Conditions: Locally Advanced Rectal Adenocarcinoma Metastatic Rectal Adenocarcinoma Rectal Adenocarcinoma Stage III Rectal Cancer AJCC v7 Stage IIIA Rectal Cancer AJCC v7 Stage IIIB Rectal Cancer AJCC v7 Stage IIIC Rectal Cancer AJCC v7 Stage IV Rectal Cancer AJCC v7 Stage IVA Rectal Cancer AJCC v7 Stage IVB Rectal Cancer AJCC v7
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 3
Healthy volunteers: no

Brief summary:
This phase I trial studies the best dose and side effects of talimogene laherparepvec in combination with 5-fluorouracil, leucovorin, oxaliplatin, capecitabine, and chemoradiation before surgery in treating patients with rectal cancer that has spread from where it started to nearby tissue and lymph nodes. Drugs used in immunotherapy, such as talimogene laherparepvec, may stimulate the body's immune system to fight tumor cells. Drugs used in chemotherapy, such as 5-fluorouracil, leucovorin, oxaliplatin, and capecitabine work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Radiation therapy uses high-energy x-rays to kill tumor cells and shrink tumors. Giving talimogene laherparepvec, 5-fluorouracil, leucovorin, oxaliplatin, and capecitabine and chemoradiation before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed.

Detailed description:
PRIMARY OBJECTIVE:

I. To determine the dose limiting toxicities (DLTs) and maximum tolerated dose (MTD) of talimogene laherparepvec in combination with chemotherapy and radiation in rectal cancer.

SECONDARY OBJECTIVES:

I. To establish safety and feasibility of the combination. II. To determine the neoadjuvant rectal (NAR) score of talimogene laherparepvec with chemotherapy and radiation.

EXPLORATORY OBJECTIVES:

I. To correlate genomic information including RAS, RAF mutation status with response, disease free survival (DFS) and/or overall survival (OS).

II. To determine immunomodulatory changes following talimogene laherparepvec, chemotherapy and radiation treatment including proportions of immune cell infiltrates in serially collected peripheral blood and/or frozen tumor samples (pre-, on treatment, and at post progression).

III. To identify magnetic resonance imaging (MRI)-based features including MRI circumferential margin (mrCRM) at baseline or post-therapy mrCRM, MRI tumor regression grade (mrTRG) to define determinants of response, DFS and OS.

IV. To determine the disease free survival (DFS) and overall survival (OS) of talimogene laherparepvec with chemotherapy and radiation in patients undergoing curative resection.

V. To determine the pathological complete response (pCR) rate of talimogene laherparepvec with chemotherapy and radiation.

OUTLINE: This is a dose-escalation study of talimogene laherparepvec.

Patients receive talimogene laherparepvec intralesionally via endoscopy on weeks 1, 4, 6, and 8. Patients receive 5-fluorouracil intravenously (IV) by bolus and over 46 hours, leucovorin IV bolus, and oxaliplatin IV over 2 hours on weeks 2 and 4. Patients also receive capecitabine orally (PO) twice daily (BID) followed by radiation therapy for 28 fractions on days 1-5 of weeks 8-13. Patients undergo resection surgery on weeks 21-25.

After completion of study treatment, patients are followed up for 30 days and up to 5 years thereafter.

Arms:
arm 1: Patients receive talimogene laherparepvec intralesionally via endoscopy on weeks 1, 4, 6, and 8. Patients receive 5-fluorouracil IV by bolus and over 46 hours, leucovorin IV bolus, and oxaliplatin IV over 2 hours on weeks 2 and 4. Patients also receive capecitabine orally PO BID followed by radiation therapy for 28 fractions on days 1-5 of weeks 8-13. Patients undergo resection surgery on weeks 21-25.

Interventions: intervention 1: Capecitabine intervention 2: Fluorouracil intervention 3: Leucovorin intervention 4: Oxaliplatin intervention 5: Radiation Therapy intervention 6: Talimogene Laherparepvec
Intervention descriptions: intervention 1: Given PO intervention 2: Given IV intervention 3: Given IV intervention 4: Given IV intervention 5: Undergo chemoradiation intervention 6: Given intralesionally

Protocol document:
Prot_SAP_000.pdf: 










NCI Protocol #: 10058 
Version Date: June 14, 2021 
 
 
1 
 
 
NCI Protocol #: 
10058 
 
Local Protocol #: 
NCI10058 
 
 
ClinicalTrials.gov Identifier:  NCT03300544 
 
TITLE:  A PHASE I STUDY OF TALIMOGENE LAHERPAREPVEC (TALIMOGENE 
LAHERPAREPVEC) WITH NEOADJUVANT CHEMOTHERAPY AND RADIATION 
IN ADENOCARCINOMA OF THE RECTUM 
 
Corresponding Organization: LAO-TX035 / University of Texas MD Anderson Cancer 
Center LAO 
 
 
Principal Investigator: 
Arvind Dasari, MD, MS 
University of Texas MD Anderson Cancer Center 
  1515 Holcombe Blvd 
  Unit 426 
  Houston, TX, 77030 
Telephone: 713-792-2828 
Fax: 713-563-0541 
adasari@mdanderson.org 
 
Participating Organizations  
LAO-TX035 / University of Texas MD Anderson Cancer Center LAO 
Participation restricted to TX035 / MD Anderson Cancer Center 
 
Non-Member Collaborators N/A 
 
 
Statistician: 
 
Study Coordinator:  
 
Xuemei Wang, MS 
Mercy David, RN  
 
1400 Pressler Street, Floor 4, FCT 4.6000 
1515 Holcombe Blvd, Unit 426  
 
Houston, TX, 77030 
Houston, TX 77030 
 
Tel: 713-745-5984 
Tel: 713-794-4869 
 
Fax: 713-563-0541 
Fax 713-745-1163
 
xuewang@mdanderson.org 
mfdavid@mdanderson.org  
 
Responsible Research Nurse: 
Responsible Data Manager: TBD 
      Kimberly Ross, RN 
Name 
 
1515 Holcombe Blvd, Unit 426 
Address 
 
Houston, TX 77030 
Address 
 
Tel: 713- 794-1355 
Telephone 


NCI Protocol #: 10058 
Version Date: June 14, 2021 
 
 
2 
 
 
Fax 713-745-1163 
Fax 
 
kdross@mdanderson.org 
e-mail address 
 
 
NCI-Supplied Agent(s):  Talimogene laherparepvec, NSC 785349 
Other Agent(s):  5-fluorouracil, capecitabine, oxaliplatin, external beam radiation (supplier for 
all agents, commercial) 
 
 
IND: TBD 
 
IND Sponsor:  DCTD, NCI  
 
Protocol Type / Version # / Version Date: 
 
Original/ version date 08/29/16 
 
 
 
 
Revision/ version date 11/20/16 
 
 
 
 
Revision 2/version date 01/10/2017 
 
 
 
 
Revision 3/version date 02/21/2017 
 
 
 
            Revision 4/version date 03/23/2017 
                                                                              Revision 5/version date 05/30/2017 
                                                                             Revision 6/version date 06/27/2017 
 
 
 
          Revision 7/version date 08/24/2017 
                                                                           Revision 8/version date 02/12/2018 
 
 
 
        Revision 9/version date 04/20/2018 
 
 
 
Revision 10/version date 07/16/2018 
                                                                                                 Revision 11/version date12/19/2018 
Revision 12/version date 03/22/2019 
Revision 13/version date 08/21/2019     
 
 
 
 
 
 
 
Revision 14/version date 04/08/2021 
                                                                                               Revision 15/version date 6/14/2021 
 
*Protocol types:  Original, Revision, or Amendment 
 
 


NCI Protocol #: 10058 
Version Date: June 14, 2021 
 
 
3 
 
SCHEMA 
 
• Patients with rectal adenocarcinoma either locally advanced or metastatic rectal 
adenocarcinoma requiring chemoradiation to the primary lesion are eligible.  
• Patients with locally advanced rectal adenocarcinoma (T3 or T4, at risk of having a positive 
surgical radial margin and/or N+), or patients with metastatic disease requiring 
chemoradiation.   
• Patients will be treated with FOLFOX chemotherapy x 4 doses over 8 weeks (weeks 1-8) 
followed by short course radiation over 5 days (weeks 9 or 10).  
• Subsequently, starting approximately 2 weeks after finishing short course RT, patients will 
receive FOLFOX chemotherapy x 4 doses (weeks 12 / 13 – 19 / 20). While surgical 
resection of the primary is not mandatory, those requiring surgery will undergo resection 
8-16 weeks later (weeks 27 - 36) and / or further systemic therapy per treating physician’s 
discretion.   
• Talimogene laherparepvec will be administered via endoscopy by a qualified physician for 
a total of 4 doses at the following time points: a) week prior to c1 FOLFOX b) weeks 3, 5 
and 7  during FOLFOX 
• Dose escalation will be done using a 3 + 3 design over 2 cohorts and a total of 15 patients 
will be treated at MTD.  
 
 Dose limiting toxicities (DLTs) will be captured until completion of FOLFOX chemotherapy 
(weeks 18/9) and will be graded according to the CTCAE ver 5.0. 
 
 
 
Dose level+ 
TALIMOGENE 
LAHERPAREPVEC Dose 
(PFU/ml) 
Capecitabine (mg/m2 
po bid on days of 
radiation) 
Radiation  
Comments 
           1 
1x 106, 1x 107, 1x 107,1x 107 
825 
50.4 Gray in 28 
fractions 
Completed prior to 
protocol amendment 
1/23/21 
          1 
(amended)  
1x 106, 1x 107, 1x 107,1x 107 
N/A 
25 Gray in 5 
fractions 
To be implemented 
if DLTs noted with 
DL 2 
           2 
1x 106, 1x 108, 1x 108, 1x 108 
N/A 
25 Gray in 5 
fractions 
 


NCI Protocol #: 10058 
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4 
 
 
 
 
 
#Patients with inadequate archival tissue for integrated biomarker analysis 
^As part of pre-surgical evaluation or at a corresponding time point in patients not undergoing surgery 
+Dose escalation will be done using a 3+3 design for a total of 15 patients that will be treated at MTD 
TVEC = talimogene laherparepvec 
Baseline
Archival 
Tissue
Blood
Pelvic MRI
Week 0
TVEC
Week 1
FOLFOX
Biopsy
Week 3
TVEC
FOLFOX
Week 5
FOLFOX
TVEC
Week 7
FOLFOX
TVEC
Biopsy
Blood
Week 9 /10
RT
Week 12 / 13 -
19 / 20
FOLFOX
Weeks 24-28
Surgical 
evaluation
Blood
Pelvic MRI^
Weeks 27-36
Surgery
Weeks 37 & 
beyond
Therapy per 
treating 
physician's 
discretion


NCI Protocol #: 10058 
Version Date: June 14, 2021 
5 
TABLE OF CONTENTS
Patient Enrollment Instructions.......................................... Error! Bookmark not defined.
Biopsy Procedure and Specimen submission .................... Error! Bookmark not defined.
TITLE:  A Phase I Study of talimogene laheRparepvec (TALIMOGENE 
LAHERPAREPVEC) with Neoadjuvant ChemoTHERAPY AND 
RADIATION in Adenocarcinoma of the Rectum ...............................................................1
SCHEMA 
3
TABLE OF CONTENTS.................................................................................................................5
1.
OBJECTIVES 8
Primary Objectives...................................................................................................8
Secondary Objectives...............................................................................................8
Exploratory Objectives ............................................................................................8
2.
BACKGROUND .................................................................................................................8
Rectal Adenocarcinoma...........................................................................................8
CTEP IND Agents .................................................................................................10
Other Agent(s)........................................................................................................16
Rationale for Proposed Starting Dose: ...................................................................21
Rationale ................................................................................................................23
Correlative Studies Background ............................................................................24
3.
PATIENT SELECTION....................................................................................................27
Inclusion Criteria ...................................................................................................27
Exclusion Criteria ..................................................................................................29
Inclusion of Women and Minorities ......................................................................31
4.
REGISTRATION PROCEDURES ...................................................................................31
Investigator and Research Associate Registration with CTEP ..............................31
Site Registration.....................................................................................................32
Patient Registration................................................................................................35
General Guidelines .................................................................................................36
5.
TREATMENT PLAN........................................................................................................37
Agent Administration .............................................................................................37
Definition of Dose-Limiting Toxicity....................................................................44
Dose Expansion Cohorts: .......................................................................................46
General Concomitant Medication and Supportive Care Guidelines ......................46
Duration of Therapy...............................................................................................46
Duration of Follow Up ...........................................................................................47
6.
DOSING DELAYS/DOSE MODIFICATIONS................................................................47
Talimogene Laherparepvec Dose Delay and Treatment Discontinuation 


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Guidelines ..............................................................................................................47
Other Agent(s) .......................................................................................................50
7.
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................54
Comprehensive Adverse Events and Potential Risks List(s) (CAEPRs) ...............54
Adverse Event Characteristics...............................................................................58
Expedited Adverse Event Reporting ......................................................................59
Routine Adverse Event Reporting .........................................................................65
Secondary Malignancy...........................................................................................66
Second Malignancy ................................................................................................66
Surgical Complications ..........................................................................................66
8.
PHARMACEUTICAL INFORMATION..........................................................................67
CTEP IND Agent(s)...............................................................................................67
Commercial Agent(s).............................................................................................73
9.
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ........................................75
9.1
Collection of Specimens ........................................................................................75
9.2
Specimen Procurement Kits and Scheduling:........................................................76
9.3
Sample Tracking System Instructions ...................................................................80
9.4
Shipping of Biospecimens from Clinical Sites to the ETCTN 
Biorepository..........................................................................................................84
9.5
Correlative Studies.................................................................................................86
9.6
Integral Laboratory or Imaging Studies.................................................................88
9.7
Investigational Device Information .......................................................................88
9.8
Integrated Correlative Studies ................................................................................88
9.9
Exploratory/Ancillary Correlative Studies ............................................................88
9.10
Exploratory Imaging Correlatives..........................................................................89
9.11
Exploratory genomic studies..................................................................................90
10.
STUDY CALENDAR .......................................................................................................91
11.
MEASUREMENT OF EFFECT........................................................................................93
Antitumor Effect – Solid Tumors ..........................................................................93
Antitumor Effect – Hematologic Tumors ............................................................100
Other Response Parameters .................................................................................100
12.
STUDY OVERSIGHT AND DATA REPORTING / REGULATORY 
REQUIREMENTS ...........................................................................................................100
Study Oversight ...................................................................................................100
Data Reporting .....................................................................................................100
CTEP Multicenter Guidelines ..............................................................................103
Collaborative Agreements Language ...................................................................103
Genomic Data Sharing Plan .................................................................................104
13.
STATISTICAL CONSIDERATIONS.............................................................................104


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Study Design/Endpoints.......................................................................................105
Sample Size/Accrual Rate ....................................................................................107
Stratification Factors ............................................................................................107
Analysis of Secondary Endpoints ........................................................................107
REFERENCES 
109
APPENDIX A
PERFORMANCE STATUS CRITERIA ................................................112
APPENDIX B
INFORMATION FOR PATIENTS, THEIR 
CAREGIVERS, AND NON-STUDY HEALTHCARE TEAM ON 
POSSIBLE INTERACTIONS WITH OTHER DRUGS AND HERBAL 
SUPPLEMENTS..............................................................................................................113
APPENDIX C-1
INFORMATION SHEET FOR PATIENTS RECEIVING 
talimogene laherparepvec ................................................................................................114
APPENDIX C-2
INFORMATION SHEET FOR FAMILY MEMBERS, 
CLOSE CONTACTS OF PATIENTS RECEIVING talimogene 
laherparepvec ON CLINICAL TRIALS, AND FOR NON-STUDY (NOT 
INVOLVED IN THE talimogene laherparepvec TRIALS) HEALTH 
CARE PROVIDERS (HCP) ............................................................................................118
APPENDIX D
BIOASSAY TEMPLATES .....................................................................122
APPENDIX E   NCI TEMPERATURE EXPOSURE LOG .......................................................123
APPENDIX F  RECEIVING INSTRUCTIONS FOR NCI SUPPLIED 
TALIMOGENE LAHERPARECVEC  (NSC 785349) ...................................................124


NCI Protocol #: 10058 
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8 
1. OBJECTIVES
Primary Objectives
1.1.1
To determine the dose limiting toxicities (DLTs) and maximum tolerated dose (MTD) of 
talimogene laherparepvec in combination with chemotherapy and radiation in rectal 
cancer
Secondary Objectives
1.2.1
To establish safety and feasibility of the combination  
1.2.2
To determine the neoadjuvant rectal (NAR) score of talimogene laherparepvec with 
chemotherapy and radiation 
Although the clinical benefit of this combination of drugs has not yet been established, 
the intent of offering this treatment is to provide a possible therapeutic benefit, and thus 
the patient will be carefully monitored for tumor response and symptom relief in addition 
to safety and tolerability.
Exploratory Objectives 
1.3.1
To correlate genomic information including RAS, RAF mutation status with response, 
DFS and / or OS.  
1.3.2
To determine immunodulatory changes following talimogene laherparepvec, 
chemotherapy and radiation treatment including proportions of immune cell infiltrates in 
serially collected peripheral blood and/or frozen tumor samples (pre-, on treatment, and at 
post progression) 
1.3.3
To identify MRI-based features including mrCRM at baseline or post-therapy mrCRM, 
mrTRG to define determinants of response, DFS and OS 
1.3.4
To determine the disease free survival (DFS) and overall survival (OS) of talimogene 
laherparepvec with chemotherapy and radiation in patients undergoing curative resection 
1.3.5
To determine the pathological complete response (pCR) rate of talimogene laherparepvec 
with chemotherapy and radiation
2. BACKGROUND
Rectal Adenocarcinoma
In the United States, approximately 40,000 new cases of rectal cancer are diagnosed annually[1]. 
The current standard of care for neoadjuvant rectal cancer in North America includes preoperative 
long course concurrent chemoradiation followed by surgery with total mesorectal excision (TME), 


NCI Protocol #: 10058 
Version Date: June 14, 2021 
 
 
9 
 
which is then followed by adjuvant systemic chemotherapy.  
 
The role of preoperative chemoradiation is based on the pivotal phase III German Rectal Cancer 
trial (CAO/ARO/AIO-94) that demonstrated that neoadjuvant fluoropyrimidine-based 
chemoradiation followed by TME was an effective strategy to reduce rates of local recurrence and 
adherence with completion of therapy. Preoperative therapy when compared to post-operative 
therapy led to significant down staging of tumor burden (25% vs 40% with positive lymph nodes, 
p < 0.001), a larger number of patients were able to avoid abdominoperineal resection requiring 
permanent colostomy (39% vs 19%; p = 0.004), lower rates of  grade 3-4 acute and chronic side 
effects (27% vs 40%, p = 0.001; 14% vs 24%, p = 0.01 respectively), and lower rate of local 
recurrence (7.1% vs 10%, p = 0.048) at 10 year follow up[2, 3]. More recently, several phase III 
trials have compared 5-FU to its oral pro-drug, capecitabine in the neoadjuvant setting noting 
equivalency in pathologic complete response (NSABP R-04, MARGIT)[4]. Due to the 
optimization of local tumor control with improved preoperative diagnostic imaging, preoperative 
radiotherapy and TME, local recurrence rates have dropped to 5-10%.  Disappointingly, these 
advances in local control have not translated into an overall survival benefit. Distant relapse rates 
continue to be high at 30-35% approaching 50% in certain high-risk cases (T3-4, N2-3, and / or 
positive radial margin). Furthermore, significant risk of morbidity remains with rectal surgery 
including the need for a temporary or permanent colostomy, anorectal sphincter dysfunction, 
urinary and sexual dysfunction. 
 
Well-established data show that degree of response to neoadjuvant therapy correlate with long 
term survival in patients with rectal cancer. For instance, a large retrospective study by our group 
suggest that patients with pathological complete response (pCR) to neoadjuvant chemoradiation 
have significantly low risk of distant metastatic recurrence (7% vs10.1% vs 26.5%, p < 0.001) and 
significantly better relapse free survival (RFS; 90.5% vs 78.7% vs 58.5%, p < 0.001) compared to 
those with intermediate or poor response. Furthermore, patients with pCR are increasingly being 
managed with conservative management without surgery[5]. However, with the current approach, 
only 15-20% of all patients have pCR. Therefore, making neoadjuvant therapy for rectal cancer 
more effective to improve pCR, and ultimately overall survival (OS) is an urgent, unmet need. The 
traditional approach of testing agents active in the metastatic setting as radiosensitizers has largely 
been abandoned given the multiple negative trials that did not demonstrate an improvement in pCR 
but resulted in increased toxicities. Novel radiosensitizers that improve response to neoadjuvant 
therapy in rectal cancer are thus needed urgently. 
 
The protocol was amended after completion of the first cohort of dose escalation to replace 
chemoradiation with short course radiation based on emerging data from ASCO 2020 and shifting 
practice patterns post COVID. The RAPIDO trial was an investigator-driven, open-label, 
randomized, controlled, phase 3 trial in patients with locally advanced rectal cancer classified as 
high risk based on pelvic MRI (with at least one of the following criteria: clinical tumor [cT] stage 
cT4a or cT4b, extramural vascular invasion, clinical nodal [cN] stage cN2, involved mesorectal 
fascia, or enlarged lateral lymph nodes). Patients allocated to the experimental treatment group 
received short-course radiotherapy (5 × 5 Gy) followed by chemotherapy with fluoropyrimidine 
and oxaliplatin for up to 18 weeks followed by total mesorectal excision. Patients allocated to the 
standard of care group received long course chemoradiation up to 50·4 Gy concomitant twice-






NCI Protocol #: 10058 
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12 
 
2.2.1.2 
Talimogene laherparepvec Safety Profile 
 
As of a June 30, 2015 data cutoff, 486 subjects have received talimogene laherparepvec 
(with doses from 104 to 108 PFU/mL) and have provided safety data across 15 studies 
(Investigator’s Brochure, 2015).  Thirty-one of these subjects continued into the 
extension phase of two of these studies; a detailed summary of safety results is available 
in Table 6-3 of the Talimogene laherparepvec Investigator’s Brochure (2015). 
 
Overall, most adverse events (AEs) reported in subjects administered talimogene 
laherparepvec are non-serious and primarily include flu-like symptoms and injection site 
reactions (Investigator’s Brochure, 2015).  Most fatal AEs reported in subjects 
administered talimogene laherparepvec were reported in the setting of disease 
progression.  In the phase 3 study (005/05), the three most frequent AEs observed in the 
talimogene laherparepvec group were fatigue (36.2% GM-CSF, 50.3% talimogene 
laherparepvec), chills (8.7%, 48.6%), and pyrexia (8.7%, 42.8%).  The following table 
also include AEs that occurred with a higher incidence in the talimogene laherparepvec 
group compared with the GM-CSF group. 
 
AEs Reported with At Least a 5% Greater Incidence in Patients Treated with talimogene 
laherparepvec vs. GM-CSF*   
(based on phase 3 trial of talimogene laherparepvec vs. GM-CSF in unresectable melanoma) 
Adverse reactions 
Talimogene Laherparepvec 
talimogene 
laherparepvec(n=292) 
GM-CSF 
(n=127) 
Any Grade 
n (%) 
Grade 3 
n (%) 
Any Grade 
n (%) 
Grade 3 
n (%) 
General disorders and administrative site conditions 
 
Fatigue 
147 (50.3) 
6 (2.1) 
46 (36.2) 
1 (<1) 
Chills 
142 (48.6) 
 
11 (8.7) 
 
Pyrexia 
125 (42.8) 
 
11 (8.7) 
 
Influenza-like illness 
89 (30.5) 
2 (<1) 
19 (15.0) 
 
Injection site pain 
81 (27.7) 
2 (<1) 
8 (6.3) 
 
Gastrointestinal disorders 
Nausea 
104 (35.6) 
1 (<1) 
25 (19.7) 
 
Vomiting 
62 (21.2) 
5 (1.7) 
12 (9.5) 
 
Diarrhea 
55 (18.8) 
1 (<1) 
14 (11.0) 
 
Constipation 
34 (11.6) 
 
8 (6.3) 
1 (<1) 
Abdominal pain 
26 (8.9) 
2 (<1) 
3 (2.4) 
 
Musculoskeletal and connective tissue disorders 
Myalgia 
51 (17.5) 
1 (<1) 
7 (5.5) 
 
Arthralgia 
50 (17.1) 
2 (<1) 
11 (8.7) 
 
Pain in extremity 
48 (16.4) 
4 (1.4) 
12 (9.5) 
1 (<1) 
Nervous system disorders 
 
 
 
 
Headache 
55 (18.8) 
2 (<1) 
12 (9.5) 
 
Dizziness 
28 (9.6) 
 
4 (3.2) 
 
Respiratory, thoracic, and mediastinal disorders 
Oropharyngeal pain 
17 (5.8) 
 
1 (<1) 
 
Investigations 
 
 
 
 


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13 
 
 
 
 
 
 
 
2.2.1.2.1 Important Identified Risks with talimogene laherparepvec: 
 
1) Injection site reactions:  Talimogene laherparepvec has been injected into cutaneous, 
subcutaneous and nodal tumor lesions.  Injection site reactions may include erythema, 
discoloration, induration and pain.  Necrosis at injected site may also occur. 
2) Cellulitis at site of injection:  Intralesional administration of talimogene 
laherparepvec has been associated with cellulitis at the injection site, and systematic 
infection may develop.  In the phase 3 melanoma clinical study, the incidence of AEs 
in the bacterial cellulitis category was 6.2% in the talimogene laherparepvecgroup 
(vs. 1.6% in the GM-CSF group). 
3) Impaired wound healing at site of injection:  Impact healing at the injection site has 
been reported, and the risk may be increased in settings with underlying risk factors 
(e.g. previously radiated or poorly vascularized areas).  One patient with peripheral 
vascular disease had an amputation of lower extremity due to infection of non-healing 
wound after talimogene laherparepvec injection.  In the phase 3 melanoma clinical 
study, the impaired wound healing occurred in 5.5% of patients in the talimogene 
laherparepvec group (vs. 2.4%) in the GM-CSF group. 
4) Immune-mediated AEs:  Across melanoma studies, immune-mediated adverse events 
considered possibly related to talimogene laherparepvec were reported in 2% of 
subjects treated with talimogene laherparepvec (and included events of vasculitis, 
glomerulonephritis, acute renal failure, pneumonitis, and worsening psoriasis.  Most 
cases were grade 2 or 3.  One grade 4 case (glomerulonephritis) was reported, which 
resolved with treatment, and no fatal cases were reported.  Other contributory factors 
were identified in several of these cases, including pre-existing immune-mediated 
conditions, other concurrent medications, and intercurrent medical events. 
5) Plasmacytoma at the injection site:  A case was reported in the phase 3 melanoma 
clinical study.  The plasmacytoma developed the area of the injected tumor on the 
scalp after 9 cycles of treatment with talimogene laherparepvec.  On medical review, 
the event was felt to be consistent with recruitment of plasma cells in response to the 
talimogene laherparepvec injections and the patient had a pre-existing (smoldering) 
multiple myeloma.  This case was considered possibly related to the treatment. No 
other cases of plasmacytoma have been reported in clinical trials with talimogene 
laherparepvec to date.  
6) Obstructive airway disorder:  In the phase 3 melanoma clinical study (005/05), one 
(0.3%) subject treated with talimogene laherparepvec reported the adverse event of 
obstructive airways disorder.  The event was grade 4 and resolved with sequelae.  The 
female subject was previously treated with high-dose interleukin-2 and experienced 
Weight decreased 
17 (5.8) 
1 (<1) 
1 (<1) 
 
*Other adverse reactions associated with talimogene laherparepvec in the open-label, randomized 
study includes 
glomerulonephritis, vitiligo, cellulitis, and oral herpes. 


