pharm.D. 
 
Clinical Pharmacy 
 
Protocol Nurse: 
   Tammy Kloythanomsup, R.N. 
 
Department of Radioimmunotherapy 
 
Biostatistics 
   Paul Frankel, Ph.D. 
 
 
Division of Information Sciences 
 
Clinical Research Associate: 
   Jennifer Simpson, B.A.  
 
Department of Biostatistics 
 
 

 
 
TABLE OF CONTENTS 
 
                                                             
 
             
 
 
Page 
 
SCHEMA 
 
 
 
 
 
 
 
 
 
2-3 
  1.0 
OBJECTIVES  
 
 
 
 
 
 
 
3 
  2.0 
BACKGROUND 
 
 
 
 
 
 
 
4-10 
  3.0 
DRUG INFORMATION 
 
 
 
 
 
 
10-12 
  4.0 
ELIGIBILITY CRITERIA 
 
 
 
 
 
 
12-14 
  5.0 
STAGING CRITERIA 
 
 
 
 
 
 
14 
  6.0 
DESCRIPTIVE FACTORS/STRATIFICATION/ 
 
RANDOMIZATION SCHEME 
 
 
 
 
 
15 
  7.0 
TREATMENT PLAN 
 
 
 
 
 
 
15-21 
  8.0 
TOXICITIES TO BE MONITORED AND  
 
DOSAGE MODIFICATIONS 
 
 
 
 
 
21-22 
  9.0 
CRITERIA FOR EVALUATION AND  
 
ENDPOINT DEFINITIONS  
 
 
 
 
 
22-25 
  10.0 DATA AND SAFETY MONITORING PLAN  
 
& DATA SUBMISSION SCHEDULE 
 
 
 
 
25-26 
  11.0 STATISTICAL CONSIDERATIONS   
 
 
 
 
26-28 
  12.0 PATHOLOGY REVIEW 
 
 
 
 
 
 
28 
  13.0 REGISTRATION GUIDELINES 
 
 
 
 
 
28 
  14.0 SPECIAL INSTRUCTIONS  
 
 
 
 
 
28 
  15.0 ETHICAL AND REGULATORY CONSIDERATIONS 
 
 
28 
  16.0 REFERENCES 
 
 
 
 
 
 
 
29-37 
   
 
Appendices 
 
I. 
ANTIBODY ADMINISTRATION  
 
 
 
 
38 
II. 
BONE MARROW PERCENTAGE  
 
 
 
 
39 
III. 
CRITERIA FOR ESTIMATION OF PERFORMANCE STATUS  
40 
IV. 
TOXICITY GRADING 
 
 
 
 
 
 
41 
V. 
PHASE I TRACKING LOG  
 
 
 
 
 
42 
 
 
 

 
 
SCHEMA: 
 
THERAPY CONSISTS OF TWO PARTS: 
 
Part I – Protocol Therapy (RIT/Gemcitabine/FUdR) 
90Y-cT84.66  (16.6 mCi/m2):  
 
 
 
 
 
 
Day 9 
Gemcitabine (105 mg/m2) infused over 30 mins. i.v.  
 
 
 
Days 9 and 11 
Continuous hepatic arterial infusion FUdR x 14 days: 
 
 
 
Days 1 – 14 
 
(starting dose level 0.10 mg/kg/day to contain Decadron 1 mg/day) 
Ca-DTPA (250 mg/m2/day): infused over 60 minutes i.v.  
 
 
Day 9 – 11 
 
A maximum of 3 cycles every 6 weeks is planned.  
 
This will be followed by: 
 
Part II – Best Systemic Therapy (see section 7.8 for details): 
 
Additional hepatic arterial infusion of FUdR permitted for a maximum of 4 cycles (including 
cycles delivered during Part I of protocol therapy with RIT/gemcitabine).  Systemic therapy may 
be given in combination with hepatic arterial infusion FUdR at the discretion of the treating 
physician.  Systemic therapy may be continued after completion of hepatic arterial infusion at the 
discretion of the treating physician.Amended 07/20/05 
 
 

 
 
FUdR/RIT/Gemcitabine Study Calendar 
 
Sunday 
Monday 
Tuesday 
Wednesday 
Thursday 
Friday 
Saturday 
  
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
  
  
 
  
  
  
  
  
FUdR/Decadron 
(starting dose level 
0.10 mg/kg) 
FUdR/Decadron 
FUdR/Decadron  FUdR/Decadron 
FUdR/Decadron  FUdR/Decadron 
  
  
 
  
  
  
  
  
  
  
  
  
  
  
Day 7 
Day 8 
Day 9 
Day 10 
Day 11 
Day 12 
Day 13 
  
  
  
 
  
  
  
FUdR/Decadron 
FUdR/Decadron 
FUdR/Decadron 
FUdR/Decadron 
FUdR/Decadron 
FudR/Decadron 
FudR/Decadron 
  
 
Gemcitabine 
(105 mg/m2) 
 
Gemcitabine 
(105 mg/m2) 
 
 
  
  
RIT (16.6 mCi/m2) 
  
  
  
  
  
Ca-DTPA 
Ca-CTPA 
Ca-DTPA 
 
  
Day 14 
Day 15 
Day 16 
Day 17 
Day 18 
Day 19 
Day 20 
  
  
  
  
  
  
  
FUdR/Decadron 
  
  
  
  
  
  
 
 
 
 
 
 
 
  
  
  
  
  
  
  
Day 21 
Day 22 
Day 23 
Day 24 
Day 25 
Day 26 
Day 27 
  
  
  
  
  
  
  
 
 
 
 
 
 
 
  
  
  
  
  
  
  
Day 28 
Day 29 
  
  
  
  
  
  
 
  
  
  
  
  
 
 
 
  
  
  
  
 
1.0 OBJECTIVES 
 
1.1 
To determine the maximum tolerated dose (MTD) and associated toxicities of concurrent 
hepatic arterial infusion (HAI) fluorodeoxypyrimidine (FUdR)/Decadron and intravenous  
gemcitabine combined with intravenous yttrium-90 (90Y) chimeric T84.66 (cT84.66) in 
colorectal cancer patients after hepatic resection or maximum surgical debulking (to < 3 
cm) of liver metastases. This is the primary objective. 
 
1.2 
To study the feasibility and toxicities of such adjuvant therapy following resection and/or 
ablation of liver metastases 
 
1.3 
To evaluate the biodistribution, clearance and metabolism of 90Y and 111In (indium-111) 
chimeric T84.66 administered intravenously. 
 
1.4 
To estimate radiation doses to whole body, normal organs, and tumor through serial 
nuclear imaging. 
 
1.5 
To correlate proteomic profiles pre and post-therapy with toxicities and anti-tumor effects. 
Amended 
7/20/05 

 
 
 
2.0 BACKGROUND 
 
Hepatic Arterial Infusion Chemotherapy: Surgical resection of liver metastases from colorectal 
carcinoma can produce a 20% 5 year survival.  However, subsequent recurrences in the liver as 
well as in extrahepatic sites are the rule.  A prospective randomized trial at the City of Hope using 
resection and intra-arterial FUdR 1 demonstrated the value of adjuvant therapy following complete 
resection of hepatic metastases in preventing disease recurrence.  Further randomized studies of 
intra-arterial FUdR have demonstrated evidence of benefit 2,3.  In one study 156 colorectal patients 
with resected liver metastasis were randomized to 6 cycles of HAI with FUdR plus systemic 5-
fluorouracil, or to systemic 5-fluorouracil alone.  After 2 year the actuarial rate of survival was 
better in the HAI group (86 vs 72%, P = 0.03).   Hepatic recurrences were also reduced in the HAI 
group (90 vs 60%, P < 0.001).  There were more hepatic side effects in the HAI group with 18% 
of patients developing serum bilirubin levels greater than 3.0 mg/dl.  Biliary stents were required 
in 4 patients with subsequent normalization in 2 of these.  Hepatic toxicity was managed by dose 
reductions and the use of intrahepatic dexamethasone.   Nevertheless, only 26%of patients 
received more than 50% of the planned dose. 
 
In another study, 109 colorectal patients with 1 –3 resected hepatic metastatses were randomized 
to no further therapy or to HAI with FUdR combined with systemic infusional 5-fluorouracil.  The 
HAI group had a 4-year recurrence free rate of 46% vs 25% for the controls (p = 0.04).  The 4-
year liver recurrence free rate was also improved ( 67 vs 43%, P = 0.03).  The HAI group 
consisting of protocol eligible patients had a longer median survival (63.7 vs 49, P = 0.60).  
Increases in liver tranaminases were seen in 8/30 patients, and 2 required biliary stenting with all 
patients eventually recovering.   Two thirds of patients received all 4 planned chemotherapy 
cycles. 
 
A German study 4 randomized 226 colorectal patients with resected liver metastases to HAI with 
5-flourouracil for 5 days plus systemic 5-fluorouracil vs observation alone.   No benefit in terms of 
survival or time to progression was noted.  Grade 4/4 toxicities including stomatitis, and nausea 
occurred in 62.9% of treated patients.  Based on this, the study was stopped at an interim analysis.  
The length of hepatic arterial  infusion of 5 days vs 14 days in other studies, as well as the use of 
5-fluorouracil as opposed to FUdR may have affected the result.  Various grade 1 – 4 liver 
function abnormalities were seen in between 12.2 and 17.6% of the treatment courses given.   
 
Attempts have been made to incorporate potentially more effective systemic therapies in 
conjuction with HAI to potentially reduce the rate on non-hepatic recurrences.  A recent study 
demonstrated the feasibility of combining irinotecan with HAI 5.  In this study colorectal patients 
with resectable hepatic metastases were treated with 6 cycles of HAI FUdR.  Inrinotecan at a dose 
of 200mg/m2 was found to be feasible in combination with a 14-day infusion of FUdR 
0.12mg/kg/day.   
 
