Clinical trial NCT01625260
Conditions: Non-muscle Invasive Bladder Cancer
Keywords: cancer immunotherapy targeted non-muscle invasive interleukin-2 antitumor TCR T-cell receptor p53 p53 gene p53 tumor supressor protein urothelial cancer bladder cancer HLA-A2 positive HLA-A*0201/p53 aa264-272 HLA complex refractory relapsed BCG multi-focal carcinoma in situ transitional cell carcinoma gemcitabine
Sponsor: Altor BioScience
Start date: 2012-03-30; Completion date: 2018-03-08
Enrollment: 12 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
This is a Phase Ib/II, open-label, multi-center and competitive enrollment study of ALT-801 combined with gemcitabine for patients who have BCG failure (defined as refractory, relapsing or intolerant), non-muscle invasive bladder cancer and refuse or are not medically fit to undergo a radical cystectomy recommended by the participating urologist as the standard next therapy per urologic guidelines. The purpose of this study is to confirm the safety and tolerability of a well-tolerated dose level of ALT-801, to determine the Recommended Dose level (RD) and characterize the immunogenicity of ALT-801 combined with gemcitabine in treated patients. The anti-tumor responses will also be assessed.

Detailed description:
Bladder cancer is the fifth most common cancer in the United States with an estimated 71,000 new cases and approximately 14,000 deaths in 2009. Bladder cancer is also the costliest to treat per patient of all cancers, with annual direct medical expenditures in excess of $3.7 billion in the United States. This is largely because approximately 70% of all new cases of bladder cancer present as non-muscle invasive bladder cancer (NMIBC), which tends to recur, requiring repeated interventions and long-term follow-up.

Altor Bioscience Corp. has developed a tumor-targeted IL-2 fusion protein, ALT-801, comprising human recombinant IL-2 genetically linked to a TCR domain capable of binding a tumor associated human p53 peptide presented in the context of HLA-A2.

ALT-801 will be evaluated as to whether it can prevent disease progression and allow for bladder preservation to maintain the quality of life for patients with BCG failure, defined as refractory, relapsing or intolerant, non-muscle invasive bladder cancer who refuse or are not medically fit to undergo a radical cystectomy recommended by the participating urologist as the standard next therapy per urologic guidelines.

Arms: arm 1: ALT-801 at 0.06 mg/kg with Gemcitabine at 1000 mg/m\^2 arm 2: ALT-801 at 0.08 mg/kg with Gemcitabine at 1000 mg/m\^2
Interventions: intervention 1: ALT-801 intervention 2: Gemcitabine
Intervention descriptions: intervention 1: Intravenous infusion: 2 treatment courses and 1 maintenance course; on Day 3, 5, 8 and 15 of each course. intervention 2: Intravenous infusion: 2 treatment courses and 1 maintenance course; on Day 1 and 8 of each course.

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
CLINICAL STUDY PROTOCOL 
 
 
Protocol Number: 
CA-ALT-801-01-12 
 
 
Protocol Title: 
A Study of ALT-801 in Patients with  Bacillus 
Calmette-Guerin (BCG) Failure Non-Muscle 
Invasive Bladder Cancer  
 
 
Date of Protocol: 
 
Version # 01 
 
January 27, 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-801-01-12 
 
 
Protocol Title: 
A Study of ALT-801 in Patients with Bacillus 
Calmette-Guerin (BCG) Failure Non-Muscle 
Invasive Bladder Cancer 
 
 
Date of Protocol: 
 
Version# 01 
 
January 27, 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 
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 
NON-MUSCLE INVASIVE BLADDER CANCER ....................................................................... 13 
2.3 
CURRENT TREATMENT OPTIONS FOR NMIBC ................................................................... 13 
2.4 
CYTOKINE-BASED IMMUNOTHERAPY FOR CANCER............................................................ 14 
2.5 
A TARGETED IL-2 FUSION PROTEIN WITH ENHANCED IMMUNE STIMULATORY ACTIVITY .. 14 
2.6 
TUMOR EFFICACY STUDIES OF ALT-801 IN ANIMAL MODELS............................................ 15 
2.6.1 Efficacy evaluation of ALT-801 dose regimens in xenograft tumor models ................ 15 
2.6.2 Efficacy evaluation of ALT-801 and non-targeted scTCR/IL-2 fusion proteins in 
xenograft human urothelial tumor models ............................................................................... 16 
2.6.2.1. Activity of ALT-801 alone and in combination with gemcitabine and cisplatin 
against xenograft human UMUC-14 bladder tumors in nude mice (Pre-clinical Study 
PS2010-24) .......................................................................................................................... 16 
2.6.2.2. Activity of ALT-801 and non-targeted scTCR/IL-2 fusion proteins against 
xenograft human UMUC-14 bladder tumors in nude mice (Pre-clinical Study PS2011-73)
 
17 
2.6.3 Efficacy evaluation of ALT-801 against human p53-negative orthotropic murine 
bladder tumors in immunocompetent mice (Pre-clinical studies PS2011-56, 57a, 85 & 93) . 17 
2.7 
NON-CLINICAL TOXICOLOGY ............................................................................................ 19 
2.7.1 Single-dose toxicity study ............................................................................................. 19 
2.7.2 Multi-dose toxicity study .............................................................................................. 19 
2.8 
PHARMACOKINETICS ......................................................................................................... 20 
2.8.1 Non-clinical pharmacokinetics .................................................................................... 20 
2.8.2 Clinical pharmacokinetics ........................................................................................... 20 
2.9 
HUMAN EXPERIENCE ......................................................................................................... 21 
2.9.1 Phase I Study of ALT-801 in Patients with Progressive Metastatic Malignancies (CA-
ALT-801-01-06) ....................................................................................................................... 21 
2.9.1.1. Pharmacodynamics .............................................................................................. 21 
2.9.1.2. Tumor assessment ................................................................................................ 22 
2.9.1.3. Safety results ........................................................................................................ 23 
2.9.1.4. Immunogenicity ................................................................................................... 24 
2.9.1.5. Repeat treatment .................................................................................................. 24 
2.9.2 Phase Ib/II Study of ALT-801 with Cisplatin in Patients with Metastatic Melanoma 
(CA-ALT-801-02-09)................................................................................................................ 24 
2.9.3 Phase Ib/II Study of ALT-801 in combination with Cisplatin  and Gemcitabine in 
Muscle Invasive or Metastatic Urotherial Cancer (CA-ALT-801-01-10) ............................... 25 
3. 
RATIONALE FOR THE CURRENT STUDY ................................................................... 26 
4. 
OVERALL STUDY DESIGN ............................................................................................... 28 
5. 
STUDY POPULATION ........................................................................................................ 30 


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5.1 
INCLUSION CRITERIA ......................................................................................................... 30 
5.2 
EXCLUSION CRITERIA ........................................................................................................ 31 
5.3 
INCLUSION OF WOMEN AND MINORITIES............................................................................ 31 
6. 
STUDY DESIGN .................................................................................................................... 32 
6.1 
STUDY FLOW DIAGRAM ..................................................................................................... 32 
6.2 
SCREENING AND ENROLLMENT ......................................................................................... 32 
6.3 
STUDY TREATMENT........................................................................................................... 32 
6.3.1 Treatment setting ......................................................................................................... 32 
6.3.2 Treatment regimen and scheme ................................................................................... 33 
6.3.3 Study drug preparation and administration ................................................................ 33 
6.3.4 Pre- & Post- therapy interventions .............................................................................. 34 
6.4 
DURATION OF PATIENT PARTICIPATION ............................................................................. 35 
6.5 
DOSE CONFIRMATION PHASE ............................................................................................. 35 
6.6 
EXPANSION PHASE ............................................................................................................ 35 
6.7 
STOPPING RULES ............................................................................................................... 36 
6.8 
PATIENT MONITORING, DISEASE RESPONSE EVALUATION, SURVIVAL ASSESSMENT ........... 36 
6.8.1 Patient monitoring ....................................................................................................... 36 
6.8.2 Disease response evaluation ........................................................................................ 36 
6.8.3 Disease progression and survival assessment ............................................................. 36 
6.9 
DOSE LIMITING TOXICITIES ............................................................................................... 36 
6.10 
STUDY TREATMENT DISCONTINUATION............................................................................. 37 
6.10.1 
Study treatment discontinuation events ................................................................... 37 
6.10.2 
Follow-ups after treatment discontinuation............................................................. 37 
6.10.2.1. 
Discontinuation due to SAEs or on-going study drug related AEs ................. 37 
6.10.2.2. 
Discontinuation due to any other reasons ........................................................ 37 
6.11 
REPLACEMENT OF PARTICIPANTS ...................................................................................... 37 
6.12 
STUDY TREATMENT MODIFICATION................................................................................... 38 
6.12.1 
Kidney dysfunction ................................................................................................... 38 
6.12.2 
Hematological dysfunction ...................................................................................... 38 
6.12.3 
Hypotension ............................................................................................................. 38 
6.12.4 
Allergic reactions and cytokine release syndrome/acute infusion reaction ............ 38 
6.13 
GENERAL SUPPORTIVE CARE GUIDELINES AND DRUG INTERACTION .................................. 38 
6.13.1 
Hypotension and capillary leak syndrome ............................................................... 39 
6.13.2 
Pulmonary dysfunction ............................................................................................ 39 
6.13.3 
Impaired kidney and liver functions ........................................................................ 39 
6.13.4 
Infection ................................................................................................................... 39 
6.13.5 
Fever and chills........................................................................................................ 39 
6.13.6 
Gastritis.................................................................................................................... 40 
6.13.7 
Diarrhea, nausea and vomiting ............................................................................... 40 
6.13.8 
Pruritus and dermatitis ............................................................................................ 40 
6.13.9 
Acidosis .................................................................................................................... 40 
6.13.10 Life-threatening toxicities ........................................................................................ 40 
6.13.11 Other supportive care .............................................................................................. 40 
6.13.12 Drug interaction....................................................................................................... 40 


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7. 
STUDY DRUG: AVAILABILITY, ACCOUNTABILITY, PACKAGING & 
LABELING .................................................................................................................................... 41 
7.1 
AVAILABILITY .................................................................................................................. 41 
7.2 
ACCOUNTABILITY ............................................................................................................. 41 
7.3 
PACKAGING ...................................................................................................................... 42 
7.4 
LABELING ......................................................................................................................... 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 Prior therapies ............................................................................................................. 44 
8.2.5 Pregnancy test .............................................................................................................. 44 
8.2.6 Physical examination ................................................................................................... 44 
8.2.7 Vital signs, body weight & height ................................................................................ 44 
8.2.8 Cardiac assessment ...................................................................................................... 44 
8.2.9 Blood tests .................................................................................................................... 45 
8.2.10 
Urinalysis ................................................................................................................. 45 
8.2.11 
Urinary Symptoms ................................................................................................... 45 
8.2.12 
Urine cytology .......................................................................................................... 45 
8.2.13 
Cystoscopy and Bladder Biopsy............................................................................... 45 
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
 
46 
8.2.17 
Adverse event assessment ........................................................................................ 46 
8.2.18 
Anti-tumor response evaluation ............................................................................... 46 
8.2.19 
Follow-up for disease progression and survival assessment ................................... 46 
9. 
MEASUREMENT OF EFFECT .......................................................................................... 46 
10. 
STATISTICAL ANALYSIS ............................................................................................. 47 
10.1 
STUDY OBJECTIVES ........................................................................................................... 47 
10.2 
SAMPLE SIZE ..................................................................................................................... 47 
10.3 
DATA COLLECTION ........................................................................................................... 47 
10.4 
DATA ANALYSIS ................................................................................................................ 47 
10.4.1 
Safety analysis .......................................................................................................... 48 
10.4.2 
Response and survival analysis ............................................................................... 48 
10.4.3 
Pharmacokinetics ..................................................................................................... 48 
11. 
REGULATORY AND REPORTING REQUIREMENTS ............................................ 49 
11.1 
ADVERSE EVENTS RECORDING, REPORTING AND COMMUNICATION .................................. 49 
11.2 
ADVERSE EVENT TERMINOLOGY AND DEFINITIONS ........................................................... 49 
11.3 
ADVERSE EVENT REPORTING PROCEDURES ...................................................................... 50 
11.4 
ADVERSE EVENT EXPEDITED REPORTING GUIDELINES ..................................................... 51 


