Clinical trial NCT01326871
Conditions: Transitional Cell Carcinoma of Bladder Urethra Cancer Ureter Cancer Malignant Tumor of Renal Pelvis
Keywords: cancer immunotherapy immunochemotherapy combinational therapy targeted metastatic muscle invasive interleukin-2 cisplatin gemcitabine antitumor TCR T-cell receptor p53 p53 gene p53 tumor supressor protein urothelial cancer bladder cancer renal pelvis cancer ureters cancer urethra cancer HLA-A2 positive HLA-A*0201/p53 aa264-272 HLA complex Muscle Invasive or Metastatic
Sponsor: Altor BioScience
Start date: 2011-09-06; Completion date: 2016-04-11
Enrollment: 68 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
This is a Phase Ib/II, open-label, multi-center, competitive enrollment and dose-escalation study of ALT-801 in a biochemotherapy regimen either containing cisplatin and gemcitabine or containing gemcitabine alone in patients who have muscle invasive or metastatic urothelial cancer of bladder, renal pelvis, ureters and urethra. The purpose of this study is to evaluate the safety, determine the maximum tolerated dose (MTD) and the recommended dose (RD), and assess the anti-tumor response of ALT-801 in combination with cisplatin and gemcitabine or ALT-801 in combination with gemcitabine alone. The pharmacokinetic profile of ALT-801 in combination with cisplatin and gemcitabine will also be assessed. The study includes a dose escalation phase (Phase Ib) and a dose expansion phase (Phase II). Phase II has two treatment groups, Expansion Group 1 and Expansion Group 2. Expansion Group 2 is for platinum-refractory patients, consisting of two treatment arms based on the patient's renal function. Patients will enroll to Expansion Group 2 after stage 1 of the Group 1 expansion is complete.

Detailed description:
Bladder cancer is the fourth most common malignancy in men and the ninth most common in women in the US, with an estimated 68,810 new cases and 14,070 deaths for the year 2008. Approximately 90% to 95% of newly diagnosed patients are with transitional cell carcinomas (TCC). Approximately 20% to 25% contain advanced (muscle invasive or metastatic) disease. Muscle invasive bladder cancer is life threatening. Clinical trials have demonstrated that TCC is a chemotherapy-sensitive malignancy. Most current cancer treatment strategies involve the use of chemotherapeutic or biological drugs that have a low therapeutic ratio. The limitations are a consequence of effects of the therapeutic drug on normal tissues. One approach to control systemic exposure effects is to target the drug itself into the site of the tumor. For example, antibodies have been developed for use as tumor targeting agents and have had success in the clinic. However, despite the promise of antibody-based immunotherapy, there are limitations with these class of reagents. Even so, immunotherapy remains a promising approach to treat cancer.

One strategy that has received attention is treatment with cytokines such as IL-2 to enhance anti-tumor immunity. IL-2 has stimulatory effects on a number of immune cell types including T and B cells, monocytes, macrophages, lymphokine-activated killer cells (LAK) and natural killer (NK) cells. Based on the ability of IL-2 to provide durable curative anti-tumor responses, systemic administration of IL-2 has been approved to treat patients with metastatic melanoma or renal carcinoma. Unfortunately, the considerable toxicity associated with this treatment makes it difficult to achieve an effective dose at the site of the tumor and limits the population that can be treated. Thus, there is critical need for innovative strategies that enhance the effects of IL-2, to reduce its toxicity without compromising the clinical benefit, and to treat other diagnoses.

The study drug, ALT-801, is a biologic compound of interleukin-2 (IL-2) genetically fused to a humanized soluble T-cell receptor directed against the p53-derived peptides expressed on tumor cells. The p53 protein is one of the most important factors that protects from developing cancer and is also one of the most frequently mutated genes in many cancers, which include muscle-invasive bladder cancer. For any given cancer type, p53 dysfunction generally correlates with poor prognosis versus other the same site-of-origin. In some tumors, p53 mutation and over-expression also is associated with resistance to chemotherapy. This study is to further evaluate whether directing IL-2 activity using ALT-801 to the patient's tumor sites that over-express p53 results in clinical benefits

Arms: arm 1: None arm 2: None arm 3: None
Interventions: intervention 1: Cisplatin intervention 2: Gemcitabine intervention 3: ALT-801
Intervention descriptions: intervention 1: Intravenous infusion; 3 initial treatment courses and an additional 3 maintenance courses for responders (maintenance revised for Phase II): on day 1 of each course (if given) intervention 2: Intravenous infusion; 3 initial treatment courses and an additional 3 maintenance courses for responders (maintenance revised for Phase II); on day 1 and 8 of each course intervention 3: Intravenous infusion; 3 initial treatment courses and an additional 3 maintenance courses for responders (maintenance revised for Phase II): on day 3, 5, 8, and 12 of each course

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
CLINICAL STUDY PROTOCOL 
 
 
Protocol Number: 
CA-ALT-801-01-10 
 
 
Protocol Title: 
A Phase Ib/II Trial of ALT-801 in Combination 
with Cisplatin and Gemcitabine in Muscle 
Invasive or Metastatic Urothelial Cancer  
 
 
 
Date of Protocol: 
 
Version # 01 
  
October 31, 2010 
 
 
 
 
 
  
Sponsor Contact: 
 
Hing C. Wong, Ph.D. 
Altor Bioscience Corporation. 
Miramar, Florida 33025 
Telephone: 
954-443-8600 
Safety Data Fax: 
954-443-8602 
 
 
 


   
 
 
 
INVESTIGATOR SIGNATURE PAGE 
 
Protocol Number: 
CA-ALT-801-01-10 
 
 
Protocol Title: 
A Phase Ib/II Trial of ALT-801 in Combination 
with Cisplatin and Gemcitabine in Muscle 
Invasive or Metastatic Urothelial Cancer 
 
 
Date of Protocol: 
 
Version# 01 
  
October 31, 2010 
 
 
 
 
 
  
Sponsor Contact: 
 
Hing C. Wong, Ph.D. 
Altor Bioscience Corporation. 
Miramar, Florida 33025 
Telephone: 
954-443-8600 
Safety Data Fax: 
954-443-8602 
 
 
 
By my signature below, I hereby attest that I have read, and that I understand and will abide by 
all the conditions, instructions, and restrictions contained in the attached protocol. 
 
Additionally, I will not initiate this study without approval of the appropriate Institutional 
Review Board (IRB), and I understand that any changes in the protocol must be approved in 
writing by the sponsor, the IRB, and, in certain cases the FDA, before they can be implemented, 
except where necessary to eliminate hazards to subjects. 
 
 
 
 
 
Principal Investigator’s Signature 
 
Date 
 
 
 
 
 
 
 
 
 
Principal Investigator’s Name (Print) 
 
 
 
 
 
 
 
 
 
 
 


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Table of Contents 
SYNOPSIS ........................................................................................................................................ 7 
1. 
OBJECTIVES ........................................................................................................................ 12 
1.1 
PRIMARY OBJECTIVES ....................................................................................................... 12 
1.2 
SECONDARY OBJECTIVES .................................................................................................. 12 
2. 
BACKGROUND .................................................................................................................... 12 
2.1 
ALT-801 – GENERAL INFORMATION ................................................................................ 12 
2.2 
BLADDER CANCER ............................................................................................................ 12 
2.3 
IMMUNOTHERAPY ............................................................................................................. 13 
2.4 
INTRATUMORAL TARGETING AND P53 AS A TARGET FOR BIOTHERAPY .............................. 13 
2.5 
P53 AS A THERAPEUTIC TARGET FOR BLADDER CANCER .................................................... 15 
2.6 
IN VITRO CHARACTERIZATION AND TUMOR EFFICACY STUDIES IN ANIMAL MODELS .......... 15 
2.7 
NON-CLINICAL TOXICOLOGY ............................................................................................ 16 
2.7.1 
Single-dose toxicity study ......................................................................................... 16 
2.7.2 
Multi-dose toxicity study .......................................................................................... 17 
2.8 
PHARMACOKINETICS ......................................................................................................... 17 
2.8.1 
Non-clinical pharmacokinetics ................................................................................ 17 
2.8.2 
Clinical pharmacokinetics ....................................................................................... 18 
2.9 
HUMAN EXPERIENCE ......................................................................................................... 18 
2.9.1 
Pharmacodynamics .................................................................................................. 18 
2.9.2 
Tumor assessment .................................................................................................... 19 
2.9.3 
Safety results ............................................................................................................ 20 
2.9.4 
Repeat treatment ...................................................................................................... 21 
3. 
RATIONAL FOR THE CURRENT STUDY ...................................................................... 21 
4. 
OVERALL STUDY DESIGN ............................................................................................... 23 
5. 
STUDY POPULATION ........................................................................................................ 24 
5.1 
INCLUSION CRITERIA ......................................................................................................... 24 
5.2 
EXCLUSION CRITERIA ........................................................................................................ 25 
5.3 
INCLUSION OF WOMEN AND MINORITIES............................................................................ 25 
6. 
STUDY DESIGN .................................................................................................................... 26 
6.1 
STUDY FLOW DIAGRAM ..................................................................................................... 26 
6.2 
SCREENING AND ENROLLMENT ......................................................................................... 26 
6.2.1 
Preliminary screening .............................................................................................. 26 
6.2.2 
Comprehensive screening & enrollment .................................................................. 27 
6.3 
STUDY TREATMENT........................................................................................................... 27 
6.3.1 
Treatment setting ..................................................................................................... 27 
6.3.2 
Treatment regimen ................................................................................................... 27 
TREATMENT DAY ...................................................................................................................... 27 
6.3.3 
Pre-therapy interventions ........................................................................................ 28 
6.3.3.1. 
Pre-medication and IV fluids for ALT-801 ..................................................... 28 


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6.3.3.2. 
Pre-medication and IV fluids for cisplatin ....................................................... 28 
6.3.3.3. 
Pre-medication and IV fluids for gemcitabine ................................................. 28 
6.3.4 
Study drug preparation and administration ............................................................ 29 
6.3.4.1. 
ALT-801 .......................................................................................................... 29 
6.3.4.2. 
Cisplatin ........................................................................................................... 29 
6.3.4.3. 
Gemcitabine ..................................................................................................... 29 
6.4 
DURATION OF PATIENT PARTICIPATION ............................................................................. 29 
6.5 
DOSE ESCALATION ............................................................................................................ 29 
6.6 
EXPANSION AT MTD ........................................................................................................ 29 
6.7 
STOPPING RULES ............................................................................................................... 30 
6.8 
PATIENT MONITORING, ANTI-TUMOR RESPONSE EVALUATION, SURVIVAL ASSESSMENT .... 30 
6.9 
TREATMENT DISCONTINUATION ........................................................................................ 31 
6.9.1 
Treatment discontinuation events ............................................................................ 31 
6.9.1.1. 
Any serious adverse event ............................................................................... 31 
6.9.1.2. 
Cardiac Arrhythmia, Ischemia/Infarction ........................................................ 31 
6.9.1.3. 
Hypotension ..................................................................................................... 31 
6.9.1.4. 
Kidney dysfunction .......................................................................................... 31 
6.9.1.5. 
Blood count ...................................................................................................... 32 
6.9.1.6. 
Allergic reactions and cytokine release syndrome/acute infusion reaction ..... 32 
6.9.1.7. 
Lymphopenia and Neutropenia ........................................................................ 32 
6.9.1.8. 
Other grade 3/4 adverse events ........................................................................ 32 
6.9.1.9. 
Other events ..................................................................................................... 32 
6.9.1.10. 
Oncological surgeries post study drug treatment ............................................. 33 
6.9.2 
Follow-ups after treatment discontinuation............................................................. 33 
6.9.2.1. 
Discontinuation due to SAEs or on-going study drug related AEs ................. 33 
6.9.2.2. 
Discontinuation due to any other reasons ........................................................ 33 
6.10 
SECOND AND THIRD COURSES OF STUDY TREATMENT ....................................................... 33 
6.10.1 
Qualification ............................................................................................................ 33 
6.10.2 
Treatment schedule and procedures ........................................................................ 33 
6.11 
GENERAL SUPPORTIVE CARE GUIDELINES AND DRUG INTERACTION .................................. 33 
6.11.1 
ALT-801 ................................................................................................................... 33 
6.11.1.1. 
Hypotension and capillary leak syndrome ....................................................... 34 
6.11.1.2. 
Pulmonary dysfunction .................................................................................... 34 
6.11.1.3. 
Impaired kidney and liver functions ................................................................ 34 
6.11.1.4. 
Infection ........................................................................................................... 34 
6.11.1.5. 
Fever and chills ................................................................................................ 35 
6.11.1.6. 
Gastritis ............................................................................................................ 35 
6.11.1.7. 
Diarrhea, nausea and vomiting ........................................................................ 35 
6.11.1.8. 
Pruritus and dermatitis ..................................................................................... 35 
6.11.1.9. 
Acidosis............................................................................................................ 35 
6.11.1.10. Life-threatening toxicities ................................................................................ 35 
6.11.1.11. Other supportive care ....................................................................................... 35 
6.11.1.12. Drug interaction ............................................................................................... 35 
6.11.2 
Cisplatin ................................................................................................................... 36 
6.11.3 
Gemcitabine ............................................................................................................. 36 


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7. 
STUDY DRUG: AVAILABILITY, ACCOUNTABILITY, PACKAGING & 
LABELING .................................................................................................................................... 37 
7.1 
ALT-801 .......................................................................................................................... 37 
7.1.1 
Availability ............................................................................................................... 37 
7.1.2 
Accountability .......................................................................................................... 37 
7.1.3 
Packaging ................................................................................................................ 37 
7.1.4 
Labeling ................................................................................................................... 37 
7.2 
CISPLATIN AND GEMCITABINE .......................................................................................... 37 
8. 
STUDY CALENDAR, CLINICAL PROCEDURES & TESTS ........................................ 38 
8.1 
STUDY CALENDAR ............................................................................................................ 38 
8.2 
PROCEDURES AND TESTS ................................................................................................... 39 
8.2.1 
HLA-A2 typing ......................................................................................................... 39 
8.2.2 
Presentation of HLA-A*0201/p53 aa264-272 complexes on tumor surfaces .......... 39 
8.2.3 
Medical history ........................................................................................................ 39 
8.2.4 
Pregnancy test .......................................................................................................... 39 
8.2.5 
Physical examination ............................................................................................... 39 
8.2.6 
Vital signs & body weight ........................................................................................ 39 
8.2.7 
Cardiac assessment .................................................................................................. 39 
8.2.8 
Blood tests ................................................................................................................ 39 
8.2.9 
Urinalysis ................................................................................................................. 40 
8.2.10 
Pulmonary functions ................................................................................................ 40 
8.2.11 
Adverse event assessment ........................................................................................ 40 
8.2.12 
Tumor assessment .................................................................................................... 40 
8.2.13 
Survival assessment ................................................................................................. 40 
8.2.14 
Pharmacokinetic (PK) testing .................................................................................. 40 
8.2.15 
Biomarker assays for INFγ and TNFα .................................................................... 41 
8.2.16 
Immunogenicity tests - detection of anti-ALT-801 and IL2-neutralizing antibodies
 
41 
9. 
MEASUREMENT OF EFFECT .......................................................................................... 41 
9.1 
DEFINITIONS ..................................................................................................................... 41 
9.1.1 
Measurable disease .................................................................................................. 41 
9.1.2 
Non-measurable disease .......................................................................................... 42 
9.1.3 
Target lesion ............................................................................................................ 42 
9.1.4 
Non-target lesions .................................................................................................... 43 
9.2 
GUIDELINES FOR EVALUATION OF MEASURABLE DISEASE ................................................. 43 
9.3 
RESPONSE CRITERIA .......................................................................................................... 44 
9.3.1 
Evaluation of target lesions ..................................................................................... 44 
9.3.2 
Evaluation of non-target lesions .............................................................................. 44 
9.3.3 
Evaluation of best overall response ......................................................................... 44 
9.4 
CONFIRMATORY ................................................................................................................ 45 
10. 
STATISTICAL ANALYSIS ............................................................................................. 45 
10.1 
STUDY OBJECTIVES ........................................................................................................... 45 
10.2 
SAMPLE SIZE ..................................................................................................................... 45 


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10.3 
DATA COLLECTION ........................................................................................................... 46 
10.4 
DATA ANALYSIS ................................................................................................................ 46 
10.4.1 
Analysis of safety...................................................................................................... 46 
10.4.2 
Analysis of response ................................................................................................. 47 
10.4.3 
Pharmacokinetics ..................................................................................................... 47 
11. 
REGULATORY AND REPORTING REQUIREMENTS ............................................ 47 
11.1 
ADVERSE EVENTS RECORDING, REPORTING AND COMMUNICATION .................................. 47 
11.2 
ADVERSE EVENT TERMINOLOGY AND DEFINITIONS ........................................................... 48 
11.3 
ADVERSE EVENT REPORTING PROCEDURES ...................................................................... 49 
11.4 
ADVERSE EVENT EXPEDITED REPORTING GUIDELINES ..................................................... 49 
11.5 
SUBMISSION OF SERIOUS ADVERSE EVENT REPORTING ...................................................... 49 
11.6 
DATA REPORTING FORMS ................................................................................................. 50 
11.7 
REPORT /DATA SUBMISSION ADDRESS & CONTACT ........................................................... 50 
11.8 
PATIENT RECORDS, QUALITY ASSURANCE, RECORDS RETENTION ...................................... 51 
11.9 
METHOD OF REVIEW ......................................................................................................... 51 
11.10 
SPECIAL REGULATORY CONSIDERATIONS ...................................................................... 51 
11.10.1 
HIPAA .................................................................................................................. 51 
11.10.2 
Protocol amendments, informed consent, and IRB approval .............................. 52 
12. 
CONFIDENTIALITY ....................................................................................................... 52 
13. 
ETHICAL STANDARDS & INVESTIGATOR OBLIGATIONS ................................ 52 
14. 
LIST OF EXPECTED ADVERSE EVENTS .................................................................. 52 
15. 
CTCAE................................................................................................................................ 55 
REFERENCES ............................................................................................................................... 56 
APPENDIX A: PERFORMANCE STATUS CRITERIA.......................................................... 59 
APPENDIX B: NEW YORK HEART ASSOCIATION CLASSIFICATION ......................... 59 
APPENDIX C: ETHICAL STANDARDS ................................................................................... 60 
APPENDIX D: INVESTIGATOR OBLIGATIONS .................................................................. 61 
APPENDIX E: CONTACT LIST - ALTOR ............................................................................... 65 
APPENDIX F: CONTACT LIST – DATA SAFETY MONITORING BOARD (DSMB) ...... 66 
APPENDIX G: CONTACT LIST - LABORATORIES ............................................................. 66 
APPENDIX H: APPROVAL PAGE ............................................................................................ 67 


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SYNOPSIS 
Sponsor: 
Altor Bioscience Corporation 
Protocol#: 
CA-ALT-801-01-10 
Study Drug Name: Not applicable 
Study Treatment 
Active agents: 
ALT-801 (c264scTCR-IL2), recombinant humanized, soluble single-chain 
TCR-cytokine fusion protein; Cisplatin; Gemcitabine. 
Study Type: 
Interventional 
Study Phase: 
Ib/II 
Protocol Title: 
A Phase Ib/II Trial of ALT-801 in Combination with Cisplatin and 
gemcitabine in Muscle Invasive or Metastatic Urothelial Cancer 
Objectives:   
To determine the safety and tolerability of the novel combination of addition 
of ALT-801 (c264scTCR-IL2) to the doublet of cisplatin and gemcitabine in 
patients with muscle invasive or metastatic urothelial cancer of bladder, 
renal pelvis, ureters and urethra.   
To estimate the anti-tumor activity of this combination of ALT-801, 
cisplatin and gemcitabine by radiologic or pathologic anti-tumor response; 
progression free survival (assessed through end of study); and overall 
survival (assessed through end of study) in treated patients.  
To characterize the pharmacokinetic profile of ALT-801 in combination 
with cisplatin and gemcitabine in treated patients. 
Study Design: 
This is a Phase Ib/II, open-label, multi-center, competitive enrollment and 
dose-escalation study of ALT-801 in a biochemotherapy regimen containing 
cisplatin and gemcitabine in patients who have muscle invasive or metastatic 
urothelial cancer of bladder, renal pelvis, ureters and urethra, who are HLA-
A2 positive by serological typing or genotyping and whose tumors present 
the HLA-A*0201/p53 aa264-272 complex.  The study will be conducted in 
conformity with Good Clinical Practice (GCP).  
The study includes a dose escalation phase to determine the maximum 
tolerated dose (MTD) of ALT-801 in combination with cisplatin and 
gemcitabine and a two-stage expansion phase at the MTD.  The dose 
escalation in this study is conducted using a (3+3) dose escalation design, 
and the two-stage expansion phase at the MTD using a modified Simon two-
stage design (1, 2).  In the dose escalation phase of this study, there are three 
dose levels of ALT-801 (0.04 mg/kg, 0.06 mg/kg and 0.08 mg/kg, in 
addition to two de-escalation dose levels).  The doses of cisplatin (75 
mg/m2/dose, day 1) and gemcitabine (1000 mg/m2/dose, day 1 & 8) will be 
fixed across all ALT-801 dose levels.  If the MTD is not reached during the 
dose escalation phase, the sponsor, the Data Safety Monitoring Board and 
the principal investigators will meet to discuss whether to amend the 
protocol to expand the dose escalation phase to include additional ALT-801 
dose levels.  


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Treatments: 
The planned on-study treatment duration will be for 3 courses.  Each course 
consists of cisplatin (Day #1), gemcitabine (Day #1), ALT-801 (Day #3 & 
Day #5), gemcitabine (Day #8), ALT-801 (Day #8 & Day #10), and a rest 
period (Days #11-21).  Delays or modifications are addressed in the 
protocol. This is illustrated in this schema: 
 
 
Course1 
Course 2 
Course 3 
Treatment Day 
1 
3 
5 
8 10 11-21 22 24 26 29 31 32-42 43 45 47 50 52 53-63 
Cisplatin 
X 
 
 
 
 
Rest 
Period 
X 
 
 
 
 
Rest 
Period 
X 
 
 
 
 
Rest 
Period 
Gemcitabine 
X 
 
 
X 
 
X 
 
 
X 
 
X 
 
 
X 
 
ALT-801 
 
X X X X 
 
X 
X 
X X 
 
X 
X X X 
Prior to commencing the second or the third course, subjects will need to 
meet the continuation criteria. Enrolled patients will receive the study 
treatment at qualified cancer treatment centers with adequate diagnostic and 
treatment facilities to provide appropriate management of therapy and 
complications. The ALT-801, the cisplatin and gemcitabine will be 
administered by intravenous infusion into a central or peripheral vein under 
the supervision of a qualified physician experienced in the use of anti-cancer 
agents including aldesleukin (Proleukin), cisplatin and gemcitabine. 
This is the schema for the dose levels during the dose-escalation phase of the 
study.  The -1 and -2 dose levels of ALT-801 are included in case of DLT 
events in the initial dose level.  
Cohort 
ALT-801 Dose (mg/kg) 
Cisplatin  (mg/m2) 
Gemcitabine (mg/m2) 
-2 
0.01 
75 
1000 
-1 
0.02 
75 
1000 
1 (initial) 
0.04 
75 
1000 
2 
0.06 
75 
1000 
3 
0.08 
75 
1000 
Dose Escalation: 
In this phase of the study, a minimum of 3 patients will be enrolled at each 
dose level.  All patients will be monitored for Dose Limiting Toxicity (DLT) 
for 8 weeks from the initial dose.  If 0/3 patients have drug-related, dose-
limiting toxicity by 8 weeks after the initial dose, the next cohort will be 
opened for enrollment. If one patient at a dose-level develops drug-related 
DLT, up to six patients will be enrolled at that dose level and each 
subsequent higher dose level.  If 0 or 1 of 6 patients in a cohort of 6 patients 
have an event that meets criteria for treatment-related DLT, then the next 
cohort will be opened for enrollment. If 2 or more out of 3-6 patients in a 
dose escalation cohort have a DLT that is drug-related, that dose level will 
be designated as exceeding the maximum tolerated dose. If there are 3 
patients in the dose level below this level, then additional patients (up to 6 
total) will be enrolled at that dose level. When there is a dose level with 0 or 
1 out of 6 patients with DLT, which is either the maximum planned dose 
level (level 3) or which is one level below a dose that was not tolerated, the 
dose that is the maximum tolerated dose will be considered defined. Further 


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changes in the treatment plan may be considered by protocol amendment at 
that point. 
If more than two of six patients experience a DLT at the initial dose level 
(level 1), then the sponsor, the Data Safety Monitoring Board and the 
principal investigators will meet to determine how to adjust downward the 
dose level of cisplatin, gemcitabine, and/or the study drug, or continue with 
the (-1) and (-2) cohorts, and to determine how to proceed with the study.  
A DLT is any toxicity that results in study treatment discontinuation and 
includes definitions below.  Study treatment discontinuation due to adverse 
events experienced prior to study drug administration, disease progression or 
patient’s decision to withdraw from the study treatment without occurrence 
of any study treatment discontinuation event will not necessarily define a 
DLT event.  Study treatment discontinuation events are defined in the 
protocol.  
Dose Expansion: 
The two-stage expansion phase at the MTD will be conducted using a 
modified Simon two-stage design (1, 2).  Both objective response (OR) 
(defined as complete response (CR) + partial response (PR)) and clinical 
benefit (CB) (defined as CR, PR + stable disease (SD)) will be evaluated and 
common set thresholds of lack of efficacy (OR rate (ORR) = 40%; CB rate 
(CBR) = 78%) and an efficacy level of interest (ORR = 60%; CBR = 92%) 
will be selected.  The sample size was driven by the parameter that had the 
larger sample size for each stage.      
Stopping Rule: 
The patient enrollment will be temporarily suspended based on occurrence 
of any the following, and the sponsor, the Data Safety Monitoring Board and 
principal investigators will meet to discuss how to proceed with future 
patient enrollment in the study: 
• 
If at any time the dose escalation phase of the study, more than one 
patient in a cohort of three, or two of six patients experience any DLT; 
• 
If at any time during the expansion phase of the study, more than 33% 
the patients experience any drug related DLT. 
Evaluations: 
Patients will be evaluated for clinical toxicities during the treatment.  
Patients’ blood samples will be collected to assess the pharmacokinetic 
profile and immunogenicity of the study drug. The anti-tumor response will 
be evaluated for up to 12 weeks from the initial dose of the first course of 
treatment.  All patients who receive at least one dose of the study drug ALT-
801 will be included in the anti-tumor response evaluation.  Between each 
cohort and at the end of the study, all clinical and safety data will be 
analyzed for all patients enrolled in the study for dose-response effects. 
Population: 
Patients of 18 years of age and above who are candidates for systemic 
cisplatin and gemcitabine for the treatment of muscle invasive or metastatic 
urothelial cancer of bladder, renal pelvis, ureters, and urethra, who are HLA-
A2 positive by serological typing or  genotyping and whose tumors present 
HLA-A*0201/p53 aa264-272 complexes (as detected by sponsor-provided 
test on tumor biopsy or surgically removed tumor samples) may be selected 


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for further evaluation of eligibility for study participation.  Patients also need 
to have adequate cardiac, pulmonary, liver and kidney functions and to have 
an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 
1 and a life expectancy of at least 12 weeks.  
Sample Size: 
A total of up to 30 assessable patients will be accrued to the initial dose 
escalation phase of the study (Phase Ib); the estimated number is 15.  Up to an 
additional 40 assessable patients will be enrolled at the expansion phase 
(Stage 1 and 2) of the study (Phase II).  A total of approximately 58 
assessable patients will be enrolled and complete the study.  Assume a 20% 
ineligible or non- assessable cases, a total of up 70 patients may be accrued 
to the study. 
Primary 
Endpoints: 
For Stage I only: 
(1) To define an MTD of ALT-801 in combination with cisplatin and 
gemcitabine in the treatment of patients with muscle invasive or 
metastatic urothelial cancer. 
For Stage I & II: 
(2) To assess the safety of the combination study treatment in treated 
patients. 
 
(3) To assess the objective response rate in treated patients. 
Secondary  
Endpoints: 
(1) To assess the progression free survival in treated patients. 
(2) To assess the overall survival in treated patients. 
(3) To evaluate the immugonenicity and pharmacokinetic profile of ALT-
801 in treated patients. 
Pharmacokinetics 
& Biomarkers: 
Blood samples for pharmacokinetic analysis of ALT-801 will be taken on  
the first day of ALT-801 administration in the first course of study 
treatment. Venous blood will be obtained at Time 0 (before the start of 
infusion), at 30 min (completion of drug infusion), and 1, 3 and 6 hours from 
Time 0 for the assessment of ALT-801 serum concentration. Non-
compartmental and compartmental analyses will be conducted.  In addition, 
the same blood samples collected for PK analysis will be used to assess the  
serum levels of INF-γ and TNF-α. 
Monitoring Tests: Urine samples for urinalysis, blood samples for standard chemistry, CBC, 
differential and coagulation will be obtained at screening, on each study drug 
infusion day, discharge days and follow-up visits.  Blood samples for 
immunogenicity testing, which include assays for anti-ALT-801 and IL-2 
neutralizing antibodies, will be collected prior to dosing on the first ALT-
801 infusion day and at Week 9 from the initial dose of study treatment. 
Anti-tumor  
Response 
Evaluation: 
The anti-tumor response will be evaluated at Week 9 and Week 13 from the 
initial dose of study treatment. Objective Response will be evaluated using 


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the new international criteria proposed by the Response Evaluation Criteria 
in Solid Tumors Committee (RECIST) 1.1.  Baseline evaluations should be 
performed up to 28 days before starting study treatment. Imaging-based 
evaluation is preferred to evaluation by clinical examination when both 
methods have been used to assess the anti-tumor effect of the treatment.  
However, cystoscopic evaluation may be used routinely in this population, in 
addition to radiologic testing. 
Survival  
Assessment: 
Progression-free survival and overall survival of all enrolled patients will be 
assessed at 3, 6, 9, 12, 18, 24, 30 and 36 months from the start of study 
treatment, or through the point designated as the end of the study follow up. 
Adverse Events: 
All patients will be monitored and evaluated for clinical toxicities during the 
treatment period and queried at each follow-up visit for Adverse Events 
(AEs).  Patients may volunteer information concerning AEs.  All adverse 
events will be graded by using the NCI Common Terminology Criteria for 
Adverse Events version 4.0 (CTCAE v4.0), and logged in the patient Case 
Report Form.  The study centers should report all SAEs and all events that 
trigger patient’s study treatment discontinuation to the sponsor via phone, 
fax or email (or a combination) up to 1 day after learning of the event.  The 
sponsor will use the information to manage and coordinate the dose 
escalation, cohort expansion and patient enrollment.  The sponsor will then 
inform all of the participating clinical sites of the current dose level and the 
number of patients to be enrolled at that level, or of any patient enrollment 
suspension via phone, fax or email within a day of its learning of the event.  
The study centers should report the other adverse events to the sponsor 
following the guidelines defined in the study protocol. All study drug related 
adverse events (AEs) that are both serious and unexpected will be reported 
to the FDA in an expedited manner in accordance with 21 CFR §312.32. 
Statistical Plan: 
For each cohort, all AEs will be tabulated and examined and all safety and 
pharmacokinetic data will be evaluated. For estimation of duration of 
response, the Kaplan-Meier method will be used. P-values of <0.05 (two-
sided) will be considered to indicate statistical significance.   