NCI Protocol #: 10058 
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14 
 
an acute respiratory failure requiring intubation.  The subject complained of breathing 
problems after discharge.  Four to 6 weeks later, she received the first dose of 
talimogene laherparepvec (two 1 - 1.5 cm lesions in the right supraclavicular fossa).  
Thirteen days after the second talimogene laherparepvec dose, the subject presented 
with acute respiratory distress requiring an emergency tracheostomy.  Imaging 
showed a mass in the larynx on the contralateral side and adjacent lymph node.  
Etiology of the laryngeal mass was unclear.  A temporal relationship to talimogene 
laherparepvec treatment was present.  Study medication was permanently 
discontinued 
7) Disseminated herpetic infection in SEVERELY immunocompromised individuals 
(defined as those with any severe congenital or acquired cellular and/or humoral 
immune deficiency):  talimogene laherparepvec has not been studied in 
immunocompromised patients.  However, based on animal data (see Section 5.2 of 
IB), patients who are severely immunocompromised (e.g., patients with severe 
congenital or acquired cellular and/or humoral immune deficiency) may be at an 
increased risk of disseminated herpetic infection and should not be treated with 
talimogene laherparepvec.  “Disseminated herpetic infection in severely 
immunocompromised individuals” is defined as an important identified risk based on 
preclinical toxicology with talimogene laherparepvec as well as clinical observations 
of wild-type HSV-1 infection in immunocompromised patients.  In preclinical studies 
in 100% SCID mice (devoid of T and B cells) and 20% BALB/c nude mice (deficient 
in T cells and partially deficient in B cell function), viral inclusion bodies and 
necrosis were observed in multiple organs, including neurons of the GI tract, adrenal 
gland, eyes, skins and brain. 
8) Deep vein thrombosis 
 
2.2.1.2.2 
Important Potential Risks with talimogene laherparepvec: 
 
1) Disseminated herpetic infection in immunocompromised individuals (defined as 
those with HIV/ AIDS, leukemia, lymphoma, common variable immunodeficiency, 
or those who require high-dose steroids or other immunosuppressive agents):  Note, 
for patients who are severely immunocompromised (completely lacking T with 
complete or partially impaired B cell function), disseminated herpetic infection is an 
“identified” AE (see section of talimogene laherparepvec Identified Risks.  It is 
unknown whether patients who are not severely immunocompromised (those with 
conditions limited to T cell dysfunction such as HIV, AIDS, or patients with common 
variable immunodeficiency or those who require chronic treatment with steroids or 
other immunosuppressive agents) are at increased risk.  The potential risk of 
disseminated herpetic infection and the potential benefits of treatment should be 
considered before administering talimogene laherparepvec to these patients. 
2) Symptomatic talimogene laherparepvec infection in normal tissues:  In mouse tumor 
models, viral lysis/tissue injury was limited to tumors in immunocompetent animals.  
There was no clinical or pathological evidence of symptomatic infection or injury to 


NCI Protocol #: 10058 
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15 
 
normal tissues after repeated intratumoral, intravenous, or subcutaneous injection, 
including mice dosed with up to 107 PFU talimogene laherparepvec (~60-fold over 
the highest proposed clinical dose, on a PFU/kg basis) via weekly subcutaneous 
injection for up to 3 months.   
No human cases of confirmed infection of non-tumor tissues by talimogene 
laherparepvec have been reported.  While 5.5% of patients treated with talimogene 
laherparepvec (vs 1.6% in the BM-CSF group) reported oral or corneal herpes 
infection, it is not confirmed whether the source was wide-type herpes or talimogene 
laherparepvec.  Patients who develop herpes-like lesions should follow stand hygienic 
practice to prevent viral transmission.   
3) Symptomatic herpetic infection due to latency and reactivation of talimogene 
laherparepvec or wild-type HSV-1:  Co-infection of neurons already harboring latent 
wild-type HSV-1 by talimogene laherparepvec could potentially stimulate the 
reactivation of latent wild-type HSV-1 in patients with prior infection.   
Talimogene laherparepvec infection of tumor or non-tumor tissues could potentially 
lead to establishment of latency and subsequent reactions of talimogene 
laherparepvec if the virus comes into contact with axonal nerve terminals and was 
transported to neuronal cell bodies.  In mice, biodistribution studies have detected low 
levels of talimogene laherparepvec in trigeminal ganglia through 28 days in 1 of 6 
animals following high-dose IV administration (0.6 × 107 PFU, ~36-fold over the 
highest proposed clinical dose).  Talimogene laherparepvec was undetectable in 
trigeminal ganglia in mice after subcutaneous administration.   
4) Recombination of talimogene laherparepvec with wild-type HSV-1:  This event has 
not been reported in the phase 3 melanoma clinical study. The genetic modifications 
made to talimogene laherparepvec only attenuate the virus, either by limiting 
replication to tumor cells and neurovirulence (by deletion of ICP34.5) or enhancing 
immune detection of infected cells (by eliminating ICP47), none of the theoretical 
products of recombination between wild-type HSV-1 and talimogene laherparepvec 
would have increased virulence.  The likelihood of recombination occurring is low, 
and if recombination occurred, the virulence of the recombinants would be no greater 
than wild-type HSV-1, and symptoms will be reduced compared to wild-type HSV-1.  
Management with systemic antivirals would be the same. 
5) Talimogene laherparepvec-mediated anti-GM-CSF antibody response:  There is a 
theoretical concern that transgene-derived expression of GM-CSF could induce an 
immune response reactive with endogenous GM-CSF.  Autoantibodies against GM-
CSF is detected in 9.6% general population.   It is not known whether such 
phenomena could be expected with the limited exposure anticipated with transgene 
expression of GM-CSF from talimogene laherparepvec. 
 
2.2.1.2.3 Special Precautions: 
 


NCI Protocol #: 10058 
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16 
1) Accidental exposure of healthcare providers (HCP) to talimogene laherparepvec:  A 
needle stick injury, spill, or splash back during administration may result in accidental 
exposure of healthcare providers (HCPs) to talimogene laherparepvec.  The ICP34.5 
gene deletion is intended to allow only tumor selective replication and limited or no 
viral replication in normal tissues.  The signs or symptoms of primary infection at the 
site of exposure are expected to be similar to what is seen with wild-type HSV-1.  
The severity of symptoms is expected to be reduced compared to what is seen with 
wild-type HSV-1.  Talimogene laherparepvec is sensitive to acyclovir.  In one case of 
exposure of study personnel to talimogene laherparepvec, the exposed physician 
developed clinical signs of a herpetic whitlow-like lesion at the site of an accidental 
needle stick that resolved after treatment with acyclovir.
2) Transmission of talimogene laherparepvec from patient to close contacts or HCPs via 
direct contact with infected lesions or body fluids resulting in symptomatic infection 
(primary or reactivation):  A clinical study is in progress to inform whether 
talimogene laherparepvec is present in saliva or oral or genital secretions of treated 
patients.  The likelihood of transfer of talimogene laherparepvec to a close contact or 
HCP increases if the contact has a break in the skin or mucous membranes.  Signs or 
symptoms of infection would be anticipated to be similar to signs and symptoms of 
wild-type HSV infection, although the reduced potential to replicate in normal tissue 
may result in less severe clinical manifestations.  Shedding results showed that 
talimogene laherparepvec was detected on the surface of injected lesions for up to 2 
weeks after injection in 8 of 72 (11%) subjects.  Virus was not detected on the 
exterior surface of tumor dressings at any time point tested.
2.1.2.2.4  Loss of efficacy in patients treated with systemic acyclovir:   
Talimogene laherparepvec retained an intact thymidine kinase gene, and is therefore 
sensitive to acyclovir and acyclovir may attenuate activity of talimogene 
laherparepvec.  The risks and benefits of talimogene laherparepvec treatment before 
administering acyclovir or other anti-viral agents indicated for management of 
herpetic infection will need to be considered.  Other treatments, such as foscarnet, 
may be used as an alternative for acyclovir.
Other Agent(s)
5-Fluorouracil (5-FU; fluorouracil) 
Chemically, fluorouracil, a fluorinated pyrimidine, is 5-fluoro-2,4 (1H,3H)-pyrimidinedione.  
Clinical Pharmacology and Pharmacokinetics: 


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17 
 
 
Following intravenous injection, fluorouracil distributes into tumors, intestinal mucosa, bone 
marrow, liver and other tissues throughout the body. In spite of its limited lipid solubility, 
fluorouracil diffuses readily across the blood-brain barrier and distributes into cerebrospinal fluid 
and brain tissue. Seven to 20 percent of the parent drug is excreted unchanged in the urine in 6 
hours; of this, over 90% is excreted in the first hour. The remaining percentage of the 
administered dose is metabolized, primarily in the liver. The catabolic metabolism of fluorouracil 
results in degradation products (e.g., CO2, urea and α-fluoro-ß-alanine) which are inactive. The 
inactive metabolites are excreted in the urine over the next 3 to 4 hours. When fluorouracil is 
labeled in the six carbon position, thus preventing the 14 C metabolism to CO2, approximately 
90% of the total radioactivity is excreted in the urine. When fluorouracil is labeled in the two 
carbon position, approximately 90% of the total radioactivity is excreted in expired CO2. Ninety 
percent of the dose is accounted for during the first 24 hours following intravenous 
administration.Following intravenous administration of fluorouracil, the mean half-life of 
elimination from plasma is approximately 16 minutes, with a range of 8 to 20 minutes, and is 
dose dependent. No intact drug can be detected in the plasma 3 hours after an intravenous 
injection. 
            
Toxicity 
Nausea, diarrhea, vomiting (mild); stomatitis: 5-8 days after treatment initiation; 
myelosuppression: granulocytopenia (9-14 days); thrombocytopenia (7-14 days); alopecia; loss 
of nails; hyperpigmentation; photosensitivity; maculopapular rash; palmar–plantar 
erythrodysethesias: (42-82% receiving continuous infusion); CNS effects: cerebral ataxia (rare); 
cardiotoxicity: infarction, angina; asymptomatic S–T changes 68%; ocular effects: excessive 
lacrimation and less commonly, tear duct stenosis. 
 
Drug Interaction 
Concomitant administration of 5-FU with warfarin has been reported to result in increased 
INR/prolonged prothrombin time. Patients receiving both drugs should be followed with weekly 
INRs. 
 
2.3.1 Oxaliplatin (Eloxatin)  
 
Oxaliplatin is an antineoplastic agent with the molecular formula C8H14N2O4Pt and the 
chemical name of cis-[(1 R,2R)-1,2-cyclohexanediamine-N,N'] [oxalato(2-)- O,O'] platinum.  
The molecular weight is 397.3. Oxaliplatin is slightly soluble in water at 6 mg/mL, very slightly 
soluble in methanol, and practically insoluble in ethanol and acetone.  
 
 
Clinical Pharmacology and Pharmacokinetics:                                                                                                     
Oxaliplatin undergoes nonenzymatic conversion in physiologic solutions to active derivatives via 
displacement of the labile oxalate ligand. Several transient reactive species are formed, including 
monoaquo and diaquo DACH platinum, which covalently bind with macromolecules. Both inter- 
and intrastrand Pt-DNA crosslinks are formed. Crosslinks are formed between the N7 positions 
of two adjacent guanines (GG), adjacent adenine-guanines (AG), and guanines separated by an 


NCI Protocol #: 10058 
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18 
 
intervening nucleotide (GNG). These crosslinks inhibit DNA replication and transcription. 
Cytotoxicity is cell-cycle nonspecific. 
The reactive oxaliplatin derivatives are present as a fraction of the unbound platinum in plasma 
ultrafiltrate. Pharmacokinetic parameters obtained after a single 2-hour intravenous infusion of 
oxaliplatin at a dose of 85 mg/m2 expressed as ultrafilterable platinum were Cmax of 0.814 
mcg/mL and volume of distribution of 440 L. Interpatient and intrapatient variability in 
ultrafilterable platinum exposure (AUC0–48hr) assessed over 3 cycles was moderate to low 
(23% and 6%, respectively).  
Distribution 
At the end of a 2-hour infusion of oxaliplatin, approximately 15% of the administered platinum is 
present in the systemic circulation. The remaining 85% is rapidly distributed into tissues or 
eliminated in the urine. In patients, plasma protein binding of platinum is irreversible and is greater 
than 90%. The main binding proteins are albumin and gamma-globulins. Platinum also binds 
irreversibly and accumulates (approximately 2-fold) in erythrocytes, where it appears to have no 
relevant activity. No platinum accumulation was observed in plasma ultrafiltrate following 85 
mg/m2every two weeks. 
Metabolism 
Oxaliplatin undergoes rapid and extensive nonenzymatic biotransformation. There is no evidence 
of cytochrome P450-mediated metabolism in vitro. 
Up to 17 platinum-containing derivatives have been observed in plasma ultrafiltrate samples from 
patients, including several cytotoxic species (monochloro DACH platinum, dichloro DACH 
platinum, and monoaquo and diaquo DACH platinum) and a number of noncytotoxic, conjugated 
species. 
Elimination 
The major route of platinum elimination is renal excretion. At five days after a single 2-hour 
infusion of oxaliplatin, urinary eliminate accounted for about 54% of the platinum eliminated, with 
fecal excretion accounting for only about 2%. Platinum was cleared from plasma at a rate (10 – 17 
L/h) that was similar to or exceeded the average human glomerular filtration rate (GFR; 7.5 L/h). 
There was no significant effect of gender on the clearance of ultrafilterable platinum. The renal 
clearance of ultrafilterable platinum is significantly correlated with GFR. 
Clinical Studies 
Adjuvant Therapy of Colorectal Cancer 


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19 
 
The benefit for adding oxaliplatin to 5-FU/leucovorin (LV) was first demonstrated in the MOSAIC 
trial that randomized 2246 patients with resected stage II (40%) or III colon cancer to infusional 
5-FU with (FOLFOX) or without oxaliplatin. After a median follow-up of 82 months, 5-year 
disease free survival (DFS) was significantly higher with FOLFOX (73% vs 67%, hazard ratio, 
HR 0.80). Six-year overall survival rates were significantly higher, both in the entire group (79 
versus 76 percent, HR 0.84, p = 0.046), and in those with stage III (73 versus 69 percent, HR 0.80, 
p = 0.023), but not stage II disease. The survival benefit of oxaliplatin was maintained with long-
term follow-up in those with stage III disease (10-year overall survival 67 versus 59 percent; HR 
0.80, p = 0.016) but not stage II disease (10-year survival 78 versus 80 percent)[12, 13].  
The NSABP-C07 trial assigned 2407 patients with stage II (29 percent) or III colon cancer to bolus 
weekly FU/LV with (FLOX) or without oxaliplatin for 6 months. With eight years of median 
follow-up, five-year DFS significantly favored FLOX (69 versus 64 percent, HR 0.82). Based on 
these results, oxaliplatin was approved for adjuvant therapy of resected stage III colon cancer. 
Since toxicities in the NSABP-C07 trial was significantly higher due to bolus FU/LV, FOLFOX 
regimen with infusional 5-FU is preferred[14].  
The combination of capecitabine plus oxaliplatin (XELOX), was compared with bolus FU/LV in 
a phase III trial involving 1886 patients with stage III colon cancer. In the latest report, after a 
median followup of 74 months, DFS was significantly superior with XELOX than with 
bolus FU/LV (HR for DFS 0.80, 95% CI 0.69-0.93, seven-year DFS of 63 versus 56 percent), as 
was overall survival (HR 0.83, 95% CI 0.70-0.99, seven-year overall survival 73 versus 67 
percent)[8].  
Additional support for the substitution of capecitabine for FU when used in combination 
with oxaliplatin comes from a pooled analysis of four randomized trials examining a variety of 
adjuvant strategies in patients with stage III colon cancer. Combination therapy with oxaliplatin 
provided consistently improved outcomes irrespective of whether the fluoropyrimidine backbone 
was capecitabine or FU/LV[15]. 
Although there are no completed randomized, phase III trials evaluating the benefit of adjuvant 
adding oxaliplatin to adjuvant 5FU/LV following fluoropyrimidine-based chemoradiation in 
rectal cancer, safety of this approach was established by the E3201 trial[16]. The randomized 
phase II ADORE trial that randomly assigned 321 patients with resected rectal cancer following 
neoadjuvant chemoradiation to FOLFOX or FU/LV showed higher three-year DFS (72% vs 
63%)[17]. Based on these results and extrapolating data from resected colon cancer, consensus 
guidelines including those from NCCN include oxaliplatin with a fluoropyrimidine as options.    
Toxicity 
 
The most commonly observed oxaliplatin toxicities include neurotoxicity, GI toxicity, and 
myelosuppression. Three neurotoxicity syndromes have been seen: acute sensory neuropathy 
develops within hours to 2 days after oxaliplatin administration. Symptoms include paresthesias, 
dysesthesias, and hypothesia of the hands, feet and perioral region. Jaw spasm, abnormal tongue 
sensation, dysarthria, eye pain and a sensation of chest pressure have also been noted. Acute 
sensory neuropathy symptoms may be exacerbated by exposure to cold temperature or cold 


NCI Protocol #: 10058 
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20 
 
objects. Symptoms are reversible, usually resolving within 14 days and commonly recurring with 
further dosing. This syndrome has been observed in about 56% of patients receiving oxaliplatin 
with 5-FU and leucovorin.  
 
Acute pharyngolaryngeal dysesthesia is reported to occur in 1-2% of patients. This syndrome is 
characterized by a subjective sensation of difficulty breathing or swallowing without 
laryngospasm or bronchospasm or objective evidence of hypoxia. Avoidance of cold drinks, food 
and air is suggested in order to minimize pharyngolaryngeal dysesthesia. Antianxiety agents 
(e.g., lorazepam) may be used to treat pharyngolaryngeal dysesthesias once oxygen saturation 
has been documented to be normal. 
 
Peripheral neuropathy persisting > 14 days is characterized by paresthesias, dysesthesias, and 
hypothesia. Abnormalities in proprioception may also be seen. Symptoms of persistent 
neuropathy may improve upon discontinuation of oxaliplatin.  
 
Gastrointestinal toxicities include nausea, vomiting (oxaliplatin is considered to be moderately 
emetogenic) and diarrhea. 
 
Neutropenia is reported in 73% of patients receiving oxaliplatin with 5-FU and leucovorin (44% 
grade 3 or 4). Grade 3 or 4 thrombocytopenia is reported to occur in 4% of patients receiving the 
combination. 
 
Allergic reactions, similar to those seen with other platinum compounds, have also been 
observed in patients treated with oxaliplatin. Reactions range from rash to anaphylaxis. 
 
Rarely, oxaliplatin has been associated with pulmonary fibrosis, which may be fatal. Oxaliplatin 
should be discontinued in the presence of unexplained pulmonary symptoms (e.g. nonproductive 
cough, dysphagia) or pulmonary infiltrates until interstitial lung disease or pulmonary fibrosis 
have been ruled out. 
 
Recent reports of oxaliplatin extravasation suggest that tissue necrosis may result and that 
oxaliplatin should be considered a vesicant. No standard treatment exists for oxaliplatin 
extravasation although heat and sodium thiosulfate have both been suggested. 
 
Veno-occlusive disease (VOD) of the liver is a rare complication associated with oxaliplatin and 
5-FU. Clinical manifestations of VOD include hepatomegaly, ascites, and jaundice. 
Histologically, VOD is characterized by diffuse damage in the centrilobular zone of the liver. 
 
Sequelae of VOD include hepatomegaly, splenomegaly, portal hypertension, and esophageal 
varices. A recent analysis of resected liver metastases in 153 patients indicated histological 
findings consistent with VOD in 6/27 patients who received 5-FU alone, 4/17 patients who 
received 5-FU and irinotecan, 20/27 patients who received 5-FU and oxaliplatin, and 14/16 who 
received 5-FU, oxaliplatin and irinotecan. The remaining 66 patients had not received 
chemotherapy prior to resection. There were no such findings in these patients. 
 


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21 
Rationale for Proposed Starting Dose and Amendment: 
Talimogene laherparepvec is currently FDA approved for advanced melanoma based on a phase 
III trial in 436 patients with advanced, unresectable melanoma randomized 2:1 to talimogene 
laherparepvec vs GM-CSF and overall demonstrated its safety. For talimogene laherparepvec 
and GM-CSF, respectively, incidence of treatment-related grade 3 or 4 AEs was 11% and 5%.
The only grade 3 or 4 AE occurring in ≥ 2% of talimogene laherparepvec–treated patients was 
cellulitis; there were no treatment-related deaths. The rate of discontinuation as a result of AEs 
was 4% and 2% with talimogene laherparepvec and GM-CSF. This trial establishes the safety 
profile of talimogene laherparepvec as a single agent.
Talimogene laherparepvec has also been evaluated in combination with chemoradiotherapy in 
patients with squamous cell cancer of the head and neck (SCCHN). In this trial, patients with 
stage III/IVA/IVB SCCHN received chemoradiotherapy (70 Gy/35 fractions with concomitant 
cisplatin 100 mg/m2 on days 1, 22, and 43) and dose-escalating TALIMOGENE 
LAHERPAREPVEC (106, 106, 106, 106 pfu/mL for cohort 1; 106, 107, 107, 107 for cohort 2; 106, 
108, 108, 108 for cohort 3) by intratumoral injection on days 1, 22, 43, and 64. Patients underwent 
neck dissection 6 to 10 weeks later. Primary end points were safety and recommended 
dose/schedule for future study. All (17) patients were treated without delays to 
chemoradiotherapy or dose-limiting toxicity. All patients experienced at least one treatment-
emergent adverse event (AE): 86% were grade 1 or 2, but at least one grade 3 or 4 AE was 
observed in each patient. However, the investigators considered just two adverse events (pyrexia 
and fatigue) to be talimogene laherparepvec related and occurred in two or more patients. Across 
all cohorts and severity grades, the most frequent AEs were consistent with chemoradiation. 
Talimogene laherparepvec has also successfully been evaluated in 17 patients with pancreatic 
adenocarcinoma in combination with chemoradiation and similar to previously reported 
experience, most adverse events were non-serious and primarily included flu-like symptoms and 
injection site reactions. Most serious events were reported in setting of disease progression[18]. 
Based on these data, and upon recommendations from CTEP, we initiated the trial with 
escalating doses of TVEC in combination with capecitabine based chemoradiation as below.  
Dose level
Talimogene 
laherparepvec Dose 
(PFU/ml)
Capecitabine (mg/m2
po bid on days of 
radiation)
Radiation 
           1
106, 107, 107,107
825
50.4 gray in 28 fractions
           2
106, 108, 108,108
825
50.4 gray in 28 fractions
Talimogene laherparepvec was administered via endoscopy by a qualified physician for a total of 
4 doses at the following time points: a) week 1 prior to initiation of FOLFOX chemotherapy b) 
weeks 2-4 during FOLFOX chemotherapy c) week 6 d) week 8-9 during chemoradiation. 
Enrollment to the first cohort was completed without any DLTs, treatment related SAEs or dose 
interruptions. TVEC was delivered safely without any local reactions being experienced by 
patients and all patients underwent surgery. 


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22 
 
 
Subsequently the protocol was amended to replace chemoradiation with short course radiation 
based on emerging data from ASCO 2020 and shifting practice patterns post COVID. The 
RAPIDO trial was an investigator-driven, open-label, randomized, controlled, phase 3 trial in 
patients with locally advanced rectal cancer classified as high risk based on pelvic MRI (with at 
least one of the following criteria: clinical tumor [cT] stage cT4a or cT4b, extramural vascular 
invasion, clinical nodal [cN] stage cN2, involved mesorectal fascia, or enlarged lateral lymph 
nodes). Patients allocated to the experimental treatment group received short-course radiotherapy 
(5 × 5 Gy over a maximum of 8 days) followed by chemotherapy with fluoropyrimidine and 
oxaliplatin for up to 18 weeks followed by total mesorectal excision. Patients allocated to the 
standard of care group received long course chemoradiation up to 50·4 Gy concomitant twice-
daily oral capecitabine 825 mg/m2 followed by total mesorectal excision and, if stipulated by 
hospital policy, adjuvant chemotherapy with eight cycles of CAPOX or 12 cycles of 
FOLFOX4. Median follow-up was 4·6 years.  At 3 years after randomization, the cumulative 
probability of disease-related treatment failure, the primary endpoint was 23·7% (95% CI 19·8–
27·6) in the experimental group versus 30·4% (26·1–34·6) in the standard of care group (hazard 
ratio 0·75, 95% CI 0·60–0·95; p=0·019). Serious adverse events occurred in 177 (38%) of 460 
participants in the experimental group and, in the standard of care group, in 87 (34%) of 254 
patients without adjuvant chemotherapy and in 64 (34%) of 187 with adjuvant chemotherapy.  
 
This trial thus established the efficacy and safety of short course radiation. 
During the COVID pandemic, with an intent towards reducing patient time in health care 
settings, short course radiation has been recommended by multiple consensus guidelines, was 
rapidly implemented across the country and is now standard of care for locally advanced rectal 
cancer patients. The protocol will be amended to replace chemoradiation with short course 
radiation for dose level 2 as below.  
 
Dose level 
Talimogene 
laherparepvec Dose 
(PFU/ml) 
Capecitabine (mg/m2 
po bid on days of 
radiation) 
Radiation  
           1 
106, 107, 107,107 
825 
50.4 gray in 28 fractions 
          1 (amended)  
1x 106, 1x 107, 1x 107,1x 
107 
N/A 
25 Gray in 5 fractions 
(To be implemented if 
DLTs noted with DL2)  
           2 (amended) 
106, 108, 108,108 
N/A 
25 Gy in 5 fractions 
 
Talimogene laherparepvec will be administered via endoscopy by a qualified physician for a 
total of 4 doses as before but at the following amended time points: a) week 1 prior to initiation 
of FOLFOX chemotherapy b) weeks 3, 5 and 7 during FOLFOX chemotherapy.  
 
In addition to monitoring patients for AEs related to talimogene laherparepvec, injection site will 
be evaluated directly during endoscopy at subsequent time points such as during pre-surgical 
evaluation and in those forgoing surgery needing endoscopic surveillance.  
 


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23 
Rationale 
The current standard of care for resectable rectal cancer is neoadjuvant therapy typically with 45 
Gray (Gy) + 5.4 Gy boost over 28 fractions along with concomitant capecitabine (825 mg /m2 by 
mouth twice daily) or infusional 5-FU 300 mg /m2 on days of radiation followed by total 
mesorectal excision surgery 6-8 weeks post-completion of neoadjuvant therapy. Following 
recovery from surgery, further fluoropyrimidine based adjuvant chemotherapy (5-FU or 
capecitabine with or without oxaliplatin) for 4-5 months is recommended to decrease risk of 
distant metastatic recurrence. However, with this approach, the pathological complete response 
rates continue to be low (15-20%), the rates of distant relapse high (up to 40% - 50% in high risk 
sub groups) and all patients experience morbidities related to surgery. Multiple attempts to 
further improve outcomes in the neoadjuvant setting by adding other agents active in the 
metastatic setting to either 5-FU or capecitabine including oxaliplatin, irinotecan, cetuximab, ziv-
aflibercept have all largely been unsuccessful. 
In contrast, talimogene laherparepvec -based oncolytic viral therapy in combination with 
neoadjuvant chemoradiation holds great promise in the management of rectal adenocarcinoma. 
Firstly, oncolytic viruses may show natural selectivity for cancers with an over-active RAS 
signaling pathway thus making colorectal cancer an attractive target[19]. It is well established 
that the majority of colorectal cancers have activated RAS signaling through various mechanisms 
including overexpression of epidermal growth factor receptor (EGFR) ligands, mutations in 
RAS, RAF genes and other mechanisms. The PKR pathway inhibits protein translation, 
production of viral particles and thus spread of the virus. However, RAS-transformed cancer 
cells do not initiate the PKR pathway, rendering them more susceptible to oncolytic viruses. In 
the case of attenuated HSV oncolytic viruses, deletions of ICP34.5 and US11 genes results in 
preferential lysis of cells with defective PKR signaling i.e. cells with activated RAS [19, 20].  
Secondly, strong evidence also points towards synergy of oncolytic viruses with current standard 
of care of fluoropyrimidine-based chemoradiation. In a preclinical study of oncolytic HSV2 in 4 
CRC cell lines (HT-29, LoVo, HCT116 and SW620), oncolytic viruses were found to be highly 
cytotoxic and showed significant synergy with 5-FU.  These results were also replicated in cell 
line xenograft models with increased tumor inhibiton, longer survival without increased toxicity 
compared to 5-FU alone [21].
Finally, growing evidence suggests that radiation-induced cancer cell death is immunogenic 
resulting in numerous immune modulatory effects in the tumor microenvironment including a) 
improvement of T-cell, dendritic cell recruitment and infiltration into the tumor b) upregulation 
of major histocompatibility class-1 (MHC-1) ligands on cancer cells leading to increased 
recognition and killing by CD8+ T cells[22]. In a phase I study of talimogene laherparepvec and 
radiation with cisplatin-based chemoradiation in SCCHN, 14 / 17 patients had tumor response by 
RECIST criteria and pathologic complete remission was confirmed in 93% of patients at neck 
dissection. No patient developed locoregional recurrence, and disease-specific survival was 
82.4% at a median follow-up of 29 months (range, 19-40 months). Of particular interest is the 
extremely high (94%) pathologic complete response rate and the fact that no locoregional 
relapses have occurred. These values exceed those in historical control series, in which rates of 


NCI Protocol #: 10058 
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24 
60% to 71% for histopathologic complete response and 30% to 50% for two-year locoregional 
relapse are typical[20].  
Therefore, in the current study, we propose to evaluate the synergistic potential of talimogene 
laherparepvec in combination with radiation and chemotherapy in rectal cancer. 
Correlative Studies Background
2.6.1
Neoadjuvant Rectal Score
2.6.1.1
Rationale 
The NAR score has been validated in clinical trials as a surrogate endpoint for overall 
survival. The score is designed to be particularly sensitive to changes in factors that 
are affected by neoadjuvant therapy.  
2.6.1.2
Background 
NAR is calculated based on the clinical T stage (cT), pathological T (pT) and pN 
stages as:
NAR = [5pN- 3 (cT- pT) + 12]2 / 9.61.  
The NAR score has been validated in the randomized NSABP R04 study which 
evaluated four different fluoropyrimidine-based radioensitizing regimens in 1479 
patients with resectable rectal cancer. NAR score in this dataset was significantly 
associated with overall survival, OS as both a continuous variable (HR/unit 1.04; 95% 
CI 1.03 – 1.05; p <0.0001) and when the observed scores were categorized into 
tertiles (p < 0.0001). The NAR score was subsequently and independently further 
validated in an international clinical trial dataset providing further evidence of utility 
as a short-term surrogate marker[23]. NAR is being used as the primary end point of 
the proposed randomized phase II modular NCTN clinical trial platform utilizing 
Total Neoadjuvant Therapy (TNT) with parallel experimental arms in LARC (Nrg-
GI002).  
2.6.1.3
Hypothesis 
We hypothesize that talimogene laherparepvec based neoadjuvant therapy will result 
in an improvement in the NAR score. We recognize that the small sample size and 
lack of control arm prevent definitive conclusions but the findings will be compared 
to historical controls and will serve as the preliminary data for designing future, larger 
trials
                 
2.6.2
      MRI-based determinants of response, DFS and OS 


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25 
 
2.6.2.1 
 Rationale 
  
Pelvic MRIs are standard of care in the management of resectable rectal cancer to 
accurately determine stage, evaluate circumferential margins and to determine the 
extent of required surgery. Emerging data show that baseline MRI features and 
changes with neoadjuvant therapy correlate with outcomes in patients. However, it is 
unknown whether pelvic MRIs are able to identify tumor regression with talimogene 
laherparepvec -based neoadjuvant therapy.  
 
