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12.3.1 irb approvals

As the Coordinating Center for a trial, it is the PI's responsibility to ascertain that no patients are entered on the trial at a participating institution without full IRB approval. Thus, the NCI IRB must approve the addition of each participating institution to the protocol and will require a copy of the local IRB approval from each participating institution before NCI IRB approval will be granted. The PI will provide the NCI IRB with a copy of the participating institution's approved yearly continuing review. Registration will be halted at any participating institution in which a current continuing approval is not on file at the NCI IRB.
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12.3.2 amendments and consents

The NCI PI will provide the NCI IRB with copies of all amendments, consents and approvals from each participating institution.
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12.3.3 data collection

The investigators will be responsible for the collection, maintenance, and quality control of the study data. All data collected for each study subject will be entered into the Cancer Central Clinical Database (C3D), an NCI electronic case report form/database, every 2 weeks. The participating sites will be able to enter the data remotely into the web-based C3D system. Each site investigator is also responsible for maintaining all source documentation related to the study, including any films, tracings, computer discs or tapes. NCI will be responsible for data management, data analysis, and reporting. Data collection forms will be provided to the participating institutions. Required data include, not exclusively: prior disease-related therapies with dates, disease type, stage, disease sites, with measurements, and concurrent medications.
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12.3.4 data and center audits

Audits will be conducted yearly to ensure data integrity and provide quality control. These audits will be conducted by the NCI research team. Selected patient charts should be audited as well as the participating institution's Standard Operating Procedures (SOP) at the time of the visit. Data from participating institutions should be available when the protocol is audited at the NCI.
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12.3.5 ctep multicenter guidelines

This protocol will adhere to the policies and requirements of the CTEP Multicenter Guidelines. The specific responsibilities of the Principal Investigator and the Coordinating Center (Study Coordinator) and the procedures for auditing are presented in Appendix C.  
x The Principal Investigator/Coordinating Center is responsible for distributing all IND
Action Letters or Safety Reports received from CTEP to all participating institutions for submission to their individual IRBs for action as required.  
x Except in very unusual circumstances, each participating institution will order DCTD-supplied agents directly from CTEP. Agents may be ordered by a participating site only after the initial IRB approval for the site has been forwarded by the Coordinating Center to the CTEP PIO (PIO@ctep.nci.nih.gov) (except for Group studies).
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12.4 cooperative research and development

The primary objective of this protocol is to determine if FdCyd/THU is associated with adequate response rates (RR) or progression-free survival (PFS) in patients with any of a variety of malignancies as defined below. PFS will be estimated using a Kaplan-Meier curve. The results obtained will be informally compared to those from other studies in similar patients to help determine the potential benefit of exploring use of these agents in a subsequent, more definitive study, if warranted. These patients will have been previously treated with multiple prior chemotherapeutic regimens, so that any reasonable evidence of benefit will be interpreted as being a positive indicator. Exploratory study objectives relate to the safety of the agents in patients with various solid tumors, and an evaluation of the impact of FdCyd/THU on extent of LINE-1 methylation in tumor biopsies. Blood samples will also be collected to evaluate the number of circulating tumor cells before and during treatment. Changes from baseline will be determined in either absolute or relative terms as appropriate, and evaluated for statistical significance, as well as to determine if the changes or the actual values at a time point are associated with clinical response. Paired comparisons with baseline will be done using a paired t-test or Wilcoxon signed rank test as appropriate, and the changes will be compared between responders and non-responders (PD) using a two-sample t-test (adequate numbers of subjects with normally distributed data in both groups) or a Wilcoxon rank sum test, if enough patients respond for this to be appropriate. In all such cases, these analyses will be considered exploratory and not formally adjusted for multiple comparisons. However, to ensure proper interpretation in the context of a potentially large number of explorations being performed, only p values <0.01 will be interpretable as being associated with statistical significance. Patients will be enrolled into one of 4 strata as follows:  
A Non-Small Cell Lung Cancer B Breast Cancer C Urothelial Transitional Cell Carcinoma D Head and Neck Cancer
In each stratum, the study will be conducted with a dual-endpoint design, based on RR and 4month (6-month for the breast cancer stratum) PFS as co-primary endpoints. In strata A, C, and D, evidence of positive results is sought in the first stage to determine if the particular stratum should be expanded into the second stage. In stratum B, a one-stage design is utilized. Also, throughout the sections below, 'response' will refer to the appearance of a positive outcome as defined for each disease.
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stratum a non-small cell lung

