Clinical trial NCT03144804
Conditions: Colorectal Cancer Metastatic
Keywords: Colorectal Cancer
Sponsor: Massachusetts General Hospital
Start date: 2017-10-31; Completion date: 2022-09-27
Enrollment: 36 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This research study is studying a drug as a possible treatment for p53 mutant metastatic colorectal cancer.

The drug involved in this study is:

-Lamivudine

Detailed description:
This research study is a Phase II clinical trial. Phase II clinical trials test the safety and effectiveness of an investigational drug to learn whether the drug works in treating a specific disease. "Investigational" means that the drug is being studied.

The FDA (the U.S. Food and Drug Administration) has not approved lamivudine for this specific disease but it has been approved for other uses.

In this research study, the investigators are studying the effects of lamivudine on this type of cancer. This drug may help prevent the growth and spread of the cancer cells to other parts of the body. The investigators have discovered that this particular type of colon cancer, which has a p53 mutation may be sensitive to treatment with lamivudine by impairing the ability of the cancer cells to grow.

Arms: arm 1: * Lamivudine administered orally every 4 weeks
* Treatment cycles will last 28 consecutive days
* The dosage will be determine by the PI
Interventions: intervention 1: Lamivudine
Intervention descriptions: intervention 1: This drug may help prevent the growth and spread of the cancer cells to other parts of the body.

Protocol documents:
Prot_SAP_000.pdf: 
Page 1
NCI Protocol #:
 
DF/HCC Protocol #:  17-044
TITLE:  A Phase 2 Study of lamivudine in patients with p53 mutant metastatic colorectal cancer
Coordinating Center:
DF-HCC
*Principal Investigator (PI):
Aparna R. Parikh, M.D.
Massachusetts General Hospital
Aparna.Parikh@mgh.harvard.edu
Other Investigators:
David T. Ting, M.D.
Massachusetts General Hospital
dting1@mgh.harvard.edu
David P. Ryan, M.D.
Massachusetts General Hospital
dpryan@mgh.harvard.edu
Statistician:
Hui Zheng
Massachusetts General Hospital
HZHENG1@PARTNERS.ORG
Study Coordinator/Data Manager: 
Ashley O’Meara
Massachusetts General Hospital
55 Fruit St.
617-643-5411
617-643-8399
alomeara@mgh.harvard.edu
Responsible Research Nurse:
 
Patricia Lynch, RN
Massachusetts General Hospital
32 Fruit St.
617-643-0816
Lynch.Patricia2@mgh.harvard.edu
Agent(s):  Lamivudine commercially obtained


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Study Exempt from IND Requirements per 21 CFR 312.2(b).  
Protocol Type / Version # / Version Date: Original/March 30, 2017
      Version 2, December 01, 2017
Version 3, January 23, 2018
Version 4, May 2, 2019
Version 5, November 14, 2019
ClinicalTrials.gov Identifier: NCT03144804


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SCHEMA
Eligible patients with p53mutant/deficient metastatic colorectal cancer
28 day treatment cycles of lamivudine until progression


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TABLE OF CONTENTS
SCHEMA.........................................................................................................................................3
1.
OBJECTIVES......................................................................................................................7
1.1
Study Design............................................................................................................7
1.2
Rationale for dose increase from 150 mg BID to 600 mg BID ...............................7
            1.3       Primary objectives………………………………………………………………7
1.4
Secondary Objectives...............................................................................................7
2.
BACKGROUND .................................................................................................................7
2.1
Study Disease(s).......................................................................................................7
2.2
IND Agent(s) ...........................................................................................................7
2.3
Other Agent(s) .........................................................................................................8
2.4
Rationale ..................................................................................................................8
2.5
Correlative Studies Background ............................................................................10
2.6
Patient-reported outcomes (PRO) background......................................................11
3.
PARTICIPANT SELECTION...........................................................................................12
3.1
Eligibility Criteria..................................................................................................12
3.2
Exclusion Criteria ..................................................................................................13
3.3
Inclusion of Women and Minorities ......................................................................14
4.
REGISTRATION PROCEDURES ...................................................................................14
4.1
General Guidelines for DF/HCC Institutions ........................................................14
4.2
Registration Process for DF/HCC Institutions.......................................................14
4.3
General Guidelines for Other Investigative Sites ..................................................14
4.4
Registration Process for Other Investigative Sites.................................................14
5.
TREATMENT AND/OR IMAGING PLAN.....................................................................14
5.1
Treatment Regimen................................................................................................14
5.2
Pre-Treatment Criteria ...........................................................................................15
5.3
Agent Administration.............................................................................................15
5.4
For phase 1 protocols only: Definition of Dose-Limiting Toxicity (DLT) ...........17
5.5
General Concomitant Medication and Supportive Care Guidelines......................17
5.6
Criteria for Taking a Participant Off Protocol Therapy.........................................18
5.7
Duration of Follow Up...........................................................................................18
5.8
Criteria for Taking a Participant Off Study ...........................................................18
6.
DOSING DELAYS/DOSE MODIFICATIONS ...............................................................19
7.
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................19
7.1
For CTEP protocols only: Comprehensive Adverse Events and Potential 
Risks List(s) (CAEPRs).........................................................................................21
7.2
For CTEP protocols only: Adverse Event Characteristics.....................................22
7.3
For CTEP protocols only: Expedited Adverse Event Reporting ...........................22


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7.4
For CTEP protocols only: Routine Adverse Event Reporting...............................22
7.5
For CTEP protocols only: Secondary Malignancy................................................22
7.6
For CTEP protocols only: Second Malignancy .....................................................22
7.7
For non-CTEP protocols only: Expected Toxicities..............................................23
7.8
For non-CTEP protocols only: Adverse Event Characteristics .............................23
7.9
For non-CTEP protocols only: Expedited Adverse Event Reporting....................24
7.10
Expedited Reporting to the Food and Drug Administration (FDA) ......................24
7.11
Expedited Reporting to the NIH Office of Biotechnology Activities 
(OBA) ....................................................................................................................24
7.12
Expedited Reporting to the Institutional Biosafety Committee (IBC)...................24
7.13
Expedited Reporting to Hospital Risk Management .............................................25
7.14
For non-CTEP protocols only: Routine Adverse Event Reporting .......................25
8.
PHARMACEUTICAL and/or IMAGING AGENT INFORMATION.............................25
8.1
Lamivudine ............................................................................................................25
8.2
IND Agent #2.........................................................................................................26
8.3
Other Agent #1.......................................................................................................26
8.4
Other Agent #2.......................................................................................................26
9.
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ........................................27
9.1
Biomarker Studies..................................................................................................27
9.2
For IDE protocols only: Investigational Device Information................................27
9.3
For IDE protocols only: Investigational Device Information................................27
9.4
Laboratory Correlative Studies..............................................................................27
9.5
Special Studies.......................................................................................................30
10.
STUDY CALENDAR .......................................................................................................30
11.
MEASUREMENT OF EFFECT .......................................................................................32
11.1
Antitumor Effect – Solid Tumors ..........................................................................32
11.2
Antitumor Effect – Hematologic Tumors..............................................................38
11.3
Other Response Parameters ...................................................................................38
12.
DATA REPORTING / REGULATORY REQUIREMENTS...........................................38
12.1
Data Reporting.......................................................................................................38
12.2
Data Safety Monitoring..........................................................................................38
12.3
Multicenter Guidelines...........................................................................................39
12.4
Collaborative Agreements Language.....................................................................39
13.
STATISTICAL CONSIDERATIONS...............................................................................39
13.1
Study Design/Endpoints ........................................................................................39
13.2
Sample Size, Accrual Rate and Study Duration ....................................................39
13.3
Stratification Factors..............................................................................................40
13.4
Interim Monitoring Plan ........................................................................................40
13.5
Analysis of Primary Endpoints..............................................................................40
13.6
Analysis of Secondary Endpoints..........................................................................40
13.7
Reporting and Exclusions ......................................................................................40


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14.
PUBLICATION PLAN .....................................................................................................41
REFERENCES ..............................................................................................................................42
1.
Berretta, J. and A. Morillon, Pervasive transcription constitutes a new level of eukaryotic 
genome regulation. EMBO Rep, 2009. 10(9): p. 973-82...................................................42
2.
Jacquier, A., The complex eukaryotic transcriptome: unexpected pervasive transcription 
and novel small RNAs. Nat Rev Genet, 2009. 10(12): p. 833-44. ....................................42
3.
Jurka, J., et al., Repbase Update, a database of eukaryotic repetitive elements. Cytogenet 
Genome Res, 2005. 110(1-4): p. 462-7..............................................................................42
4.
Ting, D.T., et al., Aberrant overexpression of satellite repeats in pancreatic and other 
epithelial cancers. Science, 2011. 331(6017): p. 593-6.....................................................42
5.
Bersani, F., et al., Pericentromeric satellite repeat expansions through RNA-derived DNA 
intermediates in cancer. Proc Natl Acad Sci U S A, 2015. 112(49): p. 15148-53.............42
6.
Wylie, A., et al., p53 genes function to restrain mobile elements. Genes Dev, 2016. 30(1): 
p. 64-77. .............................................................................................................................42
7.
Liu, M.C., et al., Circulating tumor cells: a useful predictor of treatment efficacy in 
metastatic breast cancer. J Clin Oncol, 2009. 27(31): p. 5153-9.......................................42
8.
Tol, J., et al., Circulating tumour cells early predict progression-free and overall survival 
in advanced colorectal cancer patients treated with chemotherapy and targeted agents. 
Ann Oncol, 2010. 21(5): p. 1006-12..................................................................................42
9.
Reid, A.H., et al., Significant and Sustained Antitumor Activity in Post-Docetaxel, 
Castration-Resistant Prostate Cancer With the CYP17 Inhibitor Abiraterone Acetate. J 
Clin Oncol, 2010. 28(9): p. 1489-95..................................................................................42
10.
Danila, D.C., et al., Phase II multicenter study of abiraterone acetate plus prednisone 
therapy in patients with docetaxel-treated castration-resistant prostate cancer. J Clin 
Oncol, 2010. 28(9): p. 1496-501........................................................................................42
11.
Ozkumur, E., et al., Inertial focusing for tumor antigen-dependent and -independent 
sorting of rare circulating tumor cells. Sci Transl Med, 2013. 5(179): p. 179ra47. ..........42
12.
Kishikawa, T., et al., Quantitation of circulating satellite RNAs in pancreatic cancer 
patients. JCI Insight. 1(8)...................................................................................................42
13.
Romanus, D., et al., Does health-related quality of life improve for advanced 
pancreatic cancer patients who respond to gemcitabine? Analysis of a randomized phase III trial 
of the cancer and leukemia group B (CALGB 80303). J Pain Symptom Manage, 2012. 43(2): p. 
205-17.


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14.
Gourgou-Bourgade, S., et al., Impact of FOLFIRINOX compared with gemcitabine on 
quality of life in patients with metastatic pancreatic cancer: results from the PRODIGE 
4/ACCORD 11 randomized trial. J Clin Oncol, 2013. 31(1): p. 23-9.
15.
Crippa, S., et al., Quality of life in pancreatic cancer: analysis by stage and treatment. J 
Gastrointest Surg, 2008. 12(5): p. 783-93; discussion 793-4.
16.
Kelsen, D.P., et al., Pain and depression in patients with newly diagnosed pancreas 
cancer. J Clin Oncol, 1995. 13(3): p. 748-55.
17.
Boyd, A.D. and M. Riba, Depression and pancreatic cancer. J Natl Compr Canc Netw, 
2007. 5(1): p. 113-6.
18.
Edgerly, M. and T. Fojo, Is there room for improvement in adverse event reporting in the 
era of targeted therapies? J Natl Cancer Inst, 2008. 100(4): p. 240-2.
19.
Berry, D.L., Patient-reported symptoms and quality of life integrated into clinical cancer 
care. Semin Oncol Nurs, 2011. 27(3): p. 203-10.
20.
Oberguggenberger, A., et al., Is the toxicity of adjuvant aromatase inhibitor therapy 
underestimated? Complementary information from patient-reported outcomes (PROs). 
Breast Cancer Res Treat, 2011. 128(2): p. 553-61.
21.
Meyers, F.J., et al., Simultaneous care: a model approach to the perceived conflict 
between investigational therapy and palliative care. J Pain Symptom Manage, 2004. 
28(6): p. 548-56.
23.
Aaronson, N.K., et al., The European Organization for Research and Treatment of 
Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in 
oncology. J Natl Cancer Inst, 1993. 85(5): p. 365-76.
24.
Watanabe, S.M., et al., A multicenter study comparing two numerical versions of the 
Edmonton Symptom Assessment System in palliative care patients. J Pain Symptom 
Manage, 2011. 41(2): p. 456-68.
25.
Zigmond, A.S. and R.P. Snaith, The hospital anxiety and depression scale. Acta 
Psychiatr Scand, 1983. 67(6): p. 361-70
26.
The Journal of Infectious Diseases, Volume 171, Issue 6, 1 June 1995, Pages 1438–
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27.
Aguirre, A.J., et al., Activated Kras and Ink4a/Arf deficiency cooperate to produce 
metastatic pancreatic ductal adenocarcinoma. Genes Dev, 2003. 17(24): p. 3112-26
28.
Bardeesy, N., et al., Both p16(Ink4a) and the p19(Arf)-p53 pathway constrain 
progression of pancreatic adenocarcinoma in the mouse. Proc Natl Acad Sci U S A, 
2006. 103(15): p. 5947-52.
29.
Hezel, A.F., et al., Genetics and biology of pancreatic ductal adenocarcinoma. Genes 
Dev, 2006. 20(10): p. 1218-49.
30. 
leeuwen et al. evaluation of safety and efficacy of 3tc (lamivudine) in patients with 
asymptomatic or mildly symptomatic human immunodeficiency virus infection: a phase 
i/ii study j infect dis. 1995 may;171(5):1166-71.) 
31. 
Bersani f et al. Pericentromeric satellite repeat expansions through rna-derived dna 
intermediates in cancer. PNAS 2015 December, 112 (49) 15148-15153.