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8. 
STUDY CALENDAR, CLINICAL PROCEDURES & TESTS 
8.1 
Study calendar 
 
 
1Authorization of the Part I Informed Consent is required before obtaining patients’ blood and tumor samples for HLA-A2 blood typing and HLA-A*0201/p53 aa264-
272 tumor typing.    2  Only patients with positive test result on HLA A2 blood typing will continue on the HLA-A*0201/p53 aa264-272 tumor 
typing. 3Only patients with positive results on HLA A2 blood typing and HLA-A*0201/p53 aa264-272 tumor typing will continue on the further 
screening procedures and have the possibility of being enrolled in the study.   4Any previous HLA A2 blood typing result, from serological or 
DNA-based typing, and HLA-A*0201/p53 aa264-272 tumor typing result can be used for screening.   5Screening evaluations are performed < 14 
days, scan/x-ray < 28 days prior to start of therapy.  If the patient's condition is deteriorating, laboratory evaluations should be repeated within 48 
hours prior to initiation of study treatment infusion.  6Pregnancy test is for women with childbearing potential only.  7Vital signs (especially blood 
pressure), clinical status and laboratory tests should be reviewed before start of therapy. Vital signs will be evaluated every 2 hours after the drug 
treatment and before discharge, and body weight before the study treatment infusion on study treatment infusion day. 8Patients are closely 
monitored for hypotension, arrhythmia, angina and myocardial infarction. At screening, patients who are ≥ 50 years of age or have a history of 
EKG abnormalities, symptoms of cardiac ischemia or arrhythmia will have a stress test (stress thallium, stress MUGA or dobutamine 
echocardiogram) to determine their eligibility for participation in the study. EKG will be performed at start of each treatment cycle.  9Patients who 
have an on-going study drug-related SAE upon study completion or at discontinuation of the study will be contacted by the investigator or his/her 
designee every week until the event is resolved or determined to be irreversible. 10Tumor response and progression will be evaluated in this study 
using the new international criteria proposed by the RECIST (1.1) Committee.    11Performed at Course #1 only. Collect blood samples at Time 0 
(before drug infusion), at 30 min (+/- 5 min), 1 hour (+/- 10 min), 3 hour (+/- 30 min), 6 hour (+/- 60 min) from Time 0. INFγ and TNFα assays 
are performed using the same samples and at the same schedule as PK.  12Performed at Course #1 only and before dosing. 13Residual samples may 
be used by Sponsor for research studies of other biomarkers. .  14Information about tumor assessment & other therapies received after completion 
of study treatment will be collected if available. 
TESTS & PROCEDURES 
Pre 
Screen Screen5 
TREATMENT PERIOD 
For Course 1-3 
FOLLOW-UP PERIOD  
MONTH 
 
 
 
 
3 
6 
9 12 18 24  30 36 
WEEK (Course 2 in parenthesis) 
         {Course 3 in brackets} 
 
 
1 (4){7} 
2(5){8}  
3 (6) 
9 12 
 
 
 
 
 
 
 
STUDY DAY (Course 2 in parenthesis) 
                   {Course 3 in brackets} 
 
 
1 
(22) 
{43} 
3 
(24) 
{45} 
5 
(26) 
{47} 
8 
(29) 
{50} 
10 
(31) 
{52} 
 
 
 
 
 
R 
 
E 
 
S 
 
T 
 
 
 
P 
 
E 
 
R 
 
I 
 
O 
 
D 
 
 
  
  
  
  
 
 
 
 
 
 
 
 
 
Informed consent PART I1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent PART II 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HLA A2 Typing2, 4 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HLA-A*0201/p53 aa264-272 tumor typing3,  4 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum pregnancy test6 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Complete physical exam 
 
X 
X 
 
 
 
 
X X 
 
 
 
 
 
 
 
Vital signs, weight, Height7 
 
X 
X 
X 
X 
X 
X 
X X 
 
 
 
 
 
 
 
Concurrent medication 
 
X 
X 
X 
X 
X 
X 
X X 
 
 
 
 
 
 
 
Blood tests: CBC with Differential, Blood 
Chemistry & Coagulation 
 
X 
X 
X 
X 
X 
X 
X X 
 
 
 
 
 
 
 
Urinalysis 
 
X 
X 
X 
X 
X 
X 
X X 
 
 
 
 
 
 
 
Cardiac functions8 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
Pulmonary functions 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse event assessment9 
 
X 
X 
X 
X 
X 
X 
X X 
 
 
 
 
 
 
 
Tumor assessment10 
 
X 
 
 
 
 
 
X X 
 
 
 
 
 
 
 
Survival Assessment14 
 
 
 
 
 
 
 
 
 
X 
X X X X X X 
PK11, INFγ11, TNFα11,13 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Immunogenicity tests13 
 
  
X 12 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Cisplatin therapy 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Gemcitabine therapy 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Study drug administration 
 
 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 




 
 
 
CLINICAL STUDY PROTOCOL 
 
 
Protocol Number: 
CA-ALT-801-01-10 
 
 
Protocol Title: 
A Phase Ib/II Trial of ALT-801 in Combination 
with Cisplatin and Gemcitabine in Muscle 
Invasive or Metastatic Urothelial Cancer  
 
 
 
Date of Protocol: 
 
Version # 01Version # 02 
 
October 31, 2010 
July 8, 2011 
 
 
 
 
Sponsor Contact: 
 
Hing C. Wong, Ph.D. 
Altor Bioscience Corporation. 
Miramar, Florida 33025 
Telephone: 
954-443-8600 
Safety Data Fax: 
954-443-8602 
 
 
 


   
 
 
 
INVESTIGATOR SIGNATURE PAGE 
 
Protocol Number: 
CA-ALT-801-01-10 
 
 
Protocol Title: 
A Phase Ib/II Trial of ALT-801 in Combination 
with Cisplatin and Gemcitabine in Muscle 
Invasive or Metastatic Urothelial Cancer 
 
 
Date of Protocol: 
 
Version# 01 
Version# 02 
October 31, 2010 
July 8, 2011 
 
 
 
 
Sponsor Contact: 
 
Hing C. Wong, Ph.D. 
Altor Bioscience Corporation. 
Miramar, Florida 33025 
Telephone: 
954-443-8600 
Safety Data Fax: 
954-443-8602 
 
 
 
By my signature below, I hereby attest that I have read, and that I understand and will abide by 
all the conditions, instructions, and restrictions contained in the attached protocol. 
 
Additionally, I will not initiate this study without approval of the appropriate Institutional 
Review Board (IRB), and I understand that any changes in the protocol must be approved in 
writing by the sponsor, the IRB, and, in certain cases the FDA, before they can be implemented, 
except where necessary to eliminate hazards to subjects. 
 
 
 
 
 
Principal Investigator’s Signature 
 
Date 
 
 
 
 
 
 
 
 
 
Principal Investigator’s Name (Print) 
 
 
 
 
 
 
 
 
 
 
 


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Table of Contents 
SYNOPSIS ........................................................................................................................................ 7 
1. 
OBJECTIVES ........................................................................................................................ 13 
1.1 
PRIMARY OBJECTIVES ....................................................................................................... 13 
1.2 
SECONDARY OBJECTIVES .................................................................................................. 13 
2. 
BACKGROUND .................................................................................................................... 13 
2.1 
ALT-801 – GENERAL INFORMATION ................................................................................ 13 
2.2 
BLADDER CANCER ............................................................................................................ 13 
2.3 
IMMUNOTHERAPY ............................................................................................................. 14 
2.4 
INTRATUMORAL TARGETING AND P53 AS A TARGET FOR BIOTHERAPY .............................. 14 
2.5 
P53 AS A THERAPEUTIC TARGET FOR BLADDER CANCER .................................................... 16 
2.6 
IN VITRO CHARACTERIZATION AND TUMOR EFFICACY STUDIES IN ANIMAL MODELS .......... 16 
2.6.1 
Efficacy evaluation of ALT-801 dose regimens in xenograft tumor models ............ 17 
2.6.2 
Efficacy of ALT-801 and non-targeted scTCR/IL-2 fusion proteins against 
subcutaneous xenograft tumors derived from human urothelial cancer cells. ........................ 18 
2.6.3 
Activity of ALT-801 against human p53-negative orthotropic murine bladder 
tumors in immunocompetent mice. .......................................................................................... 19 
2.7 
NON-CLINICAL TOXICOLOGY ............................................................................................ 20 
2.7.1 
Single-dose toxicity study ......................................................................................... 20 
2.7.2 
Multi-dose toxicity study .......................................................................................... 20 
2.8 
PHARMACOKINETICS ......................................................................................................... 21 
2.8.1 
Non-clinical pharmacokinetics ................................................................................ 21 
2.8.2 
Clinical pharmacokinetics ....................................................................................... 21 
2.9 
HUMAN EXPERIENCE ......................................................................................................... 22 
2.9.1 
Pharmacodynamics .................................................................................................. 22 
2.9.2 
Tumor assessment .................................................................................................... 22 
2.9.3 
Safety results ............................................................................................................ 23 
2.9.4 
Repeat treatment ...................................................................................................... 24 
3. 
RATIONALE FOR THE CURRENT STUDY ................................................................... 24 
4. 
OVERALL STUDY DESIGN ............................................................................................... 25 
5. 
STUDY POPULATION ........................................................................................................ 27 
5.1 
INCLUSION CRITERIA ......................................................................................................... 27 
5.2 
EXCLUSION CRITERIA ........................................................................................................ 28 
5.3 
INCLUSION OF WOMEN AND MINORITIES............................................................................ 28 
6. 
STUDY DESIGN .................................................................................................................... 29 
6.1 
STUDY FLOW DIAGRAM ..................................................................................................... 29 
6.2 
SCREENING AND ENROLLMENT ......................................................................................... 29 
6.3 
STUDY TREATMENT........................................................................................................... 29 
6.3.1 
Treatment setting ..................................................................................................... 30 
6.3.2 
Treatment regimen ................................................................................................... 30 
6.3.3 
Pre-therapy interventions ........................................................................................ 31 


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6.3.3.1 
Pre-medication and IV fluids for ALT-801 ......................................................... 31 
6.3.3.2 
Pre-medication and IV fluids for cisplatin ........................................................... 32 
6.3.3.3 
Pre-medication and IV fluids for gemcitabine ..................................................... 32 
6.3.4 
Study drug preparation and administration ............................................................ 32 
6.3.4.1 
ALT-801 .............................................................................................................. 32 
6.3.4.2 
Cisplatin ............................................................................................................... 32 
6.3.4.3 
Gemcitabine ......................................................................................................... 32 
6.4 
DURATION OF PATIENT PARTICIPATION ............................................................................. 32 
6.5 
DOSE ESCALATION ............................................................................................................ 33 
6.6 
EXPANSION AT MTD ........................................................................................................ 33 
6.7 
STOPPING RULES ............................................................................................................... 34 
6.8 
PATIENT MONITORING, ANTI-TUMOR RESPONSE EVALUATION, SURVIVAL ASSESSMENT .... 34 
6.8.1 
Patient monitoring ................................................................................................... 34 
6.8.2 
Anti-tumor response evaluation ............................................................................... 34 
6.8.3 
Survival assessment ................................................................................................. 34 
6.9 
DOSE LIMITING TOXICITIES ............................................................................................... 35 
6.10 
STUDY TREATMENT DISCONTINUATION............................................................................. 35 
6.10.1 
Study treatment discontinuation events ................................................................... 35 
6.10.2 
Follow-ups after treatment discontinuation............................................................. 35 
6.10.2.1. 
Discontinuation due to SAEs or on-going study drug related AEs ................. 35 
6.10.2.2. 
Discontinuation due to any other reasons ........................................................ 35 
6.11 
STUDY TREATMENT ADJUSTMENT ..................................................................................... 36 
6.11.1 
Kidney dysfunction ................................................................................................... 36 
6.11.2 
Hematological dysfunction ...................................................................................... 36 
6.11.3 
Hypotension ............................................................................................................. 36 
6.11.4 
Allergic reactions and cytokine release syndrome/acute infusion reaction ............ 36 
6.11.5 
Oncological surgeries post study treatment ............................................................ 37 
6.12 
SECOND AND THIRD COURSES OF STUDY TREATMENT ....................................................... 37 
6.12.1 
Qualification ............................................................................................................ 37 
6.12.2 
Treatment schedule and procedures ........................................................................ 37 
6.13 
REPEAT STUDY DRUG TREATMENT .................................................................................... 37 
6.13.1 
Qualification ............................................................................................................ 37 
6.13.2 
Treatment schedule and procedures ........................................................................ 37 
6.14 
GENERAL SUPPORTIVE CARE GUIDELINES AND DRUG INTERACTION .................................. 37 
6.14.1 
ALT-801 ................................................................................................................... 38 
6.14.1.1. 
Hypotension and capillary leak syndrome ....................................................... 38 
6.14.1.2. 
Pulmonary dysfunction .................................................................................... 38 
6.14.1.3. 
Impaired kidney and liver functions ................................................................ 38 
6.14.1.4. 
Infection ........................................................................................................... 39 
6.14.1.5. 
Fever and chills ................................................................................................ 39 
6.14.1.6. 
Gastritis ............................................................................................................ 39 
6.14.1.7. 
Diarrhea, nausea and vomiting ........................................................................ 39 
6.14.1.8. 
Pruritus and dermatitis ..................................................................................... 39 
6.14.1.9. 
Acidosis............................................................................................................ 39 
6.14.1.10. Life-threatening toxicities ................................................................................ 39 
6.14.1.11. Other supportive care ....................................................................................... 39 


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6.14.1.12. Drug interaction ............................................................................................... 39 
6.14.2 
Cisplatin ................................................................................................................... 40 
6.14.3 
Gemcitabine ............................................................................................................. 41 
7. 
STUDY DRUG: AVAILABILITY, ACCOUNTABILITY, PACKAGING & 
LABELING .................................................................................................................................... 41 
7.1 
ALT-801 .......................................................................................................................... 41 
7.1.1 
Availability ............................................................................................................... 41 
7.1.2 
Accountability .......................................................................................................... 41 
7.1.3 
Packaging ................................................................................................................ 41 
7.1.4 
Labeling ................................................................................................................... 41 
7.2 
CISPLATIN AND GEMCITABINE .......................................................................................... 41 
8. 
STUDY CALENDAR, CLINICAL PROCEDURES & TESTS ........................................ 42 
8.1 
STUDY CALENDAR ............................................................................................................ 42 
8.2 
PROCEDURE AND TESTS .................................................................................................... 43 
8.2.1 
HLA-A2 typing and assays for immune cell levels and phenotype .......................... 43 
8.2.2 
Presentation of HLA-A*0201/p53 aa264-272 complexes on tumor surfaces .......... 43 
8.2.3 
Medical history ........................................................................................................ 43 
8.2.4 
Pregnancy test .......................................................................................................... 43 
8.2.5 
Physical examination ............................................................................................... 43 
8.2.6 
Vital signs, body weight & height ............................................................................ 43 
8.2.7 
Cardiac assessment .................................................................................................. 43 
8.2.8 
Blood tests ................................................................................................................ 44 
8.2.9 
Urinalysis ................................................................................................................. 44 
8.2.10 
Pulmonary functions ................................................................................................ 44 
8.2.11 
Adverse event assessment ........................................................................................ 44 
8.2.12 
Tumor assessment .................................................................................................... 44 
8.2.13 
Survival assessment ................................................................................................. 44 
8.2.14 
Pharmacokinetic (PK) testing .................................................................................. 45 
8.2.15 
Biomarker assays for IFNγ and TNFα .................................................................... 45 
8.2.16 
Immunogenicity tests - detection of anti-ALT-801 and IL2-neutralizing antibodies
 
45 
9. 
MEASUREMENT OF EFFECT .......................................................................................... 45 
9.1 
DEFINITIONS ..................................................................................................................... 45 
9.1.1 
Measurable disease .................................................................................................. 45 
9.1.2 
Non-measurable disease .......................................................................................... 46 
9.1.3 
Target lesion ............................................................................................................ 46 
9.1.4 
Non-target lesions .................................................................................................... 47 
9.2 
GUIDELINES FOR EVALUATION OF MEASURABLE DISEASE ................................................. 47 
9.3 
RESPONSE CRITERIA .......................................................................................................... 48 
9.3.1 
Evaluation of target lesions ..................................................................................... 48 
9.3.2 
Evaluation of non-target lesions .............................................................................. 48 
9.3.3 
Evaluation of best overall response ......................................................................... 48 
9.4 
CONFIRMATORY ................................................................................................................ 49 


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10. 
STATISTICAL ANALYSIS ............................................................................................. 49 
10.1 
STUDY OBJECTIVES ........................................................................................................... 49 
10.2 
SAMPLE SIZE ..................................................................................................................... 49 
10.3 
DATA COLLECTION ........................................................................................................... 50 
10.4 
DATA ANALYSIS ................................................................................................................ 50 
10.4.1 
Analysis of safety...................................................................................................... 50 
10.4.2 
Analysis of response ................................................................................................. 51 
10.4.3 
Pharmacokinetics ..................................................................................................... 51 
11. 
REGULATORY AND REPORTING REQUIREMENTS ............................................ 51 
11.1 
ADVERSE EVENTS RECORDING, REPORTING AND COMMUNICATION .................................. 51 
11.2 
ADVERSE EVENT TERMINOLOGY AND DEFINITIONS ........................................................... 52 
11.3 
ADVERSE EVENT REPORTING PROCEDURES ...................................................................... 53 
11.4 
ADVERSE EVENT EXPEDITED REPORTING GUIDELINES ..................................................... 53 
11.5 
SUBMISSION OF SERIOUS ADVERSE EVENT REPORTING ...................................................... 53 
11.6 
DATA REPORTING FORMS ................................................................................................. 54 
11.7 
REPORT /DATA SUBMISSION ADDRESS & CONTACT ........................................................... 54 
11.8 
PATIENT RECORDS, QUALITY ASSURANCE, RECORDS RETENTION ...................................... 55 
11.9 
METHOD OF REVIEW ......................................................................................................... 55 
11.10 
SPECIAL REGULATORY CONSIDERATIONS ...................................................................... 55 
11.10.1 
HIPAA .................................................................................................................. 55 
11.10.2 
Protocol amendments, informed consent, and IRB approval .............................. 56 
12. 
CONFIDENTIALITY ....................................................................................................... 56 
13. 
ETHICAL STANDARDS & INVESTIGATOR OBLIGATIONS ................................ 56 
14. 
LIST OF EXPECTED ADVERSE EVENTS .................................................................. 57 
15. 
CTCAE................................................................................................................................ 59 
REFERENCES ............................................................................................................................... 60 
APPENDIX A: PERFORMANCE STATUS CRITERIA.......................................................... 63 
APPENDIX B: NEW YORK HEART ASSOCIATION CLASSIFICATION ......................... 63 
APPENDIX C: ETHICAL STANDARDS ................................................................................... 64 
APPENDIX D: INVESTIGATOR OBLIGATIONS .................................................................. 65 
APPENDIX E: CONTACT LIST - ALTOR ............................................................................... 69 
APPENDIX F: CONTACT LIST – DATA SAFETY MONITORING BOARD (DSMB) ...... 70 
APPENDIX G: CONTACT LIST - LABORATORIES ............................................................. 70 
APPENDIX H: APPROVAL PAGE ............................................................................................ 71 


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SYNOPSIS 
Sponsor: 
Altor Bioscience Corporation 
Protocol#: 
CA-ALT-801-01-10 
Study Drug Name: Not applicable 
Study Treatment 
Active agents: 
ALT-801 (c264scTCR-IL2), recombinant humanized, soluble single-chain 
TCR-cytokine fusion protein; Cisplatin; Gemcitabine. 
Study Type: 
Interventional 
Study Phase: 
Ib/II 
Protocol Title: 
A Phase Ib/II Trial of ALT-801 in Combination with Cisplatin and 
gemcitabine in Muscle Invasive or Metastatic Urothelial Cancer 
Objectives:   
To determine the safety and tolerability of the novel combination of addition 
of ALT-801 (c264scTCR-IL2) to the doublet of cisplatin and gemcitabine in 
patients with muscle invasive or metastatic urothelial cancer of bladder, 
renal pelvis, ureters and urethra.   
To estimate the anti-tumor activity of this combination of ALT-801, 
cisplatin and gemcitabine by radiologic or pathologic anti-tumor response, 
progression free survival (assessed through end of study), and overall 
survival (assessed through end of study) in treated patients.  
To characterize the immunogenicity and pharmacokinetic profile of ALT-
801 in combination with cisplatin and gemcitabine in treated patients. 
To assess the relationship between tumor presentation of HLA-A*0201/p53 
aa 264-272 complex and the safety and clinical benefit of study treatment. 
Study Design: 
This is a Phase Ib/II, open-label, multi-center, competitive enrollment and 
dose-escalation study of ALT-801 in a biochemotherapy regimen containing 
cisplatin and gemcitabine in patients who have muscle invasive or metastatic 
urothelial cancer of bladder, renal pelvis, ureters and urethra.  The study will 
be conducted in conformity with Good Clinical Practice (GCP).  
The study includes a dose escalation phase to determine the maximum 
tolerated dose (MTD) of ALT-801 in combination with cisplatin and 
gemcitabine and a two-stage expansion phase at the MTD.  The dose 
escalation in this study is conducted using a (3+3) dose escalation design, 
and the two-stage expansion phase at the MTD using a modified Simon two-
stage design (1, 2).  In the dose escalation phase of this study, there are five 
dose levels of ALT-801 (0.04 mg/kg, 0.06 mg/kg and 0.08 mg/kg, 0.10 
mg/kg and 0.12 mg/kg) in addition to two de-escalation dose levels.  The 
doses of cisplatin (70 mg/m2/dose) and gemcitabine (1000 mg/m2/dose) will 
be fixed across all ALT-801 dose levels.  If the MTD is not reached during 
the dose escalation phase, the sponsor, the Data Safety Monitoring Board 
and the principal investigators will meet to discuss whether to amend the 
protocol to expand the dose escalation phase to include additional ALT-801 
dose levels.  


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Treatments: 
The planned initial on-study treatment will be for 3 courses.  Each course 
consists of cisplatin (Day #1), gemcitabine (Day #1), ALT-801 (Day #3 & 
Day #5), gemcitabine (Day #8), ALT-801 (Day #8 & Day #10), and a rest 
period (Days #11-21). Prior to commencing the second or the third course, 
subjects will need to meet the continuation criteria. At the completion of the 
three full courses of study treatment, each patient enrolled will have been 
scheduled to have a total of 12 doses of the study drug ALT-801, 3 doses of 
cisplatin, and 6 doses of gemcitabine. After completing the 3-course initial 
study treatment, patients who have at least stable disease and meet other 
treatment criteria will repeat study treatment with four additional weekly 
doses of ALT-801.  Delays or modifications are addressed in the protocol. 
This is illustrated in the following schemas: 
 
Initial Study Treatment: 
 
 
 
 
Repeat Study Treatment: 
 
 
 
Enrolled patients will receive the study treatment at qualified cancer 
treatment centers with adequate diagnostic and treatment facilities to provide 
appropriate management of therapy and complications. ALT-801, cisplatin 
and gemcitabine will be administered by intravenous infusion into a central 
or peripheral vein under the supervision of a qualified physician experienced 
in the use of anti-cancer agents including aldesleukin (Proleukin), cisplatin 
and gemcitabine. 
This is the schema for the dose levels during the dose-escalation phase of the 
study.  The -1 and -2 dose levels of ALT-801 are included in case of DLT 
events in the initial dose level.  
Cohort 
ALT-801 Dose (mg/kg) 
Cisplatin  (mg/m2) 
Gemcitabine (mg/m2) 
-2 
0.01 
70 
1000 
-1 
0.02 
70 
1000 
1 (initial) 
0.04 
70 
1000 
2 
0.06 
70 
1000 
3 
0.08 
70 
1000 
4 
0.10 
70 
1000 
5 
0.12 
70 
1000 
 
 
Course 1 
Course 2 
Course 3 
Treatment Day 
1 
3 
5 
8 
10 11-21 22 24 26 29 31 32-42 43 45 47 50 52 53-63 
Cisplatin 
X 
 
 
 
 
Rest 
Period 
X 
 
 
 
 
Rest 
Period 
X 
 
 
 
 
Rest 
Period 
Gemcitabine 
X 
 
 
X 
 
X 
 
 
X 
 
X 
 
 
X 
 
ALT-801 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
Dose# 
1 
2 
3 
4 
Repeat 
Treatment Day 
1 
8 
15 22 
ALT-801 
X 
X 
X 
X 


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Dose Escalation: 
In this phase of the study, a minimum of 3 patients will be enrolled at each 
dose level.  All patients will be monitored for Dose Limiting Toxicity (DLT) 
for 8 weeks from the initial dose.  If 0/3 patients have study treatment-
related, dose-limiting toxicity by 8 weeks after the initial dose, the next 
cohort will be opened for enrollment. If one patient at a dose-level develops 
drug-related DLT, up to six patients will be enrolled at that dose level and 
each subsequent higher dose level.  If 0 or 1 of 6 patients in a cohort of 6 
patients have an event that meets criteria for study treatment-related DLT, 
then the next cohort will be opened for enrollment. If 2 or more out of 3-6 
patients in a dose escalation cohort have a DLT that is drug-related, that dose 
level will be designated as exceeding the maximum tolerated dose. If there 
are 3 patients in the dose level below this level, then additional patients (up 
to 6 total) will be enrolled at that dose level. When there is a dose level with 
0 or 1 out of 6 patients with DLT, which is either the maximum planned 
dose level (level 5) or which is one level below a dose that was not tolerated, 
the dose that is the maximum tolerated dose will be considered defined. 
Further changes in the treatment plan may be considered by protocol 
amendment at that point. 
If more than two of six patients experience a DLT at the initial dose level 
(level 1), then the sponsor, the Data Safety Monitoring Board and the 
principal investigators will meet to determine how to adjust downward the 
dose level of cisplatin, gemcitabine, and/or the study drug, or continue with 
the (-1) and (-2) cohorts, and to determine how to proceed with the study.  
Dose limiting toxicity (DLT) is defined as any toxicity of grade 3 that does 
not resolve to Grade 1 or lower within 72 hours and any toxicity of Grade 4 
occurring during treatment courses with exceptions and details described in 
the study protocol. Patients experiencing a DLT should discontinue study 
treatment.  Study treatment discontinuation due to adverse events 
experienced prior to study drug administration, disease progression or 
patient’s decision to withdraw from study treatment without occurrence of 
any study treatment discontinuation event will not necessarily define a DLT 
event.  Study treatment discontinuation events are defined in the protocol.  
Dose Expansion: 
The two-stage expansion phase at the MTD will be conducted using a 
modified Simon two-stage design (1, 2).  Both objective response (OR) 
(defined as complete response (CR) + partial response (PR)) and clinical 
benefit (CB) (defined as CR, PR + stable disease (SD)) will be evaluated and 
common set thresholds of lack of efficacy (OR rate (ORR) = 40%; CB rate 
(CBR) = 78%) and an efficacy level of interest (ORR = 60%; CBR = 92%) 
will be selected.  The sample size was driven by the parameter that had the 
larger sample size for each stage.      
Stopping Rule: 
The patient enrollment will be temporarily suspended based on occurrence 
of any the following, and the sponsor, the Data Safety Monitoring Board and 
principal investigators will meet to discuss how to proceed with future 
patient enrollment in the study: 


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• 
If at any time the dose escalation phase of the study, more than one 
patient in a cohort of three, or two of six patients experience any DLT; 
• 
If at any time during the expansion phase of the study, more than 33% 
the patients experience any drug related DLT. 
Evaluations: 
Patients will be evaluated for clinical toxicities during the treatment.  
Patients’ blood samples will be collected to assess the pharmacokinetic 
profile and immunogenicity of the study drug. The anti-tumor response will 
be evaluated for up to 18 weeks from the initial dose of the first course of 
treatment.  All patients who receive at least one dose of the study drug ALT-
801 will be included in the anti-tumor response evaluation.  Between each 
cohort and at the end of the study, all clinical and safety data will be 
analyzed for all patients enrolled in the study for dose-response effects. 
Population: 
Patients of 18 years of age and above who are candidates for systemic 
cisplatin and gemcitabine for the treatment of muscle invasive or metastatic 
urothelial cancer of bladder, renal pelvis, ureters, and urethra may be 
selected for further evaluation of eligibility for study participation.  Patients 
also need to have adequate cardiac, pulmonary, liver and kidney functions 
and to have an Eastern Cooperative Oncology Group (ECOG) performance 
status of 0 or 1 and a life expectancy of at least 12 weeks.  
Sample Size: 
A total of up to 30 assessable patients will be accrued to the initial dose 
escalation phase of the study (Phase Ib); the estimated number is 21.  Up to an 
additional 40 assessable patients will be enrolled at the expansion phase 
(Stage 1 and 2) of the study (Phase II).  A total of approximately 61 
assessable patients will be enrolled and complete the study.  Assume a 20% 
ineligible or non- assessable cases, a total of up 72 patients may be accrued 
to the study. 
Primary 
Endpoints: 
For Stage I only: 
(1) To define an MTD of ALT-801 in combination with cisplatin and 
gemcitabine in the treatment of patients with muscle invasive or 
metastatic urothelial cancer. 
For Stage I & II: 
(2) To assess the safety of the combination study treatment in treated 
patients. 
 
(3) To assess the objective response rate in treated patients. 
Secondary  
Endpoints: 
(1) To assess the progression free survival in treated patients. 
(2) To assess the overall survival in treated patients. 
(3) To evaluate the immunogenicity and pharmacokinetic profiles of ALT-
801 in treated patients. 


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(4) To assess the relationship between tumor presentation of HLA-
A*0201/p53 aa 264-272 complexes and the safety and clinical benefit of 
study treatment. 
Pharmacokinetics 
& Biomarkers: 
Blood samples will be collected to assess typing for HLA-A2, immune cell 
levels, phenotype, pharmacokinetics, immunogenicity of the study drug 
ALT-801, and the serum levels of IFN-γ and TNF-α.  Tumor samples will 
be collected to test HLA-A*0201/p53 aa 264-272 complex presentation. 
Blood samples for pharmacokinetic analysis of ALT-801 will be taken on 
the first day of ALT-801 administration in the first course of study 
treatment. Venous blood will be obtained at Time 0 (before the start of 
infusion), at 30 minutes (15 minutes after completion of infusion), and 1, 3 
and 6 hours from Time 0 for the assessment of ALT-801 serum 
concentration. Non-compartmental and compartmental analyses will be 
conducted.  In addition, the same blood samples collected for PK analysis 
will be used to assess the immunogenicity of study drug ALT-801 and the 
serum levels of IFN-γ and TNF-α.  Fresh blood samples for HLA-A2 typing, 
immune cell levels and phenotype testing will be collected before the start of 
the first and second courses of study treatment.  HLA-A2 typing will be 
performed only once. 
Monitoring Tests: Urine samples for urinalysis, blood samples for standard chemistry, CBC, 
differential and coagulation will be obtained at screening, on each study drug 
infusion day, discharge days and follow-up visits.  Blood samples for 
immunogenicity testing, which include assays for anti-ALT-801 and IL-2 
neutralizing antibodies, will be collected prior to dosing on the first ALT-
801 infusion day and at Week 9 from the initial dose of study treatment. 
Anti-tumor  
Response 
Evaluation: 
The anti-tumor response will be evaluated for up to 18 weeks from the initial 
dose of study treatment: for non-responders: Week 9 and 13; for early 
responders: Week 9 and 14; for late responders: Week 9, 13 and 18. 
Objective Response will be evaluated using the new international criteria 
proposed by the Response Evaluation Criteria in Solid Tumors Committee 
(RECIST) 1.1.  Baseline evaluations should be performed up to 28 days 
before starting study 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-ups. Imaging-based evaluation is 
preferred to evaluation by clinical examination when both methods have 
been used to assess the anti-tumor effect of the treatment.  However, 
cystoscopic evaluation may be used routinely in this population, in addition 
to radiologic testing. 
Survival  
Assessment: 
Progression-free survival and overall survival of all enrolled patients will be 
assessed at 6, 9, 12, 18, 24, 30 and 36 months from the start of study 
treatment, or through the point designated as the end of the study follow up. 