In another study, colorectal patients with resected, or ablated liver metastases were treated 
adjuvantly with HAI FUdR at a dose of 0.2mg/m2/day combined with dexamethasone 1 mg/day 
for 14 days 6.  Oxaliplatin on day 1 at a dose of 130mg/m2 with capecitabine 1000mg/m2 twice 
daily for 14 days were given during weeks 4-5.  Cycles were repeated every 6 weeks for a total of 
4 treatments.  An increase in grade 3 diarrhea but not hepatic toxicity was noted.   
 
A study combining oxaliplatin based treatments with HAI has also been reported 7.  In this study, 
colorectal patients with unresected liver metastases were treated with HAI 0.12mg/kg/day for 14 

 
 
days.  Systemic therapy was given every other week and consisted of oxaliplatin combined with 
either 5-fluorouracil and leucovorin or with irinotecan.  The MTD of oxaliplatin/5FU was 
100mg/m2 and 1400mg/m2 by continuous infusion over 48 hours respectively with diarrhea and 
hepatotoxity limiting therapy.  With oxaliplatin and CPT-11, the MTD was 100mg/m2 and 
150mg/m2 respectively.  Hepatotoxicity, hematologic toxicity, and diarrhea were seen at the DLT 
level. 
 
Gemcitabine:   Many clinical trials demonstrate a measurable advantage to a combination of 
chemotherapy and radiation over treatment with radiation alone.   Trials with esophageal cancer 
using combined chemoradiation demonstrate response rates of 15-30% with 5FU/CDDP or 
5FU/mitomycin C regimens with complete responses at radiation doses as low as 3000 cGy. 8.  
Clinical evidence of improvement with chemoradiation have been documented in other cancers 
including rectal cancer9, pancreatic cancer  10, anal cancer 11 and head and neck cancer 12 .   Cell 
cultures studies have demonstrated experimental radiosensitization with a variety of drugs 
including 5-fluororuracil, other antimetabolites, cisplatin 13 , topoisomerase I inhibitors  14 , as well 
as taxanes15 .  The exact mechanism of radiosensitization remains under study, but likely involves 
multiple bilateral interactions between radiation and various chemotherapy drugs  involving  
functions such as DNA repair and apoptosis 16. 
 
A drug with good preclinical radiosensitization properties is gemcitabine.  This has been approved 
by the Food and Drug Administration for the treatment of advanced pancreatic cancer based on 
results of superior clinical benefit and activity in a phase III trial 17.  It is given as a 30-minute 
infusion on a weekly basis.  It has been shown to improve the quality of life as well as improve 
survival in pancreatic cancer patients in comparison to 5-fluorouracil treatment.  The primary 
toxicity is hematologic, although other toxicities such as fluid retention, pulmonary toxicity, and 
cardiac toxicity may be significant 18,19. 
 
Laboratory studies have demonstrated strong radiosensitization properties when gemcitabine is 
tested in cell culture 20.  The exact method of radiosensitization is under investigation but likely 
relates to inhibition of ribonucleotide reductase with subsequent effects on deoxyribonucleotided 
pools, and to gemcitabine incorporation into DNA with subsequent chain termination.  
Radiosensitization was greatest in one study when cells were exposed to gemcitabine for 2- hours 
24 - 48 hours before radiation exposure.  Radiosensitization was observed for approximately 2 
days after exposure 21.  The maximal sensitization has correlated with a drop in adenosine 
diphosphospate in response to gemcitabine (which is an inhibitor of ribonucleotide reductase).  
Interestingly, radiosensitization appears to occur at relatively low, minimally cytotoxic 
gemcitabine levels.   In another study, radiosensitization is again seen when gemcitabine is given 
before radiation 22.  S-phase Chinese hamster fibroblasts (V79) and a human colon cancer cell line 
(Widr) were again exposed to gemcitabine for 2 hours followed by radiation.  The maximum 
interaction in this study appeared 2 hours after the 2-hour treatment.  In summary, it appears that 
radiosensitization occurs after gemcitabine exposure although the time course of this sensitization 
may vary depending on the conditions. 
 
Clinical studies combining gemcitabine with radiation have confirmed that gemcitabine is a potent 
radiation sensitizer.  In studies with head and neck patients 23, doses of gemcitabine  required 
progressive reduction from a starting dose of 300mg/m2 due to severe toxicity.  Doses below 
100mg/m2 were planned in an attempt to determine a tolerable dose.  Interestingly, at a dose of 150 
mg/m2, levels of gemcitabine triphosphate (dFdCTP) remained in the same range as those seen at 
the 300 mg/m2 dose level.  The levels of dFdCTP were similar to those seen in in vitro 

 
 
radiosensitization experiments suggesting that even at low doses, significant interactions were 
occurring.   
 
Other studies have reported tolerance of gemcitabine and external beam radiation in upper 
gastrointestinal tumors 24,25.  Studies with lung cancer have also been reported, noting increased 
esophagitis with the combination 26.   
 
Radioimmunotherapy with Y-90 cT84.66:  The rapidly growing field of molecular medicine 
offers exciting new strategies for targeted delivery of cancer therapy.  Through molecular and 
genetic engineering, agents can now be custom designed against specific tumor targets with 
properties optimized for therapy. Monoclonal antibodies (Mab) against tumor antigens were some 
of the first of these agents to be evaluated.  Conjugated to radionuclides, Mab guided radiation 
therapy or radioimmunotherapy (RIT), demonstrated significant promise in laboratory models. 
This promise has been realized in the clinic for the more radiosensitive hematologic malignancies, 
particularly B-cell lymphomas and myeloid leukemias, which have reported response rates ranging 
from 30-85% 27-35, with complete responses rates as high as 80% with myeloablative, bone 
marrow transplant supported doses in patients with relapsed disease 27. 
 
For the more radioresistant solid tumors, results have been less successful, but remain 
encouraging. At non-myeloablative doses in patients with chemotherapy refractory, metastatic 
disease, current RIT regimens have reported primarily stable disease and mixed, and minor 
responses in patients with colorectal, breast, medullary thyroid, and ovarian cancer 36-45. More 
encouraging are trials evaluating RIT at higher, myeloablative doses. For example, 50% partial 
responses of short duration have been reported in an ongoing trial with myeloablative, stem cell 
supported doses of 90Y-DTPA-BrE3 in patients with advanced, metastatic breast cancer 46.   
 
Current non-stem cell supported RIT regimens only achieve the biologic equivalent of 2000 cGy 
to tumor and therefore do not achieve high enough tumor doses to be used as single modality 
therapy, particularly for gross disease. This is not surprising given the experience with external 
beam radiotherapy, where 2000 cGy (at 200 cGy per day) rarely results in shrinkage of 
carcinomas, particularly for chemo- and radiation refractory recurrences. Comparable radiation 
doses to tumor are delivered by RIT and comparable results are seen in Phase I trials entering 
heavily pre-treated patients. Therefore, future therapy trial development should focus on 
increasing the tumoricidal efficacy of RIT through concomitant delivery with chemotherapy 
agents known to enhance radiation effects. The same RIT radiation dose of 2000 rads combined 
with other systemic chemotherapy agents, especially those with demonstrated radiation enhancing 
properties (e.g., 5-FU and halogenated pyrimidines), has a likelihood of increasing tumor 
responses compared to each modality alone, resulting in major responses. Successful examples of 
using partial doses of external beam radiotherapy with appropriate chemotherapy agents are found 
throughout the literature. For example, the early trials with esophageal cancer demonstrated 
pathologic complete response rates of 15-30% with 5-FU/cis-platinum or 5-FU/mitomycin-C 
regimens combined with conventionally fractionated external beam radiation doses as low as 3000 
rads. The results were improved over that of chemotherapy alone or with what would be expected 
after 3000 rads alone 47. Similar examples exist for other disease sites 48-50.  
 
Carcinoembryonic antigen (CEA) is a well-studied tumor surface antigen that has proven to be a 
useful target for RIT.  CEA is expressed in many common tumor types such as colon, breast, non-
small cell lung, gastric, pancreatic, biliary, cervix, uterine and ovarian cancer 51-54.   Radiolabeled 
anti-CEA antibodies have been successfully used in the clinic to treat and image CEA-producing 

 
 
malignancies 55,56. Radiolabeled anti-CEA antibodies have been the most extensively studied in 
colorectal cancer, since 90-95% of tumors produce CEA. Animal studies demonstrate significant 
tumor growth delay after therapy with 131I or 90Y labeled anti-CEA Mabs 57. Tumor responses 
further improved (resulting in long term tumor control in some studies) in animal models which 
explored myeloablative RIT doses with BMT 58, RIT with small micrometastases 59, and RIT 
combined with 5-FU chemotherapy 60. 
   
Murine T84.66 is an IgG1 monoclonal antibody developed at the City of Hope with high 
specificity and affinity (approximately 1.16 x 1011 M-1) for CEA 61,62.  It recognizes the A3 
domain of the CEA molecule and has little cross reactivity with normal tissues.   Using 111In 
murine T84.66 Beatty et al. 56 demonstrated successful targeting and imaging of colon cancer with 
this antibody.  Further refinements of T84.66 have been made by investigators at the City of Hope 
in preparation for using this antibody in RIT trials.  A human-mouse chimeric T84.66 has been 
developed (IgG1 isotype) by Dr. Michael Neumaeir in the Department of Immunology.  By 
humanizing the non-antigen binding portions of the molecule, the chances for development of 
anti-antibodies against T84.66 is potentially decreased, allowing for multiple administrations of 
the radiolabeled antibody for therapy.   
 