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APPENDIX A
PERFORMANCE STATUS CRITERIA ..................................................43
APPENDIX B
MULTICENTER GUIDELINES...............................................................44
APPENDIX C
INFORMATION ON POSSIBLE DRUG INTERACTIONS...................45
APPENDIX D
BIOASSAY TEMPLATES .......................................................................46
1.
OBJECTIVES
1.1
Study Design
This is an open-label, single-arm Phase II study of lamivudine in patients who have progressed 
on systemic therapy for advanced colorectal cancer with TP53 mutations. The phase II study 
would have a two-stage design, with a target accrual of 20 evaluable patients for the first stage 
and a total of 32 patients for the whole study. If no responses seen in the first 20 patients, the trial 
will be terminated. If at least 1 patient in the first stage has response, the trial would proceed to 
the second stage. Patients will be treated with lamivudine at 600 mg po bid continuously for 28-
day cycles. Patients enrolled at a dose level of 150 mg bid will have the dose increased to 600 
mg bid, the rationale for which is explained in section 1.2. Tumor assessments will be performed 
every 8 weeks until documented disease progression by RECIST criteria or drug intolerance. The 
estimated time for accrual of the patients is 6 months.
1.2
Rationale for dose increase from 150 mg BID to 600 mg BID
In a phase I/II trial assessing the safety, pharmacokinetics, and activity of lamivudine, 97 patients 
with AIDS or HIV were given lamivudine at a dose of 0.5-20.0 mg/kg/day. Median CD4 count 
was 128/mm3. The MTD was not reached. AEs at the higher doses includes mild headaches, 
insomnia, and abdominal symptoms, and the study showed a trend towards 
lower down neutrophil counts at the highest doses [26].  
Furthermore, evaluation of lamivudine (3TC) in vivo with a p53 mutant colorectal cancer cell 
line (SW620) was done at a dose of 50 mg/kg given by intraperitoneal (IP) injection 3 times a 
week. When divided per day this is 21 mg/kg/day, which is the highest dose used in the human 
Phase I trial. As can be seen in the Figure below, this dose was effective in causing a significant 
difference in xenograft tumor growth and indication of tumor reduction when compared to 
control SW620 xenografts.  Prior evaluation of a lower dose of the NRTI ddC at 25 mg/kg in 
SW620 xenografts that has been published by our group [31] showed decrease in tumor growth, 
but not as robust as the 3TC at this higher dose. 
All mice tolerated therapy and at necropsy did not have any indication of end organ damage from 
this higher dose. This indicates that the higher dose proposed would be efficacious to cause 
tumor reduction in patients without appreciable increase in adverse side effects.


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0
5
10
15
20
0
10
20
30
40
50
Days post-treatment initiation
Photon Counts (Normalized to Day 0)
Control (N=6)
3TC (N=6)
P = 0.016
 
Figure 1A


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Pancreatic cancer cell line data
In addition to colon cancer, we have additional data in mouse pancreatic cancer cell lines, which 
have been shown to be models of human disease with an activated KRASG12D mutation and 
loss of the tumor suppressor P53 [27-29].  A total of 4 of 8 mouse pancreatic cancer cell lines 
Fig. 1B: Lamivudine (3TC) with or without Azacitidine (AZA) given to colon 
cancer cell line mouse xenografts monitored by in vivo luciferase imaging. Note the 
more significant effect of combined 3TC+AZA in the HCT116 MSI colon cancer 
compared to SW620 MSS colon cancer, which is concordant with in vitro data. 
HCT116 (MSI Colon)
0
5
10
15
20
0
10
20
30
40
50
Days post-treatment initiation
Photon Counts (Normalized to Day 0)
Control (N=6)
3TC (N=6)
AZA (N=6)
3TC+AZA (N=5)
P = 0.016
P = 0.008
SW620 (MSS Colon)


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have shown synergy with the combination.  NB508 mouse pancreatic cancer (PDAC) cell line 
shown in Fig. 1C with demonstration of the highest potency of combination NRTI and AZA.
DMSO
ETV
d4T
Teno
ddA
FTC
3TC
ddC
ZDV
ABC
DMSO
ETV
d4T
Teno
ddA
FTC
3TC
ddC
ZDV
ABC
0
50
100
150
200
NB508 (Mouse PDAC cell line)
Treatment
Tumorsphere Viability (%)
DMSO
ETV
d4T
Teno
ddA
FTC
3TC
ddC
ZDV
ABC
No AZA
300 nM AZA
**
** **
** **
**
**
**
*
*
*
**
**
*
Black * indicates statistical significance when compared to DMSO No AZA (T-test)
Red * indicates statistical significance when compared to DMSO with AZA (T-test)
Black + Red star is indicative of synergy between AZA and NRTI
Fig. 1C: All NRTIs without or with Azacitidine (AZA) given to mouse PDAC cell 
line NB508 (KrasG12D, Trp53 loss) showing significant sensitivity to combination of 
AZA to NRTI in pancreatic cancer. 


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With the preclinical data suggesting that a higher dose of lamivudine is more cytotoxic and 
clinical data that suggests no significant toxicity, we have no reason to believe there will be 
additional toxicity patients in these colorectal cancer patients. We propose to increase the dosing 
of lamivudine to 600 mg bid. 
We will plan to treat 6 patients at the new dose level and not enroll any more patients until the 
end of a 28-day DLT period. If there is less than or equal to 1 DLTs, we will plan to continue 
enrollment for all patients at the 600 mg bid dose level. If 2/6 patients have a DLT, we will 
resume dosing at the 300 mg bid dose. 
Dose limiting toxicity will be defined as any of the following AEs considered possibly related to 
lamivudine that occur any time from the initial dose of study treatment with severity graded 
according to the NCI Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0
 
Hematologic Toxicity:
 
-Grade 4 neutropenia lasting ≥ 7 days
-Grade 3 or 4 neutropenia complicated by fever ≥ 38.0°C or infection
-Grade 4 thrombocytopenia
-Grade 3 thrombocytopenia complicated by hemorrhage
-Grade 4 anemia
Non-Hematologic Toxicity: Any treatment related Grade 3 or higher non-hematologic toxicity 
except elevations in GGT that is deemed clinically relevant and unmanageable by the 
investigator. 
-Grade ≥ 3 AST/ALT elevation [exceptions may be made for transient (e.g. lasting < 7 
Days) Grade 3 elevations of ALT/AST in the presence of known liver metastases and without 
evidence of other hepatic injury, if agreed by the Principal Investigator
- Grade ≥ 2 AST/ALT elevation and Grade ≥ 2 bilirubin elevation [exceptions may be made for 
transient (e.g. lasting < 7 days) elevations of ALT/AST and bilirubin in the presence of known 
liver metastases without evidence of other hepatic injury, if agreed upon by the treating 
physician and the Principal Investigator
-Grade 3 or 4 non-hematologic toxicity (excluding fatigue or anorexia lasting < 7 days, or Grade 
3 nausea and/or vomiting that persists for < 2 days following appropriate supportive care). 
As mentioned above, in a phase i/ii study, 7 levels of lamivudine therapy (from 0.5 to 20.0 
mg/kg/day) were studied in 104 human immunodeficiency virus-infected patients with cd4 cell 
counts < or = 400 x 10(6)/l. mild and transient episodes of diarrhea, headache, fatigue, nausea, 
and abdominal pain were the most frequent events reported. there were no dose-limiting 
toxicities [30].
Nine patients have been treated at 150 mg BID with no DLTs.


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1.3
Primary Objectives
To determine the response rate of lamivudine in patients with stage 4 colorectal cancer who are 
p53 mutated.
1.4
Secondary Objectives
1.1.1
To determine the progression free survival
1.1.2
To determine the overall survival
1.1.3
To document changes in HSATII expression in circulating tumor cells of patients on treatment
1.1.4
To document changes in HSATII expression in tumors of patients on lamivudine
2.
BACKGROUND
2.1
Study Disease(s)
The initial management of stage 4 colorectal cancer that is not amenable to curative surgical 
resection consists of combinations of oxaliplatin, irinotecan, 5-FU, anti-VEGF antibodies, and 
anti-EGFR antibodies (in kras wt disease).  After progression of disease on combinations of 
these agents, patients have limited therapeutic options.  Recently, it has been demonstrated that 
the <5% of patients with microsatellite unstable disease may have marked responses to anti-PD1 
therapy.  For the >95% of patients with microsatellite stable disease, treatment options are 
limited to the disease stabilizing compounds of regorafenib and lonsurf. With these agents, 
responses are rarely seen and the average progression free survival is 2-4 months.
2.2
IND Agent(s)
Lamivudine, a synthetic nucleoside analogue, is phosphorylated intracellularly to its active 5'-
triphosphate metabolite, lamivudine triphosphate. The nucleoside analogue is incorporated into 
viral DNA by HIV reverse transcriptase and HBV polymerase, resulting in DNA chain 
termination. Lamivudine triphosphate is a weak inhibitor of mammalian alpha-, beta-, and 
gamma-DNA polymerases. This study is using doses already FDA approved.
2.3
Other Agent(s)
Not applicable
2.4
Rationale
HSATII Expression
Next generation sequencing technology has recently provided unprecedented resolution of the 
cancer transcriptome and has revealed significant expression of non-coding sequences (ncRNAs) 
in normal and cancer tissues. These ncRNAs provide a previously unexplored source of novel 
cancer biomarkers and therapeutic targets [1, 2]. We performed RNA sequencing of primary 
tumors and a variety of normal tissues and identified significant transcription emanating from 
pericentromeric heterochromatic regions of the genome previously thought to be inactive due to 
heavy epigenetic silencing. Pericentromeric heterochromatin is comprised of large tandem arrays 
of repetitive elements called satellites, and these regions are known to be differentially 


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methylated in a variety of malignancies [3]. Our analysis of all human satellites identified the 
ncRNA HSATII satellite as being exquisitely specific for a wide variety of cancers including 
pancreatic, prostate, lung, ovarian, and renal cell carcinomas compared to normal tissues [4]. We 
confirmed HSATII expression in pancreatic cancer by using a branched chain nucleic acid RNA 
in situ hybridization (RNA-ISH) platform applicable to standard formalin fixed paraffin 
embedded (FFPE) tissue.  HSATII RNA-ISH demonstrated high expression across 
approximately 600 epithelial cancers including carcinomas of the pancreas, lung, prostate, breast, 
colon, thyroid, ovarian, and kidney. Moreover, RNA-ISH in both mouse models and human 
specimens indicate that HSATII derepression occurs in early preneoplastic lesions of the 
pancreas (PanIN and IPMN) and breast (DCIS). Together, this indicates that therapeutically 
targeting HSATII expression would be applicable across a broad range of epithelial cancers and 
has the opportunity to prevent the progression of preneoplastic lesions to invasive cancer. 
Sensitivity to Reverse Transcriptase Inhibitors
More recently, we have discovered that these satellite sequences are actively reverse transcribed 
(RT) in cancers and lead to progressive expansion of satellite sequences in tumor genomes [5]. 
Analysis of colon cancer TCGA whole genome sequencing data demonstrated that 50% of 
primary samples had significant copy number gain of HSATII in tumor genomes. Notably, 
HSATII expression and RT was completely absent in cancer cell lines grown in standard 
adherent 2D conditions, while is massively induced in the setting of tumorigenesis as a xenograft 
or growth as 3D tumorspheres in vitro. Using the nucleoside reverse transcriptase inhibitors 
(NRTI) ddC and d4T and HSATII specific locked nucleic acids (LNA), we have found 
significant reduction of tumor cell growth in colon cancer 3D tumorspheres and xenografts, but 
not in standard 2D growth conditions.  Together, this indicates that HSATII RT inhibition is a 
novel therapeutic anti-cancer target that is seen in vivo, but would be missed in standard 2D cell 
line screens.  
Sensitivity to Reverse Transcriptase Inhibitors in TP54 mutant colon cancer
Initial screening of active NRTIs currently used in HIV and HBV indicate lamivudine (3TC), 
zalcitabine (ddC), emtricitabine (FTC), and entecavir have similar effects across a panel of colon 
cancer cell lines in 3D tumorspheres. In colon cancer 3D tumorspheres (Fig.1, we screened a 
panel of FDA approved NRTIs) and have identified lamivudine (3TC), zalcitabine (ddC), 
emtricitabine (FTC), and entecavir as active compounds against HSATII RT with associated 
cytotoxicity. Preliminary analysis indicates that TP53 mutant colon cancers (SW620, DLD-1, 
HCT-15)  are preferentially susceptible to NRTI cytotoxicity compared to wildtype (LOVO, HT-
28, HCT-116, GP5D, HCT-8) colon cancer cell lines which is correlated to higher basal HSATII 
expression levels. This linkage between repeat RNA expression with TP53 loss has recently been 
described in model organisms. TP53 loss of function was linked to derepression of repetitive 
elements such as HSATII [6].  


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Given the lack of therapeutic modalities for patients who progress on initial combination therapy, 
we propose to evaluate lamivudine in this study in colon cancers with TP53 mutation given the 
relationship between TP53 mutation, high HSATII repeat expression, and sensitivity to NRTIs. 
HSATII RNA-ISH will be used on archived tissue specimens in formalin fixed paraffin 
embedded (FFPE) tissue to be evaluated as a correlative biomarker that may improve prediction 
of sensitivity to lamivudine. Lamivudine (2′,3′-dideoxy-3′-thiacytidine) is a nucleoside analog 
reverse transcriptase inhibitor that is approved for the management of patients with hepatitis B 
and HIV.  
2.5
Correlative Studies Background
A) RNA and DNA analysis of Pretreatment Diagnostic Sample 
Fig. 1: A panel of 9 NRTIs and DMSO control were tested in 3D tumor spheres of 8 colon 
cancer cell lines. Notably, the C and G analogues consistently had more significant effects 
across 5 of 8 cell lines. There are clear differences in sensitivity to NRTIs between cancer 
cell lines. 


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Archived formalin fixed paraffin 
embedded (FFPE) material from the 
patient’s diagnostic biopsy and/or 
resection specimen will be analyzed 
for RNA and DNA markers to predict 
response to NRTI (lamivudine) 
treatment. A pre-study biopsy will be 
required if a biopsy was not done 
after the most recent treatment 
received. The tumor biopsy should be 
collected, if medically feasible, in the 
opinion of the investigator. We have 
developed a RNA-ISH assay 
applicable to FFPE sectioned slides 
for repeat non-coding RNAs 
including HSATII (Fig. 1). The assay 
has been automated, but is not CLIA 
certified at this time.  Given this early 
trial, we will assess this HSATII 
RNA-ISH and other repeats for 
exploratory biomarker development.  
Preliminary data has already indicated that TP53 mutation/deletion may predict sensitivity to 
NRTIs.  However, the spectrum of other DNA aberrations in cancers as they relate to sensitivity 
to NRTIs has not been explored.  In addition, other RNA transcripts may prove to be useful in 
conjunction with mutations and HSATII RNA expression status as predictive biomarkers of 
response.  We will perform RNA-seq and whole exome/whole genome DNA sequencing on total 
nucleic acids extracted from FFPE archived excess tissue slides.  This analysis will also shed 
mechanistic insight into the relationship of HSATII expression with other RNAs and genomic 
features.  
B) Blood Based Biomarkers for Disease Response Monitoring
Monitoring of on target effects of NRTI on repetitive elements will be done through exploratory 
blood based biomarker assays.
CTC numbers have been shown to correlate with response to therapy in breast [7], colon [8], and 
prostate cancer [9, 10]. CTC analysis will be done using the CTC-iChip, a microfluidic device 
that relies on a combination of immunomagnetic labeling, hydrodynamic sorting, inertial 
focusing, and magnetic driven separation to isolate CTCs 
[11]. This platform has isolated CTCs from a wide variety 
of malignancies.  We have demonstrated the ability to 
detect HSATII in CTCs in metastatic cancer patients (Fig. 
2) and will evaluate CTCs in patients on enrollment and 
every 2 months on trial.  
Exosomes have also been shown to be a promising 
biomarker that can be purified from plasma or serum.  We 
Fig. 2:  RNA-ISH for HSATII (red) in primary colon 
cancer FFPE specimen.  HSATII detected in cancer 
cells, but not adjacent stroma.  Counter stain 
Hematoxylin (blue) 
Fig. 3:  CTC captured from 
metastatic PDAC patient stained by 
RNA-FISH for HSATII (green) and 
CK (red).  DAPI nuclear stain (blue)