2.6.2.2 
Background 
  
In the prospective MERCURY study with a cohort of over 350 patients with 
resectable rectal cancer, pre-treatment MRI was shown to be predictive of a curative 
resection based on involvement of the circumferential margin (mrCRM). A subgroup 
of 111 patients who had both pre- and post-neoadjuvant therapy pelvic MRI were 
retrospectively evaluated for the prognostic value of tumor regression grade (mrTRG) 
and mrCRM.   Both mrTRG and mrCRM were found to have strong prognostic 
effects on OS and DFS, as well as for local recurrence (mrCRM only). Based on these 
data, dedicated pelvic MRIs are performed before and after neoadjuvant therapy in 
rectal cancer patients routinely as standard of care including at our institution[24].      
 
2.6.2.3 
Hypothesis 
 
We hypothesize that rectal adenocarcinoma patients treated with talimogene 
laherparepvec  based neoadjuvant therapy will show improvement in mrCRM 
involvement and tumor regression and that these changes can be reliably evaluated by 
pelvic MRIs.  
 
2.6.3 Changes in PD-L1 Expression  
 
2.6.3.1 
Rationale 
 
Prior studies have shown that radiation and talimogene laherparepvec can both lead to 
increase in PD-L1 expression in tumors. However, the changes in PD-L1 expression 
with talimogene laherparepvec based neoadjuvant therapy in rectal adenocarcinoma 
remains to be determined.  
 
2.6.3.2 
Background 
 
Oncolytic viruses often induce interferon (IFN) release in the local tumor 
microenvironment, and IFN is known to upregulate PD-L1 expression on tumor cells.  
In fact, preclinical models have validated this approach and several clinical trials are 
under way. Similarly, radiation independently increases PD-L1 expression by IFN 
release and other mechanisms. In a preclinical study utilizing an MC-38 colon 
carcinoma tumors xenograft mouse model, either talimogene laherparepvec  or anti-


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26 
 
PD-1 therapy alone induced modest tumor growth inhibition/tumor regressions of 
contralateral tumors. Correlative studies showed increase in PD-L1 expression in 
tumors injected with talimogene laherparepvec. In combination, the talimogene 
laherparepvec  injected tumor displayed 8/10 complete regressions and the distant 
tumors had 2/10 complete regressions[25].  
 
2.6.3.3 
Hypothesis 
 
We hypothesize that rectal adenocarcinoma patients treated with talimogene 
laherparepvec  based neoadjuvant therapy will show increase in PD-L1 expression 
measured by immunohistochemistry in tumor biopsies as compared to baseline.  
 
2.6.4      Immune Cell Profiling 
 
2.6.4.1 
Rationale 
 
Growing evidence suggests that rectal cancer response to neoadjuvant chemo 
radiation (CRT) depends on tumor microenvironment and host immune response. 
Densities of tumor infiltrating lymphocytes (TILs) and peripheral lymphocytes have 
been correlated with response in this setting. 
 
2.6.4.2 
Background 
 
Local and distant antitumor immune responses have been reported in preclinical 
models and previous clinical studies of talimogene laherparepvec, radiation and the 
combination of both. For instance, recently, the numbers of pre-treatment peripheral 
blood helper T lymphocytes and cytotoxic T cells have been shown to be independent 
predictors of response to radiation in rectal cancer patients. Also, talimogene 
laherparepvec therapy has been shown to increase the percent of percent of PD-L1+ T 
cells associated with dramatic local responses in xenograft models of CRC. In a phase 
II study of talimogene laherparepvec in melanoma, biopsy of responding lesions 
suggested an association between response and presence of interferon γ–producing 
MART-1–specific CD8+ T cells and reduction in CD4+FoxP3+ regulatory T 
cells[26].  
 
2.6.4.3 
Hypothesis 
 
We hypothesize that the local and systemic immune effects of talimogene 
laherparepvec may cooperate with neoadjuvant therapy to increase locoregional 
control in rectal cancer. We propose to quantify changes in a) tumor immune cell 
infiltration and to characterize subtypes of the immune cells by IHC b) peripheral T 
cell subpopulations by flow cytometry with talimogene laherparepvec injection and 
radiation in rectal cancer. 
 


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27 
2.6.5
Pharmacodynamic Markers of Talimogene Laherparepvec  
2.6.5.1
Rationale 
Talimogene laherparepvec has previously been shown to be feasible to be used for 
injection into multiple tumor types including melanoma, SCCHN and pancreatic 
cancer. However, the feasibility and efficacy of talimogene laherparepvec delivery 
into rectal adenocarcinoma remains to be determined. The current trial provides a 
valuable opportunity to evaluate this.  
2.6.5.2
Background 
Prior studies have shown that all patients seronegative for HSV strongly seroconvert 
3-4 weeks after their first dose that for seropositive patients, trend was an increase in 
anti-HSV antibody with each injection that eventually plateaued. GM-CSF expression 
in injected tumors has also been shown to increase post-injection that seemed to be 
dose related in a phase I study increasing from dose level 106 to 107. This phase I and 
other phase II studies have also established talimogene laherparepvec DNA as a 
reliable marker for talimogene laherparepvec infection and replication within injected 
lesions.  
2.6.5.3
Hypothesis 
We hypothesize that endoscopic injection of talimogene laherparepvec  into rectal 
adenocarcinoma is an effective delivery method leading to adequate infection and 
proliferation of the oncolytic virus within the tumor cells as demonstrated by increase 
in serum HSV antibody titers (measured by ELISA), GM-CSF (IHC) and talimogene 
laherparepvec DNA (qRT PCR) in tumor samples
3. PATIENT SELECTION
Inclusion Criteria  


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28 
 
3.1.1 For dose escalation: Patients must have A) histologically or cytologically confirmed low 
lying (up to 6 cm of anal verge) rectal adenocarcinoma eligible for radiation therapy to 
rectal tumor, B) If the treatment is palliative in the metastatic setting, no additional 
requirements for tumor size or nodal involvement is needed. C) If the treatment is in the 
neoadjuvant setting, the tumor must ALSO be high-risk locally advanced rectal cancer 
defined as T3-4, N+, and/or at risk for a positive radial margin (as determined by the 
surgeon) 
 
3.1.2 For dose expansion: Patients must have A) histologically or cytologically confirmed 
rectal adenocarcinoma eligible for radiation therapy to rectal tumor irrespective of 
location from anal verge, B) If the treatment is palliative in the metastatic setting, no 
additional requirements for tumor size or nodal involvement is needed. C) If the 
treatment is in the neoadjuvant setting, the tumor must ALSO be high-risk locally 
advanced rectal cancer defined as T3-4, N+, and/or at risk for a positive radial margin (as 
determined by the surgeon) 
 
 
3.1.3 Age ≥18 years.  Because no dosing or adverse event data are currently available on the 
use of talimogene laherparepvec in combination with chemotherapy in patients <18 years 
of age 
 
3.1.4 ECOG performance status ≤ 2 (Karnofsky ≥60%, see Appendix A). 
 
3.1.5 Patients must have normal organ and marrow function as defined below:  
 
− 
Absolute neutrophil count (ANC) ≥1.5x109/L  
− 
Hemoglobin ≥9 g/dL 
− 
Platelets ≥100,000 x109/L  
− 
Serum bilirubin ≤1.5x institutional upper limit of normal (ULN) 
(except patients with Gilbert’s Syndrome, who can have total bilirubin < 3 mg/DL) 
− 
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5x 
institutional ULN 
− 
Serum creatinine ≤1.5 mg/dL OR calculated creatinine clearance (Cockroft-Gault 
formula) ≥50 mL/min OR 24-hour urine creatinine clearance ≥50 mL/min 
− 
Prothrombin time (PT)/International normalized ratio (INR) and partial 
thromboplastin time (PTT) ≤1.5x institutional unless the subject is on anticoagulant 
therapy ((If the subject is receiving anticoagulant therapy, PT, and aPTT must be 
within therapeutic range of intended use of anticoagulants) 
 
3.1.6 Patients must have signed informed consent indicating that they are aware of the 
investigational nature of the study, and are aware that participation is voluntary.  Patients 
must be made aware of their other treatment options. 
 


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29 
3.1.7
Talimogene laherparepvec, as well as other therapeutic agents used in this trial including 
radiation and 5-FU, may cause fetal harm when administered to a pregnant woman.   
Women of childbearing potential (WOCBP) is defined as any female who has
experienced menarche and who has not undergone surgical sterilization (hysterectomy or 
bilateral oophorectomy) or who is not postmenopausal. Menopause is defined clinically 
as 12 months of amenorrhea in a woman over 45 in the absence of other biological or
physiological causes.
WOCBP and men must agree to use adequate contraception (hormonal or barrier method 
of birth control; abstinence) prior to study entry, during the study participation, and for 
four months after the last dose of the drug.   
WOCBP must have a negative serum pregnancy test within 72 hours prior to enrollment
and agree to use effective contraception throughout the treatment period and for 4 months 
after the last dose of study treatment.  Should a woman become pregnant or suspect she is 
pregnant while she or her partner is participating in this study, she should inform her 
treating physician immediately.  
3.1.8
Ability to understand and the willingness to sign a written informed consent document. 
Exclusion Criteria
3.2.1
Patients who have had radiotherapy within < 4 weeks are ineligible.   
3.2.2
Patients who have not recovered from adverse events due to prior anti-cancer therapy 
(i.e., have residual toxicities > Grade 1) except alopecia are ineligible.  
3.2.3
Use of other investigational, chemotherapeutic or targeted drugs within 28 days (or five 
half-lives, whichever is shorter; with a minimum of 14 days from the last dose) preceding 
the first dose of talimogene laherparepvec and during the study are ineligible. 
3.2.4
Patients who have previously been treated with talimogene laherparepvec, any other 
oncolytic virus or pelvic radiation are ineligible.
3.2.5
Patients with known active central nervous system (CNS) metastases are ineligible. 
Subjects with previously treated brain metastases may participate provided they are stable 
(without evidence of progression by imaging for at least four weeks prior to the first dose 
of trial treatment and any neurologic symptoms have returned to baseline), have no 
evidence of new or enlarging brain metastases. 


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30 
 
3.2.6 Patients with a known immediate or delayed hypersensitivity reaction or idiosyncrasy to 
talimogene laherparepvec or any of its components, 5-FU and / or oxaliplatin are 
ineligible. 
 
3.2.7 Patients with a history or evidence of active autoimmune disease (e.g., pneumonitis, 
glomerulonephritis, vasculitis, or other); or history of active autoimmune disease that has 
required systemic treatment (i.e., use of corticosteroids, immunosuppressive drugs or 
biological agents used for treatment of autoimmune diseases) within 2 months of 
enrollment are ineligible.  [Replacement therapy (e.g., thyroxine for hypothyroidism, 
insulin for diabetes or physiologic corticosteroid replacement therapy for adrenal or 
pituitary insufficiency) is not considered a form of systemic treatment for autoimmune 
disease] 
 
3.2.8 Patients with evidence of clinically significant immunosuppression such as the following 
are ineligible: 
- 
Primary immunodeficiency state such as Severe Combined Immunodeficiency 
Disease 
- 
Concurrent opportunistic infection 
- 
Receiving systemic immunosuppressive therapy (>2 weeks) including oral steroid 
doses >10 mg/day of prednisone or equivalent within 2 months prior to enrollment 
3.2.9 Patients with active herpetic skin lesions or prior complications of herpetic infection 
(e.g., herpetic keratitis or encephalitis) are ineligible.  
 
3.2.10 Patients with viral infections requiring intermittent or chronic systemic (intravenous or 
oral) treatment with an antiherpetic drug (e.g., acyclovir), other than intermittent topical 
use are ineligible. 
 
3.2.11 Patients with other viral infections are ineligible: 
- 
Known to have acute or chronic active hepatitis B or hepatitis C infection 
- 
Known to have human immunodeficiency virus (HIV) infection. 
- 
Prior therapy with viral-based tumor vaccine. 
- 
Received live vaccine within 28 days prior to enrollment. 
 
3.2.12 Subject who is unwilling to minimize exposure with his/her blood or other body fluids to 
individuals who are at higher risks for HSV-1 induced complications such as 
immunosuppressed individuals, individuals known to have HIV infection, pregnant 
women, or children under the age of 1 year, during talimogene laherparepvec treatment 
and through 30 days after the last dose of talimogene laherparepvec are ineligible. 
 
3.2.13 Patients with uncontrolled intercurrent illness including, but not limited to, active, non-
colorectal malignancies requiring systemic therapy, ongoing or active infection, 
symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or 
psychiatric illness/social situations that would limit compliance with study requirements 
are ineligible. 
 


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31 
3.2.14 Although no effects on embryo-fetal development have been observed in animal studies, 
adequate and well-controlled studies with talimogene laherparepvec have not been 
conducted in pregnant women.  In addition, given the high risk of detrimental effects of 
other study agents including 5-FU, oxaliplatin and radiation on embryo-fetal 
development, the study treatment must be excluded in the following patients:
•
Female subject is pregnant or breast-feeding, or planning to become pregnant during 
study treatment and through 4 months after the last dose of talimogene laherparepvec. 
•
Female subject of childbearing potential who is unwilling to use acceptable method(s) 
of effective contraception during study treatment and through 4 months after the last 
dose of talimogene laherparepvec.  
•
Sexually active subjects and their partners unwilling to use male or female latex 
condom to avoid potential viral transmission during sexual contact while on treatment 
and within 30 days after treatment with talimogene laherparepvec. 
3.2.15 Patients that are unable to swallow oral medications are ineligible
  
3.2.16 Patients with a major surgical procedure, open biopsy, or significant traumatic injury 
within 28 days prior to initiation of therapy, or anticipation of need for major surgical 
procedure during the course of the study other than that defined by protocol are 
ineligible. 
3.2.17 Patients with a known DPD deficiency are ineligible
3.2.19 Patients who are unable to get MRIs due to any reason including pacemakers or AICD are 
ineligible 
Inclusion of Women and Minorities
Both men and women of all races and ethnic groups are eligible for this trial.   
4. REGISTRATION PROCEDURES
Investigator and Research Associate Registration with CTEP
4.1.1
CTEP Registration Procedures
Food and Drug Administration (FDA) regulations require IND sponsors to select qualified 
investigators.  NCI policy requires all persons participating in any NCI-sponsored clinical trial to 
register and renew their registration annually.  To register, all individuals must obtain a CTEP 
Identity and Access Management (IAM) account (https://ctepcore.nci.nih.gov/iam).  In addition, 




NCI Protocol #: 10058 
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33 
 
Each investigator or group of investigators at a clinical site must obtain IRB approval for this protocol 
and submit IRB approval and supporting documentation to the CTSU Regulatory Office before they can 
be approved to enroll patients.  Assignment of site registration status in the CTSU Regulatory Support 
System (RSS) uses extensive data to make a determination of whether a site has fulfilled all regulatory 
criteria including but not limited to the following:. 
• An active Federal Wide Assurance (FWA) number 
• An active roster affiliation with the Lead Network or a participating organization 
• A valid IRB approval 
• Compliance with all protocol specific requirements. 
 
In addition, the site-protocol Principal Investigator (PI) must meet the following criteria: 
• Active registration status 
• The IRB number of the site IRB of record listed on their Form FDA 1572 
• An active status on a participating roster at the registering site 
 
 
 
Sites participating on the NCI CIRB initiative that are approved by the CIRB for this study are not 
required to submit IRB approval documentation to the CTSU Regulatory Office. For sites using the 
CIRB, IRB approval information is received from the CIRB and applied to the RSS in an automated 
process.  Signatory Institutions must submit a Study Specific Worksheet for Local Context (SSW) to the 
CIRB via IRBManager to indicate their intent to open the study locally.  The CIRB’s approval of the 
SSW is then communicated to the CTSU Regulatory Office.  In order for the SSW approval to be 
processed, the Signatory Institution must inform the CTSU which CIRB-approved institutions aligned 
with the Signatory Institution are participating in the study. 
 
 
 
4.2.1 Downloading Regulatory Documents 
Site registration forms may be downloaded from the 10058 protocol page located on the 
CTSU Web site.  Permission to view and download this protocol is restricted and is based 
on person and site roster data housed in the CTSU RSS.  To participate, Investigators and 
Associates must be associated with the Corresponding or Participating protocol 
organization in the RSS.  
• Go to https://www.ctsu.org and log in using your CTEP-IAM username and 
password. 
• Click on the Protocols tab in the upper left of your screen.  
• Either enter the protocol # in the search field at the top of the protocol tree, or 
• Click on the By Lead Organization folder to expand, then select LAO-TX035, and 
protocol #10058. 
• Click on LPO Documents, select the Site Registration documents link, and 
download and complete the forms provided.  (Note: For sites under the CIRB 
initiative, IRB data will load to RSS as described above.) 
 


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34 
 
4.2.2 Requirements For 10058 Site Registration: 
• IRB approval (For sites not participating via the NCI CIRB; local IRB 
documentation, an IRB-signed CTSU IRB Certification Form, Protocol of Human 
Subjects Assurance Identification/IRB Certification/Declaration of Exemption 
Form, or combination is accepted ) 
o For applicable ETCTN studies with a radiation and/or imaging (RTI) component, 
the enrolling site must be aligned to a RTI provider.  To manage provider 
associations access the Provider Association tab on the CTSU website at 
https://www.ctsu.org/RSS/RTFProviderAssociation, to add or remove associated 
providers.  Sites must be linked to at least one IROC credentialed provider to 
participate on trials with an RT component. Enrolling sites are responsible for 
ensuring that the appropriate agreements are in place with their RTI provider, and 
that appropriate IRB approvals are in place.   
• ETCTN Specimen Tracking Training 
• At least one individual at each participating site will need to complete 
the Theradex-led training 
• Theradex will provide a certificate of completion, which will need to 
be submitted to the CTSU through the Regulatory Submission Portal 
o The training is a one-time only requirement per individual. If 
an individual has previously completed the training for another 
ETCTN study, the training does not need to be completed 
again nor does the certificate of completion need to be 
resubmitted to the CTSU. 
o This training will need to be completed before the first patient 
enrollment at a given site 
o Peter Clark is the main point of contact at Theradex for the 
training (802-456-8735, PClark@theradex.com).  Nafeesa 
Sarakhawas is the backup contact (609.480.2693, 
NSarakhawas@theradex.com). 
 
 
4.2.3 Submitting Regulatory Documents 
 
Submit required forms and documents to the CTSU Regulatory Office, where they will 
be entered and tracked in the CTSU RSS.   


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35 
Regulatory Submission Portal: www.ctsu.org (members’ area)  Regulatory Tab 
Regulatory Submission  
When applicable, original documents should be mailed to: 
CTSU Regulatory Office
1818 Market Street, Suite 3000 
Philadelphia, PA 19103 
Institutions with patients waiting that are unable to use the Portal should alert the CTSU 
Regulatory Office immediately at 1-866-651-2878 in order to receive further instruction 
and support. 
4.2.4
Checking Site Registration Status
You can verify your site registration status on the members’ section of the CTSU website.  
• Go to https://www.ctsu.org and log in to the members’ area using your CTEP-IAM
username and password
• Click on the Regulatory tab at the top of your screen
• Click on the Site Registration tab
• Enter your 5-character CTEP Institution Code and click on Go
Note: The status given only reflects compliance with IRB documentation and institutional 
compliance with protocol-specific requirements as outlined by the Lead Network. It does not 
reflect compliance with protocol requirements for individuals participating on the protocol or the 
enrolling investigator’s status with the NCI or their affiliated networks.
Patient Registration
4.3.1
OPEN / IWRS
Patient enrollment will be facilitated using the Oncology Patient Enrollment Network 
(OPEN).  OPEN is a web-based registration system available to users on a 24/7 basis.  It 
is integrated with the CTSU Enterprise System for regulatory and roster data interchange 
and with the Theradex Interactive Web Response System (IWRS) for retrieval of patient 
registration/randomization assignment.  Patient enrollment data entered by Registrars in 
OPEN / IWRS will automatically transfer to the NCI’s clinical data management system, 
Medidata Rave. Local Institutional Biosafety Committee (IBC) approval is required 
before a site can enroll patients to talimogene laherparepvec protocols
4.3.2
OPEN/IWRS User Requirements
OPEN/IWRS users must meet the following requirements:


NCI Protocol #: 10058 
Version Date: June 14, 2021 
36 
•
Have a valid CTEP-IAM account (i.e., CTEP username and password). 
•
To enroll patients:  Be on an ETCTN Corresponding or Participating Organization 
roster with the role of Registrar. Registrars must hold a minimum of an AP 
registration type.
•
Have regulatory approval for the conduct of the study at their site. 
Prior to accessing OPEN/IWRS, site staff should verify the following:
•
All eligibility criteria have been met within the protocol stated timeframes.   
If applicable, all patients have signed an appropriate consent form and HIPAA 
authorization formOPEN/IWRS Questions?
Further instructional information on OPEN is provided on the OPEN tab of the CTSU 
website at https://www.ctsu.org or at https://open.ctsu.org.  For any additional questions 
contact the CTSU Help Desk at 1-888-823-5923 or ctsucontact@westat.com.  
4.3.3
Special Instructions for Patient Enrollment
The following information will be requested:
•
Protocol Number
•
Investigator Identification 
o
Institution and affiliate name
o
Investigator’s name
•
Eligibility Verification:  Patients must meet all the eligibility requirements 
listed in Section 3. 
•
Additional Requirements:
o
Patients must provide a signed and dated, written informed consent 
form. 
Upon enrolling a patient, IWRS will communicate with OPEN, assigning two separate 
and unique identification numbers to the patient, a Universal patient ID (UPID) and a 
Treatment patient ID.  The UPID is associated with the patient and used each and every 
time the patient engages with the ETCTN Biobanking and Molecular Characterization 
portion of this protocol.  The UPID contains no information or link to the treatment 
protocol.  IWRS will maintain an association between the UPID for ETCTN biobanking 
and molecular characterization and any treatment protocols the patient participates in, 
thereby allowing analysis of the molecular characterization results with the clinical data.   
Immediately following enrollment, the institutional anatomical pathology report for the 
diagnosis under which the patient is being enrolled must be uploaded into Rave.  The 
report must include the surgical pathology ID (SPID) and the IWRS-assigned UPID for
this trial.  Important:  Remove any personally identifying information, including, but 
not limited to, the patient’s name, initials, and patient ID# for this treatment trial, 
from the institutional pathology report prior to submission.
General Guidelines


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37 
Following registration, patients should begin protocol treatment within 7 business days.* Issues 
that would cause treatment delays should be discussed with the Principal Investigator.  If a 
patient does not receive protocol therapy following registration, the patient’s registration on the 
study may be canceled.  The Study Coordinator should be notified of cancellations as soon as 
possible. 
5. TREATMENT PLAN
Agent Administration (Amended)
Treatment will be administered on an outpatient basis.  Reported adverse events and potential 
risks are described in Section 7.  Appropriate dose modifications are described in Section 6.  No 
investigational or commercial agents or therapies other than those described below may be 
administered with the intent to treat the patient's malignancy.
Week 0:   
•
Talimogene laherparepvec up to 4 mL of  1x106 PFU/mL 
Week 1: 
•
5-Fluorouracil (5-FU) 400 mg / m2 IV bolus followed by  
5-Fluorouracil (5-FU) 2400 mg / m2 continuous IV infusion over 46 hours 
•
Leucovorin 400 mg /m2 IV bolus  
•
Oxaliplatin 85 mg/m2 IV over 2 hours  
Week 3: 
•
Talimogene laherparepvec up to 4 mL of 1x107 PFU/mL Or 1x108 PFU/mL based on 
assigned dose level  
•
5-Fluorouracil (5-FU) 400 mg / m2 IV bolus followed by  
5-Fluorouracil (5-FU) 2400 mg / m2 continuous IV infusion over 46 hours 
•
Leucovorin 400 mg /m2 IV bolus  
•
Oxaliplatin 85 mg/m2 IV over 2 hours  
Week 5: 
•
Talimogene laherparepvec up to 4 mL of 1x107 PFU/mL Or 1x108 PFU/mL based on 
assigned dose level  
•
5-Fluorouracil (5-FU) 400 mg / m2 IV bolus followed by 5-Fluorouracil (5-FU) 2400 mg 
/ m2 continuous IV infusion over 46 hours 
•
Leucovorin 400 mg /m2 IV bolus  
•
Oxaliplatin 85 mg/m2 IV over 2 hours  


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38 
 
 
Week 7: 
• Talimogene laherparepvec up to 4 mL of 1x107 PFU/mL Or 1x108 PFU/mL based on 
assigned dose level   
• 5-Fluorouracil (5-FU) 400 mg / m2 IV bolus followed by 5-Fluorouracil (5-FU) 2400 mg 
/ m2 continuous IV infusion over 46 hours 
• Leucovorin 400 mg /m2 IV bolus  
• Oxaliplatin 85 mg/m2 IV over 2 hours  
 
Weeks 9 / 10: 
• Radiation 25 Gy over 5 fractions 
 
Weeks 12 / 13: 
• 5-Fluorouracil (5-FU) 400 mg / m2 IV bolus followed by 5-Fluorouracil (5-FU) 2400 mg 
/ m2 continuous IV infusion over 46 hours 
• Leucovorin 400 mg /m2 IV bolus  
• Oxaliplatin 85 mg/m2 IV over 2 hours  
 
Weeks 14 / 15: 
• 5-Fluorouracil (5-FU) 400 mg / m2 IV bolus followed by 5-Fluorouracil (5-FU) 2400 mg 
/ m2 continuous IV infusion over 46 hours 
• Leucovorin 400 mg /m2 IV bolus  
• Oxaliplatin 85 mg/m2 IV over 2 hours  
 
Weeks 16 / 17: 
• 5-Fluorouracil (5-FU) 400 mg / m2 IV bolus followed by 5-Fluorouracil (5-FU) 2400 mg 
/ m2 continuous IV infusion over 46 hours 
• Leucovorin 400 mg /m2 IV bolus  
• Oxaliplatin 85 mg/m2 IV over 2 hours  
 
Weeks 18 / 19: 


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39 
 
• 5-Fluorouracil (5-FU) 400 mg / m2 IV bolus followed by 5-Fluorouracil (5-FU) 2400 mg 
/ m2 continuous IV infusion over 46 hours 
• Leucovorin 400 mg /m2 IV bolus  
• Oxaliplatin 85 mg/m2 IV over 2 hours  
 
 
 
 
Talimogene laherparepvec will be administered via endoscopy by a qualified physician for a total 
of 4 doses as before but at the following amended time points: a) week 1 prior to initiation of 
FOLFOX chemotherapy b) weeks 3, 5 and 7 during FOLFOX chemotherapy  
 
 
 
5.1.1 Talimogene laherparepvec  
 
5.1.1.1. 
Talimogene laherparepvec dose and schedule 
 
                  Please refer to section 8.1  
 
5.1.1.2. 
Instructions for talimogene laherparepvec injection site care: 
 
Care for injection site 
 
IMPORTANT 
Dose Escalation Schedule 
 
Dose Level 
Dose 
 
Talimogene laherparepvec 
(PFU/ml) 
 
Capecitabine 
(mg/m2 po bid on 
days of radiation) 
Radiation (gray) 
Comments  
Level 1 
1x106, 1x107, 1x107,1x107 
825 
50.4 in 28 fractions 
Completed prior to 
protocol amendment 
1/23/21 
          Level 1 
(amended)  
1x 106, 1x 107, 1x 107,1x 107 
N/A 
25 Gray in 5 
fractions 
To be implemented 
if DLTs noted with 
DL 2 
Level 2 (amended) 
1x106, 1x108, 1x108,1x108 
NA 
25 in 5 fractions 
 
PFU = Plaque forming units; NA = Not applicable 
 


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 Reactions at or near the area of the injection have been seen in people administered 
talimogene laherparepvec. Symptoms include bleeding, redness, swelling and 
inflammation at the injection site. Skin infections caused by bacteria at the site of 
injection which may require hospitalization for antibiotic treatment have also been 
reported. Other symptoms may include warmth at the injection site or symptoms of 
delayed wound healing at or around the injection site such as injection site discharge, 
foul odor, or dead tissue at the injection site. If you notice symptoms of delayed wound 
healing, such as those mentioned above, at the injection site(s), you should contact the 
study doctor or his/her staff immediately. 
 If there are signs that the surrounding skin is becoming irritated/red, please contact the 
study site.  An absorbent pad may need to be applied.   
 
Do Not: 
• 
Don’t put salves or ointments on the injection site. 
• 
Don’t scratch or pick at the injection site 
• 
Avoid directly touching the area that has been injected with the study drug.  
 
Infections: Tumor necrosis may be seen with the use of talimogene laherparepvec.  The 
presence of necrotic or ulcerating lesions may pre-dispose the subject to local and/or 
systemic infections such as cellulitis, bacteremia, etc.  Careful wound care and infection 
precautions are recommended if tumor necrosis results in open wounds.  
 
In addition to monitoring patients for AEs related to talimogene laherparepvec, injection site will 
be evaluated directly during endoscopy at subsequent time points such as during pre-surgical 
evaluation and in those forgoing surgery needing endoscopic surveillance.  
 
 
5.1.1.3.   
 
Accidental Occupational Exposure: Accidental exposure may lead to transmission of 
talimogene laherparepvec and herpetic infection.  Nurses and other study staff (e.g., 
pharmacists) with open skin wounds should not come into direct contact with talimogene 
laherparepvec.  HCP who are immunocompromised or pregnant should not prepare or 
administer talimogene laherparepvec. All personnel handling the virus or material 
contaminated with talimogene laherparepvec must observe safety precautions (e.g., wear a 
laboratory coat, safety glasses and gloves).   
 