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11.5 
SUBMISSION OF SERIOUS ADVERSE EVENT REPORTING ...................................................... 51 
11.6 
DATA REPORTING FORMS ................................................................................................. 52 
11.7 
REPORT /DATA SUBMISSION ADDRESS & CONTACT ........................................................... 52 
11.8 
PATIENT RECORDS, QUALITY ASSURANCE, RECORDS RETENTION ...................................... 53 
11.9 
METHOD OF REVIEW ......................................................................................................... 53 
11.10 
SPECIAL REGULATORY CONSIDERATIONS ...................................................................... 53 
11.10.1 HIPAA ...................................................................................................................... 53 
11.10.2 Protocol amendments, informed consent, and IRB approval .................................. 54 
12. 
CONFIDENTIALITY ....................................................................................................... 54 
13. 
ETHICAL STANDARDS & INVESTIGATOR OBLIGATIONS ................................ 54 
14. 
LIST OF EXPECTED ADVERSE EVENTS .................................................................. 55 
15. 
CTCAE................................................................................................................................ 57 
REFERENCES ............................................................................................................................... 58 
APPENDIX B: NEW YORK HEART ASSOCIATION CLASSIFICATION ......................... 60 
APPENDIX C: ETHICAL STANDARDS ................................................................................... 61 
APPENDIX D: INVESTIGATOR OBLIGATIONS .................................................................. 62 
APPENDIX E: CONTACT LIST - ALTOR ............................................................................... 66 
APPENDIX F: CONTACT LIST – DATA SAFETY MONITORING BOARD (DSMB) ...... 67 
APPROVAL PAGE ....................................................................................................................... 68 


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SYNOPSIS 
Sponsor: 
Altor Bioscience Corporation 
Protocol#: 
CA-ALT-801-02-11 
Study Drug Name: Not applicable 
Study Treatment 
Active agents: 
ALT-801 (c264scTCR-IL2), recombinant humanized, soluble single-chain 
TCR-cytokine fusion protein. 
Study Type: 
Interventional 
Study Phase: 
Ib/II 
Protocol Title: 
A Study of ALT-801 in Patients with Bacillus Calmette-Guerin (BCG) 
Failure Non-Muscle Invasive Bladder Cancer 
Objectives:   
To confirm the safety and tolerability of a well-tolerated dose level of ALT-
801 and to determine the Recommended Dose level (RD) in patients with 
BCG failure, defined as refractory, relapsing or intolerant,  non-muscle 
invasive bladder cancer who refuse or are not medically fit to undergo a 
radical cystectomy recommended by the participating urolgist as the 
standard next therapy per urologic guidelines. 
To assess anti-tumor activity of study treatment in treated patients as 
determined by the disease response rate using cystoscopy, bladder biopsy, 
and urine cytology. 
To evaluate the duration of response and survival in these patients. 
To characterize the immunogenicity and pharmacokinetic profile of ALT-
801 in treated patients. 
To assess the relationship between tumor presentation of HLA-A*0201/p53 
aa 264-272 complex and the safety, immune response and clinical benefit of 
study treatment. 
Study Design: 
This is a Phase Ib/II, open-label, multi-center and competitive enrollment 
study of ALT-801 in patients with BCG failure, defined as refractory, 
relapsing or intolerant, non-muscle invasive bladder cancer who refuse or 
are not medically fit to undergo a radical cystectomy recommended by the 
participating urolgist as the standard next therapy per urologic guidelines.  
 
There are two phases in this study: a dose confirmation phase to confirm a 
well-tolerated dose in this patient population and designate it as the 
recommended dose level (RD) for study expansion and a two-stage 
expansion phase using the recommended (RD).  Each enrolled patient will 
receive up to two courses of study treatment.  
The study will be conducted in conformity with Good Clinical Practice 
(GCP).  
Treatments:  
All enrolled patients will receive up to two courses of study treatment: an 
induction treatment course and a maintenance treatment course.  The 
induction treatment course consists of two cycles of treatment with a 13-day 
rest period between cycles.  Each cycle consists of four doses of ALT-801, 


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one each on Day #1, Day #4, Day #8, and Day #15 in the cycle.  The rest 
period may be extended to include an additional week. Patients who have a 
complete response from the initial response assessment will receive 
additional 4 consecutive weekly doses of study treatment before the 
confirmatory response assessment. The schedules of initial and maintenance 
treatment courses are illustrated below:  
Induction treatment Course: 
 
 
 
 
M
Maintenance Treatment Course: 
 
 
 
There are no restrictions on further therapies, such as chemotherapy, 
radiation therapy or surgery to be used after the protocol-specified therapy.  
Clearly, additional post-study treatments could be of significant clinical 
benefit in selected patients, and these patients will be followed for outcome. 
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 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). 
Dose Confirmation 
Phase: 
In the dose-confirmation phase of the study, six patients will be enrolled at 
the dose level starting at 0.08 mg/kg, which is a well-tolerated dose level in a 
Phase Ib/II study of ALT-801 in combination with cisplatin in patients with 
metastatic melanoma.  Enrolled patients will be monitored during the 
induction treatment course for any Dose Limiting Toxicity (DLT).  
The tolerability of a dose level is defined as < 2 of 6 patients experiencing 
any DLT at this dose level.  If the tolerability of ALT-801 at a dose level 
cannot be confirmed, an additional six patients will be enrolled to repeat the 
dose confirmation phase with a step-down dose level that is 0.02 mg/kg 
lower than the previous tested dose level until a dose level is confirmed as a 
tolerated dose and is designated as the Recommended Dose (RD) for study 
expansion. Below are the dose levels of the study drug during the dose 
confirmation phase of the study.   
Treatment Cycle 
Cycle #1 
 
Cycle #2 
Treatment Week 
1 
2 
3 
4 
5 
6 
7 
Treatment Day 
1 
4 
8 
15 
Rest 
29 
32 
36 
43 
Dose# 
1 
2 
3 
4 
5 
6 
7 
8 
ALT-801 
X 
X 
X 
X 
X 
X 
X 
X 
Treatment Week 
9 
10 
11 
12 
Treatment Day 
57 
64 
71 
78 
Dose# 
9 
10 
11 
12 
ALT-801 
X 
X 
X 
X 


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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. 
 
 
Expansion 
Phase 
The two-stage expansion phase at the Recommended Dose (RD) level will 
be conducted using a modified Simon two-stage design. Objective response 
(OR) (defined as complete response (CR) + partial response (PR)) will be 
evaluated and set thresholds of lack of efficacy (OR rate (ORR) = 20%) and 
an efficacy level of interest (ORR = 40%) will be selected.   
Stopping Rule: 
Patient enrollment will be temporarily suspended based on the occurrence of 
any of the following:  
• 
During the dose confirmation phase of the study, no dose level can be 
designated as the RD. 
• 
If at any time during the expansion phase of the study, more than 33% 
of the patients experience a possible, probable or definite drug related 
DLT. 
If the above occur, then the Data Safety Monitoring Board and principal 
investigators will meet to discuss how to proceed with future patient 
enrollment in the study. 
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 activity of 
study treatment will be evaluated.  All patients who receive at least one dose 
of study drug ALT-801 will be included in the evaluation of anti-tumor 
activity of study treatment. 
Population: 
Patients of 18 years of age with BCG failure, defined as refractory, relapsing 
or intolerant, non-muscle invasive bladder cancer who refuse or are not 
medically fit to undergo a radical cystectomy recommended by the 
participating urolgist as the standard next therapy per urologic guidelines..  
Patients also need to have adequate cardiac, pulmonary, liver and kidney 
Cohort 
ALT-801 Dose (mg/kg) 
-2 
0.04 
-1 
0.06 
1 (initial) 
0.08 


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functions and to have an Eastern Cooperative Oncology Group (ECOG) 
performance status of 0, 1 or 2.  
Sample Size: 
A total of up to 18 assessable patients will be accrued to the dose confirmation 
phase of the study (Phase Ib).  Up to an additional 37 assessable patients will 
be enrolled at the expansion phase (Stage 1 and 2) of the study (Phase II).  A 
total of approximately 43 assessable patients will be enrolled and complete 
the study in the event that the RD is 0.08 mg/kg.  Assuming a 20% ineligible 
or non-assessable cases, a total of up to 52 patients may be accrued to the 
study. 
Primary 
Endpoints: 
For Phase Ib only: (1) Confirmation of the safey and tolerability of a well-tolerated dose level 
of ALT-801 and designation of the Recommended Dose level (RD).  
For Phase Ib & II: (2) Safety profile of ALT-801. 
 
(3) Disease response rate.  
Secondary  
Endpoints: 
(1) Duration of response. 
(2) Progression-free survival. 
(3) Event free survival. 
(4) Overall survival. 
(5) Immunogenicity and pharmacokinetics profile of ALT-801.  
(6) Relationship between tumor presentation of HLA-A*0201/p53 aa 264-
272 complexes and the safety, immune response and clinical benefit of 
study treatment. 
Pharmacokinetics 
& Biomarkers: 
Blood samples will be collected to assess typing for HLA-A2, immune cell 
levels and phenotype, pharmacokinetics and 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 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 initial study 
treatment cycle. 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 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 first and fourth dose of study drug infusion in 
each treatment cycle during the induction treatment course.  HLA-A2 typing 
will be performed only once. 
Monitoring Tests: Urine samples for urinalysis, blood samples for standard chemistry, and 
CBC with differential will be obtained at screening, on each study drug 
infusion day and follow-up visits.  Blood samples for immunogenicity 


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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 8 from the initial dose of study treatment. 
Response 
Assessment: 
There are two response assessments for treated patients: the initial 
assessment at week 8 and the confirmatory assessment at week 13 from the 
start of study treatment. After the induction treatment period, patients who 
have received at least one dose of study drug will have the initial response 
assessment. After the maintenance treatment period, patients who have 
received at least one dose of study drug during this treatment period will 
have the confirmatory response assessment.  Cystoscopy, bladder biopsy and 
urine cytology will be performed to evaluate the response.  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, overall survival, and duration of response of all 
treated patients will be assessed every three months during years 1 and 2, 
and then every 6 months during year 3 from the start of study treatment, or 
through the point designated, during the study, 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 Serious Adverse Events 
(SAEs) and all events that trigger patient’s study treatment discontinuation 
to the sponsor via phone, fax or email (or a combination) no more than 24 
hours after learning of the event.  The sponsor will use the information to 
manage and coordinate the dose confirmation, 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 24 hours of learning of the event.  The study centers should report all 
other adverse events to the sponsor following the guidelines defined in the 
study protocol.  All study drug related 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, 
pharmacokinetic and tumor response data will be evaluated. For estimation 
of duration of response and progression free survival, 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 
SCREEN/ 
BASELINE1 
INITIAL COURSE  
INITIAL 
ASSESSMENT 
MAINTENANCE 
COURSE 
CONFIRMATORY 
ASSESSMENT 
FOLLOW-UPS 
CYCLE #1 
 
CYCLE  #2 
Study Month 
 
1 
 
2 
3 
4 
6   
9  
12  
15 
18 
21 
24   30  36   
Study Week 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
  
Day of Week 
 
M W  M 
M 
 
M 
W 
M 
M 
  
M 
M 
M 
M 
 
 
Study Day 
 
1 
3 
8 
15 16-28 29 31  36  43 
  
57 
64 
71 
78 
 
 
Medical history/prior therapies 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum pregnancy test2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Complete physical exam 
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 
 
Concurrent medication 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Adverse event assessment4 
X 
X  
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
CBC with Differential 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Blood Chemistry  
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
EKG 
X5 
X5  
  
  
  
 
X  
  
  
  
 
X 
  
  
  
 
 
Urinalysis 
X 
X X X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Urinary symptoms  
X 
X X X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Cystoscopy & bladder biopsies 
X  
  
 
 
 
 
 
 
 
 
X  
 
 
 
 
X  
 
Urine cytology 
X 
  
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
Response assessment6 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
Disease & survival follow-up7 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
X  
X 
X 
X 
X 
X 
X 
X 
X 
Immune cell levels & phenotype8, 12 
 
X8 
 
 
X8 
 
X8 
 
 
X8 
 
X8 
  
  
X8 
 
 
HLA A2 Blood Typing9 & p53 tumor typing 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK, IFNγ, TNFα10,12 
 
X10 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Immunogenicity tests11, 12 
 
X11 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
Study drug (ALT-801) 
 
a1  a2 a3 
a4 
 
a5 
a6 
a7 
a8 
  
a9 
a10 a11 a12 
 
 
1Screening/baseline evaluations are performed < 14 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 drug infusion and before discharge, and body weight obtained before infusion on each drug infusion day. 4Patients who have an on-going study drug-related SAE upon 
study completion or at discontinuation of study will be contacted by the investigator or his/her designee every week until the event is resolved or determined to be irreversible. 5If a previous EKG was performed 
within 14 days before start of study treatment, the EKG is not required.  6Response will be evaluated by cystoscopy, bladder biopsies and urine cytology.  7Information about tumor assessment & other therapies 
received after completion of study treatment will be collected if available.  8Fresh blood samples for HLA A2 blood typing, immune cell levels & phenotype testing will be collected before dosing. 9 Use the 
same blood sample collected for immune cell levels & phenotype.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.  11Use the sample collected before dosing for PK test. 12Residual 
samples may be used by Sponsor for research studies of other biomarkers.  
 