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have recently developed a microfluidic exosome capture chip ExoHb-chip that can purify 
exosomes.  Notably, HSATII has been detected in the serum and exosomes of cancer patients 
[12].
Blood will be separated for analysis for circulating tumor cells (CTCs) and exosomes. CTCs will 
be enumerated with standard immunofluorescent markers, HSATII RNA-ISH, and RNA-
sequencing.  Exosomes will be analyzed by RNA-sequencing. Additional plasma and leukocytes 
(buffy coat) will be archived for potential future analysis.  
RNA and DNA sequencing data will be shared with collaborating investigators for correlative 
science research.  Original sequencing data will be shared with collaborators, but all samples will 
be de-identified and labeled with anonymized coding.  In addition, all original data will be 
uploaded to the appropriate NCBI archive (i.e. GEO, dbGAP, SRA) as directed by grant funding 
and publication rules.
2.6
Patient-reported outcomes (PRO) background
There are few published studies measuring patient-reported symptoms and quality of life (QOL) 
outcomes in patients with pancreatic cancer. Most of the existing studies assessing QOL in 
patients with pancreatic cancer are focused on individuals with advanced disease.[13, 14] The 
few studies that have included patients with operable pancreatic cancer included small sample 
sizes in heterogeneous patients.[15, 16] Despite the fact that depression is a frequently reported 
symptom in patients with pancreatic cancer, the prevalence among different stages of disease has 
not been thoroughly investigated.[17] A more detailed and comprehensive understanding of the 
burdens faced by patients with locally advanced pancreatic cancer will identify areas for 
clinicians to enhance their supportive care efforts.
Studying patients’ symptom burden and QOL while they are participating in a clinical trial 
provides an opportunity to better understand their disease- and treatment-related outcomes. 
Patients’ symptom burden and QOL are better indicators of their treatment tolerability than 
clinician-reported toxicity monitoring. Combining objective endpoints, such as response rate, 
with subjective patient-reported outcomes has become increasingly important in determining 
efficacy, toxicity, and safety and for allowing comparisons across treatment arms.[18] 
Additionally, evaluating patient-reported measures may help highlight patients’ difficulties with 
treatment adherence by demonstrating additional side effects and toxicities of therapy.[19] 
Increased attention to patients’ symptom burden and QOL while they are participating in a 
clinical trial provides an opportunity to improve their quality of care.[20, 21] Thus, we aim to 
describe QOL, symptom burden and mood in this study population to help us better identify the 
side effects and challenges faced by patients with locally advanced pancreatic cancer.
We will use the EORTC QLQ-C30, a validated instrument designed for prospective clinical trials 
that evaluates five functions (physical, role, cognitive, emotional, and social), and nine 
symptoms (fatigue, pain, nausea and vomiting, dyspnea, loss of appetite, insomnia, constipation, 
diarrhea, and financial difficulties) to measure QOL.[22] We will use the Edmonton Symptom 


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Assessment System-revised (ESAS-r) to measure symptoms, which has been previously 
validated in patients with advanced cancer.[23] The ESAS-r consists of ten items assessing pain, 
fatigue, drowsiness, nausea, anorexia, dyspnea, depression, anxiety, well-being, and a free-
response item. We will include diarrhea as the free-response item. The ten items are scored on a 
scale of 0-10 (0 reflecting no reported presence of the symptom and 10 reflecting the worst 
possible severity of the symptom). We will instruct patients that items are to be rated based on 
the previous 24-hour period. We will use the Hospital Anxiety and Depression Scale (HADS) to 
assess symptoms of depression and anxiety.[24] The HADS is a 14-item questionnaire that 
contains two 7-item subscales assessing depression and anxiety symptoms during the past week. 
The questionnaire consists of a four-point item response format that quantifies the degree to 
which participants experience a particular emotion. Scores on each subscale range from 0 to 21, 
with a cutoff of 8 or greater denoting clinically significant depression or anxiety symptoms.
3.
PARTICIPANT SELECTION
3.1
Eligibility Criteria 
Eligibility, particularly regarding past treatments, will be reviewed on a case by case basis and 
deviations or exceptions will be submitted to the IRB as needed.
3.1.1
Patients must have histologically confirmed adenocarcinoma of the colon that has 
metastasized (stage 4) and is TP53 mutant/deleted by a CLIA approved genetic test.  
Only known loss of function TP53 mutation/deletion will be eligible for this study. 
3.1.2
Participants must have measurable disease, defined as at least on lesion that can be 
accurately measured in at least one dimension (longest diameter to be recorded for non-
nodal lesions and short axis for nodal lesions) as > 20mm with conventional techniques 
or > 10 mm with spiral CT scan, MRI or calipers by clinical exam.  See section 11 for 
evaluation of measurable disease
3.1.3
Patients must be resistant to or intolerant of 5FU, oxaliplatin, irinotecan, bevacizumab 
and cetuximab/panitumumab (if RAS wild type)
3.1.4
Age 18 or older.  
3.1.5
ECOG performance status ≤2 (Karnofsky ≥60%, see Appendix A)
3.1.6
Life expectancy of greater than 8 weeks. 
3.1.7
Participants must have normal organ and marrow function as defined below:

absolute neutrophil count
≥1,200/mcL

platelets
≥75,000/mcL

total bilirubin
≤1.5 × institutional upper limit of normal within normal

AST(SGOT)/ALT(SGPT)
≤5 × institutional upper limit of normal

creatinine
within normal institutional limits OR

eGFR ≥60 mL/min/1.73 m2 for participants with creatinine levels not within 
institutional normal OR

Creatinine Clearance (calculated per Cockcroft-Gault equation) ≥60 mL/min for 
participants with creatinine levels not within 


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institutional normal
3.1.8
The effects of lamivudine on the developing human fetus are known to be teratogenic.  
For this reason, women of child-bearing potential and men must agree to use adequate 
contraception (hormonal or barrier method of birth control; abstinence) prior to study 
entry and for the duration of study participation.  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.  Men treated or enrolled on this protocol must 
also agree to use adequate contraception prior to the study, for the duration of study 
participation, and 4 months after completion of lamivudine administration.
3.1.9
Ability to understand and the willingness to sign a written informed consent document.
3.2
Exclusion Criteria
3.2.1
Participants who have had chemotherapy or radiotherapy within 3 weeks (6 weeks for 
nitrosourea or mitomycin C) prior to entering the study or those who have not recovered 
from adverse events due to agents administered more than 3 weeks earlier. Radiotherapy 
maybe administered within 3 weeks of study entry at the discretion of the investigator 
and treating physician.
3.2.2
Participants who are receiving any other investigational agents.
3.2.3
Participants with known brain metastases should be excluded from this clinical trial 
because of their poor prognosis and because they often develop progressive neurologic 
dysfunction that would confound the evaluation of neurologic and other adverse events.
3.2.4
History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to lamivudine.
3.2.5
Uncontrolled intercurrent illness including, but not limited to, 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.
3.2.6
Pregnant women are excluded from this study because lamivudine is an agent with the 
potential for teratogenic or abortifacient effects.  Because there is an unknown but 
potential risk for adverse events in nursing infants secondary to treatment of the mother 
with lamivudine, breastfeeding should be discontinued if the mother is treated with 
lamivudine.
3.2.7
HIV-positive participants on combination antiretroviral therapy are ineligible because of 
the potential for pharmacokinetic interactions with lamivudine
3.2.8
HBV positive participants will be excluded given the known effects of lamivudine on 
HBV. 


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3.3
Inclusion of Women and Minorities
Both men and women of all races and ethnic groups are eligible for this trial.
4.
REGISTRATION PROCEDURES
4.1
General Guidelines for DF/HCC Institutions
Institutions will register eligible participants in the Clinical Trials Management System (CTMS) 
OnCore. Registrations must occur prior to the initiation of protocol therapy. Any participant not 
registered to the protocol before protocol therapy begins will be considered ineligible and 
registration will be denied.
An investigator will confirm eligibility criteria and a member of the study team will complete the 
protocol-specific eligibility checklist.
Following registration, participants may begin protocol therapy. Issues that would cause 
treatment delays should be discussed with the Overall Principal Investigator (PI). If a participant 
does not receive protocol therapy following registration, the participant’s registration on the 
study must be canceled. Registration cancellations must be made in OnCore as soon as possible. 
4.2
Registration Process for DF/HCC Institutions
DF/HCC Standard Operating Procedure for Human Subject Research Titled Subject Protocol 
Registration (SOP #: REGIST-101) must be followed.  
4.3
General Guidelines for Other Investigative Sites
Not applicable
4.4
Registration Process for Other Investigative Sites
Not applicable
5.
TREATMENT AND/OR IMAGING PLAN
5.1
Treatment Regimen
Lamivudine will be administered every 4 weeks, with 28 consecutive days defined as a treatment 
cycle. 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 


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Regimen Description
Agent
Premedications; 
Precautions
Dose
Route***
Schedule
Cycle 
Length
Lamivudine
Take with food.
600 mg 
tablet
PO BID. 
Daily, 
28 days
Patients enrolled onto the study as of DFCI amendment # 5 received 150 mg BID dose. The 
participant will be requested to maintain a medication diary of each dose of medication.  The 
medication diary will be returned to clinic staff at the end of each cycle
5.2
Pre-Treatment Criteria
5.2.1
Cycle 1, Day 1: Patients are required to meet eligibility criteria within 14 days of starting 
therapy.  Day 1 labs must be reviewed prior to treatment. 
5.2.2
Subsequent Cycles.  Toxicity related to therapy should return to baseline function or 
grade 2 or less prior to initiating subsequent cycles of therapy.
5.3
Agent Administration
Lamivudine, a synthetic nucleoside analogue, is phosphorylated intracellularly to its active 5'-
triphosphate metabolite, lamivudine triphosphate. The nucleoside analogue is incorporated into 
viral DNA by HIV reverse transcriptase and HBV polymerase, resulting in DNA chain 
termination. Lamivudine triphosphate is a weak inhibitor of mammalian alpha-, beta-, and 
gamma-DNA polymerase
Toxicities
Frequent

Gastrointestinal: Diarrhea (adults, 18%;), Nausea (33%)

Neurologic: Headache (35%)

Respiratory: Cough (adults, 18%;), Nasal symptom (rhinorrhea) (adults, 20%; 

Other: Fever (adults, 10%;), Malaise and fatigue (27%)
Occasional  

Pancreatitis 
Rare 

Endocrine metabolic: Fat maldistribution, Lactic acidosis

Hepatic: Hepatomegaly, Relapsing type B viral hepatitis

Black Box Warning


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Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been 
reported. Severe acute exacerbations of hepatitis B have been reported in patients who have 
discontinued antihepatitis B therapy (including lamivudine) or who are coinfected with hepatitis 
B virus (HBV) and HIV-1 and have discontinued lamivudine; monitor hepatic function upon 
discontinuation of therapy. Epivir(R) tablets and oral solution (used to treat HIV-1 infection) 
contain a higher dose of the active ingredient (lamivudine) than Epivir-HBV(R) tablets and oral 
solution (used to treat chronic hepatitis B infection). Patients with HIV-1 infection should 
receive only dosage forms appropriate for treatment of HIV-1. Epivir-HBV(R) is not approved 
for the treatment of HIV-1 infection. HIV-1 resistance may emerge in chronic hepatitis B-
infected patients with unrecognized or untreated HIV-1 infection; offer HIV counseling and 
testing to all patients prior to beginning treatment with Epivir-HBV(R) and periodically during 
therapy
How Supplied
150 mg tablet
Store Lamivudine tablets at 25 degrees Celsius (77 degrees Fahrenheit) in a tightly closed 
container. Store lamivudine oral solution and tablets between 20 to 25 degrees Celsius (68 to 77 
degrees Fahrenheit) in a tightly closed bottle
Dosing Information
The starting dose of lamivudine is 600 mg po BID. Drug can not be crushed, chewed or 
dissolved in water. Should the drug be vomiting within 1 hour of administration, drug can be re 
dosed. If a patient completely misses their study drug, they should take their next scheduled 
dose. Drug may be administered with meals. There are no prohibited foods and can be taken with 
or without water. 
Dose Adjustments
Dose delays and modifications will be made using the following recommendations. Toxicity 
assessments will be done using the CTEP Active Version of the NCI Common Terminology 
Criteria for Adverse Events (CTCAE) which is identified and located on the CTEP website at: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
If possible, symptoms should be managed symptomatically. In the case of toxicity, appropriate 
medical treatment should be used (including anti-emetics, anti-diarrheals, etc.).
All adverse events experienced by participants will be collected from the time of the first dose of 
study treatment, through the study and until the final study visit. Participants continuing to 
experience toxicity at the off study visit may be contacted for additional assessments until the 
toxicity has resolved or is deemed irreversible.
Lamivudine will be held at the discretion of the provider for any >/= to grade 3 hematologic or 
non-hematologic toxicities such as headache, fatigue, cytopenias, nausea or vomitting, diarrhea, 
pancreatitis, neutropenia, infection, myalgias or respiratory symptoms  When patients recover to 
baseline or grade 2 toxicity (or toxicity at the discretion of provider) , patients will be restarted at 
600 mg po BID, unless the provider feels otherwise. 


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For grade 1 or 2 toxicity deemed to be unacceptable by the patient or the treating physician, 
doses can be lowered to 150 mg bid or 300 mg po daily. Dose may be increased up to 600 mg 
bid at the discretion of the provider.  
If toxicity doesn’t resolve within 12 weeks of last dose, permanently discontinue. 
Patients will be removed from study if they develop grade 3 or higher toxicities either at the 150 
mg bid dosing or 300 mg daily dose, unless otherwise discussed with the PI and treating 
physician.
Dose can be lowered to as low as 150 mg bid OR 300 mg qd depending on the type of toxicity.
Of note, no dose adjustments are required for patients with impaired hepatic function but should 
patients develop clinical or laboratory findings suggestive of lactic acidosis and/or 
hepatomegaly, lamivudine should be stopped. 
For renal function, should renal function become impaired, patients may continue at 600 mg 
twice daily dosing for Creatinine Clearance >/= 50. Should Creatinine clearance fall to 30 - <50, 
patients will be restarted at 300 mg once daily. For patients with a Creatinine Clearance, less 
than 30, patients should be taken off study unless deriving clinical benefit per treating physician. 
If deriving clinical benefit, patients with a Creatinine Clearance of 15-29 may remain on study at 
100 mg po once daily and for a Creatinine Clearance of 5-14, 50 mg po once daily.If >/= 3  
grade toxicity hasn’t resolved to baseline or grade 2 within 4 weeks, treatment should be 
permanently discontinued. If patient was previously deriving clinical benefit per the treating 
physician and >/= 3 grade toxicity hasn’t resolved to grade 2 or baseline by 4 weeks, treatment 
may be held for a maximum of 8 weeks. 
5.3.1
CTEP and/or CIP IND Agent(s), or other IND agent
Not applicable
5.3.2
Other Agent(s)
Palliative radiation will be allowed if clinically indicated on the study
5.3.3
Other Modality(ies) or Procedures
Not applicable
5.3.4
Investigational Imaging Agent Administration
Not applicable
5.4
For phase 1 protocols only: Definition of Dose-Limiting Toxicity (DLT) 


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Not applicable
5.5
General Concomitant Medication and Supportive Care Guidelines
Because there is a potential for interaction of lamivudine with other concomitantly administered 
drugs, the case report form must capture the concurrent use of all other drugs, over-the-counter 
medications, or alternative therapies.  
5.6
Criteria for Taking a Participant Off Protocol Therapy
Duration of therapy will depend on individual response, evidence of disease progression and 
tolerance. In the absence of treatment delays due to adverse event(s), treatment may continue for 
indefinitely or until one of the following criteria applies:

Disease progression

Intercurrent illness that prevents further administration of treatment

Unacceptable adverse event(s)

Participant demonstrates an inability or unwillingness to comply with the oral 
medication regimen and/or documentation requirements

Participant decides to withdraw from the protocol therapy

General or specific changes in the participant's condition render the participant 
unacceptable for further treatment in the judgment of the treating investigator
Participants will be removed from the protocol therapy when any of these criteria apply.  The 
reason for removal from protocol therapy, and the date the participant was removed, must be 
documented in the case report form (CRF). Alternative care options will be discussed with the 
participant.
A QACT Treatment Ended/Off Study Form will be filled out when a participant is removed from 
protocol therapy. This form can be found on the QACT website or obtained from the QACT 
registration staff.
In the event of unusual or life-threatening complications, treating investigators must immediately 
notify the Overall PI, David P. Ryan, M.D. 617-724-0245.
5.7
Duration of Follow Up
Participants will be followed for 4 weeks after removal from protocol therapy or until death, 
whichever occurs first.  Participants removed from protocol therapy for unacceptable adverse 
event(s) will be followed until resolution or stabilization of the adverse event.