Chimeric T84.66 (cT84.66) was radiolabeled with 111In and evaluated in imaging/biodistribution 
trials in patients with CEA-producing malignancies (IRB protocols 91064 and 91169/BB-IND 
4040). These two trials demonstrated the following: 1) 111In intact cT84.66 targeted CEA-
producing tumors with imaging result comparable to other 111In labeled intact anti-CEA 
antibodies.; 2) immunogenicity was less after single administration of up to 105 mg of antibody 
protein compared to intact murine monoclonal antibodies.; 3) the antibody was well tolerated,; and 
4) dosimetry estimates showed that high and potentially therapeutic radiation doses can be 
delivered to some tumors, regional metastatic lymph nodes, and small hepatic metastases.  
 
Based on these encouraging findings a Phase I therapy trial (IRB 94001) was initiated to define 
the maximum tolerated dose of intravenously administered 90Y-cT84.66 63. On this trial, twenty-
two patients received at least one cycle of therapy, with one individual receiving 2 cycles and two 
receiving 3 cycles of therapy. All were heavily pre-treated and had progressive disease prior to 
entry on this trial. Reversible leukopenia and thrombocytopenia were the primary dose-limiting 
toxicities observed. Maximum tolerated dose (MTD) was reached at 22 mCi/m2. Thirteen patients 
developed an immune response to the antibody. HACA was more frequent on this trial possibly 
due to the fact that each patient received an imaging dose of the antibody followed by the therapy 
dose a week later. Dose estimates to tumor ranged from 66 to 1670 cGy (8.7 to 52.2 cGy/mCi 90Y) 
for each cycle of therapy delivered. Although no major responses were observed, 3 patients 
demonstrated stable disease of 12 to 28 weeks duration and 2 demonstrated a mixed response. In 
addition, a 41 to 100% reduction in tumor size was observed with 5 tumor lesions.    
 
As a result a successor Phase I trial (IRB 96063) was developed evaluating the combination of Y-
90-cT84.66 given in combination with continuous infusion 5-FU. Considerable interest has been 
generated recently for continuous infusion 5-FU as an alternative dose schedule to bolus 
administration for several reasons.  At least six phase III randomized trials have compared 
continuous infusion 5-FU for > 5 days versus bolus administration and have reported comparable 
or improved response rates to varying degrees 64-68.  Furthermore, phase II trials of continuous 
infusion 5-FU have reported response rates in the 30-40% range in advanced metastatic colorectal 
cancer.  Second, myelotoxicity in all studies is significantly reduced making it a more attractive 
alternative in combination with other myelotoxic agents, such as RIT.  Continuous infusion 5-FU 

 
 
may provide an improved approach toward 5-FU sensitization of radiation tumoricidal activity 69 
70.  Finally, Remmenga et al. demonstrated a significant decrease in tumor growth when 
combining continuous infusion 5-FU with 90Y-CC49 in an LS174T nude mouse model 60. 
 
IRB 96063 has been completed and results recently published 71. Dose escalation to the highest 
planned dose level of 5-FU has been achieved (1000 mg/m2/day x 5 days). Twenty-one heavily 
pretreated patients (almost all having failed previous 5-FU) have been treated. Dose-limiting 
toxicity was defined as grade 4 hematologic and/or grade 3 non-hematologic toxicity on this trial. 
As in previous RIT studies, dose-limiting toxicities were hematologic, primarily 
thrombocytopenia and leukopenia. All 21 patients demonstrated hematologic toxicity. Other 
toxicities observed were similar to those observed with 5-FU. These include: grade 1 GI 
(nausea/vomiting or loose stool) toxicity in 16 patients and grade 2 GI toxicity in 2 patients; grade 
1 fatigue in 14 patients; grade 1 erythema or skin rash in 8 patients; grade 1 mucositis in 9 
patients, grade 3 mucosits in 1 patient and grade 4 mucositis in 1 patient. In addition 2 patients had 
transient grade 1 flu-like symptoms.  No hepatotoxicty was observed. Three patients had grade 1 
elevations in transaminases felt secondary to disease progression. 5-FU did not appear to alter 
antibody pharmacokinetics, but did appear to decrease the HACA response possibly due to its 
effects on the immune system, with only 3 of 17 demonstrating HACA. Of 18 evaluable patients, 
9 demonstrated stable disease of 3-8 months duration. One patient demonstrated a mixed response. 
A decrease in size of 53-100% was seen in 3 lesions. This trial demonstrated the feasibility of 
combining chemotherapy with radioimmunotherapy.   
 
This first concomitant RIT/chemotherapy trial at COH was followed by IRB 00148, a Phase I trial 
evaluating 90Y-cT84.66 RIT at 16.6 mCi/m2 given on day 1 with concomitant IV gemcitabine 
given on Days 1 and 3. The gemcitabine dose level cohorts studied thus far have been 30, 45, 60, 
75,90 and 105 mg/m2. This trial was initiated based on pre-clinical studies document an additive to 
supra-additive increase in anti-tumor effect with the combination 72-74. To date 17 patients have 
been treated on this study, with 1 partial response and 10 patients with stable disease observed. In 
addition, one patient had stable disease of multiple lung metastases after one cycle but developed a 
new brain metastasis. Toxicity has been primarily hematologic, and dose-limiting toxicity has not 
yet been reached. 
 
The proposed Phase I trial is a successor trial to IRB 00148 and IRB 96063 and integrates the 
experience of HAI FUdR. Patients post attempted hepatic resection or ablation for liver metastases 
with all hepatic and extra-hepatic disease debulked to <3.0 cm will receive FUdR by HAI in 
combination with systemic gemcitabine and Y-90-cT84.66. This trial therefore incorporates three 
important concepts felt to be critical for successful application of RIT. First, it evaluates RIT in 
combination with radiation-enhancing chemotherapy. The feasibility of combining RIT with 
systemic gemcitabine was established in the earlier trial. The proposed trial builds on this 
experience and evaluates the feasibility of adding HAI FUdR to systemic gemcitabine and Y-90 
cT84.66 RIT as adjuvant therapy. 
 
Second, this trial will evaluate hepatic regional combined modality therapy. Patients post hepatic 
metastases resection, who are therefore at high risk of liver progression or recurrences present the 
ideal patient population for study. Potential subclinical tumor deposits are irradiated by specific 
tumor targeting of antibody to tumor as well as non-specific Y-90-cT84.66 activity that localizes 
in surrounding liver. Radiation is deposited concomitantly with regional delivery of FUdR. 
 
 
 

 
 
Finally, patients on this study will have smaller volume or subclinical disease. Studies predict that 
RIT will have its greatest impact on subclinical disease. In small tumors, factors such as tumor 
vascularity and tumor interstitial pressure are more favorable for antibody delivery 75, allowing for 
greater antibody penetration, higher antibody uptake, more uniform distribution and, hence, more 
effective radiation doses to tumor 8,76. For example, Behr et al. 77 in a colon cancer liver metastases 
mouse model, improved survival and prevention of liver metastases in mice receiving I-131 
radiolabeled anti-CEA. Results were superior to that observed with 5-FU or irinotecan. These 
encouraging results led to a clinical trial by the same group evaluating I-131-hMN14 anti-CEA in 
patients with hepatic metastases from colon cancer after hepatic resection 78. Of 9 patients 
receiving adjuvant RIT, 8 remain disease free at 24+ months which compares favorably to other 
therapies delivered post-hepatic resection. Of 19 evaluable patients with measurable disease, 3 
demonstrated a PR of 3-15 months duration and 8 demonstrated a minor response of 3-14 months 
duration. Promising results have been reported by Hird et al. 79 who reported on 15 patients with 
FIGO stage IIb-IV ovarian cancer who had negative second look laparotomies after surgery and 
chemotherapy. Median survival after single dose intraperitoneal therapy with 90Y-DOTA-HMFG1 
or 90Y-DTPA-HMFG1 was 11 months (range 2-31 months), which was superior to historical 
controls from the same institution. Based on these encouraging results, a randomized Phase III 
trial was initiated to compare standard chemotherapy versus standard chemotherapy and Y-90-
HMFG1. The proposed study will enter patients who have potentially resectable liver metastases 
and potentially resectable limited extra-hepatic disease.  Those with resection/maximum debulking 
(to less than or equal to 3.0 cm) will receive protocol therapy consisting of RIT/Gemzar and 
intrahepatic pump infusion of FUdR. 
 
Proteomic Studies: Proteomics involves the analysis of biological samples for their protein 
content usually in a differential analysis to determine which proteins change during the course of 
treatment or other changes to the biological system 80-83.  Although the ultimate goal is to develop 
protein chips analogous to other microarray technologies, the field is still at the discovery stage 
and often uses mass spectrometry as a high throughput sensitive method that can rapidly identify 
proteins in complex biological samples.  Although many mass spectrometric approaches have 
been applied to proteomics, MALDI-TOF-MS (matrix assisted laser desorption time of flight mass 
spectrometry) remains a method of choice because it can rapidly analyze peptides and proteins 
ranging from low to high mass without interference from salts and low molecular compounds 
usually present in biological samples.  This approach requires only microliter amounts of sample 
and can be spotted on 100 well format plates with an analysis time of seconds for each sample.  In 
the context of this study, we are interested in analyzing serum samples from patients undergoing a 
combination of RIT and chemotherapy to determine if any protein signatures correlate to their 
course of treatment.  Since the number of patients is small, we do not expect to reach statistical 
significance.  Instead we propose to determine if the patients undergoing this therapy exhibit a 
common protein signature that can lead to the identification of markers to be more thoroughly 
screened in larger patient number studies.  
  