 
 
 
CLINICAL STUDY PROTOCOL 
 
 
Protocol Number: 
CA-ALT-801-01-12 
 
 
Protocol Title: 
A Study of ALT-801 in Patients with  Bacillus 
Calmette-Guerin (BCG) Failure Non-Muscle 
Invasive Bladder Cancer  
 
 
Date of Protocol: 
 
Version# 01 
Version# 02 
January 27, 2012 
April 5, 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-801-01-12 
 
 
Protocol Title: 
A Study of ALT-801 in Patients with Bacillus 
Calmette-Guerin (BCG) Failure Non-Muscle 
Invasive Bladder Cancer 
 
 
Date of Protocol: 
 
Version# 01 
Version# 02 
January 27, 2012 
April 5, 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 
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 
NON-MUSCLE INVASIVE BLADDER CANCER ....................................................................... 13 
2.3 
CURRENT TREATMENT OPTIONS FOR NMIBC ................................................................... 13 
2.4 
CYTOKINE-BASED IMMUNOTHERAPY FOR CANCER............................................................ 14 
2.5 
A TARGETED IL-2 FUSION PROTEIN WITH ENHANCED IMMUNE STIMULATORY ACTIVITY .. 14 
2.6 
TUMOR EFFICACY STUDIES OF ALT-801 IN ANIMAL MODELS............................................ 15 
2.6.1 Efficacy evaluation of ALT-801 dose regimens in xenograft tumor models ................ 15 
2.6.2 Efficacy evaluation of ALT-801 and non-targeted scTCR/IL-2 fusion proteins in 
xenograft human urothelial tumor models ............................................................................... 16 
2.6.2.1. Activity of ALT-801 alone and in combination with gemcitabine and cisplatin 
against xenograft human UMUC-14 bladder tumors in nude mice (Pre-clinical Study 
PS2010-24) .......................................................................................................................... 16 
2.6.2.2. Activity of ALT-801 and non-targeted scTCR/IL-2 fusion proteins against 
xenograft human UMUC-14 bladder tumors in nude mice (Pre-clinical Study PS2011-73)
 
17 
2.6.3 Efficacy evaluation of ALT-801 against human p53-negative orthotropic murine 
bladder tumors in immunocompetent mice (Pre-clinical studies PS2011-56, 57a, 85 & 93) . 17 
2.7 
NON-CLINICAL TOXICOLOGY ............................................................................................ 19 
2.7.1 Single-dose toxicity study ............................................................................................. 19 
2.7.2 Multi-dose toxicity study .............................................................................................. 19 
2.8 
PHARMACOKINETICS ......................................................................................................... 20 
2.8.1 Non-clinical pharmacokinetics .................................................................................... 20 
2.8.2 Clinical pharmacokinetics ........................................................................................... 20 
2.9 
HUMAN EXPERIENCE ......................................................................................................... 21 
2.9.1 Phase I Study of ALT-801 in Patients with Progressive Metastatic Malignancies (CA-
ALT-801-01-06) ....................................................................................................................... 21 
2.9.1.1. Pharmacodynamics .............................................................................................. 21 
2.9.1.2. Tumor assessment ................................................................................................ 22 
2.9.1.3. Safety results ........................................................................................................ 23 
2.9.1.4. Immunogenicity ................................................................................................... 24 
2.9.1.5. Repeat treatment .................................................................................................. 24 
2.9.2 Phase Ib/II Study of ALT-801 with Cisplatin in Patients with Metastatic Melanoma 
(CA-ALT-801-02-09)................................................................................................................ 24 
2.9.3 Phase Ib/II Study of ALT-801 in combination with Cisplatin  and Gemcitabine in 
Muscle Invasive or Metastatic Urotherial Cancer (CA-ALT-801-01-10) ............................... 25 
3. 
RATIONALE FOR THE CURRENT STUDY ................................................................... 26 
4. 
OVERALL STUDY DESIGN ............................................................................................... 28 
5. 
STUDY POPULATION ........................................................................................................ 30 


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5.1 
INCLUSION CRITERIA ......................................................................................................... 30 
5.2 
EXCLUSION CRITERIA ........................................................................................................ 31 
5.3 
INCLUSION OF WOMEN AND MINORITIES............................................................................ 31 
6. 
STUDY DESIGN .................................................................................................................... 32 
6.1 
STUDY FLOW DIAGRAM ..................................................................................................... 32 
6.2 
SCREENING AND ENROLLMENT ......................................................................................... 32 
6.3 
STUDY TREATMENT........................................................................................................... 32 
6.3.1 Treatment setting ......................................................................................................... 32 
6.3.2 Treatment regimen and scheme ................................................................................... 33 
6.3.3 Study drug preparation and administration ................................................................ 33 
6.3.4 Pre- & Post- therapy interventions .............................................................................. 34 
6.4 
DURATION OF PATIENT PARTICIPATION ............................................................................. 35 
6.5 
DOSE CONFIRMATION PHASE ............................................................................................. 35 
6.6 
EXPANSION PHASE ............................................................................................................ 35 
6.7 
STOPPING RULES ............................................................................................................... 36 
6.8 
PATIENT MONITORING, DISEASE RESPONSE EVALUATION, SURVIVAL ASSESSMENT ........... 36 
6.8.1 Patient monitoring ....................................................................................................... 36 
6.8.2 Disease response evaluation ........................................................................................ 36 
6.8.3 Disease progression and survival assessment ............................................................. 36 
6.9 
DOSE LIMITING TOXICITIES ............................................................................................... 36 
6.10 
STUDY TREATMENT DISCONTINUATION............................................................................. 37 
6.10.1 
Study treatment discontinuation events ................................................................... 37 
6.10.2 
Follow-ups after treatment discontinuation............................................................. 37 
6.10.2.1. 
Discontinuation due to SAEs or on-going study drug related AEs ................. 37 
6.10.2.2. 
Discontinuation due to any other reasons ........................................................ 37 
6.11 
REPLACEMENT OF PARTICIPANTS ...................................................................................... 37 
6.12 
STUDY TREATMENT MODIFICATION................................................................................... 38 
6.12.1 
Kidney dysfunction ................................................................................................... 38 
6.12.2 
Hematological dysfunction ...................................................................................... 38 
6.12.3 
Hypotension ............................................................................................................. 38 
6.12.4 
Allergic reactions and cytokine release syndrome/acute infusion reaction ............ 38 
6.13 
GENERAL SUPPORTIVE CARE GUIDELINES AND DRUG INTERACTION .................................. 38 
6.13.1 
Hypotension and capillary leak syndrome ............................................................... 39 
6.13.2 
Pulmonary dysfunction ............................................................................................ 39 
6.13.3 
Impaired kidney and liver functions ........................................................................ 39 
6.13.4 
Infection ................................................................................................................... 39 
6.13.5 
Fever and chills........................................................................................................ 39 
6.13.6 
Gastritis.................................................................................................................... 40 
6.13.7 
Diarrhea, nausea and vomiting ............................................................................... 40 
6.13.8 
Pruritus and dermatitis ............................................................................................ 40 
6.13.9 
Acidosis .................................................................................................................... 40 
6.13.10 Life-threatening toxicities ........................................................................................ 40 
6.13.11 Other supportive care .............................................................................................. 40 
6.13.12 Drug interaction....................................................................................................... 40 


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7. 
STUDY DRUG: AVAILABILITY, ACCOUNTABILITY, PACKAGING & 
LABELING .................................................................................................................................... 41 
7.1 
AVAILABILITY .................................................................................................................. 41 
7.2 
ACCOUNTABILITY ............................................................................................................. 41 
7.3 
PACKAGING ...................................................................................................................... 42 
7.4 
LABELING ......................................................................................................................... 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 Prior therapies ............................................................................................................. 44 
8.2.5 Pregnancy test .............................................................................................................. 44 
8.2.6 Physical examination ................................................................................................... 44 
8.2.7 Vital signs, body weight & height ................................................................................ 44 
8.2.8 Cardiac assessment ...................................................................................................... 44 
8.2.9 Blood tests .................................................................................................................... 45 
8.2.10 
Urinalysis ................................................................................................................. 45 
8.2.11 
Urinary Symptoms ................................................................................................... 45 
8.2.12 
Urine cytology .......................................................................................................... 45 
8.2.13 
Cystoscopy and Bladder Biopsy............................................................................... 45 
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 
8.2.17 
Adverse event assessment ........................................................................................ 46 
8.2.18 
Anti-tumor response evaluation ............................................................................... 46 
8.2.19 
Follow-up for disease progression and survival assessment ................................... 46 
9. 
MEASUREMENT OF EFFECT .......................................................................................... 46 
10. 
STATISTICAL ANALYSIS ............................................................................................. 47 
10.1 
STUDY OBJECTIVES ........................................................................................................... 47 
10.2 
SAMPLE SIZE ..................................................................................................................... 47 
10.3 
DATA COLLECTION ........................................................................................................... 47 
10.4 
DATA ANALYSIS ................................................................................................................ 47 
10.4.1 
Safety analysis .......................................................................................................... 48 
10.4.2 
Response and survival analysis ............................................................................... 48 
10.4.3 
Pharmacokinetics ..................................................................................................... 48 
11. 
REGULATORY AND REPORTING REQUIREMENTS ............................................ 49 
11.1 
ADVERSE EVENTS RECORDING, REPORTING AND COMMUNICATION .................................. 49 
11.2 
ADVERSE EVENT TERMINOLOGY AND DEFINITIONS ........................................................... 49 
11.3 
ADVERSE EVENT REPORTING PROCEDURES ...................................................................... 50 
11.4 
ADVERSE EVENT EXPEDITED REPORTING GUIDELINES ..................................................... 51 


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11.5 
SUBMISSION OF SERIOUS ADVERSE EVENT REPORTING ...................................................... 51 
11.6 
DATA REPORTING FORMS ................................................................................................. 52 
11.7 
REPORT /DATA SUBMISSION ADDRESS & CONTACT ........................................................... 52 
11.8 
PATIENT RECORDS, QUALITY ASSURANCE, RECORDS RETENTION ...................................... 53 
11.9 
METHOD OF REVIEW ......................................................................................................... 53 
11.10 
SPECIAL REGULATORY CONSIDERATIONS ...................................................................... 53 
11.10.1 HIPAA ...................................................................................................................... 53 
11.10.2 Protocol amendments, informed consent, and IRB approval .................................. 54 
12. 
CONFIDENTIALITY ....................................................................................................... 54 
13. 
ETHICAL STANDARDS & INVESTIGATOR OBLIGATIONS ................................ 54 
14. 
LIST OF EXPECTED ADVERSE EVENTS .................................................................. 55 
15. 
CTCAE................................................................................................................................ 57 
REFERENCES ............................................................................................................................... 58 
APPENDIX B: NEW YORK HEART ASSOCIATION CLASSIFICATION ......................... 60 
APPENDIX C: ETHICAL STANDARDS ................................................................................... 61 
APPENDIX D: INVESTIGATOR OBLIGATIONS .................................................................. 62 
APPENDIX E: CONTACT LIST - ALTOR ............................................................................... 66 
APPENDIX F: CONTACT LIST – DATA SAFETY MONITORING BOARD (DSMB) ...... 67 
APPROVAL PAGE ....................................................................................................................... 68 


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SYNOPSIS 
Sponsor: 
Altor Bioscience Corporation 
Protocol#: 
CA-ALT-801-02-11 
Study Drug Name: Not applicable 
Study Treatment 
Active agents: 
ALT-801 (c264scTCR-IL2), recombinant humanized, soluble single-chain 
TCR-cytokine fusion protein. 
Study Type: 
Interventional 
Study Phase: 
Ib/II 
Protocol Title: 
A Study of ALT-801 in Patients with Bacillus Calmette-Guerin (BCG) 
Failure Non-Muscle Invasive Bladder Cancer 
Objectives:   
To confirm the safety and tolerability of a well-tolerated dose level of ALT-
801 and to determine the Recommended Dose level (RD) in patients with 
BCG failure, defined as refractory, relapsing or intolerant,  non-muscle 
invasive bladder cancer who refuse or are not medically fit to undergo a 
radical cystectomy recommended by the participating urolgist as the 
standard next therapy per urologic guidelines. 
To assess anti-tumor activity of study treatment in treated patients as 
determined by the disease response rate using cystoscopy, bladder biopsy, 
and urine cytology. 
To evaluate the duration of response and survival in these patients. 
To characterize the immunogenicity and pharmacokinetic profile of ALT-
801 in treated patients. 
To assess the relationship between tumor presentation of HLA-A*0201/p53 
aa 264-272 complex and the safety, immune response and clinical benefit of 
study treatment. 
Study Design: 
This is a Phase Ib/II, open-label, multi-center and competitive enrollment 
study of ALT-801 in patients with BCG failure, defined as refractory, 
relapsing or intolerant, non-muscle invasive bladder cancer who refuse or 
are not medically fit to undergo a radical cystectomy recommended by the 
participating urolgist as the standard next therapy per urologic guidelines.  
 