Stratum A will use a trial design for patients with NSCLC that judges the agents as promising if we achieve either tumor response rates of 20% vs. 5% or 4-month PFS rates of 50% vs. 25% (corresponding to median PFS of 4 vs. 2 months). The design requires a maximum of 45 evaluable patients. For each stratum, if at least 6 objective responses (at least 13%), or at least 18 instances of 4-month PFS (at least 40%), are observed among the 45 evaluable patients, this regimen will be considered worthy of further testing in this disease. If no more than one objective response (no more than 5%), and no more than 6 instances of 4-month PFS (no more than 30%), are observed among the initial 20 patients, the stratum will be terminated early and declared negative. This design yields at least 87% power to detect a true objective response rate of at least 20%. It yields at least 90% power to detect a true 4-month PFS rate of at least 50% (median PFS of 4 months). It yields at least .96 probability of a negative result if the true objective response rate is no more than 5% and the true 4-month PFS rate is no more than 25% (median PFS of 2 months), with approximately .58 probability, at least, of early negative stopping in this case. In addition, the over-all probability of negative results across all 4 strata, under the over-all null hypothesis, is .85. These last three probabilities are calculated assuming that tumor response rate and PFS rate are uncorrelated. If they are positively correlated, as is likely, the probabilities will be a bit higher.
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stratum b breast cancer

Stratum B will use a trial design for patients with breast cancer that judges the agents as promising if we achieve either tumor response rates of 20% vs. 5% or 6-month PFS rates of 50% vs. 25% (corresponding to median PFS of 6 vs. 3 months). The design requires a maximum of 35 evaluable patients. If at least 5 objective responses (at least 14%), or at least 15 instances of 6-month PFS (at least 43%), are observed among the 35 evaluable patients, this regimen will be considered worthy of further testing in this disease. This design yields at least 85% power to detect a true objective response rate of at least 20%. It yields at least 84% power to detect a true 6-month PFS rate of at least 50% (median PFS of 6 months). It yields at least .95 probability of a negative result if the true objective response rate is no more than 5% and the true 6-month PFS rate is no more than 25% (median PFS of 3 months). In addition, the over-all probability of negative results across all 4 strata, under the over-all null hypothesis, is .85. These last three probabilities are calculated assuming that tumor response rate and PFS rate are uncorrelated. If they are positively correlated, as is likely, the probabilities will be a bit higher.  
If accrual onto this stratum is slow, and the target to demonstrate promising response rate (5 responders) or PFS rate (15 patients with 6-month PFS) has already been met among the initial 30 patients, consideration will be given to stopping the trial and declaring the regimen promising. The likelihood of demonstrating such promise under the alternative hypothesis is at least .57.
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stratum c urothelial transitional cell

Stratum C will use a trial design for patients with urothelial transitional cell carcinoma that judges the agents as promising if we achieve either tumor response rates of 20% vs. 5% or 4month PFS rates of 50% vs. 25% (corresponding to median PFS of 4 vs. 2 months). The design requires a maximum of 45 evaluable patients. If at least 6 objective responses (at least 13%), or at least 18 instances of 4-month PFS (at least 40%) are observed among the 45 evaluable patients, this regimen will be considered worthy of further testing in this disease. If no more than one objective response (no more than 5%), and no more than 6 instances of 4month PFS (no more than 30%), are observed among the initial 20 patients, the stratum will be terminated early and declared negative. This design yields at least 87% power to detect a true objective response rate of at least 20%. It yields at least 90% power to detect a true 4-month PFS rate of at least 50% (median PFS of 4 months). It yields at least .96 probability of a negative result if the true objective response rate is no more than 5% and the true 4-month PFS rate is no more than 25% (median PFS of 2 months), with approximately .58 probability, at least, of early negative stopping in this case. In addition, the over-all probability of negative results across all 4 strata, under the over-all null hypothesis, is .85. These last three probabilities are calculated assuming that tumor response rate and PFS rate are uncorrelated. If they are positively correlated, as is likely, the probabilities will be a bit higher.
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stratum d head and neck