• In the event of an accidental occupational exposure through a splash to the eyes or 
mucous membranes, flush with clean water for at least 15 minutes.  In the event of 
exposure to broken skin or needle stick, clean the site thoroughly with soap and water 
or a virucidal disinfectant such as 1% sodium hypochlorite or Virkon®.   
 
Exposure of Non-treated Individuals to talimogene laherparepvec: As there is a potential 
risk for exposure of talimogene laherparepvec from subjects to anyone in direct contact with 
the subject, persons with open skin lesions or who are immunosuppressed, pregnant women 


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and newborns should avoid direct contact with the injected lesions, dressings or body fluids 
of the treated patients.   
 
• In the event of a secondary exposure (e.g., leakage through occlusive dressing to 
subject or contacts) to talimogene laherparepvec, clean the site thoroughly with soap 
and water or a virucidal disinfectant such as 1% sodium hypochlorite or Virkon®.   
 
Persons should seek a healthcare provider for signs of systemic (fever, aches, nausea, and 
malaise) or local (fever, pain, redness and swelling) infection.  Talimogene laherparepvec is 
sensitive to acyclovir which may be administered, if clinically indicated.   
 
Accidental Spills: Spills should be treated with a virucidal agent.  All disposable materials 
contaminated with talimogene laherparepvec must be destroyed and disposed of in 
compliance with local institutional guidelines. 
 
 
5.1.2 Other Agent(s) 
 
 
5.1.2.1 
5-Fluorouracil 
 
Patients will receive FOLFOX chemotherapy before and after radiation and after surgery per 
treating physician’s discretion 
 
5-FU is commercially available as a 50 mg/mL solution for injection in 10 mL, 20 mL, 50 mL 
and 100 mL vials. Inspect for precipitate; if found, agitate or gently heat in water bath. Bolus 
injections are prepared using undiluted drug. 46 hour infusion of 5-FU should be prepared for 
administration via ambulatory infusion pump according to the institution’s standards. These 
solutions may be prepared in D5W or 0.9% NaCl. 5-FU should not be mixed in the same 
solution with most parenteral antiemetics. 
 
Intact vials should be stored at room temperature and protected from light. Slight yellow discolor 
does not usually indicate decomposition. Stability in ambulatory pumps varies according to the 
pump, manufacturer of drug, concentration and diluent. Please refer to appropriate reference 
sources for additional information. 
 
In this study, 5-FU is administered as a 400 mg/m2 IV bolus followed by 2400 mg/m2 by IV 
infusion over 46 hours starting immediately after the bolus.      
 
5.1.2.2 
Oxaliplatin       
 
Patients will receive FOLFOX chemotherapy before and after radiation and after surgery per 
treating physician’s discretion 
 


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Oxaliplatin is commercially available as an aqueous solution in vials containing 50 mg and 100  
mg at a concentration of 5 mg/mL. The vials do not contain any preservative and they are  
intended for single use. 
 
Intact vials should be stored at room temperature. Solutions diluted in D5W are stable for 6 
hours at room temperature or 24 hours under refrigeration. 
 
The calculated dose of oxaliplatin (85 mg/m2 in this protocol) should be diluted for infusion with 
250 mL to 500 mL D5W. Oxaliplatin should not be diluted with a sodium chloride solution. 
Needles, syringes, catheters or IV administration sets containing aluminum should not be used 
with oxaliplatin. As with other platinum compounds, contact with aluminum may result in a 
black precipitate. 
 
Oxaliplatin will be administered by intravenous infusion over 2 hours. Infusion time may be 
prolonged (up to 6 hours) in patients experiencing pharyngolaryngeal dysesthesia or mild grade 
1delayed hypersensitivity reactions. Oxaliplatin is unstable in the presence of chloride or alkaline 
solutions. Do NOT mix or administer oxaliplatin with saline or other chloride-containing 
solutions. Do NOT administer other drugs or solutions in the same infusion line. Flush IV 
lines/catheters with Dextrose 5% in Water both before and after oxaliplatin administration.      
 
 
5.1.3 Other Modality(ies) or Procedures 
 
5.1.3.1 
Radiation Therapy 
 
Radiation Therapy Schema:  
The target dose to the pelvic PTV is 25 Gy with 5 Gy in 5 fractions during one week. The boost 
volume is included. An extra boost of 2 Gy x 2 – 3 is also possible to deliver in certain 
circumstances. 
Target volumes 
Boost GTV 
Gross tumor volume (GTV) is the visible primary tumor and visible pathological lymph 
nodes. 
CTV boost 
GTV boost plus a margin of 2 cm within the same anatomical compartment as the tumor is in, 
for the dose from 45 to 50.4 Gy, also around radiologically engaged lymph nodes! If the tumor 
is entirely within mesorectum with no threatened MRF, the 2 cm extension for uncertainties in 
tumor spread does not need to go outside the fascia. The margin of 2 cm will thus chiefly be 


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43 
 
added cranially and caudally. If the tumor e.g. grows into the sacral bone or the urinary bladder, 
the 2 cm margin does apply within those organs. 
GTV boost plus a margin of 1 cm within the same anatomical compartment if an additional 
boost is given above 50.4 ( or 50.0) or 25 Gy. 
Pelvic CTV 
1. The primary tumor 
2. Primary lymph nodes in the bowel wall and within mesorectum. Mesorectum is composed 
of the surrounding fat around the bowel and extends dorsally towards sacrum. Distally, only 
lymph nodes or tumor deposits up to 4 cm are included. For tumors in lower rectum this 
means that the entire mesorectum down to the pelvic floor is included whereas in tumors 
high up in rectum, the most distal part of mesorectum is not included. The reason for this is 
to diminish radiation towards the sphincters. 
3. The closest secondary lymph node stations consisting of presacral nodes and nodes along the 
rectal superior artery. These lymph nodes are partly overlapping with the primary mesorectal 
lymph nodes and they are important for all tumors within the rectum. Since local recurrences are 
very unusual above S1 – S2, lymph nodes above this level should not be included unless there 
are signs of pathological lymph nodes presacrally. If this is the case, the cranial limit of CTV 
should be at least 1 cm above the most cranial pathological lymph node.  
4. The lateral lymph node stations along the medial rectal and obturator arteries until they reach 
the level of the obturator canal should be included if the primary tumor is below the peritoneal 
reflection or up to about 8 to 10 cm from the anal verge. In higher tumors, these nodes are rarely 
involved.  
5. The lateral lymph node stations also include lymph nodes along the internal iliac artery up to 
the bifurcation from the external iliac artery. The cranial border for the CTV is in most cases just 
below the bifurcation of the internal and external iliac arteries. In most patients this is at the level 
of S1 – S2. In certain individuals, the bifurcation can be above L5 – S1. In these instances the 
cranial CTV border is at the level of S1-S2, unless lymph nodes along the internal iliac artery is 
seen. Then a margin of at least 1 cm above the most cranial lymph nodes must be drawn.  
6. Inguinal lymph nodes are included in CTV only if the tumor grows into the anal canal and 
distal to the dentate line or if it grows into the distal part of vagina.  
7. The entire ischio-rectal fossa, the anal canal and peritoneum is included in pelvic CTV only if 
the tumor grows into the levators or down into the anal canal. In these instances, rectal excision 
is always required.  


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8. Lymph nodes along the external iliac artery are included if the tumor grows into anterior 
organs like the prostate, urinary bladder, cervix, vagina or uterus to such an extent that the 
external nodes are at risk for metastases. Therefore, napping or minimal overgrowth dorsally is 
not sufficient. 
PTV 
The above description relates to the CTV. A PTV should normally be defined and includes CTV 
and internal target volume (ITV) and a margin necessary for the setup. These margins are 
depending upon several factors that are related to the equipment at the radiotherapy center.  
Treatment verification 
Treatment verification should be performed according to institutional guidelines. Acceptable 
deviations should be in line with the chosen CTV-PTV margin.  
5.1.4
Investigational Imaging Agent Administration 
N/A
Definition of Dose-Limiting Toxicity
Dose limiting toxicities (DLTs) will be captured until completion of FOLFOX chemotherapy 
(weeks 18/19) and will be graded according to the CTCAE ver 5. DLTs will be defined as 
clinically significant grade 3 or 4 toxicities possibly or probably related to study treatment. The 
following AEs will not be considered DLTs:

any grade of alopecia, 

grade 3 arthralgia or myalgia, 

brief (< 1 week) grade 3 fatigue,  

grade 3 fever  

grade 3 diarrhea or vomiting responding to supportive care. 

grade 3 radiation dermatitis
All patients who have received at least one dose of the study regimen are evaluable for toxicities; 
for dose escalation decisions, patients should have completed ≥ 80% of the planned 
chemotherapy and radiation doses unless the reason for discontinuation is an AE that qualifies 
for DLT. 
AEs that are considered “Dose Limiting” for talimogene laherparepvec
1) Herpetic events that should be considered DLTs: 
o
Serious herpetic events such as herpetic encephalitis, encephalomyelitis or 
disseminated herpetic infection 


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o Any herpetic events confirmed due to talimogene laherparepvec that require treatment 
with acyclovir or similar anti-viral agent.  Talimogene laherparepvec treatment 
should be held if systemic acyclovir or other anti-viral is indicated.  If ongoing anti-
viral treatment is required, talimogene laherparepvec treatment should be 
permanently discontinued 
* Herpetic events due to wild-type HSV-1 or wild-type HSV-2 which require acyclovir 
and are not due to talimogene laherparepvec (as confirmed by PCR testing) should not be 
considered as DLTs caused by talimogene laherparepvec. 
2)   DLT will also be defined as any of the following talimogene laherparepvec-related 
toxicity:   
o Grade 2 or greater immune-mediated AEs. 
o Grade 2 or greater allergic reactions. 
o Any grade plasmacytoma 
o Any other grade 3 or greater hematologic or non-hematologic toxicity, with the 
exceptions of:  
 any grade of alopecia, 
 grade 3 arthralgia or myalgia,  
 brief (< 1 week) grade 3 fatigue,  
 grade 3 fever,  
 grade 3 diarrhea or vomiting responding to supportive case. 
 
For other study treatments, DLT will be defined as clinically significant (ie excluding any grade 
alopecia, grade 3 arthralgia or myalgia, < 1 week grade 3 fatigue, grade 3 diarrhea, nausea, 
vomiting responding to supportive care), grade 3 or 4 toxicities possibly or probably related to 
study treatment or AEs.  
 
 
Management and dose modifications associated with the above adverse events are outlined in 
Section 6. 
 
Dose escalation will proceed within each cohort according to the following scheme.  Dose-
limiting toxicity (DLT) is defined above.   
 
Number of Patients with DLT at a 
Given Dose Level 
Escalation Decision Rule 
0 out of 3 
Enter 3 patients at the next dose level. 
≥2 
Dose escalation will be stopped.  This dose level will be 
declared the maximally administered dose (highest dose 
administered).  Three (3) additional patients will be 
entered at the next lowest dose level if only 3 patients 
were treated previously at that dose. 


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46 
1 out of 3 
Enter at least 3 more patients at this dose level.
• If 0 of these 3 patients experience DLT, proceed to 
the next dose level. 
• If 1 or more of this group suffer DLT, then dose 
escalation is stopped, and this dose is declared the 
maximally administered dose.  Three (3) additional 
patients will be entered at the next lowest dose level 
if only 3 patients were treated previously at that dose.
≤1 out of 6 at highest dose level 
This is generally the maximum tolerated dose, MTD. At 
least 6 patients must be entered at the MTD.
Dose Expansion Cohorts: 
A total of 15 patients will be treated at the MTD (including the 6 from dose expansion) to assess 
safety and feasibility of this dose level. The MTD will be deemed to be recommended phase II 
dose (RP2D) if ≥ 80% of the patients are able to receive ≥ 80% of the planned treatment doses. If 
≥ 1/3 of all patients at this dose experience DLTs, enrollment will be stopped and the Principal 
Investigator will discuss with all study investigators and with CTEP whether further addition of 
patients is needed to re-assess the RP2D.  Monitoring of all safety and toxicity data is done by 
the Principal Investigator and the Corresponding Organization on a real-time basis as data are 
entered into Medidata Rave using the Web Reporting Module.   
General Concomitant Medication and Supportive Care Guidelines
5.4.1 Talimogene laherparepvec is sensitive to acyclovir and other antiherpetic viral drugs, and 
would be rendered ineffective.  Thus, if systemic anti-herpetic medication is indicated, 
talimogene laherparepvec should be discontinued.
5.4.2 Where to locate information:
•
For “Instructions for talimogene laherparepvec Injection Site Care”, refer to Section 
5.1.1.2  
•
For “Information Related to Exposure to talimogene laherparepvec”, refer to 5.1.1.3, 
Appendices C1, C2
•
For Information Sheet for Patient, Close Contacts and Non-study HCP, please refer to 
Appendix C.  This Information should be provided to the care giver, family members, 
and close contacts of patients receiving talimogene laherparepvec on this trial
Duration of Therapy
In the absence of treatment delays due to adverse event(s), treatment may continue for the 


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47 
duration of the therapy per protocol or until one of the following criteria applies:
•
Disease progression
•
Intercurrent illness that prevents further administration of treatment
•
Unacceptable adverse event(s)  Please refer to section 6 Treatment Modification 
Guidelines 
•
Patient decides to withdraw from the study
•
General or specific changes in the patient's condition render the patient unacceptable 
for further treatment in the judgment of the investigator
•
Clinical progression
•
Patient non-compliance 
•
Pregnancy 
o
All women of child bearing potential should be instructed to contact the 
investigator immediately if they suspect they might be pregnant (e.g., missed 
or late menstrual period) at any time during study participation.
o
The investigator must immediately notify CTEP in the event of a confirmed 
pregnancy in a patient participating in the study. 
•
Termination of the study by sponsor 
•
The drug manufacturer can no longer provide the study agent 
The reason(s) for protocol therapy discontinuation, the reason(s) for study removal, and the 
corresponding dates must be documented in the Case Report Form (CRF). 
Duration of Follow Up 
Patients will be followed for 30 days after removal from study or until death, whichever occurs 
first. Patients who have undergone curative resection will be monitored for a minimum of 2 years 
(and up to 5 years) for disease recurrence.  Patients removed from study for unacceptable adverse 
event(s) will be followed until resolution or stabilization of the adverse event. 
6. DOSING DELAYS/DOSE MODIFICATIONS
Talimogene Laherparepvec Dose Delay and Treatment Discontinuation Guidelines


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48 
 
AEs that are considered “Dose Limiting” for talimogene laherparepvec Treatment 
Modification Guidelines 
1) Herpetic events that should be considered DLTs: 
a. Serious herpetic events such as herpetic encephalitis, encephalomyelitis or 
disseminated herpetic infection  
b. Any herpetic events confirmed due to talimogene laherparepvec that require 
treatment with acyclovir or similar anti-viral agent.  Talimogene laherparepvec 
treatment should be held if systemic acyclovir or other anti-viral is indicated.  If 
ongoing anti-viral treatment is required, talimogene laherparepvec treatment 
should be permanently discontinued 
*Herpetic events due to wild-type HSV-1 or wild-type HSV-2 which require acyclovir 
and are not due to talimogene laherparepvec (as confirmed by PCR testing) should not be 
considered as DLTs caused by talimogene laherparepvec. 
2) A DLT will also be defined as any of the following talimogene laherparepvec-related 
toxicity  
o Grade 2 or greater immune-mediated AEs. 
o Grade 2 or greater allergic reactions. 
o Any grade plasmacytoma 
o Any other grade 3 or greater hematologic or non-hematologic toxicity, with the 
exceptions of:  
 any grade of alopecia, 
 grade 3 arthralgia or myalgia,  
 brief (< 1 week) grade 3 fatigue,  
 grade 3 fever,  
 grade 3 diarrhea or vomiting responding to supportive care. 
 
Dose Reductions/delay:  
• Dose reductions with regards to changes in the concentrations of talimogene 
laherparepvec are not permitted. However, patients may require a reduction in the volume 
injected due to a disease response (defined in dosing section) or due to local toxicity at 
the injection site. 
• If talimogene laherparepvec treatment was delayed due to AEs or other reasons by >1 
week, that dose will be deemed to have been missed and the subject will proceed to the 
next scheduled treatment visit.  
• If DLTs occur, talimogene laherparepvec administration should be delayed until the DLT 
has resolved to at least CTCAE version 5.0 Grade 1.  (AEs less than DLT may also 
require talimogene laherparepvec dose delay.  See instructions in Table below) 
• If talimogene laherparepvec dosing is delayed by more than 4 weeks (approximately 6 
weeks from the previous dose) due to treatment related AEs, talimogene laherparepvec 
should be permanently discontinued.   
• If talimogene laherparepvec dosing is delayed by more than 4 weeks (approximately 6 
weeks from the previous dose) for reasons other than treatment-related toxicity, the case 


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49 
 
must be reviewed by the sponsor of the study (CTEP) to determine if the subject can 
resume talimogene laherparepvec therapy. 
 
Treatment delays and discontinuation due to Specific AEs 
Condition 
Grade 
talimogene laherparepvec 
modification 
• Injection site reactions 
 
Volume of talimogene 
laherparepvec injection may 
be adjusted and should be held 
based on the degree of local 
toxicities 
 
• Active herpetic cutaneous or mucosal lesions, 
herpes labialis, or active dermatosis in the 
region of the injected tumor (s)  
 
Mild: continue talimogene 
laherparepvec;  
If requiring systemic acyclovir 
or similar anti-viral agents: 
Hold talimogene 
laherparepvec.   
• Serious herpetic events such as herpetic 
encephalitis, encephalomyelitis or 
disseminated herpetic infection  
Any grade  
Discontinue talimogene 
laherparepvec 
• Any condition requiring corticosteroid dosing 
of >10 mg prednisone daily (or equivalent) 
and/or other immunosuppressive medication 
for related toxicities 
N/A 
Hold talimogene 
laherparepvec dosing until 
corticosteroid dose has 
decreased to <10 mg 
prednisone daily (or 
equivalent) and the other 
immunosuppressive 
medication has been stopped. 
• Plasmacytoma   
Any grade 
Permanently discontinue 
talimogene laherparepvec 
• Immune-mediated AEs (These may include 
pauci-immune glomerulonephritis, vasculitis, 
and pneumonitis, but may involve any organ 
system)  
Grade 2 or 
greater 
Hold talimogene 
laherparepvec (with the 
exception of vitiligo).  If delay 
is > 4 weeks, discontinue 
talimogene laherparepvec 
• Allergic reactions, or urticaria   
Grade 2 or 
greater 
Hold talimogene 
laherparepvec.  If delay is > 4 
weeks, permanently 
discontinue talimogene 
laherparepvec 


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50 
• Other talimogene laherparepvec related grade 
3+ AEs or intolerable grade 2 AEs (Except 
brief grade 3 fever, fatigue, pain, or 
nausea/vomiting responding to supportive 
care)
Hold talimogene 
laherparepvec until AE is 
grade 0-1.   
• If delay is > 4 weeks, 
discontinue talimogene 
laherparepvec
• If the AE was grade 4, 
decision to resume 
talimogene laherparepvec
upon recovery should be 
reviewed with the sponsor 
(CTEP)
Other Agent(s)
Dose modification guidelines for talimogene laherparepvec are listed in Section 6.1.  
Event Name
Oxaliplatin Neuropathy
Duration of Toxicity 
Grade of Event
1-7 days 
>7 days
Persistent between cycles
Grade 1 
Paresthesias/dysesthesiasb
that do not interfere with 
function
No change in dose
No change in dose
No change
Grade 2
Paresthesias/dysesthesiasb
interfering with function, 
but not activities of daily 
living (ADL)
No change in dose
No change in dose
Decrease by 1 dose level
Grade 3
Paresthesias/dysesthesiasb
with pain or with 
functional impairment 
that also interfere with 
ADL
No change
Decrease by 1 dose 
level 
Stop oxaliplatin
Grade 4
Persistent 
paresthesias/dysesthesias 
that are disabling or life-
threatening
Stop oxaliplatin
Stop oxaliplatin
Stop oxaliplatin
Laryngopharyngeal 
dysesthesia
↑ duration of next infusion  
to 6 hoursc
a Not resolved by the beginning of the next cycle.


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b     May be cold induced.    
 
 
 
 
 
Event Name 
Oxaliplatin hypersensitivity  
Grade of Event 
Management/Next Dose for Oxaliplatin 
≤ Grade 1 
Premedications with antihistamines, steroids and slow rate of oxaliplatin 
by half with future doses 
 
Grade 2 
Premedications with antihistamines, steroids and slow rate of oxaliplatin 
by half with future doses or discontinue oxaliplatin per discretion of 
treating physician 
 
Grade 3 
Discontinue oxaliplatin 
Grade 4 
Discontinue oxaliplatin 
 
*Patients requiring a delay of >2 weeks should go off protocol therapy. 
 
 
 
Event Name 
Hand Foot Syndrome 
Grade of Event 
Management/Next Dose for 
Oxaliplatin 
Management/Next Dose for 5-FU  
≤ Grade 1 
No change in dose 
No change in dose 
Grade 2 
No change in dose 
No change in dose 
Grade 3 
Hold all treatment until recovery ≤ 
grade 1 but may continue radiation 
if deemed safe by investigators; No 
change in dose 
Hold all treatment until recovery ≤ 
grade 1 but may continue radiation 
if deemed safe by investigators; No 
change in dose 
Grade 4 
Off protocol therapy 
Off protocol therapy 
*Patients requiring a delay of >2 weeks should go off protocol therapy. 
 
 
 
Event Name 
Vomiting 
Grade of Event 
Management/Next Dose for 
Oxaliplatin 
Management/Next Dose for 5-FU  
≤ Grade 1 
No change in dose 
No change in dose 
Grade 2 
Hold until ≤ Grade 1.  Resume at 
same dose level. 
Hold until ≤ Grade 1.  Resume at 
same dose level. 
Grade 3 
Hold* until < Grade 2.  Resume at 
one dose level lower, if indicated. 
Hold* until < Grade 2.  Resume at 
one dose level lower, if indicated.** 


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Grade 4 
Off protocol therapy 
Off protocol therapy 
*Patients requiring a delay of >2 weeks should go off protocol therapy. 
 
Recommended management:  ondansetron 4-8 mg ODT or by mouth every 6-8 hours and / or 
prochlorperazine 5-10 mg po every 4-6 hours or other anti-emetics per treating physician  
 
 
Event Name 
Diarrhea 
Grade of Event 
Management/Next Dose for 
Oxaliplatin 
Management/Next Dose for 5-FU  
≤ Grade 1 
No change in dose 
No change in dose 
Grade 2 
No change in dose  
No change in dose 
Recurrent / persistent 
grade 2 
Decrease by 1 dose level 
Decrease by 1 dose level 
Grade 3 
Hold* until < Grade 2.  Resume at 
one dose level lower, if indicated. 
Hold* until < Grade 2.  Resume at 
one dose level lower, if indicated.** 
Grade 4 
Off protocol therapy 
Off protocol therapy 
*Patients requiring a delay of >2 weeks should go off protocol therapy. 
 
Recommended management:  Loperamide antidiarrheal therapy 
Dosage schedule:  4 mg at first onset, followed by 2 mg with each loose motion until diarrhea-
free for 12 hours (maximum dosage:  16 mg/24 hours) 
Adjunct anti-diarrheal therapy is permitted and should be recorded when used. 
 
 
Event Name 
Neutropenia 
Grade of Event 
Management/Next Dose for 
Oxaliplatin 
Management/Next Dose for 5-FU  
≤ Grade 1 
No change in dose 
No change in dose 
Grade 2 
Hold until ≤ Grade 1.  Resume at 
same dose level; consider growth 
factor with next cycle 
Hold until ≤ Grade 1.  Resume at 
same dose level; consider growth 
factor with next cycle. 
Grade 3 
Hold* until < Grade 2.  Resume at 
one dose level lower, if indicated; 
consider growth factor with next 
cycle especially if dose reduction 
not done. 
Hold* until < Grade 2.  Resume at 
one dose level lower, if indicated; 
consider growth factor with next 
cycle especially if dose reduction 
not done. 
Grade 4 
Off protocol therapy 
Off protocol therapy 
*Patients requiring a delay of >2 weeks should go off protocol therapy. 
 
Consider GM-CSF per recommended doses  
 
 
Event Name 
Thrombocytopenia 


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53 
 
Grade of Event 
Management/Next Dose for 
[Agent Name] 
Management/Next Dose for 
[Agent Name] 
≤ Grade 1 
No change in dose 
No change in dose 
Grade 2 
Hold until ≤ Grade 1.  Resume at 
same dose level. 
Hold until ≤ Grade 1.  Resume at 
same dose level. 
Recurrent Grade 2  Hold until ≤ Grade 1.  Decrease by 
one dose level 
Hold until ≤ Grade 1.  Decrease by 
one dose level 
Grade 3 
Hold* until < Grade 2.  Resume at 
one dose level lower 
Hold* until < Grade 2.  Resume at 
one dose level lower 
Grade 4 
Off protocol therapy 
Off protocol therapy 
*Patients requiring a delay of >2 weeks should go off protocol therapy. 
 
 
 
Event Name 
Mucositis 
Grade of Event 
Oxaliplatin 
5-FU  
≤ Grade 1 or grade 2 
but tolerable to 
patient 
No change in dose  
No change in dose 
Grade 2 but 
intolerable to patient 
No change in dose 
Decrease by one dose level 
Grade 3 
Hold all treatment until < Grade 2. 
No change in dose  
Hold all treatment until < Grade 2. 
Decrease by one dose level  
Grade 4 
Discontinue treatment  
Discontinue treatment  
* Patients requiring a delay of >2 weeks should go off protocol therapy. 
 
Recommended Management: Oral hygiene, topical mucosal coating agents such as 
diphenhydramine, compounded mixtures of topical anaesthetics 
 
Event Name 
Fatigue 
Grade of Event 
Oxaliplatin 
5-FU  
≤ Grade 1 or grade 2 
but tolerable to 
patient 
No change in dose  
No change in dose 
Grade 2 but 
intolerable to patient 
Decrease by one dose level 
Decrease by one dose level 
Grade 3 
Hold all treatment until < Grade 2. 
Decrease by one dose level  
Hold all treatment until < Grade 2. 
Decrease by one dose level  
Grade 4 
Discontinue treatment  
Discontinue treatment  
* Patients requiring a delay of >2 weeks should go off protocol therapy. 
 
Recommended Management: Physical exercise / therapy, light exposure, evaluate for 
contributing factors including medications, anemia, poor sleep hygiene 
 


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54 
7. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial. The 
following list of AEs (Section 7 .1) and the characteristics of an observed AE (Sections 7.2 and 
7.3) will determine whether the event requires expedited reporting via the CTEP Adverse Event 
Reporting System (CTEP-AERS) in addition to routine reporting 
Comprehensive Adverse Events and Potential Risks List(s) (CAEPRs)
The Comprehensive Adverse Event and Potential Risks list (CAEPR) provides a single list of 
reported and/or potential adverse events (AE) associated with an agent using a uniform 
presentation of events by body system.  In addition to the comprehensive list, a subset of AEs, 
the Specific Protocol Exceptions to Expedited Reporting (SPEER), appears in a separate column 
and is identified with bold and italicized text.  The SPEER is a list of events that are protocol-
specific exceptions to expedited reporting to NCI (except as noted below).  Refer to the 'CTEP, 
NCI Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/adverse effects.htm for further clarification. 
The CAEPR may not provide frequency data; if not, refer to the Investigator’s Brochure for this 
information. 
NOTE:  The highest grade currently reported is noted in parentheses next to the AE in the 
SPEER.  Report ONLY AEs higher than this grade expeditiously.  If this CAEPR is part of a 
combination protocol using multiple investigational agents and has an AE listed on different 
SPEERs, use the lower of the grades to determine if expedited reporting is required.
7.1.1
CAEPRs for CTEP IND Agent(s)
7.1.1.1
CAEPR for talimogene laherparepvec
Comprehensive Adverse Events and Potential Risks list (CAEPR)
for
Talimogene Laherparepvec(NSC 785349)
Comprehensive Adverse Events and Potential Risks list (CAEPR)
for
Talimogene laherparepvec (T-VEC, IMLYGIC, NSC 785349)
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of reported 
and/or potential adverse events (AE) associated with an agent using a uniform presentation of events by 
body system. In addition to the comprehensive list, a subset, the Specific Protocol Exceptions to 
Expedited Reporting (SPEER), appears in a separate column and is identified with bold and italicized 
text. This subset of AEs (SPEER) is a list of events that are protocol specific exceptions to expedited 
reporting to NCI (except as noted below).  Refer to the 'CTEP, NCI Guidelines: Adverse Event Reporting 
Requirements' http://ctep.cancer.gov/protocolDevelopment/electronic applications/docs/aeguidelines.pdf
for further clarification. Frequency is provided based on 517 patients. Below is the CAEPR for Talimogene 






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57 
 
7Obstructive airway disorder has occurred in one patient with Head and Neck Squamous cell carcinoma 
(HNSCC) with a suproventricular mass who developed acute respiratory distress requiring a trachetomy 
13 days after the second dose of T-VEC.  Imaging showed a mass in the larynx and adjacent lymph 
nodes on the contralateral side. 
 
8Rash may include rash maculo-papular and erythematous rash. 
 
9Carotid artery blowout syndrome was observed in a HNSCC patient treated with T-VEC in combination 
with anti-PD-1 who had been previously treated with localized (neck) radiation and lymph node 
dissection. 
 