There are two phases in this study: a dose confirmation phase to confirm a 
well-tolerated dose in this patient population and designate it as the 
recommended dose level (RD) for study expansion and a two-stage 
expansion phase using the recommended (RD).  Each enrolled patient will 
receive up to two courses of study treatment.  
The study will be conducted in conformity with Good Clinical Practice 
(GCP).  
Treatments:  
All enrolled patients will receive up to two courses of study treatment: an 
induction treatment course and a maintenance treatment course.  The 
induction treatment course consists of two cycles of treatment with a 13-day 
rest period between cycles.  Each cycle consists of four doses of ALT-801, 


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one each on Day #1, Day #4, Day #8, and Day #15 in the cycle.  The rest 
period may be extended to include an additional week. Patients who have a 
complete response from the initial response assessment will receive 
additional 4 consecutive weekly doses of study treatment before the 
confirmatory response assessment. The schedules of initial and maintenance 
treatment courses are illustrated below:  
Induction treatment Course: 
 
 
 
 
M
Maintenance Treatment Course: 
 
 
 
There are no restrictions on further therapies, such as chemotherapy, 
radiation therapy or surgery to be used after the protocol-specified therapy.  
Clearly, additional post-study treatments could be of significant clinical 
benefit in selected patients, and these patients will be followed for outcome. 
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 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). 
Dose Confirmation 
Phase: 
In the dose-confirmation phase of the study, six patients will be enrolled at 
the dose level starting at 0.08 mg/kg, which is a well-tolerated dose level in a 
Phase Ib/II study of ALT-801 in combination with cisplatin in patients with 
metastatic melanoma.  Enrolled patients will be monitored during the 
induction treatment course for any Dose Limiting Toxicity (DLT).  
The tolerability of a dose level is defined as < 2 of 6 patients experiencing 
any DLT at this dose level.  If the tolerability of ALT-801 at a dose level 
cannot be confirmed, an additional six patients will be enrolled to repeat the 
dose confirmation phase with a step-down dose level that is 0.02 mg/kg 
lower than the previous tested dose level until a dose level is confirmed as a 
tolerated dose and is designated as the Recommended Dose (RD) for study 
expansion. Below are the dose levels of the study drug during the dose 
confirmation phase of the study.   
Treatment Cycle 
Cycle #1 
 
Cycle #2 
Treatment Week 
1 
2 
3 
4 
5 
6 
7 
Treatment Day 
1 
4 
8 
15 
Rest 
29 
32 
36 
43 
Dose# 
1 
2 
3 
4 
5 
6 
7 
8 
ALT-801 
X 
X 
X 
X 
X 
X 
X 
X 
Treatment Week 
9 
10 
11 
12 
Treatment Day 
57 
64 
71 
78 
Dose# 
9 
10 
11 
12 
ALT-801 
X 
X 
X 
X 


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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. 
 
 
Expansion 
Phase 
The two-stage expansion phase at the Recommended Dose (RD) level will 
be conducted using a modified Simon two-stage design. Objective response 
(OR) (defined as complete response (CR) + partial response (PR)) will be 
evaluated and set thresholds of lack of efficacy (OR rate (ORR) = 20%) and 
an efficacy level of interest (ORR = 40%) will be selected.   
Stopping Rule: 
Patient enrollment will be temporarily suspended based on the occurrence of 
any of the following:  
• 
During the dose confirmation phase of the study, no dose level can be 
designated as the RD. 
• 
If at any time during the expansion phase of the study, more than 33% 
of the patients experience a possible, probable or definite drug related 
DLT. 
If the above occur, then the Data Safety Monitoring Board and principal 
investigators will meet to discuss how to proceed with future patient 
enrollment in the study. 
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 activity of 
study treatment will be evaluated.  All patients who receive at least one dose 
of study drug ALT-801 will be included in the evaluation of anti-tumor 
activity of study treatment. 
Population: 
Patients of 18 years of age with BCG failure, defined as refractory, relapsing 
or intolerant, non-muscle invasive bladder cancer who refuse or are not 
medically fit to undergo a radical cystectomy recommended by the 
participating urolgist as the standard next therapy per urologic guidelines..  
Patients also need to have adequate cardiac, pulmonary, liver and kidney 
Cohort 
ALT-801 Dose (mg/kg) 
-2 
0.04 
-1 
0.06 
1 (initial) 
0.08 


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functions and to have an Eastern Cooperative Oncology Group (ECOG) 
performance status of 0, 1 or 2.  
Sample Size: 
A total of up to 18 assessable patients will be accrued to the dose confirmation 
phase of the study (Phase Ib).  Up to an additional 37 assessable patients will 
be enrolled at the expansion phase (Stage 1 and 2) of the study (Phase II).  A 
total of approximately 43 assessable patients will be enrolled and complete 
the study in the event that the RD is 0.08 mg/kg.  Assuming a 20% ineligible 
or non-assessable cases, a total of up to 52 patients may be accrued to the 
study. 
Primary 
Endpoints: 
For Phase Ib only: (1) Confirmation of the safey and tolerability of a well-tolerated dose level 
of ALT-801 and designation of the Recommended Dose level (RD).  
For Phase Ib & II: (2) Safety profile of ALT-801. 
 
(3) Disease response rate.  
Secondary  
Endpoints: 
(1) Duration of response. 
(2) Progression-free survival. 
(3) Event free survival. 
(4) Overall survival. 
(5) Immunogenicity and pharmacokinetics profile of ALT-801.  
(6) Relationship between tumor presentation of HLA-A*0201/p53 aa 264-
272 complexes and the safety, immune response and clinical benefit of 
study treatment. 
Pharmacokinetics 
& Biomarkers: 
Blood samples will be collected to assess typing for HLA-A2, immune cell 
levels and phenotype, pharmacokinetics and 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 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 initial study 
treatment cycle. 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 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 first and fourth dose of study drug infusion in 
each treatment cycle during the induction treatment course.  HLA-A2 typing 
will be performed only once. 
Monitoring Tests: Urine samples for urinalysis, blood samples for standard chemistry, and 
CBC with differential will be obtained at screening, on each study drug 
infusion day and follow-up visits.  Blood samples for immunogenicity 


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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 8 from the initial dose of study treatment. 
Response 
Assessment: 
There are two response assessments for treated patients: the initial 
assessment at week 8 and the confirmatory assessment at week 13 from the 
start of study treatment. After the induction treatment period, patients who 
have received at least one dose of study drug will have the initial response 
assessment. After the maintenance treatment period, patients who have 
received at least one dose of study drug during this treatment period will 
have the confirmatory response assessment.  Cystoscopy, bladder biopsy and 
urine cytology will be performed to evaluate the response.  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, overall survival, and duration of response of all 
treated patients will be assessed every three months during years 1 and 2, 
and then every 6 months during year 3 from the start of study treatment, or 
through the point designated, during the study, 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 Serious Adverse Events 
(SAEs) and all events that trigger patient’s study treatment discontinuation 
to the sponsor via phone, fax or email (or a combination) no more than 24 
hours after learning of the event.  The sponsor will use the information to 
manage and coordinate the dose confirmation, 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 24 hours of learning of the event.  The study centers should report all 
other adverse events to the sponsor following the guidelines defined in the 
study protocol.  All study drug related 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, 
pharmacokinetic and tumor response data will be evaluated. For estimation 
of duration of response and progression free survival, 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 
SCREEN/ 
BASELINE1 
INITIAL COURSE  
INITIAL 
ASSESSMENT 
MAINTENANCE 
COURSE 
CONFIRMATORY 
ASSESSMENT 
FOLLOW-UPS 
CYCLE #1 
 
CYCLE  #2 
Study Month 
 
1 
 
2 
3 
4 
6   
9  
12  
15 
18 
21 
24   30  36   
Study Week 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
  
Day of Week 
 
M W  M 
M 
 
M 
W 
M 
M 
  
M 
M 
M 
M 
 
 
Study Day 
 
1 
4 
8 
15 16-28 29 32  36  43 
  
57 
64 
71 
78 
 
 
Medical history/prior therapies 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum pregnancy test2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Complete physical exam 
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 
 
Concurrent medication 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Adverse event assessment4 
X 
X  
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
CBC with Differential 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Blood Chemistry  
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
EKG 
X5 
X5  
  
  
  
 
X  
  
  
  
 
X 
  
  
  
 
 
Urinalysis 
X 
X X X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Urinary symptoms  
X 
X X X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Cystoscopy13 & bladder biopsies13 
X  
  
 
 
 
 
 
 
 
 
X  
 
 
 
 
X  
 
Urine cytology 
X 
  
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
Response assessment6 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
Disease & survival follow-up7 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
X  
X 
X 
X 
X 
X 
X 
X 
X 
Immune cell levels & phenotype8, 12 
 
X8 
 
 
X8 
 
X8 
 
 
X8 
 
X8 
  
  
X8 
 
 
HLA A2 Blood Typing9 & p53 tumor typing 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK, IFNγ, TNFα10,12 
 
X10 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Immunogenicity tests11, 12 
 
X11 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
Study drug (ALT-801) 
 
a1  a2 a3 
a4 
 
a5 
a6 
a7 
a8 
  
a9 
a10 a11 a12 
 
 
1Screening/baseline evaluations are performed < 14 days prior to start of therapy except cystoscopy and biopsies.  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 drug infusion and before discharge, and body weight obtained before infusion on each drug infusion day. 4Patients who have an 
on-going study drug-related SAE upon study completion or at discontinuation of study will be contacted by the investigator or his/her designee every week until the event is resolved or determined to be 
irreversible. 5If a previous EKG was performed within 14 days before start of study treatment, the EKG is not required.  6Response will be evaluated by cystoscopy, bladder biopsies and urine cytology.  7Information 
about tumor assessment & other therapies received after completion of study treatment will be collected if available.  8Fresh blood samples for HLA A2 blood typing, immune cell levels & phenotype testing 
will be collected before dosing. 9 Use the same blood sample collected for immune cell levels & phenotype.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.  11Use the sample 
collected before dosing for PK test. 12Residual samples may be used by Sponsor for research studies of other biomarkers.13Screening cystoscopy is performed within 4 weeks prior to start of therapy, screening 
biopsies are performed within 3 months  prior to start of therapy. 
 




 
 
 
CLINICAL STUDY PROTOCOL 
 
 
Protocol Number: 
CA-ALT-801-01-12 
 
 
Protocol Title: 
A Study of ALT-801 in Patients with  Bacillus 
Calmette-Guerin (BCG) Failure Non-Muscle 
Invasive Bladder Cancer  
 
 
Date of Protocol: 
 
Version# 01 
Version# 02 
Version# 03 
January 27, 2012 
April 5, 2012 
October 24, 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-801-01-12 
 
 
Protocol Title: 
A Study of ALT-801 in Patients with Bacillus 
Calmette-Guerin (BCG) Failure Non-Muscle 
Invasive Bladder Cancer 
 
 
Date of Protocol: 
 
Version# 01 
Version# 02 
Version# 03 
January 27, 2012 
April 5, 2012 
October 24, 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 
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 
NON-MUSCLE INVASIVE BLADDER CANCER ....................................................................... 13 
2.3 
CURRENT TREATMENT OPTIONS FOR NMIBC ................................................................... 13 
2.4 
CYTOKINE-BASED IMMUNOTHERAPY FOR CANCER............................................................ 14 
2.5 
A TARGETED IL-2 FUSION PROTEIN WITH ENHANCED IMMUNE STIMULATORY ACTIVITY .. 14 
2.6 
TUMOR EFFICACY STUDIES OF ALT-801 IN ANIMAL MODELS............................................ 15 
2.6.1 Efficacy evaluation of ALT-801 dose regimens in xenograft tumor models ................ 15 
2.6.2 Efficacy evaluation of ALT-801 and non-targeted scTCR/IL-2 fusion proteins in 
xenograft human urothelial tumor models ............................................................................... 16 
2.6.2.1. Activity of ALT-801 alone and in combination with gemcitabine and cisplatin 
against xenograft human UMUC-14 bladder tumors in nude mice (Pre-clinical Study 
PS2010-24) .......................................................................................................................... 16 
2.6.2.2. Activity of ALT-801 and non-targeted scTCR/IL-2 fusion proteins in 
combination with gemcitabine  against xenograft human bladder tumors in nude mice (Pre-
clinical studies PS2011-73  & PS2011-73-3) ...................................................................... 17 
2.6.3 Efficacy evaluation of ALT-801 against human p53-negative orthotropic murine 
bladder tumors in immunocompetent mice (Pre-clinical studies PS2011-56, 57a, 85 & 93) . 18 
2.6.4 Immune cell-based mechanism-of-action of ALT-801 efficacy against orthotropic 
murine bladder tumors in immunocompetent mice (Pre-clinical studies PS2012-103, PS2012-
116 and PS2012-121) .............................................................................................................. 20 
2.7 
EFFECTS OF OPTIMIZED ALT-801-CHEMOTHERAPY REGIMENS IN ORTHOTROPIC MURINE 
BLADDER TUMOR MODELS............................................................................................................. 21 
2.7.1 Role of myeloid-derived suppressive cells (MDSCs) in human and murine bladder 
cancer (Pre-clinical studies PS2012-116 & PS2012-121) ...................................................... 21 
2.7.2 Enhancement of ALT-801 efficacy against bladder cancer by gemcitabine-mediated 
inhibition of MDSCs (Pre-clinical studies PS2012-120 & PS2012-121) ................................ 22 
2.8 
NON-CLINICAL TOXICOLOGY ............................................................................................ 23 
2.8.1 Single-dose toxicity study ............................................................................................. 23 
2.8.2 Multi-dose toxicity study .............................................................................................. 23 
2.9 
PHARMACOKINETICS ......................................................................................................... 24 
2.9.1 Non-clinical pharmacokinetics .................................................................................... 24 
2.9.2 Clinical pharmacokinetics ........................................................................................... 25 
2.10 
HUMAN EXPERIENCE ......................................................................................................... 25 
2.10.1 
Phase I Study of ALT-801 in Patients with Progressive Metastatic Malignancies 
(CA-ALT-801-01-06)................................................................................................................ 25 
2.10.1.1. 
Pharmacodynamics .......................................................................................... 25 
2.10.1.2. 
Tumor assessment ............................................................................................ 26 
2.10.1.3. 
Safety results .................................................................................................... 27 
2.10.1.4. 
Immunogenicity ............................................................................................... 28 