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Adverse Events: 
All patients will be monitored and evaluated for clinical toxicities during the 
treatment period and queried at each follow-up visit for Adverse Events 
(AEs).  Patients may volunteer information concerning AEs.  All adverse 
events will be graded by using the NCI Common Terminology Criteria for 
Adverse Events version 4.0 (CTCAE v4.0), and logged in the patient Case 
Report Form.  The study centers should report all SAEs and all events that 
trigger patient’s study treatment discontinuation to the sponsor via phone, 
fax or email (or a combination) up to 1 day after learning of the event.  The 
sponsor will use the information to manage and coordinate the dose 
escalation, cohort expansion and patient enrollment.  The sponsor will then 
inform all of the participating clinical sites of the current dose level and the 
number of patients to be enrolled at that level, or of any patient enrollment 
suspension via phone, fax or email within a day of its learning of the event.  
The study centers should report the other adverse events to the sponsor 
following the guidelines defined in the study protocol. All study drug related 
adverse events (AEs) that are both serious and unexpected will be reported 
to the FDA in an expedited manner in accordance with 21 CFR §312.32. 
Statistical Plan: 
For each cohort, all AEs will be tabulated and examined and all safety and 
pharmacokinetic data will be evaluated. For estimation of duration of 
response, the Kaplan-Meier method will be used. P-values of <0.05 (two-
sided) will be considered to indicate statistical significance.   
 


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8. 
STUDY CALENDAR, CLINICAL PROCEDURES & TESTS 
8.1 
Study calendar 
TESTS & PROCEDURES 
SCREEN1 
INITIAL TREATMENT PERIOD 
SCAN #1 
SCAN #2 
REPEAT 
TREATMENT 
SCAN #3 
FOLLOW-UPS 
COURSE 1 
COURSE 2 
COURSE 3 
Month(late responders in parentheses) 
 
1 
2 
3 
4 
3 – 4/(4-5) 
4/(5)  6 
9 
12 
18 24 
30 
36 
Week (late responders in parentheses) 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
13 
10/ 
(14) 
11/ 
(15) 
12/ 
(16) 
13/ 
(17) 
14/ 
(18) 
 
 
 
 
 
 
 
Week Day 
 
M 
W 
F  
M 
W 
 
M 
W 
F 
M 
W 
 
M 
W 
F 
M 
W 
  
  
M 
M  M  M 
 
 
 
 
 
 
 
 
Treatment Day 
 
1 
3 
5 
8 
10 
 
22 
24 
26 
29 
31 
 
43 
45 
47 
50 
52 
  
  
  
  
   
 
 
 
 
 
 
 
 
 
Informed consent   
X 
 
 
 
 
 
 
R 
e 
s 
t 
 
P 
e 
r 
i 
o 
d 
 
 
 
 
 
 
 
R 
e 
s 
t 
 
P 
e 
r 
i 
o 
d 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum pregnancy test2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Complete physical exam 
X 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
X 
X 
 
  
  
X 
 
 
 
 
 
 
 
Vital signs, weight, Height3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
Concurrent medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
CBC with Differential, Blood Chemistry 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
Coagulation (PT/INR)4 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
X 
X 
 
  
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Cardiac functions5 
X 
X5 
X 
X 
X 
X 
X5 
X 
X 
X 
X 
X5 
X 
X 
X 
X 
  
  
X5 
X 
X 
X 
 
 
 
 
 
 
 
 
Pulmonary functions 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse event assessment6 
X 
X 
X 
X  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
Tumor assessment7 
X 
  
  
  
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
Survival Assessment8 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
HLA A2 Typing, immune cell levels & phenotype11 
 
 
X9 
 
 
 
  
X9 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HLA-A*0201/p53 tumor typing 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK, IFNγ, TNFα11 
 
 
X10 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
Immunogenicity tests11 
 
 
X12 
  
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
  
  
  
  
  
  
Cisplatin
 
c1 
 
 
 
 
c2 
 
 
 
 
c3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Gemcitabine
 
g1 
 
 
g2 
 
g3 
 
 
g4 
 
g5 
 
 
g6 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study drug (ALT-801
 
  
a1 
a2 
a3 
a4 
  
a5 
a6 
a7 
a8 
  
a9 
a10 
a11 
a12 
  
  
a13 
a14 a15 a16 
 
 
 
 
 
 
 
 
1Screening evaluations are performed < 14 days, scan/x-ray < 28 days prior to start of therapy.  If the patient's condition is deteriorating, laboratory evaluations should be repeated within 48 hours prior to initiation of study treatment 
infusion.  2Pregnancy test is for women with childbearing potential only.  3Vital signs (especially blood pressure), clinical status and laboratory tests should be reviewed before start of therapy. Vital signs will be evaluated every 2 
hours after the drug treatment and before discharge, and body weight before study treatment infusion on study treatment infusion day. 4PT/INR should be performed for any bleeding issues. 5Patients are closely monitored for 
hypotension, arrhythmia, angina and myocardial infarction. At screening, patients who are ≥ 50 years of age or have a history of EKG abnormalities, symptoms of cardiac ischemia or arrhythmia will have a stress test (stress 
thallium, stress MUGA or dobutamine echocardiogram) to determine their eligibility for participation in the study. EKG will be performed at start of each treatment course and the repeat study drug treatment course. At the start of 
1st course, EKG is performed only when >14 days since last EKG. 6Patients who have an on-going study drug-related SAE upon study completion or at discontinuation of the study will be contacted by the investigator or his/her 
designee every week until the event is resolved or determined to be irreversible. 7Tumor response and progression will be evaluated in this study using the new international criteria proposed by the RECIST (1.1). 8Information about 
tumor assessment & other therapies received after completion of study treatment will be collected if available  9Fresh blood samples for HLA A2 blood typing, immune cell levels & phenotype testing will be collected before dosing. 
10Collect blood samples at Time 0 (before drug infusion), at 30 min (15 min after completion of infusion, +/- 5 min), 1 hour (+/- 10 min), 3 hour (+/- 30 min), 6 hour (+/- 60 min) from Time 0. IFNγ and TNFα assays are performed 
using the same samples and at the same schedule as PK.  11Residual samples may be used by Sponsor for research studies of other biomarkers. 12Use the same blood sample collected before dosing for PK test. 




 
 
 
CLINICAL STUDY PROTOCOL 
 
 
Protocol Number: 
CA-ALT-801-01-10 
 
 
Protocol Title: 
A Phase Ib/II Trial of ALT-801 in Combination 
with Cisplatin and Gemcitabine in Muscle 
Invasive or Metastatic Urothelial Cancer  
 
 
 
Date of Protocol: 
 
Version # 01 
Version # 02 
Version # 03 
 
October 31, 2010 
July 8, 2011 
November 10, 2011 
 
 
 
Sponsor Contact: 
 
Hing C. Wong, Ph.D. 
Altor Bioscience Corporation. 
Miramar, Florida 33025 
Telephone: 
954-443-8600 
Safety Data Fax: 
954-443-8602 
 
 
 


   
 
 
 
INVESTIGATOR SIGNATURE PAGE 
 
Protocol Number: 
CA-ALT-801-01-10 
 
 
Protocol Title: 
A Phase Ib/II Trial of ALT-801 in Combination 
with Cisplatin and Gemcitabine in Muscle 
Invasive or Metastatic Urothelial Cancer 
 
 
Date of Protocol: 
 
Version# 01 
Version# 02 
Version # 03 
October 31, 2010 
July 8, 2011 
November 10, 2011 
 
 
 
 
Sponsor Contact: 
 
Hing C. Wong, Ph.D. 
Altor Bioscience Corporation. 
Miramar, Florida 33025 
Telephone: 
954-443-8600 
Safety Data Fax: 
954-443-8602 
 
 
 
By my signature below, I hereby attest that I have read, and that I understand and will abide by 
all the conditions, instructions, and restrictions contained in the attached protocol. 
 
Additionally, I will not initiate this study without approval of the appropriate Institutional 
Review Board (IRB), and I understand that any changes in the protocol must be approved in 
writing by the sponsor, the IRB, and, in certain cases the FDA, before they can be implemented, 
except where necessary to eliminate hazards to subjects. 
 
 
 
 
 
Principal Investigator’s Signature 
 
Date 
 
 
 
 
 
 
 
 
 
Principal Investigator’s Name (Print) 
 
 
 
 
 
 
 
 
 
 
 


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Table of Contents 
SYNOPSIS ........................................................................................................................................ 7 
1. 
OBJECTIVES ........................................................................................................................ 13 
1.1 
PRIMARY OBJECTIVES ....................................................................................................... 13 
1.2 
SECONDARY OBJECTIVES .................................................................................................. 13 
2. 
BACKGROUND .................................................................................................................... 13 
2.1 
ALT-801 – GENERAL INFORMATION ................................................................................ 13 
2.2 
BLADDER CANCER ............................................................................................................ 13 
2.3 
IMMUNOTHERAPY ............................................................................................................. 14 
2.4 
INTRATUMORAL TARGETING AND P53 AS A TARGET FOR BIOTHERAPY .............................. 14 
2.5 
P53 AS A THERAPEUTIC TARGET FOR BLADDER CANCER .................................................... 16 
2.6 
IN VITRO CHARACTERIZATION AND TUMOR EFFICACY STUDIES IN ANIMAL MODELS .......... 16 
2.6.1 
Efficacy evaluation of ALT-801 dose regimens in xenograft tumor models ............ 17 
2.6.2 
Efficacy of ALT-801 and non-targeted scTCR/IL-2 fusion proteins against 
subcutaneous xenograft tumors derived from human urothelial cancer cells. ........................ 18 
2.6.3 
Activity of ALT-801 against human p53-negative orthotropic murine bladder 
tumors in immunocompetent mice. .......................................................................................... 19 
2.7 
NON-CLINICAL TOXICOLOGY ............................................................................................ 20 
2.7.1 
Single-dose toxicity study ......................................................................................... 20 
2.7.2 
Multi-dose toxicity study .......................................................................................... 20 
2.8 
PHARMACOKINETICS ......................................................................................................... 21 
2.8.1 
Non-clinical pharmacokinetics ................................................................................ 21 
2.8.2 
Clinical pharmacokinetics ....................................................................................... 21 
2.9 
HUMAN EXPERIENCE ......................................................................................................... 22 
2.9.1 
Pharmacodynamics .................................................................................................. 22 
2.9.2 
Tumor assessment .................................................................................................... 22 
2.9.3 
Safety results ............................................................................................................ 23 
2.9.4 
Repeat treatment ...................................................................................................... 24 
3. 
RATIONALE FOR THE CURRENT STUDY ................................................................... 24 
4. 
OVERALL STUDY DESIGN ............................................................................................... 25 
5. 
STUDY POPULATION ........................................................................................................ 27 
5.1 
INCLUSION CRITERIA ......................................................................................................... 27 
5.2 
EXCLUSION CRITERIA ........................................................................................................ 27 
5.3 
INCLUSION OF WOMEN AND MINORITIES............................................................................ 28 
6. 
STUDY DESIGN .................................................................................................................... 29 
6.1 
STUDY FLOW DIAGRAM ..................................................................................................... 29 
6.2 
SCREENING AND ENROLLMENT ......................................................................................... 29 
6.3 
STUDY TREATMENT........................................................................................................... 29 
6.3.1 
Treatment setting ..................................................................................................... 30 
6.3.2 
Treatment regimen ................................................................................................... 30 
6.3.3 
Pre-therapy interventions ........................................................................................ 31 


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6.3.3.1 
Pre-medication and IV fluids for ALT-801 ......................................................... 31 
6.3.3.2 
Pre-medication and IV fluids for cisplatin ........................................................... 32 
6.3.3.3 
Pre-medication and IV fluids for gemcitabine ..................................................... 32 
6.3.4 
Study drug preparation and administration ............................................................ 32 
6.3.4.1 
ALT-801 .............................................................................................................. 32 
6.3.4.2 
Cisplatin ............................................................................................................... 32 
6.3.4.3 
Gemcitabine ......................................................................................................... 32 
6.4 
DURATION OF PATIENT PARTICIPATION ............................................................................. 32 
6.5 
DOSE ESCALATION ............................................................................................................ 33 
6.6 
EXPANSION AT MTD ........................................................................................................ 33 
6.7 
STOPPING RULES ............................................................................................................... 34 
6.8 
PATIENT MONITORING, ANTI-TUMOR RESPONSE EVALUATION, SURVIVAL ASSESSMENT .... 34 
6.8.1 
Patient monitoring ................................................................................................... 34 
6.8.2 
Anti-tumor response evaluation ............................................................................... 34 
6.8.3 
Survival assessment ................................................................................................. 35 
6.9 
DOSE LIMITING TOXICITIES ............................................................................................... 35 
6.10 
STUDY TREATMENT DISCONTINUATION............................................................................. 35 
6.10.1 
Study treatment discontinuation events ................................................................... 35 
6.10.2 
Follow-ups after treatment discontinuation............................................................. 35 
6.10.2.1. 
Discontinuation due to SAEs or on-going study drug related AEs ................. 35 
6.10.2.2. 
Discontinuation due to any other reasons ........................................................ 36 
6.11 
STUDY TREATMENT ADJUSTMENT ..................................................................................... 36 
6.11.1 
Kidney dysfunction ................................................................................................... 36 
6.11.2 
Hematological dysfunction ...................................................................................... 36 
6.11.3 
Hypotension ............................................................................................................. 37 
6.11.4 
Allergic reactions and cytokine release syndrome/acute infusion reaction ............ 37 
6.11.5 
Oncological surgeries post study treatment ............................................................ 37 
6.12 
SECOND AND THIRD COURSES OF STUDY TREATMENT ....................................................... 37 
6.12.1 
Qualification ............................................................................................................ 37 
6.12.2 
Treatment schedule and procedures ........................................................................ 38 
6.13 
REPEAT STUDY DRUG TREATMENT .................................................................................... 38 
6.13.1 
Qualification ............................................................................................................ 38 
6.13.2 
Treatment schedule and procedures ........................................................................ 38 
6.14 
GENERAL SUPPORTIVE CARE GUIDELINES AND DRUG INTERACTION .................................. 38 
6.14.1 
ALT-801 ................................................................................................................... 38 
6.14.1.1. 
Hypotension and capillary leak syndrome ....................................................... 38 
6.14.1.2. 
Pulmonary dysfunction .................................................................................... 39 
6.14.1.3. 
Impaired kidney and liver functions ................................................................ 39 
6.14.1.4. 
Infection ........................................................................................................... 39 
6.14.1.5. 
Fever and chills ................................................................................................ 39 
6.14.1.6. 
Gastritis ............................................................................................................ 39 
6.14.1.7. 
Diarrhea, nausea and vomiting ........................................................................ 39 
6.14.1.8. 
Pruritus and dermatitis ..................................................................................... 40 
6.14.1.9. 
Acidosis............................................................................................................ 40 
6.14.1.10. Life-threatening toxicities ................................................................................ 40 
6.14.1.11. Other supportive care ....................................................................................... 40 


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6.14.1.12. Drug interaction ............................................................................................... 40 
6.14.2 
Cisplatin ................................................................................................................... 41 
6.14.3 
Gemcitabine ............................................................................................................. 41 
7. 
STUDY DRUG: AVAILABILITY, ACCOUNTABILITY, PACKAGING & 
LABELING .................................................................................................................................... 42 
7.1 
ALT-801 .......................................................................................................................... 42 
7.1.1 
Availability ............................................................................................................... 42 
7.1.2 
Accountability .......................................................................................................... 42 
7.1.3 
Packaging ................................................................................................................ 42 
7.1.4 
Labeling ................................................................................................................... 42 
7.2 
CISPLATIN AND GEMCITABINE .......................................................................................... 42 
8. 
STUDY CALENDAR, CLINICAL PROCEDURES & TESTS ........................................ 43 
8.1 
STUDY CALENDAR ............................................................................................................ 43 
8.2 
PROCEDURE AND TESTS .................................................................................................... 44 
8.2.1 
HLA-A2 typing and assays for immune cell levels and phenotype .......................... 44 
8.2.2 
Presentation of HLA-A*0201/p53 aa264-272 complexes on tumor surfaces .......... 44 
8.2.3 
Medical history ........................................................................................................ 44 
8.2.4 
Pregnancy test .......................................................................................................... 44 
8.2.5 
Physical examination ............................................................................................... 44 
8.2.6 
Vital signs, body weight & height ............................................................................ 44 
8.2.7 
Cardiac assessment .................................................................................................. 44 
8.2.8 
Blood tests ................................................................................................................ 45 
8.2.9 
Urinalysis ................................................................................................................. 45 
8.2.10 
Pulmonary functions ................................................................................................ 45 
8.2.11 
Adverse event assessment ........................................................................................ 45 
8.2.12 
Tumor assessment .................................................................................................... 45 
8.2.13 
Survival assessment ................................................................................................. 45 
8.2.14 
Pharmacokinetic (PK) testing .................................................................................. 46 
8.2.15 
Biomarker assays for IFNγ and TNFα .................................................................... 46 
8.2.16 
Immunogenicity tests - detection of anti-ALT-801 and IL2-neutralizing antibodies
 
46 
9. 
MEASUREMENT OF EFFECT .......................................................................................... 46 
9.1 
DEFINITIONS ..................................................................................................................... 46 
9.1.1 
Measurable disease .................................................................................................. 46 
9.1.2 
Non-measurable disease .......................................................................................... 47 
9.1.3 
Target lesion ............................................................................................................ 47 
9.1.4 
Non-target lesions .................................................................................................... 48 
9.2 
GUIDELINES FOR EVALUATION OF MEASURABLE DISEASE ................................................. 48 
9.3 
RESPONSE CRITERIA .......................................................................................................... 49 
9.3.1 
Evaluation of target lesions ..................................................................................... 49 
9.3.2 
Evaluation of non-target lesions .............................................................................. 49 
9.3.3 
Evaluation of best overall response ......................................................................... 49 
9.4 
CONFIRMATORY ................................................................................................................ 50 


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10. 
STATISTICAL ANALYSIS ............................................................................................. 50 
10.1 
STUDY OBJECTIVES ........................................................................................................... 50 
10.2 
SAMPLE SIZE ..................................................................................................................... 50 
10.3 
DATA COLLECTION ........................................................................................................... 51 
10.4 
DATA ANALYSIS ................................................................................................................ 51 
10.4.1 
Analysis of safety...................................................................................................... 51 
10.4.2 
Analysis of response ................................................................................................. 52 
10.4.3 
Pharmacokinetics ..................................................................................................... 52 
11. 
REGULATORY AND REPORTING REQUIREMENTS ............................................ 52 
11.1 
ADVERSE EVENTS RECORDING, REPORTING AND COMMUNICATION .................................. 52 
11.2 
ADVERSE EVENT TERMINOLOGY AND DEFINITIONS ........................................................... 53 
11.3 
ADVERSE EVENT REPORTING PROCEDURES ...................................................................... 54 
11.4 
ADVERSE EVENT EXPEDITED REPORTING GUIDELINES ..................................................... 54 
11.5 
SUBMISSION OF SERIOUS ADVERSE EVENT REPORTING ...................................................... 54 
11.6 
DATA REPORTING FORMS ................................................................................................. 55 
11.7 
REPORT /DATA SUBMISSION ADDRESS & CONTACT ........................................................... 55 
11.8 
PATIENT RECORDS, QUALITY ASSURANCE, RECORDS RETENTION ...................................... 56 
11.9 
METHOD OF REVIEW ......................................................................................................... 56 
11.10 
SPECIAL REGULATORY CONSIDERATIONS ...................................................................... 56 
11.10.1 
HIPAA .................................................................................................................. 56 
11.10.2 
Protocol amendments, informed consent, and IRB approval .............................. 57 
12. 
CONFIDENTIALITY ....................................................................................................... 57 
13. 
ETHICAL STANDARDS & INVESTIGATOR OBLIGATIONS ................................ 57 
14. 
LIST OF EXPECTED ADVERSE EVENTS .................................................................. 58 
15. 
CTCAE................................................................................................................................ 60 
REFERENCES ............................................................................................................................... 61 
APPENDIX A: PERFORMANCE STATUS CRITERIA.......................................................... 64 
APPENDIX B: NEW YORK HEART ASSOCIATION CLASSIFICATION ......................... 64 
APPENDIX C: ETHICAL STANDARDS ................................................................................... 65 
APPENDIX D: INVESTIGATOR OBLIGATIONS .................................................................. 66 
APPENDIX E: CONTACT LIST - ALTOR ............................................................................... 70 
APPENDIX F: CONTACT LIST – DATA SAFETY MONITORING BOARD (DSMB) ...... 71 
APPENDIX G: CONTACT LIST - LABORATORIES ............................................................. 71 
APPENDIX H: APPROVAL PAGE ............................................................................................ 72 


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SYNOPSIS 
Sponsor: 
Altor Bioscience Corporation 
Protocol#: 
CA-ALT-801-01-10 
Study Drug Name: Not applicable 
Study Treatment 
Active agents: 
ALT-801 (c264scTCR-IL2), recombinant humanized, soluble single-chain 
TCR-cytokine fusion protein; Cisplatin; Gemcitabine. 
Study Type: 
Interventional 
Study Phase: 
Ib/II 
Protocol Title: 
A Phase Ib/II Trial of ALT-801 in Combination with Cisplatin and 
gemcitabine in Muscle Invasive or Metastatic Urothelial Cancer 
Objectives:   
To determine the safety and tolerability of the novel combination of addition 
of ALT-801 (c264scTCR-IL2) to the doublet of cisplatin and gemcitabine in 
patients with muscle invasive or metastatic urothelial cancer of bladder, 
renal pelvis, ureters and urethra.   
To estimate the anti-tumor activity of this combination of ALT-801, 
cisplatin and gemcitabine by radiologic or pathologic anti-tumor response, 
progression free survival (assessed through end of study), and overall 
survival (assessed through end of study) in treated patients.  
To characterize the immunogenicity and pharmacokinetic profile of ALT-
801 in combination with cisplatin and gemcitabine in treated patients. 
To assess the relationship between tumor presentation of HLA-A*0201/p53 
aa 264-272 complex and the safety and clinical benefit of study treatment. 
Study Design: 
This is a Phase Ib/II, open-label, multi-center, competitive enrollment and 
dose-escalation study of ALT-801 in a biochemotherapy regimen containing 
cisplatin and gemcitabine in patients who have muscle invasive or metastatic 
urothelial cancer of bladder, renal pelvis, ureters and urethra.  The study will 
be conducted in conformity with Good Clinical Practice (GCP).  
The study includes a dose escalation phase to determine the maximum 
tolerated dose (MTD) of ALT-801 in combination with cisplatin and 
gemcitabine and a two-stage expansion phase at the MTD.  The dose 
escalation in this study is conducted using a (3+3) dose escalation design, 
and the two-stage expansion phase at the MTD using a modified Simon two-
stage design (1, 2).  In the dose escalation phase of this study, there are five 
dose levels of ALT-801 (0.04 mg/kg, 0.06 mg/kg and 0.08 mg/kg, 0.10 
mg/kg and 0.12 mg/kg) in addition to two de-escalation dose levels.  The 
doses of cisplatin (70 mg/m2/dose) and gemcitabine (1000 mg/m2/dose) will 
be fixed across all ALT-801 dose levels.  If the MTD is not reached during 
the dose escalation phase, the sponsor, the Data Safety Monitoring Board 
and the principal investigators will meet to discuss whether to amend the 
protocol to expand the dose escalation phase to include additional ALT-801 
dose levels.  


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Treatments: 
The planned initial on-study treatment will be for 3 courses.  Each course 
consists of cisplatin (Day #1), gemcitabine (Day #1), ALT-801 (Day #3 & 
Day #5), gemcitabine (Day #8), ALT-801 (Day #8 & Day #10), and a rest 
period (Days #11-21). Prior to commencing the second or the third course, 
subjects will need to meet the continuation criteria. At the completion of the 
three full courses of study treatment, each patient enrolled will have been 
scheduled to have a total of 12 doses of the study drug ALT-801, 3 doses of 
cisplatin, and 6 doses of gemcitabine. After completing the 3-course initial 
study treatment, patients who have at least stable disease and meet other 
treatment criteria will repeat study treatment with four additional weekly 
doses of ALT-801.  Delays or modifications are addressed in the protocol. 
This is illustrated in the following schemas: 
 
Initial Study Treatment: 
 
 
 
 
Repeat Study Treatment: 
 
 
 
Enrolled patients will receive the study treatment at qualified cancer 
treatment centers with adequate diagnostic and treatment facilities to provide 
appropriate management of therapy and complications. ALT-801, cisplatin 
and gemcitabine will be administered by intravenous infusion into a central 
or peripheral vein under the supervision of a qualified physician experienced 
in the use of anti-cancer agents including aldesleukin (Proleukin), cisplatin 
and gemcitabine. 
This is the schema for the dose levels during the dose-escalation phase of the 
study.  The -1 and -2 dose levels of ALT-801 are included in case of DLT 
events in the initial dose level.  
Cohort 
ALT-801 Dose (mg/kg) 
Cisplatin  (mg/m2) 
Gemcitabine (mg/m2) 
-2 
0.01 
70 
1000 
-1 
0.02 
70 
1000 
1 (initial) 
0.04 
70 
1000 
2 
0.06 
70 
1000 
3 
0.08 
70 
1000 
4 
0.10 
70 
1000 
5 
0.12 
70 
1000 
 
 
Course 1 
Course 2 
Course 3 
Treatment Day 
1 
3 
5 
8 
10 11-21 22 24 26 29 31 32-42 43 45 47 50 52 53-63 
Cisplatin 
X 
 
 
 
 
Rest 
Period 
X 
 
 
 
 
Rest 
Period 
X 
 
 
 
 
Rest 
Period 
Gemcitabine 
X 
 
 
X 
 
X 
 
 
X 
 
X 
 
 
X 
 
ALT-801 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
Dose# 
1 
2 
3 
4 
Repeat 
Treatment Day 
1 
8 
15 22 
ALT-801 
X 
X 
X 
X 


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Dose Escalation: 
In this phase of the study, a minimum of 3 patients will be enrolled at each 
dose level.  All patients will be monitored for Dose Limiting Toxicity (DLT) 
for 8 weeks from the initial dose.  If 0/3 patients have study treatment-
related, dose-limiting toxicity by 8 weeks after the initial dose, the next 
cohort will be opened for enrollment. If one patient at a dose-level develops 
drug-related DLT, up to six patients will be enrolled at that dose level and 
each subsequent higher dose level.  If 0 or 1 of 6 patients in a cohort of 6 
patients have an event that meets criteria for study treatment-related DLT, 
then the next cohort will be opened for enrollment. If 2 or more out of 3-6 
patients in a dose escalation cohort have a DLT that is drug-related, that dose 
level will be designated as exceeding the maximum tolerated dose. If there 
are 3 patients in the dose level below this level, then additional patients (up 
to 6 total) will be enrolled at that dose level. When there is a dose level with 
0 or 1 out of 6 patients with DLT, which is either the maximum planned 
dose level (level 5) or which is one level below a dose that was not tolerated, 
the dose that is the maximum tolerated dose will be considered defined. 
Further changes in the treatment plan may be considered by protocol 
amendment at that point. 
If more than two of six patients experience a DLT at the initial dose level 
(level 1), then the sponsor, the Data Safety Monitoring Board and the 
principal investigators will meet to determine how to adjust downward the 
dose level of cisplatin, gemcitabine, and/or the study drug, or continue with 
the (-1) and (-2) cohorts, and to determine how to proceed with the study.  
Dose limiting toxicity (DLT) is defined as any toxicity of grade 3 that does 
not resolve to Grade 1 or lower within 72 hours and any toxicity of Grade 4 
occurring during treatment courses with exceptions and details described in 
the study protocol. Patients experiencing a DLT should discontinue study 
treatment.  Study treatment discontinuation due to adverse events 
experienced prior to study drug administration, disease progression or 
patient’s decision to withdraw from study treatment without occurrence of 
any study treatment discontinuation event will not necessarily define a DLT 
event.  Study treatment discontinuation events are defined in the protocol.  
Dose Expansion: 
The two-stage expansion phase at the MTD will be conducted using a 
modified Simon two-stage design (1, 2).  Both objective response (OR) 
(defined as complete response (CR) + partial response (PR)) and clinical 
benefit (CB) (defined as CR, PR + stable disease (SD)) will be evaluated and 
common set thresholds of lack of efficacy (OR rate (ORR) = 40%; CB rate 
(CBR) = 78%) and an efficacy level of interest (ORR = 60%; CBR = 92%) 
will be selected.  The sample size was driven by the parameter that had the 
larger sample size for each stage.      
Stopping Rule: 
The patient enrollment will be temporarily suspended based on occurrence 
of any the following, and the sponsor, the Data Safety Monitoring Board and 
principal investigators will meet to discuss how to proceed with future 
patient enrollment in the study: 


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• 
If at any time the dose escalation phase of the study, more than one 
patient in a cohort of three, or two of six patients experience any DLT; 
• 
If at any time during the expansion phase of the study, more than 33% 
the patients experience any drug related DLT. 
Evaluations: 
Patients will be evaluated for clinical toxicities during the treatment.  
Patients’ blood samples will be collected to assess the pharmacokinetic 
profile and immunogenicity of the study drug. The anti-tumor response will 
be evaluated for up to 18 weeks from the initial dose of the first course of 
treatment.  All patients who receive at least one dose of the study drug ALT-
801 will be included in the anti-tumor response evaluation.  Between each 
cohort and at the end of the study, all clinical and safety data will be 
analyzed for all patients enrolled in the study for dose-response effects. 
Population: 
Patients of 18 years of age and above who are candidates for systemic 
cisplatin and gemcitabine for the treatment of muscle invasive or metastatic 
urothelial cancer of bladder, renal pelvis, ureters, and urethra may be 
selected for further evaluation of eligibility for study participation.  Patients 
also need to have adequate cardiac, pulmonary, liver and kidney functions 
and to have an Eastern Cooperative Oncology Group (ECOG) performance 
status of 0 or 1 and a life expectancy of at least 12 weeks.  
Sample Size: 
A total of up to 30 assessable patients will be accrued to the initial dose 
escalation phase of the study (Phase Ib); the estimated number is 21.  Up to an 
additional 40 assessable patients will be enrolled at the expansion phase 
(Stage 1 and 2) of the study (Phase II).  A total of approximately 60 
assessable patients will be enrolled and complete the study.  Assume a 20% 
ineligible or non- assessable cases, a total of up 72 patients may be accrued 
to the study. 
Primary 
Endpoints: 
For Stage I only: 
(1) To define an MTD of ALT-801 in combination with cisplatin and 
gemcitabine in the treatment of patients with muscle invasive or 
metastatic urothelial cancer. 
For Stage I & II: 
(2) To assess the safety of the combination study treatment in treated 
patients. 
 