3.0   DRUG INFORMATION  
 
3.1 
5-Fluoro-2'-deoxyuridine (FUdR)  
 
3.1.1 Mechanism of Action:  FUdR is an antimetabolite which is rapidly converted into 5-
FU.  The actions and toxicity of FUdR are similar to 5-FU, the primary cytotoxic 
effect being a block of thymidylate synthesis with resulting interference with DNA 
synthesis.  Also, the drug blocks the incorporation of uracil and orotic acid into 
 

 
 
RNA, thereby depressing RNA synthesis. When given via the hepatic artery, 95% of 
FUdR is extracted by the liver with only 5% having systemic circulation or effect. 
 
3.1.2 Toxicity:  anorexia, nausea, vomiting, stomatitis, diarrhea, hepatitis, gastritis, 
leukopenia, thrombocytopenia, anemia, alopecia, dermatitis, skin hyperpigmentation, 
and cerebellar ataxia.  In patients receiving continuous hepatic artery infusions 
biliary sclerosis can also occur. 
 
3.1.3 Formulation and Storage:  FUdR is supplied in vials containing 500 mg of crystalline 
drug which can be reconstituted in 30 cc of normal saline for parenteral (intra-
arterial) use. 
 
3.2 
Gemcitabine 
 
3.2.1 Chemistry/ Mechanism of action:  Gemcitabine is a nucleoside analogue in which 
2’ position of the carbohydrate moiety has been changed to form 2’-deoxy –2’,2’ 
difluorocytidine.  Gemcitabine is metabolized by tumor cells to the di- and 
triphosphate nucleotide.  Ribonucleotide reductase activity is inhibited by the active 
metabolite dfdCDP.  DNA polymerase is also inhibited by dFdCTP and dFdCMP 
incorporated into DNA.   
 
 
 
3.2.2  
Human toxicities:  Gemcitabine therapy is associated with nausea, vomiting, 
diarrhea, stomatitis, myelosuppression, and renal insufficiency.  Long-term animal 
studies to evaluate the carcinogenic potential of gemcitabine have not been 
conducted.  Gemcitabine induced forward mutations in vitro in a mouse lymphoma 
assay.  Gemicitabine is embryotoxic causing fetal malformation and should not be 
used in pregnant women. 
 
3.2.3 Formulation:  Gemcitabine is available in 200 mg or 1 gram vials as a sterile 
powder with NaOH added to achieve pH adjustment upon the addition of sterile 
water. 
 
3.2.4 Administration:  Gemcitabine will be diluted in 5% dextrose (or half-normal saline 
in patients with diabetes) IV solution. 
 
 
3.3       Y-90-DTPA-cT84.66 
 
3.3.1.  Chemistry/Mechanism of Action:  cT84.66 is a chimeric human/murine IgG1 
monoclonal antibody developed at the City of Hope National Medical Center.  It 
recognizes the A3 domain of the CEA molecule and has little cross reactivity with 
other molecules.  It binds CEA with a high affinity (approximately 2 x 1010 /M) and 
is able to bring a bound radioisotope into close proximity.   It is labeled with 
indium -111 or yttrium- 90 to form the imaging and therapeutic agent. 
 
3.3.2  Human toxicities:  In phase I trials, the primary toxicity has been hematologic.   A 
possible complication of treatment is also the development of human anti-chimeric 
antibodies (HACA).   
 

 
 
3.3.3.  Formulation:  Yttrium-90 and indium-111 cT84.66 anti-CEA antibody is produced 
and labeled at the City of Hope by the Divisions of Immunology and 
Radioimmunotherapy.  
 
3.3.4. Supplier: cT84.66 anti-CEA antibody is an investigational agent produced and 
labeled at the City of Hope by the Divisions of Immunology and 
Radioimmunotherapy. 
 
3.4  
DTPA (Diethyltriaminepenatacetic acid) 
 
3.4.1.  Drug Formulation and Procurement 
DTPA will be purchased from Heyl Pharmaceuticals, Berlin, Germany. It is 
supplied as a 1 gram ampule in 5 mls. 
 
3.4.2  Drug toxicity 
DTPA has been known to cause headaches, fever, chills, flu-like symptoms, nasal 
stuffiness, nausea, vomiting, abdominal cramping, and diarrhea. Other side effects 
that are less common include pain at the injection site, dehydration, decreased 
blood pressure, irregularities of heart rhythm, decreased blood counts, increased 
calcium, numbness and tingling, sneezing, excessive tearing, kidney damage, and 
zinc deficiency (which can result in a facial and perianal rash and tongue and 
mouth sores). In addition, there is always a risk of a very uncommon or previously 
unknown side effect occurring. Stopping the infusion or reducing the dose of 
DTPA normally reverses the side effects. Headaches and tingling have been 
observed at the City of Hope but were reversible.  
 
3.4.3.  Drug Storage, Reconstitution and Stability 
The DTPA solution will be diluted with 100 mls normal saline and administered IV 
over 1 hour. DTPA has a long aqueous stability but should be used within 48 hours 
of being drawn up by the pharmacy. DTPA will be administered intravenously at a 
dose of 125 mg/m2 every 12 hours for a total of six administrations. 
 
3.5 
Decadron 
 
3.5.1 Chemistry/Mechanism of Action 
 
 
Decadron is a corticosteroid with anti-inflammatory action.  Multiple 
glucocorticoid and mineralocorticoid effects occur.  The agent is metabolized in the 
liver and excreted out through the urinary system. 
 
3.5.2 Human Toxicities 
 
 
Reported reactions, particularly with long-term use of Decadron, include peptic 
ulcer disease, osteoporosis, adrenal insufficiency, weight gain, immunosuppression, 
nausea, dyspepsia, increased appetite, edema, headache, dizziness, mood swings, 
insomnia, anxiety, exacerbation of hypertension, hyperglycemia, cushingoid 
features, Cushing’s syndrome, menstrual irregularities, ecchymoses, acne, skin 
atrophy, impaired wound healing with long-term use. 
 
3.5.3 Formulation and Administration 
Amended 
7/20/05 

 
 
Decadron will be administered along with hepatic arterial infusion of FUdR at a 
dose of 1 mg per day x 14 days per cycle of treatment. 
 
4.0 ELIGIBILITY CRITERIA 
 
4.1 
Pre-operative eligibility criteria: 
 
4.1.1 
Patients must have a physiological age of > 18 years and < 70 years. 
 
 
4.1.2 
Patients must have a Karnofsky performance status of > 60%. This must be met 
pre-surgery and pre-study therapy. 
 
4.1.3 
Patients must have histological confirmation of colorectal carcinoma and present 
with potentially resectable or ablatable metachronous or synchronous hepatic 
metastases. 
 
4.1.4 
Patients must have colorectal tumors that produce CEA as documented by either 
immunohistochemistry or by an elevated serum CEA. 
 
4.1.5 
Prior radiotherapy, immunotherapy, or chemotherapy must have been completed at 
least four weeks prior to start of FUdR/RIT therapy on this study (6 weeks if 
mitomycin-C or nitrosoureas were part of last therapy) and patients must have 
recovered from all expected side effects of the prior therapy. 
 
4.1.6 
Adequate bone marrow function as evidenced by hemoglobin > 10 gm %, WBC 
>4000/ul, an absolute granulocyte count of > 1,500/mm3, and platelets > 
150,000/ul.  Patients may be transfused to reach a hemoglobin >10 gm %.  These 
must be met pre-surgery and pre-study therapy. 
4.1.7 
Patients may have history of prior malignancy for which the patient has been 
disease-free for five years with the exception of basal or squamous cell skin cancers 
or carcinoma in situ of the cervix. 
 
4.1.8 
Patients must have no prior history of radiation therapy to the liver. 
 
4.1.9 
Patients must have a total bilirubin < 1.5 (unless reversibly obstructed due to the 
metastatic tumor) and a serum creatinine of < 2.0.  This must be met pre-surgery 
and pre-study therapy. 
 
4.1.10 
Patients must have evidence of intrahepatic metastases involving < 60% of the 
functioning liver. 
 
4.1.11 
Patients cannot have evidence of extrahepatic disease with the following 
exceptions: 
 
4.1.11.1 
Patients known to have a resectable "anastomotic" or local recurrence of 
their tumor.   
 
 
 
 

 
 
4.1.11.2 
Patients who undergoing their initial surgery for resection of their primary 
colorectal carcinoma can have potentially resectable porta hepatis and/or 
mesenteric lymph node involvement in addition to liver metastases. 
 
4.1.11.3 
Patients who have disease extension from the liver metastasis that can be 
resected en bloc (eg., diaphragm, kidney, and abdominal wall). 
 
4.1.11.4 
Patients who have minimal, potentially resectable to less than 3 cm 
extrahepatic disease. 
 
4.1.12 
The pre-operative eligibility checklist must be completed. 
 
4.1.13 
If a patient has previously received murine or chimeric antibody, then serum anti-
antibody testing must be negative. This must be met pre-surgery if possible. 
 
4.1.14 
Serum HIV testing and hepatitis B surface antigen and C antibody testing must be 
negative. 
 
4.1.15 
Women of childbearing potential must have a negative serum pregnancy test prior 
to entry and while on study must be practicing an effective form of contraception.  
This must be met pre-surgery and pre-study therapy. 
 
4.2 
Intra-operative and post-operative eligibility 
 
4.2.1 Patients must have resectable or ablatable liver metastases as determined by the 
attending surgeon. 
 
4.2.2 Colorectal carcinoma must be confined to the liver except as noted in 4.1.11 above. 
 
4.2.3 Patients with limited extrahepatic disease as defined in 4.1.11 (primary, lymph 
node, or anastomotic recurrence) must have disease resected or debulked to less 
than 3 cm in greatest dimension.  
 