Stratum D will use a trial design for patients with head and neck cancer that judges the agents as promising if we achieve either tumor response rates of 20% vs. 5% or 4-month PFS rates of 50% vs. 25% (corresponding to median PFS of 4 vs. 2 months). The design requires a maximum of 45 evaluable patients. If at least 6 objective responses (at least 13%), or at least 18 instances of 4-month PFS (at least 40%), are observed among the 45 evaluable patients, this regimen will be considered worthy of further testing in this disease. If no more than one objective response (no more than 5%), and no more than 6 instances of 4-month PFS (no more than 30%) are observed among the initial 20 patients, the stratum will be terminated early and declared negative.  
This design yields at least 87% power to detect a true objective response rate of at least 20%. It yields at least 90% power to detect a true 4-month PFS rate of at least 50% (median PFS of 4 months). It yields at least .96 probability of a negative result if the true objective response rate is no more than 5% and the true 4-month PFS rate is no more than 25% (median PFS of 2 months), with approximately .58 probability, at least, of early negative stopping in this case. In addition, the over-all probability of negative results across all 4 strata, under the over-all null hypothesis, is .85. These last three probabilities are calculated assuming that tumor response rate and PFS rate are uncorrelated. If they are positively correlated, as is likely, the probabilities will be a bit higher. For all strata, toxicity data will be obtained, and if there are 5 or more patients in a given stratum who experience Grade 3 or greater toxicity attributable to the agent, then comparisons between cohorts across grades of toxicity may be done using a Kruskal-Wallis test for ordered columns. Otherwise, toxicities will be tabulated and described. Comparisons between extent of LINE-PHWK\ODWLRQ DQGȖ- WRȕ-globin ratio will be made by subtracting pre-treatment from post-treatment levels and determining the statistical significance of the difference using a Wilcoxon signed rank test. These measures will all be evaluated with exploratory intent, and findings will be reported without formal adjustment for multiple comparisons, but in the context of a study with multiple exploratory analyses performed. A total of 160 evaluable patients may be required if the study enrolls patients onto the second stage of cohorts A and D. The diseases studied are quite different from one another; thus, imposing an overall rule about responses in the full spectrum of patients, prior to enrolling to the first stage is not practical. To allow for inevaluable patients, a total of 165 patients will be set as the accrual ceiling. It is anticipated that approximately 8- 9 patients per month will be accrued such that approximately 21 months will be required to accrue up to 165 patients.
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appendix a performance status

| Karnofsky Performance Scale   |                                                                                 |       |
|-------------------------------|---------------------------------------------------------------------------------|-------|
| Percent                       | Description                                                                     |       |
| 100                           | Normal, no complaints, no evidence of disease.                                  |       |
| 90                            | Able to carry on normal activity; minor signs or  symptoms of disease.          |       |
| 80                            | Normal activity with effort; some signs or symptoms  of disease.                |       |
| 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. |       |
| 50                            | Requires considerable assistance and frequent  medical care.                    |       |
| 40                            | Disabled, requires special care and assistance.                                 |       |
| 30                            | Severely disabled, hospitalization indicated.                                   | Death |
| not imminent.                 |                                                                                 |       |
| 20                            | Very sick, hospitalization indicated. Death not  imminent.                      |       |
| 10                            | Moribund, fatal processes progressing rapidly.                                  |       |
| 0                             | Dead.                                                                           |       |  
| Appendix B: Study Diary               | Patient Name: ____________________________________   | Please note any side effects you experienced on this day Do not list your daily medications, but note any other medication you took on this day (both prescription and non-prescription) and the reason why taken   | Monday Date:   | Tuesday Date:   | Wednesday Date:   | Thursday Date:   | Friday Date:   | Saturday Date:   | Sunday Date:   | Signature of person completing form: ____________________________________ Date: ____________________   | 72   |
|---------------------------------------|------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------|-----------------|-------------------|------------------|----------------|------------------|----------------|--------------------------------------------------------------------------------------------------------|------|
| Clinical Center #09-C-0214 CTEP #8351 |                                                      |                                                                                                                                                                                                                     |                |                 |                   |                  |                |                  |                |                                                                                                        |      |
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appendix c ctep multicenter guidelines

If an institution wishes to collaborate with other participating institutions in performing a CTEP sponsored research protocol, then the following guidelines must be followed. Responsibility of the Protocol Chair x The Protocol Chair will be the single liaison with the CTEP Protocol and Information Office
(PIO). The Protocol Chair is responsible for the coordination, development, submission, and approval of the protocol as well as its subsequent amendments. The protocol must not be rewritten or modified by anyone other than the Protocol Chair. There will be only one version of the protocol, and each participating institution will use that document. The Protocol Chair is responsible for assuring that all participating institutions are using the correct version of the protocol.  
x The Protocol Chair is responsible for the overall conduct of the study at all participating institutions and for monitoring its progress. All reporting requirements to CTEP are the responsibility of the Protocol Chair.  
x The Protocol Chair is responsible for the timely review of Adverse Events (AE) to assure safety of the patients.  
x The Protocol Chair will be responsible for the review of and timely submission of data for study analysis.  
Responsibilities of the Coordinating Center x Each participating institution will have an appropriate assurance on file with the Office for Human Research Protection (OHRP), NIH. The Coordinating Center is responsible for assuring that each participating institution has an OHRP assurance and must maintain copies of IRB approvals from each participating site.  
x Prior to the activation of the protocol at each participating institution, an OHRP Form 310
(documentation of IRB approval) must be submitted to the CTEP PIO.  
x The Coordinating Center is responsible for central patient registration. The Coordinating Center is responsible for assuring that IRB approval has been obtained at each participating site prior to the first patient registration from that site.  
x The Coordinating Center is responsible for the preparation of all submitted data for review by the Protocol Chair.  
x The Coordinating Center will maintain documentation of AE reports. There are two options for AE reporting: (1) participating institutions may report directly to CTEP with a copy to the Coordinating Center, or (2) participating institutions report to the Coordinating Center who in turn report to CTEP. The Coordinating Center will submit AE reports to the Protocol Chair for timely review.  
x Audits may be accomplished in one of two ways: (1) source documents and research records for selected patients are brought from participating sites to the Coordinating Center for audit, or (2) selected patient records may be audited on-site at participating sites. If the NCI chooses to have an audit at the Coordinating Center, then the Coordinating Center is responsible for having all source documents, research records, all IRB approval documents, NCI Drug Accountability Record forms, patient registration lists, response assessments scans, x-rays, etc. available for the audit.  
Inclusion of Multicenter Guidelines in the Protocol x The protocol must include the following minimum information: x The title page must include the name and address of each participating institution and the name, telephone number and e-mail address of the responsible investigator at each participating institution.  
x The Coordinating Center must be designated on the title page. x Central registration of patients is required. The procedures for registration must be stated in the protocol.  
x Data collection forms should be of a common format. Sample forms should be submitted with the protocol. The frequency and timing of data submission forms to the Coordinating Center should be stated.  
x Describe how AEs will be reported from the participating institutions, either directly to CTEP or through the Coordinating Center.  
x Describe how Safety Reports and Action Letters from CTEP will be distributed to participating institutions.
untitled h1
agent ordering