(3) To assess the objective response rate in treated patients. 
Secondary  
Endpoints: 
(1) To assess the progression free survival in treated patients. 
(2) To assess the overall survival in treated patients. 
(3) To evaluate the immunogenicity and pharmacokinetic profiles of ALT-
801 in treated patients. 


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(4) To assess the relationship between tumor presentation of HLA-
A*0201/p53 aa 264-272 complexes and the safety and clinical benefit of 
study treatment. 
Pharmacokinetics 
& Biomarkers: 
Blood samples will be collected to assess typing for HLA-A2, immune cell 
levels, phenotype, pharmacokinetics, immunogenicity of the study drug 
ALT-801, and the serum levels of IFN-γ and TNF-α.  Tumor samples will 
be collected to test HLA-A*0201/p53 aa 264-272 complex presentation. 
Blood samples for pharmacokinetic analysis of ALT-801 will be taken on 
the first day of ALT-801 administration in the first course of study 
treatment. Venous blood will be obtained at Time 0 (before the start of 
infusion), at 30 minutes (15 minutes after completion of infusion), and 1, 3 
and 6 hours from Time 0 for the assessment of ALT-801 serum 
concentration. Non-compartmental and compartmental analyses will be 
conducted.  In addition, the same blood samples collected for PK analysis 
will be used to assess the immunogenicity of study drug ALT-801 and the 
serum levels of IFN-γ and TNF-α.  Fresh blood samples for HLA-A2 typing, 
immune cell levels and phenotype testing will be collected before the start of 
the first and second courses of study treatment.  HLA-A2 typing will be 
performed only once. 
Monitoring Tests: Urine samples for urinalysis, blood samples for standard chemistry, CBC, 
differential and coagulation will be obtained at screening, on each study drug 
infusion day, discharge days and follow-up visits.  Blood samples for 
immunogenicity testing, which include assays for anti-ALT-801 and IL-2 
neutralizing antibodies, will be collected prior to dosing on the first ALT-
801 infusion day and at Week 9 from the initial dose of study treatment. 
Anti-tumor  
Response 
Evaluation: 
The anti-tumor response will be evaluated for up to 18 weeks from the initial 
dose of study treatment: for non-responders: Week 9 and 13; for early 
responders: Week 9 and 14; for late responders: Week 9, 13 and 18. 
Objective Response will be evaluated using the new international criteria 
proposed by the Response Evaluation Criteria in Solid Tumors Committee 
(RECIST) 1.1.  Baseline evaluations should be performed up to 28 days 
before starting study 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-ups. Imaging-based evaluation is 
preferred to evaluation by clinical examination when both methods have 
been used to assess the anti-tumor effect of the treatment.  However, 
cystoscopic evaluation may be used routinely in this population, in addition 
to radiologic testing. 
Survival  
Assessment: 
Progression-free survival and overall survival of all enrolled patients will be 
assessed at 6, 9, 12, 18, 24, 30 and 36 months from the start of study 
treatment, or through the point designated as the end of the study follow up. 


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Adverse Events: 
All patients will be monitored and evaluated for clinical toxicities during the 
treatment period and queried at each follow-up visit for Adverse Events 
(AEs).  Patients may volunteer information concerning AEs.  All adverse 
events will be graded by using the NCI Common Terminology Criteria for 
Adverse Events version 4.0 (CTCAE v4.0), and logged in the patient Case 
Report Form.  The study centers should report all SAEs and all events that 
trigger patient’s study treatment discontinuation to the sponsor via phone, 
fax or email (or a combination) up to 1 day after learning of the event.  The 
sponsor will use the information to manage and coordinate the dose 
escalation, cohort expansion and patient enrollment.  The sponsor will then 
inform all of the participating clinical sites of the current dose level and the 
number of patients to be enrolled at that level, or of any patient enrollment 
suspension via phone, fax or email within a day of its learning of the event.  
The study centers should report the other adverse events to the sponsor 
following the guidelines defined in the study protocol. All study drug related 
adverse events (AEs) that are both serious and unexpected will be reported 
to the FDA in an expedited manner in accordance with 21 CFR §312.32. 
Statistical Plan: 
For each cohort, all AEs will be tabulated and examined and all safety and 
pharmacokinetic data will be evaluated. For estimation of duration of 
response, the Kaplan-Meier method will be used. P-values of <0.05 (two-
sided) will be considered to indicate statistical significance.   
 


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8. 
STUDY CALENDAR, CLINICAL PROCEDURES & TESTS 
8.1 
Study calendar 
TESTS & PROCEDURES 
SCREEN1 
INITIAL TREATMENT PERIOD 
SCAN #1 
SCAN #2 
REPEAT 
TREATMENT 
SCAN #3 
FOLLOW-UPS 
COURSE 1 
COURSE 2 
COURSE 3 
Month(late responders in parentheses) 
 
1 
2 
3 
4 
3 – 4/(4-5) 
4/(5)  6 
9 
12 
18 24 30 
36 
Week (late responders in parentheses) 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
13 
10/ 
(14) 
11/ 
(15) 
12/ 
(16) 
13/ 
(17) 
14/ 
(18) 
 
 
 
 
 
 
 
Week Day 
 
M 
W 
F  
M 
W 
 
M 
W 
F 
M 
W 
 
M 
W 
F 
M 
W 
  
  
M 
M  M  M 
 
 
 
 
 
 
 
 
Treatment Day 
 
1 
3 
5 
8 
10 
 
22 
24 
26 
29 
31 
 
43 
45 
47 
50 
52 
  
  
  
  
   
 
 
 
 
 
 
 
 
 
Informed consent   
X 
 
 
 
 
 
 
R 
e 
s 
t 
 
P 
e 
r 
i 
o 
d 
 
 
 
 
 
 
 
R 
e 
s 
t 
 
P 
e 
r 
i 
o 
d 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum pregnancy test2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Complete physical exam 
X 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
X 
X 
 
  
  
X 
 
 
 
 
 
 
 
Vital signs, weight, Height3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
Concurrent medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
CBC with Differential, Blood Chemistry 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
Coagulation (PT/INR)4 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
X 
X 
 
  
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Cardiac functions5 
X 
X5 
X 
X 
X 
X 
X5 
X 
X 
X 
X 
X5 
X 
X 
X 
X 
  
  
X5 
X 
X 
X 
 
 
 
 
 
 
 
 
Pulmonary functions 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse event assessment6 
X 
X 
X 
X  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
Tumor assessment7 
X 
  
  
  
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
Survival Assessment8 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
HLA A2 Typing, immune cell levels & phenotype11 
 
 
X9 
 
 
 
  
X9 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HLA-A*0201/p53 tumor typing 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK, IFNγ, TNFα11 
 
 
X10 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
Immunogenicity tests11 
 
 
X12 
  
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
  
  
  
  
  
  
Cisplatin
 
c1 
 
 
 
 
c2 
 
 
 
 
c3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Gemcitabine
 
g1 
 
 
g2 
 
g3 
 
 
g4 
 
g5 
 
 
g6 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study drug (ALT-801
 
  
a1 
a2 
a3 
a4 
  
a5 
a6 
a7 
a8 
  
a9 
a10 
a11 
a12 
  
  
a13 
a14 a15 a16 
 
 
 
 
 
 
 
 
1Screening evaluations are performed < 14 days, scan/x-ray < 28 days prior to start of therapy.  If the patient's condition is deteriorating, laboratory evaluations should be repeated within 48 hours prior to initiation of study treatment 
infusion.  2Pregnancy test is for women with childbearing potential only.  3Vital signs (especially blood pressure), clinical status and laboratory tests should be reviewed before start of therapy. Vital signs will be evaluated every 2 
hours after the drug treatment and before discharge, and body weight before study treatment infusion on study treatment infusion day. 4PT/INR should be performed for any bleeding issues. 5Patients are closely monitored for 
hypotension, arrhythmia, angina and myocardial infarction. At screening, patients who are ≥ 50 years of age or have a history of EKG abnormalities, symptoms of cardiac ischemia or arrhythmia will have a stress test (stress 
thallium, stress MUGA or dobutamine echocardiogram) to determine their eligibility for participation in the study. EKG will be performed at start of each treatment course and the repeat study drug treatment course. At the start of 
1st course, EKG is performed only when >14 days since last EKG. 6Patients who have an on-going study drug-related SAE upon study completion or at discontinuation of the study will be contacted by the investigator or his/her 
designee every week until the event is resolved or determined to be irreversible. 7Tumor response and progression will be evaluated in this study using the new international criteria proposed by the RECIST (1.1). 8Information about 
tumor assessment & other therapies received after completion of study treatment will be collected if available  9Fresh blood samples for HLA A2 blood typing, immune cell levels & phenotype testing will be collected before dosing. 
10Collect blood samples at Time 0 (before drug infusion), at 30 min (15 min after completion of infusion, +/- 5 min), 1 hour (+/- 10 min), 3 hour (+/- 30 min), 6 hour (+/- 60 min) from Time 0. IFNγ and TNFα assays are performed 
using the same samples and at the same schedule as PK.  11Residual samples may be used by Sponsor for research studies of other biomarkers. 12Use the same blood sample collected before dosing for PK test. 




 
 
 
CLINICAL STUDY PROTOCOL 
 
 
Protocol Number: 
CA-ALT-801-01-10 
 
 
Protocol Title: 
A Phase Ib/II Trial of ALT-801 in Combination 
with Cisplatin and Gemcitabine in Muscle 
Invasive or Metastatic Urothelial Cancer  
 
 
 
Date of Protocol: 
 
Version # 01 
Version # 02 
Version # 03 
Version # 04 
 
October 31, 2010 
July 8, 2011 
November 10, 2011 
December 23, 2011 
 
 
Sponsor Contact: 
 
Hing C. Wong, Ph.D. 
Altor Bioscience Corporation. 
Miramar, Florida 33025 
Telephone: 
954-443-8600 
Safety Data Fax: 
954-443-8602 
 
 
 


   
 
 
 
INVESTIGATOR SIGNATURE PAGE 
 
Protocol Number: 
CA-ALT-801-01-10 
 
 
Protocol Title: 
A Phase Ib/II Trial of ALT-801 in Combination 
with Cisplatin and Gemcitabine in Muscle 
Invasive or Metastatic Urothelial Cancer 
 
 
Date of Protocol: 
 
Version # 01 
Version # 02 
Version # 03 
Version # 04 
October 31, 2010 
July 8, 2011 
November 10, 2011 
December 23, 2011 
 
 
 
Sponsor Contact: 
 
Hing C. Wong, Ph.D. 
Altor Bioscience Corporation. 
Miramar, Florida 33025 
Telephone: 
954-443-8600 
Safety Data Fax: 
954-443-8602 
 
 
 
By my signature below, I hereby attest that I have read, and that I understand and will abide by 
all the conditions, instructions, and restrictions contained in the attached protocol. 
 
Additionally, I will not initiate this study without approval of the appropriate Institutional 
Review Board (IRB), and I understand that any changes in the protocol must be approved in 
writing by the sponsor, the IRB, and, in certain cases the FDA, before they can be implemented, 
except where necessary to eliminate hazards to subjects. 
 
 
 
 
 
Principal Investigator’s Signature 
 
Date 
 
 
 
 
 
 
 
 
 
Principal Investigator’s Name (Print) 
 
 
 
 
 
 
 
 
 
 
 


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Table of Contents 
SYNOPSIS ........................................................................................................................................ 7 
1. 
OBJECTIVES ........................................................................................................................ 13 
1.1 
PRIMARY OBJECTIVES ....................................................................................................... 13 
1.2 
SECONDARY OBJECTIVES .................................................................................................. 13 
2. 
BACKGROUND .................................................................................................................... 13 
2.1 
ALT-801 – GENERAL INFORMATION ................................................................................ 13 
2.2 
BLADDER CANCER ............................................................................................................ 13 
2.3 
IMMUNOTHERAPY ............................................................................................................. 14 
2.4 
INTRATUMORAL TARGETING AND P53 AS A TARGET FOR BIOTHERAPY .............................. 14 
2.5 
P53 AS A THERAPEUTIC TARGET FOR BLADDER CANCER .................................................... 16 
2.6 
IN VITRO CHARACTERIZATION AND TUMOR EFFICACY STUDIES IN ANIMAL MODELS .......... 16 
2.6.1 
Efficacy evaluation of ALT-801 dose regimens in xenograft tumor models ............ 17 
2.6.2 
Efficacy of ALT-801 and non-targeted scTCR/IL-2 fusion proteins against 
subcutaneous xenograft tumors derived from human urothelial cancer cells. ........................ 18 
2.6.3 
Activity of ALT-801 against human p53-negative orthotropic murine bladder 
tumors in immunocompetent mice. .......................................................................................... 19 
2.7 
NON-CLINICAL TOXICOLOGY ............................................................................................ 20 
2.7.1 
Single-dose toxicity study ......................................................................................... 20 
2.7.2 
Multi-dose toxicity study .......................................................................................... 20 
2.8 
PHARMACOKINETICS ......................................................................................................... 21 
2.8.1 
Non-clinical pharmacokinetics ................................................................................ 21 
2.8.2 
Clinical pharmacokinetics ....................................................................................... 21 
2.9 
HUMAN EXPERIENCE ......................................................................................................... 22 
2.9.1 
Pharmacodynamics .................................................................................................. 22 
2.9.2 
Tumor assessment .................................................................................................... 22 
2.9.3 
Safety results ............................................................................................................ 23 
2.9.4 
Repeat treatment ...................................................................................................... 24 
3. 
RATIONALE FOR THE CURRENT STUDY ................................................................... 24 
4. 
OVERALL STUDY DESIGN ............................................................................................... 25 
5. 
STUDY POPULATION ........................................................................................................ 27 
5.1 
INCLUSION CRITERIA ......................................................................................................... 27 
5.2 
EXCLUSION CRITERIA ........................................................................................................ 28 
5.3 
INCLUSION OF WOMEN AND MINORITIES............................................................................ 28 
6. 
STUDY DESIGN .................................................................................................................... 29 
6.1 
STUDY FLOW DIAGRAM ..................................................................................................... 29 
6.2 
SCREENING AND ENROLLMENT ......................................................................................... 29 
6.3 
STUDY TREATMENT........................................................................................................... 29 
6.3.1 
Treatment setting ..................................................................................................... 30 
6.3.2 
Treatment regimen ................................................................................................... 30 
6.3.3 
Pre-therapy interventions ........................................................................................ 31 


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6.3.3.1 
Pre-medication and IV fluids for ALT-801 ......................................................... 31 
6.3.3.2 
Pre-medication and IV fluids for cisplatin ........................................................... 32 
6.3.3.3 
Pre-medication and IV fluids for gemcitabine ..................................................... 32 
6.3.4 
Study drug preparation and administration ............................................................ 32 
6.3.4.1 
ALT-801 .............................................................................................................. 32 
6.3.4.2 
Cisplatin ............................................................................................................... 32 
6.3.4.3 
Gemcitabine ......................................................................................................... 32 
6.4 
DURATION OF PATIENT PARTICIPATION ............................................................................. 32 
6.5 
DOSE ESCALATION ............................................................................................................ 33 
6.6 
EXPANSION AT MTD ........................................................................................................ 33 
6.7 
STOPPING RULES ............................................................................................................... 34 
6.8 
PATIENT MONITORING, ANTI-TUMOR RESPONSE EVALUATION, SURVIVAL ASSESSMENT .... 34 
6.8.1 
Patient monitoring ................................................................................................... 34 
6.8.2 
Anti-tumor response evaluation ............................................................................... 34 
6.8.3 
Survival assessment ................................................................................................. 35 
6.9 
DOSE LIMITING TOXICITIES ............................................................................................... 35 
6.10 
STUDY TREATMENT DISCONTINUATION............................................................................. 35 
6.10.1 
Study treatment discontinuation events ................................................................... 35 
6.10.2 
Follow-ups after treatment discontinuation............................................................. 35 
6.10.2.1. 
Discontinuation due to SAEs or on-going study drug related AEs ................. 35 
6.10.2.2. 
Discontinuation due to any other reasons ........................................................ 36 
6.11 
STUDY TREATMENT ADJUSTMENT ..................................................................................... 36 
6.11.1 
Kidney dysfunction ................................................................................................... 36 
6.11.2 
Hematological dysfunction ...................................................................................... 36 
6.11.3 
Hypotension ............................................................................................................. 37 
6.11.4 
Allergic reactions and cytokine release syndrome/acute infusion reaction ............ 37 
6.11.5 
Oncological surgeries post study treatment ............................................................ 37 
6.12 
SECOND AND THIRD COURSES OF STUDY TREATMENT ....................................................... 37 
6.12.1 
Qualification ............................................................................................................ 37 
6.12.2 
Treatment schedule and procedures ........................................................................ 38 
6.13 
REPEAT STUDY DRUG TREATMENT .................................................................................... 38 
6.13.1 
Qualification ............................................................................................................ 38 
6.13.2 
Treatment schedule and procedures ........................................................................ 38 
6.14 
GENERAL SUPPORTIVE CARE GUIDELINES AND DRUG INTERACTION .................................. 38 
6.14.1 
ALT-801 ................................................................................................................... 38 
6.14.1.1. 
Hypotension and capillary leak syndrome ....................................................... 38 
6.14.1.2. 
Pulmonary dysfunction .................................................................................... 39 
6.14.1.3. 
Impaired kidney and liver functions ................................................................ 39 
6.14.1.4. 
Infection ........................................................................................................... 39 
6.14.1.5. 
Fever and chills ................................................................................................ 39 
6.14.1.6. 
Gastritis ............................................................................................................ 39 
6.14.1.7. 
Diarrhea, nausea and vomiting ........................................................................ 39 
6.14.1.8. 
Pruritus and dermatitis ..................................................................................... 39 
6.14.1.9. 
Acidosis............................................................................................................ 40 
6.14.1.10. Life-threatening toxicities ................................................................................ 40 
6.14.1.11. Other supportive care ....................................................................................... 40 


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6.14.1.12. Drug interaction ............................................................................................... 40 
6.14.2 
Cisplatin ................................................................................................................... 41 
6.14.3 
Gemcitabine ............................................................................................................. 41 
7. 
STUDY DRUG: AVAILABILITY, ACCOUNTABILITY, PACKAGING & 
LABELING .................................................................................................................................... 42 
7.1 
ALT-801 .......................................................................................................................... 42 
7.1.1 
Availability ............................................................................................................... 42 
7.1.2 
Accountability .......................................................................................................... 42 
7.1.3 
Packaging ................................................................................................................ 42 
7.1.4 
Labeling ................................................................................................................... 42 
7.2 
CISPLATIN AND GEMCITABINE .......................................................................................... 42 
8. 
STUDY CALENDAR, CLINICAL PROCEDURES & TESTS ........................................ 43 
8.1 
STUDY CALENDAR ............................................................................................................ 43 
8.2 
PROCEDURE AND TESTS .................................................................................................... 44 
8.2.1 
HLA-A2 typing and assays for immune cell levels and phenotype .......................... 44 
8.2.2 
Presentation of HLA-A*0201/p53 aa264-272 complexes on tumor surfaces .......... 44 
8.2.3 
Medical history ........................................................................................................ 44 
8.2.4 
Pregnancy test .......................................................................................................... 44 
8.2.5 
Physical examination ............................................................................................... 44 
8.2.6 
Vital signs, body weight & height ............................................................................ 44 
8.2.7 
Cardiac assessment .................................................................................................. 44 
8.2.8 
Blood tests ................................................................................................................ 45 
8.2.9 
Urinalysis ................................................................................................................. 45 
8.2.10 
Pulmonary functions ................................................................................................ 45 
8.2.11 
Adverse event assessment ........................................................................................ 45 
8.2.12 
Tumor assessment .................................................................................................... 45 
8.2.13 
Survival assessment ................................................................................................. 46 
8.2.14 
Pharmacokinetic (PK) testing .................................................................................. 46 
8.2.15 
Biomarker assays for IFNγ and TNFα .................................................................... 46 
8.2.16 
Immunogenicity tests - detection of anti-ALT-801 and IL2-neutralizing antibodies
 
46 
9. 
MEASUREMENT OF EFFECT .......................................................................................... 46 
9.1 
DEFINITIONS ..................................................................................................................... 46 
9.1.1 
Measurable disease .................................................................................................. 46 
9.1.2 
Non-measurable disease .......................................................................................... 47 
9.1.3 
Target lesion ............................................................................................................ 48 
9.1.4 
Non-target lesions .................................................................................................... 48 
9.2 
GUIDELINES FOR EVALUATION OF MEASURABLE DISEASE ................................................. 48 
9.3 
RESPONSE CRITERIA .......................................................................................................... 49 
9.3.1 
Evaluation of target lesions ..................................................................................... 49 
9.3.2 
Evaluation of non-target lesions .............................................................................. 49 
9.3.3 
Evaluation of best overall response ......................................................................... 49 
9.4 
CONFIRMATORY ................................................................................................................ 50 


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10. 
STATISTICAL ANALYSIS ............................................................................................. 50 
10.1 
STUDY OBJECTIVES ........................................................................................................... 50 
10.2 
SAMPLE SIZE ..................................................................................................................... 50 
10.3 
DATA COLLECTION ........................................................................................................... 51 
10.4 
DATA ANALYSIS ................................................................................................................ 51 
10.4.1 
Analysis of safety...................................................................................................... 51 
10.4.2 
Analysis of response ................................................................................................. 52 
10.4.3 
Pharmacokinetics ..................................................................................................... 52 
11. 
REGULATORY AND REPORTING REQUIREMENTS ............................................ 52 
11.1 
ADVERSE EVENTS RECORDING, REPORTING AND COMMUNICATION .................................. 52 
11.2 
ADVERSE EVENT TERMINOLOGY AND DEFINITIONS ........................................................... 53 
11.3 
ADVERSE EVENT REPORTING PROCEDURES ...................................................................... 54 
11.4 
ADVERSE EVENT EXPEDITED REPORTING GUIDELINES ..................................................... 54 
11.5 
SUBMISSION OF SERIOUS ADVERSE EVENT REPORTING ...................................................... 54 
11.6 
DATA REPORTING FORMS ................................................................................................. 55 
11.7 
REPORT /DATA SUBMISSION ADDRESS & CONTACT ........................................................... 55 
11.8 
PATIENT RECORDS, QUALITY ASSURANCE, RECORDS RETENTION ...................................... 56 
11.9 
METHOD OF REVIEW ......................................................................................................... 56 
11.10 
SPECIAL REGULATORY CONSIDERATIONS ...................................................................... 56 
11.10.1 
HIPAA .................................................................................................................. 56 
11.10.2 
Protocol amendments, informed consent, and IRB approval .............................. 57 
12. 
CONFIDENTIALITY ....................................................................................................... 57 
13. 
ETHICAL STANDARDS & INVESTIGATOR OBLIGATIONS ................................ 57 
14. 
LIST OF EXPECTED ADVERSE EVENTS .................................................................. 58 
15. 
CTCAE................................................................................................................................ 60 
REFERENCES ............................................................................................................................... 61 
APPENDIX A: PERFORMANCE STATUS CRITERIA.......................................................... 64 
APPENDIX B: NEW YORK HEART ASSOCIATION CLASSIFICATION ......................... 64 
APPENDIX C: ETHICAL STANDARDS ................................................................................... 65 
APPENDIX D: INVESTIGATOR OBLIGATIONS .................................................................. 66 
APPENDIX E: CONTACT LIST - ALTOR ............................................................................... 70 
APPENDIX F: CONTACT LIST – DATA SAFETY MONITORING BOARD (DSMB) ...... 71 
APPENDIX G: CONTACT LIST - LABORATORIES ............................................................. 71 
APPENDIX H: APPROVAL PAGE ............................................................................................ 72 


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SYNOPSIS 
Sponsor: 
Altor Bioscience Corporation 
Protocol#: 
CA-ALT-801-01-10 
Study Drug Name: Not applicable 
Study Treatment 
Active agents: 
ALT-801 (c264scTCR-IL2), recombinant humanized, soluble single-chain 
TCR-cytokine fusion protein; Cisplatin; Gemcitabine. 
Study Type: 
Interventional 
Study Phase: 
Ib/II 
Protocol Title: 
A Phase Ib/II Trial of ALT-801 in Combination with Cisplatin and 
gemcitabine in Muscle Invasive or Metastatic Urothelial Cancer 
Objectives:   
To determine the safety and tolerability of the novel combination of addition 
of ALT-801 (c264scTCR-IL2) to the doublet of cisplatin and gemcitabine in 
patients with muscle invasive or metastatic urothelial cancer of bladder, 
renal pelvis, ureters and urethra.   
To estimate the anti-tumor activity of this combination of ALT-801, 
cisplatin and gemcitabine by radiologic or pathologic anti-tumor response, 
progression free survival (assessed through end of study), and overall 
survival (assessed through end of study) in treated patients.  
To characterize the immunogenicity and pharmacokinetic profile of ALT-
801 in combination with cisplatin and gemcitabine in treated patients. 
To assess the relationship between tumor presentation of HLA-A*0201/p53 
aa 264-272 complex and the safety and clinical benefit of study treatment. 
Study Design: 
This is a Phase Ib/II, open-label, multi-center, competitive enrollment and 
dose-escalation study of ALT-801 in a biochemotherapy regimen containing 
cisplatin and gemcitabine in patients who have muscle invasive or metastatic 
urothelial cancer of bladder, renal pelvis, ureters and urethra.  The study will 
be conducted in conformity with Good Clinical Practice (GCP).  
The study includes a dose escalation phase to determine the maximum 
tolerated dose (MTD) of ALT-801 in combination with cisplatin and 
gemcitabine and a two-stage expansion phase at the MTD.  The dose 
escalation in this study is conducted using a (3+3) dose escalation design, 
and the two-stage expansion phase at the MTD using a modified Simon two-
stage design (1, 2).  In the dose escalation phase of this study, there are five 
dose levels of ALT-801 (0.04 mg/kg, 0.06 mg/kg and 0.08 mg/kg, 0.10 
mg/kg and 0.12 mg/kg) in addition to two de-escalation dose levels.  The 
doses of cisplatin (70 mg/m2/dose) and gemcitabine (1000 mg/m2/dose) will 
be fixed across all ALT-801 dose levels.  If the MTD is not reached during 
the dose escalation phase, the sponsor, the Data Safety Monitoring Board 
and the principal investigators will meet to discuss whether to amend the 
protocol to expand the dose escalation phase to include additional ALT-801 
dose levels.  


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Treatments: 
The planned initial on-study treatment will be for 3 courses.  Each course 
consists of cisplatin (Day #1), gemcitabine (Day #1), ALT-801 (Day #3 & 
Day #5), gemcitabine (Day #8), ALT-801 (Day #8 & Day #10), and a rest 
period (Days #11-21). Prior to commencing the second or the third course, 
subjects will need to meet the continuation criteria. At the completion of the 
three full courses of study treatment, each patient enrolled will have been 
scheduled to have a total of 12 doses of the study drug ALT-801, 3 doses of 
cisplatin, and 6 doses of gemcitabine. After completing the 3-course initial 
study treatment, patients who have at least stable disease and meet other 
treatment criteria will repeat study treatment with four additional weekly 
doses of ALT-801.  Delays or modifications are addressed in the protocol. 
This is illustrated in the following schemas: 
 
Initial Study Treatment: 
 
 
 
 
Repeat Study Treatment: 
 
 
 
Enrolled patients will receive the study treatment at qualified cancer 
treatment centers with adequate diagnostic and treatment facilities to provide 
appropriate management of therapy and complications. ALT-801, cisplatin 
and gemcitabine will be administered by intravenous infusion into a central 
or peripheral vein under the supervision of a qualified physician experienced 
in the use of anti-cancer agents including aldesleukin (Proleukin), cisplatin 
and gemcitabine. 
This is the schema for the dose levels during the dose-escalation phase of the 
study.  The -1 and -2 dose levels of ALT-801 are included in case of DLT 
events in the initial dose level.  
Cohort 
ALT-801 Dose (mg/kg) 
Cisplatin  (mg/m2) 
Gemcitabine (mg/m2) 
-2 
0.01 
70 
1000 
-1 
0.02 
70 
1000 
1 (initial) 
0.04 
70 
1000 
2 
0.06 
70 
1000 
3 
0.08 
70 
1000 
4 
0.10 
70 
1000 
5 
0.12 
70 
1000 
 
 
Course 1 
Course 2 
Course 3 
Treatment Day 
1 
3 
5 
8 
10 11-21 22 24 26 29 31 32-42 43 45 47 50 52 53-63 
Cisplatin 
X 
 
 
 
 
Rest 
Period 
X 
 
 
 
 
Rest 
Period 
X 
 
 
 
 
Rest 
Period 
Gemcitabine 
X 
 
 
X 
 
X 
 
 
X 
 
X 
 
 
X 
 
ALT-801 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
Dose# 
1 
2 
3 
4 
Repeat 
Treatment Day 
1 
8 
15 22 
ALT-801 
X 
X 
X 
X 


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Dose Escalation: 
In this phase of the study, a minimum of 3 patients will be enrolled at each 
dose level.  All patients will be monitored for Dose Limiting Toxicity (DLT) 
for 8 weeks from the initial dose.  If 0/3 patients have study treatment-
related, dose-limiting toxicity by 8 weeks after the initial dose, the next 
cohort will be opened for enrollment. If one patient at a dose-level develops 
drug-related DLT, up to six patients will be enrolled at that dose level and 
each subsequent higher dose level.  If 0 or 1 of 6 patients in a cohort of 6 
patients have an event that meets criteria for study treatment-related DLT, 
then the next cohort will be opened for enrollment. If 2 or more out of 3-6 
patients in a dose escalation cohort have a DLT that is drug-related, that dose 
level will be designated as exceeding the maximum tolerated dose. If there 
are 3 patients in the dose level below this level, then additional patients (up 
to 6 total) will be enrolled at that dose level. When there is a dose level with 
0 or 1 out of 6 patients with DLT, which is either the maximum planned 
dose level (level 5) or which is one level below a dose that was not tolerated, 
the dose that is the maximum tolerated dose will be considered defined. 
Further changes in the treatment plan may be considered by protocol 
amendment at that point. 
If more than two of six patients experience a DLT at the initial dose level 
(level 1), then the sponsor, the Data Safety Monitoring Board and the 
principal investigators will meet to determine how to adjust downward the 
dose level of cisplatin, gemcitabine, and/or the study drug, or continue with 
the (-1) and (-2) cohorts, and to determine how to proceed with the study.  
Dose limiting toxicity (DLT) is defined as any toxicity of grade 3 that does 
not resolve to Grade 1 or lower within 72 hours and any toxicity of Grade 4 
occurring during treatment courses with exceptions and details described in 
the study protocol. Patients experiencing a DLT should discontinue study 
treatment.  Study treatment discontinuation due to adverse events 
experienced prior to study drug administration, disease progression or 
patient’s decision to withdraw from study treatment without occurrence of 
any study treatment discontinuation event will not necessarily define a DLT 
event.  Study treatment discontinuation events are defined in the protocol.  
Dose Expansion: 
The two-stage expansion phase at the MTD will be conducted using a 
modified Simon two-stage design (1, 2).  Both objective response (OR) 
(defined as complete response (CR) + partial response (PR)) and clinical 
benefit (CB) (defined as CR, PR + stable disease (SD)) will be evaluated and 
common set thresholds of lack of efficacy (OR rate (ORR) = 40%; CB rate 
(CBR) = 78%) and an efficacy level of interest (ORR = 60%; CBR = 92%) 
will be selected.  The sample size was driven by the parameter that had the 
larger sample size for each stage.      
Stopping Rule: 
The patient enrollment will be temporarily suspended based on occurrence 
of any the following, and the sponsor, the Data Safety Monitoring Board and 
principal investigators will meet to discuss how to proceed with future 
patient enrollment in the study: 


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• 
If at any time the dose escalation phase of the study, more than one 
patient in a cohort of three, or two of six patients experience any DLT; 
• 
If at any time during the expansion phase of the study, more than 33% 
the patients experience any drug related DLT. 
Evaluations: 
Patients will be evaluated for clinical toxicities during the treatment.  
Patients’ blood samples will be collected to assess the pharmacokinetic 
profile and immunogenicity of the study drug. The anti-tumor response will 
be evaluated for up to 18 weeks from the initial dose of the first course of 
treatment.  All patients who receive at least one dose of the study drug ALT-
801 will be included in the anti-tumor response evaluation.  Between each 
cohort and at the end of the study, all clinical and safety data will be 
analyzed for all patients enrolled in the study for dose-response effects. 
Population: 
Patients of 18 years of age and above who are candidates for systemic 
cisplatin and gemcitabine for the treatment of muscle invasive or metastatic 
urothelial cancer of bladder, renal pelvis, ureters, and urethra may be 
selected for further evaluation of eligibility for study participation.  Patients 
also need to have adequate cardiac, pulmonary, liver and kidney functions 
and to have an Eastern Cooperative Oncology Group (ECOG) performance 
status of 0 or 1 and a life expectancy of at least 12 weeks.  
Sample Size: 
A total of up to 30 assessable patients will be accrued to the initial dose 
escalation phase of the study (Phase Ib); the estimated number is 21.  Up to an 
additional 40 assessable patients will be enrolled at the expansion phase 
(Stage 1 and 2) of the study (Phase II).  A total of approximately 60 
assessable patients will be enrolled and complete the study.  Assume a 20% 
ineligible or non- assessable cases, a total of up 72 patients may be accrued 
to the study. 
Primary 
Endpoints: 
For Stage I only: 
(1) To define an MTD of ALT-801 in combination with cisplatin and 
gemcitabine in the treatment of patients with muscle invasive or 
metastatic urothelial cancer. 
For Stage I & II: 
(2) To assess the safety of the combination study treatment in treated 
patients. 
 