 
Adverse events reported on talimogene laherparepvec (T-VEC, IMLYGIC) trials, but for which there 
is insufficient evidence to suggest that there was a reasonable possibility that talimogene 
laherparepvec (T-VEC, IMLYGIC) caused the adverse event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Febrile neutropenia 
CARDIAC DISORDERS - Sinus tachycardia 
EAR AND LABYRINTH DISORDERS - Tinnitus 
GASTROINTESTINAL DISORDERS - Ascites; Dry mouth; Dysphagia; Gastrointestinal disorders - Other 
(odynophagia); Mucositis oral 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Edema limbs; Malaise 
INFECTIONS AND INFESTATIONS - Infections and infestations - Other (oral candidiasis) 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Bruising; Dermatitis radiation; Fracture 
INVESTIGATIONS - Neutrophil count decreased; White blood cell decreased 
METABOLISM AND NUTRITION DISORDERS - Hypokalemia 
NERVOUS SYSTEM DISORDERS - Cognitive disturbance; Dysgeusia 
PSYCHIATRIC DISORDERS - Anxiety; Confusion; Insomnia 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Dyspnea; Pneumonitis4 
 
 
Note: Talimogene laherparepvec (T-VEC, IMLYGIC) in combination with other agents could cause an 
exacerbation of any adverse event currently known to be caused by the other agent, or the combination 
may result in events never previously associated with either agent. 
 
Note: In animal models talimogene laherparepvec has demonstrated several potential risks as detailed 
below: 
1) Talimogene laherparepvec has not been tested in severely immune compromised patients.  In 
animal models, injection of talimogene laherparepvec in immune-deficient mice resulted in 
disseminated infection. 
2) Transmission of talimogene laherparepvec to health care professionals and personnel in close 
contact is possible. 
3) Latent infection of talimogene laherparepvec in the neurological system has been observed in 
mice at high dose of T-VEC, although the clinical implication in human patients is not clear. 
 
7.1.2 Adverse Event List(s) for Commercial Agent(s) 
 
7.1.2.1 
5-FU: 
 
Gastrointestinal Disorders: Diarrhea, nausea, stomatitis, vomiting, abdominal pain, 
constipation, dyspepsia, elevated liver function tests 
 


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58 
Skin and Subcutaneous Tissue Disorders: Hand-foot syndrome, alopecia, rash, erythema, 
skin discoloration
General Disorders: Fatigue, Pyrexia, asthenia, lethargy, anorexia 
Nervous System Disorders: Dizziness, headache, dysgeusia
Blood and Lymphatic Disorders: Anemia, thrombocytopenia and neutropenia 
7.1.2.2
Oxaliplatin:
Gastrointestinal Disorders: Diarrhea, nausea, stomatitis, vomiting, constipation, 
dyspepsia, elevated liver function tests 
Cardiovascular Disorders: Hypotension
Skin and Subcutaneous Tissue Disorders: Hand-foot syndrome, alopecia, rash, erythema, 
skin discoloration
General Disorders: Fatigue, Pyrexia, asthenia, lethargy, anorexia 
Nervous System Disorders: Dizziness, headache, dysgeusia, paresthesias, pharyngo-
laryngeal dysthesias
Blood and Lymphatic Disorders: Anemia, thrombocytopenia and neutropenia 
Hypersensitivity and injection site reactions
For further details regarding adverse events, please refer to the package insert for each 
agent 
Adverse Event Characteristics 
•
CTCAE term (AE description) and grade:  The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
5.0 will be utilized for AE reporting. All appropriate treatment areas should have access 
to a copy of the CTCAE version 5.0.  A copy of the CTCAE version 5.0 can be 
downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic applications/ctc.htm
•
For expedited reporting purposes only:  
-
AEs for the agent that are bold and italicized in the CAEPR (i.e., those listed in the 
SPEER column, Section 7.1.1) should be reported through CTEP-AERS only if the 
grade is above the grade provided in the SPEER. 


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59 
-
Other AEs for the protocol that do not require expedited reporting are outlined in 
section 7.3.5. 
•
Attribution of the AE: 
-
Definite – The AE is clearly related to the study treatment.
-
Probable – The AE is likely related to the study treatment.
-
Possible – The AE may be related to the study treatment.
-
Unlikely – The AE is doubtfully related to the study treatment.
-
Unrelated – The AE is clearly NOT related to the study treatment. 
Expedited Adverse Event Reporting
7.3.1
Expedited AE reporting for this study must use CTEP-AERS (CTEP Adverse Event 
Reporting System), accessed via the CTEP Web site (https://eapps-
ctep.nci.nih.gov/ctepaers).  The reporting procedures to be followed are presented in the 
“NCI Guidelines for Investigators: Adverse Event Reporting Requirements for DCTD 
(CTEP and CIP) and DCP INDs and IDEs” which can be downloaded from the CTEP 
Web site
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm
).  These requirements are briefly outlined in the tables below (Section 7.3.3). 
In the rare occurrence when Internet connectivity is lost, a 24-hour notification is to be 
made to CTEP by telephone at 301-897-7497.  Once Internet connectivity is restored, the 
24-hour notification phoned in must be entered electronically into CTEP-AERS by the 
original submitter at the site.
7.3.2
Distribution of Adverse Event Reports
CTEP-AERS is programmed for automatic electronic distribution of reports to the 
following individuals:  Principal Investigator and Adverse Event Coordinator(s) (if 
applicable) of the Corresponding Organization or Lead Organization, the local treating 
physician, and the Reporter and Submitter.  CTEP-AERS provides a copy feature for 
other e-mail recipients. 
7.3.3
Expedited Reporting Guidelines 
Use the NCI protocol number and the protocol-specific patient ID assigned during trial 
registration on all reports.
Note:  A death on study requires both routine and expedited reporting, regardless of 
causality.  Attribution to treatment or other cause must be provided.
Death due to progressive disease should be reported as Grade 5 “Disease progression”
in the system organ class (SOC) “General disorders and administration site conditions”. 
Evidence that the death was a manifestation of underlying disease (e.g., radiological 




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61 
 
 
 
7.3.4 Additional talimogene laherparepvec specific Reporting Guidelines –  
 
Reporting is required for: (1) suspected herpetic events in treated patients; (2) suspected 
herpetic events in at-risk HCPs with direct or indirect exposure to talimogene 
laherparepvec; and 3) suspected herpetic events in the treated patient’s close contacts.  
The mechanism, timing, and follow-up procedures are summarized in the table below and 
described in Section 7.3.4.1 (for treated patients) and 7.3.4.2 (HCPs and close contacts). 
 
Accidental Exposure and Herpetic Event Reporting Requirement Summary 
Exposed Person 
Reporter 
Timeframe 
for 
Reporting 
to Amgen 
Report 
Mechanism 
Timing of 
Swab 
Collection 
qPCR 
Testing 
Required? 
Responsible 
Party for 
Lesion 
Swabbing 
qPCR Test 
Result 
Distribution
* 
Treated Patients 
with suspected 
herpetic lesions 
Investigator 
Within 24 
hours of 
Investigator 
awareness 
Contact 
Amgen at 1-
855-IMLYGIC 
(1-855-465-
9442)  
AND 
Report to 
CTEP through 
CTEP-AERS  
Collect 
swabs from 
suspected 
lesions 
ideally within 
3 days of 
appearance 
of symptoms 
Yes, if 
consent 
obtained 
Investigator 
Sponsor, 
Investigator, 
and Amgen 
HCP directly 
exposed to 
product (e.g., 
needle stick, 
splash back) 
without signs or 
symptoms of 
herpetic illness 
HCP’s 
Personal 
Physician or 
impacted 
person 
Within 24 
hours of 
Reporter 
awareness 
Contact 
Amgen at 1-
855-IMLYGIC 
(1-855-465-
9442) to 
report event 
N/A 
N/A 
N/A 
N/A 
HCP directly or 
indirectly exposed 
to product with 
suspected 
herpetic lesions 
HCP’s 
Personal 
Physician or 
impacted 
person 
Within 24 
hours of 
Reporter 
awareness 
Contact 
Amgen at 1-
855-IMLYGIC 
(1-855-465-
9442) to 
report event 
Collect swabs 
from 
suspected 
lesions within 
3 days of 
appearance of 
symptoms 
Yes, if 
consent 
obtained 
HCP or 
HCP’s 
Personal 
Physician 
HCP’s 
Personal 
Physician 
and Amgen 
Close Contact 
(e.g., caregiver, 
spouse, child) 
with suspected 
herpetic lesions 
Close 
Contact’s 
Personal 
Physician or 
Close 
Contact 
Within 24 
hours of 
Reporter 
awareness 
Contact 
Amgen at 1-
855-IMLYGIC 
(1-855-465-
9442) to 
report event 
Collect swabs 
from 
suspected 
lesions within 
3 days of 
appearance of 
symptoms 
Yes, if 
consent 
obtained 
Close 
Contact’s 
Personal 
Physician 
Close 
Contact’s 
Personal 
Physician 
and Amgen 
 


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62 
 
Accidental talimogene laherparepvec exposure and suspected infection in study patients 
receiving talimogene laherparepvec:   
If the patient receiving talimogene laherparepvec on study has developed signs or 
symptoms of herpetic infection, the event must be reported to Amgen AND CTEP-
AERS and patient should be followed up by the study team for viral assays:  
1) Report to CTEP-AERS as SAE.  
2) Notify Amgen immediately (within 24 hours) upon knowledge of suspected 
infection).  Contact the Amgen Call Center at 1-855-IMLYGIC (1-855-465-
9442). 
• 
Patient should be seen by the study physician.  The herpetic lesions should be 
tested for DNA specific to talimogene laherparepvec.  This testing must 
occur within three days of the appearance of the symptoms:  
• 
Swabs of cold sore, vesicles or any other lesions suspected to be herpetic in 
origin should be obtained. 
• 
Amgen will provide the qPCR test manual for sample collection and 
shipment to Viracor  
• 
qPCR or other testing for wild type HSV-1 is not required.  A commercially 
available test should be ordered if the investigator believes it is clinically 
indicated. 
 
Accidental Exposure of Health Care Provider (HCP) to talimogene laherparepvec without 
herpetic symptoms and signs:  
If the HCP is suspected to have been exposed to talimogene laherparepvec (direct 
exposure, e.g. needle sticks, splash) without signs or symptoms of herpetic infection, 
the event must be reported to Amgen.   
1) Report to Amgen by calling Amgen Call Center at 1-855-IMLYGIC (1-855-
465-9442).  
 
Accidental Exposure and Secondary Transmission of talimogene laherparepvec to Close 
Contacts or Health Care Provider (HCP) with symptoms/signs of herpetic 
infection:  
If a close contact or HCP is suspected to have been exposed to talimogene 
laherparepvec (with signs or symptoms of herpetic infection, the event must be 
reported to Amgen.  Amgen will provide instructions regarding follow up with 
physicians and talimogene laherparepvec testing. 
2) Report to Amgen immediately (within 24 hours) as symptoms or signs are 
observed.  Contact the Amgen Call Center at 1-855-IMLYGIC (1-855-465-
9442).  
• Amgen will provide close contacts/HPC with instructions to see physicians for 
management and evaluation of talimogene laherparepvec DNA.  This testing 
must occur within three days of the appearance of the symptoms: 
• The physicians of HCP or Close Contacts will be responsible for obtaining the 
swab of herpetic lesions and submitting it to talimogene laherparepvec testing, 


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63 
 
per instructions from Amgen.  
3) Also refer to instructions in the Information Sheet for Close Contacts. 
  
*NOTE:  Close contacts in regions where talimogene laherparepvec is commercially 
available should contact their HCP to evaluate the lesions.  In the US, suspected 
herpetic lesions should be reported to Amgen as instructed above.  Close contacts 
have the option of follow-up testing for further characterization of the infection.  This 
test is likely to be more reliable if it can be performed within the first three days of 
symptoms appearing. 
 
*NOTE:  Close contacts in regions where talimogene laherparepvec is not 
commercially available (e.g. Canada) may contact their HCP for evaluation and 
appropriate treatment.  They should come to the study site for sample collections for 
qPCR testing for suspected herpetic lesions.  This test is likely to be more reliable if it 
can be performed in the first three days of symptoms appearing.  
 
 
 
7.3.5. Reporting requirements to NIH Office of Scientific Policy (OSP) and local Institutional 
Biosafety Committee (IBC) 
 
Because talimogene laherparepvec (T-VEC) is a gene transfer agent, all protocols should follow 
the NIH Office of Scientific Policy (OSP) guidelines, including protocol submission, AE 
reporting and Annual Reports to OSP 
(http://osp.od.nih.gov/sites/default/files/resources/NIH_Guidelines_PRN_1-sided.pdf.  
Compliance with the OSP requirements is the responsibility of the Principle and 
Participating Investigators.  In addition, all participating sites should follow the guidelines of 
local IBCs.   
 
Investigators should review the OSP website (above) for complete instructions.  Key (not all) 
OSP requirements are outlined below: 
• Registration of the protocol with OSP (no less than 10 days before anticipated protocol 
activation) – to be done by Principle Investigator (see Section 7.3.5.1) 
• Reporting of the initiation of the protocol (within 30 days of the first patient enrollment 
on the protocol) – by Principle Investigator (Section 7.3.5.2) 
• Submission of IBC approval to OSP (within 30 days of first patient enrollment at the site) 
– by Participating Sites (Section 7.3.5.3) 
• Annual reports to OSP - By Principle investigator or delegate (Section 7.3.5.4) 
• IND safety reports to OSP - by Principle Investigator or delegate (Section 7.3.5.5) 
 
7.3.5.1. Registration of protocol with OSP: This should occur before protocol activation.  
(Appendix M-I-A and M-I-B of the OSP guidelines 
http://osp.od.nih.gov/sites/default/files/NIH_Guidelines.html#_Toc446948493) 
 


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64 
 
The Principle Investigator or coordinating site IBC should submit the following to OSP no less 
than 10 days before the anticipated protocol activation. 
• The proposed protocol and Inform Consent Form (these documents does not have to be 
the final, IRB-approved version) 
• Institutional Biosafety Committee (IBC)’s review or letter  
 
Submission to OSP should be done preferably by e-mail to: HGTprotocols@mail.nih.gov; 
additional contact information is also available on the OSP website 
http://www.osp.od.nih.gov/about/contact-us/ 
 
An NIH OSP acknowledgement that the protocol registration process is complete will occur 
within the 10 working days prior to the anticipated date of enrollment.  Final IBC approval may 
then be granted 
 
7.3.5.2. Reporting of Initiation of the Clinical Investigation (Appendix M-I-C-1 Packet of 
OSP guidelines http://osp.od.nih.gov/sites/default/files/NIH Guidelines.html# Toc446948493):  
 
The Principle Investigator of the protocol should submit the following documents to NIH OSP, 
no later than 30 working days after the first patient enrollment to the trial.   
1) A cover letter with the following information: applicable NIH grant number(s), the FDA 
IND number, any modifications to the protocol as required by FDA, the date of the 
initiation of the trial.  
2) A copy of the protocol approved by the local Institutional Biosafety Committee (IBC) and 
IRB;  
3) A copy of the informed consent document (ICD) approved by the Institutional Review 
Board (IRB);  
4) A copy of the final IBC approval from the clinical trial site, 
5) A copy of the final IRB approval;  
  
7.3.5.3. Requirement for all Participating Institutions (Appendix M-I-C-2 Packet of OSP 
guidelines http://osp.od.nih.gov/sites/default/files/NIH_Guidelines.html#_Toc446948493) 
 
• For patient enrollment, all participating sites should obtain approval from the local IBC 
before patients can be enrolled at the site.    Local IBC guidelines such as safety reporting 
requirements should also be followed.   
• The following should be submitted to OSP within 30 days of the first patient enrollment at 
the site: 
1) IBC approval from the participating site;  
2) IRB approval (if CIRB is used, submit CIRB approval);  
3) IRB-approved informed consent document (ICD); 


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65 
4)
NIH grant number(s) if applicable.
7.3.5.4. Annual Reports (Appendix M-I-C-3 Annual Report 
http://osp.od.nih.gov/sites/default/files/NIH_Guidelines.html#_Toc446948493) – by 
Principle Investigator or delegate 
Within 60 days after the one-year anniversary of the date on which the investigational new drug 
(IND) application went into effect, and after each subsequent anniversary until the trial is 
completed, the Principal Investigator (or delegate) shall submit the information set forth in (a), 
(b), and (c) (see Appendix M-I-C-3 in the link above), which shall include Clinical Trial 
Information, Progress Reports and Analysis, and Updated Protocol.  When multiple studies are 
conducted under the single IND, the Principal Investigator (or delegate) may choose to submit a 
single annual report covering all studies, provided that each study is identified by its OSP 
protocol number. 
7.3.5.5: Reporting of SAEs  
Principle investigators (or delegate) should submit SAEs that are serious, unexpected and related 
(i.e. IND Safety Reports) to OSP at the same timeline as for FDA reporting.  
In addition, SAEs or other AEs should be reported to local IBC per local IBC guidelines. 
Additional Protocol-Specific Expedited Adverse Event Reporting Exclusions 
For this protocol only, the AEs/grades listed below do not require expedited reporting via 
CTEP-AERS.  However, they still must be reported through the routine reporting 
mechanism (Section 7.4):
CTCAE 
SOC
Adverse 
Event
Grade
Hospitalization/ 
Prolongation of 
Hospitalization
Attribution
Comments
Diarrhea
≤ 3
< 7 days
Any
Vomiting
≤ 3
< 7 days
Any
Fatigue
≤ 3
< 7 days
Any
Radiation 
Dermatitis
≤ 3
< 7 days
Any
Routine Adverse Event Reporting
All Adverse Events must be reported in routine study data submissions.  AEs reported 
expeditiously through CTEP-AERS must also be reported in routine study data 
submissions.


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Adverse event data collection and reporting, which are required as part of every clinical trial, are 
done to ensure the safety of patients enrolled in the studies as well as those who will enroll in 
future studies using similar agents.  AEs are reported in a routine manner at scheduled times 
during the trial using Medidata Rave.  For this trial the Adverse Event CRF is used for routine 
AE reporting in Rave. 
Secondary Malignancy 
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., 
treatment with investigational agent/intervention, radiation or chemotherapy). A secondary 
malignancy is not considered a metastasis of the initial neoplasm.
CTEP requires all secondary malignancies that occur following treatment with an agent under an 
NCI IND/IDE be reported expeditiously via CTEP-AERS.  Three options are available to 
describe the event: 
•
Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia 
[AML]) 
•
Myelodysplastic syndrome (MDS) 
•
Treatment-related secondary malignancy  
Any malignancy possibly related to cancer treatment (including AML/MDS) should also be 
reported via the routine AE reporting mechanisms outlined in this protocol i.e. the adverse event 
CRF in Rave. Pathology report may be uploaded when available but is not required.  
Second Malignancy
A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT a 
metastasis from the initial malignancy).  Second malignancies in talimogene laherparepvec 
protocols should also be reported expeditiously via CTEP-AERS.
Surgical Complications
Surgical complications will be graded and reported using the Clavein Dindo classification as 
follows:
Grade I: Any deviation from the normal postoperative course without the need for 
pharmacological treatment or surgical, endoscopic and radiological interventions.  
Allowed therapeutic regimens are: drugs as antiemetic, antipyretics, analgesics, diuretics and 
electrolytes and physiotherapy. This grade also includes wound infections opened at the bedside. 
Grade II: Requiring pharmacological treatment with drugs other than such allowed for grade I 
complications. Blood transfusions and total parenteral nutrition are also included.  


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Grade III: Requiring surgical, endoscopic or radiological intervention  
Grade III-a: Intervention not under general anesthesia  
Grade III-b: Intervention under general anesthesia  
Grade IV: Life-threatening complication (including CNS complications: brain hemorrhage, 
ischemic stroke, subarachnoid bleeding, but excluding transient ischemic attacks) requiring 
IC/ICU management.
Grade IV-a: Single organ dysfunction (including dialysis)  
Grade IV-b: Multi-organ dysfunction
Grade V: Death of a patient
. 
8. PHARMACEUTICAL INFORMATION
A list of the adverse events and potential risks associated with the investigational or commercial 
agents administered in this study can be found in Section 7.1. 
CTEP IND Agent(s)
8.1.1
Talimogene laherparepvec(NSC 785349) 
Other Names: talimogene laherparepvec, AMG 678; OncoVEXGM-CSF, IMLYGIC™
Classification: Oncolytic immunotherapy
Product Description:  talimogene laherparepvec is an oncolytic immunotherapy based on a modified 
herpes simplex virus type-1 (HSV-1).  It selectively replicates and induces viral lysis of tumor cells 
resulting in an immune response specific to subjects’ tumor.     
8.1.2
How Supplied:  Amgen supplies talimogene laherparepvec and the Pharmaceutical 
Management Branch distributes.  There are two nominal vials concentrations: 
•
1x 106 PFU/mL packaged as 10 vials per box
•
1x 108 PFU/mL Packaged as 20 vials per box
Both vials strengths contain 1 mL extractable volume (with approximately0.1 mL overfills volume) 
of talimogene laherparepvec solution consisting of disodium hydrogen phosphate dehydrate, sodium 
dihydrogen phosphate dehydrate, sodium chloride, sorbitol, myo-inositol and Water for Injection. T-
vec is a sterile, semi-translucent to opaque suspension, practically free from particles, preservative 


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free frozen liquid packaged in a single-use 2 mL Crystal Zenith Resin vial. Each vial is sealed with a 
gray stopper (latex-free) and is Fluorotec-coated on the product side. 
 
Current supplies of talimogene laherparepvec are provided as a preservative-free solution in a single-
use vial without a clear copolyester plastic sleeve. 
 
In early 2019, talimogene laherparepvec vials will change in appearance only. Supplies will be 
transitioned to single-use vials permanently inserted into a clear copolyester plastic sleeve. The 
product label will be found on the vial sleeve. Talimogene laherparepvec vial is compatible with the 
Closed System Transfer Device (CSTD), PhaSeal CSTD. 
  
Preparation (1x 106 PFU/mL and 1x 108 PFU/mL):  
Thawing process: 
o Remove the number of frozen vials from the box that have been calculated for administration 
and immediately (within 90 seconds) return the remaining vials to the freezer. Care should 
be taken to avoid unintended thawing of vials that will not be used. The time the vials are 
removed from the freezer must be recorded. Thaw frozen vial(s) at room temperature, 15℃ 
to 30℃ (59℉ to 86℉) until liquid (approximately 30 minutes).  Do not expose vial(s) to 
higher temperatures. Protect vial(s) from light during the thaw process.   
o Do not shake vial(s) 
o Gently swirl vial(s) for completion of thaw 
o Carefully check the vial(s) for cracks 
o DO NOT re-freeze thawed vial(s) 
After thawing: 
o Gently swirl the vial(s) to ensure the contents are mixed to a homogeneous solution free of ice. 
o Carefully check the vial(s) for damage (e.g., cracks).  Dispose of damaged vial(s) according to 
the institutional policy and guidelines and notify PMB at pmbafterhours@mail.nih.gov. 
o Draw required dose volume according to the tumor size injection volume (see below) into a 
syringe that is properly labeled. 
o Protect from light until administration 




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70 
 
> 5 cm 
4mL 
> 2.5 cm to 5cm 
2 mL 
> 1.5 cm to 2.5 cm 
1 mL 
> 0.5 cm to 1.5 cm 
0.5 mL 
≤ 0.5 cm 
0.1 mL 
 
Please replace the storage and stability as follow: 
 
Storage:  Talimogene laherparepvec intact vials are stable between -900C and -700C, protect from 
light. [Note: Frost-free, auto defrosts freezers must not be used since they cycle to warmer 
temperatures several times a day.]  
 
Freezer Set Point  
Acceptable Range 
-800C 
-900 C to - 700 C 
 
Stability: Shelf-life surveillance of the intact vials is on-going. 
 
If a storage temperature excursion is identified, promptly return talimogene laherparepvec to 
between -900 C and - 700 C and quarantine the supplies.  Provide a detailed report of the 
excursion (including documentation of temperature monitoring and duration of the excursion) to 
PMBAfterHours@mail.nih.gov for determination of suitability.  
NOTE:  Upon receipt of the agent supplies, the site has 90 seconds to verify the contents and place 
the agent supplies in the -800C (+/- 100 C) freezer once the inner shipping container lid is opened and 
the supply exposed to room temperature (See Appendices F & G). 
 
Route of Administration: Intratumoral / intralesional injection 
 
Method of Administration: talimogene laherparepvec is to be administered by intralesional injection 
into cutaneous, subcutaneous and nodal lesions with or without image ultrasound guidance. 
Talimogene laherparepvec must not be administered into visceral organ metastases. 
 
Injection site may be pre-treated with a topical or a local anesthetic agent; however, a local anesthetic 
must not be injected directly into the lesion.   
 
Intralesional injection guidance: 
o A single point of injection is recommended; multiple insertion points may be used if the tumor 
is larger than the radial reach of the needle.  


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71 
 
o Inject talimogene laherparepvec along multiple different tracks within the lesion in order to 
obtain as wide a dispersion as possible 
o Distribute talimogene laherparepvec within the lesion through the insertion point using the 
radial reach of the needle in different directions to evenly distribute 
 
 
 
 
 
o Avoid premature extraction of needle 
o After dosing, the injection site should be swabbed with alcohol and pressure should be applied 
with gauze for several seconds after injection 
o Cover the injection site with an absorbent pad and dry occlusive dressing 
 
Special Handling:  Talimogene laherparepvec is an attenuated version of HSV-1.  Use protective 
equipment when preparing and administering this agent according to the institutional guidelines.  In 
the event of an accidental occupational exposure through a splash to the eyes or mucous membranes, 
flush with clean water for at least 15 minutes.  In the event of exposure to broken skin or needle stick, 
clean the site thoroughly with soap and water or a virucidal disinfectant such as 1% sodium 
hypochlorite or Virkon®.  
 
In the event of a secondary exposure (e.g., leakage through occlusive dressing to subject or contacts) 
to talimogene laherparepvec, clean the site thoroughly with soap and water or a virucidal disinfectant. 
Seek healthcare provider for signs of systemic (fever, aches, nausea, and malaise) or local (fever, pain, 
redness and swelling) infection. 
 
Patient Care Implications:  
o Advise patients on the potential for secondary exposure, e.g., broken skin.  Advise patients on 
careful wound care. 
o Necrotic or ulcerating lesions may occur and may be predisposed to local and/or systemic 
infections such as cellulitis, bacteremia, etc.  Advise patients on careful wound care. Infection 
precautions are recommended for tumor necrosis that results in open wounds.   
o There is a potential risk for exposure of talimogene laherparepvec from patients to anyone in 
direct contact with the patient.  Individual with open skin lesions and immunosuppressant 
should not come in contact with talimogene laherparepvec injection site or its protective 
dressing.  
o An Information Sheet about talimogene laherparepvec and the risk of transmission and 
accidental exposure should be provided to patient’s Health Care Providers and Close Contacts 
(see Appendix C) 
o  


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Availability 
 
Talimogene laherparepvec is an investigational agent supplied to investigators by the 
Division of Cancer Treatment and Diagnosis (DCTD), NCI. 
 
Talimogene laherparepvec is provided to the NCI under a Collaborative Agreement 
between the Pharmaceutical Collaborator and the DCTD, NCI (see Section 12.3). 
 
8.1.3 Agent Ordering and Agent Accountability 
 
8.1.3.1 
NCI-supplied agents may be requested by the responsible investigator (or their 
authorized designee) at each participating institution.  Pharmaceutical Management 
Branch (PMB) policy requires that agent be shipped directly to the institution where 
the patient is to be treated.  PMB does not permit the transfer of agents between 
institutions (unless prior approval from PMB is obtained).  The CTEP-assigned 
protocol number must be used for ordering all CTEP-supplied investigational agents.  
The responsible investigator at each participating institution must be registered with 
CTEP, DCTD through an annual submission of FDA Form 1572 (Statement of 
Investigator), Biosketch, Agent Shipment Form, and Financial Disclosure Form 
(FDF).  If there are several participating investigators at one institution, CTEP-
supplied investigational agents for the study should be ordered under the name of one 
lead investigator at that institution. 
 
 
Active CTEP-registered investigators and investigator-designated shipping designees 
and ordering designees can submit agent requests through the PMB Online Agent 
Order Processing (OAOP) application.  Access to OAOP requires the establishment 
of a CTEP Identity and Access Management (IAM) account and the maintenance of 
an “active” account status and a “current” password.  For questions about drug orders, 
transfers, returns, or accountability, call or email PMB any time.  Refer to the PMB’s 
website for specific policies and guidelines related to agent management.   
 
SPECIAL INSTRUCTIONS: 
 
Initial agent supplies may be requested only when subject enrollment onto the study 
is confirmed. 
There will be NO next day delivery of Talimogene laherparepvec requests available. 
Sites must plan agent ordering and study subject treatment accordingly.  
Agent order requests received on Monday, Tuesday, or Wednesday of the week, will 
be shipped on Tuesday, Wednesday and Thursday, respectively.  Agent order requests 
received on Thursday or Friday of the week will be shipped on Monday of the 
following week.  There will be no exceptions to this planned schedule. Sites should 
also consider planned Federal Government holidays when submitting agent requests 
and scheduling study subject treatment.    