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5.8
Criteria for Taking a Participant Off Study
Participants will be removed from study when any of the following criteria apply:

Lost to follow-up

Withdrawal of consent for data submission

Death
The reason for taking a participant off study, and the date the participant was removed, must be 
documented in the case report form (CRF).
For Centralized Subject Registrations, the research team submits a completed Off Treatment/Off 
Study form to ODQ when a participant comes off study. This form can be found on the ODQ 
website or obtained from the ODQ registration staff. 
For Decentralized Subject Registrations, the research team updates the relevant Off 
Treatment/Off Study information in OnCore. 
6.
DOSING DELAYS/DOSE MODIFICATIONS
Dose delays and modifications will be made as indicated in the following table(s). The 
descriptions and grading scales found in the revised NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.0 will be utilized for dose delays and dose modifications. A 
copy of the CTCAE version 4.0 can be downloaded from the CTEP website
 http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
Dose Level
Lamivudine Dose
Starting dose
600 mg po q 12 hours +/- 2 hours
-1
300 mg po q 12 hours +/- 2 hours 
-2 ***
150 mg po q 12 hours +/- 2 hours
*** For Creatinine Clearance 30 - <50 mL/min, 300 mg qd is okay. 
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 reported and/or potential AEs (Section 7.1) and the characteristics of an 
observed AE (Section 7.2) will determine whether the event requires expedited reporting in 
addition to routine reporting.
Expedited Reporting Guidelines
Use the NCI protocol number and the protocol-specific participant ID assigned during 
trial registration on all reports.


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Note:  A death on study requires both routine and expedited reporting regardless of 
causality, unless as noted below.  Attribution to treatment or other cause must be 
provided.
Death due to progressive disease should be reported as Grade 5 “Neoplasms benign, 
malignant and unspecified (incl cysts and polyps) - Other (Progressive Disease)” 
under the system organ class (SOC) of the same name.  Evidence that the death was a 
manifestation of underlying disease (e.g., radiological changes suggesting tumor 
growth or progression: clinical deterioration associated with a disease process) should 
be submitted. 
Phase 1 and Early Phase 2 Studies:  Expedited Reporting Requirements for Adverse 
Events that Occur on Studies under an IND/IDE within 30 Days of the Last Administration 
of the Investigational Agent/Intervention 1, 2
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312)
NOTE:  Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether or not 
they are considered related to the investigational agent(s)/intervention (21 CFR 312.64)
An adverse event is considered serious if it results in ANY of the following outcomes:  
1)
Death
2)
A life-threatening adverse event 
3)
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 
hours 
4)
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions 
5)
A congenital anomaly/birth defect. 
6)
Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization 
may be considered serious when, based upon medical judgment, they may jeopardize the patient or 
subject and may require medical or surgical intervention to prevent one of the outcomes listed in this 
definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6).
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via AdEERS 
within the timeframes detailed in the table below.
Hospitalization
Grade 1 and Grade 2 Timeframes
Grade 3-5
Timeframes
Resulting in 
Hospitalization 
≥ 24 hrs
10 Calendar Days
Not resulting in 
Hospitalization 
≥ 24 hrs
Not required
24-Hour 5 Calendar 
Days
NOTE:  Protocol specific exceptions to expedited reporting of serious adverse events are found in the Specific 
Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR.
Expedited AE reporting timelines are defined as:
o
“24-Hour; 5 Calendar Days” - The AE must initially be reported via AdEERS within 24 hours of learning of 
the AE, followed by a complete expedited report within 5 calendar days of the initial 24-hour report.
o
“10 Calendar Days” - A complete expedited report on the AE must be submitted within 10 calendar days of 
learning of the AE.
1Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows: 
Expedited 24-hour notification followed by complete report within 5 calendar days for:

All Grade 3, 4, and Grade 5 AEs
Expedited 10 calendar day reports for:


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
Grade 2 AEs resulting in hospitalization or prolongation of hospitalization
2For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, 
rounded UP to the nearest whole day, after the agent/intervention was last administered.  Footnote “1” above 
applies after this reporting period.
Effective Date:  May 5, 2011
Late Phase 2 and Phase 3 Studies: Expedited Reporting Requirements for Adverse Events 
that Occur on Studies under an IND/IDE within 30 Days of the Last Administration of the 
Investigational Agent/Intervention1, 2
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312)
NOTE:  Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether or not 
they are considered related to the investigational agent(s)/intervention (21 CFR 312.64)
An adverse event is considered serious if it results in ANY of the following outcomes:  
1)
Death
2)
A life-threatening adverse event 
3)
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 
hours 
4)
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions 
5)
A congenital anomaly/birth defect. 
6)
Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization 
may be considered serious when, based upon medical judgment, they may jeopardize the patient or 
subject and may require medical or surgical intervention to prevent one of the outcomes listed in this 
definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6).
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via AdEERS 
within the timeframes detailed in the table below.
Hospitalization
Grade 1 
Timeframes
Grade 2 
Timeframes
Grade 3 Timeframes
Grade 4 & 5 
Timeframes
Resulting in 
Hospitalization 
≥ 24 hrs
10 Calendar Days
Not resulting in
Hospitalization 
≥ 24 hrs
Not required
10 Calendar Days
24-Hour 5 
Calendar Days
NOTE:  Protocol specific exceptions to expedited reporting of serious adverse events are found in the Specific 
Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR
Expedited AE reporting timelines are defined as:
o
“24-Hour; 5 Calendar Days” - The AE must initially be reported via AdEERS within 24 hours of learning of 
the AE, followed by a complete expedited report within 5 calendar days of the initial 24-hour report.
o
“10 Calendar Days” - A complete expedited report on the AE must be submitted within 10 calendar days of 
learning of the AE.
1Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows: 
Expedited 24-hour notification followed by complete report within 5 calendar days for:

All Grade 4, and Grade 5 AEs
Expedited 10 calendar day reports for:

Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization 

Grade 3 adverse events
2For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, 
rounded UP to the nearest whole day, after the agent/intervention was last administered.  Footnote “1” above 
applies after this reporting period.


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Effective Date:  May 5, 2011
7.1
For CTEP protocols only: Comprehensive Adverse Events and Potential Risks List(s) (CAEPRs)
Not applicable 
7.1.1
CAEPRs for CTEP IND Agent(s)
Not applicable
7.1.1.1
CAEPR for [CTEP IND Agent #1]
Not applicable
7.1.1.2
CAEPR for [CTEP IND Agent #2]
Not applicable
7.1.2
Adverse Event List(s) for [Other Investigational Agent(s)]
Not applicable
7.1.3
Adverse Event List(s) for Commercial Agent(s)
Not applicable
7.1.4
CAEPR for [CIP IND Agent #1)]
Not applicable
7.1.5
Adverse Event List(s) for CIP (e.g. Study-Specific) Commercial Imaging Agents
Not applicable
7.2
For CTEP protocols only: Adverse Event Characteristics 
Not applicable


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7.3
For CTEP protocols only: Expedited Adverse Event Reporting
Not applicable
7.4
For CTEP protocols only: Routine Adverse Event Reporting
Not applicable
7.5
For CTEP protocols only: Secondary Malignancy
Not applicable
7.6
For CTEP protocols only: Second Malignancy
Not applicable
7.7
For non-CTEP protocols only: Expected Toxicities
Toxicities
Common

Gastrointestinal: Diarrhea (adults, 18%; pediatrics, 8%), Nausea (33%)

Neurologic: Headache (35%)

Respiratory: Cough (adults, 18%; pediatrics, 15%), Nasal symptom (adults, 20%; pediatrics, 
8%)

Other: Fever (adults, 10%; pediatrics, 25%), Malaise and fatigue (27%)
Serious

Endocrine metabolic: Fat maldistribution, Lactic acidosis

Gastrointestinal: Pancreatitis, Nausea and Abdominal Pain

Hepatic: Hepatomegaly (pediatrics, 11%), Relapsing type B viral hepatitis

Black Box Warning
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been 
reported. Severe acute exacerbations of hepatitis B have been reported in patients who have 
discontinued antihepatitis B therapy (including lamivudine) or who are coinfected with hepatitis 
B virus (HBV) and HIV-1 and have discontinued lamivudine; monitor hepatic function upon 
discontinuation of therapy. Epivir(R) tablets and oral solution (used to treat HIV-1 infection) 
contain a higher dose of the active ingredient (lamivudine) than Epivir-HBV(R) tablets and oral 
solution (used to treat chronic hepatitis B infection). Patients with HIV-1 infection should 
receive only dosage forms appropriate for treatment of HIV-1. Epivir-HBV(R) is not approved 
for the treatment of HIV-1 infection. HIV-1 resistance may emerge in chronic hepatitis B-
infected patients with unrecognized or untreated HIV-1 infection; offer HIV counseling and 
testing to all patients prior to beginning treatment with Epivir-HBV(R) and periodically during 
therapy
Patients will be given a higher dose of lamivudine that what is currently approved but the dose 
was studied and deemed to be safe in HIV patients. As described above, we will also plan to do a 


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safety run in ensuring safety on the higher dose before accruing the rest of the study.
7.8
For non-CTEP protocols only: 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 
4.0 will be utilized for AE reporting.  All appropriate treatment areas should have access 
to a copy of the CTCAE version 4.0.  A copy of the CTCAE version 4.0 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(s) that are listed above should be reported only if the adverse event 
varies in nature, intensity or frequency from the expected toxicity information which 
is provided.
-
Other AEs for the protocol that do not require expedited reporting are outlined in the 
next section (Expedited Adverse Event Reporting) under the sub-heading of Protocol-
Specific Expedited Adverse Event Reporting Exclusions.

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.
7.9
For non-CTEP protocols only: Expedited Adverse Event Reporting 
7.9.1
Investigators must report to the Overall PI any serious adverse event (SAE) that occurs 
after the initial dose of study treatment, during treatment, or within 30 days of the last 
dose of treatment on the local institutional SAE form. 
7.9.2
DF/HCC Expedited Reporting Guidelines
Investigative sites within DF/HCC will report AEs directly to the DFCI Office for 
Human Research Studies (OHRS) per the DFCI IRB reporting policy. 
DF/HCC Reportable AEs
Attribution
Gr. 2 & 3 AE
Expected
Gr. 2 & 3 AE 
Unexpected
Gr. 4 AE Expected
Gr. 4 AE
Unexpected
Gr. 5 AE 
Expected or 
Unexpected
Unrelated
Unlikely
Not required
Not required
5 calendar days#
5 calendar days
24 hours*


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Possible
Probable
Definite
Not required
5 calendar days
5 calendar days#
5 calendar days
24 hours*
# If listed in protocol as expected and not requiring expedited reporting, event does not need to be reported.
* For participants enrolled and actively participating in the study or for AEs occurring within 30 days of the last 
intervention, the AE should be reported within 1 business day of learning of the event.
7.10
Expedited Reporting to the Food and Drug Administration (FDA)
The Overall PI, as study sponsor, will be responsible for all communications with the FDA. The 
Overall PI will report to the FDA, regardless of the site of occurrence, any serious adverse event 
that meets the FDA’s criteria for expedited reporting following the reporting requirements and 
timelines set by the FDA.
7.11
Expedited Reporting to the NIH Office of Biotechnology Activities (OBA)
Not applicable
7.12
Expedited Reporting to the Institutional Biosafety Committee (IBC)
Not applicable
7.13
Expedited Reporting to Hospital Risk Management
Participating investigators will report to their local Risk Management office any participant 
safety reports or sentinel events that require reporting according to institutional policy. 
7.14
For non-CTEP protocols only: Routine Adverse Event Reporting
All Adverse Events must be reported in routine study data submissions to the Overall PI on the 
toxicity case report forms.  AEs reported through expedited processes (e.g., reported to the 
IRB, FDA, etc.) must also be reported in routine study data submissions.
8.
PHARMACEUTICAL AND/OR IMAGING AGENT INFORMATION
A list of the adverse events and potential risks associated with the investigational or other agents 
administered in this study can be found in Section 7.1.
8.1
Lamivudine
8.1.1
Description
Lamivudine, a synthetic nucleoside analogue, is phosphorylated intracellularly to its active 5'-


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triphosphate metabolite, lamivudine triphosphate. The nucleoside analogue is incorporated into 
viral DNA by HIV reverse transcriptase and HBV polymerase, resulting in DNA chain 
termination. Lamivudine triphosphate is a weak inhibitor of mammalian alpha-, beta-, and 
gamma-DNA polymerase
8.1.2
Form
150mg tablet
8.1.3
Storage and Stability
Store Lamivudine tablets at 25 degrees Celsius (77 degrees Fahrenheit) in a tightly closed 
container. Store lamivudine oral solution and tablets between 20 to 25 degrees Celsius (68 to 77 
degrees Fahrenheit) in a tightly closed bottle
8.1.4
Compatibility
Not applicable 
8.1.5
Handling
Qualified personnel, familiar with procedures that minimize undue exposure to themselves and 
the environment, should undertake the preparation, handling, and safe disposal of the 
chemotherapeutic agent in a self-contained and protective environment. 
8.1.6
Availability
Lamivudine will be obtained commercially
.
8.1.7
Preparation
Not applicable 
8.1.8
Administration
Lamivudine will be administered at a starting dose of 600 mg po BID. For the purposes of this 
protocol the term BID is equivalent to every 12 hours +/- 2 hours.
8.1.9
Ordering
Lamivudine will be stored by the MGH Research Pharmacy. Please check with the MGH 
Research Pharmacy for each new patient enrolled.
8.1.10 Accountability
The investigator, or a responsible party designated by the investigator, should maintain a 