(3) To assess the objective response rate in treated patients. 
Secondary  
Endpoints: 
(1) To assess the progression free survival in treated patients. 
(2) To assess the overall survival in treated patients. 
(3) To evaluate the immunogenicity and pharmacokinetic profiles of ALT-
801 in treated patients. 


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(4) To assess the relationship between tumor presentation of HLA-
A*0201/p53 aa 264-272 complexes and the safety and clinical benefit of 
study treatment. 
Pharmacokinetics 
& Biomarkers: 
Blood samples will be collected to assess typing for HLA-A2, immune cell 
levels, phenotype, pharmacokinetics, immunogenicity of the study drug 
ALT-801, and the serum levels of IFN-γ and TNF-α.  Tumor samples 
obtained from surgeries or biopsies performed prior to screening for the 
study will be collected to test the HLA-A*0201/p53 aa 264-272 complex 
presentation. Blood samples for pharmacokinetic analysis of ALT-801 will 
be taken on the first day of ALT-801 administration in the first course of 
study treatment. Venous blood will be obtained at Time 0 (before the start of 
infusion), at 30 minutes (15 minutes after completion of infusion), and 1, 3 
and 6 hours from Time 0 for the assessment of ALT-801 serum 
concentration. Non-compartmental and compartmental analyses will be 
conducted.  In addition, the same blood samples collected for PK analysis 
will be used to assess the immunogenicity of study drug ALT-801 and the 
serum levels of IFN-γ and TNF-α.  Fresh blood samples for HLA-A2 typing, 
immune cell levels and phenotype testing will be collected before the start of 
the first and second courses of study treatment.  HLA-A2 typing will be 
performed only once. 
Monitoring Tests: Urine samples for urinalysis, blood samples for standard chemistry, CBC, 
differential and coagulation will be obtained at screening, on each study drug 
infusion day, discharge days and follow-up visits.  Blood samples for 
immunogenicity testing, which include assays for anti-ALT-801 and IL-2 
neutralizing antibodies, will be collected prior to dosing on the first ALT-
801 infusion day and at Week 9 from the initial dose of study treatment. 
Anti-tumor  
Response 
Evaluation: 
The anti-tumor response will be evaluated for up to 18 weeks from the initial 
dose of study treatment: for non-responders: Week 9 and 13; for early 
responders: Week 9 and 14; for late responders: Week 9, 13 and 18. 
Objective Response will be evaluated using the new international criteria 
proposed by the Response Evaluation Criteria in Solid Tumors Committee 
(RECIST) 1.1.  Baseline evaluations should be performed up to 28 days 
before starting study 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-ups. Imaging-based evaluation is 
preferred to evaluation by clinical examination when both methods have 
been used to assess the anti-tumor effect of the treatment.  However, 
cystoscopic evaluation may be used routinely in this population, in addition 
to radiologic testing.  If surgeries or biopsies are performed after patients 
receive and respond to study treatment, tumor or tissue samples from these 
procedures will be collected to assess histopathological and immuno-cellular 
responses to study treatment. 
 


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Survival  
Assessment: 
Progression-free survival and overall survival of all enrolled patients will be 
assessed at 6, 9, 12, 18, 24, 30 and 36 months from the start of study 
treatment, or through the point designated as the end of the study follow up. 
Adverse Events: 
All patients will be monitored and evaluated for clinical toxicities during the 
treatment period and queried at each follow-up visit for Adverse Events 
(AEs).  Patients may volunteer information concerning AEs.  All adverse 
events will be graded by using the NCI Common Terminology Criteria for 
Adverse Events version 4.0 (CTCAE v4.0), and logged in the patient Case 
Report Form.  The study centers should report all SAEs and all events that 
trigger patient’s study treatment discontinuation to the sponsor via phone, 
fax or email (or a combination) up to 1 day after learning of the event.  The 
sponsor will use the information to manage and coordinate the dose 
escalation, cohort expansion and patient enrollment.  The sponsor will then 
inform all of the participating clinical sites of the current dose level and the 
number of patients to be enrolled at that level, or of any patient enrollment 
suspension via phone, fax or email within a day of its learning of the event.  
The study centers should report the other adverse events to the sponsor 
following the guidelines defined in the study protocol. All study drug related 
adverse events (AEs) that are both serious and unexpected will be reported 
to the FDA in an expedited manner in accordance with 21 CFR §312.32. 
Statistical Plan: 
For each cohort, all AEs will be tabulated and examined and all safety and 
pharmacokinetic data will be evaluated. For estimation of duration of 
response, the Kaplan-Meier method will be used. P-values of <0.05 (two-
sided) will be considered to indicate statistical significance.   
 


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8. 
STUDY CALENDAR, CLINICAL PROCEDURES & TESTS 
8.1 
Study calendar 
TESTS & PROCEDURES 
SCREEN1 
INITIAL TREATMENT PERIOD 
SCAN #1 
SCAN #2 
REPEAT 
TREATMENT 
SCAN #3 
FOLLOW-UPS 
COURSE 1 
COURSE 2 
COURSE 3 
Month(late responders in parentheses) 
 
1 
2 
3 
4 
3 – 4/(4-5) 
4/(5)  6 
9 
12 
18 24 30 
36 
Week (late responders in parentheses) 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
13 
10/ 
(14) 
11/ 
(15) 
12/ 
(16) 
13/ 
(17) 
14/ 
(18) 
 
 
 
 
 
 
 
Week Day 
 
M 
W 
F  
M 
W 
 
M 
W 
F 
M 
W 
 
M 
W 
F 
M 
W 
  
  
M 
M  M  M 
 
 
 
 
 
 
 
 
Treatment Day 
 
1 
3 
5 
8 
10 
 
22 
24 
26 
29 
31 
 
43 
45 
47 
50 
52 
  
  
  
  
   
 
 
 
 
 
 
 
 
 
Informed consent   
X 
 
 
 
 
 
 
R 
e 
s 
t 
 
P 
e 
r 
i 
o 
d 
 
 
 
 
 
 
 
R 
e 
s 
t 
 
P 
e 
r 
i 
o 
d 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum pregnancy test2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Complete physical exam 
X 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
X 
X 
 
  
  
X 
 
 
 
 
 
 
 
Vital signs, weight, Height3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
Concurrent medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
CBC with Differential, Blood Chemistry 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
Coagulation (PT/INR)4 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
X 
X 
 
  
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Cardiac functions5 
X 
X5 
X 
X 
X 
X 
X5 
X 
X 
X 
X 
X5 
X 
X 
X 
X 
  
  
X5 
X 
X 
X 
 
 
 
 
 
 
 
 
Pulmonary functions 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse event assessment6 
X 
X 
X 
X  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
Tumor assessment7 
X 
  
  
  
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
Survival Assessment8 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
HLA A2 Typing, immune cell levels & phenotype11 
 
 
X9 
 
 
 
  
X9 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HLA-A*0201/p53 tumor typing 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK, IFNγ, TNFα11 
 
 
X10 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
Immunogenicity tests11 
 
 
X12 
  
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
  
  
  
  
  
  
Cisplatin
 
c1 
 
 
 
 
c2 
 
 
 
 
c3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Gemcitabine
 
g1 
 
 
g2 
 
g3 
 
 
g4 
 
g5 
 
 
g6 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study drug (ALT-801)13
 
  
a1 
a2 
a3 
a4 
  
a5 
a6 
a7 
a8 
  
a9 
a10 
a11 
a12 
  
  
a13 
a14 a15 a16 
 
 
 
 
 
 
 
 
1Screening evaluations are performed < 14 days, scan/x-ray < 28 days prior to start of therapy.  If the patient's condition is deteriorating, laboratory evaluations should be repeated within 48 hours prior to initiation of study treatment 
infusion.  2Pregnancy test is for women with childbearing potential only.  3Vital signs (especially blood pressure), clinical status and laboratory tests should be reviewed before start of therapy. Vital signs will be evaluated every 2 
hours after the drug treatment and before discharge, and body weight before study treatment infusion on study treatment infusion day. 4PT/INR should be performed for any bleeding issues. 5Patients are closely monitored for 
hypotension, arrhythmia, angina and myocardial infarction. At screening, patients who are ≥ 50 years of age or have a history of EKG abnormalities, symptoms of cardiac ischemia or arrhythmia will have a stress test (stress 
thallium, stress MUGA or dobutamine echocardiogram) to determine their eligibility for participation in the study. EKG will be performed at start of each treatment course and the repeat study drug treatment course. At the start of 
1st course, EKG is performed only when >14 days since last EKG. 6Patients who have an on-going study drug-related SAE upon study completion or at discontinuation of the study will be contacted by the investigator or his/her 
designee every week until the event is resolved or determined to be irreversible. 7Tumor response and progression will be evaluated in this study using the new international criteria proposed by the RECIST (1.1). 8Information about 
tumor assessment & other therapies received after completion of study treatment will be collected if available  9Fresh blood samples for HLA A2 blood typing, immune cell levels & phenotype testing will be collected before dosing. 
10Collect blood samples at Time 0 (before drug infusion), at 30 min (15 min after completion of infusion, +/- 5 min), 1 hour (+/- 10 min), 3 hour (+/- 30 min), 6 hour (+/- 60 min) from Time 0. IFNγ and TNFα assays are performed 
using the same samples and at the same schedule as PK.  11Residual samples may be used by Sponsor for research studies of other biomarkers. 12Use the same blood sample collected before dosing for PK test.13On the days when 
gemcitabine and ALT-801 are both given, gemcitabine should be dosed first.  




 
 
 
CLINICAL STUDY PROTOCOL 
 
 
Protocol Number: 
CA-ALT-801-01-10 
 
 
Protocol Title: 
A Phase Ib/II Trial of ALT-801 in Combination 
with Cisplatin and Gemcitabine in Muscle 
Invasive or Metastatic Urothelial Cancer  
 
 
 
Date of Protocol: 
 
Version # 01 
Version # 02 
Version # 03 
Version # 04 
Version # 05 
 
October 31, 2010 
July 8, 2011 
November 10, 2011 
December 23, 2011 
May 11, 2012 
 
 
Sponsor Contact: 
 
Hing C. Wong, Ph.D. 
Altor Bioscience Corporation. 
Miramar, Florida 33025 
Telephone: 
954-443-8600 
Safety Data Fax: 
954-443-8602 
 
 
 


   
 
 
 
INVESTIGATOR SIGNATURE PAGE 
 
Protocol Number: 
CA-ALT-801-01-10 
 
 
Protocol Title: 
A Phase Ib/II Trial of ALT-801 in Combination 
with Cisplatin and Gemcitabine in Muscle 
Invasive or Metastatic Urothelial Cancer 
 
 
Date of Protocol: 
 
Version # 01 
Version # 02 
Version # 03 
Version # 04 
Version # 05 
October 31, 2010 
July 8, 2011 
November 10, 2011 
December 23, 2011 
May 11, 2012 
 
 
Sponsor Contact: 
 
Hing C. Wong, Ph.D. 
Altor Bioscience Corporation. 
Miramar, Florida 33025 
Telephone: 
954-443-8600 
Safety Data Fax: 
954-443-8602 
 
 
 
By my signature below, I hereby attest that I have read, and that I understand and will abide by 
all the conditions, instructions, and restrictions contained in the attached protocol. 
 
Additionally, I will not initiate this study without approval of the appropriate Institutional 
Review Board (IRB), and I understand that any changes in the protocol must be approved in 
writing by the sponsor, the IRB, and, in certain cases the FDA, before they can be implemented, 
except where necessary to eliminate hazards to subjects. 
 
 
 
 
 
Principal Investigator’s Signature 
 
Date 
 
 
 
 
 
 
 
 
 
Principal Investigator’s Name (Print) 
 
 
 
 
 
 
 
 
 
 
 


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Table of Contents 
SYNOPSIS ........................................................................................................................................ 7 
1. 
OBJECTIVES ........................................................................................................................ 13 
1.1 
PRIMARY OBJECTIVES ....................................................................................................... 13 
1.2 
SECONDARY OBJECTIVES .................................................................................................. 13 
2. 
BACKGROUND .................................................................................................................... 13 
2.1 
ALT-801 – GENERAL INFORMATION ................................................................................ 13 
2.2 
BLADDER CANCER ............................................................................................................ 13 
2.3 
IMMUNOTHERAPY ............................................................................................................. 14 
2.4 
INTRATUMORAL TARGETING AND P53 AS A TARGET FOR BIOTHERAPY .............................. 14 
2.5 
P53 AS A THERAPEUTIC TARGET FOR BLADDER CANCER .................................................... 16 
2.6 
IN VITRO CHARACTERIZATION AND TUMOR EFFICACY STUDIES IN ANIMAL MODELS .......... 16 
2.6.1 Efficacy evaluation of ALT-801 dose regimens in xenograft tumor models ................ 17 
2.6.2 Efficacy of ALT-801 and non-targeted scTCR/IL-2 fusion proteins against 
subcutaneous xenograft tumors derived from human urothelial cancer cells. ........................ 18 
2.6.3 Activity of ALT-801 against human p53-negative orthotropic murine bladder tumors 
in immunocompetent mice. ....................................................................................................... 19 
2.7 
NON-CLINICAL TOXICOLOGY ............................................................................................ 20 
2.7.1 Single-dose toxicity study ............................................................................................. 20 
2.7.2 Multi-dose toxicity study .............................................................................................. 20 
2.8 
PHARMACOKINETICS ......................................................................................................... 21 
2.8.1 Non-clinical pharmacokinetics .................................................................................... 21 
2.8.2 Clinical pharmacokinetics ........................................................................................... 21 
2.9 
HUMAN EXPERIENCE ......................................................................................................... 22 
2.9.1 Pharmacodynamics ...................................................................................................... 22 
2.9.2 Tumor assessment ........................................................................................................ 22 
2.9.3 Safety results ................................................................................................................ 23 
2.9.4 Repeat treatment .......................................................................................................... 24 
3. 
RATIONALE FOR THE CURRENT STUDY ................................................................... 24 
4. 
OVERALL STUDY DESIGN ............................................................................................... 26 
5. 
STUDY POPULATION ........................................................................................................ 28 
5.1 
INCLUSION CRITERIA ......................................................................................................... 28 
5.2 
EXCLUSION CRITERIA ........................................................................................................ 29 
5.3 
INCLUSION OF WOMEN AND MINORITIES............................................................................ 29 
6. 
STUDY DESIGN .................................................................................................................... 30 
6.1 
STUDY FLOW DIAGRAM ..................................................................................................... 30 
6.2 
SCREENING AND ENROLLMENT ......................................................................................... 30 
6.3 
STUDY TREATMENT........................................................................................................... 30 
6.3.1 Treatment setting ......................................................................................................... 31 
6.3.2 Treatment regimen ....................................................................................................... 31 
6.3.3 Pre-therapy and post-therapy interventions ................................................................ 32 


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6.3.4 Study drug preparation and administration ................................................................ 34 
6.3.4.1 
ALT-801 .............................................................................................................. 34 
6.3.4.2 
Cisplatin ............................................................................................................... 34 
6.3.4.3 
Gemcitabine ......................................................................................................... 34 
6.4 
DURATION OF PATIENT PARTICIPATION ............................................................................. 34 
6.5 
DOSE ESCALATION ............................................................................................................ 34 
6.6 
EXPANSION AT RD ............................................................................................................ 35 
6.7 
STOPPING RULES ............................................................................................................... 35 
6.8 
PATIENT MONITORING, ANTI-TUMOR RESPONSE EVALUATION, SURVIVAL ASSESSMENT .... 36 
6.8.1 Patient monitoring ....................................................................................................... 36 
6.8.2 Anti-tumor response evaluation ................................................................................... 36 
6.8.3 Survival assessment ..................................................................................................... 37 
6.9 
DOSE LIMITING TOXICITIES ............................................................................................... 37 
6.10 
STUDY TREATMENT DISCONTINUATION............................................................................. 37 
6.10.1 
Study treatment discontinuation events ................................................................... 37 
6.10.2 
Follow-ups after treatment discontinuation............................................................. 38 
6.10.2.1. 
Discontinuation due to SAEs or on-going study drug related AEs ................. 38 
6.10.2.2. 
Discontinuation due to any other reasons ........................................................ 38 
6.11 
STUDY TREATMENT ADJUSTMENT ..................................................................................... 38 
6.11.1 
Modifications & delays for creatinine clearance (kidney dysfunction) ................... 38 
6.11.1.1. 
On cycles that have treatment with cisplatin, gemcitabine and ALT-801 ....... 38 
6.11.1.2. 
On cycles that have only ALT-801 .................................................................. 39 
6.11.1.3. 
Interventions .................................................................................................... 39 
6.11.2 
Hematological dysfunction ...................................................................................... 39 
6.11.2.1. 
On cycles that have treatment with cisplatin, gemcitabine and ALT-801 ....... 39 
6.11.2.2. 
On cycles that only have ALT-801 .................................................................. 40 
6.11.2.3. 
Transfusion and growth factor interventions ................................................... 40 
6.11.3 
Hypotension ............................................................................................................. 41 
6.11.4 
Allergic reactions and cytokine release syndrome/acute infusion reaction ............ 41 
6.11.5 
Oncological surgeries post study treatment ............................................................ 41 
6.12 
SECOND AND THIRD COURSES OF STUDY TREATMENT ....................................................... 41 
6.12.1 
Qualification ............................................................................................................ 41 
6.12.2 
Treatment schedule and procedures ........................................................................ 41 
6.13 
REPEAT STUDY DRUG TREATMENT .................................................................................... 41 
6.13.1 
Qualification ............................................................................................................ 41 
6.13.2 
Treatment schedule and procedures ........................................................................ 42 
6.14 
GENERAL SUPPORTIVE CARE GUIDELINES AND DRUG INTERACTION .................................. 42 
6.14.1 
ALT-801 ................................................................................................................... 42 
6.14.1.1. 
Hypotension and capillary leak syndrome ....................................................... 42 
6.14.1.2. 
Pulmonary dysfunction .................................................................................... 43 
6.14.1.3. 
Impaired kidney and liver functions ................................................................ 43 
6.14.1.4. 
Infection ........................................................................................................... 43 
6.14.1.5. 
Fever and chills ................................................................................................ 43 
6.14.1.6. 
Gastritis ............................................................................................................ 43 
6.14.1.7. 
Diarrhea, nausea and vomiting ........................................................................ 43 
6.14.1.8. 
Pruritus and dermatitis ..................................................................................... 43 


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6.14.1.9. 
Acidosis............................................................................................................ 43 
6.14.1.10. Life-threatening toxicities ................................................................................ 43 
6.14.1.11. Other supportive care ....................................................................................... 44 
6.14.1.12. Drug interaction ............................................................................................... 44 
6.14.2 
Cisplatin ................................................................................................................... 45 
6.14.3 
Gemcitabine ............................................................................................................. 45 
7. 
STUDY DRUG: AVAILABILITY, ACCOUNTABILITY, PACKAGING & 
LABELING .................................................................................................................................... 46 
7.1 
ALT-801 .......................................................................................................................... 46 
7.1.1 Availability ................................................................................................................... 46 
7.1.2 Accountability .............................................................................................................. 46 
7.1.3 Packaging .................................................................................................................... 46 
7.1.4 Labeling ....................................................................................................................... 46 
7.2 
CISPLATIN AND GEMCITABINE .......................................................................................... 46 
8. 
STUDY CALENDAR, CLINICAL PROCEDURES & TESTS ........................................ 47 
8.1 
STUDY CALENDAR ............................................................................................................ 47 
8.2 
PROCEDURE AND TESTS .................................................................................................... 48 
8.2.1 HLA-A2 typing and assays for immune cell levels and phenotype .............................. 48 
8.2.2 Presentation of HLA-A*0201/p53 aa264-272 complexes on tumor surfaces .............. 48 
8.2.3 Medical history ............................................................................................................ 48 
8.2.4 Pregnancy test .............................................................................................................. 48 
8.2.5 Physical examination ................................................................................................... 48 
8.2.6 Vital signs, body weight & height ................................................................................ 48 
8.2.7 Cardiac assessment ...................................................................................................... 48 
8.2.8 Blood tests .................................................................................................................... 49 
8.2.9 Urinalysis ..................................................................................................................... 49 
8.2.10 
Pulmonary functions ................................................................................................ 49 
8.2.11 
Adverse event assessment ........................................................................................ 49 
8.2.12 
Tumor assessment .................................................................................................... 49 
8.2.13 
Survival assessment ................................................................................................. 50 
8.2.14 
Pharmacokinetic (PK) testing .................................................................................. 50 
8.2.15 
Biomarker assays for IFNγ and TNFα .................................................................... 50 
8.2.16 
Immunogenicity tests - detection of anti-ALT-801 and IL2-neutralizing antibodies
 
50 
9. 
MEASUREMENT OF EFFECT .......................................................................................... 50 
9.1 
DEFINITIONS ..................................................................................................................... 50 
9.1.1 Measurable disease ...................................................................................................... 51 
9.1.2 Non-measurable disease .............................................................................................. 51 
9.1.3 Target lesion ................................................................................................................ 52 
9.1.4 Non-target lesions ........................................................................................................ 52 
9.2 
GUIDELINES FOR EVALUATION OF MEASURABLE DISEASE ................................................. 52 
9.3 
RESPONSE CRITERIA .......................................................................................................... 53 
9.3.1 Evaluation of target lesions ......................................................................................... 53 
9.3.2 Evaluation of non-target lesions .................................................................................. 53 


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9.3.3 Evaluation of best overall response ............................................................................. 54 
9.4 
CONFIRMATORY ................................................................................................................ 54 
10. 
STATISTICAL ANALYSIS ............................................................................................. 54 
10.1 
STUDY OBJECTIVES ........................................................................................................... 54 
10.2 
SAMPLE SIZE ..................................................................................................................... 55 
10.3 
DATA COLLECTION ........................................................................................................... 55 
10.4 
DATA ANALYSIS ................................................................................................................ 55 
10.4.1 
Analysis of safety...................................................................................................... 56 
10.4.2 
Analysis of response ................................................................................................. 56 
10.4.3 
Pharmacokinetics ..................................................................................................... 56 
11. 
REGULATORY AND REPORTING REQUIREMENTS ............................................ 56 
11.1 
ADVERSE EVENTS RECORDING, REPORTING AND COMMUNICATION .................................. 56 
11.2 
ADVERSE EVENT TERMINOLOGY AND DEFINITIONS ........................................................... 57 
11.3 
ADVERSE EVENT REPORTING PROCEDURES ...................................................................... 58 
11.4 
ADVERSE EVENT EXPEDITED REPORTING GUIDELINES ..................................................... 58 
11.5 
SUBMISSION OF SERIOUS ADVERSE EVENT REPORTING ...................................................... 58 
11.6 
DATA REPORTING FORMS ................................................................................................. 59 
11.7 
REPORT /DATA SUBMISSION ADDRESS & CONTACT ........................................................... 59 
11.8 
PATIENT RECORDS, QUALITY ASSURANCE, RECORDS RETENTION ...................................... 60 
11.9 
METHOD OF REVIEW ......................................................................................................... 60 
11.10 
SPECIAL REGULATORY CONSIDERATIONS ...................................................................... 60 
11.10.1 HIPAA ...................................................................................................................... 60 
11.10.2 Protocol amendments, informed consent, and IRB approval .................................. 61 
12. 
CONFIDENTIALITY ....................................................................................................... 61 
13. 
ETHICAL STANDARDS & INVESTIGATOR OBLIGATIONS ................................ 61 
14. 
LIST OF EXPECTED ADVERSE EVENTS .................................................................. 62 
15. 
CTCAE................................................................................................................................ 64 
REFERENCES ............................................................................................................................... 65 
APPENDIX A: PERFORMANCE STATUS CRITERIA.......................................................... 68 
APPENDIX B: NEW YORK HEART ASSOCIATION CLASSIFICATION ......................... 68 
APPENDIX C: ETHICAL STANDARDS ................................................................................... 69 
APPENDIX D: INVESTIGATOR OBLIGATIONS .................................................................. 70 
APPENDIX E: CONTACT LIST - ALTOR ............................................................................... 74 
APPENDIX F: CONTACT LIST – DATA SAFETY MONITORING BOARD (DSMB) ...... 75 
APPENDIX G: CONTACT LIST - LABORATORIES ............................................................. 75 
APPENDIX H: APPROVAL PAGE ............................................................................................ 76 


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SYNOPSIS 
Sponsor: 
Altor Bioscience Corporation 
Protocol#: 
CA-ALT-801-01-10 
Study Drug Name: Not applicable 
Study Treatment 
Active agents: 
ALT-801 (c264scTCR-IL2), recombinant humanized, soluble single-chain 
TCR-cytokine fusion protein; Cisplatin; Gemcitabine. 
Study Type: 
Interventional 
Study Phase: 
Ib/II 
Protocol Title: 
A Phase Ib/II Trial of ALT-801 in Combination with Cisplatin and 
gemcitabine in Muscle Invasive or Metastatic Urothelial Cancer 
Objectives:   
To determine the safety and tolerability of the novel combination of addition 
of ALT-801 (c264scTCR-IL2) to the doublet of cisplatin and gemcitabine in 
patients with muscle invasive or metastatic urothelial cancer of bladder, 
renal pelvis, ureters and urethra.   
To estimate the anti-tumor activity of this combination of ALT-801, 
cisplatin and gemcitabine by radiologic or pathologic anti-tumor response, 
progression free survival (assessed through end of study), and overall 
survival (assessed through end of study) in treated patients.  
To characterize the immunogenicity and pharmacokinetic profile of ALT-
801 in combination with cisplatin and gemcitabine in treated patients. 
To assess the relationship between tumor presentation of HLA-A*0201/p53 
aa 264-272 complex and the safety and clinical benefit of study treatment. 
Study Design: 
This is a Phase Ib/II, open-label, multi-center, competitive enrollment and 
dose-escalation study of ALT-801 in a biochemotherapy regimen containing 
cisplatin and gemcitabine in patients who have muscle invasive or metastatic 
urothelial cancer of bladder, renal pelvis, ureters and urethra.  The study will 
be conducted in conformity with Good Clinical Practice (GCP).  
The study includes a dose escalation phase to determine the maximum 
tolerated dose (MTD) and the recommended dose (RD) for dose expansion 
of ALT-801 in combination with cisplatin and gemcitabine and a two-stage 
expansion phase at the RD.  The dose escalation in this study is conducted 
using a (3+3) dose escalation design, and the two-stage expansion phase at 
the RD using a modified Simon two-stage design (1, 2).  In the dose 
escalation phase of this study, there are five dose levels of ALT-801 (0.04 
mg/kg, 0.06 mg/kg, 0.08 mg/kg, 0.10 mg/kg and 0.12 mg/kg) in addition to 
two de-escalation dose levels.  The doses of cisplatin (70 mg/m2/dose) and 
gemcitabine (1000 mg/m2/dose) will be fixed across all ALT-801 dose 
levels.  If the MTD cannot be determined after the maximum planned 
escalating dose level has been reached, or the RD for dose expansion cannot 
be determined during the dose escalation phase, the sponsor, the Data Safety 
Monitoring Board (DSMB) and the principal investigators will meet to 


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discuss whether to amend the protocol to expand the dose escalation phase to 
include additional ALT-801 dose levels.  
Treatments: 
The planned initial on-study treatment will be for 3 courses of chemo-
immunotherapy.  Each course consists of cisplatin (Day #1), gemcitabine 
(Day #1), ALT-801 (Day #3 & Day #5), gemcitabine (Day #8), ALT-801 
(Day #8 & Day #12 or #15), and a rest period (Days #13 (or #16) - #21). The 
alternative dosing day (Day #15) for the last dose (dose #4) of ALT-801 in 
each course is provided to allow sufficient recovery from transient study 
drug related toxicities. Prior to commencing the second or the third course of 
study treatment, subjects will need to meet the treatment continuation 
criteria. At completion of the three full courses of study treatment, each 
patient enrolled will have received a total of 12 doses of the study drug 
ALT-801, 3 doses of cisplatin, and 6 doses of gemcitabine. After completing 
the 3-course initial study treatment, patients who have at least stable disease 
and meet other treatment criteria will repeat study treatment with four 
additional weekly doses of ALT-801.  Treatment delays or dose 
modifications or omissions are addressed in the protocol. The treatment 
schedule is illustrated in the following schemas: 
 
Initial Study Treatment: 
 
 
 
 
RRepeat Study Treatment: 
 
 
 
Enrolled patients will receive the study treatment at qualified cancer 
treatment centers with adequate diagnostic and treatment facilities to provide 
appropriate management of therapy and complications. ALT-801, cisplatin 
and gemcitabine will be administered by intravenous infusion into a central 
or peripheral vein under the supervision of a qualified physician experienced 
in the use of anti-cancer agents including aldesleukin (Proleukin), cisplatin 
and gemcitabine. 
This is the schema for the dose levels during the dose-escalation phase of the 
study.  The -1 and -2 dose levels of ALT-801 are included in case of DLT 
events in the initial dose level.  
Cohort 
ALT-801 Dose (mg/kg) 
Cisplatin  (mg/m2) 
Gemcitabine (mg/m2) 
-2 
0.01 
70 
1000 
-1 
0.02 
70 
1000 
1 (initial) 
0.04 
70 
1000 
2 
0.06 
70 
1000 
3 
0.08 
70 
1000 
4 
0.10 
70 
1000 
5 
0.12 
70 
1000 
 