Except in very unusual circumstances, each participating institution will order DCTD-supplied investigational agents directly from CTEP (See Section 8). Investigational agents may be ordered by a participating site only after the initial IRB approval for the site has been forwarded by the Coordinating Center to the CTEP PIO.
untitled h1
appendix d preparation of pk

Zebularine (ZEB) will be provided upon request as bulk powder. Participating center pharmacies will make up a stock solution of ZEB at 100 mg/mL (wt of zebularine/volume of water added) and will prepare 1-mL frozen aliquots. Requests for Zebularine powder can be sent to:
Rao Vishnuvajjala, PhD Pharmaceutical Resources Branch, NCI, NIH 9609 Medical Center Drive MSC 9734 Rockville, MD 20850-9734 Phone: (240) 276-5962 E-mail: raov@dtpepn.nci.nih.gov *Please note: vacutainers and/or other supplies will not be provided by the NCI
untitled h1
blood draw tubes

Zebularine can be added to Vacutainer tubes up to one day in advance without causing significant loss of vacuum. Using a 3/10 cc insulin syringe or other similar sized syringe with a fine needle, GUDZXSȝ/RIWKH=(% VROXWLRQDQGWUDQVIHULWWRD-mL heparinized Vacutainer tube (cat \# 366667) by piercing the stopper. Do not draw up ZEB for more than one tube at a time. You will not be able to control the amount of ZEB solution that leaves the needle, as it is sucked out by the vacuum. Because of the fine needle, you will not lose the vacuum (apart from the volume added) in the collection tube.
untitled h1
urine storage cryogenic vials

Five (5) μL of the 100 mg/mL ZEB solution should be added to each cryogenic vial to accommodate the 0.5 mL urine sample. Because the cryogenic tubes are not under vacuum, you can use any appropriate device to measure the 5 μL, e.g., a micropipettor such as Pipetman. This will yield the same final concentration of ZEB in the urine samples as in the blood samples (final concentration 1 mg/mL).
a p pe n di
pl as ma

S up pli es f or e a c h s a mpl e:  
O ne ( 1) 3- m L he pari ni ze d ( gr ee n-t o p) t ube ( Vac utai ner cat \# 3 6 6 6 6 7 or e q ui val e nt) wit h z e b ul ari ne ( Z E B, s e e A p pe ndi x D .)  
It is criti c al t hat t he vi als c o ntai ni ng Z E B be us e d t o mi ni mi ze e x vi v o dea mi nati o n of F d C yd d uri ng pr ocessi ng a nd st or a ge.  
T hr ee ( 3) 1- m L cr yo ge ni c vi als Pr oce d ure : O btai n bl o o d i n a 3- m L he pari ni ze d ( gr ee n-t o p) t ube ( Vac utai ner cat \# 3 6 6 6 6 7 or Z E B . Ge ntl y i nvert 3 ti mes t o mi x a nd pl ace i m me di atel y o n i ce. F or eac h ti me p oi nt, l a bel 3 cr yo ge ni c vi als wit h t he c o or di nati ng ce nter pati e nt \#, date, a nd ti me. D o not i ncl ude pati e nt i de ntifi ers o n t he s a mpl e l a bels. Ce ntrif uge t he bl o o d at 6 0 0 x g f or 1 0 mi nutes at 4 C. Tr a nsfer 0. 5 m L of t he pl as ma i nt o eac h of 2 cr yo ge ni c vi als a nd t he r e mai nder of t he pl as ma i nt o t he t hir d cr yo ge ni c vi al, if p ossi bl e wit ho ut dist ur bi ng t he c ell pell et. Ke e p t he pl as ma o n i c e a nd fr e e ze at or bel o w - 2 0 C wit hi n o ne ho ur.
a p pe n di
uri ne