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2.10.1.5. 
Repeat treatment .............................................................................................. 28 
2.10.2 
Phase Ib/II Study of ALT-801 with Cisplatin in Patients with Metastatic Melanoma 
(CA-ALT-801-02-09)................................................................................................................ 28 
2.10.3 
Phase Ib/II Study of ALT-801 in combination with Cisplatin  and Gemcitabine in 
Muscle Invasive or Metastatic Urotherial Cancer (CA-ALT-801-01-10) ............................... 30 
3. 
RATIONALE FOR THE CURRENT STUDY ................................................................... 31 
4. 
OVERALL STUDY DESIGN ............................................................................................... 33 
5. 
STUDY POPULATION ........................................................................................................ 35 
5.1 
INCLUSION CRITERIA ......................................................................................................... 35 
5.2 
EXCLUSION CRITERIA ........................................................................................................ 36 
5.3 
INCLUSION OF WOMEN AND MINORITIES............................................................................ 36 
6. 
STUDY DESIGN .................................................................................................................... 37 
6.1 
STUDY FLOW DIAGRAM ..................................................................................................... 37 
6.2 
SCREENING AND ENROLLMENT ......................................................................................... 37 
6.3 
STUDY TREATMENT........................................................................................................... 37 
6.3.1 Treatment setting ......................................................................................................... 37 
6.3.2 Treatment regimen and scheme ................................................................................... 38 
6.3.3 Study drug preparation and administration ................................................................ 39 
6.3.4 Pre- & Post- therapy interventions .............................................................................. 39 
6.4 
DURATION OF PATIENT PARTICIPATION ............................................................................. 40 
6.5 
DOSE CONFIRMATION PHASE ............................................................................................. 40 
6.6 
EXPANSION PHASE ............................................................................................................ 40 
6.7 
STOPPING RULES ............................................................................................................... 41 
6.8 
PATIENT MONITORING, DISEASE RESPONSE EVALUATION, SURVIVAL ASSESSMENT ........... 41 
6.8.1 Patient monitoring ....................................................................................................... 41 
6.8.2 Disease response evaluation ........................................................................................ 41 
6.8.3 Disease progression and survival assessment ............................................................. 41 
6.9 
DOSE LIMITING TOXICITIES ............................................................................................... 42 
6.10 
STUDY TREATMENT DISCONTINUATION............................................................................. 42 
6.10.1 
Study treatment discontinuation events ................................................................... 42 
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 
6.11 
REPLACEMENT OF PARTICIPANTS ...................................................................................... 43 
6.12 
STUDY TREATMENT MODIFICATION................................................................................... 43 
6.12.1 
Kidney dysfunction ................................................................................................... 43 
6.12.1.1. 
Calculated GFR ≥50 mL/min/1.73m2 .............................................................. 43 
6.12.1.2. 
Calculated GFR <50 mL/min/1.73m2 .............................................................. 43 
6.12.1.3. 
Interventions .................................................................................................... 43 
6.12.2 
Hematological dysfunction ...................................................................................... 43 
6.12.3 
Hypotension ............................................................................................................. 45 
6.12.4 
Allergic reactions and cytokine release syndrome/acute infusion reaction ............ 45 
6.13 
GENERAL SUPPORTIVE CARE GUIDELINES AND DRUG INTERACTION .................................. 45 
6.13.1 
ALT-801 ................................................................................................................... 46 


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6.13.1.1. 
Hypotension and capillary leak syndrome ....................................................... 46 
6.13.1.2. 
Pulmonary dysfunction .................................................................................... 46 
6.13.1.3. 
Impaired kidney and liver functions ................................................................ 46 
6.13.1.4. 
Infection ........................................................................................................... 46 
6.13.1.5. 
Fever and chills ................................................................................................ 46 
6.13.1.6. 
Gastritis ............................................................................................................ 46 
6.13.1.7. 
Diarrhea, nausea and vomiting ........................................................................ 47 
6.13.1.8. 
Pruritus and dermatitis ..................................................................................... 47 
6.13.1.9. 
Acidosis............................................................................................................ 47 
6.13.1.10. Life-threatening toxicities ................................................................................ 47 
6.13.1.11. Other supportive care ....................................................................................... 47 
6.13.1.12. Drug interaction ............................................................................................... 47 
6.13.2 
Gemcitabine ............................................................................................................. 48 
7. 
STUDY DRUG: AVAILABILITY, ACCOUNTABILITY, PACKAGING & 
LABELING .................................................................................................................................... 49 
7.1 
ALT-801 .......................................................................................................................... 49 
7.1.1 Availability ................................................................................................................... 49 
7.1.2 Accountability .............................................................................................................. 49 
7.1.3 Packaging .................................................................................................................... 49 
7.1.4 Labeling ....................................................................................................................... 49 
7.2 
GEMCITABINE ................................................................................................................... 49 
8. 
STUDY CALENDAR, CLINICAL PROCEDURES & TESTS ........................................ 50 
8.1 
STUDY CALENDAR ............................................................................................................ 50 
8.2 
PROCEDURE AND TESTS .................................................................................................... 51 
8.2.1 HLA-A2 typing and assays for immune cell levels and phenotype .............................. 51 
8.2.2 Presentation of HLA-A*0201/p53 aa264-272 complexes on tumor surfaces .............. 51 
8.2.3 Medical history ............................................................................................................ 51 
8.2.4 Prior therapies ............................................................................................................. 51 
8.2.5 Pregnancy test .............................................................................................................. 51 
8.2.6 Physical examination ................................................................................................... 51 
8.2.7 Vital signs, body weight & height ................................................................................ 51 
8.2.8 Cardiac assessment ...................................................................................................... 51 
8.2.9 Blood tests .................................................................................................................... 52 
8.2.10 
Urinalysis ................................................................................................................. 52 
8.2.11 
Urinary Symptoms ................................................................................................... 52 
8.2.12 
Urine cytology .......................................................................................................... 52 
8.2.13 
Cystoscopy and Bladder Biopsy............................................................................... 52 
8.2.14 
Biomarker assay for IFN-γ ...................................................................................... 52 
8.2.15 
Immunogenicity tests - detection of anti-ALT-801 and IL2-neutralizing antibodies
 
52 
8.2.16 
Adverse event assessment ........................................................................................ 53 
8.2.17 
Anti-tumor response evaluation ............................................................................... 53 
8.2.18 
Follow-up for disease progression and survival assessment ................................... 53 
9. 
MEASUREMENT OF EFFECT .......................................................................................... 53 


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10. 
STATISTICAL ANALYSIS ............................................................................................. 54 
10.1 
STUDY OBJECTIVES ........................................................................................................... 54 
10.2 
SAMPLE SIZE ..................................................................................................................... 54 
10.3 
DATA COLLECTION ........................................................................................................... 54 
10.4 
DATA ANALYSIS ................................................................................................................ 54 
10.4.1 
Safety analysis .......................................................................................................... 55 
10.4.2 
Response and survival analysis ............................................................................... 55 
11. 
REGULATORY AND REPORTING REQUIREMENTS ............................................ 55 
11.1 
ADVERSE EVENTS RECORDING, REPORTING AND COMMUNICATION .................................. 55 
11.2 
ADVERSE EVENT TERMINOLOGY AND DEFINITIONS ........................................................... 56 
11.3 
ADVERSE EVENT REPORTING PROCEDURES ...................................................................... 57 
11.4 
ADVERSE EVENT EXPEDITED REPORTING GUIDELINES ..................................................... 57 
11.5 
SUBMISSION OF SERIOUS ADVERSE EVENT REPORTING ...................................................... 57 
11.6 
DATA REPORTING FORMS ................................................................................................. 58 
11.7 
REPORT /DATA SUBMISSION ADDRESS & CONTACT ........................................................... 58 
11.8 
PATIENT RECORDS, QUALITY ASSURANCE, RECORDS RETENTION ...................................... 59 
11.9 
METHOD OF REVIEW ......................................................................................................... 59 
11.10 
SPECIAL REGULATORY CONSIDERATIONS ...................................................................... 59 
11.10.1 HIPAA ...................................................................................................................... 59 
11.10.2 Protocol amendments, informed consent, and IRB approval .................................. 60 
12. 
CONFIDENTIALITY ....................................................................................................... 60 
13. 
ETHICAL STANDARDS & INVESTIGATOR OBLIGATIONS ................................ 60 
14. 
LIST OF EXPECTED ADVERSE EVENTS .................................................................. 61 
15. 
CTCAE................................................................................................................................ 63 
REFERENCES ............................................................................................................................... 64 
APPENDIX B: NEW YORK HEART ASSOCIATION CLASSIFICATION ......................... 67 
APPENDIX C: ETHICAL STANDARDS ................................................................................... 68 
APPENDIX D: INVESTIGATOR OBLIGATIONS .................................................................. 69 
APPENDIX E: CONTACT LIST - ALTOR ............................................................................... 73 
APPENDIX F: CONTACT LIST – DATA SAFETY MONITORING BOARD (DSMB) ...... 74 
APPROVAL PAGE ....................................................................................................................... 75 


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SYNOPSIS 
Sponsor: 
Altor Bioscience Corporation 
Protocol#: 
CA-ALT-801-02-11 
Study Drug Name: Not applicable 
Study Treatment 
Active agents: 
ALT-801 (c264scTCR-IL2), recombinant humanized, soluble single-chain 
TCR-cytokine fusion protein. 
Study Type: 
Interventional 
Study Phase: 
Ib/II 
Protocol Title: 
A Study of ALT-801  in Patients with Bacillus Calmette-Guerin (BCG) 
Failure Non-Muscle Invasive Bladder Cancer 
Objectives:   
To confirm the safety and tolerability of a well-tolerated dose level of ALT-
801 combined with gemcitabine and to determine the Recommended Dose 
level (RD) in patients who are BCG failure (defined as refractory, relapsing 
or intolerant),  non-muscle invasive bladder cancer and refuse or are not 
medically fit to undergo a radical cystectomy recommended by the 
participating urologist as the standard next therapy per urologic guidelines. 
To assess anti-tumor activity of study treatment in treated patients as 
determined by the disease response rate using cystoscopy, bladder biopsy, 
and urine cytology. 
To evaluate the duration of response and survival in these patients. 
To characterize the immunogenicity of ALT-801 in treated patients. 
To assess the relationship between tumor presentation of HLA-A*0201/p53 
aa 264-272 complex and the safety, immune response and clinical benefit of 
study treatment. 
Study Design: 
This is a Phase Ib/II, open-label, multi-center and competitive enrollment 
study of ALT-801 combined with gemcitabine in patients with BCG failure, 
defined as refractory, relapsing or intolerant, non-muscle invasive bladder 
cancer who refuse or are not medically fit to undergo a radical cystectomy 
recommended by the participating urologist as the standard next therapy per 
urologic guidelines.  
 