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73 
Talimogene laherparepvec will be shipped on dry ice.  Only one strength of the agent 
will be in a single shipping container. You may receive multiple shipping containers 
for a single strength depending on the number vials being shipped. Upon receipt of 
the agent supplies, the site has 90 seconds to verify the contents and place the agent 
supplies in the -800C (+/- 100 C) freezer (see Appendix…) once the inner shipping 
container lid is opened and the supply exposed to room temperature.  Record 
exposure time in the temperature exposure tracking log (see Appendices F & G). The 
log must be retained with your study records. If exposure time exceeds 90 seconds, 
quarantine the agent supplies in the -800C (+/- 100 C) freezer and call PMB 
immediately at 240-276-6575 for guidance. 
8.1.3.2
Agent Inventory Records – The investigator, or a responsible party designated by the 
investigator, must maintain a careful record of the receipt, dispensing and final 
disposition of all agents received from the PMB using the appropriate NCI 
Investigational Agent (Drug) Accountability Record (DARF) available on the CTEP 
forms page.  Store and maintain separate NCI Investigational Agent Accountability 
Records for each agent, strength, formulation and ordering investigator on this 
protocol. 
8.1.3.3
Useful Links and Contacts 
•
CTEP Forms, Templates, Documents:  http://ctep.cancer.gov/forms/
•
NCI CTEP Investigator Registration:  RCRHelpDesk@nih.gov
•
PMB policies and guidelines: 
http://ctep.cancer.gov/branches/pmb/agent management.htm  
•
PMB Online Agent Order Processing (OAOP) application: 
https://ctepcore.nci.nih.gov/OAOP 
•
CTEP Identity and Access Management (IAM) account: 
https://ctepcore.nci.nih.gov/iam/
•
CTEP IAM account help: ctepreghelp@ctep.nci.nih.gov
•
IB Coordinator: IBCoordinator@mail.nih.gov
•
PMB email:  PMBAfterHours@mail.nih.gov
Commercial Agent(s)
8.2.1
5-fluorouracil (5-FU) & Leucovorin (LV) 
5-FU 
Product description:  5-FU is commercially available as a 50 mg/mL solution for injection in 
10 mL, 20 mL, 50 mL and 100 mL vials. Intact vials should be stored at room temperature and 
protected from light. Slight yellow discolor does not usually indicate decomposition. Stability in 
ambulatory pumps varies according to the pump, manufacturer of drug, concentration and 
diluent.  
Solution preparation: Inspect for precipitate; if found, agitate or gently heat in water bath. 


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Bolus injections are prepared using undiluted drug. 
46 hour infusion of 5-FU should be prepared for administration via ambulatory infusion pump 
according to the institution’s standards. These solutions may be prepared in D5W or 0.9% NaCl. 
5-FU should not be mixed in the same solution with most parenteral anti-emetics. 
 
Route of administration:  In this study, 5-FU is administered as an IV bolus on day 1 on 
FOLFOX followed by IV infusion over 46 hours starting immediately after the bolus. 
 
Agent Ordering:  5-FU is commercially available 
 
Please refer to package insert for complete product information 
 
Leucovorin (LV) 
Product description:  LV is commercially available as a 10 mg/mL in sterile, single use vials. 
Intact vials should be stored at 68 F – 77 F and protected from light.  
 
Solution preparation: Parenteral products should be inspected visually for particulate matter 
and discoloration prior to administration. Leucovorin for injection should be reconstituted with 
sterile water  
 
Route of administration:  In this study, LV is administered as an IV bolus on day 1. 5-
Fluorouracil and leucovorin should be administered separately to avoid the formation of a 
precipitate. 
 
Agent Ordering:  LV is commercially available 
 
Please refer to package insert for complete product information 
 
 
8.2.2 Oxaliplatin 
 
Product description:  Oxaliplatin is commercially available as an aqueous solution in vials 
containing 50 mg and 100 mg at a concentration of 5 mg/mL. The vials do not contain any 
preservative and they are intended for single use. Intact vials should be stored at room 
temperature. Solutions diluted in D5W are stable for 6 hours at room temperature or 24 hours 
under refrigeration. 
 
Solution preparation: The calculated dose of oxaliplatin should be diluted for infusion with 250 
mL to 500 mL D5W. Oxaliplatin should not be diluted with a sodium chloride solution. Needles, 
syringes, catheters or IV administration sets containing aluminum should not be used with 
oxaliplatin. As with other platinum compounds, contact with aluminum may result in a black 
precipitate. 
 
Route of administration:  Oxaliplatin will be administered by intravenous infusion over 2 hours 
on day 1 of FOLFOX in this study. Infusion time may be prolonged (up to 6 hours) in patients 






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on them. 
Other frozen specimens such as serum may be collected, processed and shipped to the 
ETCTN Biorepository on Monday through Thursday, since the Repository does not 
need to perform additional processing. 
Fresh blood specimens may be collected and shipped Monday through Friday.  Saturday 
delivery is only available for shipments of fresh blood. 
 
9.2.1 Biopsy Collection Procedure (Formalin Kits)-Cores #1 And #2 
Up to four core biopsies at least 1 cm in length will be obtained (if possible). Biopsies 
will be sent for analyses as defined in the protocol.  
Note: Two cores (#1-2) biopsies will be fixed in formalin and placed in 70% Ethanol.  
Additional cores (#3) and (#4) will be immediately snap- frozen in vapor phase of Liquid 
Nitrogen (LN2) (see instructions below). If more than four biopsies are obtained, then 
additional biopsies will be collected in formalin and sent to the biorepository in 70% 
Ethanol for embedding. Kits are supplied by the ETCTN Biorepository only for 
specimens shipped to the Biorepository by the ETCTN Biorepository at Nationwide 
Children’s Hospital. Kits should be ordered before specimen collection. 
 
Standard Operating Procedure for collection of formalin-fixed specimen using kits 
(Core 1 and 2):  
 
General Considerations:  
Cores #1 and #2: Pre-label formalin specimen jars with the Rave generated 
specimen ID (which includes the protocol number and universal patient ID) and 
Intrinsic ID (See Specimen Tracking instructions below). 
 
Specimen size requirement is as follows:  
Surface area of 25mm2 is optimal. Minimum is 5mm2 and  
Volume: 1mm3 optimal. Minimum volume is 0.2mm3. 
 
Biopsy Collection Methodology: 
 


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9.2.1.1 
Ensure that biopsies are only performed by qualified personnel. Follow institutional 
policies in collecting biopsies. 
9.2.1.2 
Ensure that specimen transportation to the pathology laboratory or designated 
processing laboratory is arranged to allow for quick tissue preservation.   
9.2.1.3 
Prior to specimen collection, ensure that all materials and equipment for collection 
and processing are ready for use, including prelabeling cassettes and formalin jars 
with the Rave generated specimen ID, Intrinsic ID, specimen type (e.g. P for primary, 
M for metastatic, and B for Baseline, I for Injected, AND U FOR Uninjected), and 
collection date.  
9.2.1.4 
 Immediately transfer the first 2 core biopsy specimens into a specimen jar, 
containing 10% neutral-buffered formalin 30 mL (e.g., Leica 3800770 or similar, 
formalin provided by site), using one jar per core sample. Small or soft biopsies may 
be contained in a biopsy bag or tissue cassette to prevent specimen damage.  
9.2.1.5 
Perform fixation at room temperature (20-25°C). Record the date and time tissue 
added to formalin, and enter in the Comment field into the Sample Tracking System 
(Rave) for all submitted specimens. The optimal duration of fixation should be 16-24 
hours by the time it is received at the ETCTN Biorepository. 
9.2.1.6 
After 24 hours of fixation in formalin, transfer the tissue cores to 70% Ethanol and 
ship the specimen to the ETCTN Biorepository (FedEx Priority Overnight required) 
for processing to allow for paraffin-embedding within 72 hours of time the tissue is 
held in Ethanol. 
9.2.1.7 
See section 9.5 for instructions for shipping to the ETCTN Biorepository at 
Nationwide Children’s Hospital 
 
 
9.2.2 Collection of Snap-Frozen Biopsy (Cores #3 And #4) 
 
Pre-label the cryovial with the Rave generated specimen ID (which includes the protocol 
number and universal patient ID) and Intrinsic ID.  (See Specimen Tracking instructions 
below). 
 
The sites should follow the SOP described below for collection of snap-frozen tissue 
and make sure that they have required materials, reagents and equipment to collect 
the specimens.   
 
1) Tissue should be frozen as soon as possible. Optimally, freeze within 30 
minutes from collection. 
 
2) Using clean forceps, place each of the second 2 core biopsy specimens into a 
pre-labeled cryovial. 
 
3) Flash freeze each specimen contained in its cryovial using a dry ice/alcohol 
slurry or liquid nitrogen, according to institutional SOP. Keep frozen until 
shipment to ETCTN Biorepository. 


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4) Ship frozen specimens to the ETCTN Biorepository at Nationwide Children’s 
Hopsital on the day of collection via FedEx Priority Overnight on dry ice in an 
insulated shipper or dual temperature-chambered kit. 
5) See section 4.0 for instructions for shipping to the ETCTN Biorepository at 
Nationwide Children’s Hospital. 
 
 
 
9.2.3 Whole Blood  
 
Whole blood collection in green-top tubes  
1) Label 10-20 ml green-top (NaHep) tubes, Becton Dickinson Cat No. 367874 
or equivalent, with Rave generated specimen ID (which includes the protocol 
number and Universal Patient ID), an Intrinsic ID, specimen type (blood), and 
collection date.  
2) Collect 10-20 ml of peripheral blood in 10ml green-top (NaHep) tubes. Collect 
20 mL at Baseline, and 10 mL at Week 8 and Week 21-25.  
3) After collection, gently invert tube(s) 5-10 times to ensure adequate mixing of 
sodium heparin. Maintain specimens at ambient temperature (room 
temperature) during collection and transport. 
4) All green top tubes (or 10 mL of blood) will be shipped to the ETCTN 
Biorepository.   
5) See section 9.5 for instructions for shipping to the ETCTN Biorepository at 
Nationwide Children’s Hospital. 
Collection in cfDNA Streck tubes:  
 
1) Label one 10 mL cfDNA Streck tube, with Rave generated specimen ID (which 
includes the protocol number and Universal Patient ID), an Intrinsic ID, 
specimen type (blood), and collection date.  
2) At all-time points, collect 10 ml of blood into the pre-labeled tube an invert to 
mix. Note: blood must be thoroughly mixed to ensure preservation of 
specimen. 
3) After collection, blood in cfDNA Streck tubes should never be refrigerated, 
as this will compromise the specimen.  Blood collected in cfDNA Streck tubes 
is stable at room temperature.  
Whole blood collection in K2 EDTA purple-top tubes 
1) Collect 2 mL of peripheral blood into a labeled K2 EDTA Purple-Top Tube; 
each tube must be filled completely to ensure the correct blood/anticoagulant 
ratio.  


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2) After collection, gently invert tube(s) 8-10 times to ensure adequate mixing of 
EDTA. Maintain specimens at ambient temperature (room temperature) during 
collection and transport. 
3) See section 4.0 for instructions for shipping to the ETCTN Biorepository at 
Nationwide Children’s Hospital. 
 
An external sample label should be fixed to the shipping container to alert the 
Biorepository of blood sample collection time and date (this helps to identify and 
prioritize received samples that have processing time requirements). 
 
Blood should be shipped ambient FedEx Priority Overnight to the biorepository where 
it is processed the day of receipt within 24 hours of collection (not to exceed 48 hours).  
 
9.3 
Sample Tracking System Instructions 
 
All biospecimens collected for this trial must be submitted using the ETCTN Rave 
Specimen Tracking System (STS) unless otherwise noted.  The system is accessed 
through special Rave user roles: “CRA Specimen Tracking” for data entry at the treating 
institutions and “Biorepository” for users receiving the specimens for processing and 
storage at reference labs and the Biorepository. Please refer to the Medidata Account 
Activation and Study Invitation Acceptance link on the CTSU website under the 
Rave/DQP tab. 
 
 
 
Important: Failure to complete required fields in STS may result in a delay in 
sample processing.  Any case reimbursements associated with sample submissions will 
not be credited if samples requiring STS submission are not logged into STS. 
 
Additionally, please note that the STS software creates pop-up windows when reports are 
generated, so you will need to enable pop-ups within your web browser while using the 
software.   
 
For questions regarding the Specimen Tracking System, please contact the Theradex 
Help Desk at CTMSSupport@theradex.com. 
 
A shipping manifest must be included with all sample submissions. 
 
Pre-Analytic Information 
Collection site must record all preanalytical information and enter the following into a specimen 
tracking system (STS) used by each trial network or record and provide with shipping manifest:  


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81 
 
1) Time/date blood or tissue sample collection was made as Time/Date Specimen 
Collected. 
2) Ischemia start time (time when sample was devascularized OR estimated time of 
surgery)—Tissue Collection Time/Date.  
3) Ischemic end time for each tissue core and surgical segment (time when sample was 
moved to preservative such as formalin or dry ice)—Tissue Processing (Formalin 
Start) Time/Date. 
4) Completion of formalin fixation should be recorded as Formalin End Time/Date in 
the STS (or under “comments” if field is not available).  
5) Start of 70% Ethanol dehydration should be recorded as Ethanol Start Time/Date in 
STS (or under “comments” if field is not available) 
6) Time when fixed tissue, held in Ethanol, was placed into an automated processor 
should be recorded as Ethanol End Time/Date in the STS (or under “comments” if 
field is not available).   
7) Core # for each core needle biopsy obtained.  Each core should be recorded in the 
STS as a separate specimen with a unique Specimen ID that captures the 
chronological order in which the biopsy cores were obtained.  
 
Biorepository will collect the following information for received specimens: 
1) Date of sample receipt. 
2) Time/date formalin-fixed tissue in Ethanol is moved into an automated processor—
recorded as Ethanol End Time.  
3) Record if frozen tissue sample arrived with insufficient amount of dry ice.  
4) Collected pre-analytic information will be entered into the shipping manifest (NCI 
specimen tracking system). 
 
 
 
9.3.1 Specimen Labeling  
 
9.3.2.1 
Blood Specimen Labels 
Include the following on blood specimens (including whole blood and frozen, processed blood 
products – like serum and plasma): 
• 
Patient study ID 
• 
Universal Patient ID (UPID) 
• 
Specimen ID (automatically generated by Rave) 
• 
Time point 
• 
Specimen type (e.g. blood, serum) 
• 
Collection date (to be added by hand) 
 
9.3.2.2 
Tissue Specimen Labels 
Include the following on all tissue specimens or containers (e.g. formalin jar).  
• 
Patient study ID 


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• 
Universal Patient ID (UPID) 
• 
Specimen ID (automatically generated by Rave) 
• 
Time point 
• 
Specimen type (e.g. FFPE Block, Formalin Fixed Tissue, Fresh Tissue in Media, 
etc.) 
• 
Tissue type (P for primary or M for metastatic, and B for baseline, I for Injected, 
AND U FOR Uninjected) 
• 
Surgical pathology ID (SPID) number   
• 
Block number from the corresponding pathology report (archival only) 
• 
Collection date (to be added by hand) 
 
9.3.2.3 Example of Specimen Label 
 
The following image is an example of a tissue specimen label printed on a standard Avery label 
that is 1” high and 2.625” wide. 
 
  
 
The QR code in the above example is for the Specimen ID shown on the second line.   
NOTE:  The QR code label is currently under development at Theradex as of 31-Aug-2018; 
therefore, labels generated by the STS for this study may not include a QR code. 
 
The second line item from the end includes four data points joined together: 
1. Tissue only: Primary (P), Metastatic (M), Normal (N) tissue indicated at the 
beginning of the specimen ID; this field is blank if not relevant (e.g., for blood) 
2. Block ID or blank if not relevant 
3. SPID (Surgical Pathology ID) or blank if none 
4. The last alpha-numeric code is protocol specific and is only included if the protocol 
requires an additional special code classification 
 
The last line on the example label is for the handwritten date and optional time. 
 
9.3.2 Overview of Process at Treating Site 
 
9.3.2.1 OPEN Registration 
 
All registrations will be performed using the Oncology Patient Enrollment Network (OPEN) 


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system. OPEN communicates automatically with the Interactive Web Response System (IWRS) 
which handles identifier assignments, any study randomization and any prescribed slot 
assignments. If specimen analysis is required to determine eligibility, the protocol will be setup 
with multi-step registration. 
 
Registration without eligibility specimen analysis:  
1. Site enters registration data into OPEN during one or more steps. 
2. IWRS receives data from OPEN, generates the Patient Study ID and the Universal 
Patient ID, both of which are sent back to OPEN. 
3. IWRS sends all applicable registration data directly to Rave at the end of the final 
registration step. 
 
Any data entry errors made during enrollment should be corrected in Rave. 
 
9.3.2.2 Rave Specimen Tracking Process Steps 
 
Step 1:  Complete the Histology and Disease form (but do not upload reports until a 
specimen label can be applied to them) and the Baseline forms regarding Prior 
Therapies. Enter the initial clinical specimen data:  
• Specimen Tracking Enrollment CRF:  Enter Time Point, Specimen Category, 
Specimen Type, Block number, Tissue type, Surgical Path ID, number of labels 
needed (include extra labels to apply to reports to be uploaded). CRF generates 
unique Specimen ID.  
 
Step 2:  Print labels using report in EDC and collect specimen. 
• Label specimen containers and write collection date on each label. 
• After collection, store labeled specimens as described in Section. 
• Apply an extra specimen label to each report before scanning. Return to the 
Histology and Disease form to upload any initial Pathology, Radiology, 
Molecular Reports (up to 4), Surgical reports and Pathology Verification form 
(when applicable). Return to Specimen Tracking Enrollment CRF to upload any 
molecular report (one per specimen) and/or specimen specific pathology or 
related report (one per specimen).   Uploaded reports should have PHI data like 
name, mailing address, medical record number or SSN redacted. Do not redact 
SPID, block number or relevant dates.  
 
Step 3:  Complete specimen data entry. 
• Specimen Transmittal Form: Enter Collection date and time and other required 
specimen details. 
 
Step 4:  When ready to ship, enter shipment information. 
• Shipping Status CRF:  Enter tracking number, your contact information, 
recipient, number of containers and ship date once for the 1st specimen in a 
shipment. 
• Copy Shipping CRF:  Select additional specimens to add to an existing shipment 


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referenced by the tracking number. 
 
Step 5:  Print shipping list report and prepare to ship.  
• Print two copies of the shipping list, one to provide in the box, the other for your 
own records. 
• Print pathology or other required reports to include in the box. Be sure the printed 
copy includes the specimen label. 
 
Step 6:  Send email notification.  
• For only one of the specimens in the shipment, click “Send Email Alert” 
checkbox on the Shipping Status CRF to email recipient. 
 
Step 7:  Ship the specimen(s). 
 
 
 
 
 
9.4 Shipping of Biospecimens from Clinical Sites to the ETCTN Biorepository 
 
 
 
Shipping of Specimen(s): 
Ambient temperature shipments: include core biopsies in formalin, blood in 
cfDNA Streck tube, and blood in green-top tubes (at Baseline only) in one 
shipment to the Biorepository on Monday through Wednesday, using the same box 
to ship that was used to receive the kit contents. Note: If blood is collected on 
Wednesday through Friday then it may be shipped separately from the tissue, on 
the day of collection. 
 
• Place specimens (separated by specimen type) in zip-lock bags. 
• Place zip-lock bags in a biohazard envelope containing absorbent materials.  
Next, place the biohazard envelope into a Tyvek envelope.  Expel as much air 
as possible before sealing each envelope. 
• Place the Tyvek envelope into the shipping container.  In warm months, place 
a cold (NOT frozen) gel pack into the container with the specimens. 
• Insert a copy of the shipping manifest and any other required paperwork, 
including operative and radiology, and/or pathology reports, into the container 
with the specimens. Place paperwork in a plastic zip-lock bag to prevent 
potential contamination in case of specimen leakage. 
• Place the cover on the shipping container. Tape the shipping container closed 
with durable tape.  
• Attach the FedEx air bill and attach to top of shipping container.  
• Attach an Exempt Human Specimen sticker to the side of the shipping 
container. 
• Make arrangements for courier pickup. 


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Frozen shipments: Serum (four aliquots) and snap-frozen core biopsies may be 
combined as one shipment on dry ice to the biorepository. Ensure that sufficient 
dry ice is included to completely encase the specimens to maintain specimen 
integrity during shipment.  Frozen specimens may be shipped on Monday through 
Thursday.  
Pre-fill the shipping container about 1/3 full with dry ice. 
Place specimens (separated by specimen type) in   zip-lock bags. 
Place zip-lock bags in a biohazard envelope containing absorbent materials.  
Next, place the biohazard envelope into a Tyvek envelope.  Expel as much air as 
possible before sealing each envelope. 
Place the Tyvek envelope into the shipping container and fill the container to the 
top with additional dry ice.   
Insert a copy of the shipping manifest and any other required paperwork, such as 
a pathology report, into the container with the specimens. Place paperwork in a 
plastic zip-lock bag in case of sample leakage. 
Place the cover on the container. Tape the shipping container closed with durable 
tape. 
Complete a FedEx air bill and attach to top of shipping container. 
Complete a dry ice label. 
Attach the dry ice label and an Exempt Human Specimen sticker to the side of 
the shipping container. 
Make arrangements for courier pickup. 
In cases of delays in shipment, store at -80 C.  
 
Biorepository Shipping Address 
 
Ship to the address below. Ship formalin-fixed and fresh blood specimens the 
same day of specimen collection, when possible. Do not ship specimens the day 
before a holiday. 
 
FedEx Priority Overnight is strongly recommended to prevent delay in package 
receipt. 
ETCTN Biorepository 
The Research Institute at Nationwide Children's Hospital 
700 Children's Drive., WA1340 
Columbus, Ohio 43205 
PH:  (614)-722-2865 
FAX:  (614)-722-2897 
Email:BPCBank@nationwidechildrens.org 
 
There is no central Courier account for this study. Sites are responsible for all costs for 
overnight shipments to the ETCTN Biorepository, utilizing the site screening and base 
intervention payments.  
 




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87 
 






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90 
 
resolution T2 weighted images to distinguish well from poor responders. However this approach 
is subject to significant inter-observer variability. When supplemented with DWI there is a 
significant improvement in accuracy and the prediction of complete response.  
 
In the current trial, we tumors will be characterized into good and poor responders to enable 
binary comparison. mrTRG is based on similar principles to the pathologic TRG and is based on 
the degree of tumor replaced by fibrotic stroma on post-treatment pelvic MRI. mrTRG-5 (no 
fibrosis, only tumor signal visible), mrTRG4 (predominantly tumor signal with minimal fibrotic 
single) will be defined as poor responders whereas mrTRG-1 (no tumor signal) to mrTRG-3 
(50%or greater fibrotic stroma) will be defined as good. For the purposes of CRM, a margin 
greater than or equal to 1 mm between the tumor and the resection margin will be defined as 
clear (good responder) and the rest as poor responders. Prognosis of good responders including 
DFS, OS and local recurrence will be compared to that of poor responders. Furthermore, mrTRG 
will be compared to ypTRG to validate its accuracy. Two radiologists with extensive experience 
with rectal MRIs (Drs. Randy Ernst & Harmeet Kaur) will read all the scans to minimize inter-
observer variability.   
 
 
9.11 
Exploratory genomic studies 
 
Genomic testing results including but not limited to RAS, RAF mutations and / or microsatellite 
instability will be utilized to correlate with radiographic & pathologic response to talimogene 
laherparepvec based therapy, survival including DFS and OS. Mutation testing will be performed 
utilizing institutional next generation sequencing platform. Microsatellite status will be 
determined by either analysis of mismatch repair protein expression by immunohistochemistry or 
by microsatellite testing by polymerase chain reaction.  
 


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91 
 
10. STUDY CALENDAR 
 
Baseline evaluations (including laboratory tests) need not be repeated at start of protocol therapy 
if done within 1 week.  Scans, x-rays must be done <4 weeks prior to the start of therapy.  In the 
event that the patient’s condition is deteriorating, laboratory evaluations should be repeated 
within 48 hours prior to initiation of the next cycle of therapy. On-study tests/visits that must 
occur within a defined time frame shall have a standing window of allowance that is equal to +/- 
2 days for any laboratory testing and +/- 4 days for any re-staging/disease assessment criteria.  
Surgery in eligible patients may occur within a window of + / - 2 weeks 
 
 
Pre- 
Study 
Week 0 
Wk 
1 
Wk 
2 
Wk 
3 
Wk 
4 
Wk 
5 
Wk 
6 
Wk 
7 
Wk 
8g 
Wk 
9/10
g 
Wk 
12/1
3 – 
19/2
0m 
Wk 
27 -
36 
Wk 
27 & 
beyo
ndf 
Off Studyc 
TALIMOGENE 
LAHERPAREPVEC
B 
 
X 
 
 
X 
 
X 
 
X 
 
 
 
 
 
 
FOLFOXA 
 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
 
 
RTk 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
Surgeryn  
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concurrent medsh 
X 
 
X-------------------------------------------------------------------------------------------X 
 
Physical exam 
X 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
 
 
X 
Vital signs 
X 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
 
 
X 
Height 
X 
 
 
 
X 
 
X 
 
X 
X 
X 
X 
 
 
 
Weight 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
 
 
X 
Performance status 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
X 
 
 
X 
CBC w/diff, plts 
X 
X 
X 
 
X 
 
X 
 
X 
X 
 
X 
 
 
X 
PT / INR / aPTTd 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum chemistrya 
X 
X 
X 
 
X 
 
X 
 
X 
X 
 
X 
 
 
X 
Tumor Markerse 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
EKG (as indicated) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse event 
evaluationh 
X 
 
X------------------------------------------------------------------------------------------X 
X 
Tumor 
measurements 
X 
 
In addition to baseline, tumor measurements will be obtained prior to surgery (wk 21-25).   
Documentation (radiologic) must be provided for patients removed from study for 
progressive disease. 
X 
Radiologic 
evaluation 
X 
 
In addition to baseline, radiographic evaluation will be obtained prior to surgery (wk 21-25).   
X 
B-HCG 
Xb 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CORRELATIVE STUDIES  
Archival Tissue 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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92 
 
Pelvic MRI 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Tumor Biopsiesi 
 
 
Xj 
 
 
 
 
 
X 
 
 
 
X 
 
 
Peripheral Bloodl 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
A:        FOLFOX: Dose as assigned; administration schedule 
 
B:       TALIMOGENE LAHERPAREPVEC:  Dose as assigned; administration schedule 
a: 
Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, LDH, phosphorus, potassium, 
total protein, SGOT [AST], SGPT [ALT], sodium. 
b: 
Serum pregnancy test (women of childbearing potential). 
c: 
Off-study evaluation.   
d.       At baseline and subsequently as required per treating physician’s discretion 
e.       Tumor markers include CEA and CA 19-9 at baseline, if above normal, repeat within 1 week of day 1 of radiation and with presurgical 
evaluation 
f.      Chemotherapy regimen / dosing / schedule, imaging and follow up post-surgery per treating physician’s discretion 
g.     Evaluation by any involved provider (medical oncology / surgical oncology and / or radiation oncology)  
h.     Adverse event evaluation until 4 weeks out of surgery 
i.      Optional 
j.      In patients without adequate archival tissue 
k. Radiation will be 25 Gy over 5 fractions. 
l. Refer to Section 9 for tube types and volumes. 
m. On day 1 of each cycle of FOLFOX 
n. In those deemed needing surgical resection per clinical evaluation; not mandatory per protocol 
 
 
 


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93 
11. MEASUREMENT OF EFFECT
Although the clinical benefit of these drugs has not yet been established, the intent of offering 
this treatment is to provide a possible additional therapeutic benefit to the known benefit of 
concurrent chemoradiation therapy to primary rectal cancer for palliation of symptoms and 
reduction in tumor burden.  Thus the patient will be carefully monitored for tumor response and 
symptom relief in addition to safety and tolerability.  Patients with measurable disease will be 
assessed by standard criteria.  For the purposes of this study, patients will be re-evaluated prior to 
surgery.  In patients with completely resected tumors, further evaluation for disease recurrence 
will follow standard NCCN/ASCO guidelines and can be modified based on clinical symptoms 
at the treating physician’s discretion. In surgically resected patients, disease-free survival and 
overall survival will be evaluated. In patients with metastatic disease at the time of treatment, 
overall survival will be evaluated in addition to response at distant sites (by diagnostic imaging) 
due to potential abscopal effect.  
Antitumor Effect – Solid Tumors
For the purposes of this study, patients should be evaluated per study calendar (section 10).  
Response and progression will be evaluated in this study using the new international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline 
(version 1.1) [Eur J Ca 45:228-247, 2009].  Changes in the largest diameter (unidimensional 
measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph 
nodes are used in the RECIST criteria.
Definitions
Evaluable for toxicity.  All patients will be evaluable for toxicity from the time of their 
first treatment with talimogene laherparepvec.  
Evaluable for objective response.  All patients who start treatment will be considered 
evaluable for response.  These patients will have their response classified according to the 
definitions stated below.  (Note:  Patients who exhibit objective disease progression prior 
to the end of cycle 1 will also be considered evaluable.) 
Evaluable Non-Target Disease Response.  Patients who have lesions present at baseline 
that are evaluable but do not meet the definitions of measurable disease, have received at 
least one cycle of therapy, and have had their disease re-evaluated will be considered 
evaluable for non-target disease.  The response assessment is based on the presence, 
absence, or unequivocal progression of the lesions.  
Disease Parameters
Measurable disease.  Measurable lesions are defined as those that can be accurately 


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94 
 
measured in at least one dimension (longest diameter to be recorded) as ≥20 mm (≥2 cm) 
by chest x-ray or as ≥10 mm (≥1 cm) with CT scan, MRI, or calipers by clinical exam.  
All tumor measurements must be recorded in millimeters (or decimal fractions of 
centimeters). 
 
Note:  Tumor lesions that are situated in a previously irradiated area might or might not 
be considered measurable.  If the investigator thinks it appropriate to include them, the 
conditions under which such lesions should be considered must be defined in the 
protocol. 
 