Course 1 
Course 2 
Course 3 
Treatment Day 1 
3 
5 
8 12(15) 13(16)-21 22 24 26 29 33(36) 34(37)-42 43 45 47 
50 54(57) 
Cisplatin 
X 
 
 
 
 
Rest 
Period 
X 
 
 
 
 
Rest 
Period 
X 
 
 
 
 
Gemcitabine 
X 
 
 
X 
 
X 
 
 
X 
 
X 
 
 
X 
 
ALT-801 
 
X 
X 
X 
X 
 
X X X 
X 
 
X X 
X 
X 
Dose# 
1 
2 
3 
4 
Repeat 
Treatment Day 1 
8 
15 22 
ALT-801 
X 
X 
X 
X 


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Dose Escalation: 
In this phase of the study, a minimum of 3 patients will be enrolled at each 
dose level.  All patients will be monitored for Dose Limiting Toxicity (DLT) 
for 8 weeks from the initial dose.  If 0/3 patients have study treatment-
related, dose-limiting toxicity by 8 weeks after the initial dose, the next 
cohort will be opened for enrollment. If one patient at a dose-level develops 
drug-related DLT, up to six patients will be enrolled at that dose level and 
each subsequent higher dose level.  If 0 or 1 of 6 patients in a cohort of 6 
patients have an event that meets criteria for study treatment-related DLT, 
then the next cohort will be opened for enrollment. If 2 or more out of 3-6 
patients in a dose escalation cohort have a DLT that is drug-related, that dose 
level will be designated as exceeding the maximum tolerated dose. If there 
are 3 patients in the dose level below this level, then additional patients (up 
to 6 total) will be enrolled at that dose level. When there is a dose level with 
0 or 1 out of 6 patients with DLT, which is either the maximum planned 
dose level (level 5) or which is one level below a dose that was not tolerated, 
the dose that is the maximum tolerated dose (MTD) will be considered 
defined. Further changes in the treatment plan may be considered by 
protocol amendment at that point.  
If more than two of six patients experience a DLT at the initial dose level 
(level 1), then the sponsor, the Data Safety Monitoring Board (DSMB) and 
the principal investigators will meet to determine how to adjust downward 
the dose level of cisplatin, gemcitabine, and/or the study drug, or continue 
with the (-1) and (-2) cohorts, and to determine how to proceed with the 
study.  
At any time during the dose escalation phase of the study, whether or not the 
MTD or the maximum planned escalating dose level is reached, the dose 
escalation phase may be concluded due to favorable anti-tumor effect 
observed in the enrolled patients.  The DSMB will recommend a dose level 
of ALT-801 (RD) for the dose expansion phase of the study. 
Dose limiting toxicity (DLT) is defined as any toxicity of grade 3 that does 
not resolve to Grade 1 or lower within 72 hours and any toxicity of Grade 4 
occurring during treatment courses with exceptions and details described in 
the study protocol. Patients experiencing a DLT should discontinue study 
treatment.  Study treatment discontinuation due to adverse events 
experienced prior to study drug administration, disease progression or 
patient’s decision to withdraw from study treatment without occurrence of 
any study treatment discontinuation event will not necessarily define a DLT 
event.  Study treatment discontinuation events are defined in the protocol.  
Dose Expansion: 
The two-stage expansion phase at the recommended dose (RD) will be 
conducted using a modified Simon two-stage design (1, 2).  Both objective 
response (OR) (defined as complete response (CR) + partial response (PR)) 
and clinical benefit (CB) (defined as CR, PR + stable disease (SD)) will be 
evaluated and common set thresholds of lack of efficacy (OR rate (ORR) = 
40%; CB rate (CBR) = 78%) and an efficacy level of interest (ORR = 60%; 


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CBR = 92%) will be selected.  The sample size was driven by the parameter 
that had the larger sample size for each stage.      
Stopping Rules: 
The patient enrollment will be temporarily suspended based on occurrence 
of any the following, and the sponsor, the Data Safety Monitoring Board and 
principal investigators will meet to discuss how to proceed with future 
patient enrollment in the study: 
• 
If at any time during the dose escalation phase of the study,  
 
more than one patient in a cohort of three, or two of six patients 
experience any DLT or, 
 favorable anti-tumor response data collected from enrolled patients 
that indicates a dose level with significant therapeutic effect may 
have been found 
• 
If at any time during the expansion phase of the study, more than 33% 
the patients experience any drug related DLT. 
Evaluations: 
Patients will be evaluated for clinical toxicities during the treatment.  
Patients’ blood samples will be collected to assess the pharmacokinetic 
profile and immunogenicity of the study drug. The anti-tumor response will 
be evaluated for up to 18 weeks from the initial dose of the first course of 
treatment.  All patients who receive at least one dose of the study drug ALT-
801 will be included in the anti-tumor response evaluation.  Between each 
cohort and at the end of the study, all clinical and safety data will be 
analyzed for all patients enrolled in the study for dose-response effects. 
Population: 
Patients of 18 years of age and above who are candidates for systemic 
cisplatin and gemcitabine for the treatment of muscle invasive or metastatic 
urothelial cancer of bladder, renal pelvis, ureters, and urethra may be 
selected for further evaluation of eligibility for study participation.  Patients 
also need to have adequate cardiac, pulmonary, liver and kidney functions 
and to have an Eastern Cooperative Oncology Group (ECOG) performance 
status of 0 or 1 .  
Sample Size: 
A total of up to 30 assessable patients will be accrued to the initial dose 
escalation phase of the study (Phase Ib); the estimated number is 21.  Up to an 
additional 40 assessable patients will be enrolled at the expansion phase 
(Stage 1 and 2) of the study (Phase II).  A total of approximately 60 
assessable patients will be enrolled and complete the study.  Assume a 20% 
ineligible or non- assessable cases, a total of up 72 patients may be accrued 
to the study. 
Primary 
Endpoints: 
For Stage I only: 
(1) To define an MTD and RD for dose expansion of ALT-801 in 
combination with cisplatin and gemcitabine in the treatment of patients 
with muscle invasive or metastatic urothelial cancer. 


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For Stage I & II: 
(2) To assess the safety of the combination study treatment in treated 
patients. 
 
(3) To assess the objective response rate in treated patients. 
Secondary  
Endpoints: 
(1) To assess the progression free survival in treated patients. 
(2) To assess the overall survival in treated patients. 
(3) To evaluate the immunogenicity and pharmacokinetic profiles of ALT-
801 in treated patients. 
(4) To assess the relationship between tumor presentation of HLA-
A*0201/p53 aa 264-272 complexes and the safety and clinical benefit of 
study treatment. 
Pharmacokinetics 
& Biomarkers: 
Blood samples will be collected to assess typing for HLA-A2, immune cell 
levels, phenotype, pharmacokinetics, immunogenicity of the study drug 
ALT-801, and the serum levels of IFN-γ and TNF-α.  Tumor samples 
obtained from surgeries or biopsies performed prior to screening for the 
study will be collected to test the HLA-A*0201/p53 aa 264-272 complex 
presentation. Blood samples for pharmacokinetic analysis of ALT-801 will 
be taken on the first day of ALT-801 administration in the first course of 
study treatment. Venous blood will be obtained at Time 0 (before the start of 
infusion), at 30 minutes (15 minutes after completion of infusion), and 1, 3 
and 6 hours from Time 0 for the assessment of ALT-801 serum 
concentration. Non-compartmental and compartmental analyses will be 
conducted.  In addition, the same blood samples collected for PK analysis 
will be used to assess the immunogenicity of study drug ALT-801 and the 
serum levels of IFN-γ and TNF-α.  Fresh blood samples for HLA-A2 typing, 
immune cell levels and phenotype testing will be collected before the start of 
the first and second courses of study treatment.  HLA-A2 typing will be 
performed only once. 
Monitoring Tests: Urine samples for urinalysis, blood samples for standard chemistry, CBC, 
differential and coagulation will be obtained at screening, on each study drug 
infusion day, discharge days and follow-up visits.  Blood samples for 
immunogenicity testing, which include assays for anti-ALT-801 and IL-2 
neutralizing antibodies, will be collected prior to dosing on the first ALT-
801 infusion day and at Week 9 from the initial dose of study treatment. 
Anti-tumor  
Response 
Evaluation: 
The anti-tumor response will be evaluated for up to 18 weeks from the initial 
dose of study treatment: for non-responders: Week 9 and 13; for early 
responders: Week 9 and 14; for late responders: Week 9, 13 and 18. 
Objective Response will be evaluated using the new international criteria 
proposed by the Response Evaluation Criteria in Solid Tumors Committee 
(RECIST) 1.1.  Baseline evaluations should be performed up to 28 days 
before starting study treatment. The same method of assessment and the 


CA-ALT-801-01-10 
 
 
 
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same technique should be used to characterize each identified and reported 
lesion at baseline and during follow-ups. Imaging-based evaluation is 
preferred to evaluation by clinical examination when both methods have 
been used to assess the anti-tumor effect of the treatment.  However, 
cystoscopic evaluation may be used routinely in this population, in addition 
to radiologic testing.  If surgeries or biopsies are performed after patients 
receive and respond to study treatment, tumor or tissue samples from these 
procedures will be collected to assess histopathological and immuno-cellular 
responses to study treatment. 
 
Survival  
Assessment: 
Progression-free survival and overall survival of all enrolled patients will be 
assessed at 6, 9, 12, 18, 24, 30 and 36 months from the start of study 
treatment, or through the point designated as the end of the study follow up. 
Adverse Events: 
All patients will be monitored and evaluated for clinical toxicities during the 
treatment period and queried at each follow-up visit for Adverse Events 
(AEs).  Patients may volunteer information concerning AEs.  All adverse 
events will be graded by using the NCI Common Terminology Criteria for 
Adverse Events version 4.0 (CTCAE v4.0), and logged in the patient Case 
Report Form.  The study centers should report all SAEs and all events that 
trigger patient’s study treatment discontinuation to the sponsor via phone, 
fax or email (or a combination) up to 1 day after learning of the event.  The 
sponsor will use the information to manage and coordinate the dose 
escalation, cohort expansion and patient enrollment.  The sponsor will then 
inform all of the participating clinical sites of the current dose level and the 
number of patients to be enrolled at that level, or of any patient enrollment 
suspension via phone, fax or email within a day of its learning of the event.  
The study centers should report the other adverse events to the sponsor 
following the guidelines defined in the study protocol. All study drug related 
adverse events (AEs) that are both serious and unexpected will be reported 
to the FDA in an expedited manner in accordance with 21 CFR §312.32. 
Statistical Plan: 
For each cohort, all AEs will be tabulated and examined and all safety and 
pharmacokinetic data will be evaluated. For estimation of duration of 
response, the Kaplan-Meier method will be used. P-values of <0.05 (two-
sided) will be considered to indicate statistical significance.   
 


CA-ALT-801-01-10 
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8. 
STUDY CALENDAR, CLINICAL PROCEDURES & TESTS 
8.1 
Study calendar 
TESTS & PROCEDURES 
SCREEN1 
INITIAL TREATMENT PERIOD 
SCAN #1 
SCAN #2 
REPEAT 
TREATMENT 
SCAN #3 
FOLLOW-UPS 
COURSE 1 
COURSE 2 
COURSE 3 
Month(late responders in parentheses) 
 
1 
2 
3 
4 
3 – 4/(4-5) 
4/(5)  6 
9 
12 
18 24 30 
36 
Week (late responders in parentheses) 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
13 
10/ 
(14) 
11/ 
(15) 
12/ 
(16) 
13/ 
(17) 
14/ 
(18) 
 
 
 
 
 
 
 
Week Day 
 
M 
W 
F  
M 
F 
 
M 
W 
F 
M 
F 
 
M 
W 
F 
M 
F 
  
  
M 
M  M  M 
 
 
 
 
 
 
 
 
Treatment Day 
 
1 
3 
5 
8 
12 
 
22 
24 
26 
29 
33 
 
43 
45 
47 
50 
54 
  
  
  
  
   
 
 
 
 
 
 
 
 
 
Informed consent   
X 
 
 
 
 
 
 
R 
e 
s 
t 
 
P 
e 
r 
i 
o 
d 
 
 
 
 
 
 
 
R 
e 
s 
t 
 
P 
e 
r 
i 
o 
d 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum pregnancy test2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Complete physical exam 
X 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
X 
X 
 
  
  
X 
 
 
 
 
 
 
 
Vital signs, weight, Height3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
Concurrent medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
CBC with Differential, Blood Chemistry 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
Coagulation (PT/INR)4 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
X 
X 
 
  
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Cardiac functions5 
X 
X5 
X 
X 
X 
X 
X5 
X 
X 
X 
X 
X5 
X 
X 
X 
X 
  
  
X5 
X 
X 
X 
 
 
 
 
 
 
 
 
Pulmonary functions 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse event assessment6 
X 
X 
X 
X  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
Tumor assessment7 
X 
  
  
  
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
Survival Assessment8 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
HLA A2 Typing, immune cell levels & phenotype11 
 
 
X9 
 
 
 
  
X9 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HLA-A*0201/p53 tumor typing 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK, IFNγ, TNFα11 
 
 
X10 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
Immunogenicity tests11 
 
 
X12 
  
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
  
  
  
  
  
  
Cisplatin
 
c1 
 
 
 
 
c2 
 
 
 
 
c3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Gemcitabine
 
g1 
 
 
g2 
 
g3 
 
 
g4 
 
g5 
 
 
g6 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study drug (ALT-801)13
 
  
a1 
a2 
a3 
a414 
  
a5 
a6 
a7 
a814 
  
a9 
a10 
a11 a1214 
  
  
a13 
a14 a15 a16 
 
 
 
 
 
 
 
 
1Screening evaluations are performed < 14 days, scan/x-ray < 28 days prior to start of therapy.  If the patient's condition is deteriorating, ECOG status and laboratory evaluations should be repeated within 48 hours prior to initiation 
of study treatment infusion.  2Pregnancy test is for women with childbearing potential only.  3Vital signs (especially blood pressure), clinical status and laboratory tests should be reviewed before start of therapy. Vital signs will be 
evaluated every 2 hours after the drug treatment and before discharge, and body weight before study treatment infusion on study treatment infusion day. 4PT/INR should be performed for any bleeding issues. 5Patients are closely 
monitored for hypotension, arrhythmia, angina and myocardial infarction. At screening, patients who are ≥ 50 years of age or have a history of EKG abnormalities, symptoms of cardiac ischemia or arrhythmia will have a stress test 
(stress thallium, stress MUGA or dobutamine echocardiogram) to determine their eligibility for participation in the study. EKG will be performed for all patients at start of each treatment course and the repeat study drug treatment 
course. At the start of 1st course, EKG is performed only when >14 days since last EKG. 6Patients who have an on-going study drug-related SAE upon study completion or at discontinuation of the study will be contacted by the 
investigator or his/her designee every week until the event is resolved or determined to be irreversible. 7Tumor response and progression will be evaluated in this study using the new international criteria proposed by the RECIST (1.1). 
8Information about tumor assessment & other therapies received after completion of study treatment will be collected if available  9Fresh blood samples for HLA A2 blood typing, immune cell levels & phenotype testing will be 
collected before dosing. 10Collect blood samples at Time 0 (before drug infusion), at 30 min (15 min after completion of infusion, +/- 5 min), 1 hour (+/- 10 min), 3 hour (+/- 30 min), 6 hour (+/- 60 min) from Time 0. IFNγ and 
TNFα assays are performed using the same samples and at the same schedule as PK.  11Residual samples may be used by Sponsor for research studies of other biomarkers. 12Use the same blood sample collected before dosing for 
PK test.13On the days when gemcitabine and ALT-801 are both given, gemcitabine should be dosed first.  14This dose can be delayed to the following Monday.  




 
 
 
CLINICAL STUDY PROTOCOL 
 
 
Protocol Number: 
CA-ALT-801-01-10 
 
 
Protocol Title: 
A Phase Ib/II Trial of ALT-801 in Combination 
with Cisplatin and Gemcitabine in Muscle 
Invasive or Metastatic Urothelial Cancer  
 
 
 
Date of Protocol: 
 
Version # 01 
Version # 02 
Version # 03 
Version # 04 
Version # 05 
Version # 06 
 
October 31, 2010 
July 8, 2011 
November 10, 2011 
December 23, 2011 
May 11, 2012 
October 18, 2012 
 
Sponsor Contact: 
 
Hing C. Wong, Ph.D. 
Altor Bioscience Corporation. 
Miramar, Florida 33025 
Telephone: 
954-443-8600 
Safety Data Fax: 
954-443-8602 
 
 
 


   
 
 
 
INVESTIGATOR SIGNATURE PAGE 
 
Protocol Number: 
CA-ALT-801-01-10 
 
 
Protocol Title: 
A Phase Ib/II Trial of ALT-801 in Combination 
with Cisplatin and Gemcitabine in Muscle 
Invasive or Metastatic Urothelial Cancer 
 
 
Date of Protocol: 
 
Version # 01 
Version # 02 
Version # 03 
Version # 04 
Version # 05 
Version # 06 
October 31, 2010 
July 8, 2011 
November 10, 2011 
December 23, 2011 
May 11, 2012 
October 18, 2012 
 
Sponsor Contact: 
 
Hing C. Wong, Ph.D. 
Altor Bioscience Corporation. 
Miramar, Florida 33025 
Telephone: 
954-443-8600 
Safety Data Fax: 
954-443-8602 
 
 
 
By my signature below, I hereby attest that I have read, and that I understand and will abide by 
all the conditions, instructions, and restrictions contained in the attached protocol. 
 
Additionally, I will not initiate this study without approval of the appropriate Institutional 
Review Board (IRB), and I understand that any changes in the protocol must be approved in 
writing by the sponsor, the IRB, and, in certain cases the FDA, before they can be implemented, 
except where necessary to eliminate hazards to subjects. 
 
 
 
 
 
Principal Investigator’s Signature 
 
Date 
 
 
 
 
 
 
 
 
 
Principal Investigator’s Name (Print) 
 
 
 
 
 
 
 
 
 
 
 


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Table of Contents 
SYNOPSIS .............................................................................................................................................. 7 
1. 
OBJECTIVES .............................................................................................................................. 14 
1.1 
PRIMARY OBJECTIVES ............................................................................................................. 14 
1.2 
SECONDARY OBJECTIVES ........................................................................................................ 14 
2. 
BACKGROUND .......................................................................................................................... 14 
2.1 
ALT-801 – GENERAL INFORMATION ...................................................................................... 14 
2.2 
BLADDER CANCER .................................................................................................................. 14 
2.3 
IMMUNOTHERAPY ................................................................................................................... 15 
2.4 
INTRATUMORAL TARGETING AND P53 AS A TARGET FOR BIOTHERAPY .................................... 15 
2.5 
P53 AS A THERAPEUTIC TARGET FOR BLADDER CANCER .......................................................... 17 
2.6 
IN VITRO CHARACTERIZATION AND TUMOR EFFICACY STUDIES IN ANIMAL MODELS ................. 17 
2.6.1 
Efficacy evaluation of ALT-801 dose regimens in xenograft tumor models ..................... 18 
2.6.2 
Efficacy of ALT-801 and non-targeted scTCR/IL-2 fusion proteins against subcutaneous 
xenograft tumors derived from human urothelial cancer cells. .................................................... 19 
2.6.3 
Activity of ALT-801 against human p53-negative orthotropic murine bladder tumors in 
immunocompetent mice. ................................................................................................................ 20 
2.7 
NON-CLINICAL TOXICOLOGY .................................................................................................. 21 
2.7.1 
Single-dose toxicity study .................................................................................................. 21 
2.7.2 
Multi-dose toxicity study ................................................................................................... 22 
2.8 
PHARMACOKINETICS .............................................................................................................. 23 
2.8.1 
Non-clinical pharmacokinetics ......................................................................................... 23 
2.8.2 
Clinical pharmacokinetics ................................................................................................ 23 
2.9 
HUMAN EXPERIENCE............................................................................................................... 23 
2.9.1 
Pharmacodynamics ........................................................................................................... 24 
2.9.2 
Tumor assessment ............................................................................................................. 24 
2.9.3 
Safety results ..................................................................................................................... 25 
2.9.4 
Repeat treatment ............................................................................................................... 26 
3. 
RATIONALE FOR THE CURRENT STUDY ......................................................................... 26 
3.1 
HIGH POTENCY OF ALT-801 AGAINST UROTHELIAL CARCINOMA IN HUMANS & ANIMAL 
MODELS............................................................................................................................................... 26 
3.2 
ALT-801 IN COMBINATION WITH CHEMOTHERAPY AGAINST UROTHELIAL CARCINOMA: ......... 28 
3.2.1 
Myeloid-Derived Suppressive Cells in Patients with Bladder Cancer ............................. 29 
3.2.2 
Enhancement of ALT-801 Anti-Tumor Immune Responses by Gemcitabine .................... 29 
4. 
OVERALL STUDY DESIGN ..................................................................................................... 30 
5. 
STUDY POPULATION .............................................................................................................. 33 
5.1 
INCLUSION CRITERIA............................................................................................................... 33 
5.2 
EXCLUSION CRITERIA ............................................................................................................. 34 
5.3 
INCLUSION OF WOMEN AND MINORITIES .................................................................................. 34 
6. 
STUDY DESIGN ......................................................................................................................... 35 
6.1 
STUDY FLOW DIAGRAM ........................................................................................................... 35 
6.2 
SCREENING AND ENROLLMENT ............................................................................................... 35 
6.3 
STUDY TREATMENT ................................................................................................................ 35 


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6.3.1 
Treatment setting ............................................................................................................... 36 
6.3.2 
Treatment regimen ............................................................................................................ 36 
6.3.3 
Pre-therapy and post-therapy interventions ..................................................................... 37 
6.3.4 
Study drug preparation and administration ...................................................................... 39 
6.3.4.1 
ALT-801 ................................................................................................................... 39 
6.3.4.2 
Cisplatin .................................................................................................................... 39 
6.3.4.3 
Gemcitabine .............................................................................................................. 39 
6.4 
DURATION OF PATIENT PARTICIPATION ................................................................................... 39 
6.5 
DOSE ESCALATION .................................................................................................................. 39 
6.6 
EXPANSION AT RD ................................................................................................................. 40 
6.7 
STOPPING RULES ..................................................................................................................... 41 
6.8 
PATIENT MONITORING, ANTI-TUMOR RESPONSE EVALUATION, SURVIVAL ASSESSMENT ........... 41 
6.8.1 
Patient monitoring ............................................................................................................ 41 
6.8.2 
Anti-tumor response evaluation ........................................................................................ 42 
6.8.3 
Survival assessment ........................................................................................................... 42 
6.9 
DOSE LIMITING TOXICITIES ..................................................................................................... 42 
6.10 
STUDY TREATMENT DISCONTINUATION ................................................................................... 43 
6.10.1 
Study treatment discontinuation events......................................................................... 43 
6.10.2 
Follow-ups after treatment discontinuation .................................................................. 43 
6.10.2.1. 
Discontinuation due to SAEs or on-going study drug related AEs ...................... 43 
6.10.2.2. 
Discontinuation due to any other reasons ............................................................. 43 
6.10.3 
Patient replacement ...................................................................................................... 43 
6.11 
STUDY TREATMENT ADJUSTMENT ........................................................................................... 44 
6.11.1 
Kidney dysfunction ........................................................................................................ 44 
6.11.1.1. 
On days planned study treatment includes cisplatin ............................................. 44 
6.11.1.2. 
On days planned study treatment includes gemcitabine and/or ALT-801............ 44 
6.11.1.3. 
Interventions ......................................................................................................... 44 
6.11.2 
Hematological dysfunction ........................................................................................... 45 
6.11.2.1. 
On first dosing day of each study treatment week ................................................ 45 
6.11.2.2. 
On intra-week dosing days ................................................................................... 45 
6.11.2.3. 
Transfusion and growth factor interventions ........................................................ 46 
6.11.3 
Hypotension .................................................................................................................. 46 
6.11.4 
Allergic reactions and cytokine release syndrome/acute infusion reaction.................. 46 
6.11.5 
Oncological surgeries post study treatment.................................................................. 46 
6.12 
SECOND AND THIRD COURSES OF STUDY TREATMENT ............................................................. 46 
6.12.1 
Qualification ................................................................................................................. 46 
6.12.2 
Treatment schedule and procedures ............................................................................. 46 
6.13 
MAINTENANCE STUDY TREATMENT ........................................................................................ 47 
6.13.1 
Qualification ................................................................................................................. 47 
6.13.2 
Treatment schedule and procedures ............................................................................. 47 
6.14 
GENERAL SUPPORTIVE CARE GUIDELINES AND DRUG INTERACTION ........................................ 47 
6.14.1 
ALT-801 ........................................................................................................................ 47 
6.14.1.1. 
Hypotension and capillary leak syndrome ............................................................ 47 
6.14.1.2. 
Pulmonary dysfunction ......................................................................................... 48 
6.14.1.3. 
Impaired kidney and liver functions ..................................................................... 48 
6.14.1.4. 
Infection ................................................................................................................ 48 
6.14.1.5. 
Fever and chills ..................................................................................................... 48 
6.14.1.6. 
Gastritis ................................................................................................................. 48 


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6.14.1.7. 
Diarrhea, nausea and vomiting ............................................................................. 48 
6.14.1.8. 
Pruritus and dermatitis .......................................................................................... 48 
6.14.1.9. 
Acidosis ................................................................................................................ 49 
6.14.1.10. 
Life-threatening toxicities ..................................................................................... 49 
6.14.1.11. 
Other supportive care ............................................................................................ 49 
6.14.1.12. 
Drug interaction .................................................................................................... 49 
6.14.2 
Cisplatin ........................................................................................................................ 50 
6.14.3 
Gemcitabine .................................................................................................................. 50 
7. 
STUDY DRUG: AVAILABILITY, ACCOUNTABILITY, PACKAGING & LABELING. 51 
7.1 
ALT-801 ................................................................................................................................ 51 
7.1.1 
Availability ........................................................................................................................ 51 
7.1.2 
Accountability ................................................................................................................... 51 
7.1.3 
Packaging .......................................................................................................................... 51 
7.1.4 
Labeling ............................................................................................................................ 51 
7.2 
CISPLATIN AND GEMCITABINE ................................................................................................ 51 
8. 
STUDY CALENDAR, CLINICAL PROCEDURES & TESTS .............................................. 52 
8.1 
STUDY CALENDAR .................................................................................................................. 52 
8.2 
PROCEDURE AND TESTS .......................................................................................................... 53 
8.2.1 
HLA-A2 typing and assays for immune cell levels and phenotype ................................... 53 
8.2.2 
Presentation of HLA-A*0201/p53 aa264-272 complexes on tumor surfaces ................... 53 
8.2.3 
Medical history.................................................................................................................. 53 
8.2.4 
Pregnancy test ................................................................................................................... 53 
8.2.5 
Physical examination ........................................................................................................ 53 
8.2.6 
Vital signs, body weight & height ..................................................................................... 53 
8.2.7 
Cardiac assessment ........................................................................................................... 53 
8.2.8 
Blood tests ......................................................................................................................... 54 
8.2.9 
Urinalysis .......................................................................................................................... 54 
8.2.10 
Pulmonary functions ..................................................................................................... 54 
8.2.11 
Adverse event assessment ............................................................................................. 54 
8.2.12 
Tumor assessment ......................................................................................................... 54 
8.2.13 
Survival assessment ...................................................................................................... 55 
8.2.14 
Pharmacokinetic (PK) testing ....................................................................................... 55 
8.2.15 
Biomarker assays for IFN and TNF ....................................................................... 55 
8.2.16 
Immunogenicity tests - detection of anti-ALT-801 and IL2-neutralizing antibodies .... 55 
9. 
MEASUREMENT OF EFFECT ................................................................................................ 55 
9.1 
DEFINITIONS ........................................................................................................................... 55 
9.1.1 
Measurable disease ........................................................................................................... 56 
9.1.2 
Non-measurable disease ................................................................................................... 56 
9.1.3 
Target lesion...................................................................................................................... 57 
9.1.4 
Non-target lesions ............................................................................................................. 57 
9.2 
GUIDELINES FOR EVALUATION OF MEASURABLE DISEASE ....................................................... 57 
9.3 
RESPONSE CRITERIA ............................................................................................................... 58 
9.3.1 
Evaluation of target lesions .............................................................................................. 58 
9.3.2 
Evaluation of non-target lesions ....................................................................................... 58 
9.3.3 
Evaluation of best overall response .................................................................................. 59 
9.4 
CONFIRMATORY ..................................................................................................................... 59 


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10. 
STATISTICAL ANALYSIS ................................................................................................... 59 
10.1 
STUDY OBJECTIVES ................................................................................................................. 59 
10.2 
SAMPLE SIZE ........................................................................................................................... 60 
10.3 
DATA COLLECTION ................................................................................................................. 61 
10.4 
DATA ANALYSIS ..................................................................................................................... 61 
10.4.1 
Analysis of safety ........................................................................................................... 61 
10.4.2 
Analysis of response ...................................................................................................... 61 
10.4.3 
Pharmacokinetics .......................................................................................................... 62 
11. 
REGULATORY AND REPORTING REQUIREMENTS .................................................. 62 
11.1 
ADVERSE EVENTS RECORDING, REPORTING AND COMMUNICATION ......................................... 62 
11.2 
ADVERSE EVENT TERMINOLOGY AND DEFINITIONS ................................................................. 62 
11.3 
ADVERSE EVENT REPORTING PROCEDURES ............................................................................ 63 
11.4 
ADVERSE EVENT EXPEDITED REPORTING GUIDELINES ........................................................... 64 
11.5 
SUBMISSION OF SERIOUS ADVERSE EVENT REPORTING ............................................................ 64 
11.6 
DATA REPORTING FORMS ....................................................................................................... 65 
11.7 
REPORT /DATA SUBMISSION ADDRESS & CONTACT ................................................................. 65 
11.8 
PATIENT RECORDS, QUALITY ASSURANCE, RECORDS RETENTION ............................................. 66 
11.9 
METHOD OF REVIEW ............................................................................................................... 66 
11.10 
SPECIAL REGULATORY CONSIDERATIONS ............................................................................ 66 
11.10.1 
HIPAA ........................................................................................................................... 66 
11.10.2 
Protocol amendments, informed consent, and IRB approval ....................................... 67 
12. 
CONFIDENTIALITY ............................................................................................................. 67 
13. 
ETHICAL STANDARDS & INVESTIGATOR OBLIGATIONS ..................................... 67 
14. 
LIST OF EXPECTED ADVERSE EVENTS ........................................................................ 68 
15. 
CTCAE ..................................................................................................................................... 70 
REFERENCES ..................................................................................................................................... 71 
APPENDIX A: PERFORMANCE STATUS CRITERIA ................................................................ 74 
APPENDIX B: NEW YORK HEART ASSOCIATION CLASSIFICATION ............................... 74 
APPENDIX C: ETHICAL STANDARDS ......................................................................................... 75 
APPENDIX D: INVESTIGATOR OBLIGATIONS ........................................................................ 76 
APPENDIX E: CONTACT LIST - ALTOR ..................................................................................... 80 
APPENDIX F: CONTACT LIST – DATA SAFETY MONITORING BOARD (DSMB) ............ 81 
APPENDIX G: CONTACT LIST - LABORATORIES ................................................................... 81 
APPENDIX H: APPROVAL PAGE .................................................................................................. 82 


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Page 7 of 82 
SYNOPSIS 
Sponsor: 
Altor Bioscience Corporation 
Protocol#: 
CA-ALT-801-01-10 
Study Drug Name: Not applicable 
Study Treatment 
Active agents: 
ALT-801 (c264scTCR-IL2), recombinant humanized, soluble single-chain 
TCR-cytokine fusion protein; Cisplatin; Gemcitabine. 
Study Type: 
Interventional 
Study Phase: 
Ib/II 
Protocol Title: 
A Phase Ib/II Trial of ALT-801 in Combination with Cisplatin and 
gemcitabine in Muscle Invasive or Metastatic Urothelial Cancer 
Objectives:   
To determine the safety and tolerability of the novel combination of ALT-
801 (c264scTCR-IL2) with cisplatin and gemcitabine or the combination of 
ALT-801 with gemcitabine alone in patients with muscle invasive or 
metastatic urothelial cancer of bladder, renal pelvis, ureters and urethra.   
To estimate the anti-tumor activity of ALT-801 in combination with 
cisplatin and gemcitabine or ALT-801 in combination with gemcitabine 
alone by radiologic or pathologic anti-tumor response, progression free 
survival (assessed through the end of the study), and overall survival 
(assessed through the end of the study) in treated patients.  
To characterize the immunogenicity and pharmacokinetic profile of ALT-
801 in combination with cisplatin and gemcitabine and the immunogenicity 
of ALT-801 in combination with gemcitabine alone in treated patients. 
To assess the relationship between tumor presentation of HLA-A*0201/p53 
aa 264-272 complex and the safety and clinical benefit of study treatment. 
Study Design: 
This is a Phase Ib/II, open-label, multi-center, competitive enrollment and 
dose-escalation study of ALT-801 in a biochemotherapy regimen either 
containing cisplatin and gemcitabine or containing gemcitabine alone in 
patients who have muscle invasive or metastatic urothelial cancer of bladder, 
renal pelvis, ureters and urethra. The study will be conducted in conformity 
with Current Good Clinical Practices (cGCP).  
The study includes a dose escalation phase (Phase Ib), to determine the 
maximum tolerated dose (MTD) and the recommended dose (RD) of ALT-
801, and a dose expansion phase (Phase II) with study treatment containing 
ALT-801 at the RD level, to assess the effectiveness of study treatment 
The Phase Ib dose escalation study is conducted using traditional (3+3) dose 
escalation rules. Patients enrolled in his phase will all receive the cisplatin-
containing study treatment (ALT-801, cisplatin and gemcitabine). 
In the Phase II expansion study, conducted with the study treatment 
containing ALT-801 at the RD level, patients are enrolled into two treatment 
groups – Expansion Group 1, treated with a cisplatin containing regimen: 


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ALT-801, cisplatin and gemcitabine; Expansion Group 2, for platinum-
refractory patients, treated with a non-cisplatin containing regimen: ALT-
801 and gemcitabine. The Group 1 expansion will be conducted using a 
modified Simon two-stage design (1, 2). The Group 2 expansion will be 
conducted based an exact single-stage design [1]. After completion of Stage 
I expansion with the Expansion Group 1, patients with disease refractory to 
platinum-based therapies will be enrolled to the Expansion Group 2 to 
receive the non-cisplatin-containing study treatment as a “second-line” 
regimen. 
 