There are two phases in this study: a dose confirmation phase to confirm a 
well-tolerated dose in this patient population and designate it as the 
recommended dose level (RD) for study expansion and a two-stage 
expansion phase using the recommended (RD). Each enrolled patient will 
receive up to two courses of study treatment.  
The study will be conducted in conformity with Good Clinical Practice 
(GCP).  
Treatments:  
All enrolled patients will receive up to two courses of study treatment: an 
induction treatment course consisting of two study treatment cycles, with a 
13-day rest period between cycles, and a maintenance treatment course 
consisting of one study treatment cycle. The rest period may be extended to 


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include an additional week. . . Each cycle consists of four doses of ALT-801, 
one each on Day #3, Day #5, Day #8, and Day #15 and two doses of 
gemcitabine, one each on Day #1 and Day #8. Patients who have a complete 
response from the initial response assessment by bladder biopsy will receive 
the maintenance treatment and then have the confirmatory response 
assessment. The schedules of induction and maintenance treatment courses 
are illustrated below:  
Induction treatment Course: 
 
 
 
 
M
Maintenance Treatment Course: 
 
 
 
There are no restrictions on further therapies, such as chemotherapy, 
radiation therapy or surgery to be used after the protocol-specified therapy. 
Clearly, additional post-study treatments could be of significant clinical 
benefit in selected patients, and these patients will be followed for outcome. 
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. Gemcitabine and 
ALT-801 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). 
Dose Confirmation 
Phase: 
In the dose-confirmation phase of the study, six patients will be enrolled to 
receive the study treatment with gemcitabine, at 1000 mg/m2/dose, and ALT-
801, at the dose level starting at 0.08 mg/kg, which is a well-tolerated dose 
level in a Phase Ib/II study of ALT-801 in combination with cisplatin in 
patients with metastatic melanoma. Enrolled patients will be monitored 
during the induction treatment course for any Dose Limiting Toxicity (DLT).  
The tolerability of a dose level is defined as <2 of 6 patients experiencing 
any DLT at this dose level. If the tolerability of ALT-801 at a dose level 
cannot be confirmed, an additional six patients will be enrolled to repeat the 
dose confirmation phase with a step-down dose level that is 0.02 mg/kg 
lower than the previous tested dose level until a dose level is confirmed as a 
tolerated dose and is designated as the Recommended Dose (RD) for study 
Treatment Cycle 
Cycle #1 
 
Cycle #2 
Treatment Week 
1 
2 
3 
4 
5 
6 
7 
Treatment Day 
1 
3 
5 
8 
15 
Rest 
29 
31 
33 
36 
43 
Gemcitabine  
X 
 
 
X 
 
X 
 
 
X 
  
ALT-801 
 
X 
X 
X 
X 
  
X 
X 
X 
X 
Treatment Week 
9 
10 
11 
Treatment Day 
1 
3  
5 
8 
15 
Gemcitabine 
X 
 
 
X 
 
ALT-801 
 
X 
X 
X 
X 


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expansion. Below are the dose levels of the study treatment during the dose 
confirmation phase of the study.  
  
 
 
 
 
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 investigator’s and/or patient’s 
decision to withdraw from study treatment without occurrence of any study 
treatment discontinuation adverse event will not necessarily define a DLT 
event. Study treatment discontinuation events are defined in the protocol. 
 
 
Expansion 
Phase 
The two-stage expansion phase will be conducted with ALT-801, at the RD 
level confirmed in the dose confirmation stage, and gemcitabine, at the same 
level as in the dose confirmation stage,  using a modified Simon two-stage 
design. Objective response (OR) (defined as complete response (CR) + 
partial response (PR)) will be evaluated and set thresholds of lack of efficacy 
(OR rate (ORR) = 20%) and an efficacy level of interest (ORR = 40%) will 
be selected.  
Stopping Rule: 
Patient enrollment will be temporarily suspended based on the occurrence of 
any of the following:  
• 
During the dose confirmation phase of the study, no dose level can be 
designated as the RD. 
• 
If at any time during the expansion phase of the study, more than 33% 
of the patients experience a possible, probable or definite drug related 
DLT. 
If the above occur, then the Data Safety Monitoring Board and principal 
investigators will meet to discuss how to proceed with future patient 
enrollment in the study. 
Evaluations: 
Patients will be evaluated for clinical toxicities during the treatment. 
Patients’ blood samples will be collected to assess the immunogenicity of 
the study drug. The anti-tumor activity of study treatment will be evaluated. 
All patients who receive at least one dose of study drug ALT-801 will be 
included in the evaluation of anti-tumor activity of study treatment. 
Population: 
Patients of 18 years of age who have BCG failure (defined as refractory, 
relapsing or intolerant), non-muscle invasive bladder cancer and refuse or 
Cohort 
ALT-801 Dose (mg/kg) 
Gemcitabine ( mg/m2/dose) 
-2 
0.04 
1,000 
-1 
0.06 
1,000 
1 (initial) 
0.08 
1,000 


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are not medically fit to undergo a radical cystectomy recommended by the 
participating urologist as the standard next therapy per urologic guidelines. 
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, 1 or 2.  
Sample Size: 
A total of up to 18 assessable patients will be accrued to the dose confirmation 
phase of the study (Phase Ib). Up to an additional 37 assessable patients will 
be enrolled at the expansion phase (Stage 1 and 2) of the study (Phase II). A 
total of approximately 43 assessable patients will be enrolled and complete 
the study in the event that the RD is 0.08 mg/kg. Assuming a 20% ineligible 
or non-assessable cases, a total of up to 52 patients may be accrued to the 
study. 
Primary 
Endpoints: 
For Phase Ib only: (1) Confirmation of the safety and tolerability of a well-tolerated dose level 
of ALT-801 combined with gemcitabine and designation of the 
Recommended Dose level (RD).  
For Phase Ib & II: (2) Safety profile of ALT-801 combined with gemcitabine. 
 
(3) Disease response rate.  
Secondary  
Endpoints: 
(1) Duration of response. 
(2) Progression-free survival. 
(3) Event free survival. 
(4) Overall survival. 
(5) Immunogenicity of ALT-801.  
(6) Relationship between tumor presentation of HLA-A*0201/p53 aa 264-
272 complexes and the safety, immune response and clinical benefit of 
study treatment. 
Biomarkers: 
Blood samples will be collected to assess typing for HLA-A2 and immune 
cell levels and phenotype. Serum samples will be collected for testing 
immunogenicity of the study drug ALT-801and the serum level of IFN-γ. 
Tumor samples obtained from surgeries or biopsies performed prior to 
screening for the study will be collected to test HLA-A*0201/p53 aa 264-
272 complex presentation. . . .  
Monitoring Tests: Urine samples for urinalysis, blood samples for standard chemistry, and 
CBC with differential will be obtained at screening, on each study drug 
infusion day 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 8 from the initial dose of study treatment. 
Response 
Assessment: 
There are two response assessments for treated patients: the initial 
assessment at week 8 and the confirmatory assessment at week 12 from the 
start of study treatment. After the induction treatment period, patients who 
have received at least one dose of study drug will have the initial response 


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assessment. After the maintenance treatment period, patients who have 
received at least one dose of study drug during this treatment period will 
have the confirmatory response assessment. Cystoscopy, bladder biopsy and 
urine cytology will be performed to evaluate the response. 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, overall survival, and duration of response of all 
treated patients will be assessed every three months during years 1 and 2, 
and then every 6 months during year 3 from the start of study treatment, or 
through the point designated, during the study, 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 Serious Adverse Events 
(SAEs) and all events that trigger patient’s study treatment discontinuation 
to the sponsor via phone, fax or email (or a combination) no more than 24 
hours after learning of the event. The sponsor will use the information to 
manage and coordinate the dose confirmation, 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 
24 hours of learning of the event. The study centers should report all other 
adverse events to the sponsor following the guidelines defined in the study 
protocol. All study drug related 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 
tumor response data will be evaluated. For estimation of duration of 
response and progression free survival, 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 
SCREEN/ 
BASELINE1 
INITIAL COURSE  
INITIAL 
ASSESSMENT 
MAINTENANCE 
COURSE 
CONFIRMATORY 
ASSESSMENT 
FOLLOW-UPS 
CYCLE #1 
 
CYCLE  #2 
Study Month 
 
1 
 
2 
3 
3 
6 
9  12  15 18 21 24 30  36  
Study Week
 
1 
2 
3 
4 
5 
6 
7 
8 
9  
10 
11 
12 
  
Day of Week
 
M W  F M 
M 
 
M W F 
M M 
  
M W 
F 
M 
M 
 
 
Study Day 
 
1 
3 
5 
8 
15 16-28 29 31 33 36  43 
  
57 59 61 64 
71 
 
 
Medical history/prior therapies 
X 
 
 
 
 
 
R 
e 
s 
t 
 
P 
e 
r 
i 
o 
d 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum pregnancy test2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Complete physical exam 
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 
 
Concurrent medication 
X 
X 
X X 
X 
X 
X 
X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Adverse event assessment4 
X 
X  X X 
X 
X 
X 
X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
CBC with Differential 
X 
X 
X X 
X 
X 
X 
X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Blood Chemistry  
X 
X 
X X 
X 
X 
X 
X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
EKG 
X5 
X5  
    
  
  
X  
 
 
  
  
 
X 
 
 
  
  
 
 
Urinalysis 
X 
X 
X X 
X 
X 
X X X X X 
X 
X X X X 
X 
X 
 
Urinary symptoms  
X 
X 
X X 
X 
X 
X X X X X 
X 
X X X X 
X 
X 
 
Cystoscopy13 & bladder biopsies13 
X  
  
 
 
 
 
 
 
 
 
 
X  
 
 
 
 
 
X  
 
Urine cytology 
X 
  
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
Response assessment6 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
Disease & survival follow-up7 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
X  
X 
X 
X 
X 
X 
X 
X 
X 
Immune cell levels & phenotype8, 12 
 
X8 X8  
X8 
 
X8 
 
 
 
 
 
 
 
 
  
 
 
 
HLA A2 Blood Typing9 & p53 tumor typing 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IFN-γ10,12 
 
X10  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Immunogenicity tests11, 12 
 
 
X11  
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Gemcitabine 
 
g1 
 
 
g2 
 
g3 
 
 
g4 
 
 
g5 
 
 
g6 
 
 
 
Study drug (ALT-801)
 
 
a1 a2 a3 a4 
 
a5 a6 a7 a8 
  
 
a9 a10 a11 a12 
 
 
1Screening/baseline evaluations are performed <14 days prior to start of therapy except TTE, cystoscopy and biopsies. If TTE is required for cardiac assessments, it can be performed <28 days. 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 drug infusion and before discharge, 
and body weight obtained before infusion on each drug infusion day. 4Patients who have an on-going study drug-related SAE upon study completion or at discontinuation of study will be contacted by the 
investigator or his/her designee every week until the event is resolved or determined to be irreversible. 5If a previous EKG was performed within 14 days before start of study treatment, the EKG is not required. 
6Response will be evaluated by cystoscopy, bladder biopsies and urine cytology. 7Information about tumor assessment & other therapies received after completion of study treatment will be collected if 
available. 8Fresh blood samples for HLA A2 blood typing, immune cell levels & phenotype testing will be collected before any dosing starts. 9 Use the same blood sample collected for immune cell levels & 
phenotype.10Collect blood samples at Time 0 (before dosing) and at 6 hour (+/- 60 min) from Time 0. . . 11Use the same sample collected for  IFN-γ assay. 12Residual samples may be used by Sponsor for 
research studies of other biomarkers.13Screening cystoscopy is performed within 4 weeks prior to start of therapy, screening biopsies are performed within 3 months  prior to start of therapy. 
 