S up pli es f or e a c h s a mpl e:  
O ne ( 1) s cr e w- ca p pe d ce ntrif uge t ube ( 1 5 m L)  
T hr ee ( 3) 1- m L cr yo ge ni c vi als wit h 5 μ L of 1 0 0 mg/ m L ze b ul ari ne ( Z E B, A p pe ndi x D  
It is criti c al t hat t he vi als c o ntai ni ng Z E B be us e d t o mi ni mi ze e x vi v o dea mi nati o n of F d C yd d uri ng st or a ge.  
Pr oce d ure : O btai n a p pr o xi matel y 1 0 m L of uri ne fr o m t he pati e nt a nd pl ace i m me di atel y o n i ce.  
E xce pt f or t he pr etr eat me nt s peci me n, o btai n t he 1 0 m L ali q uot after t he t otal v ol u me of t he 2 4- hr c oll e cti o n has be e n me as ur e d. Ma ke s ur e t he 2 4- hr uri ne is mi xe d bef or e ta ki ng t he ali q uot. If t he ali q uot is fr oze n, t ha w o n i ce or t ha w at r o o m te mper at ur e, b ut pl a c e o n i c e as s o o n as t ha w e d, mi x, a nd pr ocess as s o o n as p ossi bl e. P o ur t he uri ne s peci me n i nt o a scr e w- ca p pe d ce ntrif uge t ube a nd ce ntrif uge at 6 0 0 g f or 1 mi nute at 4 C t o s e di me nt de bris. Tr a nsfer 0. 5 m L of t he uri ne i nt o eac h of 3 cr yo ge ni c vi als wit h Z E B . La bel t he vi als wit h t he c o or di nati ng ce nter pati e nt \# a nd date ( no pati e nt i de ntifi ers). Fr e e ze t he cr yo ge ni c vi als of uri ne at or bel o w - 2 0 C.
a p pe n di
all p k s a

J a n H. Be u mer, P har m D, P h D  
Uni versit y of Pitts b ur gh Ca ncer I nstit ute R o o m G 2 7 E Hill ma n Res ear c h La b or at ori es 5 1 1 7 Ce ntr e A ve nue Pitts b ur gh, P A 1 5 2 1 3 Pl eas e notif y eit her Mr. R o bert Paris e or Ms. S us a n C hrist ner ( 4 1 2- 6 2 3- 3 2 4 8) b y tel e p ho ne or fa x  
( 4 1 2- 6 2 3- 1 2 1 2) at l east 2 4 ho urs pri or t o s hi p me nt. Sa mpl es s ho ul d be s hi p pe d t o arri ve T ues da y, Wednesday, Thursday, or Friday. A name, phone number, fax number, or e-mail address should be included with samples so that receipt can be acknowledged. The shipment of human blood samples must comply with appropriate regulations as specified by the carrier. At a minimum, all samples must be packaged within two containers with absorbent material between containers to control any spill or leakage. The outer container must be punctureresistant (e.g., cardboard mailing tube, corrugated cardboard box). A biohazard sticker must be affixed to both the inner and outer containers. All samples should be shipped via overnight express courier in insulated containers with enough dry ice to maintain the samples in a frozen state. A copy of each of the pharmacokinetic sample collection forms for the respective patients should be included with each shipment. Appendix F: Procedure for Tumor Biopsy and Blood Samples for Pharmacodynamic Studies
a p pe n di
tumor biopsy samples

Biopsies (once initial processing is complete in the procedure room; Section 9.1.2) will be flashfrozen in a pre-chilled cryovial prelabeled with a Unique Identifier Code for the specimen per NCTVL HUSOP340507UH (Sample Handling Section 9.1), see the DCTD Web site for detailed instructions on biopsy collection and handling: https://dctd.cancer.gov/ResearchResources/biomarkers/docs/par/SOP340507_Biopsy_Frozen.pdf. At the NCI, frozen specimens will be transported on dry ice by Clinical Service Program courier to the PADIS lab at Frederick National Laboratory for Cancer Research, where they will be logged into the record keeping system and held in liquid nitrogen until processing. Biopsy specimens from participating sites will be sent to:
Attention: Dan Danner NCI-F/FNLCR 1073 Beasley Street, Building 1073 Fort Detrick Frederick, MD 21701 Phone: 301-846-5748 NCI_PD_Support_CellSearch@mail.nih.gov Please send an email to FNLCR PD Specimen Central Receiving (NCI_PD_Support@mail.nih.gov) to advise that biopsy samples are being prepared for shipment. State "*Protocol Name* PD Specimens Ready for Shipment" in the subject line. If needed, FNLCR PD Central Receiving can be contacted directly at 301-846-1951 (primary) or 240-344-5697 (mobile). All shipments should include a description of contents on the outside label/shipping slip and detailed packing slip included with the samples. If the biopsy specimen is large enough (i.e., 10 mm or longer), the specimen will be cut into two parts for subsequent DNA extraction (CpG island methylation analysis) and RNA extraction. If the sample is not sufficient, it will be processed for DNA extraction only. Processing for CpG island methylation analysis will consist of DNA extraction (DNA-Easy kit, Ambion), purification and quantitation, and aliquoting in barcoded tubes. LINE1 methylation analysis will be performed on the Biotage Pyromark in the PADIS laboratory. An additional analysis in Dr. Yang's laboratory at USC will be performed with a blind aliquot of DNA isolated from the patient biopsy specimen should this prove necessary to confirm results.
a p pe n di
isolation of ctcs