Malignant lymph nodes.  To be considered pathologically enlarged and measurable, a 
lymph node must be ≥15 mm (≥1.5 cm) in short axis when assessed by CT scan (CT scan 
slice thickness recommended to be no greater than 5 mm [0.5 cm]).  At baseline and in 
follow-up, only the short axis will be measured and followed. 
 
Non-measurable disease.  All other lesions (or sites of disease), including small lesions 
(longest diameter <10 mm [<1 cm] or pathological lymph nodes with ≥10 to <15 mm [≥1 
to <1.5 cm] short axis), are considered non-measurable disease.  Bone lesions, 
leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis 
cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not followed by 
CT or MRI), are considered as non-measurable. 
 
Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts 
should not be considered as malignant lesions (neither measurable nor non-measurable) 
since they are, by definition, simple cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non-
cystic lesions are present in the same patient, these are preferred for selection as target 
lesions. 
 
Target lesions.  All measurable lesions up to a maximum of 2 lesions per organ and 5 
lesions in total, representative of all involved organs, should be identified as target 
lesions and recorded and measured at baseline.  Target lesions should be selected on the 
basis of their size (lesions with the longest diameter), be representative of all involved 
organs, but in addition should be those that lend themselves to reproducible repeated 
measurements.  It may be the case that, on occasion, the largest lesion does not lend itself 
to reproducible measurement in which circumstance the next largest lesion which can be 
measured reproducibly should be selected.  A sum of the diameters (longest for non-
nodal lesions, short axis for nodal lesions) for all target lesions will be calculated and 
reported as the baseline sum diameters.  If lymph nodes are to be included in the sum, 
then only the short axis is added into the sum.  The baseline sum diameters will be used 
as reference to further characterize any objective tumor regression in the measurable 
dimension of the disease. 
 


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95 
 
Non-target lesions.  All other lesions (or sites of disease) including any measurable 
lesions over and above the 5 target lesions should be identified as non-target lesions and 
should also be recorded at baseline.  Measurements of these lesions are not required, but 
the presence, absence, or in rare cases unequivocal progression of each should be noted 
throughout follow-up.  
 
Methods for Evaluation of Measurable Disease 
 
All measurements should be taken and recorded in metric notation using a ruler or 
calipers.  All baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than 4 weeks before the beginning of the 
treatment. 
 
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up. Imaging-based 
evaluation is preferred to evaluation by clinical examination unless the lesion(s) being 
followed cannot be imaged but are assessable by clinical exam. 
 
Clinical lesions Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and ≥10 mm (≥1 cm) diameter 
as assessed using calipers (e.g., skin nodules).  In the case of skin lesions, documentation 
by color photography, including a ruler to estimate the size of the lesion, is 
recommended.  
 
Chest x-ray Lesions on chest x-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung.  However, CT is preferable.  
 
Conventional CT and MRI This guideline has defined measurability of lesions on CT 
scan based on the assumption that CT slice thickness is 5 mm (0.5 cm) or less.  If CT 
scans have slice thickness greater than 5 mm (0.5 cm), the minimum size for a 
measurable lesion should be twice the slice thickness.  MRI is also acceptable in certain 
situations (e.g. for body scans).   
 
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which 
greatly impact image quality, lesion conspicuity, and measurement.  Furthermore, the 
availability of MRI is variable globally.  As with CT, if an MRI is performed, the 
technical specifications of the scanning sequences used should be optimized for the 
evaluation of the type and site of disease.  Furthermore, as with CT, the modality used at 
follow-up should be the same as was used at baseline and the lesions should be 
measured/assessed on the same pulse sequence.  It is beyond the scope of the RECIST 
guidelines to prescribe specific MRI pulse sequence parameters for all scanners, body 
parts, and diseases.  Ideally, the same type of scanner should be used and the image 
acquisition protocol should be followed as closely as possible to prior scans.  Body scans 
should be performed with breath-hold scanning techniques, if possible. 


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96 
 
 
PET-CT  At present, the low dose or attenuation correction CT portion of a combined 
PET-CT is not always of optimal diagnostic CT quality for use with RECIST 
measurements.  However, if the site can document that the CT performed as part of a 
PET-CT is of identical diagnostic quality to a diagnostic CT (with IV and oral contrast), 
then the CT portion of the PET-CT can be used for RECIST measurements and can be 
used interchangeably with conventional CT in accurately measuring cancer lesions over 
time.  Note, however, that the PET portion of the CT introduces additional data which 
may bias an investigator if it is not routinely or serially performed.   
 
Ultrasound  Ultrasound is not useful in assessment of lesion size and should not be used 
as a method of measurement.  Ultrasound examinations cannot be reproduced in their 
entirety for independent review at a later date and, because they are operator dependent, it 
cannot be guaranteed that the same technique and measurements will be taken from one 
assessment to the next.  If new lesions are identified by ultrasound in the course of the 
study, confirmation by CT or MRI is advised.  If there is concern about radiation 
exposure at CT, MRI may be used instead of CT in selected instances. 
 
Endoscopy, Laparoscopy  The utilization of these techniques for objective tumor 
evaluation is not advised.  However, such techniques may be useful to confirm complete 
pathological response when biopsies are obtained or to determine relapse in trials where 
recurrence following complete response (CR) or surgical resection is an endpoint. 
 
Tumor markers  Tumor markers alone cannot be used to assess response.  If markers are 
initially above the upper normal limit, they must normalize for a patient to be considered 
in complete clinical response.  Specific guidelines for both CA-125 response (in recurrent 
ovarian cancer) and PSA response (in recurrent prostate cancer) have been published 
[JNCI 96:487-488, 2004; J Clin Oncol 17, 3461-3467, 1999; J Clin Oncol 26:1148-1159, 
2008].  In addition, the Gynecologic Cancer Intergroup has developed CA-125 
progression criteria which are to be integrated with objective tumor assessment for use in 
first-line trials in ovarian cancer [JNCI 92:1534-1535, 2000]. 
 
Cytology, Histology  These techniques can be used to differentiate between partial 
responses (PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor 
types, such as germ cell tumors, where known residual benign tumors can remain). 
 
The cytological confirmation of the neoplastic origin of any effusion that appears or 
worsens during treatment when the measurable tumor has met criteria for response or 
stable disease is mandatory to differentiate between response or stable disease (an 
effusion may be a side effect of the treatment) and progressive disease. 
 
FDG-PET  While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in 
assessment of progression (particularly possible 'new' disease).  New lesions on the basis 
of FDG-PET imaging can be identified according to the following algorithm:  


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97 
 
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of 
PD based on a new lesion. 
b. No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the positive FDG-
PET at follow-up corresponds to a new site of disease confirmed by CT, this is PD.  If 
the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT  scans are needed to determine if there is truly progression 
occurring at that site (if so, the date of PD will be the date of the initial abnormal 
FDG-PET scan).  If the positive FDG-PET at follow-up corresponds to a pre-existing 
site of disease on CT that is not progressing on the basis of the anatomic images, this 
is not PD. 
c. FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy 
in cases where a residual radiographic abnormality is thought to represent fibrosis or 
scarring.  The use of FDG-PET in this circumstance should be prospectively 
described in the protocol and supported by disease-specific medical literature for the 
indication.  However, it must be acknowledged that both approaches may lead to false 
positive CR due to limitations of FDG-PET and biopsy resolution/sensitivity. 
 
Note:  A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake 
greater than twice that of the surrounding tissue on the attenuation corrected image. 
 
Response Criteria 
 
Evaluation of Target Lesions 
 
Complete Response (CR):  Disappearance of all target lesions.  Any pathological 
lymph nodes (whether target or non-target) must have reduction in short axis to <10 
mm (<1 cm). 
 
Partial Response (PR):  At least a 30% decrease in the sum of the diameters of target 
lesions, taking as reference the baseline sum diameters. 
 
Progressive Disease (PD):  At least a 20% increase in the sum of the diameters of 
target lesions, taking as reference the smallest sum on study (this includes the 
baseline sum if that is the smallest on study).  In addition to the relative increase of 
20%, the sum must also demonstrate an absolute increase of at least 5 mm (0.5 cm).  
(Note:  the appearance of one or more new lesions is also considered progressions). 
 
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum diameters while on 
study. 
 
Evaluation of Non-Target Lesions 
 
Complete Response (CR):  Disappearance of all non-target lesions and normalization 
of tumor marker level.  All lymph nodes must be non-pathological in size (<10 mm 


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98 
 
[<1 cm] short axis). 
 
Note:  If tumor markers are initially above the upper normal limit, they must 
normalize for a patient to be considered in complete clinical response. 
 
Non-CR/Non-PD:  Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal limits. 
 
Progressive Disease (PD):  Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions.  Unequivocal progression 
should not normally trump target lesion status.  It must be representative of overall 
disease status change, not a single lesion increase. 
 
Although a clear progression of “non-target” lesions only is exceptional, the opinion 
of the treating physician should prevail in such circumstances, and the progression 
status should be confirmed at a later time by the review panel (or Principal 
Investigator). 
 
Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the treatment 
until disease progression/recurrence (taking as reference for progressive disease the 
smallest measurements recorded since the treatment started).  The patient's best 
response assignment will depend on the achievement of both measurement and 
confirmation criteria. 
 
For Patients with Measurable Disease (i.e., Target Disease) 
 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation is Required* 
CR 
CR 
No 
CR 
≥Not Required** 
CR 
Non-CR/Non-
PD 
No 
PR 
≥Not Required** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-
PD/not 
evaluated 
No 
PR 
SD 
Non-CR/Non-
PD/not 
evaluated 
No 
SD 
Not Required** 
PD 
Any 
Yes or No 
PD 
no prior SD, PR or CR 
Any 
PD*** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
∗ 
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
**    Not Required as some patients may go to surgery and / or pursue other systemic therapies. 


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99 
 
***  In exceptional circumstances, unequivocal progression in non-target lesions may be 
accepted as disease progression. 
 
Note:  Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
reported as “symptomatic deterioration.”  Every effort should be made to document the 
objective progression even after discontinuation of treatment. 
 
For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
∗ 
‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly used as an endpoint for assessment of efficacy in some trials so to assign this 
category when no lesions can be measured is not advised 
 
Duration of Response 
 
Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first 
date that recurrent or progressive disease is objectively documented (taking as reference 
for progressive disease the smallest measurements recorded since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are first met 
for CR until the first date that progressive disease is objectively documented. 
 
 
Duration of stable disease:  Stable disease is measured from the start of the treatment 
until the criteria for progression are met, taking as reference the smallest measurements 
recorded since the treatment started, including the baseline measurements.  
 
Progression-Free Survival 
 
Include this section if time to progression or progression-free survival (PFS) is to be 
used.  PFS is defined as the duration of time from start of treatment to time of 
progression or death, whichever occurs first. 
 
Response Review 
 
For trials where the response rate is the primary endpoint, it is strongly recommended 
that all responses be reviewed by an expert(s) independent of the study at the study’s 
completion.  Simultaneous review of the patients’ files and radiological images is the best 


NCI Protocol #: 10058 
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100 
approach.  
Antitumor Effect – Hematologic Tumors
Please provide appropriate criteria for evaluation of response and methods of measurement. 
Other Response Parameters
Other endpoints and the criteria for their measurement should be entered below or reference 
should be made to the protocol section where these criteria may be found. 
12. STUDY OVERSIGHT AND DATA REPORTING / REGULATORY 
REQUIREMENTS
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.0 
(Adverse Events: List and Reporting Requirements).
Study Oversight
This protocol is monitored at several levels, as described in this section.  The Protocol Principal 
Investigator is responsible for monitoring the conduct and progress of the clinical trial, including 
the ongoing review of accrual, patient-specific clinical and laboratory data, and routine and 
serious adverse events; reporting of expedited adverse events; and accumulation of reported 
adverse events from other trials testing the same drug(s).  The Protocol Principal Investigator and 
statistician have access to the data at all times through the CTMS web-based reporting portal.   
For the Phase 1 portion of this study, all decisions regarding dose escalation/expansion/de-
escalation require sign-off by the Protocol Principal Investigator through the CTMS/IWRS.  In 
addition, for the Phase 1 portion, the Protocol Principal Investigator will have at least monthly, 
or more frequently, conference calls with the Study Investigators and the CTEP Medical 
Officer(s) to review accrual, progress, and adverse events and unanticipated problems.   
All Study Investigators at participating sites who register/enroll patients on a given protocol are 
responsible for timely submission of data via Medidata Rave and timely reporting of adverse 
events for that particular study.  This includes timely review of data collected on the electronic 
CRFs submitted via Medidata Rave.
All studies are also reviewed in accordance with the enrolling institution’s data safety monitoring 
plan. 
Data Reporting 


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101 
 
 
Data collection for this study will be done exclusively through Medidata Rave.  Access to the 
trial in Rave is granted through the iMedidata application to all persons with the appropriate 
roles assigned in the Regulatory Support System (RSS).  To access Rave via iMedidata, the site 
user must have an active CTEP IAM account (https://eapps-ctep.nci.nih.gov/iam) and the 
appropriate Rave role (Rave CRA, Rave Read-Only, Rave CRA(Lab Admin), Rave SLA or Rave 
Investigator) on either the LPO or participating organization roster at the enrolling site. To the 
hold Rave CRA role or Rave CRA (Lab Admin), the user must hold a minimum of an AP 
registration type.  To hold the Rave Investigator role, the individual must be registered as an 
NPIVR or IVR.  Associates can hold read-only roles in Rave.  
 
Upon initial site registration approval for the study in RSS, all persons with Rave roles assigned 
on the appropriate roster will be sent a study invitation e-mail from iMedidata.  To accept the 
invitation, site users must log into the Select Login (https://login.imedidata.com/selectlogin) 
using their CTEP-IAM user name and password, and click on the “accept” link in the upper 
right-corner of the iMedidata page.  Please note, site users will not be able to access the study in 
Rave until all required Medidata and study specific trainings are completed.  Trainings will be in 
the form of electronic learnings (eLearnings), and can be accessed by clicking on the link in the 
upper right pane of the iMedidata screen.   
 
Users that have not previously activated their iMedidata/Rave account at the time of initial site 
registration approval for the study in RSS will also receive a separate invitation from iMedidata 
to activate their account. Account activation instructions are located on the CTSU website, Rave 
tab under the Rave resource materials (Medidata Account Activation and Study Invitation 
Acceptance).  Additional information on iMedidata/Rave is available on the CTSU members’ 
website under the Rave tab or by contacting the CTSU Help Desk at 1-888-823-5923 or by e-
mail at ctsucontact@westat.com. 
 
12.2.1 Method 
 
CTMS Comprehensive Monitoring: 
This study will be monitored by the Clinical Trials Monitoring Service (CTMS).  Data 
will be submitted to CTMS at least once every two weeks via Medidata Rave (or other 
modality if approved by CTEP).  Information on CTMS reporting is available at 
http://www.theradex.com/clinicalTechnologies/?National-Cancer-Institute-NCI-11.  On-
site audits will be conducted three times annually (one annual site visit and two data 
audits).  For CTMS monitored studies, after users have activated their accounts, please 
contact the Theradex Help Desk at (609) 799-7580 or by email at 
CTMSSupport@theradex.com for additional support with Rave and completion of CRFs. 
 
12.2.2 Responsibility for Data Submission 
 
 
For ETCTN trials, it is the responsibility of the PI(s) at the site to ensure that all 
investigators at the ETCTN Sites understand the procedures for data submission for each 


NCI Protocol #: 10058 
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102 
 
ETCTN protocol and that protocol specified data are submitted accurately and in a timely 
manner to the CTMS via the electronic data capture system, Medidata Rave.   
 
Data are to be submitted via Medidata Rave to CTMS on a real-time basis, but no less 
than once every 2 weeks.  The timeliness of data submissions and timeliness in resolving 
data queries will be tracked by CTMS.  Metrics for timeliness will be followed and 
assessed on a quarterly basis.  For the purpose of Institutional Performance Monitoring, 
data will be considered delinquent if it is greater than 4 weeks past due. 
 
Data from Medidata Rave and CTEP-AERS is reviewed by the CTMS on an ongoing 
basis as data is received.  Queries will be issued by CTMS directly within Rave.  The 
queries will appear on the Task Summary Tab within Rave for the CRA at the ETCTN to 
resolve.  Monthly web-based reports are posted for review by the Drug Monitors in the 
IDB, CTEP.  Onsite audits will be conducted by the CTMS to ensure compliance with 
regulatory requirements, GCP, and NCI policies and procedures with the overarching 
goal of ensuring the integrity of data generated from NCI-sponsored clinical trials, as 
described in the ETCTN Program Guidelines, which may be found on the CTEP 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm
)  and CTSU websites. 
 
An End of Study CRF is to be completed by the PI, and is to include a summary of study 
endpoints not otherwise captured in the database, such as (phase 1 trials) the 
recommended phase 2 dose (RP2D), and a description of any dose-limiting toxicities 
(DLTs).  CTMS will utilize a core set of eCRFs that are Cancer Data Standards Registry 
and Repository (caDSR) compliant (http://cbiit.nci.nih.gov/ncip/biomedical-informatics-
resources/interoperability-and-semantics/metadata-and-models).  Customized eCRFs will 
be included when appropriate to meet unique study requirements.  The PI is encouraged 
to review the eCRFs, working closely with CTMS to ensure prospectively that all 
required items are appropriately captured in the eCRFs prior to study activation.  CTMS 
will prepare the eCRFs with built-in edit checks to the extent possible to promote data 
integrity. 
 
CDUS data submissions for ETCTN trials activated after March 1, 2014, will be carried 
out by the CTMS contractor, Theradex.  CDUS submissions are performed by Theradex 
on a monthly basis.  The trial’s lead institution is responsible for timely submission to 
CTMS via Rave, as above. 
 
Further information on data submission procedures can be found in the ETCTN Program 
Guidelines 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm
). 
 
 


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103 
CTEP Multicenter Guidelines
N/A
Collaborative Agreements Language 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the NCI 
under a Collaborative Agreement (CRADA, CTA, CSA) between the Pharmaceutical 
Company(ies) (hereinafter referred to as “Collaborator(s)”) and the NCI Division of Cancer 
Treatment and Diagnosis.  Therefore, the following obligations/guidelines, in addition to the 
provisions in the “Intellectual Property Option to Collaborator” 
(http://ctep.cancer.gov/industryCollaborations2/intellectual property.htm) contained within the 
terms of award, apply to the use of the Agent(s) in this study: 
1. Agent(s) may not be used for any purpose outside the scope of this protocol, nor can 
Agent(s) be transferred or licensed to any party not participating in the clinical study.  
Collaborator(s) data for Agent(s) are confidential and proprietary to Collaborator(s) and shall 
be maintained as such by the investigators. The protocol documents for studies utilizing 
Agents contain confidential information and should not be shared or distributed without the 
permission of the NCI.  If a copy of this protocol is requested by a patient or patient’s family 
member participating on the study, the individual should sign a confidentiality agreement.  A 
suitable model agreement can be downloaded from: http://ctep.cancer.gov. 
2. For a clinical protocol where there is an investigational Agent used in combination with 
(an)other Agent(s), each the subject of different Collaborative Agreements, the access to and 
use of data by each Collaborator shall be as follows (data pertaining to such combination use 
shall hereinafter be referred to as "Multi-Party Data”):
a.
NCI will provide all Collaborators with prior written notice regarding the existence and 
nature of any agreements governing their collaboration with NCI, the design of the 
proposed combination protocol, and the existence of any obligations that would tend to 
restrict NCI's participation in the proposed combination protocol.
b. Each Collaborator shall agree to permit use of the Multi-Party Data from the clinical trial 
by any other Collaborator solely to the extent necessary to allow said other Collaborator 
to develop, obtain regulatory approval or commercialize its own Agent. 
c. Any Collaborator having the right to use the Multi-Party Data from these trials must 
agree in writing prior to the commencement of the trials that it will use the Multi-Party 
Data solely for development, regulatory approval, and commercialization of its own 
Agent. 
3. Clinical Trial Data and Results and Raw Data developed under a Collaborative Agreement
will be made available to Collaborator(s), the NCI, and the FDA, as appropriate and unless 
additional disclosure is required by law or court order as described in the IP Option to 


NCI Protocol #: 10058 
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104 
Collaborator (http://ctep.cancer.gov/industryCollaborations2/intellectual property.htm).  
Additionally, all Clinical Data and Results and Raw Data will be collected, used and 
disclosed consistent with all applicable federal statutes and regulations for the protection of 
human subjects, including, if applicable, the Standards for Privacy of Individually 
Identifiable Health Information set forth in 45 C.F.R. Part 164. 
4. When a Collaborator wishes to initiate a data request, the request should first be sent to the 
NCI, who will then notify the appropriate investigators (Group Chair for Cooperative Group 
studies, or PI for other studies) of Collaborator's wish to contact them.
5. Any data provided to Collaborator(s) for Phase 3 studies must be in accordance with the 
guidelines and policies of the responsible Data Monitoring Committee (DMC), if there is a 
DMC for this clinical trial.
6. Any manuscripts reporting the results of this clinical trial must be provided to CTEP by the 
Group office for Cooperative Group studies or by the principal investigator for non-
Cooperative Group studies for immediate delivery to Collaborator(s) for advisory review and 
comment prior to submission for publication.  Collaborator(s) will have 30 days from the 
date of receipt for review.  Collaborator shall have the right to request that publication be 
delayed for up to an additional 30 days in order to ensure that Collaborator’s confidential and 
proprietary data, in addition to Collaborator(s)’s intellectual property rights, are protected.  
Copies of abstracts must be provided to CTEP for forwarding to Collaborator(s) for courtesy 
review as soon as possible and preferably at least three (3) days prior to submission, but in 
any case, prior to presentation at the meeting or publication in the proceedings.  Press 
releases and other media presentations must also be forwarded to CTEP prior to release.  
Copies of any manuscript, abstract and/or press release/ media presentation should be sent to:
Email:  ncicteppubs@mail.nih.gov
The Regulatory Affairs Branch will then distribute them to Collaborator(s).  No publication, 
manuscript or other form of public disclosure shall contain any of Collaborator’s confidential/ 
proprietary information.
Genomic Data Sharing Plan 
If genomic data will be studied, analyzed, collected, and stored in an NIH/NCI Genomic Data 
Biorepository (e.g., dbGaP, Cancer Genomic Database, other), please describe the genomic 
data sharing plan for this trial.  Please refer to the NCI Genomic Data Sharing Policy at 
http://www.cancer.gov/grants-training/grants-management/nci-policies/genomic-data for 
considerations regarding the sharing of data, protection of patient confidential information, and 
the provision of adequate information in the patient informed consent. 
13. STATISTICAL CONSIDERATIONS


NCI Protocol #: 10058 
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105 
Study Design/Endpoints
Primary Endpoint: 
To determine the dose limiting toxicities and maximum tolerated dose of TALIMOGENE 
LAHERPAREPVEC in combination with chemotherapy and radiation in rectal cancer
Study Design:  
Chemoradiation will be at current standard of care doses i.e. 50.4 Gy over 28 fractions in 
combination with capecitabine 825 mg/m2 po bid, days of radiation only (M-F). TALIMOGENE 
LAHERPAREPVEC will be escalated in 2 dose levels (PFU /ml) as indicated below using a 
standard 3 + 3 design.  
•
Talimogene laherparepvec will be administered via endoscopy by a qualified physician for 
a total of 4 doses at the following time points: a) week 1 prior to initiation of FOLFOX 
chemotherapy b) weeks 2-4 during FOLFOX chemotherapy c) week 6 d) week 8-9 during 
chemoradiation 
•
The first cohort of 3 patients will be treated at dose level 1.  
•
The next cohort of patients will not be treated until toxicity has been evaluated in the 
current cohort of patients.  
•
The algorithm is as follows: (1) If 0 out of 3 patients experiences dose-limiting toxicity 
(DLT), the next cohort of 3 patients will be treated at the next higher dose level.  (2) If 1 
out of 3 patients develops DLT, additional 3 patients will be treated at the same dose 
level.  If no more DLT develops at the dose, i.e. 1 out of a total of 6 patients develops 
DLT, the dose escalation continues to next higher level for a cohort of 3 patients.  (3) At 
any given dose, if more than 1 out of 3 patients or 6 patients experience DLT, the dose 
level exceeds the MTD and 3 patients will be treated at the next lower dose level if there 
are less than 6 patients already treated at that dose.  If this is the lowest dose level tested, 
the trial will be terminated and MTD is not found.  Following the above algorithm, MTD 
is defined as the highest dose level in which 6 patients have been treated with at most 1 
instance of DLT
Dose level
TALIMOGENE 
LAHERPAREPVEC
Dose (PFU/ml)
Capecitabine (mg/m2
po bid on days of 
radiation)
Radiation 
           1
106, 107, 107,107
825
50.4 gray in 28 fractions
           2
106, 108, 108,108
825
50.4 gray in 28 fractions
Based on the 3+3 design, the MTD is defined as the highest dose level in which 6 patients have 
been treated with at most 1 instance of DLT. Thus the target DLT rate is <=16.7%. The study 
only includes two dose levels, and the following table shows the operating characteristics of the 
3+3 design under four different scenarios.  For each scenario, the % time selecting a dose as the 
MTD, the average sample size treated at each dose level, and the probability of stopping the trial 
early are presented. 


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106 
 
Scenario 
Doses 
1 
2 
#1 
Trued DLT 
0.10 
0.17 
 
% MTD 
21% 
70% 
 
Average # patients 
3.7 
3.7 
 
Prob(early 
stopping) 
0.1 
 
 
 
 
#2 
Trued DLT 
0.10 
0.25 
 
% MTD 
36% 
57% 
 
Average # patients 
3.8 
3.9 
 
Prob(early 
stopping) 
0.08 
 
 
 
 
#3 
Trued DLT 
0.40 
0.50 
 
% MTD 
26% 
5% 
 
Average # patients 
4.3 
1.3 
 
Prob(early 
stopping) 
0.69 
 
 
 
 
#4 
Trued DLT 
0.05 
0.10 
 
% MTD 
9% 
88% 
 
Average # patients 
3.4 
3.6 
 
Prob(early 
stopping) 
0.02 
 
Given the novelty and complexity of this study, a review of the data with the sponsor will occur 
before initiation of new dose levels. A total of 15 patients will be treated at the MTD (including 
the 6 from dose escalation phase and an addition 9 patients in expansion cohort) to assess safety 
of this dose level. Up to 15 patients (including the 6 patients treated at the MTD during dose 
escalation) will be enrolled into the expansion cohort to further confirm the safety of the MTD 
(as described in the study primary objective) and to assess efficacy and biomarker change (as 
described in the study secondary & exploratory objectives). With a total sample size of 15 and 
assuming the true DLT rate is 0.167, then the probability of observing at least one DLT event is 
93.5%.  If the true DLT rate is 0.30, then the probability of observing at least one DLT event is 
99.5%. The MTD will be deemed to be recommended phase II dose (RP2D) if ≥ 80% of the 
patients are able to receive ≥ 80% of the planned treatment doses. If ≥ 1/3 of all patients at this 
dose experience DLTs, enrollment will be stopped and the Principal Investigator will discuss 
with all study investigators and with CTEP whether further addition of patients is needed to re-
assess the RP2D.  Monitoring of all safety and toxicity data is done by the Principal Investigator 
and the Corresponding Organization on a real-time basis as data are entered into Medidata Rave 
using the Web Reporting Module.  
 
 




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108 
 
be characterized into good and poor responders to enable binary comparison. mrTRG is based on 
similar principles to the pathologic TRG and is based on the degree of tumor replaced by fibrotic 
stroma on post-treatment pelvic MRI. mrTRG-5 (no fibrosis, only tumor signal visible), 
mrTRG4 (predominantly tumor signal with minimal fibrotic single) will be defined as poor 
responders whereas mrTRG-1 (no tumor signal) to mrTRG-3 (50%or greater fibrotic stroma) 
will be defined as good. For the purposes of CRM, a margin greater than or equal to 1 mm 
between the tumor and the resection margin will be defined as clear (good responder) and the 
rest as poor responders. Prognosis of good responders including DFS, OS and local recurrence 
will be compared to that of poor responders. Furthermore, mrTRG will be compared to 
histological TRG (ypTRG)to validate its accuracy. Two radiologists with extensive experience 
with rectal MRIs (Drs. Randy Ernst & Harmeet Kaur) will read all the scans to minimize inter-
observer variability. 
 