4.2.4 To receive study therapy, patients must be at least 3 weeks post-surgery but no 
more than 16 weeks post surgery and without evidence of post-operative 
complications, such as infection or poor wound healing. 
 
4.2.5 Patients must have <40% liver resected at the close of completion of the hepatic 
resection. 
 
4.3 
Ineligibility Criteria: 
 
4.3.1 Patients that have received radiation therapy to greater than 50% of their bone 
marrow (see Appendix II). 
 
4.3.2 Patients with any nonmalignant intercurrent illness (example cardiovascular, 
pulmonary, or central nervous system disease) which is either poorly controlled 
with currently available treatment or which is of such severity that the investigators 
deem it unwise to enter the patient on protocol shall be ineligible. 
 
Amended 
10/07/05 
Amended 
1/23/06 
Amended 
11/28/06 

 
 
 
4.3.3 Biopsy-proven chronic active hepatitis. 
 
4.4 
Note:  for patients who have had surgery prior to signing the consent form, the pre-
operative and intra-operative eligibility criteria may be verified retrospectively, prior to study 
therapy. 
 
 
5.0  STAGING CRITERIA 
 
 
Staging will be by the TNM system of the AJCC. 
 
 
 
 
6.0  DESCRIPTIVE FACTORS/STRATIFICATION/RANDOMIZATION SCHEME 
 
This is a Phase I study.  Patients shall be entered according to the treatment plan in section 
7.0.  There shall be no randomization nor stratification.  Descriptive factors shall include 
patient age, previous treatment, primary malignancy, location and extent of metastases. 
 
7.0 TREATMENT PLAN 
 
Patients fulfilling all pre-operative and intra-operative requirements (as noted in section 4.0 
above) will have attempt at complete resection or ablation of hepatic metastases and 
implantation of infusion pump with the catheter in the hepatic artery. 
 
Post-hepatic resection therapy on this trial consists of two parts: 
 
Part I – Protocol Therapy: 
90Y-MxDTPA-cT84.66/Gemcitabine/hepatic arterial 
FUdR/Decadron for a maximum of 3 cycles every 6-10 weeks between cycles.  There can 
be up to 10 weeks between cycles if more time is needed for recovery from toxicities.  If 
more than 10 weeks are required, then the patient will be off-study. 
 
 
Part II – Additional courses of hepatic arterial infusion FUdR/Decadron with best 
systemic therapy. 
 
Additional hepatic arterial infusion of FUdR permitted for a maximum of 4 cycles 
(including cycles delivered during Part I of protocol therapy with RIT/gemcitabine).  
Systemic therapy may be given in combination with hepatic arterial infusion FUdR at the 
discretion of the treating physician.  Systemic therapy may be continued after completion 
of hepatic arterial infusion at the discretion of the treating physician. 
 
7.1 
General Principles of Protocol Therapy (Part I) 
 
7.1.1 All patients will receive combined modality therapy consisting of 
chemotherapy and concomitant radioimmunotherapy (Y-90-DTPA-
cT84.66).  A therapy cycle will consist of systemic gemcitabine, systemic 
Y-90-DTPA-cT84.66 and the HAI administration of FUdR/Decadron. Each 
 
Amended 
7/20/05 
Amended 
7/20/05 
Amended 
7/20/05 

 
 
treatment cycle will be 6 weeks for a maximum of 3 cycles in Part I 
(protocol therapy). 
 
7.1.2 Patients will begin treatment on day 1 with HAI FUdR/Decadron for 14 
days. On day 9, Y-90-cT84.66 will be given as a single IV bolus infusion.  
On days 9 and 11, gemcitabine will be administered as a single IV bolus 
infusion. 
 
7.1.3 Any patient who has an actual body weight or surface area that is > 10% in 
excess of ideal body weight or surface area will have chemotherapy doses 
calculated by averaging the ideal and actual values. 
 
7.1.4 Protocol therapy can be initiated as early as 3 weeks post-surgery but no 
later than 16 weeks post-surgery. 
 
7.2 
Administration of FUdR/Decadron (Day 1-14 of each cycle) (Part I) 
 
7.2.1 Patients will receive a dose of FUdR/Decadron administered for 14 
consecutive days.  Solutions used to fill the intrahepatic infusion pump 
should contain 1000 units of heparin/ml.  Decadron will be given at a dose 
of 1mg/day x14 days mixed with the FUdR in the infusion pump. 
 
7.2.2 During times when the patient is not receiving chemotherapy with the 
intrahepatic infusion pump a solution of normal saline with 1000 units/ml of 
heparin or alternatively a glycerol water solution will be used to maintain 
the patency of the pump catheter. 
 
7.2.3 The starting dose level (dose level 1) on this Phase I trial will be 0.10 
mg/kg/day. Per phase I protocol design using a modified Fibonacci scheme 
the dose will be escalated in cohorts of 3-6 patients, until an MTD is 
defined and dose-limiting toxicities are reached. (Table 1) 
 
7.2.4 A maximum of three dose levels are anticipated to be required to reach the 
MTD.  Following a standard phase I dose escalation design (see Table 1), 
three to six patients will be entered per dose level.  The maximum dose 
level will be 0.2 mg/kg/day. 
 
 
TABLE I 
DOSE ESCALATION SCHEME 
 
 
Dose Level 1 
Dose Level 2 
Dose Level 3 
 
 
 
 
FUdR dose 
0.10 mg/kg/day 
0.15 mg/kg/day 
0.20 mg/kg/day 
 
 
7.2.5 Each cycle of treatment for a given patient will be at the same dose, unless 
there is toxicity requiring a dose modification (see Section 8.2). A patient 
will be removed from protocol treatment if there is unacceptable toxicity, 
Amended  
7/20/05 
7/11/06 
 
Amended 
7/20/05 
Amended 
03/06/06 

 
 
progressive disease, or development of an anti-antibody response (see 
Section 7.5) 
 
 

 
 
 
7.3         Administration of gemcitabine (Day 9 and 11 of each cycle) (Part I) 
 
7.3.1 Patients will receive gemcitabine at a dose of 105 mg/m2/day by bolus 
intravenous infusion over 30 minutes. 
 
7.3.2 Each cycle of treatment for a given patient will be at the same dose, unless 
there is toxicity requiring a dose modification (see Section 8.2). A patient 
will be removed from protocol treatment if there is unacceptable toxicity, 
progressive disease, or development of an anti-antibody response (see 
Section 6.6). 
 
7.4 
Intravenous infusion of radiolabeled anti-CEA antibody (chimeric T84.66) (Part I) 
 
7.4.1 The infusion will contain 5 mCi of Indium-111 (111In) labeled cT84.66 and 
the therapeutic dose of Yttrium-90 (90Y) labeled cT84.66.  The 111In labeled 
cT84.66 will be used to track antibody activity and to estimate absorbed 
radiation dose to tumor and normal organs.  The total amount of antibody 
protein infused will be kept constant at 5 mg.  Intravenous infusion will 
involve first a test infusion of 100 ug of antibody.  If there is no adverse 
reaction the rest of the antibody will be infused over approximately 25 
minutes. The 90Y cT84.66 infusion will be on Day 9 approximately 4 hours 
after gemcitabine infusion.  
 
7.4.2. The dose level on this trial will be 16.6 mCi/m2 Y-90-cT84.66.  
 
7.4.3. Each cycle of treatment for a given patient will be at the same dose, unless 
there is toxicity requiring a dose modification (see Section 8.2). A patient 
will be removed from protocol treatment if there is unacceptable toxicity, 
progressive disease, or development of an anti-antibody response (see 
Section 7.5). 
 
 
7.4.4 DTPA infusion.   Although the Mx-DTPA chelate binds Y-90 tightly, it is 
not possible to have an off-rate of zero. Since any free Y-90 can target to 
bone, resulting in increased bone marrow toxicity, patients will receive a 
DTPA infusion for 3 days after Y-90 chimeric T84.66 infusion.  The dose 
of DTPA will be 250 mg/m2/24 hours for 3 days (given in equally divided 
doses every 12 hours for a total of 6 doses).  Each infusion is only 60 mins. 
i.v.  DTPA will be administered as a calcium salt.  This dose and schedule 
has been used by other investigators administering Y-90 labeled antibodies 
and has resulted in increased urinary excretion of free Y-90 and less 
hematologic toxicity. 
 
7.4.5 Serial nuclear scans.  Radionuclide total body planar imaging will be done 
at approximately 1-3 hours post start of infusion, and at 1 day, 2 days, 3-5 
days, and at a late time point between 6-7 days post infusion.  A SPECT 
nuclear scan will also be performed at 2 days and a time point between 3-5 
days post infusion.  These studies will be used to estimate absorbed 
Amended 
7/11/06 
Amended  
7/11/06 

 
 
radiation doses to tumor, normal organs (liver, lung, kidney, bone marrow), 
and whole body.  
 
7.4.6 Serial blood and urine collections.  Serial blood (5 cc) samples will be 
collected at pre-main infusion (post test dose), approximately 1 hour and 3-
4 hours post start of infusion, and at scan times of 1 day, 2 days, 3-5 days 
and 6-7 days post antibody infusion.  Urine collections will be done daily 
for 5 consecutive days.  Blood and urine samples will be analyzed for total 
activity and by radiometric HPLC.  These studies will acquire data on 
antibody metabolism and pharmacokinetics. 
 