 [2, 3] In the dose escalation phase of this study, there are five dose levels of 
ALT-801 (0.04 mg/kg, 0.06 mg/kg, 0.08 mg/kg, 0.10 mg/kg and 0.12 
mg/kg) in addition to two de-escalation dose levels. The doses of cisplatin 
(70 mg/m2/dose) and gemcitabine (1000 mg/m2/dose) will be fixed across all 
ALT-801 dose levels. If the MTD cannot be determined after the maximum 
planned escalating dose level has been reached, or the RD for dose 
expansion cannot be determined during the dose escalation phase, the 
sponsor, the Data Safety Monitoring Board (DSMB) and the principal 
investigators will meet to discuss whether to amend the protocol to expand 
the dose escalation phase to include additional ALT-801 dose levels.  
Treatments: 
The planned initial on-study treatment will be for 3 courses of chemo-
immunotherapy. Each course consists of cisplatin (Day #1), gemcitabine 
(Day #1), ALT-801 (Day #3 & Day #5), gemcitabine (Day #8), ALT-801 
(Day #8 & Day #12 or #15), and a rest period (Days #13 (or #16) - #21). The 
alternative dosing day (Day #15) for the last dose (dose #4) of ALT-801 in 
each course is provided to allow sufficient recovery from transient study 
drug related toxicities. Patients with disease refractory to platinum-based 
therapies who are enrolled in the Expansion Group 2 will receive 
gemcitabine without cisplatin on Day # 1 of each treatment course. Prior to 
commencing the second or the third course of study treatment, subjects will 
need to meet the treatment continuation criteria. At completion of the three 
full courses of study treatment, each patient enrolled will have received a 
total of 12 doses of the study drug ALT-801; 3 doses of cisplatin (no dose of 
cisplatin for patients enrolled to the Expansion Group 2); and 6 doses of 
gemcitabine. After completing the 3-course initial study treatment, patients 
who have at least stable disease and meet other treatment criteria will have 
maintenance study treatment with an additional 3-week course of ALT-801 
and gemcitabine: Gemcitabine and ALT-801 on Day #1 and Day #15, ALT-
801 on Day #3 and Day #17, and a rest period (Day #4 to Day #14).  
Treatment delays or dose modifications or omissions are addressed in the 
protocol. The treatment schedule is illustrated in the following schemas: 
 
 
 
 
 


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Initial Study Treatment: 
 
 
 
 
*not given to patients who are enrolled in the Expansion Group 2 with 
disease refractory to platinum-based therapy. 
Maintenance Study Treatment: 
 
 
 
 
Enrolled patients will receive the study treatment at qualified cancer 
treatment centers with adequate diagnostic and treatment facilities to provide 
appropriate management of therapy and complications. ALT-801, cisplatin 
and gemcitabine will be administered by intravenous infusion into a central 
or peripheral vein under the supervision of a qualified physician experienced 
in the use of anti-cancer agents including aldesleukin (Proleukin), cisplatin 
and gemcitabine. 
This is the schema for the dose levels during the dose-escalation phase of the 
study. The -1 and -2 dose levels of ALT-801 are included in case of DLT 
events in the initial dose level.  
Cohort 
ALT-801 Dose (mg/kg) 
Cisplatin (mg/m2) 
Gemcitabine (mg/m2) 
-2 
0.01 
70 
1000 
-1 
0.02 
70 
1000 
1 (initial) 
0.04 
70 
1000 
2 
0.06 
70 
1000 
3 
0.08 
70 
1000 
4 
0.10 
70 
1000 
5 
0.12 
70 
1000 
Dose Escalation: 
In this phase of the study, a minimum of 3 patients will be enrolled at each 
dose level. All patients will be monitored for Dose Limiting Toxicity (DLT) 
for 8 weeks from the initial dose. If 0/3 patients has study treatment-related, 
dose-limiting toxicity by 8 weeks after the initial dose, the next cohort will 
be opened for enrollment. If one patient at a dose-level develops drug-related 
DLT, up to six patients will be enrolled at that dose level and each 
subsequent higher dose level. If 0 or 1 of 6 patients in a cohort of 6 patients 
has an event that meets criteria for study treatment-related DLT, then the 
next cohort will be opened for enrollment. If 2 or more out of 3-6 patients in 
a dose escalation cohort have a DLT that is drug-related, that dose level will 
be designated as exceeding the maximum tolerated dose. If there are 3 
patients in the dose level below this level, then additional patients (up to 6 
total) will be enrolled at that dose level. When there is a dose level with 0 or 
 
Course 1 
Course 2 
Course 3 
Treatment Day 1 
3 
5 
8 12(15) 13(16)-21 22 24 26 29 33(36) 34(37)-42 43 45 47 50 54(57) 
Cisplatin 
X*  
 
 
 
Rest 
Period 
X* 
 
 
 
 
Rest 
Period 
X* 
 
 
 
 
Gemcitabine 
X 
 
 
X 
 
X 
 
 
X 
 
X 
 
 
X 
 
ALT-801 
 
X X X 
X 
 
X X X 
X 
 
X X 
X 
X 
 
Maintenance Course  
Treatment Day 
1 
3 
4-14 
15 
17 
Gemcitabine 
X 
 
Rest 
Period 
X 
 
ALT-801 
X 
X 
X 
X 


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1 out of 6 patients with DLT, which is either the maximum planned dose 
level (level 5) or which is one level below a dose that was not tolerated, the 
dose that is the maximum tolerated dose (MTD) will be considered defined. 
Further changes in the treatment plan may be considered by protocol 
amendment at that point.  
If more than two of six patients experience a DLT at the initial dose level 
(level 1), then the sponsor, the Data Safety Monitoring Board (DSMB) and 
the principal investigators will meet to determine how to adjust the dose 
level of cisplatin, gemcitabine, and/or the study drug downward, or continue 
with the (-1) and (-2) cohorts, and to determine how to proceed with the 
study.  
At any time during the dose escalation phase of the study, whether or not the 
MTD or the maximum planned escalating dose level is reached, the dose 
escalation phase may be concluded due to favorable anti-tumor effect 
observed in the enrolled patients. The DSMB will recommend a dose level 
of ALT-801, the recommended dose (RD), for the dose expansion phase of 
the study. 
Dose limiting toxicity (DLT) is defined as any toxicity of grade 3 that does 
not resolve to Grade 1 or lower within 7 days and any toxicity of Grade 4 
occurring during treatment courses with exceptions and details described in 
the study protocol. Patients experiencing a DLT should discontinue study 
treatment. Study treatment discontinuation due to adverse events experienced 
prior to study drug administration, disease progression or patient’s decision 
to withdraw from study treatment without occurrence of any study treatment 
discontinuation event will not necessarily define a DLT event. Study 
treatment discontinuation events are defined in the protocol.  
Dose Expansion: 
The Phase II dose expansion study, conducted with study treatment 
containing ALT-801 at the RD level, patients are enrolled to two treatment 
groups – Expansion Group 1, treated with a cisplatin containing regimen: 
ALT-801, cisplatin and gemcitabine; Expansion Group 2, for platinum-
refractory patients, treated with a non-cisplatin containing regimen: ALT-
801 and gemcitabine. Both objective response (OR) (defined as complete 
response (CR) + partial response (PR)) and clinical benefit (CB) (defined as 
CR, PR + stable disease (SD)) will be evaluated. 
The Group 1 expansion will be conducted using a modified Simon two-stage 
design (1, 2). [2, 3]Common set thresholds of lack of efficacy (OR rate 
(ORR) = 40%; CB rate (CBR) = 78%) and an efficacy level of interest (ORR 
= 60%; CBR = 92%) will be selected. The sample size was driven by the 
parameter that had the larger sample size for each stage. The Group 2 
expansion will be conducted based on an exact single-stage design [1]. 
Sample size for the expansion was calculated according to the single-stage 
design of A’Hern [1] to reject a baseline ORR of 10% when the true ORR is 
40%. 


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Stopping Rules: 
The patient enrollment will be temporarily suspended based on occurrence 
of any of the following, and the sponsor, the Data Safety Monitoring Board 
and principal investigators will meet to discuss how to proceed with future 
patient enrollment in the study: 
• 
If at any time during the dose escalation phase of the study,  
 more than one patient in a cohort of three, or two patients in a 
cohort of six patients experience any DLT or, 
 favorable anti-tumor response data collected from enrolled patients 
that indicates a dose level with significant therapeutic effect may 
have been found 
• 
If at any time during the expansion phase of the study, more than 33% 
the patients experience any drug related DLT. 
Evaluations: 
Patients will be evaluated for clinical toxicities during the treatment. 
Patients’ blood samples will be collected to assess the pharmacokinetic 
profile and immunogenicity of the study drug. The anti-tumor response will 
be evaluated for up to 18 weeks from the initial dose of the first course of 
treatment. All patients who receive at least one dose of the study drug ALT-
801 will be included in the anti-tumor response evaluation. Between each 
cohort and at the end of the study, all clinical and safety data will be 
analyzed for all patients enrolled in the study for dose-response effects. 
Population: 
Patients of 18 years of age and above who are candidates for systemic 
cisplatin and gemcitabine for the treatment of muscle invasive or metastatic 
urothelial cancer of bladder, renal pelvis, ureters, and urethra may be 
selected for further evaluation of eligibility for study participation. Patients 
also need to have adequate cardiac, pulmonary, liver and kidney functions 
and to have an Eastern Cooperative Oncology Group (ECOG) performance 
status of 0 or 1.  
Sample Size: 
A total of up to 30 assessable patients will be accrued to the initial dose 
escalation phase of the study (Phase Ib); the estimated number is 9. In the dose 
expansion phase, up to an additional 40 assessable patients will be enrolled to 
receive cisplatin-containing study treatment in the Expansion Group 1  and 
up to 14 patients will be enrolled to receive non-cisplatin-containing study 
treatment in the Expansion Group 2. A total of approximately 63 assessable 
patients will be enrolled and complete the study. Assuming a 20% ineligible 
or non-assessable cases, a total of up to 76 patients may be accrued to the 
study. 
Primary 
Endpoints: 
For Stage I only: 
(1) To define an MTD and/or RD for dose expansion of ALT-801 in 
combination with cisplatin and gemcitabine or ALT-801 in combination 
with gemcitabine alone in the treatment of patients with muscle invasive 
or metastatic urothelial cancer. 


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For Stage I & II: 
(2) To assess the safety of the combination study treatment in treated 
patients. 
 
(3) To assess the objective response rate in treated patients. 
Secondary  
Endpoints: 
(1) To assess the progression free survival in treated patients. 
(2) To assess the overall survival in treated patients. 
(3) To evaluate the immunogenicity and pharmacokinetic profiles of ALT-
801 in treated patients. 
(4) To assess the relationship between tumor presentation of HLA-
A*0201/p53 aa264-272 complexes and the safety and clinical benefit of 
study treatment. 
Pharmacokinetics 
& Biomarkers: 
Blood samples will be collected to assess typing for HLA-A2, immune cell 
levels, phenotype, pharmacokinetics, immunogenicity of the study drug 
ALT-801, and the serum levels of IFN-γ and TNF-α. Tumor samples 
obtained from surgeries or biopsies performed prior to screening for the 
study will be collected to test the HLA-A*0201/p53 aa 264-272 complex 
presentation. Blood samples for pharmacokinetic analysis of ALT-801 will 
be taken on the first day of ALT-801 administration in the first course of 
study treatment. Venous blood will be obtained at Time 0 (before the start of 
infusion), at 30 minutes (15 minutes after completion of infusion), and 1, 3 
and 6 hours from Time 0 for the assessment of ALT-801 serum 
concentration. Non-compartmental and compartmental analyses will be 
conducted. In addition, the same blood samples collected for PK analysis 
will be used to assess the immunogenicity of study drug ALT-801 and the 
serum levels of IFN-γ and TNF-α. Fresh blood samples for HLA-A2 typing, 
immune cell levels and phenotype testing will be collected before the start of 
the first and second courses of study treatment. HLA-A2 typing will be 
performed only once. 
Monitoring Tests: Urine samples for urinalysis, blood samples for standard chemistry, CBC, 
differential and coagulation will be obtained for tests required at screening 
for study entry eligibility evaluation or for tests required throughout the 
treatment and follow-up periods for patient safety monitoring. Blood 
samples for immunogenicity testing, which include assays for anti-ALT-801 
and IL-2 neutralizing antibodies, will be collected prior to dosing on the first 
ALT-801 infusion day and at Week 9 from the initial dose of study 
treatment. 
Anti-tumor  
Response 
Evaluation: 
The anti-tumor response will be evaluated for up to 18 weeks from the initial 
dose of study treatment: for non-responders: Week 9 and 13; for early 
responders: Week 9 and 14; for late responders: Week 9, 13 and 18. 
Objective Response will be evaluated using the new international criteria 


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proposed by the Response Evaluation Criteria in Solid Tumors Committee 
(RECIST) 1.1. Baseline evaluations should be performed up to 28 days 
before starting study 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-ups. Imaging-based evaluation is 
preferred to evaluation by clinical examination when both methods have 
been used to assess the anti-tumor effect of the treatment. However, 
cystoscopic evaluation may be used routinely in this population, in addition 
to radiologic testing. If surgeries or biopsies are performed after patients 
receive and respond to study treatment, tumor or tissue samples from these 
procedures will be collected to assess histopathological and immuno-cellular 
responses to study treatment. 
 
Survival  
Assessment: 
Progression-free survival and overall survival of all enrolled patients will be 
assessed at 6, 9, 12, 18, 24, 30 and 36 months from the start of study 
treatment, or through the point designated as the end of the study follow up. 
Adverse Events: 
All patients will be monitored and evaluated for clinical toxicities during the 
treatment period and queried at each follow-up visit for Adverse Events 
(AEs). Patients may volunteer information concerning AEs. All adverse 
events will be graded by using the NCI Common Terminology Criteria for 
Adverse Events version 4.0 (CTCAE v4.0), and logged in the patient Case 
Report Form. The study centers should report all SAEs and all events that 
trigger patient’s study treatment discontinuation to the sponsor via phone, 
fax or email (or a combination) up to 1 day after learning of the event. The 
sponsor will use the information to manage and coordinate the dose 
escalation, cohort expansion and patient enrollment. The sponsor will then 
inform all of the participating clinical sites of the current dose level and the 
number of patients to be enrolled at that level, or of any patient enrollment 
suspension via phone, fax or email within a day of its learning of the event. 
The study centers should report the other adverse events to the sponsor 
following the guidelines defined in the study protocol. All study drug related 
adverse events (AEs) that are both serious and unexpected will be reported 
to the FDA in an expedited manner in accordance with 21 CFR §312.32. 
Statistical Plan: 
For each cohort, all AEs will be tabulated and examined and all safety and 
pharmacokinetic data will be evaluated. For estimation of duration of 
response, the Kaplan-Meier method will be used. P-values of <0.05 (two-
sided) will be considered to indicate statistical significance.  
 


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8. 
STUDY CALENDAR, CLINICAL PROCEDURES & TESTS 
8.1 
Study calendar 
TESTS & PROCEDURES 
SCREEN1 
INITIAL TREATMENT PERIOD 
SCAN #1 
SCAN #2 
MAINTENANCE 
TREATMENT 
SCAN #3 
FOLLOW-UPS 
COURSE 1 
COURSE 2 
COURSE 3 
Month(late responders in parentheses) 
 
1 
2 
3 
4 
3 – 4/(4-5) 
4/(5)  6 
9 
12 
18 24 30 
36 
Week (late responders in parentheses) 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
13 
10/ 
(14) 
11/ 
(15) 
12/ 
(16) 
13/ 
(17) 
 
 
 
 
 
 
 
Week Day 
 
M 
W 
F  
M 
F 
 
M 
W 
F 
M 
F 
 
M 
W 
F 
M 
F 
  
  
M 
W  
 
M  
W 
 
 
 
 
 
 
 
 
Treatment Day 
 
1 
3 
5 
8 
12 
 
22 
24 
26 
29 
33 
 
43 
45 
47 
50 
54 
  
  
 1 
3  
 
15   17 
 
 
 
 
 
 
 
 
Informed consent   
X 
 
 
 
 
 
 
R 
e 
s 
t 
 
P 
e 
r 
i 
o 
d 
 
 
 
 
 
 
 
R 
e 
s 
t 
 
P 
e 
r 
i 
o 
d 
 
 
 
 
 
 
 
 
 
 
 
R 
e 
s 
t 
 
P 
e 
r 
i 
o 
d 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum pregnancy test2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Complete physical exam 
X 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
X 
X 
 
  
  
X 
 
 
 
 
 
 
 
Vital signs, weight, Height3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
Concurrent medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
CBC with Differential, Blood Chemistry 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
Coagulation (PT/INR)4 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
X 
X 
 
  
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Cardiac functions5 
X 
X5 
X 
X 
X 
X 
X5 
X 
X 
X 
X 
X5 
X 
X 
X 
X 
  
  
X5 
X 
X 
X 
 
 
 
 
 
 
 
 
Pulmonary functions 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse event assessment6 
X 
X 
X 
X  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
Tumor assessment7 
X 
  
  
  
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
Survival Assessment8 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
HLA A2 Typing, immune cell levels & 
phenotype11 
 
X9 
X9 
 
X9 
 
  
X9 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HLA-A*0201/p53 tumor typing 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK, IFNγ, TNFα11 
 
 
X10 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
Immunogenicity tests11 
 
 
X12 
  
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
  
  
  
  
  
  
Cisplatin 
 
c1 
 
 
 
 
c2 
 
 
 
 
c3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Gemcitabine 
 
g1 
 
 
g2 
 
g3 
 
 
g4 
 
g5 
 
 
g6 
 
 
 
g7 
 
g8 
 
 
 
 
 
 
 
 
 
Study drug (ALT-801)13 
 
  
a1 
a2 
a3 
a414 
  
a5 
a6 
a7 
a814 
  
a9 
a10 
a11 a1214 
  
  
a13 a14 
a15 a16 
 
 
 
 
 
 
 
 
1Screening evaluations are performed < 14 days; stress test, if required, scan/x-ray <28 days prior to start of therapy. If the patient's condition is deteriorating, ECOG status and laboratory evaluations should be repeated within 48 
hours prior to initiation of study treatment infusion.  2Pregnancy test is for women with childbearing potential only.  3Vital signs (especially blood pressure), clinical status and laboratory tests should be reviewed before start of 
therapy. Vital signs will be evaluated every 2 hours after the drug treatment and before discharge, and body weight before study treatment infusion on study treatment infusion day. 4PT/INR should be performed for any bleeding 
issues. 5Patients are closely monitored for hypotension, arrhythmia, angina and myocardial infarction. At screening, patients who are ≥ 50 years of age or have a history of EKG abnormalities, symptoms of cardiac ischemia or 
arrhythmia will have a stress test (stress thallium, stress MUGA or dobutamine echocardiogram) to determine their eligibility for participation in the study. EKG will be performed for all patients at start of each initial treatment 
course and the maintenance study treatment course. At the start of 1st course, EKG is performed only when >14 days since last EKG. 6Patients who have an on-going study drug-related SAE upon study completion or at 
discontinuation of the study will be contacted by the investigator or his/her designee every week until the event is resolved or determined to be irreversible. 7Tumor response and progression will be evaluated in this study using the 
new international criteria proposed by the RECIST (1.1). 8Information about tumor assessment & other therapies received after completion of study treatment will be collected if available   9Fresh blood samples for HLA A2 blood 
typing, immune cell levels & phenotype testing will be collected before dosing. 10Collect blood samples at Time 0 (before drug infusion), at 30 min (15 min after completion of infusion, +/- 5 min), 1 hour (+/- 10 min), 3 hour (+/- 30 
min), 6 hour (+/- 60 min) from Time 0. PK and TNF-α analyses will not be performed and serum sample collection only at Time 0 and 6 hours after completion of Stage 1 expansion.  11Residual samples may be used by Sponsor for 
research studies of other biomarkers. 12Use the same blood sample collected before dosing for PK test.13On the days when gemcitabine and ALT-801 are both given, gemcitabine should be dosed first.  14This dose can be delayed to the 
following Monday.  




 
 
 
CLINICAL STUDY PROTOCOL 
 
 
Protocol Number: 
CA-ALT-801-01-10 
 
 
Protocol Title: 
A Phase Ib/II Trial of ALT-801 in Combination 
with Cisplatin and Gemcitabine in Muscle 
Invasive or Metastatic Urothelial Cancer  
 
 
 
Date of Protocol: 
 
Version # 01 
Version # 02 
Version # 03 
Version # 04 
Version # 05 
Version # 06 
Version # 07 
 
October 31, 2010 
July 8, 2011 
November 10, 2011 
December 23, 2011 
May 11, 2012 
October 18, 2012 
March 29, 2013 
 
Sponsor Contact: 
 
Hing C. Wong, Ph.D. 
Altor Bioscience Corporation. 
Miramar, Florida 33025 
Telephone: 
954-443-8600 
Safety Data Fax: 
954-443-8602 
 
 
 


 
INVESTIGATOR SIGNATURE PAGE 
 
Protocol Number: 
CA-ALT-801-01-10 
 
 
Protocol Title: 
A Phase Ib/II Trial of ALT-801 in Combination 
with Cisplatin and Gemcitabine in Muscle 
Invasive or Metastatic Urothelial Cancer 
 
 
Date of Protocol: 
 
Version # 01 
Version # 02 
Version # 03 
Version # 04 
Version # 05 
Version # 06 
Version # 07 
October 31, 2010 
July 8, 2011 
November 10, 2011 
December 23, 2011 
May 11, 2012 
October 18, 2012 
March 29, 2013 
 
Sponsor Contact: 
 
Hing C. Wong, Ph.D. 
Altor Bioscience Corporation. 
Miramar, Florida 33025 
Telephone: 
954-443-8600 
Safety Data Fax: 
954-443-8602 
 
 
 
By my signature below, I hereby attest that I have read, and that I understand and will abide by all 
the conditions, instructions, and restrictions contained in the attached protocol. 
 
Additionally, I will not initiate this study without approval of the appropriate Institutional Review 
Board (IRB), and I understand that any changes in the protocol must be approved in writing by the 
sponsor, the IRB, and, in certain cases the FDA, before they can be implemented, except where 
necessary to eliminate hazards to subjects. 
 
 
 
 
 
Principal Investigator’s Signature 
 
Date 
 
 
 
 
 
 
 
 
 
Principal Investigator’s Name (Print) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table of Contents 
SYNOPSIS .............................................................................................................................................. 7 
1. 
OBJECTIVES .............................................................................................................................. 14 
1.1 
PRIMARY OBJECTIVES ............................................................................................................. 14 
1.2 
SECONDARY OBJECTIVES ........................................................................................................ 14 
2. 
BACKGROUND .......................................................................................................................... 14 
2.1 
ALT-801 – GENERAL INFORMATION ...................................................................................... 14 
2.2 
BLADDER CANCER .................................................................................................................. 14 
2.3 
IMMUNOTHERAPY ................................................................................................................... 15 
2.4 
INTRATUMORAL TARGETING AND P53 AS A TARGET FOR BIOTHERAPY .................................... 15 
2.5 
P53 AS A THERAPEUTIC TARGET FOR BLADDER CANCER .......................................................... 17 
2.6 
IN VITRO CHARACTERIZATION AND TUMOR EFFICACY STUDIES IN ANIMAL MODELS ................. 17 
2.6.1 
Efficacy evaluation of ALT-801 dose regimens in xenograft tumor models ..................... 18 
2.6.2 
Efficacy of ALT-801 and non-targeted scTCR/IL-2 fusion proteins against subcutaneous 
xenograft tumors derived from human urothelial cancer cells. .................................................... 19 
2.6.3 
Activity of ALT-801 against human p53-negative orthotropic murine bladder tumors in 
immunocompetent mice. ................................................................................................................ 21 
2.7 
NON-CLINICAL TOXICOLOGY .................................................................................................. 22 
2.7.1 
Single-dose toxicity study .................................................................................................. 22 
2.7.2 
Multi-dose toxicity study ................................................................................................... 22 
2.8 
PHARMACOKINETICS .............................................................................................................. 23 
2.8.1 
Non-clinical pharmacokinetics ......................................................................................... 23 
2.8.2 
Clinical pharmacokinetics ................................................................................................ 23 
2.9 
HUMAN EXPERIENCE............................................................................................................... 24 
2.9.1 
Pharmacodynamics ........................................................................................................... 24 
2.9.2 
Tumor assessment ............................................................................................................. 24 
2.9.3 
Safety results ..................................................................................................................... 25 
2.9.4 
Repeat treatment ............................................................................................................... 26 
3. 
RATIONALE FOR THE CURRENT STUDY ......................................................................... 26 
3.1 
HIGH POTENCY OF ALT-801 AGAINST UROTHELIAL CARCINOMA IN HUMANS & ANIMAL 
MODELS............................................................................................................................................... 26 
3.2 
ALT-801 IN COMBINATION WITH CHEMOTHERAPY AGAINST UROTHELIAL CARCINOMA: ......... 28 
3.2.1 
Myeloid-Derived Suppressive Cells in Patients with Bladder Cancer ............................. 29 
3.2.2 
Enhancement of ALT-801 Anti-Tumor Immune Responses by Gemcitabine .................... 30 
4. 
OVERALL STUDY DESIGN ..................................................................................................... 30 
5. 
STUDY POPULATION .............................................................................................................. 33 
5.1 
INCLUSION CRITERIA............................................................................................................... 33 
5.2 
EXCLUSION CRITERIA ............................................................................................................. 34 
5.3 
INCLUSION OF WOMEN AND MINORITIES .................................................................................. 34 
6. 
STUDY DESIGN ......................................................................................................................... 35 
6.1 
STUDY FLOW DIAGRAM ........................................................................................................... 35 
6.2 
SCREENING AND ENROLLMENT ............................................................................................... 35 
6.3 
STUDY TREATMENT ................................................................................................................ 35 


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6.3.1 
Treatment setting ............................................................................................................... 36 
6.3.2 
Treatment regimen ............................................................................................................ 36 
6.3.3 
Pre-therapy and post-therapy interventions ..................................................................... 37 
6.3.4 
Study drug preparation and administration ...................................................................... 39 
6.3.4.1 
ALT-801 ................................................................................................................... 39 
6.3.4.2 
Cisplatin .................................................................................................................... 39 
6.3.4.3 
Gemcitabine .............................................................................................................. 39 
6.4 
DURATION OF PATIENT PARTICIPATION ................................................................................... 39 
6.5 
DOSE ESCALATION .................................................................................................................. 39 
6.6 
EXPANSION AT RD ................................................................................................................. 40 
6.7 
STOPPING RULES ..................................................................................................................... 41 
6.8 
PATIENT MONITORING, ANTI-TUMOR RESPONSE EVALUATION, SURVIVAL ASSESSMENT ........... 42 
6.8.1 
Patient monitoring ............................................................................................................ 42 
6.8.2 
Anti-tumor response evaluation ........................................................................................ 42 
6.8.3 
Survival assessment ........................................................................................................... 42 
6.9 
DOSE LIMITING TOXICITIES ..................................................................................................... 42 
6.10 
STUDY TREATMENT DISCONTINUATION ................................................................................... 43 
6.10.1 
Study treatment discontinuation events......................................................................... 43 
6.10.2 
Follow-ups after treatment discontinuation .................................................................. 43 
6.10.2.1. 
Discontinuation due to SAEs or on-going study drug related AEs ...................... 43 
6.10.2.2. 
Discontinuation due to any other reasons ............................................................. 44 
6.10.3 
Patient replacement ...................................................................................................... 44 
6.11 
STUDY TREATMENT ADJUSTMENT ........................................................................................... 44 
6.11.1 
Kidney dysfunction ........................................................................................................ 44 
6.11.1.1. 
On days planned study treatment includes cisplatin ............................................. 44 
6.11.1.2. 
On days planned study treatment includes gemcitabine and/or ALT-801............ 45 
6.11.1.3. 
Interventions ......................................................................................................... 45 
6.11.2 
Hematological dysfunction ........................................................................................... 45 
6.11.2.1. 
On first dosing day of each study treatment week ................................................ 45 
6.11.2.2. 
On intra-week dosing days ................................................................................... 46 
6.11.2.3. 
Transfusion and growth factor interventions ........................................................ 46 
6.11.3 
Hypotension .................................................................................................................. 46 
6.11.4 
Allergic reactions and cytokine release syndrome/acute infusion reaction.................. 46 
6.11.5 
Oncological surgeries post study treatment.................................................................. 46 
6.12 
SECOND AND THIRD COURSES OF STUDY TREATMENT ............................................................. 46 
6.12.1 
Qualification ................................................................................................................. 47 
6.12.2 
Treatment schedule and procedures ............................................................................. 47 
6.13 
MAINTENANCE STUDY TREATMENT ........................................................................................ 47 
6.13.1 
Qualification ................................................................................................................. 47 
6.13.2 
Treatment schedule and procedures ............................................................................. 47 
6.14 
GENERAL SUPPORTIVE CARE GUIDELINES AND DRUG INTERACTION ........................................ 47 
6.14.1 
ALT-801 ........................................................................................................................ 47 
6.14.1.1. 
Hypotension and capillary leak syndrome ............................................................ 48 
6.14.1.2. 
Pulmonary dysfunction ......................................................................................... 48 
6.14.1.3. 
Impaired kidney and liver functions ..................................................................... 48 
6.14.1.4. 
Infection ................................................................................................................ 48 
6.14.1.5. 
Fever and chills ..................................................................................................... 48 
6.14.1.6. 
Gastritis ................................................................................................................. 49 