Prior to CTC collection, each participating site should e-mail a request for specimen collection and shipping materials from NCI_PD_Support_CellSearch@mail.nih.gov. Allow at least six business days for receipt of the blood shipment containers; a confirmation e-mail with the expected shipping date will be sent. Blood (~8 mL) will be collected aseptically by venipuncture or from a venous port into a CellSave preservative tube pre-labeled with a unique identifier code for the specimen per PADIS SOP LHTP003.8.1 http://dctd.cancer.gov/ResearchResources/biomarkers/docs/ctc/LHTP003.08.03_CellSave_Collecti on_Subm.pdfU; the collected blood samples are stable for up to 96 KRXUVDWURRPWHPSHUDWXUH Û& WRÛ&SULRUWRSURFHVsing. At the NCI, blood will be transported by Clinical Service Program courier to the PADIS lab at Frederick National Lab. Do not ship on ice. Once at PADIS, samples will be logged into a record keeping system and processed within the 96-hour window from sample collection.  
Samples from participating sites will be sent to: Attention: Dan Danner NCI-F/FNLCR 1073 Beasley Street, Building 1073 Fort Detrick Frederick, MD 21701 Phone: 301 846-5748  
E-mail NCI_PD_Support_CellSearch@mail.nih.gov prior to shipping with expected arrival date/time and a description of contents. All shipments should include a description of contents on the outside label/shipping slip and detailed packing slip included with the samples. Because of the 96-hour window of sample stability, CTC samples should be shipped to arrive within a 96-hour window as specified below: Testing and data analysis will be performed by Dr. Kinders (PADIS/LHTP/NCI-Frederick). Each ~8 mL of blood will be transferred from the CellSave preservative tube into a correspondingly labeled 15 mL AutoPrep conical tube. The sample will be processed on the CellTracks AutoPrep system, using the CellSearch CTC kit, which contains a ferrofluid-based capture reagent (monoclonal antibody to EpCam) and immunofluorescent reagents. After immunomagnetic capture and enrichment, fluorescently labeled monoclonal antibodies will be added for identification and enumeration of CTCs.  
| Collection Day   | Day/time samples must arrive at PADIS   |
|------------------|-----------------------------------------|
| Monday           | Thursday (early morning)                |
| Tuesday          | Friday (early morning)                  |
| Wednesday        | Friday (early morning)                  |
| Thursday         | Friday (early morning)                  |
| Friday           | Monday (early morning)                  |
| Saturday         | Tuesday (early morning)                 |
| Sunday           | Wednesday (early morning)               |  
Is ol ati o n of pl as ma f or D N A met hyl ati o n a nal ysis, a n d mo no n ucle ar cells f or D N A  
met hylt r a nsf e r as e acti vit y
a p pe n di
re a ge nts