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careful record of the inventory and disposition of the agent using the NCI Drug 
Accountability Record Form (DARF) or another comparable drug accountability form.  
(See the NCI Investigator’s Handbook for Procedures for Drug Accountability and 
Storage.)
8.1.11 Destruction and Return
Unused drug will be returned to study staff for proper handling and destruction.
8.2
IND Agent #2
Not applicable
8.3
Other Agent #1
Not applicable
8.4
Other Agent #2
Not applicable
9.
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES
9.1
Biomarker Studies
No paired biomarker for Ph II but biomarker work planned as detailed in 9.4 as correlative work
9.2
For IDE protocols only: Investigational Device Information
Not applicable
9.3
For IDE protocols only: Investigational Device Information
Not applicable
9.4
Laboratory Correlative Studies
9.4.1
RNA in situ Hybridization of Repeats as Novel Biomarker of Response
Preliminary data in colon cancer cell lines indicate that HSATII high cell lines are much more 
sensitive to NRTI treatment [5].  The LINE-1, TERRA, and HERV-H repeats are known to also 
be affected by NRTI treatment and will be analyzed in parallel with HSATII.  
We will utilize is RNA in situ hybridization (RNA-ISH) for targeted elements in standard 
archived formalin fixed paraffin embedded (FFPE) slides using the Affymetrix ViewRNA 
platform [4].  This assay has been optimized on the automated Leica Bond RX platform and 


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sequential slides will be stained for HSATII, LINE-1, TERRA, HERV-H, and GAPDH (RNA 
control). Only archived excess tissue will be utilized for this work. A pre-study biopsy will be 
required if a biopsy was not done after the most recent treatment received. The tumor biopsy 
should be collected, if medically feasible, in the opinion of the investigator.
9.4.1.1
Collection of Specimen(s)
Archived FFPE blocks will be obtained from the Department of Pathology
9.4.1.2
Handling of Specimens(s)
FFPE blocks will be sectioned on a microtome according to standard procedure in the MGH 
histopathology core facility.
9.4.1.3
Shipping of Specimen(s)
FFPE blocks will be sent to the MGH core through standard internal transport mechanisms.
9.4.1.4
Site(s) Performing Correlative Study
MGH Cancer Center – Charlestown Navy Yard Building 149
9.4.2
DNA and RNA sequencing of tumor for exploratory science
Preliminary analysis indicates TP53 mutation/deletion status may predict sensitivity to NRTIs.  
However, the full spectrum of other genomic aberrations has not been evaluated. If a CLIA 
certified molecular pathology targeted sequencing assay is requested for clinical care on these 
specimens, we will utilize that mutation data for correlative analysis. If the assay is not 
requested, total nucleic acids will be extracted from 1-5 10 micron thick slides in archived excess 
FFPE tissue per protocol (RecoverAll ThermoFisher #AM1975).  DNA will be prepped for 
whole exome sequencing using the Illumina whole exome sequencing kit and sequenced on the 
Illumina NextSeq platform. Given repetitive elements are not represented in whole exome 
sequencing, additional whole genome sequencing analysis to assess repeat genomic copy number 
changes may be performed.
RNA markers including innate immune response genes (i.e. interferon response genes) have also 
shown to be linked to repeat expression and we will perform RNA-seq on FFPE total nucleic 
acid extracted material. RNA-seq data will be analyzed with unsupervised clustering, principal 
component analysis, differential expression, and machine learning algorithms to determine if 
there is a transcriptional signature associated with response to NRTIs.  
RNA and DNA sequencing data will be shared with collaborating investigators for correlative 
science research. Original sequencing data will be shared with collaborators, but all samples will 
be de-identified and labeled with anonymized coding.  In addition, all original data will be 
uploaded to the appropriate NCBI archive (i.e. GEO, dbGAP, SRA) as directed by grant funding 
and publication rules.  


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9.4.2.1
Collection of Specimen(s)
Archived FFPE blocks will be obtained from the Department of Pathology
9.4.2.2
Handling of Specimens(s)
FFPE blocks will be sectioned on a microtome according to standard procedure in the MGH 
histopathology core facility.
9.4.2.3
Shipping of Specimen(s)
FFPE blocks will be sent to the MGH core through standard internal transport mechanisms.
9.4.2.4
Site(s) Performing Correlative Study
MGH Cancer Center – Charlestown Navy Yard Building 149
9.4.3
Blood Based Biomarkers to Monitor Disease Response 
Blood will be processed 
for CTC purification, 
plasma collection, and 
mononuclear cell 
isolation (Fig. 3).  
Approximately 10 mL of 
blood will be processed 
through the CTC-iChip 
platform for CTC 
isolation. We will divide 
the CTC product into 
three different analyses 
including 1) Standard IF 
staining 2) RNA-ISH 
staining and 3) bulk 
frozen CTC product for 
future qRT-PCR or 
sequencing analysis.  
The bulk frozen CTC product will be preserved using RNAlater stabilization solution (Qiagen 
Cat No. 76106).  RNAlater has been shown to significantly increase RNA recovery from CTC 
products and still permits the isolation and analysis of DNA and proteins from CTC product.  
One tube of RNAlater stabilized CTC product will be purified for RNA using the RNeasy Micro 
Kit (Qiagen Cat No. 74004). The other tube of RNAlater stabilized CTC product will be flash 
frozen and stored at -80°C for future exploratory research. 
The other 10 mL of blood will have plasma and mononuclear cells separated by Ficoll based 
Fig. 3:  Schematic of blood processing from patients on protocol.
CTC Purification
7-10 mL
(CTCs)
Ficoll Separation
7-10 mL
15-20 mL EDTA
Flash Frozen
CTC product
2 Tubes
Tube 1
RNA Purification
Qiagen RNEasy
Megafunnel
Cytology Slides
RNA-ISH
IF
25%
75%
Tube 2
Archived
CTC product
Plasma
(4-5 mL)
4 Tubes
Mononuclear Cells
(“Buffy Coat”)
2 Tubes
Archived
Plasma
Exosomes
(1-2 mL)
Archived
Buffy
Coat


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density centrifugation followed by immediate flash freezing and storage at -80°C. A 1-2 mL 
aliquot of plasma will be thawed and processed for exosomes capture on the HB-ExoChip and/or 
ultracentrifugation based methods. RNA will be isolated from exosomes using TRIzol (Thermo 
Fisher Cat No. 10296028) based purification. This RNA will be either used immediately for 
analysis or stored at -80°C.
9.4.3.1
Collection of Specimen(s)
All patients will have blood drawn into two 10 mL EDTA purple top tubes for analysis before 
treatment and then every two months on treatment for the duration of the study.  
9.4.3.2
Handling of Specimens(s)
Specimens will be stored at room temperature and sent within 1 hour to the CTC laboratory for 
processing at the MGH Cancer Center, Building 149, Charlestown, MA.  
9.4.3.3
Shipping of Specimen(s)
Blood will be transported to MGH Cancer Center, Building 149, Charlestown, MA via Partners 
Healthcare approved vendor US Ground.
9.4.3.4
Site(s) Performing Correlative Study:
MGH Cancer Center – Charlestown Navy Yard Building 149
9.4.4
Post Treatment Biopsies 
9.4.4.1
Collection of Specimen(s)
Mandatory fresh post-treatment biopsies will be collected and divided from 32 patients in 2 for 
1) formalin for standard formalin fixed paraffin embedding (FFPE) and 2) fresh frozen in liquid 
nitrogen or dry ice bath. FFPE slides will be stained using the Affymetrix ViewRNA platform on 
the automated Leica Bond RX platform. Sequential slides will be stained for HSATII, LINE-1, 
TERRA, HERV-H, and GAPDH (RNA control). Fresh frozen tumors will be processed for RNA 
and DNA extraction with the AllPrep spin column kit (Qiagen 80204).  RNA will be analyzed by 
RNA-sequencing using the Illumina Total RNA-seq library construction and sequencing on the 
NextSeq 2500 platform.  Excess RNA and DNA will be archived and stored at -80 degrees 
C.  DNA may be analyzed by whole genome, whole exome, or targeted gene sequencing. These 
mandatory post treatment biopsies will be done around cycle 2 day 1 of treatment. This biopsy 
should be +/- 1 week of treatment and of same lesion as pre-study biopsy if safe to do.
9.4.4.2
Handling of Specimens(s)
Fresh post-treatment biopsies will be collected and divided in 2 for 1) formalin for standard 
formalin fixed paraffin embedding (ffpe) and 2) fresh frozen in liquid nitrogen or dry ice bath.


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9.4.4.3
Shipping of Specimen(s)
Fresh post-treatment biopsies will be transported to MGH Cancer Center, Building 149, 
Charlestown, MA via Partners Healthcare approved vendor US Ground.
9.4.4.4
Site(s) Performing Correlative Study:
MGH Cancer Center – Charlestown Navy Yard Building 149
9.5
Special Studies
Not applicable
10. STUDY CALENDAR
Baseline evaluations are to be conducted within 2 weeks prior to start of protocol therapy.  Scans 
and x-rays must be done <4 weeks prior to the start of therapy.  In the event that the participant’s 
condition is deteriorating, laboratory evaluations should be repeated within 48 hours prior to 
initiation of the next cycle of therapy.
Assessments must be performed prior to administration of any study agent. Study assessments 
and agents should be administered within + 3 days of the protocol-specified date, unless 
otherwise noted.
Cycle 1*
Cycle 2+
Pre-Study
Day1
Day 8
Day 15
Day 22
Day1
Cycle 2 Day15I
2 months
Off StudyG
LAMIVUDINEA
X
X
X
X
X
X
Informed consent
X
Demographics
X
Medical history
X
Concurrent meds
X
X
X
X
X
X
X
Physical exam
X
X
X
X
X
X
X
X
Vital signs
X
X
X
X
X
X
X
X
Height
X
Weight
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
Serum chemistryB
X
X
X
X
X
X
X
X
EKG (as indicated)
X
Adverse event 
evaluation
X
X
X
X
X
X
Tumor 
measurements
X
Tumor measurements are repeated every 8 weeks. Documentation 
(radiologic) must be provided for participants removed from study 
for progressive disease.
X
Radiologic 
X
Radiologic measurements should be performed every 8 weeks.
X


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evaluation
B-HCGC
X
Tumor biopsy 
(archival)D***
X
Post treatment 
biopsy 
X**
Correlative studiesF
X
SurveysH
X
X
HIV test
X
HBV test
X
CEA
X
X
*Patient can remain on treatment until progression
**Patient will have biopsy at cycle 2 day 1 or prior should treatment be stopped prior. This biopsy should be +/- 1 week of treatment and of same lesion as pre-study biopsy if safe to 
do. 
***A pre-study biopsy will be required if a biopsy was not done after the most recent treatment received. The tumor biopsy should be collected, if medically feasible, in the opinion 
of the investigator
A.
Lamivudine is to be taken twice daily for all 28 days of the cycle
B.
Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, LDH, phosphorus, potassium, total protein, SGOT [AST], SGPT 
[ALT], sodium.
C.
Serum pregnancy test (women of childbearing potential.)
D.
See section 9.4.1
E.
See section 9.4.4
F.
Two 10ml EDTA tubes will be collected prior to the start of therapy and every 8 weeks while on therapy 
G.
Off-study evaluation. Note: for IND/IDE trials, follow up visits or other contact are required in order to identify SAEs during the 30 days following the end of study 
treatment.
H.
Surveys will be administered at baseline on the date of enrollment or prior to start and then at every 2 months at the time of scans.
I.
Cycle2 Day15 Visit will only be done at the discretion of the provider.
11. MEASUREMENT OF EFFECT
11.1
Antitumor Effect – Solid Tumors
For the purposes of this study, participants should be re-evaluated for response every 8 weeks.  
In addition to a baseline scan, confirmatory scans should also be obtained 8 weeks (not less than 
4) weeks following initial documentation of objective response.
Response and progression will be evaluated in this study using the new international criteria 
proposed by the 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.
11.1.1 Definitions
Evaluable for Target Disease response.  Only those participants who have measurable 
disease present at baseline, have received at least one cycle of therapy, and have had their 
disease re-evaluated will be considered evaluable for target disease response.  These 
participants will have their response classified according to the definitions stated below.  


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(Note:  Participants who exhibit objective disease progression prior to the end of cycle 1 
will also be considered evaluable.)
Evaluable Non-Target Disease Response.  Participants 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. 
11.1.2 Disease Parameters
Measurable disease.  Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) as ≥ 20 mm by 
chest x-ray or ≥10 mm 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. 
Malignant lymph nodes.  To be considered pathologically enlarged and measurable, a 
lymph node must be ≥15 mm in short axis when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm).  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 or pathological lymph nodes with ≥10 to <15 mm short axis), 
are considered non-measurable disease.  Bone lesions, leptomeningeal disease, ascites, 
pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, 
abdominal masses (not followed by CT or MRI), and cystic lesions are all considered 
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 participant, 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 


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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. 
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. 
11.1.3 Methods for Evaluation of Disease
All measurements should be taken and recorded in metric notation using a ruler, calipers, 
or a digital measurement tool.  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 in 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. 
Conventional CT and MRI. This guideline has defined measurability of lesions on CT 
scan based on the assumption that CT thickness is 5mm or less. If CT scans have slice 
thickness greater than 5 mm, the minimum size of 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 


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acquisition protocol should be followed as closely as possible to prior scans.  Body scans 
should be performed with breath-hold scanning techniques, if possible.
11.1.4 Response Criteria
11.1.4.1
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.
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.  (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.
11.1.4.2
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 
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).


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11.1.4.3
Evaluation of New Lesions
The finding of a new lesion should be unequivocal (i.e. not due to difference in 
scanning technique, imaging modality, or findings thought to represent something 
other than tumor (for example, some ‘new’ bone lesions may be simply healing or 
flare of pre-existing lesions). However, a lesion identified on a follow-up scan in an 
anatomical location that was not scanned at baseline is considered new and will 
indicate PD. If a new lesion is equivocal (because of small size etc.), follow-up 
evaluation will clarify if it truly represents new disease and if PD is confirmed, 
progression should be declared using the date of the initial scan on which the lesion 
was discovered.
11.1.4.4
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 Participants 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
>4 wks Confirmation**
CR
Non-CR/Non-
PD
No
PR
CR
Not evaluated
No
PR
PR
Non-CR/Non-
PD/not 
evaluated
No
PR
>4 wks Confirmation**
SD
Non-CR/Non-
PD/not 
evaluated
No
SD
Documented at least once >4 
wks from baseline**
PD
Any
Yes or No
PD
Any
PD***
Yes or No
PD
Any
Any
Yes
PD
no prior SD, PR or CR

See RECIST 1.1 manuscript for further details on what is evidence of a new lesion.
**        Only for non-randomized trials with response as primary endpoint.
***      In exceptional circumstances, unequivocal progression in non-target lesions may be
            accepted as disease progression.
Note:  Participants 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 


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43
objective progression even after discontinuation of treatment.
For Participants 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
11.1.5 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, or 
death due to any cause. Participants without events reported are censored at the last 
disease evaluation).
Duration of overall complete response: 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, or death due to any cause. Participants without events 
reported are censored at the last disease evaluation.
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. 
11.1.6 Progression-Free Survival
Overall Survival: Overall Survival (OS) is defined as the time from randomization (or 
registration) to death due to any cause, or censored at date last known alive.
Progression-Free Survival: Progression-Free Survival (PFS) is defined as the time from 
randomization (or registration) to the earlier of progression or death due to any cause. 
Participants alive without disease progression are censored at date of last disease 
evaluation.
Time to Progression: Time to Progression (TTP) is defined as the time from 
randomization (or registration) to progression, or censored at date of last disease 
evaluation for those without progression reported.