7.5 (Part I)  Subsequent cycles (up to three total) will be given six weeks apart.  A 
subsequent cycle can be delayed up to a total of 10 weeks between cycles if more time 
is needed for recovery from toxicity (expected to be primarily hematologic).  If more 
than 10 weeks is required the patient is off protocol treatment.  The subsequent courses 
will consist of the same dose of In-111 chimeric T84.66 and Y-90 chimeric T84.66, 
gemcitabine and FUdR (i.e., no dose escalation within a patient).  However, if toxicity 
occurs, a dose reduction with the next cycle for a given patient is warranted (see 
Section 8.2).  A patient will receive no further protocol therapy (but still evaluable) if 
he/she develops unacceptable toxicity, disease progression, or an anti-antibody 
response. 
 
7.6 Proteomic analysis of blood samples.  (Part I)  Before the first cycle of protocol 
therapy, and after each subsequent cycle, a blood sample will be obtained for 
proteomic analysis to evaluate any correlations to toxicities and anti-tumor effects.   
Protocol:  plasma or serum samples are diluted 3-5 fold with water or PBS usually 
containing 20% acetonitrile.  High molecular weight proteins components are 
precipitated using either acetone or trichloroacetic acid and separated by centrifugation.  
The supernatant containing the low molecular weight peptide and protein fraction is 
concentrated in a vacuum centrifuge and then bound to a C18 reverse phase support.  
After washing with water to remove salts, the bound components are eluted with an 
aqueous solvent containing 50-80% acetonitrile.  An aliquot of the sample solution is 
spotted onto a matrix assisted laser desorption ionization (MALDI) sample plate along 
with a solution of the MALDI matrix, typically sinapinic acid or a-cyano-4-
hydroxycinnamic acid.  Protein profiles are acquired on a MALDI time-of-flight (TOF) 
mass spectrometer.  Components of interest in the protein profile are identified by 
comparisons to samples taken from the same patient at different time points, and/or 
comparisons to other patient or control samples.  Those components are further 
characterized by fractionation of the low molecular weight fraction by liquid 
chromatography, enzyme digestion, tandem MS analysis and database matching to 
identify the proteins.  Since the number of patients sampled is limited, the objective is 
not to perform a statistical analysis, but instead, to identify potential markers of therapy 
or toxicity for future studies.  
 
7.7 Once the MTD has been established, an additional 10 patient expanded cohort will be 
accrued for proteomic correlative studies. 
 
 
7.8  Part II – Conventional Therapy: 
 
Amended  
7/11/06 
Amended 
7/11/06 

 
 
 
 
After treatment with 90Y-MxDTPA-cT84.66/gemcitabine/HAI FUdR, patients will 
proceed to further systemic therapy.  Systemic therapy, at the discretion of the treating 
physician, will be combined with additional cycles of HAI FUdR.  Additional hepatic 
arterial infusion of FUdR permitted for a maximum of 4 cycles (including cycles 
delivered during Part I of protocol therapy with RIT/gemcitabine).  Systemic therapy 
may be given in combination with hepatic arterial infusion FUdR at the discretion of 
the treating physician.  Systemic therapy may be continued after completion of hepatic 
arterial infusion at the discretion of the treating physician. 
 
7.9 The following tests and procedures will be performed prior to each cycle of therapy 
and for the study: 
 
 

 
 
Study Parameters 
 
*or at the discretion of the treating physician 
# If a complete or partial response is noted, this must be confirmed by measurements at least 4 
weeks apart.  During part II of therapy, tumor measurements should be obtained after every 2 
cycles of therapy. If there is evidence of tumor response and patient goes off study, we will 
perform tumor measurements and CEA measurements at 3 mo and 6 mo off-study or as 
indicated by ongoing treatment. 
$ Anti-Ab assay and CEA should also be performed at 3 mo and 6 mo post last antibody infusion. 
% For pts who signed the ICF prior to surgery, these tests must be repeated prior to study therapy. 
@ Tumor measurements are not required on the pre-surgery CT scan. 
 
 
Baseline 
(pre-
surgery)  
Weekly  
between RIT 
cycles (starting 
1 week post Y-
90 dose) 
Before ea cy of 
RIT & Off Part 
I of study 
Every other 
week during 
FUdR therapy* 
Off Part II 
of study 
History & 
Physical 
X% 
X 
X 
X 
X 
Vital Signs 
X% 
X 
X 
X 
X 
Weight 
X% 
X 
X 
X 
X 
KPS 
X% 
X 
X 
X 
X 
CT/MRI Tumor 
X% 
 
X 
 
X 
Tumor 
Measurement# 
X%,@ 
 
X 
 
X 
CBC, ANC, 
PLT 
X% 
X 
X 
X 
X 
CMP + Mg 
X% 
X 
X 
X 
X 
HIV 
X 
 
 
 
 
Serum CEA 
X% 
 
X$ 
 
 
CXR 
X 
 
 
 
 
EKG 
X 
 
 
 
 
Anti-Antibody 
Assay 
X 
 
X$ 
 
 
Proteomic 
Analysis of 
blood sample 
X 
 
X 
 
 
Creatinine 
clearance 
X% 
 
X 
 
 
Hep B Surf Ag 
& Hep C Ab 
X 
 
 
 
 
Amended 
7/20/05 
10/07/05 
01/23/06 
7/11/06 

 
 
7.9 
Criteria for Removal from Protocol Treatment 
 
7.9.1 Patients with progressive disease: 25% increase in the sum of products of 
measurable lesions over smallest sum observed, OR reappearance of any lesion 
which had disappeared, OR clear worsening of any evaluable disease (see 9.1 and 
9.2), OR appearance of any new lesion/site.  For scan only bone disease, increased 
uptake does not constitute clear worsening.  Worsening of existing non-evaluable 
disease does not constitute progression.   
 
7.9.2 Patients developing unacceptable toxicity after any cycle (see Section 8.0). 
 
 
7.9.3 Patients developing anti-antibody response after any course. 
 
7.9.4 Patient refusal of further therapy. 
 
7.9.5 Investigator's decision to remove the patient.  The reason must be clearly 
documented on the case report forms. 
 
8.0 TOXICITIES TO BE MONITORED AND DOSAGE MODIFICATIONS 
 
8.1 
Both hematologic and non-hematologic toxicity will be monitored.  Hepatic, renal, 
pulmonary, cardiac, and hematologic toxicity will be monitored through studies outlined 
in Section 7.6.  Dose-limiting toxicity is expected to be hematologic, GI, or hepatic. 
Lymphopenia is not a dose limiting toxicity. Toxicity will be scored by Common Toxicity 
Criteria outlined in Appendix IV. 
 
8.2 
Dose modification of subsequent cycles of  Part I PROTOCOL therapy 
(RIT/GEMCITABINE/FUdR)for a given patient.   
 
Patients with > grade 3 non-hematologic or grade 4 hematologic toxicity will be taken off 
study.  In all other patients, the therapy is to be repeated only after toxicity has reversed to 
at least grade 1 within 10 weeks from the last RIT therapy infusion.  Dose modification for 
the next cycle should be made in a given patient experiencing adverse effects as follows: 
 
 
 
If grade 3 or 4 non-hematologic, or grade 4 hematologic toxicity is observed at any dose 
level, that patient will be taken off protocol therapy. Two occurrences of grade 3 non-
 
Grade 3 or 4 non-
hematologic or  
Grade 4 hematologic 
toxicity 
Grade 2 non-
hematologic or 
Grade 3 
hematologic 
Grade 0, 1, or 
Grade 2 
hematologic 
FUdR 
No further protocol 
treatment 
Decrease one level 
No Change 
Gemcitabine 
No further protocol 
treatment 
Decrease one level 
90 mg/m2 
No Change 
90Y cT84.66 
No further protocol 
treatment 
Decrease one level 
12 mCi/m2 
No Change 
 
Amended 
1/23/06 

 
 
hematologic toxicity, two occurrences of grade 4 hematologic or one occurrence of grade 4 
non-hematologic toxicity at the starting dosage level one will necessitate revision of 
starting dosages. 
 
The next cycle of treatment can be delayed for up to 4 weeks to allow for recovery from 
toxicity.  After more than 10 weeks between treatments, the patient is off protocol 
treatment. 
 
A patient will receive no further protocol therapy if: 
a) any grade  4 toxicity occurs,  
b) any grade 3 non-hematologic toxicity occurs 
c) a second grade 3 hematologic toxicity occurs after dose modification, or 
d) toxicity not reversible to grade 1 or less occurs. 
 
 
9.0 CRITERIA FOR EVALUATION AND ENDPOINT DEFINITIONS 
 
9.1 
The response endpoints will be:  a)  Progression-free survival, defined as first documented 
evidence of treatment failure.  Recurrence should be diagnosed by biopsy if at all possible 
(see below); b) Overall Survival; c) Sites of recurrence. 
 
9.2 
Diagnosis of Treatment Failure 
 
Every effort to biopsy recurrence of malignant disease should be made whenever possible.   
 
Suspicious findings do not constitute treatment failure and patients should not be taken off 
study on this basis. 
 
Below are listed examples of acceptable and unacceptable evidence for treatment failure at 
various sites. 
 
9.2.1 
Abdominal and/or Pelvic 
 
(1) 
Anastomotic 
 
(a) 
Acceptable -- positive cytology or biopsy 
 
(b) 
Suspicious -- abnormal barium enema, change in bowel habit, palpable mass, abnormal 
PET scan. 
 