 
 
 
CLINICAL STUDY PROTOCOL 
 
 
Protocol Number: 
CA-ALT-801-01-12 
 
 
Protocol Title: 
A Study of ALT-801 in Patients with  Bacillus 
Calmette-Guerin (BCG) Failure Non-Muscle 
Invasive Bladder Cancer  
 
 
Date of Protocol: 
 
Version# 01 
Version# 02 
Version# 03 
Version# 04 
January 27, 2012 
April 5, 2012 
October 24, 2012 
July 1, 2015 
 
 
 
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-801-01-12 
 
 
Protocol Title: 
A Study of ALT-801 in Patients with Bacillus 
Calmette-Guerin (BCG) Failure Non-Muscle 
Invasive Bladder Cancer 
 
 
Date of Protocol: 
 
Version# 01 
Version# 02 
Version# 03 
Version# 04 
January 27, 2012 
April 5, 2012 
October 24, 2012 
July 1, 2015 
 
 
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 
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 
NON-MUSCLE INVASIVE BLADDER CANCER ....................................................................... 13 
2.3 
CURRENT TREATMENT OPTIONS FOR NMIBC ................................................................... 13 
2.4 
CYTOKINE-BASED IMMUNOTHERAPY FOR CANCER............................................................ 14 
2.5 
A TARGETED IL-2 FUSION PROTEIN WITH ENHANCED IMMUNE STIMULATORY ACTIVITY .. 14 
2.6 
TUMOR EFFICACY STUDIES OF ALT-801 IN ANIMAL MODELS............................................ 15 
2.6.1 Efficacy evaluation of ALT-801 dose regimens in xenograft tumor models ................ 15 
2.6.2 Efficacy evaluation of ALT-801 and non-targeted scTCR/IL-2 fusion proteins in 
xenograft human urothelial tumor models ............................................................................... 16 
2.6.2.1. Activity of ALT-801 alone and in combination with gemcitabine and cisplatin 
against xenograft human UMUC-14 bladder tumors in nude mice (Pre-clinical Study 
PS2010-24) .......................................................................................................................... 16 
2.6.2.2. Activity of ALT-801 and non-targeted scTCR/IL-2 fusion proteins in 
combination with gemcitabine  against xenograft human bladder tumors in nude mice (Pre-
clinical studies PS2011-73  & PS2011-73-3) ...................................................................... 17 
2.6.3 Efficacy evaluation of ALT-801 against human p53-negative orthotropic murine 
bladder tumors in immunocompetent mice (Pre-clinical studies PS2011-56, 57a, 85 & 93) . 18 
2.6.4 Immune cell-based mechanism-of-action of ALT-801 efficacy against orthotropic 
murine bladder tumors in immunocompetent mice (Pre-clinical studies PS2012-103, PS2012-
116 and PS2012-121) .............................................................................................................. 20 
2.7 
EFFECTS OF OPTIMIZED ALT-801-CHEMOTHERAPY REGIMENS IN ORTHOTROPIC MURINE 
BLADDER TUMOR MODELS............................................................................................................. 21 
2.7.1 Role of myeloid-derived suppressive cells (MDSCs) in human and murine bladder 
cancer (Pre-clinical studies PS2012-116 & PS2012-121) ...................................................... 21 
2.7.2 Enhancement of ALT-801 efficacy against bladder cancer by gemcitabine-mediated 
inhibition of MDSCs (Pre-clinical studies PS2012-120 & PS2012-121) ................................ 22 
2.8 
NON-CLINICAL TOXICOLOGY ............................................................................................ 23 
2.8.1 Single-dose toxicity study ............................................................................................. 23 
2.8.2 Multi-dose toxicity study .............................................................................................. 23 
2.9 
PHARMACOKINETICS ......................................................................................................... 24 
2.9.1 Non-clinical pharmacokinetics .................................................................................... 24 
2.9.2 Clinical pharmacokinetics ........................................................................................... 25 
2.10 
HUMAN EXPERIENCE ......................................................................................................... 25 
2.10.1 
Phase I Study of ALT-801 in Patients with Progressive Metastatic Malignancies 
(CA-ALT-801-01-06)................................................................................................................ 25 
2.10.1.1. 
Pharmacodynamics .......................................................................................... 25 
2.10.1.2. 
Tumor assessment ............................................................................................ 26 
2.10.1.3. 
Safety results .................................................................................................... 27 
2.10.1.4. 
Immunogenicity ............................................................................................... 28 


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2.10.1.5. 
Repeat treatment .............................................................................................. 28 
2.10.2 
Phase Ib/II Study of ALT-801 with Cisplatin in Patients with Metastatic Melanoma 
(CA-ALT-801-02-09)................................................................................................................ 28 
2.10.3 
Phase Ib/II Study of ALT-801 in combination with Cisplatin  and Gemcitabine in 
Muscle Invasive or Metastatic Urothelial Cancer (CA-ALT-801-01-10) ................................ 30 
3. 
RATIONALE FOR THE CURRENT STUDY ................................................................... 31 
4. 
OVERALL STUDY DESIGN ............................................................................................... 34 
5. 
STUDY POPULATION ........................................................................................................ 36 
5.1 
INCLUSION CRITERIA ......................................................................................................... 36 
5.2 
EXCLUSION CRITERIA ........................................................................................................ 37 
5.3 
INCLUSION OF WOMEN AND MINORITIES............................................................................ 37 
6. 
STUDY DESIGN .................................................................................................................... 38 
6.1 
STUDY FLOW DIAGRAM ..................................................................................................... 38 
6.2 
SCREENING AND ENROLLMENT ......................................................................................... 38 
6.3 
STUDY TREATMENT........................................................................................................... 38 
6.3.1 Treatment setting ......................................................................................................... 38 
6.3.2 Treatment regimen and scheme ................................................................................... 39 
6.3.3 Study drug preparation and administration ................................................................ 40 
6.3.4 Pre- & Post- therapy interventions .............................................................................. 41 
6.4 
DURATION OF PATIENT PARTICIPATION ............................................................................. 42 
6.5 
DOSE CONFIRMATION PHASE ............................................................................................. 42 
6.6 
EXPANSION PHASE ............................................................................................................ 42 
6.7 
STOPPING RULES ............................................................................................................... 43 
6.8 
PATIENT MONITORING, DISEASE RESPONSE EVALUATION, SURVIVAL ASSESSMENT ........... 43 
6.8.1 Patient monitoring ....................................................................................................... 43 
6.8.2 Disease response evaluation ........................................................................................ 43 
6.8.3 Disease progression and survival assessment ............................................................. 43 
6.9 
DOSE LIMITING TOXICITIES ............................................................................................... 44 
6.10 
STUDY TREATMENT DISCONTINUATION............................................................................. 44 
6.10.1 
Study treatment discontinuation events ................................................................... 44 
6.10.2 
Follow-ups after treatment discontinuation............................................................. 45 
6.10.2.1. 
Discontinuation due to SAEs or on-going study drug related AEs ................. 45 
6.10.2.2. 
Discontinuation due to any other reasons ........................................................ 45 
6.11 
REPLACEMENT OF PARTICIPANTS ...................................................................................... 45 
6.12 
STUDY TREATMENT MODIFICATION................................................................................... 45 
6.12.1 
Kidney dysfunction ................................................................................................... 45 
6.12.1.1. 
Calculated GFR ≥50 mL/min/1.73m2 .............................................................. 45 
6.12.1.2. 
Calculated GFR <50 mL/min/1.73m2 .............................................................. 45 
6.12.1.3. 
Interventions .................................................................................................... 45 
6.12.2 
Hematological dysfunction ...................................................................................... 45 
6.12.3 
Hypotension ............................................................................................................. 47 
6.12.4 
Allergic reactions and cytokine release syndrome/acute infusion reaction ............ 47 
6.12.5 
Non-hematological dysfunction (excluding Kidney dysfunction) ............................ 47 
6.12.6 
Other grade 3/4 AEs not covered in previous sections ............................................ 47 


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6.13 
GENERAL SUPPORTIVE CARE GUIDELINES AND DRUG INTERACTION .................................. 47 
6.13.1 
ALT-801 ................................................................................................................... 49 
6.13.1.1. 
Hypotension and capillary leak syndrome ....................................................... 49 
6.13.1.2. 
Pulmonary dysfunction .................................................................................... 49 
6.13.1.3. 
Impaired kidney and liver functions ................................................................ 49 
6.13.1.4. 
Infection ........................................................................................................... 49 
6.13.1.5. 
Fever and chills ................................................................................................ 49 
6.13.1.6. 
Gastritis ............................................................................................................ 49 
6.13.1.7. 
Diarrhea, nausea and vomiting ........................................................................ 50 
6.13.1.8. 
Pruritus and dermatitis ..................................................................................... 50 
6.13.1.9. 
Acidosis............................................................................................................ 50 
6.13.1.10. Life-threatening toxicities ................................................................................ 50 
6.13.1.11. Other supportive care ....................................................................................... 50 
6.13.1.12. Drug interaction ............................................................................................... 50 
6.13.2 
Gemcitabine ............................................................................................................. 51 
7. 
STUDY DRUG: AVAILABILITY, ACCOUNTABILITY, PACKAGING & 
LABELING .................................................................................................................................... 52 
7.1 
ALT-801 .......................................................................................................................... 52 
7.1.1 Availability ................................................................................................................... 52 
7.1.2 Accountability .............................................................................................................. 52 
7.1.3 Packaging .................................................................................................................... 52 
7.1.4 Labeling ....................................................................................................................... 52 
7.2 
GEMCITABINE ................................................................................................................... 52 
8. 
STUDY CALENDAR, CLINICAL PROCEDURES & TESTS ........................................ 53 
8.1 
STUDY CALENDAR ............................................................................................................ 53 
8.2 
PROCEDURE AND TESTS .................................................................................................... 54 
8.2.1 HLA-A2 typing and assays for immune cell levels and phenotype .............................. 54 
8.2.2 Presentation of HLA-A*0201/p53 aa264-272 complexes on tumor surfaces .............. 54 
8.2.3 Medical history ............................................................................................................ 54 
8.2.4 Prior therapies ............................................................................................................. 54 
8.2.5 Pregnancy test .............................................................................................................. 54 
8.2.6 Physical examination ................................................................................................... 54 
8.2.7 Vital signs, body weight & height ................................................................................ 54 
8.2.8 Cardiac assessment ...................................................................................................... 54 
8.2.9 Blood tests .................................................................................................................... 55 
8.2.10 
Urinalysis ................................................................................................................. 55 
8.2.11 
Urine cytology .......................................................................................................... 55 
8.2.12 
Cystoscopy and Bladder Biopsy............................................................................... 55 
8.2.13 
Biomarker assay for IFN-γ ...................................................................................... 55 
8.2.14 
Immunogenicity tests - detection of anti-ALT-801 and IL2-neutralizing antibodies
 
55 
8.2.15 
Adverse event assessment ........................................................................................ 55 
8.2.16 
Anti-tumor response evaluation ............................................................................... 56 
8.2.17 
Follow-up for disease progression and survival assessment ................................... 56 


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9. 
MEASUREMENT OF EFFECT .......................................................................................... 56 
10. 
STATISTICAL ANALYSIS ............................................................................................. 57 
10.1 
STUDY OBJECTIVES ........................................................................................................... 57 
10.2 
SAMPLE SIZE ..................................................................................................................... 57 
10.3 
DATA COLLECTION ........................................................................................................... 57 
10.4 
DATA ANALYSIS ................................................................................................................ 57 
10.4.1 
Safety analysis .......................................................................................................... 58 
10.4.2 
Response and survival analysis ............................................................................... 58 
11. 
REGULATORY AND REPORTING REQUIREMENTS ............................................ 58 
11.1 
ADVERSE EVENTS RECORDING, REPORTING AND COMMUNICATION .................................. 58 
11.2 
ADVERSE EVENT TERMINOLOGY AND DEFINITIONS ........................................................... 59 
11.3 
ADVERSE EVENT REPORTING PROCEDURES ...................................................................... 60 
11.4 
ADVERSE EVENT EXPEDITED REPORTING GUIDELINES ..................................................... 60 
11.5 
SUBMISSION OF SERIOUS ADVERSE EVENT REPORTING ...................................................... 60 
11.6 
DATA REPORTING FORMS ................................................................................................. 62 
11.7 
REPORT /DATA SUBMISSION ADDRESS & CONTACT ........................................................... 62 
11.8 
PATIENT RECORDS, QUALITY ASSURANCE, RECORDS RETENTION ...................................... 63 
11.9 
METHOD OF REVIEW ......................................................................................................... 63 
11.10 
SPECIAL REGULATORY CONSIDERATIONS ...................................................................... 63 
11.10.1 HIPAA ...................................................................................................................... 63 
11.10.2 Protocol amendments, informed consent, and IRB approval .................................. 64 
12. 
CONFIDENTIALITY ....................................................................................................... 64 
13. 
ETHICAL STANDARDS & INVESTIGATOR OBLIGATIONS ................................ 64 
14. 
LIST OF EXPECTED ADVERSE EVENTS .................................................................. 65 
15. 
CTCAE................................................................................................................................ 67 
REFERENCES ............................................................................................................................... 68 
APPENDIX B: NEW YORK HEART ASSOCIATION CLASSIFICATION ......................... 71 
APPENDIX C: ETHICAL STANDARDS ................................................................................... 72 
APPENDIX D: INVESTIGATOR OBLIGATIONS .................................................................. 73 
APPENDIX E: CONTACT LIST - ALTOR ............................................................................... 77 
APPENDIX F: CONTACT LIST – DATA SAFETY MONITORING BOARD (DSMB) ...... 78 


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SYNOPSIS 
Sponsor: 
Altor Bioscience Corporation 
Protocol#: 
CA-ALT-801-01-12 
Study Drug Name: Not applicable 
Study Treatment 
Active agents: 
ALT-801 (c264scTCR-IL2), recombinant humanized, soluble single-chain 
TCR-cytokine fusion protein. 
Study Type: 
Interventional 
Study Phase: 
Ib/II 
Protocol Title: 
A Study of ALT-801  in Patients with Bacillus Calmette-Guerin (BCG) 
Failure Non-Muscle Invasive Bladder Cancer 
Objectives:   
To confirm the safety and tolerability of a well-tolerated dose level of ALT-
801 combined with gemcitabine and to determine the Recommended Dose 
level (RD) in patients who are BCG failure (defined as refractory, relapsing 
or intolerant),  non-muscle invasive bladder cancer and refuse or are not 
medically fit to undergo a radical cystectomy recommended by the 
participating urologist as the standard next therapy per urologic guidelines. 
To assess anti-tumor activity of study treatment in treated patients as 
determined by the disease response rate using cystoscopy, bladder biopsy, 
and urine cytology. 
To evaluate the duration of response and survival in these patients. 
To characterize the immunogenicity of ALT-801 in treated patients. 
To assess the relationship between tumor presentation of HLA-A*0201/p53 
aa 264-272 complex and the safety, immune response and clinical benefit of 
study treatment. 
Study Design: 
This is a Phase Ib/II, open-label, multi-center and competitive enrollment 
study of ALT-801 combined with gemcitabine in patients with BCG failure, 
defined as refractory, relapsing or intolerant, non-muscle invasive bladder 
cancer who refuse or are not medically fit to undergo a radical cystectomy 
recommended by the participating urologist as the standard next therapy per 
urologic guidelines.  
 