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11.2
Antitumor Effect – Hematologic Tumors
Not applicable 
11.3
Other Response Parameters
Not applicable 
12. 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).
12.1
Data Reporting
12.1.1 Method
The QACT will collect, manage, and perform quality checks on the data for this study.
12.1.2 Responsibility for Data Submission
Investigative sites within DF/HCC or DF/PCC are responsible for submitting data and/or data 
forms to the QACT according to the schedule set by the QACT.
12.2
Data Safety Monitoring
The DF/HCC Data and Safety Monitoring Committee (DSMC) will review and monitor toxicity 
and accrual data from this study. The committee is composed of clinical specialists with 
experience in oncology and who have no direct relationship with the study. Information that 
raises any questions about participant safety will be addressed with the Overall PI and study 
team.
The DSMC will review each protocol up to four times a year or more often if required to review 
toxicity and accrual data. Information to be provided to the committee may include: up-to-date 
participant accrual; current dose level information; DLT information; all grade 2 or higher 
unexpected adverse events that have been reported; summary of all deaths occurring with 30 
days of intervention for Phase I or II protocols; for gene therapy protocols, summary of all deaths 
while being treated and during active follow-up; any response information; audit results, and a 
summary provided by the study team. Other information (e.g. scans, laboratory values) will be 
provided upon request. 
12.3
Multicenter Guidelines
Not applicable


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12.4
Collaborative Agreements Language
Not applicable
13. STATISTICAL CONSIDERATIONS
13.1
Study Design/Endpoints
The primary endpoint for this study is to describe the ORR. All patients with measurable disease 
who receive at least one dose of lamivudine will be considered evaluable. The two-stage design 
to test the null hypothesis that the response rate is <=1% versus the alternative that response rate 
is >=10%. After testing the drug on 20 patients in the first stage, the trial will be terminated if 0 
respond. If the trial goes on to the second stage, a total of 32 patients will be studied. If the total 
number responding is less than or equal to 1, the treatment is rejected. The type I error is 3.6% 
and the power of the test is 80%.
Secondary endpoint includes median progression-free survival (PFS), overall disease control 
rate, and median overall survival (OS). We will apply Kaplan-Meier method to estimate the 
distribution of overall patient survival and progression free survival. Kaplan-Meier curves will 
be plotted to illustrate survival probabilities in OS and PFS. Estimated median survival time with 
95 % confidence intervals will be estimated and reported. Cox proportional hazards model will 
be applied to estimate the effect of confounding factors such as demographic and clinical factors
13.2
Sample Size, Accrual Rate and Study Duration
After testing the drug on 20 patients in the first stage, the trial will be terminated if 0 respond. If 
the trial goes on to the second stage, a total of 32 patients will be studied. We anticipate being 
able to accrue 32 patients in one year of study duration for an average of 3-4 patients a month, 
which we do not anticipate being a problem given our mCRC volume and the prevalence of p53 
mutations in this segment. A total of 12 evaluable participants will be accrued in 3 months. Up to 
an additional 2 months of follow-up will be required after the last participant to observe the 
participant’s response. Should there be 1 response; the study will continue to enroll the 
additional patients over an expected time course of 3 months with an additional 2 months of 
follow-up for an expected study duration of approximately 1 year. 
Accrual Targets
Sex/Gender
Ethnic Category
Females
Males
Total
Hispanic or Latino
1
+
2
=
3
Not Hispanic or Latino
11
+
18
=
29


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Ethnic Category: Total of all subjects
12
(A1)
+
20
(B1) =
32
(C1)
Racial Category
American Indian or Alaskan Native
0
+
0
=
0
Asian
1
+
3
=
4
Black or African American
2
+
3
=
5
Native Hawaiian or other Pacific 
Islander
0
+
0
=
0
White
9
+
14
=
23
Racial Category: Total of all subjects
12
(A2)
+
20
(B2) =
32
(C2)
(A1 = A2)
(B1 = B2)
(C1 = C2)
13.3
Stratification Factors
Not applicable
13.4
Interim Monitoring Plan
See 13.1 for two-staged design
13.5
Analysis of Primary Endpoints
See 13.1 for two-staged design
13.6
Analysis of Secondary Endpoints
Secondary correlative science endpoints will describe HSATTII expression in circulating tumor 
cells, archived resected/biopsied tumors as well as mandatory post treatment biopsies. This will 
be evaluated in correlation with outcome parameters as described in detail in the biomarker and 
correlative science section 9.4.  These correlative endpoints are exploratory in nature.  
13.7
Reporting and Exclusions
13.7.1 Evaluation of Toxicity
All patients who receive study drug will be considered evaluable for toxicity.
13.7.2 Evaluation of the Primary Efficacy Endpoint
Analysis will be by intent to treat.   
Total accrual may be adjusted to account for patients inevaluable for response, ie those patients 
not completing 1 cycle of therapy. 


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14. PUBLICATION PLAN
The results should be made public within 24 months of reaching the end of the study. The end of 
the study is the time point at which the last data items are to be reported, or after the outcome 
data are sufficiently mature for analysis, as defined in the section on Sample Size, Accrual Rate 
and Study Duration. If a report is planned to be published in a peer-reviewed journal, then that 
initial release may be an abstract that meets the requirements of the International Committee of 
Medical Journal Editors. A full report of the outcomes should be made public no later than 3 (3) 
years after the end of the study. 


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1.
BERRETTA, J. AND A. MORILLON, PERVASIVE TRANSCRIPTION 
CONSTITUTES A NEW LEVEL OF EUKARYOTIC GENOME REGULATION. EMBO REP, 
2009. 10(9): P. 973-82.
2.
JACQUIER, A., THE COMPLEX EUKARYOTIC TRANSCRIPTOME: 
UNEXPECTED PERVASIVE TRANSCRIPTION AND NOVEL SMALL RNAS. NAT REV 
GENET, 2009. 10(12): P. 833-44.
3.
JURKA, J., ET AL., REPBASE UPDATE, A DATABASE OF EUKARYOTIC 
REPETITIVE ELEMENTS. CYTOGENET GENOME RES, 2005. 110(1-4): P. 462-7.
4.
TING, D.T., ET AL., ABERRANT OVEREXPRESSION OF SATELLITE REPEATS 
IN PANCREATIC AND OTHER EPITHELIAL CANCERS. SCIENCE, 2011. 331(6017): P. 593-
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5.
BERSANI, F., ET AL., PERICENTROMERIC SATELLITE REPEAT EXPANSIONS 
THROUGH RNA-DERIVED DNA INTERMEDIATES IN CANCER. PROC NATL ACAD SCI U 
S A, 2015. 112(49): P. 15148-53.
6.
WYLIE, A., ET AL., P53 GENES FUNCTION TO RESTRAIN MOBILE 
ELEMENTS. GENES DEV, 2016. 30(1): P. 64-77.
7.
LIU, M.C., ET AL., CIRCULATING TUMOR CELLS: A USEFUL PREDICTOR OF 
TREATMENT EFFICACY IN METASTATIC BREAST CANCER. J CLIN ONCOL, 2009. 27(31): 
P. 5153-9.
8.
TOL, J., ET AL., CIRCULATING TUMOUR CELLS EARLY PREDICT 
PROGRESSION-FREE AND OVERALL SURVIVAL IN ADVANCED COLORECTAL CANCER 
PATIENTS TREATED WITH CHEMOTHERAPY AND TARGETED AGENTS. ANN ONCOL, 
2010. 21(5): P. 1006-12.
9.
REID, A.H., ET AL., SIGNIFICANT AND SUSTAINED ANTITUMOR ACTIVITY IN 
POST-DOCETAXEL, CASTRATION-RESISTANT PROSTATE CANCER WITH THE CYP17 
INHIBITOR ABIRATERONE ACETATE. J CLIN ONCOL, 2010. 28(9): P. 1489-95.
10.
DANILA, D.C., ET AL., PHASE II MULTICENTER STUDY OF ABIRATERONE 
ACETATE PLUS PREDNISONE THERAPY IN PATIENTS WITH DOCETAXEL-TREATED 
CASTRATION-RESISTANT PROSTATE CANCER. J CLIN ONCOL, 2010. 28(9): P. 1496-501.
11.
OZKUMUR, E., ET AL., INERTIAL FOCUSING FOR TUMOR ANTIGEN-
DEPENDENT AND -INDEPENDENT SORTING OF RARE CIRCULATING TUMOR CELLS. 
SCI TRANSL MED, 2013. 5(179): P. 179RA47.
12.
KISHIKAWA, T., ET AL., QUANTITATION OF CIRCULATING SATELLITE RNAS 
IN PANCREATIC CANCER PATIENTS. JCI INSIGHT. 1(8).
13.
Romanus, D., et al., Does health-related quality of life improve for advanced 
pancreatic cancer patients who respond to gemcitabine? Analysis of a randomized phase III trial 
of the cancer and leukemia group B (CALGB 80303). J Pain Symptom Manage, 2012. 43(2): p. 
205-17.
14.
Gourgou-Bourgade, S., et al., Impact of FOLFIRINOX compared with gemcitabine on 
quality of life in patients with metastatic pancreatic cancer: results from the PRODIGE 
4/ACCORD 11 randomized trial. J Clin Oncol, 2013. 31(1): p. 23-9.
15.
Crippa, S., et al., Quality of life in pancreatic cancer: analysis by stage and treatment. J 
Gastrointest Surg, 2008. 12(5): p. 783-93; discussion 793-4.


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16.
Kelsen, D.P., et al., Pain and depression in patients with newly diagnosed pancreas 
cancer. J Clin Oncol, 1995. 13(3): p. 748-55.
17.
Boyd, A.D. and M. Riba, Depression and pancreatic cancer. J Natl Compr Canc Netw, 
2007. 5(1): p. 113-6.
18.
Edgerly, M. and T. Fojo, Is there room for improvement in adverse event reporting in the 
era of targeted therapies? J Natl Cancer Inst, 2008. 100(4): p. 240-2.
19.
Berry, D.L., Patient-reported symptoms and quality of life integrated into clinical cancer 
care. Semin Oncol Nurs, 2011. 27(3): p. 203-10.
20.
Oberguggenberger, A., et al., Is the toxicity of adjuvant aromatase inhibitor therapy 
underestimated? Complementary information from patient-reported outcomes (PROs). 
Breast Cancer Res Treat, 2011. 128(2): p. 553-61.
21.
Meyers, F.J., et al., Simultaneous care: a model approach to the perceived conflict 
between investigational therapy and palliative care. J Pain Symptom Manage, 2004. 
28(6): p. 548-56.
22.
Aaronson, N.K., et al., The European Organization for Research and Treatment of 
Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in 
oncology. J Natl Cancer Inst, 1993. 85(5): p. 365-76.
23.
Watanabe, S.M., et al., A multicenter study comparing two numerical versions of the 
Edmonton Symptom Assessment System in palliative care patients. J Pain Symptom 
Manage, 2011. 41(2): p. 456-68.
24.
Zigmond, A.S. and R.P. Snaith, The hospital anxiety and depression scale. Acta 
Psychiatr Scand, 1983. 67(6): p. 361-70
25.
Zigmond, A.S. and R.P. Snaith, The hospital anxiety and depression scale. Acta 
Psychiatr Scand, 1983. 67(6): p. 361-70
26.
The Journal of Infectious Diseases, Volume 171, Issue 6, 1 June 1995, Pages 1438–
1447
27.
Aguirre, A.J., et al., Activated Kras and Ink4a/Arf deficiency cooperate to produce 
metastatic pancreatic ductal adenocarcinoma. Genes Dev, 2003. 17(24): p. 3112-26
28.
Bardeesy, N., et al., Both p16(Ink4a) and the p19(Arf)-p53 pathway constrain 
progression of pancreatic adenocarcinoma in the mouse. Proc Natl Acad Sci U S A, 2006. 
103(15): p. 5947-52.
29.
Hezel, A.F., et al., Genetics and biology of pancreatic ductal adenocarcinoma. 
Genes Dev, 2006. 20(10): p. 1218-49.
30. leeuwen et al. evaluation of safety and efficacy of 3tc (lamivudine) in patients with 
asymptomatic or mildly symptomatic human immunodeficiency virus infection: a phase i/ii 
study j infect dis. 1995 may;171(5):1166-71.) 
31. Bersani f et al. Pericentromeric satellite repeat expansions through rna-derived dna 
intermediates in cancer. PNAS 2015 December, 112 (49) 15148-15153


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


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APPENDIX B
MULTICENTER GUIDELINES
Not applicable 


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52
APPENDIX C
INFORMATION ON POSSIBLE DRUG INTERACTIONS
Not applicable 


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Protocol Version Date: November 14, 2019
53
APPENDIX D
BIOASSAY TEMPLATES
Not applicable 

ICF_001.pdf: 
 
 
 
 
Research Consent Form                  
for Biomedical Research 
Dana-Farber/ Harvard Cancer Center 
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates  
OHRS 09.23.16a 
 
Page 1 of 17 
 
DFCI Protocol Number:     17-044 
Approved Date (DFCI IRB Approval):  
08/23/2019 
Date Posted for Use:  
08/27/2019 
 
Protocol Title:   
A Phase 2 Study of lamivudine in patients with p53 mutant metastatic colorectal 
cancer 
DF/HCC Principal Research Doctor / Institution:   
Aparna Raj Parikh, MD / Massachusetts General Hospital 
Phase II Consent 
 
A. INTRODUCTION 
 
You are invited to take part in a clinical trial, a type of research study, because 
you have p53 mutant metastatic colorectal cancer.  This research study is 
studying a drug as a possible treatment for this diagnosis.   
 
The name of the study drug involved in this study is: 
• Lamivudine 
 
For purposes of this research, you will be referred to as a “participant”.   
 
It is expected that about 32 people will take part in this research study.  
 
An Internal Fund at MGH, is supporting this research study by providing funding 
for the research study. 
 
This research consent form explains why this research study is being done, what 
is involved in participating in the research study, the possible risks and benefits 
of participation, alternatives to participation, and your rights as a research 
participant.  The decision to participate is yours.  If you decide to participate, 
please sign and date at the end of this form. We will give you a copy so that you 
can refer to it while you are involved in this research study. If you choose not to 
participate in this research study, the research doctors will discuss other 
treatment options with you and/or refer you back to your primary doctor.  
 
We encourage you to take some time to think this over, to discuss it with other 
people and your primary doctor, and to ask questions now and at any time in the 
future. 
 
B. WHY IS THIS RESEARCH STUDY BEING DONE?  
   
5/1/2021 2:08 am


 
 
 
 
Research Consent Form                  
for Biomedical Research 
Dana-Farber/ Harvard Cancer Center 
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates  
OHRS 09.23.16a 
 
Page 2 of 17 
 
DFCI Protocol Number:     17-044 
Approved Date (DFCI IRB Approval):  
08/23/2019 
Date Posted for Use:  
08/27/2019 
 
This research study is a Phase II clinical trial.  Phase II clinical trials test the 
safety and effectiveness of an investigational drug to learn whether the drug 
works in treating a specific disease.  “Investigational” means that the drug is 
being studied.   
 
The FDA (the U.S. Food and Drug Administration) has not approved lamivudine 
for your specific disease but it has been approved for other uses. 
 