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6.14.1.7. 
Diarrhea, nausea and vomiting ............................................................................. 49 
6.14.1.8. 
Pruritus and dermatitis .......................................................................................... 49 
6.14.1.9. 
Acidosis ................................................................................................................ 49 
6.14.1.10. 
Life-threatening toxicities ..................................................................................... 49 
6.14.1.11. 
Other supportive care ............................................................................................ 49 
6.14.1.12. 
Drug interaction .................................................................................................... 49 
6.14.2 
Cisplatin ........................................................................................................................ 50 
6.14.3 
Gemcitabine .................................................................................................................. 50 
7. 
STUDY DRUG: AVAILABILITY, ACCOUNTABILITY, PACKAGING & LABELING. 51 
7.1 
ALT-801 ................................................................................................................................ 51 
7.1.1 
Availability ........................................................................................................................ 51 
7.1.2 
Accountability ................................................................................................................... 51 
7.1.3 
Packaging .......................................................................................................................... 51 
7.1.4 
Labeling ............................................................................................................................ 51 
7.2 
CISPLATIN AND GEMCITABINE ................................................................................................ 51 
8. 
STUDY CALENDAR, CLINICAL PROCEDURES & TESTS .............................................. 52 
8.1 
STUDY CALENDAR .................................................................................................................. 52 
8.2 
PROCEDURE AND TESTS .......................................................................................................... 53 
8.2.1 
HLA-A2 typing and assays for immune cell levels and phenotype ................................... 53 
8.2.2 
Presentation of HLA-A*0201/p53 aa264-272 complexes on tumor surfaces ................... 53 
8.2.3 
Medical history.................................................................................................................. 53 
8.2.4 
Pregnancy test ................................................................................................................... 53 
8.2.5 
Physical examination ........................................................................................................ 53 
8.2.6 
Vital signs, body weight & height ..................................................................................... 53 
8.2.7 
Cardiac assessment ........................................................................................................... 53 
8.2.8 
Blood tests ......................................................................................................................... 54 
8.2.9 
Urinalysis .......................................................................................................................... 54 
8.2.10 
Pulmonary functions ..................................................................................................... 54 
8.2.11 
Adverse event assessment ............................................................................................. 54 
8.2.12 
Tumor assessment ......................................................................................................... 54 
8.2.13 
Survival assessment ...................................................................................................... 55 
8.2.14 
Pharmacokinetic (PK) testing ....................................................................................... 55 
8.2.15 
Biomarker assays for IFN and TNF ....................................................................... 55 
8.2.16 
Immunogenicity tests - detection of anti-ALT-801 and IL2-neutralizing antibodies .... 55 
9. 
MEASUREMENT OF EFFECT ................................................................................................ 55 
9.1 
DEFINITIONS ........................................................................................................................... 55 
9.1.1 
Measurable disease ........................................................................................................... 56 
9.1.2 
Non-measurable disease ................................................................................................... 56 
9.1.3 
Target lesion...................................................................................................................... 57 
9.1.4 
Non-target lesions ............................................................................................................. 57 
9.2 
GUIDELINES FOR EVALUATION OF MEASURABLE DISEASE ....................................................... 57 
9.3 
RESPONSE CRITERIA ............................................................................................................... 58 
9.3.1 
Evaluation of target lesions .............................................................................................. 58 
9.3.2 
Evaluation of non-target lesions ....................................................................................... 58 
9.3.3 
Evaluation of best overall response .................................................................................. 59 
9.4 
CONFIRMATORY ..................................................................................................................... 59 


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10. 
STATISTICAL ANALYSIS ................................................................................................... 59 
10.1 
STUDY OBJECTIVES ................................................................................................................. 59 
10.2 
SAMPLE SIZE ........................................................................................................................... 60 
10.3 
DATA COLLECTION ................................................................................................................. 61 
10.4 
DATA ANALYSIS ..................................................................................................................... 61 
10.4.1 
Analysis of safety ........................................................................................................... 61 
10.4.2 
Analysis of response ...................................................................................................... 61 
10.4.3 
Pharmacokinetics .......................................................................................................... 62 
11. 
REGULATORY AND REPORTING REQUIREMENTS .................................................. 62 
11.1 
ADVERSE EVENTS RECORDING, REPORTING AND COMMUNICATION ......................................... 62 
11.2 
ADVERSE EVENT TERMINOLOGY AND DEFINITIONS ................................................................. 62 
11.3 
ADVERSE EVENT REPORTING PROCEDURES ............................................................................ 63 
11.4 
ADVERSE EVENT EXPEDITED REPORTING GUIDELINES ........................................................... 64 
11.5 
SUBMISSION OF SERIOUS ADVERSE EVENT REPORTING ............................................................ 64 
11.6 
DATA REPORTING FORMS ....................................................................................................... 65 
11.7 
REPORT /DATA SUBMISSION ADDRESS & CONTACT ................................................................. 65 
11.8 
PATIENT RECORDS, QUALITY ASSURANCE, RECORDS RETENTION ............................................. 66 
11.9 
METHOD OF REVIEW ............................................................................................................... 66 
11.10 
SPECIAL REGULATORY CONSIDERATIONS ............................................................................ 66 
11.10.1 
HIPAA ........................................................................................................................... 66 
11.10.2 
Protocol amendments, informed consent, and IRB approval ....................................... 67 
12. 
CONFIDENTIALITY ............................................................................................................. 67 
13. 
ETHICAL STANDARDS & INVESTIGATOR OBLIGATIONS ..................................... 67 
14. 
LIST OF EXPECTED ADVERSE EVENTS ........................................................................ 68 
15. 
CTCAE ..................................................................................................................................... 70 
REFERENCES ..................................................................................................................................... 71 
APPENDIX A: PERFORMANCE STATUS CRITERIA ................................................................ 74 
APPENDIX B: NEW YORK HEART ASSOCIATION CLASSIFICATION ............................... 74 
APPENDIX C: ETHICAL STANDARDS ......................................................................................... 75 
APPENDIX D: INVESTIGATOR OBLIGATIONS ........................................................................ 76 
APPENDIX E: CONTACT LIST - ALTOR ..................................................................................... 80 
APPENDIX F: CONTACT LIST – DATA SAFETY MONITORING BOARD (DSMB) ............ 81 
APPENDIX G: CONTACT LIST - LABORATORIES ................................................................... 81 
APPENDIX H: APPROVAL PAGE .................................................................................................. 82 


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SYNOPSIS 
Sponsor: 
Altor Bioscience Corporation 
Protocol#: 
CA-ALT-801-01-10 
Study Drug Name: Not applicable 
Study Treatment 
Active agents: 
ALT-801 (c264scTCR-IL2), recombinant humanized, soluble single-chain 
TCR-cytokine fusion protein; Cisplatin; Gemcitabine. 
Study Type: 
Interventional 
Study Phase: 
Ib/II 
Protocol Title: 
A Phase Ib/II Trial of ALT-801 in Combination with Cisplatin and 
gemcitabine in Muscle Invasive or Metastatic Urothelial Cancer 
Objectives:   
To determine the safety and tolerability of the novel combination of ALT-
801 (c264scTCR-IL2) with cisplatin and gemcitabine or the combination of 
ALT-801 with gemcitabine alone in patients with muscle invasive or 
metastatic urothelial cancer of bladder, renal pelvis, ureters and urethra.   
To estimate the anti-tumor activity of ALT-801 in combination with 
cisplatin and gemcitabine or ALT-801 in combination with gemcitabine 
alone by radiologic or pathologic anti-tumor response, progression free 
survival (assessed through the end of the study), and overall survival 
(assessed through the end of the study) in treated patients.  
To characterize the immunogenicity and pharmacokinetic profile of ALT-
801 in combination with cisplatin and gemcitabine and the immunogenicity 
of ALT-801 in combination with gemcitabine alone in treated patients. 
To assess the relationship between tumor presentation of HLA-A*0201/p53 
aa 264-272 complex and the safety and clinical benefit of study treatment. 
Study Design: 
This is a Phase Ib/II, open-label, multi-center, competitive enrollment and 
dose-escalation study of ALT-801 in a biochemotherapy regimen either 
containing cisplatin and gemcitabine or containing gemcitabine alone in 
patients who have muscle invasive or metastatic urothelial cancer of bladder, 
renal pelvis, ureters and urethra. The study will be conducted in conformity 
with Current Good Clinical Practices (cGCP).  
The study includes a dose escalation phase (Phase Ib), to determine the 
maximum tolerated dose (MTD) and the recommended dose (RD) of ALT-
801, and a dose expansion phase (Phase II) with study treatment containing 
ALT-801 at the RD level, to assess the effectiveness of study treatment 
The Phase Ib dose escalation study is conducted using traditional (3+3) dose 
escalation rules. Patients enrolled in his phase will all receive the cisplatin-
containing study treatment (ALT-801, cisplatin and gemcitabine). 
The Phase II expansion study is conducted with the study treatment 
containing ALT-801 at the RD level.  Patients are enrolled into two 
treatment groups – Expansion Group 1, treated with a cisplatin-containing 


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regimen (ALT-801, cisplatin and gemcitabine) and Expansion Group 2, for 
platinum-refractory patients, consisting of two regimen arms based on the 
patient’s renal function. In this study, platinum-refractory is defined as 
disease progression while on prior platinum-based therapies or disease 
recurrence within 12 months after the last dose of a platinum-based therapy. 
The Group 1 expansion will be conducted using a modified Simon two-stage 
design [2, 3]. The Group 2 expansion will be conducted based an exact 
single-stage design [1]. After completion of Stage I expansion with the 
Expansion Group 1, platinum-refractory patients will be enrolled to the 
Expansion Group 2 to receive either the cisplatin-containing or non-
cisplatin-containing regimen as a “second-line” therapy.  
In the dose escalation phase of this study, there are five dose levels of ALT-
801 (0.04 mg/kg, 0.06 mg/kg, 0.08 mg/kg, 0.10 mg/kg and 0.12 mg/kg) in 
addition to two de-escalation dose levels. The doses of cisplatin (70 
mg/m2/dose) and gemcitabine (1000 mg/m2/dose) will be fixed across all 
ALT-801 dose levels. If the MTD cannot be determined after the maximum 
planned escalating dose level has been reached, or the RD for dose 
expansion cannot be determined during the dose escalation phase, the 
sponsor, the Data Safety Monitoring Board (DSMB) and the principal 
investigators will meet to discuss whether to amend the protocol to expand 
the dose escalation phase to include additional ALT-801 dose levels.  
Treatments: 
Each enrolled patient will receive up to two 3-course study treatments with a 
cisplatin-containing regimen or a non-cisplatin-containing regimen. Each 
treatment regimen consists of 3 courses of the following chemo-
immunotherapy: cisplatin (Day #1, only for cisplatin-containing regimen), 
gemcitabine (Day #1), ALT-801 (Day #3 & Day #5), gemcitabine (Day #8), 
ALT-801 (Day #8 & Day #12 or #15), and a rest period (Days #13 (or #16) - 
#21). The alternative dosing day (Day #15) for the last dose (dose #4) of 
ALT-801 is provided to allow sufficient recovery from transient study drug 
related toxicities. Prior to commencing the second or the third course of 
study treatment, subjects will need to meet the treatment continuation 
criteria. At completion of the three full courses of study treatment in the 
initial treatment period, each patient enrolled and treated will have received a 
total of up to 12 doses of the study drug ALT-801; 3 doses of cisplatin (no 
doses of cisplatin for patients enrolled to the non-cisplatin-containing arm in 
Expansion Group 2); and 6 doses of gemcitabine. After completing the 3-
course initial study treatment, patients who have at least stable disease and 
meet other treatment criteria will receive an additional 3 courses of chemo-
immunotherapy, during the maintenance treatment period, at the same dose 
level and with the same dosing schedule as the initial treatment regimen. 
Treatment delays, dose modifications, or omissions are addressed in the 
protocol. The treatment schedule for a 3-course study treatment regimen 
given during the initial and maintenance treatment periods is illustrated 
below: 
 
 


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3-Course Study Treatment: 
 
 
 
*not given to patients who are enrolled in the non-cisplatin-containing arm 
of Expansion Group 2. 
 
Enrolled patients will receive the study treatment at qualified cancer 
treatment centers with adequate diagnostic and treatment facilities to provide 
appropriate management of therapy and complications. ALT-801, cisplatin 
and gemcitabine will be administered by intravenous infusion into a central 
or peripheral vein under the supervision of a qualified physician experienced 
in the use of anti-cancer agents including aldesleukin (Proleukin), cisplatin 
and gemcitabine. 
This is the schema for the dose levels during the dose-escalation phase of the 
study. The -1 and -2 dose levels of ALT-801 are included in case of DLT 
events in the initial dose level.  
Cohort 
ALT-801 Dose (mg/kg) 
Cisplatin (mg/m2) 
Gemcitabine (mg/m2) 
-2 
0.01 
70 
1000 
-1 
0.02 
70 
1000 
1 (initial) 
0.04 
70 
1000 
2 
0.06 
70 
1000 
3 
0.08 
70 
1000 
4 
0.10 
70 
1000 
5 
0.12 
70 
1000 
Dose Escalation: 
In this phase of the study, a minimum of 3 patients will be enrolled at each 
dose level. All patients will be monitored for Dose Limiting Toxicity (DLT) 
for 8 weeks from the initial dose. If 0/3 patients has study treatment-related, 
dose-limiting toxicity by 8 weeks after the initial dose, the next cohort will 
be opened for enrollment. If one patient at a dose-level develops drug-related 
DLT, up to six patients will be enrolled at that dose level and each 
subsequent higher dose level. If 0 or 1 of 6 patients in a cohort of 6 patients 
has an event that meets criteria for study treatment-related DLT, then the 
next cohort will be opened for enrollment. If 2 or more out of 3-6 patients in 
a dose escalation cohort have a DLT that is drug-related, that dose level will 
be designated as exceeding the maximum tolerated dose. If there are 3 
patients in the dose level below this level, then additional patients (up to 6 
total) will be enrolled at that dose level. When there is a dose level with 0 or 
1 out of 6 patients with DLT, which is either the maximum planned dose 
level (level 5) or which is one level below a dose that was not tolerated, the 
dose that is the maximum tolerated dose (MTD) will be considered defined. 
Further changes in the treatment plan may be considered by protocol 
amendment at that point.  
 
Course 1 
Course 2 
Course 3 
Treatment Day 1 
3 
5 
8 12(15) 13(16)-21 22 24 26 29 33(36) 34(37)-42 43 45 47 50 54(57) 
Cisplatin 
X*  
 
 
 
Rest 
Period 
X* 
 
 
 
 
Rest 
Period 
X* 
 
 
 
 
Gemcitabine 
X 
 
 
X 
 
X 
 
 
X 
 
X 
 
 
X 
 
ALT-801 
 
X X X 
X 
 
X X X 
X 
 
X X 
X 
X 


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If more than two of six patients experience a DLT at the initial dose level 
(level 1), then the sponsor, the Data Safety Monitoring Board (DSMB) and 
the principal investigators will meet to determine how to adjust the dose 
level of cisplatin, gemcitabine, and/or the study drug downward, or continue 
with the (-1) and (-2) cohorts, and to determine how to proceed with the 
study.  
At any time during the dose escalation phase of the study, whether or not the 
MTD or the maximum planned escalating dose level is reached, the dose 
escalation phase may be concluded due to favorable anti-tumor effect 
observed in the enrolled patients. The DSMB will recommend a dose level 
of ALT-801, the recommended dose (RD), for the dose expansion phase of 
the study. 
Dose limiting toxicity (DLT) is defined as any toxicity of grade 3 that does 
not resolve to Grade 1 or lower within 7 days and any toxicity of Grade 4 
occurring during treatment courses with exceptions and details described in 
the study protocol. Patients experiencing a DLT should discontinue study 
treatment. Study treatment discontinuation due to adverse events experienced 
prior to study drug administration, disease progression or patient’s decision 
to withdraw from study treatment without occurrence of any study treatment 
discontinuation event will not necessarily define a DLT event. Study 
treatment discontinuation events are defined in the protocol.  
Dose Expansion: 
The Phase II dose expansion study, conducted with study treatment 
containing ALT-801 at the RD level, patients are enrolled to two treatment 
groups – Expansion Group 1, treated with a cisplatin-containing regimen, 
and Expansion Group 2, for platinum-refractory patients, consisting of two 
treatment arms based on the patient’s renal function. The cisplatin-
containing regimen arm is for patients who have sufficient renal function. 
The non-cisplatin-containing regimen arm is for patients who do not have 
sufficient renal function for platinum-based therapies. In this study, platinum 
refractory is defined as disease progression while on prior platinum-based 
therapies or disease recurrence within 12 months after the last dose of a 
platinum-based therapy.  Both objective response (OR) (defined as complete 
response (CR) + partial response (PR)) and clinical benefit (CB) (defined as 
CR, PR + stable disease (SD)) will be evaluated. 
Group 1 expansion will be conducted using a modified Simon two-stage 
design [2, 3]. The sample size was driven by the parameter that had the 
larger sample size for each stage [2, 3]. Common set thresholds of lack of 
efficacy (OR rate (ORR) = 40%; CB rate (CBR) = 78%) and an efficacy 
level of interest (ORR = 60%; CBR = 92%) will be selected. For Group 2 
expansion, each treatment arm will be conducted based on an exact single-
stage design [1]. Sample size for the expansion was calculated according to 
the single-stage design of A’Hern [1] to reject a baseline ORR of 10% when 
the true ORR is 40%. 


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Stopping Rules: 
The patient enrollment will be temporarily suspended based on occurrence 
of any of the following, and the sponsor, the Data Safety Monitoring Board 
and principal investigators will meet to discuss how to proceed with future 
patient enrollment in the study: 
If at any time during the dose escalation phase of the study,  
 more than one patient in a cohort of three, or two patients in a 
cohort of six patients experience any DLT or, 
 favorable anti-tumor response data collected from enrolled patients 
that indicates a dose level with significant therapeutic effect may 
have been found 
If at any time during the expansion phase of the study,  
 
more than 33% the patients experience any drug related DLT, 
 
if favorable anti-tumor response data collected from patients 
enrolled in an expansion group demonstrates significant therapeutic 
effect 
Evaluations: 
Patients will be evaluated for clinical toxicities during the treatment. 
Patients’ blood samples will be collected to assess the pharmacokinetic 
profile and immunogenicity of the study drug. The anti-tumor response will 
be evaluated for up to 22 weeks from the initial dose of the first course of 
treatment. All patients who receive at least three doses of the study drug 
ALT-801 will be included in the anti-tumor response evaluation. Between 
each cohort and at the end of the study, all clinical and safety data will be 
analyzed for all patients enrolled in the study for dose-response effects. 
Population: 
Patients of 18 years of age and above who are candidates for systemic 
cisplatin and gemcitabine for the treatment of muscle invasive or metastatic 
urothelial cancer of bladder, renal pelvis, ureters, and urethra may be 
selected for further evaluation of eligibility for study participation. Patients 
also need to have adequate cardiac, pulmonary, liver and kidney functions 
and to have an Eastern Cooperative Oncology Group (ECOG) performance 
status of 0 or 1.  
Sample Size: 
A total of up to 30 assessable patients will be accrued to the initial dose 
escalation phase of the study (Phase Ib); the estimated number is 9. In the dose 
expansion phase, up to an additional 40 assessable patients will be enrolled to 
receive cisplatin-containing study treatment in the Expansion Group 1 and 
up to 13 assessable patients will be enrolled to each of the two treatment 
arms in the Expansion Group 2. A total of approximately 75 assessable 
patients will be enrolled and complete the study. Assuming a 20% ineligible 
or non-assessable cases, a total of up to 90 patients may be accrued to the 
study. 
 
 


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Primary 
Endpoints: 
For Stage I only: 
(1) To define an MTD and/or RD for dose expansion of ALT-801 in 
combination with cisplatin and gemcitabine or ALT-801 in combination 
with gemcitabine alone in the treatment of patients with muscle invasive 
or metastatic urothelial cancer. 
For Stage I & II: 
(2) To assess the safety of the combination study treatment in treated 
patients. 
 
(3) To assess the objective response rate in treated patients. 
Secondary  
Endpoints: 
(1) To assess the progression free survival in treated patients. 
(2) To assess the overall survival in treated patients. 
(3) To evaluate the immunogenicity and pharmacokinetic profiles of ALT-
801 in treated patients. 
(4) To assess the relationship between tumor presentation of HLA-
A*0201/p53 aa264-272 complexes and the safety and clinical benefit of 
study treatment. 
Pharmacokinetics 
& Biomarkers: 
Blood samples will be collected to assess typing for HLA-A2, immune cell 
levels, phenotype, pharmacokinetics, immunogenicity of the study drug 
ALT-801, and the serum levels of IFN-γ and TNF-α. Tumor samples 
obtained from surgeries or biopsies performed prior to screening for the 
study will be collected to test the HLA-A*0201/p53 aa 264-272 complex 
presentation. Blood samples for pharmacokinetic analysis of ALT-801 will 
be taken on the first day of ALT-801 administration in the first course of 
study treatment. Venous blood will be obtained at Time 0 (before the start of 
infusion), at 30 minutes (15 minutes after completion of infusion), and 1, 3 
and 6 hours from Time 0 for the assessment of ALT-801 serum 
concentration. Non-compartmental and compartmental analyses will be 
conducted. In addition, the same blood samples collected for PK analysis 
will be used to assess the immunogenicity of study drug ALT-801 and the 
serum levels of IFN-γ and TNF-α. Fresh blood samples for HLA-A2 typing, 
immune cell levels and phenotype testing will be collected before the start of 
the first and second courses of study treatment. HLA-A2 typing will be 
performed only once. 
Monitoring Tests: Urine samples for urinalysis, blood samples for standard chemistry, CBC, 
differential and coagulation will be obtained for tests required at screening 
for study entry eligibility evaluation or for tests required throughout the 
treatment and follow-up periods for patient safety monitoring. Blood 
samples for immunogenicity testing, which include assays for anti-ALT-801 
and IL-2 neutralizing antibodies, will be collected prior to dosing on the first 
ALT-801 infusion day and at Week 9 from the initial dose of study 
treatment. 


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Anti-tumor  
Response 
Evaluation: 
The anti-tumor response will be evaluated for up to 22 weeks from the initial 
dose of study treatment: for non-responders: Week 9 and 13; for early 
responders: Week 9 and 18; for late responders: Week 9, 13 and 22. 
Objective Response will be evaluated using the new international criteria 
proposed by the Response Evaluation Criteria in Solid Tumors Committee 
(RECIST) 1.1. Baseline evaluations should be performed up to 28 days 
before starting study 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-ups. Imaging-based evaluation is 
preferred to evaluation by clinical examination when both methods have 
been used to assess the anti-tumor effect of the treatment. However, 
cystoscopic evaluation may be used routinely in this population, in addition 
to radiologic testing. If surgeries or biopsies are performed after patients 
receive and respond to study treatment, tumor or tissue samples from these 
procedures will be collected to assess histopathological and immuno-cellular 
responses to study treatment. 
 
Survival  
Assessment: 
Progression-free survival and overall survival of all enrolled patients will be 
assessed at 6, 9, 12, 18, 24, 30 and 36 months from the start of study 
treatment, or through the point designated as the end of the study follow up. 
Adverse Events: 
All patients will be monitored and evaluated for clinical toxicities during the 
treatment period and queried at each follow-up visit for Adverse Events 
(AEs). Patients may volunteer information concerning AEs. All adverse 
events will be graded by using the NCI Common Terminology Criteria for 
Adverse Events version 4.0 (CTCAE v4.0), and logged in the patient Case 
Report Form. The study centers should report all SAEs and all events that 
trigger patient’s study treatment discontinuation to the sponsor via phone, 
fax or email (or a combination) up to 1 day after learning of the event. The 
sponsor will use the information to manage and coordinate the dose 
escalation, cohort expansion and patient enrollment. The sponsor will then 
inform all of the participating clinical sites of the current dose level and the 
number of patients to be enrolled at that level, or of any patient enrollment 
suspension via phone, fax or email within a day of its learning of the event. 
The study centers should report the other adverse events to the sponsor 
following the guidelines defined in the study protocol. All study drug related 
adverse events (AEs) that are both serious and unexpected will be reported 
to the FDA in an expedited manner in accordance with 21 CFR §312.32. 
Statistical Plan: 
For each cohort, all AEs will be tabulated and examined and all safety and 
pharmacokinetic data will be evaluated. For estimation of duration of 
response, the Kaplan-Meier method will be used. P-values of <0.05 (two-
sided) will be considered to indicate statistical significance.  
 


CA-ALT-801-01-10 
CONFIDENTIAL 
Version#: 07 
IND 100174 
March 29, 2013 
 
 
Page 52 of 82 
8. 
STUDY CALENDAR, CLINICAL PROCEDURES & TESTS 
8.1 
Study calendar  
TESTS & PROCEDURES 
SCREEN1 
INITIAL STUDY TREATMENT  
SCAN #1 
SCAN #2 
MAINTENANCE 
STUDY 
TREATMENT  
SCAN #3 
FOLLOW-UPS 
COURSE 1 
COURSE 2 
COURSE 3 
Month(late responders in parentheses) 
 
1 
2 
3 
4 
3-5/(4-6) 
5/(6) 
6 
9 
12 18 24 30 
36 
Week (late responders in parentheses) 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
13 
10-17/(14-21) 
18/ 
(22) 
 
Treatment Day 
 
1 
3 
5 
8 
12 
 
22 
24 
26 
29 
33 
 
43 
45 
47 
50 
54 
  
  
1 - 54 
 
Informed consent   
X 
 
 
 
 
 
 
R 
e 
s 
t 
 
P 
e 
r 
i 
o 
d 
 
 
 
 
 
 
 
R 
e 
s 
t 
 
P 
e 
r 
i 
o 
d 
 
 
 
 
 
 
 
 
 
 
 
Follow 
Institution’s 
standard of care 
(SOC) policy. If 
performed, follow 
the same schedule 
as the Initial 
study treatment.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum pregnancy test2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Complete physical exam16 
X 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
X 
X 
 
 
 
 
 
 
 
Vital signs, weight, Height3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
Concurrent medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
CBC with Differential, Blood Chemistry16 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
Coagulation (PT/INR)4 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
X 
X 
 
  
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cardiac functions5, 16 
X 
X5 
X 
X 
X 
X 
X5 
X 
X 
X 
X 
X5 
X 
X 
X 
X 
  
  
 
 
 
 
 
 
 
 
Pulmonary functions 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse event assessment6 
X 
X 
X 
X  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
Tumor assessment7 
X 
  
  
  
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
 
 
 
 
 
 
 
Survival Assessment8 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
X X 
X 
X 
X 
X 
X 
HLA A2 Typing, immune cell levels & 
phenotype11 
 
X9 
X9 
 
X9 
 
  
X9 
 
 
 
 
 
 
 
 
 
 
Not required  
 
 
 
 
 
 
 
 
HLA-A*0201/p53 tumor typing 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK, IFNγ, TNFα11 
 
 
X10 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Immunogenicity tests11 
 
 
X12 
  
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
  
  
  
  
  
  
Cisplatin
 
c115 
 
 
 
 
c215 
 
 
 
 
c315 
 
 
 
 
 
 
Follow the same 
schedule as the Initial 
study treatment 
 
 
 
 
 
 
 
 
Gemcitabine
 
g1 
 
 
g2 
 
g3 
 
 
g4 
 
g5 
 
 
g6 
 
 
 
 
 
 
 
 
 
 
 
Study drug (ALT-801)13
 
  
a1 
a2 
a3 
a414 
  
a5 
a6 
a7 
a814 
  
a9 
a10 
a11 a1214 
  
  
 
 
 
 
 
 
 
 
1 Obtain signed consent any time before performing screening evaluations. Screening evaluations are performed < 14 days; stress test, if required, scan/x-ray < 28 days prior to start of therapy. If patient's condition is 
deteriorating, ECOG status and laboratory evaluations should be repeated within 48 hours prior to initiation of study treatment infusion 2Pregnancy test is for women with childbearing potential only.  3Vital signs 
(especially blood pressure), clinical status and laboratory tests should be reviewed before start of therapy. Vital signs will be evaluated every 2 hours after study treatment and before discharge (or at completion of dose 
monitoring), and body weight before study treatment infusion on study treatment infusion day. 4PT/INR should be performed for any bleeding issues. 5Patients are closely monitored for hypotension, arrhythmia, angina and 
myocardial infarction. At screening, patients who are ≥ 50 years of age or have a history of EKG abnormalities, symptoms of cardiac ischemia or arrhythmia will have a stress test (stress thallium, stress MUGA or 
dobutamine echocardiogram) to determine their eligibility for participation in the study. EKG will be performed for all patients at start of each study treatment course. At the start of 1st course, EKG is performed only 
when >14 days since last EKG. 6Patients who have an on-going study drug-related SAE upon study completion or at discontinuation of the study will be contacted by the investigator or his/her designee every week until 
the event is resolved or determined to be irreversible. 7Tumor response and progression will be evaluated in this study using the new international criteria proposed by the RECIST (1.1). 8Information about tumor 
assessment & other therapies received after completion of study treatment will be collected if available   9Fresh blood samples for HLA A2 blood typing, immune cell levels & phenotype testing will be collected before 
dosing. 10After Stage 1 expansion is completed, PK and TNF-α analyses will not be performed and serum sample collection only at Time 0 and 6 hours. 11Residual samples may be used by Sponsor for research studies of 
other biomarkers. 12Use the same blood sample collected before dosing for PK test.13On the days when gemcitabine and ALT-801 are both given, gemcitabine should be dosed first.  14This dose can be delayed to Day 15 of 
each course. 15Not required for patients enrolled to the non-cisplatin-containing arm of Expansion Group 2. 16Labs, physical exam, and EKG can be performed within 48 hours prior to start of each study treatment course.