 
 


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109 
 
REFERENCES 
 
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Park, I.J., et al., Neoadjuvant treatment response as an early response indicator for 
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Hoff, P.M., et al., Comparison of oral capecitabine versus intravenous fluorouracil plus 
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Twelves, C., et al., Capecitabine as adjuvant treatment for stage III colon cancer. N Engl 
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Das, P., et al., Preoperative chemoradiotherapy with capecitabine versus protracted 
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Biol Phys, 2006. 66(5): p. 1378-83. 
10. 
Fernandez-Martos, C., et al., The role of capecitabine in locally advanced rectal cancer 
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11. 
Cassidy, J., et al., First-line oral capecitabine therapy in metastatic colorectal cancer: a 
favorable safety profile compared with intravenous 5-fluorouracil/leucovorin. Ann 
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12. 
Andre, T., et al., Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for 
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13. 
Andre, T., et al., Improved overall survival with oxaliplatin, fluorouracil, and leucovorin 
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Hochster, H.S., et al., Safety and efficacy of oxaliplatin and fluoropyrimidine regimens 
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Schmoll, H.J., et al., Effect of adjuvant capecitabine or fluorouracil, with or without 
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Tournigand, C., et al., FOLFIRI followed by FOLFOX6 or the reverse sequence in 
advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol, 2004. 22(2): p. 
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17. 
Hong, Y.S., et al., Oxaliplatin, fluorouracil, and leucovorin versus fluorouracil and 


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leucovorin as adjuvant chemotherapy for locally advanced rectal cancer after 
preoperative chemoradiotherapy (ADORE): an open-label, multicentre, phase 2, 
randomised controlled trial. Lancet Oncol, 2014. 15(11): p. 1245-53. 
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Harrington, K.J., et al., Phase I/II study of oncolytic HSV GM-CSF in combination with 
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neck. Clin Cancer Res, 2010. 16(15): p. 4005-15. 
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Kohlhapp, F.J. and H.L. Kaufman, Molecular Pathways: Mechanism of Action for 
Talimogene Laherparepvec, a New Oncolytic Virus Immunotherapy. Clin Cancer Res, 
2016. 22(5): p. 1048-54. 
20. 
Harrington, K.J., et al., Clinical development of talimogene laherparepvec(talimogene 
laherparepvec): a modified herpes simplex virus type-1-derived oncolytic 
immunotherapy. Expert Rev Anticancer Ther, 2015. 15(12): p. 1389-403. 
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Yang, H., et al., Treatment of colon cancer with oncolytic herpes simplex virus in 
preclinical models. Gene Ther, 2016. 23(5): p. 450-9. 
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Herrera, F.G., J. Bourhis, and G. Coukos, Radiotherapy combination opportunities 
leveraging immunity for the next oncology practice. CA Cancer J Clin, 2016. 
23. 
George, T.J., Jr., C.J. Allegra, and G. Yothers, Neoadjuvant Rectal (NAR) Score: a New 
Surrogate Endpoint in Rectal Cancer Clinical Trials. Curr Colorectal Cancer Rep, 2015. 
11(5): p. 275-280. 
24. 
Taylor, F.G., et al., Preoperative magnetic resonance imaging assessment of 
circumferential resection margin predicts disease-free survival and local recurrence: 5-
year follow-up results of the MERCURY study. J Clin Oncol, 2014. 32(1): p. 34-43. 
25. 
Piasecki J, R.J., Le T. Talimogene laherparepvecactivates systemic T-cell-mediated anti-
tumor immunity in AACR. 2015. Cancer Research. 
26. 
Demaria, S., E.B. Golden, and S.C. Formenti, Role of Local Radiation Therapy in Cancer 
Immunotherapy. JAMA Oncol, 2015. 1(9): p. 1325-32. 
27. 
This table will be updated as the toxicity profile of the agent is revised.  Updates will be 
distributed to all Principal Investigators at the time of revision.  The current version can 
be obtained by contacting PIO@CTEP.NCI.NIH.GOV.  Your name, the name of the 
investigator, the protocol and the agent should be included in the e-mail. 
28. 
Injection site reactions may include redness, swelling, and bleeding. 
29. 
Pain can occur in the tumor, injection sites and nodal draining (axilla and groin etc) 
lymph nodes. 
30. 
Several events which are autoimmune-mediated, such as acute kidney injury (acute renal 
failure), glomerulonephritis (nephritis), worsening of psoriasis, pneumonitis, vasculitis, 
and vitiligo (areas of skin with loss of color) have been observed in clinical trials of 
talimogene laherparepvec. 
31. 
Skin infection (cellulitis) can be complicated with local and systemic infection, tissue 
necrosis, and ulceration, or wound complications. 
32. 
Obstructive airway disorder has occurred in one patient with Squamous cell carcinoma 
of the head and neck (SCCHN) with a suproventricular mass who developed acute 
respiratory distress requiring a trachetomy 13 days after the second dose of talimogene 
laherparepvec.  Imaging showed a mass in the larynx and adjacent lymph nodes on the 
contralateral side. 
33. 
Liakou, C.I., et al., CTLA-4 blockade increases IFNgamma-producing CD4+ICOShi 


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111 
 
cells to shift the ratio of effector to regulatory T cells in cancer patients. Proc Natl Acad 
Sci U S A, 2008. 105(39): p. 14987-92. 
34. 
Carthon, B.C., et al., Preoperative CTLA-4 blockade: tolerability and immune monitoring 
in the setting of a presurgical clinical trial. Clin Cancer Res, 2010. 16(10): p. 2861-71. 
35. 
Tang, M.J. and Z.B. Zhou, Association of the CTLA-4 +49A/G polymorphism with 
rheumatoid arthritis in Chinese Han population. Mol Biol Rep, 2013. 40(3): p. 2627-31. 
36. 
Chen, H., et al., CD4 T cells require ICOS-mediated PI3K signaling to increase T-Bet 
expression in the setting of anti-CTLA-4 therapy. Cancer Immunol Res, 2014. 2(2): p. 
167-76. 
 
 


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


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APPENDIX B 
INFORMATION FOR PATIENTS, THEIR CAREGIVERS, AND 
NON-STUDY HEALTHCARE TEAM ON POSSIBLE INTERACTIONS WITH OTHER 
DRUGS AND HERBAL SUPPLEMENTS 
 
The patient ____________________________ is enrolled on a clinical trial using the 
experimental study drug, talimogene laherparepvec. In this trial, talimogene 
laherparepvec is given along with other chemotherapy drugs including capecitabine, 5-
FU and oxaliplatin. This clinical trial is sponsored by the National Cancer Institute.  This 
form is addressed to the patient, but includes important information for others who care 
for this patient.  
 
These are the things that you as a healthcare provider need to know: 
 
Capecitabine (and to a lesser extent fluorouracil) interacts with certain specific 
enzyme(s) in your liver.  
• The enzyme in question is cytochrome P450, and capecitabine and fluorouracil 
may reduce the activity of this enzyme. For this reason, while receiving these 
medications, the levels of other medications cleared by these enzymes may be 
increased.  
 
To the patient: Take this paper with you to your medical appointments and keep 
the attached information card in your wallet.   
 
Talimogene laherparepvec and chemoradiation may interact with other drugs which can 
cause side effects. For this reason, it is very important to tell your study doctors of any 
medicines you are taking before you enroll onto this clinical trial.  It is also very 
important to tell your doctors if you stop taking any regular medicines, or if you start 
taking a new medicine while you take part in this study.  When you talk about your 
current medications with your doctors, include medicine you buy without a prescription 
(over-the-counter remedy), or any herbal supplements such as St. John’s Wort.  It is 
helpful to bring your medication bottles or an updated medication list with you. 
 
Many health care providers can write prescriptions.  You must tell all of your health care 
providers (doctors, physician assistants, nurse practitioners, pharmacists) you are 
taking part in a clinical trial.  
 
These are the things that you and they need to know:  
 
Capecitabine and to a lesser extent fluorouracil must be used very carefully with other 
medicines that use cytochrome p450.  Before you enroll onto the clinical trial, your study 
doctor will work with your regular health care providers to review any medicines and 
herbal supplements  that are considered strong inducers/inhibitors or substrates of 
cytochrome P450   
 


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114 
 
• Please be very careful!  Over-the-counter drugs (including herbal supplements) 
may contain ingredients that could interact with your study drug.  Speak to your 
doctors or pharmacist to determine if there could be any side effects.  
• Warfarin, allopurinol, cimetidine, sorivudine, brivudine and phenytoin are known to 
interact with capecitabine and to a lesser extent with fluorouracil. Speak to your 
doctors or pharmacist if you need to be on these medications at the same time.  
• Since antiviral medications including but not limited to acyclovir may decrease the 
efficacy of talimogene laherparepvec, do not start these medications without 
discussing with your health care team first.  
• Your regular health care provider should check a frequently updated medical 
reference or call your study doctor before prescribing any new medicine or 
discontinuing any medicine.  Your study doctor’s name is Dr. Arvind Dasari at 
and he can be contacted at 713-792-2828 
 
APPENDIX C-1 
 INFORMATION SHEET FOR PATIENTS RECEIVING 
TALIMOGENE LAHERPAREPVEC  
Study Title:__________________________________________________________________    
NCI protocol #:_______________________ Amgen Tracking #:_______________________ 
 
The patient ____________________________ is enrolled on the clinical trial above using the 
experimental drug Talimogene laherparepvec(talimogene laherparepvec).  This clinical trial is 
sponsored by the National Cancer Institute.   
 
The PI Name:____________________ and PI contact # _______________________ 
 
_____________________________________________________________________________________________ 
This form is addressed to the patient, but includes important information for others who care for this 
patient.  
 
Dear Patient: 
This Information Sheet is being provided to patients who has been enrolled in a clinical trial of Talimogene 
laherparepvec(talimogene laherparepvec).  A separate Information Sheet is also being provided for you 
close contacts and Healthcare Providers not involved in the trial.   A close contact is considered a person 
that lives with the Patient (household member), care-giver, sex partner, or shares a bed with the Patient or 
conducts other activities that could involve exchange of bodily fluids through close physical contact. 
The purpose of this Sheet is to inform you of 1) Potential risk of exposure to talimogene 
laherparepvec, 2) Precautions and 3) Instructions in the case of talimogene laherparepvec 
transmission.  In the end of this document, additional information is also provided for Instructions for 
talimogene laherparepvec injected sites care. 
 
I. 
What is the Study Drug, Talimogene laherparepvec(talimogene laherparepvec)? 
Talimogene laherparepvec is an investigational drug that is being studied for the treatment of certain 
types of cancer. talimogene laherparepvec contains a weakened form of the Herpes Simplex Virus Type 
1 (the “cold sore” virus or “HSV-1”).  
  
II. 
Can talimogene laherparepvec be spread to family members or other close contacts? 
Talimogene laherparepvec could potentially be spread to family or people who have close physical or 


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115 
 
intimate contact with the Patient after tumor(s) are injected with the study drug.  So far there have been 
no reported cases in clinical trial participants who have received talimogene laherparepvec of spreading 
talimogene laherparepvec to family members or other close contacts.  In clinical trials so far, no talimogene 
laherparepvec has been detected outside of the dressing that is placed on top of the site where it was 
injected.   
The naturally occurring herpes simplex virus is not transmitted through the air or water droplets (such as 
when coughing or sneezing).  Spreading occurs through direct contact from one person to another, 
particularly if a cold sore or genital sore is present (for example, through kissing or having sexual 
intercourse or other intimate contact). It may also be spread by sharing a razor, towel, dish that has come 
in contact with a sore or bodily fluids..   
Spreading (transmission) of talimogene laherparepvec may be similar to spreading of the naturally 
occurring herpes simplex virus, and spreading may be more likely if you have a break in your skin or a 
mucous membrane comes into contact with an injection site or body fluids of a treated patient.  Unlike the 
naturally occurring virus, however, talimogene laherparepvec is administered into tumor lesions  and is 
not expected to be able to replicate effectively in other noncancerous tissues.  There have been no cases 
of spreading of talimogene laherparepvec to close contacts reported in clinical studies to date.   
Small amounts of talimogene laherparepvec have been detected in subjects’ blood and urine for up to 1 
week after injection. In subjects treated with talimogene laherparepvec in clinical trials, talimogene 
laherparepvec has been found on the surface of the injected tumors, into the second week after the 
injection, but not on the outside of the dressings that covered these injection sites. Close contacts should 
avoid direct contact with the injection sites. 
It is unknown if talimogene laherparepvec is shed through stool. Patients should consider using 
precautions while using shared toilet facilities such as; wearing gloves while using a shared roll of toilet 
paper or a separate roll and thoroughly washing hands and wiping the toilet seat or any other areas that 
may potentially be contaminated with a disinfectant wipe.  
It is not known if talimogene laherparepvec virus can appear in mucous membranes of the lips and mouth 
or genitals of treated subjects. A clinical study is ongoing to determine if talimogene laherparepvec can be 
detected in the mouth area and genital area of treated subjects.  
To reduce the risk of exposure to and transmission of talimogene laherparepvec, please read 
carefully the Instructions below.   
 
III. 
Who Should Not Have Contact with talimogene laherparepvec? 
Persons with weakened immune systems, newborns and pregnant women should not come in contact 
with the lesions that have been injected with talimogene laherparepvec or body fluids of treated subjects.   
Close contacts or family members who are pregnant or have weakened immune systems should not 
touch injection sites, change dressings or clean injection sites. Newborns should not come into contact 
with the injection sites. Used dressings and cleaning materials should be kept away from pregnant 
women, newborns and those with weakened immune systems. 
 
IV. 
What Precautions Should Be Taken to Avoid Being Exposed to talimogene laherparepvec? 
• 
Avoid direct contact with the treated patient’s injection sites and body fluids. 
• 
Wear gloves if changing dressings which cover the treated patient’s injection sites. 
• 
Place all used dressings and cleaning materials in a sealed, plastic bag, and throw them away as 
household waste or return to the study site for disposal depending on local guidance. 
• 
The patient should avoid touching or scratching the injection site. 


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• 
If you notice any weeping or oozing from the injection site, please contact your healthcare team.  
(please also refer to Instructions for talimogene laherparepvec Injection Site Care) 
• 
Observe proper hygiene (wash hands with warm water and soap after touching the injected lesions or 
handling the dressings) to avoid spreading talimogene laherparepvec to other persons.  If there is direct 
contact with the injected sites, you should clean the affected area on your body with soap and water 
and/or a disinfectant.  
• 
If the treated subject develops any mouth or genital herpetic lesions (for example a painful fluid filled 
blister) during treatment with talimogene laherparepvec or during the follow-up period of the clinical 
trial, they should avoid activities that could increase the possibility of transmission such as sharing 
straws, drinking glasses or engaging in sexual activity until the lesions fully resolve.    
• 
The naturally occurring herpes simplex virus (HSV-1) can be transmitted through sexual contact. It is 
not known if talimogene laherparepvec will behave the same way, thus treated subjects or their 
partners should use a latex condom when engaging in sexual activity to prevent possible 
transmission of talimogene laherparepvec during the treatment with talimogene laherparepvec and 
until 30 days after the end of treatment. For those with latex allergies, polyurethane condoms may be 
used. 
 
V. 
What Can Happen if Family Members or Close Contacts are Exposed to talimogene 
laherparepvec?  
The naturally occurring type of HSV can cause a variety of symptoms. Due to the changes in talimogene 
laherparepvec that make it different from the naturally occurring HSV, the chance of developing a herpes 
type infection is low, but you should know how to recognize these symptoms.   
If talimogene laherparepvec  were transmitted from a talimogene laherparepvec  treated patients to a 
third party, the potential symptoms might be similar to those of the naturally occurring herpes simplex 
virus such as:  
• 
Sores around the mouth (“cold sore”, “fever blister”) or genitals (“genital sore”).   
• 
Blisters may develop on the fingers, ears or face. 
• 
Eye infection (herpetic keratitis) with eye pain, light sensitivity, discharge from the eyes or blurry 
vision. 
• 
Abdominal pain and infections, and inflammation inside the abdomen (infrequently). 
• 
Rarely, serious infections of the brain (encephalitis) or spinal cord causing paralysis (unable to move) 
have been reported. Signs may include fever, confusion or other behavior changes, headache, 
numbness and pain in the legs, constipation or difficulty with urination. 
• 
Life-threatening infections (disseminated herpes) can develop in people with a weakened immune 
system. 
In addition, after the acute infection, the naturally occurring herpes virus may travel to spinal nerve roots .  
The virus can reactivate from the nerve roots and cause recurrent cold sores or other signs of infection as 
described above. Stress, other illness, or menstruation are common triggers for reactivation of the 
naturally occurring herpes simplex virus.   
 
Persons should seek a healthcare provider for signs of systems suggestive of herpes infection 
occur.  talimogene laherparepvec is sensitive to the antiviral drug acyclovir and any possible 
infection may be treated with this drug in its usual doses by your doctor.   
 
VI. 
INSTRUCTIONS for Reporting of Suspected talimogene laherparepvec Exposure or 
Infection: 


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1) Instructions for patients treated with talimogene laherparepvec: If you develop symptoms of 
herpes infection:    
• 
IMMEDIATELY inform the talimogene laherparepvec trial doctor by contacting: <<insert study 
site contact>>.  The talimogene laherparepvec trial doctor will provide further instructions for 
management and evaluation.   You doctor may need to obtain test for the virus within 3 days 
of your notification of the symptoms 
• 
If you are seeing a doctor who is not part of the clinical trial, please give this information sheet 
to the Doctor and have them contact the talimogene laherparepvec trial staff: <<insert study 
site contact>>. 
2) Instructions for Close Contact or non-study Healthcare providers with suspected exposure to 
talimogene laherparepvec:  
• 
Please refer to the Information Sheet for Close Contacts.    
 
 
 


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APPENDIX C-2 
 INFORMATION SHEET FOR FAMILY MEMBERS, CLOSE 
CONTACTS OF PATIENTS RECEIVING TALIMOGENE LAHERPAREPVEC ON 
CLINICAL TRIALS, AND FOR NON-STUDY (NOT INVOLVED IN THE 
TALIMOGENE LAHERPAREPVEC TRIALS) HEALTH CARE PROVIDERS (HCP) 
 
Study Title:__________________________________________________________________    
NCI protocol #:_______________________ Amgen Tracking #:_______________________ 
 
The patient ____________________________ is enrolled on the clinical trial above using the 
experimental drug Talimogene laherparepvec(talimogene laherparepvec).  This clinical trial is 
sponsored by the National Cancer Institute.   
 
The PI Name:____________________ and PI contact # _______________________ 
 
_____________________________________________________________________________________________ 
 
Dear Family Members, Caregivers, other Close Contacts and non-study Healthcare 
Providers: 
This Information Sheet is being provided to patients who has been enrolled in a clinical trial of Talimogene 
laherparepvec(talimogene laherparepvec), and their close contacts and Healthcare Providers not involved 
in the trial.   A close contact is considered a person that lives with the Patient (household member), care-
giver, sex partner, or shares a bed with the Patient or conducts other activities that could involve exchange 
of bodily fluids through close physical contact.  Non-study HCP are HCPs not involved in the talimogene 
laherparepvec clinical trials but are seeing patients receiving talimogene laherparepvec or their close 
contacts. 
The purpose of this Sheet is to inform you of 1) Potential risk of exposure to talimogene 
laherparepvec, 2) Precautions and 3) Instructions in the case of talimogene laherparepvec 
transmission.  In the end of this document, Additional information about talimogene laherparepvec for 
Healthcare Providers who are not involved in this trial 
 
I. 
What is the Study Drug, Talimogene laherparepvec(talimogene laherparepvec)? 
talimogene laherparepvec is an investigational drug that is being studied for the treatment of certain types 
of cancer. talimogene laherparepvec contains a weakened form of the Herpes Simplex Virus Type 1 (the 
“cold sore” virus or “HSV-1”).  
 
II. 
Can talimogene laherparepvec be spread to family members or other close contacts? 
talimogene laherparepvec could potentially be spread to family or people who have close physical or 
intimate contact with the Patient after tumor(s) are injected with the study drug.  So far there have been 
no reported cases in clinical trial participants who have received talimogene laherparepvec of spreading 
talimogene laherparepvec to family members or other close contacts.  In clinical trials so far, no talimogene 
laherparepvec has been detected outside of the dressing that is placed on top of the site where it was 
injected.   
The naturally occurring herpes simplex virus is not transmitted through the air or water droplets (such as 
when coughing or sneezing).  Spreading occurs through direct contact from one person to another, 
particularly if a cold sore or genital sore is present (for example, through kissing or having sexual 
intercourse or other intimate contact). It may also be spread by sharing a razor, towel, dish that has come 
in contact with a sore or bodily fluids..   
Spreading (transmission) of talimogene laherparepvec may be similar to spreading of the naturally 


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119 
 
occurring herpes simplex virus, and spreading may be more likely if you have a break in your skin or a 
mucous membrane comes into contact with an injection site or body fluids of a treated patient.  Unlike the 
naturally occurring virus, however, talimogene laherparepvec is administered into tumor lesions  and is 
not expected to be able to replicate effectively in other noncancerous tissues.  There have been no cases 
of spreading of talimogene laherparepvec to close contacts reported in clinical studies to date.   
Small amounts of talimogene laherparepvec have been detected in subjects’ blood and urine for up to 1 
week after injection. In subjects treated with talimogene laherparepvec in clinical trials, talimogene 
laherparepvec has been found on the surface of the injected tumors, into the second week after the 
injection, but not on the outside of the dressings that covered these injection sites. Close contacts should 
avoid direct contact with the injection sites. 
It is not known if talimogene laherparepvec virus can appear in mucous membranes of the lips and mouth 
or genitals of treated subjects. A clinical study is ongoing to determine if talimogene laherparepvec can be 
detected in the mouth area and genital area of treated subjects.  
To reduce the risk of exposure to and transmission of talimogene laherparepvec, please read 
carefully the Instructions below.   
 
III. 
Who Should Not Have Contact with talimogene laherparepvec? 
Persons with weakened immune systems, newborns and pregnant women should not come in contact 
with the lesions that have been injected with talimogene laherparepvec or body fluids of treated subjects.   
Close contacts or family members who are pregnant or have weakened immune systems should not 
touch injection sites, change dressings or clean injection sites. Newborns should not come into contact 
with the injection sites. Used dressings and cleaning materials should be kept away from pregnant 
women, newborns and those with weakened immune systems. 
 
IV. 
What Precautions Should Be Taken to Avoid Being Exposed to talimogene laherparepvec? 
• 
Avoid direct contact with the treated patient’s injection sites and body fluids. 
• 
Wear gloves if changing dressings which cover the treated patient’s injection sites. 
• 
Place all used dressings and cleaning materials in a sealed, plastic bag, and throw them away as 
household waste or return to the study site for disposal depending on local guidance. 
• 
The patient should avoid touching or scratching the injection site. 
• 
The injection sites should be covered for at least 7 days after the last injection with watertight dressings 
which allow for air exchange. If the dressing comes loose or falls off prior to 7 days after the injection, 
it should be replaced right away with a clean dressing. However, you may need to keep the dressing 
on longer if the lesions at the injection sites  are weeping or oozing.  (please also refer to Instructions 
for talimogene laherparepvec Injection Site Care) 
• 
Observe proper hygiene (wash hands with warm water and soap after touching the injected lesions or 
handling the dressings) to avoid spreading talimogene laherparepvec to other persons.  If there is direct 
contact with the injected sites, you should clean the affected area on your body with soap and water 
and/or a disinfectant.  
• 
If the treated subject develops any mouth or genital herpetic lesions (for example a painful fluid filled 
blister) during treatment with talimogene laherparepvec or during the follow-up period of the clinical 
trial, they should avoid activities that could increase the possibility of transmission such as sharing 
straws, drinking glasses or engaging in sexual activity until the lesions fully resolve.    
• 
The naturally occurring herpes simplex virus (HSV-1) can be transmitted through sexual contact. It is 
not known if talimogene laherparepvec will behave the same way, thus treated subjects or their 
partners should use a latex condom when engaging in sexual activity to prevent possible 


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transmission of talimogene laherparepvec during the treatment with talimogene laherparepvec and 
until 30 days after the end of treatment. For those with latex allergies, polyurethane condoms may be 
used. 
 
V. 
What Can Happen if Family Members or Close Contacts are Exposed to talimogene 
laherparepvec?  
The naturally occurring type of HSV can cause a variety of symptoms. Due to the changes in talimogene 
laherparepvec that make it different from the naturally occurring HSV, the chance of developing a herpes 
type infection is low, but you should know how to recognize these symptoms.   
If talimogene laherparepvec  were transmitted from a talimogene laherparepvec  treated patients to a 
third party, the potential symptoms might be similar to those of the naturally occurring herpes simplex 
virus such as:  
• 
Sores around the mouth (“cold sore”, “fever blister”) or genitals (“genital sore”).   
• 
Blisters may develop on the fingers, ears or face. 
• 
Eye infection (herpetic keratitis) with eye pain, light sensitivity, discharge from the eyes or blurry 
vision. 
• 
Abdominal pain and infections, and inflammation inside the abdomen (infrequently). 
• 
Rarely, serious infections of the brain (encephalitis) or spinal cord causing paralysis (unable to move) 
have been reported. Signs may include fever, confusion or other behavior changes, headache, 
numbness and pain in the legs, constipation or difficulty with urination. 
• 
Life-threatening infections (disseminated herpes) can develop in people with a weakened immune 
system. 
In addition, after the acute infection, the naturally occurring herpes virus may travel to spinal nerve roots .  
The virus can reactivate from the nerve roots and cause recurrent cold sores or other signs of infection as 
described above. Stress, other illness, or menstruation are common triggers for reactivation of the 
naturally occurring herpes simplex virus.   
 
Persons should seek a healthcare provider for signs of systems suggestive of herpes infection 
occur.  talimogene laherparepvec is sensitive to the antiviral drug acyclovir and any possible 
infection may be treated with this drug in its usual doses by your doctor.   
 
VI. 
INSTRUCTIONS for Reporting of Suspected talimogene laherparepvec Exposure or 
Infection: 
 
1) Instructions for Close Contact with suspected exposure to talimogene laherparepvec:  If a close 
contact or non-study HCP is suspected to have been exposed to talimogene laherparepvec (e.g. 
symptoms suggestive of herpes infection or contact of open skin/mucosa with talimogene 
laherparepvec), you should inform the individuals below and seek medical attention.  Your doctor 
may want to determine if talimogene laherparepvec is present, depending on the symptoms observed.  
For example if a cold sore appears, a swab may be taken for analysis.  These tests will be most reliable 
if done within the first 3 days of symptoms occurring, but you should report to your health care provider 
at any time symptoms appear.  Before any samples or information about your health or symptoms is 
collected your authorization will be requested in writing. 
1. Call the Amgen Call Center at 1-855-IMLYGIC (1-855-465-9442) immediately when the close 
contacts/HCP noticed symptoms/signs of herpes infection, as testing of the virus must occur 
within 3 days.   


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• 
Amgen will provide close contacts/HPC with instructions to seek medical 
consultations for management and potentially for talimogene laherparepvec DNA 
test.  The talimogene laherparepvec DNA test must be done within three days of the 
appearance of the symptoms. 
• 
The physicians of Close Contacts will be responsible for obtaining the swab of 
herpetic lesions submit it to talimogene laherparepvec testing, per instructions from 
Amgen.   
• 
The Amgen Call Center is open 24 hours a day, 7 days a week (24/7).  Please have 
this Information Sheet handy when you call Amgen.   
2. Also inform the talimogene laherparepvec clinical trial doctor of the incident by contacting: 
<<insert study site contact>>.  
3. When seeing a doctor for your symptom or talimogene laherparepvec exposure, please give 
this Information Sheet to the Doctor. 
 
 
 
 
 


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APPENDIX D 
BIOASSAY TEMPLATES 
 
NA 
 
 


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APPENDIX E   NCI TEMPERATURE EXPOSURE LOG 
Talimogene laherparepvec (NSC 785349) 
NCI Protocol Number: _____________________ 
PMB Order Number: ______________________ (obtain from Shipment Record) 
Date Received: ______________ 
Maximum exposure time: 90 Seconds 
Exposure Time 
Start Time = time inner shipping container lid is removed 
Stop Time = time --80oC freezer door is closed 
 
Start Time: _____:_____:_____ (hour:minute:second - example: 09:50:01) 
Stop Time: _____:_____:_____ (hour:minute:second - example: 09:50:58) 
 
Confirm time difference from start time to stop time does not exceed 90 seconds: 
□     YES 
 
□     NO 
 
Comments: ________________________________________________________ 
 
Name: __________________________________ Date: _____________________ 
 
Complete one log for each shipping container received. 
Retain log with your study records. If exposure time exceeds 90 seconds, quarantine the 
agent supplies in the -80oC freezer and call PMB immediately at 240-276-6575 for 
guidance. 
 
 


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APPENDIX F  RECEIVING INSTRUCTIONS FOR NCI SUPPLIED TALIMOGENE 
LAHERPARECVEC  (NSC 785349) 
IMPORTANT: READ THE ENTIRE INSTRUCTIONS BEFORE OPENING 
THE INNER SHIPPING CONTAINER 
Step 1:  
Verify all shipment documents are present: 
• NCI Shipment Record of Clinical Drug Request 
• Temperature Exposure Log 
Step 2:  
Transfer Talimogene laherparepvec vials to -800C (+/- 100 C) freezer 
You have 90 seconds to verify the contents of the shipping container and 
place the agent supplies in the -80oC freezer once the inner container lid 
is opened and the supply exposed to room temperature 
• Place the shipping container near the -80oC freezer 
• Don gloves per your institutional procedures for handling dry ice 
• Open the lid of the inner shipping container 
• A second person should record the start time on the temperature exposure log 
once the lid of inner shipping container is removed 
• Open the payload box sleeve and remove the payload box containing the 
carton(s) of Talimogene laherparepvec  
• Open the payload box and remove carton(s) of Talimogene laherparepvec 
• Verify agent, strength, quantity and lot number received against NCI 
Shipment Record of Clinical Drug Request 
• Place carton(s) of Talimogene laherparepvec in the -80oC freezer and close 
the freezer door 
• Record the stop time on the temperature exposure log 
Step 3:  
Complete documentation 
• Confirm the time difference from start time to stop time does not exceed 90 
seconds 
• Complete remainder for temperature exposure log and retain with your study 
records 
• If exposure time exceeds 90 seconds, quarantine the agent supplies in the -800C 
(+/- 100 C) freezer and call PMB immediately at 240-276-6575 for guidance. 
 
 


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This table will be updated as the toxicity profile of the agent is revised.  Updates will be 
distributed to all Principal Investigators at the time of revision.  The current version can 
be obtained by contacting PIO@CTEP.NCI.NIH.GOV.  Your name, the name of the 
investigator, the protocol and the agent should be included in the e-mail. 
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31. 
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respiratory distress requiring a trachetomy 13 days after the second dose of talimogene 
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contralateral side. 


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