T w el ve m L of fi c oll- hypa q ue ( or e q ui val e nt l y mp hoc yte s e par ati o n me di u m wit h de nsit y =  
1. 0 7 7), at r o o m te mper at ur e.  
A p pr o xi matel y 5 0 m L of steril e Ca + + a nd M g+ + -fr ee p hos p hate- b uffer e d s ali ne ( P B S) or ot her is ot o ni c dil ue nt at r o o m te mper at ur e.  
A p pr o xi matel y 5 0 m L of steril e 0. 1 5 M Na Cl (s ali ne).  
Se ve n steril e 1 5 m L c o ni c al c e ntrif uge t ubes.  
Ei ght 2- m L cr yo ge ni c vi als.  
Pr oce d ure : O btai n t w o 4- m L E D T A (l a ve nder-t o p) t ubes of bl o o d fr o m t he pati e nt.  
M o no n ucle ar cells (t o ass ess D N A met hylt r a nsf e r as es acti vit y) : Ce ntrif uge o ne ( 1) 4- m L E D T A  
t ube of bl o o d at 1, 0 0 0 g f or 5 mi nutes. Tr a nsfer as muc h pl as ma fr o m e a c h t ube as c a n be s afel y r e mo ve d wit ho ut dist ur bi ng t he b uff y c oat t o a not her t ube. Ge ntl y r es us pe nd t he c ell pell et ba c k t o t he ori gi nal bl o o d v ol u me i n r o o m-te mper at ur e P B S b y i nverti ng s e ver al ti mes. Di vi de t he p o ol e d, r es us pe nde d bl o o d i nt o t w o 1 5- m L ce ntrif uge t ubes. Ta ki ng car e t o mai ntai n sterilit y of t he st oc k b ottl e, dr a w 3 m L of fi c oll- hypa q ue f or e a c h of t he f o ur t ubes i nt o a s yri nge. ( T he fi c oll- hypa q ue c a n be dr a w n up i n a d va nc e s o t hat it w ar ms t o r o o m te mper at ur e i n t he s yri nge i nstea d of w ar mi ng t he e ntir e b ottl e.) Usi ng a 2 0- ga s pi nal nee dl e (l o ng), car ef ull y l a yer 3 m L of t he fi c oll- hypa q ue under t he dil ute d bl o o d cells i n eac h t ube. Ce ntrif uge at 4 0 0 g f or 3 0 mi nutes at r o o m te mper at ur e.  
Tr a nsfer t he o pa q ue i nterfa c e fr o m e a c h t ube wit h a Past ur e pi p ette i nt o a cl ea n c o ni cal ce ntrif uge t ube c o ntai ni ng 3 m L of P B S a nd dil ute t he c o mbi ne d cell s us pe nsi o n t o a p pr o xi matel y 7 m L wit h a d diti o nal P B S. Ce ntrif uge at 2 5 0 g f or 1 0 mi nutes. As pir ate a nd dis car d t he s uper nata nt P B S.  
Res us pe nd t he cell pell et i n 1 0 m L of P B S. Ce ntrif uge at 2 5 0 g f or 1 0 mi nutes. As pir ate t he s uper nata nt P B S, l ea vi ng 0. 5 t o 1 m L of P B S i n w hi c h t o r es us pe nd t he cell pell et. Tr a nsfer t he cell s us pe nsi o n i nt o a cr yo ge ni c vi al a nd ce ntrif uge at 6 0 0 g f or 1 0 mi nutes or at a p pr o xi matel y 1 0, 0 0 0 g i n a mi cr of uge f or 1 mi nute. As pir ate a nd dis car d t he s uper nata nt P B S. Ca p t he cr yo ge ni c vi al a nd v orte x it t o "s mear" t he pell et o n t he i nsi de of t he vi al, t he n fr eeze at - 8 0° C. La bel t he vi al:  
Pr ot oc ol # < dat e >  
P B M C <c ycle # >  
< Pt Acc # > < da y of c ycle >.  
Pl as ma (t o ass ess D N A met hyl ati o n st at us): Usi ng t he r e mai ni ng 4- m L E D T A t ube, s pi n bl o o d f or pl as ma. P o ol wit h t he pl as ma deri ve d fr o m t he mo no nucl ear cell bl o o d t ube a nd tr a nsfer 1. 5m L ali q uots i nt o 2- m L cr yo ge ni c vi als. St or e at or bel o w - 2 0 C (- 7 0 C pr eferr e d). La bel t he  
vi als:  
Pr ot oc ol # < dat e >  
Pl as ma <c ycle # >  
< Pt Acc # > < da y of c ycle >.  
The isolated samples should be stored as directed above then shipped with the sample obtained with the first interim weekly labs. At the NCI, specimens will be transported by Clinical Service Program courier to the PADIS lab at Frederick National Laboratory for Cancer Research. At participating sites, send the samples packed in dry ice to: Attention: Dan Danner NCI-F/FNLCR 1073 Beasley Street, Building 1073 Fort Detrick Frederick, MD 21701 Phone: 301-846-5748 NCI_PD_Support_CellSearch@mail.nih.gov Please send an email to FNLCR PD Specimen Central Receiving (NCI_PD_Support@mail.nih.gov) prior to shipping with expected arrival date/time and a description of contents. State "Protocol Name PD Specimens Ready for Shipment" in the subject line. If needed, FNLCR PD Central Receiving can be contacted directly at 301-846-1951 (primary) or 240-344-5697 (mobile). All shipments should include a description of contents on the outside label/shipping slip and detailed packing slip included with the samples. Note: With Amendment E (3/16/11 protocol version), isolation of RBCs from blood samples for analysis of fetal hemoglobin expression levels was suspended. RBCs collected prior to this will be stored frozen for future analysis.
appendix g chemotherapy administration log
(first cycle - first week)