In this research study, we are studying the effects of lamivudine on your type of 
cancer.  This drug may help prevent the growth and spread of the cancer cells to 
other parts of your body. We have discovered that your particular type of colon 
cancer, which has a p53 mutation may be sensitive to treatment with lamivudine 
by impairing the ability of the cancer cells to grow.  
 
C. WHAT OTHER OPTIONS ARE THERE? 
 
Taking part in this research study is voluntary. Instead of being in this research 
study, you have other options which may include the following 
 
• Receive standard treatment including TAS-102 or Regorafenib 
• Take part in another research study.  
• Receive no therapy specific to your cancer. 
• Comfort care, also called palliative care.  This type of care may help to 
reduce pain, tiredness, appetite problems and other problems caused 
by the cancer.  It does not treat the cancer directly, but instead tries to 
treat the symptoms.   
 
Please talk to the research doctor about your options before you decide whether 
you will take part in this research study. 
 
D. WHAT IS INVOLVED IN THE RESEARCH STUDY? 
 
Sometimes it is hard to keep track of all of the details and procedures that are 
part of a research study.  We will describe them in this consent form and you can 
refer to this at any time during the research study. 
 
 
Before the research starts (screening):   
After signing this consent form, you will be asked to undergo some screening 
tests or procedures to find out if you can be in the research study.  Many of these 
5/1/2021 2:08 am


 
 
 
 
Research Consent Form                  
for Biomedical Research 
Dana-Farber/ Harvard Cancer Center 
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates  
OHRS 09.23.16a 
 
Page 3 of 17 
 
DFCI Protocol Number:     17-044 
Approved Date (DFCI IRB Approval):  
08/23/2019 
Date Posted for Use:  
08/27/2019 
 
tests and procedures are likely to be part of regular cancer care and may be 
done even if it turns out that you do not take part in the research study.  If you 
have had some of these tests or procedures recently, they may or may not have 
to be repeated.   
 
• A medical history, which includes questions about your health, current 
medications, and any allergies. 
• Physical exam, Including your height and weight measurements and your 
vital signs. 
• Performance status, which evaluates how you are able to carry on with 
your usual activities.  
• Blood Tests. You will have 15-20 ml of blood drawn to see how your body 
is reacting to this treatment. 
• Electrocardiogram (EKG), which measures your heart’s electrical activity 
• An assessment of your tumor by one or more of the following standard 
assessment tools: X-ray, CT (Computerized Tomography) scan, MRI 
(Magnetic Resonance Imaging) or PET (Positron Emission Tomography) 
scans 
• Your previously collected and stored tissue (archival tissue) will be 
obtained for tests. No additional tissue will be collected. 
• Tumor Biopsies. A  pre study biopsy will be required if a biopsy was not 
done after the most recent treatment received. The tumor biopsy should 
be collected, if medically feasible, in the opinion of the investigator. There 
will also be a biopsy at cycle 2 day 1 of treatment or prior if participants 
come off study prior. This biopsy should be +/- 1 week of treatment and of 
same lesion as pre-study biopsy if safe to do. These biopsies will help us 
understand the tumor at the time of starting treatment and the effect of the 
drug on the tumor. We do what we call sequencing of the tumor and we 
will look at the DNA and RNA of the tumor which can help us understand 
how the tumor reacts to the treatment.  We also will look at how the 
immune system is working in the tumor based on the effect of the 
lamivudine. 
 
These screening procedures may be repeated at each study visit. 
 
If these tests show that you are eligible to participate in the research study, you 
may begin the study treatment.  If you do not meet the eligibility criteria, you will 
not be able to participate in this research study. 
 
Study Treatment Overview: 
5/1/2021 2:08 am


 
 
 
 
Research Consent Form                  
for Biomedical Research 
Dana-Farber/ Harvard Cancer Center 
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates  
OHRS 09.23.16a 
 
Page 4 of 17 
 
DFCI Protocol Number:     17-044 
Approved Date (DFCI IRB Approval):  
08/23/2019 
Date Posted for Use:  
08/27/2019 
 
• Oral Study Drug(s):  Each study treatment cycle lasts 28 days during 
which time you will be taking the study drug Lamivudine 2 times per day.  
This will continue until disease progression or you are taken off of the 
study.     
 
You will come into the clinic once a week for all cycles and once again at the off-
study appointment.  You will be followed for up to 4 months after you have 
completed the study, or once you are taken off of the study. 
If you take part in this research study you will be given a drug diary.  You will be 
asked to document information in the drug diary about the study treatment you 
are being asked to take. 
 
Research Study Plan: 
 
 
Pre-
Study 
Cycle 1* 
Cycle 2+* 
 
2 months Off Study 
Day1 
Day 8 
Day 15 
Day 22 
Day1 
Cycle 2 
Day15§ 
 
 
Medical history* 
X 
X 
X 
X 
X 
X 
X 
 
 
Physical exam* 
X 
X 
X 
X 
X 
X 
X 
 
X 
Performance 
status* 
X 
X 
X 
X 
X 
X 
X 
 
X 
Blood Tests* 
X 
X 
X 
X 
X 
X 
X 
 
X 
EKG (as 
indicated)* 
X 
 
 
 
 
 
 
 
 
Tumor 
Assessment** 
X 
Tumor measurements are repeated 
every 8 weeks. Documentation 
(radiologic) must be provided for 
participants removed from study for 
progressive disease. 
 
 
 
X 
Archival Tissue 
X 
 
 
 
 
 
 
 
 
Tumor Biopsy 
X**** 
 
 
 
 
X*** 
 
 
 
Lamivudine 
 
X 
X 
X 
X 
X 
X 
 
 
Surveys¶ 
X 
 
 
 
 
 
 
X 
 
HIV test 
X 
 
 
 
 
 
 
 
 
5/1/2021 2:08 am


 
 
 
 
Research Consent Form                  
for Biomedical Research 
Dana-Farber/ Harvard Cancer Center 
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates  
OHRS 09.23.16a 
 
Page 5 of 17 
 
DFCI Protocol Number:     17-044 
Approved Date (DFCI IRB Approval):  
08/23/2019 
Date Posted for Use:  
08/27/2019 
 
HBV test 
X 
 
 
 
 
 
 
 
 
CEA 
 
X 
 
 
 
X 
 
 
 
 
*All Assessment will occur +/- 3 days 
**Tumor Assessments will occur every 8 weeks 
***On treatment biopsy will occur at cycle 2 day 1 or prior should treatment be 
stopped prior. This biopsy should be +/- 1 week of treatment and of same lesion 
as pre-study biopsy if safe to do. 
****A pre study biopsy will be required if a biopsy was not done after the most 
recent treatment received. The tumor biopsy should be collected, if medically 
feasible, in the opinion of the investigator 
§  Cycle2 Day15 visit will only be done at the discretion of the provider. 
¶  Surveys will be administered at baseline on the date of enrollment or prior to 
start and then at every 2 months at the time of scans 
 
Planned Follow-up:  
We would like to keep track of your medical condition.  We would like to do this 
by having you come into the clinic for a follow-up visit.  Keeping in touch with you 
and checking your condition helps us look at the long-term effects of the research 
study.  
 
E. HOW LONG WILL I BE IN THIS RESEARCH STUDY? 
 
You will be on the study treatment until the time of disease progression or if you 
are taken off of the protocol.  You will be followed for an additional 4 months. 
 
You may be taken off the research study drug for many reasons including if: 
• It is considered to be in your best interest 
• The study treatment or procedures are found to be unsafe or ineffective 
• There is any problem with following study treatments and procedures 
• You are a female and become pregnant or plan to become pregnant 
• Your condition worsens 
• A decision is made to close the study 
• Or for other unforeseen reasons that make it necessary to stop your 
participation in the research study 
 
If you are removed from the research study, the research doctor will explain to 
you why you were removed. 
 
5/1/2021 2:08 am


 
 
 
 
Research Consent Form                  
for Biomedical Research 
Dana-Farber/ Harvard Cancer Center 
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates  
OHRS 09.23.16a 
 
Page 6 of 17 
 
DFCI Protocol Number:     17-044 
Approved Date (DFCI IRB Approval):  
08/23/2019 
Date Posted for Use:  
08/27/2019 
 
In addition, you can stop participating in the research study at any time, however, 
the FDA requires that any information collected up to the point of your withdrawal 
cannot be removed from the study.  If you decide to stop participating in this 
research study, we encourage you to talk to the research doctor and your 
primary doctor first. 
 
F. WHAT ARE THE RISKS OR DISCOMFORTS OF THE RESEARCH STUDY? 
 
There are risks to taking part in any research study. One risk is that you may get 
a study drug that does not help treat your disease or that makes your condition or 
disease worse.  Another risk is that there may be side effects.   
 
All cancer treatments can have side effects, which can range from mild and 
reversible to severe, long lasting and possibly life-threatening.  There is a great 
deal of variability among side effects of different cancer treatments and between 
individuals.  In a research study, all of the risks or side effects may not be known 
before you start the study. You need to tell your doctor or a member of the 
study team immediately if you experience any side effects.  
Everyone in the research study will be watched carefully for side effects.  You will 
be monitored during the administration of study drugs to keep track of your blood 
counts and organ function, particularly your kidney and liver function.  If you 
experience side effects, they may go away after you stop taking the study drug.  
Some side effects can be mild; but others can be long lasting and may never go 
away.  Some may be life-threatening or fatal.  
 
Since the effect of the study drug taken with other medications may not be 
known, it is important that you tell the research doctor about all prescription and 
non-prescription drugs, herbal preparations and nutritional supplements that you 
are taking or planning to take. There may also be some foods that you should 
avoid while on this research study and your research doctor will review this 
information with you. 
 
During the research study, you will be notified of newly discovered side effects or 
significant findings, which may affect your health or willingness to participate.  
You may be asked to sign a new consent form that shows that you have been 
informed of new information relating to this research study. 
 
Risks Associated with Lamivudine: 
 
You will be given a higher dose of lamivudine that what is currently approved but 
the dose was studied and deemed to be safe in HIV patients. We will also plan to 
5/1/2021 2:08 am


 
 
 
 
Research Consent Form                  
for Biomedical Research 
Dana-Farber/ Harvard Cancer Center 
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates  
OHRS 09.23.16a 
 
Page 7 of 17 
 
DFCI Protocol Number:     17-044 
Approved Date (DFCI IRB Approval):  
08/23/2019 
Date Posted for Use:  
08/27/2019 
 
enroll a few patients and ensure they are safe on the higher dose before accruing 
the rest of the study. In HIV patients, mild diarrhea, headache, fatigue, nausea 
and abdominal pain were most commonly reported events. 
 
 
Frequent (Between a 10-50% chance that this will happen) 
• Diarrhea 
• Nausea 
• Headache 
• Cough 
• Your nasal cavity may fill with a significant amount of mucus fluid 
which may lead to a runny nose (rhinorrhea) 
• Fever 
• Pain in your abdomen, muscles, and bones 
• Fatigue 
 
Occasional (Between a 1-10% chance that this will happen) 
• Inflammation of the pancreas (Pancreatitis) which may cause upper 
abdominal pain, abdominal pain that radiates to your back, abdominal 
pain that feels worse after eating, fever, rapid pulse, nausea, vomiting, 
and tenderness when touching the abdomen. 
 
Rare (Less than a 1% chance that this will happen) 
• Fat in your body will not be distributed evenly (fat maldistribution) 
• Lactic acid build up in your body (lactic acidosis) which may cause 
stomach discomfort, decreased appetite, diarrhea, fast, shallow 
breathing, discomfort, muscle pain, fatigue (tiredness), and weakness. 
• Enlarged liver (Hepatomegaly) which may cause yellowing of the skin 
or eyes, muscle aches, fatigue, itching, nausea, vomiting, abdominal 
pain, and poor appetite. 
• Relapsing (return of) Type B Viral Hepatitis which may cause dark 
urine, stomach pain, yellowing of the skin or eyes, pale/clay-colored 
stool, low-grad fever, loss of appetite, fatigue, feeling sick to the 
stomach and a lack of nutrition. 
 
Cancer research often includes biopsies, scans, x-rays that are also provided as 
routine care.  The following describes the side effects of procedures done only 
for the purposes of research.  
 
5/1/2021 2:08 am


 
 
 
 
Research Consent Form                  
for Biomedical Research 
Dana-Farber/ Harvard Cancer Center 
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates  
OHRS 09.23.16a 
 
Page 8 of 17 
 
DFCI Protocol Number:     17-044 
Approved Date (DFCI IRB Approval):  
08/23/2019 
Date Posted for Use:  
08/27/2019 
 
Risks Associated with Biopsies: 
 
Biopsies are normally performed under the guidance of an imaging technique. 
Each procedure requires a separate consent prior to the biopsy. The risks may 
include: 
• Pain and discomfort. The amount of pain and discomfort will vary, 
depending on the location of the biopsy site. These risks can be discussed 
with the study doctor. 
• Minor bleeding at the biopsy site. 
• Tenderness at the biopsy site. 
• Scarring at the biopsy site. 
• Rarely, an infection at the biopsy site. 
 
Uncommonly, complications from biopsies can be life threatening. As with any 
interventional procedure, other potentially serious complications from bleeding or 
organ damage may occur. These might require additional surgical intervention. 
 
Risks Associated with MRI Scans:  
When having an MRI (Magnetic Resonance Imaging) scan, you will lie still on a 
table that slides into a tunnel slightly wider than your body. People who feel 
uncomfortable in confined spaces (claustrophobia) may feel uncomfortable in the 
narrow cylinder. If you feel uncomfortable in confined spaces, please tell your 
research doctor. Your doctor may give you a medication to make you feel more 
comfortable. As images are taken, a loud banging noise will be produced.  
Earplugs or headphones will be available if needed. The MRI can be stopped at 
any time at your request, but the scan may not be complete. 
 
The MRI has the potential, during normal routine use, to cause localized warming 
of your skin and the underlying tissues.  You should immediately inform us if you 
experience discomfort due to warming and the procedure will be stopped. 
 
Risks Associated with Contrast Agents Used During Scans: 
There is a small risk with using a contrast agent that is injected into a vein during 
the PET-CT.  The contrast agent is a special dye that highlights organs, blood 
vessels or tissue to make them more visible.  Depending on the type of contrast 
agent that is used, it may cause decreased kidney function or worsen kidney 
function in people who already have decreased kidney function.  Therefore, we 
will monitor your kidney function closely while you participate in this study.  If 
there is any change in your kidney function, we may have to remove you from the 
study. 
 
5/1/2021 2:08 am


 
 
 
 
Research Consent Form                  
for Biomedical Research 
Dana-Farber/ Harvard Cancer Center 
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates  
OHRS 09.23.16a 
 
Page 9 of 17 
 
DFCI Protocol Number:     17-044 
Approved Date (DFCI IRB Approval):  
08/23/2019 
Date Posted for Use:  
08/27/2019 
 
Uncommonly, some people have allergic reactions (such as hives and itching) to 
the contrast agent.  Serious reactions (for example, drop in blood pressure, 
difficulty breathing or severe allergic reaction and death) are rare.   
 