(2) 
Abdominal, pelvic and retroperitoneal nodes 
 
(a) 
Acceptable -- positive cytology or biopsy, progressively enlarging node (> 2 cm) as 
evidenced by 2 CT scans separated by at least a 4 week interval, ureteral obstruction in the 
presence of a mass as documented on CT scan 
 
(b) 
Suspicious -- abnormal sonogram PET scan or CT scan or ureteral obstruction without 
mass 
 
 

 
 
(3) 
Peritoneum (including visceral and parietal peritoneum, omentum) 
 
(a) 
Acceptable -- positive cytology or biopsy, progressively enlarging intraperitoneal solid 
mass as evidenced by 2 CT scans separated by at least a 4 week interval 
 
(b) 
Suspicious -- abnormal sonogram or CT scan without solid mass 
 
(4) 
Ascites 
 
(a) 
Acceptable - Positive cytology or biopsy 
 
(b) 
Suspicious -- ascites without proof of tumor cells present 
 
(5) 
Liver 
 
(a) 
Acceptable - Positive cytology or biopsy 
 
(b) 
Suspicious: Any 3 of the following which are not associated with benign disease: 
 
 
a. 
Recent or progressive hepatomegaly, abnormal liver contour 
 
 
b. 
Positive radionuclide liver scan, PET scan, MRI scan, sonogram or CT scan 
 
 
c. 
Abnormal liver function studies defined as > 3 times the upper limit of normal 
 
 
d. 
Elevated CEA:  A persistent rise in CEA titer confirmed on 2 determinations 
separated by a 4 week interval.  The determination should be performed by the same 
laboratory using the same method. 
 
NOTE:  An elevated CEA level will, as of itself, not be considered acceptable evidence of 
treatment failure.  Non-protocol therapy will not be instituted on the basis of an abnormal 
CEA level.   
 
(6) 
Pelvic mass 
 
(a) 
Acceptable -- positive cytology or biopsy, progressively enlarging intrapelvic solid mass 
(> 2 cm) as evidenced by 2 CT scans separated by at least a 4 week interval 
 
(b) 
Suspicious -- abnormal sonogram PET scan or CT scan without solid mass 
 
(7) 
Abdominal wall, perineum and scar 
 
(a) 
Acceptable -- positive cytology or biopsy 
 
9.2.2  Non-abdominal and non-pelvic sites 
 
(1) 
Skeletal 
 

 
 
(a) 
Acceptable --  (i) x-ray evidence of lytic, blastic, or mixed lytic/blastic lesions on skeletal 
films with or without bone scan confirmation, (ii) biopsy proof of bone metastasis, (iii) 
bone scan consistent with bone metastases in a patient with bone pain, or (iv) progressive 
bone scan changes over at least a 4 week period are necessary in asymptomatic patients 
with only bone scan abnormalities (v) progressive changes on MRI scan. 
 
NOTE:  In the absence of progressive disease by scan, a biopsy is strongly recommended.  
Any positive bone scan in the joints or in a recent area of trauma (surgical or otherwise) 
cannot be used as an indication of treatment failure. 
 
(2) 
Lung 
 
(a) 
Acceptable -- (i) positive cytology or biopsy or (ii) the presence of multiple pulmonary 
nodules which are felt to be consistent with pulmonary metastases 
 
NOTE: If a solitary lung lesions is found and no other lesions are present on CT scan, 
further investigations such as biopsy, needle aspiration or resection should be performed.  
Proof of neoplastic pleural effusion should be established by cytology or pleural biopsy. 
 
 (3) 
Bone marrow 
 
(a) 
Acceptable -- positive cytology, aspiration or biopsy 
 
(b) 
Suspicious -- unexplained depression of peripheral counts and/or erythroblastic blood 
picture 
 
(4) 
Central nervous system 
 
(a) 
Acceptable -- (i) positive MRI or CT scan, usually in a patient with neurological symptoms 
or (ii) biopsy or cytology (for a diagnosis of meningeal involvement) 
 
9.2.3  Post-mortem examination 
 
Autopsies should be done whenever possible and reports sent to Biostatistics. 
 
 
 
10.0 DATA AND SAFETY MONITORING PLAN & DATA SUBMISSION SCHEDULE 
 
A. 
Definition of Risk Level  
 
This is a Risk Level 4 study, as defined in the Guidance, Policy and Procedures for Data and 
Safety Monitoring for In-House Trials at City of Hope”, 
http//www.infosci.coh.org/gcrc/doc/dsmp.doc, involving hepatic arterial infusion of chemotherapy 
(Fluorodeoxypyrimidine (FUdR)) and radiation therapy (Yttrium-90-labeled chimeric 
T84.66 anti CEA antibody). 
 
B. 
Monitoring and Personnel Responsible for Monitoring 
 
Amended 
10/7/05 
11/22/05 

 
 
The Protocol Management Team (PMT) consisting of the PI, Collaborating Investigator, 
CRA/protocol nurse, and statistician are responsible for monitoring the data and safety of 
this study, including implementation of the stopping rules for the safety and efficacy. 
 
 
Monitoring by the PMT will be done using the Phase I tracking log (see attached Appendix 
VI of protocol) to monitor data and safety for dose escalation. Data and safety will be 
reported to the COH DSMB after each dose level.  Reporting of data and safety to the 
DSMB will occur at each dose level using the PMT report. 
 
C. 
Adverse Events 
  
Reporting:  Adverse events must be reported to the COH DSMB, IRB, and GCRC 
according to definitions and guidelines at http://www.infosci.coh.org/gcrc/doc/dsmp.doc and 
http://resadmin.coh.org/doc/irb3810.doc, which are defined below. AEs will be monitored by the 
PMT. Less than serious adverse events will be reported only at the time of protocol 
continuation reports.  Grade 4 lymphopenia is not a reportable event. 
 
All IND reports that are submitted to the FDA on this protocol will also be submitted to the 
DSMB for review. 
 
A record of any interventional radiologic complications related to antibody infusion will be 
recorded on the Case Report Form. 
 
Adverse Event - An adverse event (AE) is any untoward medical experience or change of an 
existing condition that occurs during or after treatment, whether or not it is considered to be 
related to the protocol intervention. All AEs occurring during this study, whether observed by 
the physician, nurse, or reported by the patient, will be recorded on the City of Hope National 
Medical Center Adverse Events (COH AER) form (http://resadmin.coh.org/doc/irb3820.doc) form.   
 
Serious Adverse Event - A serious adverse event (SAE) is defined as any expected or 
unexpected adverse event (AE, generally equivalent to CTCAE grades 3, 4 or 5) that is related 
or unrelated to the intervention that results in any of the following outcomes: 
 
 Death 
 A life-threatening event 
 In-patient hospitalization (not required as part of the treatment) or  prolongation of existing 
hospitalization 
 A persistent or significant disability/incapacity 
 A congenital anomaly/birth defect 
 Causes cancer 
 Is an overdose 
 
Certain medical events that may not result in death, be life-threatening, or require 
hospitalization, may also be considered a serious adverse event when appropriate medical or 
surgical intervention is necessary to prevent one of the outcomes listed above. 
 

 
 
Unexpected Adverse Event – Any event in which the severity or specificity is not 
consistent with the risk information described in the protocol, and the event is not anticipated 
from the subject's disease history or status. 
 
Expected Adverse Event - Any event in which the severity or specificity is consistent with 
the risk information described in the protocol or is anticipated based on the subject's medical 
history. 
 
Attribution - For reporting purposes, attribution is the assessment of the likelihood that an AE 
is caused by the research agent or protocol intervention.  The attribution is assigned by the 
Principal Investigator after considering the clinical information, the medical history of the 
subject, and past experience with the research agent/intervention.  This is recorded using the 
Adverse Event Report (COH AER) form (http://resadmin.coh.org/doc/irb3820.doc)  in one of 5 categories 
scored as the following: 5=related, 4=probably related, 3=possibly related, 2=unlikely related 
and 1=unrelated.  The attribution is subject to change as follow-up information becomes 
available, and it can be changed by the DSMB or by the IRB in the process of review. 
 
All primary data will be maintained by the assigned Data Manager from the Department of 
Biostatistics.  Data will be submitted to the Data Manager at the time of each patient evaluation.  
These will include flow sheets, pathology reports, as well as off-study information.  Records will 
be stored in a secure location within the Department of Biostatistics.                                                                 
 
11.0 STATISTICAL CONSIDERATIONS 
 
This is a Phase I/II trial.  The primary objective of this trial is to determine the maximum tolerated 
dose and associated toxicities of intravenously administered gemcitabine and Y-90 cT84.66 delivered 
in combination with hepatic arterial infusion FUdR.  Secondary objectives of the trial include the 
evaluation of the biodistribution, clearance and metabolism of Y-90 and In-111-cT84.66 and the 
estimation of radiation doses to whole body, normal organs, and tumor through serial nuclear 
imaging.    
 
The maximum tolerated dose (MTD) and level at which dose-limiting toxicity (DLT) is 
experienced will be determined as follows: 
 
Three patients will be enrolled at each dose level.  If none of the three patients has Grade 3 non-
hematologic toxicity or Grade 4 hematologic toxicity after the first cycle, then three patients may 
be enrolled at the next dose level. 
 
At each dose level, if in two of three patients, Grade 4 hematologic toxicity or Grade 3 non-
hematologic toxicity related to therapy occurs after the first cycle, then the level at which DLT 
occurs is established. 
 
If Grade 3 non-hematologic toxicity or Grade 4 hematologic toxicity occurs in one of three 
patients, then three additional patients are entered at the same dose level.  Then if Grade 3 non-
hematologic toxicity or Grade 4 hematologic toxicity occurs after the first cycle in: 
 
1.  1 of 6 patients, proceed to the next dose level 
2.  2 of 6 patients, that dose is the dose level at which DLT occurs. 
 

 
 
If Grade 4 non-hematologic toxicity related to therapy occurs after the first cycle at a dose level, 
no further patients will be treated at that dose level and the DLT will be established. 
 