There are two phases in this study: a dose confirmation phase to confirm a 
well-tolerated dose in this patient population and designate it as the 
recommended dose level (RD) for study expansion and a two-stage 
expansion phase using the recommended (RD). Each enrolled patient will 
receive up to two courses of study treatment.  
The study will be conducted in conformity with Good Clinical Practice 
(GCP).  
Treatments:  
All enrolled patients will receive up to two courses of study treatment: an 
induction treatment course consisting of two study treatment cycles, with a 
13-day rest period between cycles, and a maintenance treatment course 
consisting of one study treatment cycle. The rest period may be extended to 


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include an additional week. Each cycle consists of four doses of ALT-801, 
one each on Day #3, Day #5, Day #8, and Day #15 and two doses of 
gemcitabine, one each on Day #1 and Day #8. Patients who have a complete 
response from the initial response assessment by bladder biopsy will receive 
the maintenance treatment and then have the confirmatory response 
assessment. The schedules of induction and maintenance treatment courses 
are illustrated below:  
Induction treatment Course: 
 
 
 
 
M
Maintenance Treatment Course: 
 
 
 
There are no restrictions on further therapies, such as chemotherapy, 
radiation therapy or surgery to be used after the protocol-specified therapy. 
Clearly, additional post-study treatments could be of significant clinical 
benefit in selected patients, and these patients will be followed for outcome. 
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. Gemcitabine and 
ALT-801 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). 
Dose Confirmation 
Phase: 
In the dose-confirmation phase of the study, six patients will be enrolled to 
receive the study treatment with gemcitabine, at 1000 mg/m2/dose, and ALT-
801, at the dose level starting at 0.08 mg/kg, which is a well-tolerated dose 
level in a Phase Ib/II study of ALT-801 in combination with cisplatin in 
patients with metastatic melanoma. Enrolled patients will be 
monitored during the induction treatment course for any Dose Limiting 
Toxicity (DLT).  
The tolerability of a dose level is defined as <2 of 6 patients experiencing 
any DLT at this dose level. If the tolerability of ALT-801 at a dose level 
cannot be confirmed, an additional six patients will be enrolled to repeat the 
dose confirmation phase with a step-down dose level that is 0.02 mg/kg 
lower than the previous tested dose level until a dose level is confirmed as a 
Treatment Cycle 
Cycle #1 
 
Cycle #2 
Treatment Week 
1 
2 
3 
4 
5 
6 
7 
Treatment Day 
1 
3 
5 
8 
15 
Rest 
29 
31 
33 
36 
43 
Gemcitabine  
X 
 
 
X 
 
X 
 
 
X 
  
ALT-801 
 
X 
X 
X 
X 
  
X 
X 
X 
X 
Treatment Week 
9 
10 
11 
Treatment Day 
1 
3  
5 
8 
15 
Gemcitabine 
X 
 
 
X 
 
ALT-801 
 
X 
X 
X 
X 


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tolerated dose and is designated as the Recommended Dose (RD) for study 
expansion. Below are the dose levels of the study treatment during the dose 
confirmation phase of the study.  
  
 
 
 
 
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 investigator’s and/or patient’s 
decision to withdraw from study treatment without occurrence of any study 
treatment discontinuation adverse event will not necessarily define a DLT 
event. Study treatment discontinuation events are defined in the protocol. 
 
 
Expansion 
Phase 
The two-stage expansion phase will be conducted with ALT-801, at the RD 
level confirmed in the dose confirmation stage, and gemcitabine, at the same 
level as in the dose confirmation stage,  using a modified Simon two-stage 
design. Objective response (OR) (defined as complete response (CR) + 
partial response (PR)) will be evaluated and set thresholds of lack of efficacy 
(OR rate (ORR) = 20%) and an efficacy level of interest (ORR = 40%) will 
be selected.  
Stopping Rule: 
Patient enrollment will be temporarily suspended based on the occurrence of 
any of the following:  
• 
During the dose confirmation phase of the study, no dose level can be 
designated as the RD. 
• 
If at any time during the expansion phase of the study, more than 33% 
of the patients experience a possible, probable or definite drug related 
DLT. 
If the above occur, then the Data Safety Monitoring Board and principal 
investigators will meet to discuss how to proceed with future patient 
enrollment in the study. 
Evaluations: 
Patients will be evaluated for clinical toxicities during the treatment. 
Patients’ blood samples will be collected to assess the immunogenicity of 
the study drug. The anti-tumor activity of study treatment will be evaluated. 
All patients who receive at least one complete dose of study drug ALT-801 
will be included in the evaluation of anti-tumor activity of study treatment. 
Cohort 
ALT-801 Dose (mg/kg) 
Gemcitabine ( mg/m2/dose) 
-2 
0.04 
1,000 
-1 
0.06 
1,000 
1 (initial) 
0.08 
1,000 


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Population: 
Patients of 18 years of age who have BCG failure (defined as refractory, 
relapsing or intolerant), non-muscle invasive bladder cancer and refuse or 
are not medically fit to undergo a radical cystectomy recommended by the 
participating urologist as the standard next therapy per urologic guidelines. 
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, 1 or 2.  
Sample Size: 
A total of up to 18 assessable patients will be accrued to the dose confirmation 
phase of the study (Phase Ib). Up to an additional 37 assessable patients will 
be enrolled at the expansion phase (Stage 1 and 2) of the study (Phase II). A 
total of approximately 43 assessable patients will be enrolled and complete 
the study in the event that the RD is 0.08 mg/kg. Assuming a 20% ineligible 
or non-assessable cases, a total of up to 52 patients may be accrued to the 
study. 
Primary 
Endpoints: 
For Phase Ib only: (1) Confirmation of the safety and tolerability of a well-tolerated dose level 
of ALT-801 combined with gemcitabine and designation of the 
Recommended Dose level (RD).  
For Phase Ib & II: (2) Safety profile of ALT-801 combined with gemcitabine. 
 
(3) Disease response rate.  
Secondary  
Endpoints: 
(1) Duration of response. 
(2) Progression-free survival. 
(3) Event free survival. 
(4) Overall survival. 
(5) Immunogenicity of ALT-801.  
(6) Relationship between tumor presentation of HLA-A*0201/p53 aa 264-
272 complexes and the safety, immune response and clinical benefit of 
study treatment. 
Biomarkers: 
Blood samples will be collected to assess typing for HLA-A2 and immune 
cell levels and phenotype. Serum samples will be collected for testing 
immunogenicity of the study drug ALT-801 and the serum level of IFN-γ. 
Tumor samples obtained from surgeries or biopsies performed prior to 
screening for the study will be collected to test HLA-A*0201/p53 aa 264-
272 complex presentation.   
Monitoring Tests: Urine samples for urinalysis, blood samples for standard chemistry, and 
CBC with differential will be obtained at screening, on each study drug 
infusion day 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 8 from the initial dose of study treatment. 
Response 
Assessment: 
There are two response assessments for treated patients: the initial 
assessment at week 8 and the confirmatory assessment at week 12 from the 


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start of study treatment. After the induction treatment period, patients who 
have received at least one complete dose of study drug will have the initial 
response assessment. After the maintenance treatment period, patients who 
have received at least one dose of study drug during this treatment period 
will have the confirmatory response assessment. Cystoscopy, bladder biopsy 
and urine cytology will be performed to evaluate the response. 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, overall survival, and duration of response of 
patients who have received at least one complete dose of ALT-801, will be 
assessed every three months during years 1 and 2, and then every 6 months 
during year 3 from the start of study treatment, or through the point 
designated, during the study, 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 Serious Adverse Events 
(SAEs) and all events that trigger patient’s study treatment discontinuation 
to the sponsor via phone, fax or email (or a combination) no more than 24 
hours after learning of the event. The sponsor will use the information to 
manage and coordinate the dose confirmation, 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 
24 hours of learning of the event. The study centers should report all other 
adverse events to the sponsor following the guidelines defined in the study 
protocol. All study drug related 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 
tumor response data will be evaluated. For estimation of duration of 
response and progression free survival, 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 
SCREEN/ 
BASELINE1 
INITIAL COURSE  
INITIAL 
ASSESSMENT 
MAINTENANCE 
COURSE 
CONFIRMATORY 
ASSESSMENT 
FOLLOW-UPS 
CYCLE #1 
 
CYCLE  #2 
Study Month 
 
1 
 
2 
3 
3 
6 
9  12  15 18 21 24 30  36  
Study Week 
 
1 
2 
3 
4 
5 
6 
7 
8 
9  
10 
11 
12 
  
Day of Week
 
M W  F M 
M 
 
M W F 
M M 
  
M W 
F 
M 
M 
 
 
Study Day 
 
1 
3 
5 
8 
15 16-28 29 31 33 36  43 
  
57 59 61 64 
71 
 
 
Medical history/prior therapies 
X 
 
 
 
 
 
R 
e 
s 
t 
 
P 
e 
r 
i 
o 
d 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum pregnancy test2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Complete physical exam 
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 
 
Concurrent medication 
X 
X 
X X 
X 
X 
X 
X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Adverse event assessment4 
X 
X  X X 
X 
X 
X 
X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
CBC with Differential 
X 
X 
X X 
X 
X 
X 
X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Blood Chemistry  
X 
X 
X X 
X 
X 
X 
X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
EKG 
X5 
X5  
    
  
  
X  
 
 
  
  
 
X 
 
 
  
  
 
 
Urinalysis 
X 
X 
X X 
X 
X 
X X X X X 
X 
X X X X 
X 
X 
 
Cystoscopy13 & bladder biopsies13 
X  
  
 
 
 
 
 
 
 
 
 
X  
 
 
 
 
 
X  
 
Urine cytology 
X 
  
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
Response assessment6 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
Disease & survival follow-up7 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
X  
X 
X 
X 
X 
X 
X 
X 
X 
Immune cell levels & phenotype8, 12 
 
X8 X8  
X8 
 
X8 
 
 
 
 
 
 
 
 
  
 
 
 
HLA A2 Blood Typing9 & p53 tumor typing12 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IFN-γ10,12 
 
X10  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Immunogenicity tests11, 12 
 
 
X11  
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Gemcitabine 
 
g1 
 
 
g2 
 
g3 
 
 
g4 
 
 
g5 
 
 
g6 
 
 
 
Study drug (ALT-801)
 
 
a1 a2 a3 a4 
 
a5 a6 a7 a8 
  
 
a9 a10 a11 a12 
 
 
1Screening/baseline evaluations are performed <14 days prior to start of therapy except TTE, cystoscopy and biopsies. If TTE is required for cardiac assessments, it can be performed <28 days. 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 drug infusion and before discharge or 
until the completion of dose monitoring, body weight is obtained before infusion on each drug infusion day and height collected at baseline. 4Patients who have an on-going study drug-related SAE upon 
study completion or at discontinuation of study will be contacted by the investigator or his/her designee every week until the event is resolved or determined to be irreversible. 5If a previous EKG was 
performed within 14 days before start of study treatment, the EKG is not required. 6Response will be evaluated by cystoscopy, bladder biopsies and urine cytology. 7Information about tumor assessment & other 
therapies received after completion of study treatment will be collected if available. 8Fresh blood samples for HLA A2 blood typing, immune cell levels & phenotype testing will be collected before any 
dosing starts. 9 Use the same blood sample collected for immune cell levels & phenotype.10Collect blood samples at Time 0 (before dosing) and at 6 hour (+/- 60 min) from Time 0.  11Use the same sample 
collected for  IFN-γ assay. 12Residual samples may be used by Sponsor for research studies of other biomarkers. All attempts will be made to collect research samples but missed samples will not be 
considered a protocol deviation.13Screening cystoscopy is performed within 4 weeks prior to start of therapy, screening biopsies are performed within 3 months  prior to start of therapy.