Reproductive Risks:  
The drugs used in this research study may affect a fetus.  While participating in 
this research study and for 4 months after, you should not become pregnant or 
father a baby, and should not nurse a baby.  We can provide counseling about 
preventing pregnancy for either male or female study participants. Let your 
doctor know immediately if you become pregnant or find out that you are going to 
be the father of a child. 
 
In the event that your partner becomes pregnant, it may be critical to share 
information regarding your participation in this research study with that person.  
Your research doctor should also be told if this happens.   
 
Non-Physical Risks:  
Because of side effects or the time required for tests and clinic visits while you 
are on this research study, you may be unable to keep up with your normal daily 
activities.  
 
G. WHAT ARE THE BENEFITS OF THE RESEARCH STUDY? 
 
We do not know if taking part in this study will help you. This study may help 
researchers learn information that could help people in the future. 
 
 
 
 
H. CAN I STOP BEING IN THE RESEARCH STUDY AND WHAT ARE MY RIGHTS? 
 
You have the right to choose not to sign this form.  If you decide not to sign this 
form, you cannot participate in this research study.  
 
You can stop being in the research study at any time.  Tell the research doctor if 
you are thinking about stopping or decide to stop.  He or she will tell you how to 
stop.  Leaving the research study will not affect your medical care outside of the 
research study.   
 
If you choose not to participate, are not eligible to participate, or withdraw from 
this research study, this will not affect your present or future care and will not 
cause any penalty or loss of benefits to which you are otherwise entitled.  
 
5/1/2021 2:08 am


 
 
 
 
Research Consent Form                  
for Biomedical Research 
Dana-Farber/ Harvard Cancer Center 
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates  
OHRS 09.23.16a 
 
Page 10 of 17 
 
DFCI Protocol Number:     17-044 
Approved Date (DFCI IRB Approval):  
08/23/2019 
Date Posted for Use:  
08/27/2019 
 
It is important to tell the research doctor if you are thinking about stopping so 
your research doctor can evaluate the risks from stopping the drug. 
 
I. WILL I BE PAID TO TAKE PART IN THIS RESEARCH STUDY? 
 
You will not be paid for participating in this study.  
 
We may use your samples and information to develop a new product or medical 
test to be sold.  The sponsor and hospital may benefit if this happens. There are 
no plans to pay you if your samples are used for this purpose.  
 
J. WHAT ARE THE COSTS? 
 
Taking part in this research study might lead to added costs to you or your 
insurance company. 
 
You will not be charged for lamivudine.  It is possible that lamivudine may not 
continue to be supplied free for some reason.  If this would occur, your research 
doctor will talk with you about your options. 
 
You or your insurance company will be charged for portions of your care during 
this research study that are considered standard care. You may be responsible 
for co-payments and deductibles that are typical for your insurance coverage. 
 
If you have questions about your insurance coverage, or the items you might be 
required to pay for, please call financial services for information.  The contact 
information for financial services are:   
 
• Massachusetts General Hospital: (617) 726-2191 
 
The National Cancer Institute provides an online resource to help people 
participating in cancer clinical trials understand which services their insurance 
company is required by law to pay.  This can be found at the website below or 
can be provided by the study team: 
 
www.cancer.gov or 1-800-4-CANCER (1-800-422-6237) 
 
K. WHAT HAPPENS IF I AM INJURED OR BECOME SICK BECAUSE I TOOK PART IN 
THIS RESEARCH STUDY? 
 
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Research Consent Form                  
for Biomedical Research 
Dana-Farber/ Harvard Cancer Center 
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates  
OHRS 09.23.16a 
 
Page 11 of 17 
 
DFCI Protocol Number:     17-044 
Approved Date (DFCI IRB Approval):  
08/23/2019 
Date Posted for Use:  
08/27/2019 
 
If you think you have been injured as a result of taking part in this research study, 
tell the person in charge of this research study as soon as possible.  The 
research doctor’s name and phone number are listed in this consent form. 
 
The treating hospital will offer you the care needed to treat injuries directly 
resulting from taking part in this research.  These treatments will be billed to your 
insurance company. You will be responsible for deductibles and co-payments. 
There are no plans to pay you or give you other compensation for the injury. You 
do not give up your legal rights by signing this form.  
 
 We will need to collect certain personal information about you for insurance or 
payment reporting purposes, such as your name, date of birth, gender, social 
security number or Medicare identification number and information related to this 
research study. We may be required to report this information to the Centers for 
Medicare & Medicaid Services. We will not use this information for any other 
purpose. 
 
L. Future use of data and Specimens 
 
Your personal information and/or biospecimens collected during this study may 
be stored and used for future research.  Any personal identifiers will be removed, 
before they are shared, so that the information or samples cannot be linked back 
to you.  
 
Investigators, including investigators from collaborating institutions, can request 
this data and samples for new research.  Samples and data may also be shared 
with outside non-profit academic investigators as well as with for-profit 
pharmaceutical investigators or commercial entities, with whom we collaborate. 
 
You will not be asked to provide additional informed consent for the use of your 
identifiable information or samples in future research. 
 
Future research studies may include genetic research.  Your genes are unique to 
you.  At this time, you cannot be identified through this research, if the samples 
and specimens are anonymized. There is a risk that you might be reidentified in 
the future as genetic research progresses 
 
 
M. GENETIC RESEARCH 
 
This research will involve genomic and germline testing. 
5/1/2021 2:08 am


 
 
 
 
Research Consent Form                  
for Biomedical Research 
Dana-Farber/ Harvard Cancer Center 
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates  
OHRS 09.23.16a 
 
Page 12 of 17 
 
DFCI Protocol Number:     17-044 
Approved Date (DFCI IRB Approval):  
08/23/2019 
Date Posted for Use:  
08/27/2019 
 
 
The Genetic Information Nondiscrimination Act of 2008 (GINA) is a federal law 
that protects Americans from being treated unfairly because of differences in 
their DNA that may affect their health, and may prevent discrimination by health 
insurers and employers based on genetic information.  GINA is intended to ease 
concerns about discrimination that might keep some people from getting genetic 
tests that could benefit their health, and enable people to take part in research 
studies such as this without fear that their DNA information might be used 
against them by health insurers or their workplace.  This protection does not 
extend to disability or life insurance. Additional information can be found at 
http://www.genome.gov/10002328. 
 
As part of this study, your anonymized specimens or genetic data may be placed 
into one or more publicly-accessible scientific databases, such as the National 
Institutes of Health's Database for Genotypes and Phenotypes (dbGaP). Through 
such databases, researchers from around the world will have access to 
anonymized samples or data for future research. 
 
 
N. WHAT ABOUT CONFIDENTIALITY? 
 
We will take measures to protect the privacy and security of all your personal 
information, but we cannot guarantee complete confidentiality of study data.  
 
Medical information created by this research study may become part of your 
hospital medical record and may be forwarded to your primary doctor. 
Information that does not become part of your medical record will be stored in 
your study file.  It may also become part of a DF/HCC research database.   
 
The results of this research study may be published. You will not be identified in 
publications without your permission. 
 
As participation in this study involves providing a specimen of your tissue, please 
know that if the research doctor leaves the institution, the research and the tissue 
might remain at the DF/HCC or might be transferred to another institution. 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, 
as required by U.S. Law.  This Web site will not include information that can 
identify you.  At most, the Web site will include a summary of the results.  You 
can search this Web site at any time. 
 
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Research Consent Form                  
for Biomedical Research 
Dana-Farber/ Harvard Cancer Center 
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates  
OHRS 09.23.16a 
 
Page 13 of 17 
 
DFCI Protocol Number:     17-044 
Approved Date (DFCI IRB Approval):  
08/23/2019 
Date Posted for Use:  
08/27/2019 
 
O. WHOM DO I CONTACT IF I HAVE QUESTIONS ABOUT THE RESEARCH STUDY? 
 
If you have questions about the study, please contact the research doctor or 
study staff as listed below: 
 
Massachusetts General Hospital 
• Aparna Raj Parikh, MD: (617) 724-4000 
 
24-hour contact: Please contact Massachusetts General Hospital at 617-724-
4000 and ask that your doctor be paged. 
 
For questions about your rights as a research participant, please contact a 
representative of the Office for Human Research Studies at DFCI (617) 632-
3029. This can include questions about your participation in the study, concerns 
about the study, a research related injury, or if you feel/felt under pressure to 
enroll in this research study or to continue to participate in this research study.  
 
P. PRIVACY OF PROTECTED HEALTH INFORMATION 
 
Federal law requires Dana-Farber/Harvard Cancer Center (DF/HCC) and its 
affiliated research doctors, health care providers, and physician network to 
protect the privacy of information that identifies you and relates to your past, 
present, and future physical and mental health conditions (“protected health 
information”).  If you enroll in this research study, your “protected health 
information” will be used and shared with others as explained below. 
 
1. What protected health information about me will be used or shared with 
others during this research? 
 
• Existing medical records, including mental health records. 
• New health information created from study-related tests, procedures, 
visits, and/or questionnaires 
 
2. Why will protected information about me be used or shared with others? 
 
The main reasons include the following: 
• To conduct and oversee the research described earlier in this form; 
• To ensure the research meets legal, institutional, and accreditation 
requirements;  
5/1/2021 2:08 am


 
 
 
 
Research Consent Form                  
for Biomedical Research 
Dana-Farber/ Harvard Cancer Center 
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates  
OHRS 09.23.16a 
 
Page 14 of 17 
 
DFCI Protocol Number:     17-044 
Approved Date (DFCI IRB Approval):  
08/23/2019 
Date Posted for Use:  
08/27/2019 
 
• To conduct public health activities (including reporting of adverse events 
or situations where you or others may be at risk of harm); and 
• To provide the study sponsor with information arising from an adverse 
event or other event that relates to the safety or toxicity of the drug(s) 
used in the study and for the purpose of this or other research relating the 
study drug(s) and their use in cancer;  
• To better understand the diseases being studied and to improve the 
design of future studies; and, 
• Other reasons may include for treatment, payment, or health care 
operations.  For example, some medical information produced by this 
research study may become part of your hospital medical record because 
the information may be necessary for your medical care. (You will also be 
given a notice for use and sharing of protected health information.) 
 
3. Who will use or share protected health information about me? 
 
• DF/HCC and its affiliated research doctors and entities participating in the 
research will use and share your protected health information.  In addition, 
other DF/HCC offices that deal with research oversight, billing or quality 
assurance will be able to use and share your protected health information. 
 
 
 
 
4. With whom outside of DF/HCC may my protected health information be 
shared? 
 
While all reasonable efforts will be made to protect the confidentiality of your 
protected health information, it may also be shared with the following entities: 
 
• Outside individuals or entities that have a need to access this information 
to perform functions relating to the conduct of this research such as 
analysis by outside laboratories on behalf of DF/HCC and its affiliates (for 
example, data storage companies, insurers, or legal advisors). 
• The sponsor(s) of the study, its subcontractors, representatives, business 
partners, and its agent(s): DF/HCC 
• The funder(s) of the study, its subcontractors, representatives, business 
partners, and its agent(s): Sundry  
• Other research doctors and medical centers participating in this research, 
if applicable 
5/1/2021 2:08 am


 
 
 
 
Research Consent Form                  
for Biomedical Research 
Dana-Farber/ Harvard Cancer Center 
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates  
OHRS 09.23.16a 
 
Page 15 of 17 
 
DFCI Protocol Number:     17-044 
Approved Date (DFCI IRB Approval):  
08/23/2019 
Date Posted for Use:  
08/27/2019 
 
 
• Federal and state agencies (for example, the Department of Health and 
Human Services, the Food and Drug Administration, the National 
Institutes of Health, and/or the Office for Human Research Protections), or 
other domestic or foreign government bodies if required by law and/or 
necessary for oversight purposes. A qualified representative of the FDA 
and the National Cancer Institute may review your medical records. 
• Hospital accrediting agencies 
• A data safety monitoring board organized to oversee this research, if 
applicable 
 
Some who may receive your protected health information may not have to 
satisfy the privacy rules and requirements.  They, in fact, may share your 
information with others without your permission.  
 
5. For how long will protected health information about me be used or 
shared with others? 
 
• There is no scheduled date at which your protected health information that 
is being used or shared for this research will be destroyed, because 
research is an ongoing process.   
 
6. Statement of privacy rights: 
 
• You have the right to withdraw your permission for the research doctors 
and participating DF/HCC entities to use or share your protected health 
information.  We will not be able to withdraw all the information that 
already has been used or shared with others to carry out related activities 
such as oversight, or that is needed to ensure quality of the study. To 
withdraw your permission, you must do so in writing by contacting the 
researcher listed above in the section: “Whom do I contact if I have 
questions about the research study?” 
• You have the right to request access to your protected health information 
that is used or shared during this research and that is related to your 
treatment or payment for your treatment, but you may access this 
information only after the study is completed.  To request this information, 
please contact the researcher listed above in the section: “Whom do I 
contact if I have questions about the research study?” 
 
 
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Research Consent Form                  
for Biomedical Research 
Dana-Farber/ Harvard Cancer Center 
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates  
OHRS 09.23.16a 
 
Page 16 of 17 
 
DFCI Protocol Number:     17-044 
Approved Date (DFCI IRB Approval):  
08/23/2019 
Date Posted for Use:  
08/27/2019 
 
Q. DOCUMENTATION OF CONSENT 
 
My signature below indicates: 
• I have had enough time to read the consent and think about 
participating in this study; 
• I have had all of my questions answered to my satisfaction; 
• I am willing to participate in this study; 
• I have been told that my participation is voluntary and I can withdraw at 
any time 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Participant 
 
 
 
Date 
or Legally Authorized Representative   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Relationship of Legally Authorized Representative to Participant   
 
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Research Consent Form                  
for Biomedical Research 
Dana-Farber/ Harvard Cancer Center 
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates  
OHRS 09.23.16a 
 
Page 17 of 17 
 
DFCI Protocol Number:     17-044 
Approved Date (DFCI IRB Approval):  
08/23/2019 
Date Posted for Use:  
08/27/2019 
 
 
To be completed by person obtaining consent: 
Adult Participant 
 
The consent discussion was initiated on   
 (date). 
Signature of individual obtaining consent:  
 
 
Printed name of above:   
 
 
Date:  
 
 A copy of this signed consent form will be given to the participant or legally authorized 
representative. 
 1)  The participant is an adult and provided consent to participate. 
 
 1a)  Participant (or legally authorized representative) is a non-English speaker and 
 
signed the translated Short Form in lieu of English consent document: 
 
As someone who understands both English and the language spoken by the participant, I 
interpreted and/or witnessed, in the participant’s language, the researcher’s presentation 
of the English consent form.  The participant was given the opportunity to ask questions.  
Signature of Interpreter/Witness:  
 
Printed Name of Interpreter/Witness:  
 
Date:  
 
 
 1b)  Participant is physically unable to sign the consent form because:  
 
 
 
 The participant is illiterate. 
 
 
 
 The participant has a physical disability. 
 
 
 
 Other (please describe): _________________________________________ 
 
The consent form was presented to the participant who was given the opportunity  
 
to ask questions and who communicated agreement to participate in the research.  
Signature of Witness:  
 
Printed Name of Witness:  
 
Date:  
 
 2)  The participant is an adult who lacks capacity to provide consent and his/her legally 
authorized representative: 
 2a) gave permission for the adult participant to participate  
 2b) did not give permission for the adult participant to participate  
5/1/2021 2:08 am