Once the dose level at which DLT is established, three additional patients will be enrolled at the 
preceding dose level to a total of six patients.  The study will be closed after six patients have been 
accrued at a preceding level with the occurrence of no Grade 4 non-hematologic toxicity, and at 
most one Grade 3 non-hematologic toxicity or Grade 4 hematologic toxicity. The level at which 
DLT occurs will be defined as the minimum intolerable dose (MID). The preceding dose level at 
which no more than 1 of 6 patients experience Grade 3 non-hematologic toxicity and Grade 4 
hematologic toxicity and no patients experience reversible Grade 4 non-hematologic toxicity, will 
be defined as the maximum tolerated dose (MTD). 
 
MTD and MID will based on toxicities observed with the first cycle of therapy. 
The two major endpoints will be 2 year progression-free survival and sites of recurrence (liver or 
distant sites).  Since our City of Hope feasibility study (IRB 89188) suggested that only fewer than 
40% of the entered patients will actually undergo surgical resection and adjuvant therapy, twice as 
many patients will be entered on study as will receive treatment. 
 
The duration of progression-free and overall survival will be estimated using the product-limit 
method of Kaplan-Meier, and 95% confidence limits calculated for these estimates.  The historical 
control data will then be compared to the Kaplan-Meier estimates of the 2-year progression-free 
survival rates. 
 
Proteomic parameters will be compared with clinical response and toxicities in an exploratory 
manner. However, the heterogeneity of the population and the small number of patients treated 
make formal statistical analysis of these correlative studies unlikely. 
 
 
 
 
12.0 PATHOLOGY REVIEW 
 
All patients will have advanced malignancy confirmed by review of their biopsy specimens by the 
Division of Pathology of the City of Hope National Medical Center. 
 
13.0 REGISTRATION GUIDELINES 
 
Once a signed, written informed consent has been obtained and all pretreatment evaluations have 
been performed, patients will be entered on study, after review of patient eligibility criteria by the 
assigned Data Manager from the City of Hope Department of Biostatistics. Patients may be 
screened for registration by calling the Department of Biostatistics, ext. 2468. 
 
14.0 SPECIAL INSTRUCTIONS 
 
None. 
 
15.0 ETHICAL AND REGULATORY CONSIDERATIONS 
 
 

 
 
This study is to be approved by the Institutional Review Board according to City of Hope ethical 
and regulatory guidelines.  All patients will have signed an informed consent for participation in 
research activities, and will have been given a copy of the Experimental Subject's Bill of Rights. 
 
When results of this study are reported in medical journals or at meetings, identification of those 
taking part will be withheld.  Medical records of patients will be maintained in strictest 
confidence, according to current legal requirements.  However, they will be made available for 
review, as required by the Food and Drug Administration (FDA) or other authorized users such as 
the National Cancer Institute (NCI), under the guidelines established by the Federal Privacy Act.

 
 
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APPENDIX I 
 
ADMINISTRATION OF INTRAVENOUS RADIOLABELED ANTIBODY:    
 
First, 100 ug of the antibody will administered intravenously over 2-3 minutes as a test dose. If 
there is no acute reaction after 15 minutes, the remainder of the dose will be administered 
intravenously over approximately 25 minutes.  Although uncommon, possible adverse reactions 
that may occur include: 1) chills and fever, 2) itching, rash, or erythema, 3) pain in chest, flank or 
back (signs of anaphylaxis), 4) bronchospasm (may be sign of anaphylaxis), 5) hypotension (rare, 
may be sign of anaphylaxis), and 6) anaphylaxis. Infusion will be terminated for any of the 
following reasons:  1) fall in blood pressure > 25 mm Hg systolic, 2) respiratory distress, 3) pulse 
greater than 130/min, 4) temperature > 102°F, 5) clinician's judgment, or 6) patient's request.  
Nursing and physician personnel will be present at all times during the administration and post 
administration period.  Vital signs will be monitored prior to administration, every 5-15 minutes 
during administration and in the immediate post administration period.  After administration, the 
IV will be flushed with IV fluid and then discontinued.  IV tubing, and any bottles or syringes 
used for administration of radiolabeled antibody will be counted post administration to ensure no 
excessive remaining activity in the tubing.  A special 1" Plexiglass and lead holder for a 60 cc 
syringe has been constructed for shielding of the syringe which will contain the administered 90Y 
antibody.  

 
 
APPENDIX II 
 
Percent Red Marrow in Irradiated Bone 
 
Anatomic Site 
Percent Total Red Marrow 
 
 
Head  
 
 
13.1 
 
Cranium 
 
 
12 
 
Mandible 
 
        1.1 
 
 
Upper Limbs 
8.3 
 
2 Humerus 
 
     2.0 
 
2 Scapulae 
 
     4.8 
 
2 Clavicles 
 
     1.5 
 
 
Sternum 
 
 
2.3 
 
 
Ribs  
 
 
7.9 
 
 
Vertebrae 
 
 
42.3 
 
Cervical 
 
     3.4 
 
Thoracic 
 
     14.1 
 
Lumbar 
 
     10.9 
 
Sacral  
 
     13.9 
 
 
Lower Limb Girdle  
26.1 
 
2 Os Coxae 
 
     22 
 
2 Femoral Head and neck       4 
 
 
From Phys. Med. Biol. 5:255, 1961. 
 
 
 
 

 
 
APPENDIX III 
 
 
KARNOFSKY PERFORMANCE SCALE 
 
 
100 
Normal; no complaints; no evidence of disease 
 
  90 
Able to carry on normal activity; minor signs or symptoms of disease 
 
  80 
Normal activity with effort; some sign or symptoms of disease 
 
  70 
Cares for self, unable to carry on normal activity or do active work 
 
  60 
Requires occasional assistance, but is able to care for most personal needs 
 
  50 
Requires considerable assistance and frequent medical care 
 
  40 
Disabled; requires special care and assistance 
 
  30 
Severely disabled; hospitalization is indicated, although death is not imminent 
 
  20 
Very sick; hospitalization necessary; active support treatment is necessary 
 
  10 
Moribund; fatal processes progressing rapidly 
 
    0 
Dead 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
 
APPENDIX IV. 
 
COMMON TOXICITY GRADING 
 
 
USE CTC VERSION 3.0 
 
http://ctep.cancer.gov/forms/CTCAEv3.pdf 
 
 
 
 
 
 
 
 
 
 
 

 
 
PHASE I TRACKING LOG FOR IRB #: _______________ 
 
Pt# 
Med Rec #c 
Name 
Dose* 
Level 
(Arm) 
Eval-
uable for 
DLT? 
> = Grade 
3? 
If Yes: 
Highest Grade (3,4) Toxicities  
Per Organ System During Cycles 
 used for MTD Evaluation 
DLT                               Non-DLT 
Decision 
Re: Next Pt’s Dose 
Level 
Reason for Decision 
(Complete for each 
patient) 
 
 
 
 
 
 
  Grd    Organ Sys         Grd     Organ Sys 
 
 
___  
________-___ 
L _____________ 
____ 
___Yes 
___Yes 
 ____   __________ 
____   __________ 
___ Same Dose 
_______________ 
 
 
F _____________ 
 
___ No 
___ No 
 ____   __________ 
____   __________ 
___ Escalate 
_______________ 
 
Date 
on-Study:  
 
 
 
 
 ____   __________ 
____   __________ 
___ De-escalate 
_______________ 
 
____/____/_____ 
 
 
 
 ____   __________ 
____   __________ 
___ MD Initials 
_______________ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  Grd    Organ Sys         Grd     Organ Sys 
 
 
___  
________-___ 
L _____________ 
____ 
___Yes 
___Yes 
 ____   __________ 
____   __________ 
___ Same Dose 
_______________ 
 
 
F _____________ 
 
___ No 
___ No 
 ____   __________ 
____   __________ 
___ Escalate 
_______________ 
 
Date 
on-Study:  
 
 
 
 
 ____   __________ 
____   __________ 
___ De-escalate 
_______________ 
 
____/____/_____ 
 
 
 
 ____   __________ 
____   __________ 
___ MD Initials 
_______________ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  Grd    Organ Sys         Grd     Organ Sys 
 
 
___  
________-___ 
L _____________ 
____ 
___Yes 
___Yes 
 ____   __________ 
____   __________ 
___ Same Dose 
_______________ 
 
 
F _____________ 
 
___ No 
___ No 
 ____   __________ 
____   __________ 
___ Escalate 
_______________ 
 
Date 
on-Study:  
 
 
 
 
 ____   __________ 
____   __________ 
___ De-escalate 
_______________ 
 
____/____/_____ 
 
 
 
 ____   __________ 
____   __________ 
___ MD Initials 
_______________ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  Grd    Organ Sys         Grd     Organ Sys 
 
 
___  
________-___ 
L _____________ 
____ 
___Yes 
___Yes 
 ____   __________ 
____   __________ 
___ Same Dose 
_______________ 
 
 
F _____________ 
 
___ No 
___ No 
 ____   __________ 
____   __________ 
___ Escalate 
_______________ 
 
Date 
on-Study:  
 
 
 
 
 ____   __________ 
____   __________ 
___ De-escalate 
_______________ 
 
____/____/_____ 
 
 
 
 ____   __________ 
____   __________ 
___ MD Initials 
_______________ 
 
 
 
 
 
 
 
 
 
 
 
1.1.1 
What is the waiting period for evaluating toxicities prior to entering the next patient?  _______________ 
  
* Dose Levels:  
1. 
 
2. 
                  
3. 
 
  4. 
 
  5. 
 
  6. 
 
 
7. 
 
8. 
 
9. 
 
10. 
 
11. 
 
12.