| Patient ID____________________                                                                                                                                                                                             | Institution: NCI / COH / USC / UCD / PENN (circle one)   |                             |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------|-----------------------------|
| Height ________ cm                                                                                                                                                                                                         | Weight: ____ . __ kg                                     | BSA __ . __ __ m2           |
| Days 1-5: THU ___________mg/day rapid IV infusion (push) THU ___________mg/day continuous IV infusion over 3 hrs, with FdCyd ___________mg/day continuous IV infusion over 3 hrs. WEEK 1: Day 1 Exact Day/Time of THU Push | ___/___/___, ____:____am/pm                              |                             |
| (Hr 0)                                                                                                                                                                                                                     | Exact Day/Time of Start of THU/FdCyd Infusion            | ___/___/___, ____:____am/pm |
| Exact Day/Time of End of THU/FdCyd Infusion                                                                                                                                                                                | ___/___/___, ____:____am/pm                              |                             |
| Day 2                                                                                                                                                                                                                      | Exact Day/Time of THU Push                               | ___/___/___, ____:____am/pm |
| (Hr 24)                                                                                                                                                                                                                    | Exact Day/Time of Start of THU/FdCyd Infusion            | ___/___/___, ____:____am/pm |
| Exact Day/Time of End of THU/FdCyd Infusion                                                                                                                                                                                | ___/___/___, ____:____am/pm                              |                             |
| Day 3                                                                                                                                                                                                                      | Exact Day/Time of THU Push                               | ___/___/___, ____:____am/pm |
| (Hr 48)                                                                                                                                                                                                                    | Exact Day/Time of Start of THU/FdCyd Infusion            | ___/___/___, ____:____am/pm |
| Exact Day/Time of End of THU/FdCyd Infusion                                                                                                                                                                                | ___/___/___, ____:____am/pm                              |                             |
| Day 4                                                                                                                                                                                                                      | Exact Day/Time of THU Push                               | ___/___/___, ____:____am/pm |
| (Hr 72)                                                                                                                                                                                                                    | Exact Day/Time of Start of THU/FdCyd Infusion            | ___/___/___, ____:____am/pm |
| Exact Day/Time of End of THU/FdCyd Infusion                                                                                                                                                                                | ___/___/___, ____:____am/pm                              |                             |
| Day 5                                                                                                                                                                                                                      | Exact Day/Time of THU Push                               | ___/___/___, ____:____am/pm |
| (Hr 96)                                                                                                                                                                                                                    | Exact Day/Time of Start of THU/FdCyd Infusion            | ___/___/___, ____:____am/pm |
| Exact Day/Time of End of THU/FdCyd Infusion                                                                                                                                                                                | ___/___/___, ____:____am/pm                              |                             |
(see separate pd flow sheet
(first cycle - first week)

Combined Specimen Collection Form (**PK/PD Flow Sheet**) for Pharmacokinetic and Pharmacodynamic Studies **for Cycle 1 - Page 1 of 4**
Patient ID ____________________  
| Cycle 1, Day 1: Date Hr:Min                                                                                           | Sample                                           | Planned Time   | Actual         | RN     | Comments   |
|-----------------------------------------------------------------------------------------------------------------------|--------------------------------------------------|----------------|----------------|--------|------------|
| Time                                                                                                                  | Init.                                            |                |                |        |            |
| ______                                                                                                                | :                                                | #1             | Pretreatment - |        |            |
| (Day 1)                                                                                                               | (P1)                                             | 3 mL of blood in a greentopped tube with ZEB                | :              | ______ |            |
| :                                                                                                                     | #2                                               | Pretreatment - |                |        |            |
| (B1)                                                                                                                  | 2 lavender-topped tubes  with 4 mL of blood each | :              | ______         |        |            |
| :                                                                                                                     | #3                                               | Pretreatment - |                |        |            |
| (B2)                                                                                                                  | 7.5 mL of blood in a  CellSave tube              | :              | ______         |        |            |
| :                                                                                                                     | #4                                               | Pretreatment - | :              | ______ |            |
| (U1)                                                                                                                  | 10 mL of urine                                   |                |                |        |            |
| Then ask patient to void completely prior to 24-hr urine collection. Start 24-hr urine collection for FdCyd Analysis. |                                                  |                |                |        |            |  
Send each sample when drawn to local lab for processing and interim storage according to Appendix E
for Pharmacokinetic (green-top) samples and Appendix F for Pharmacodynamic (lavender-top) and CTC (CellSave) samples. Urine Collection Guidelines for the First 24 Hours Post-Drug Administration Collect and pool urine for the first 24 hours post drug (0-24 hours), and refrigerate. Please note the total volume of urine collected. At end of 24 hours, mix the urine and take a 10 mL aliquot in a sterile urine cup, refrigerate, and discard the rest.
(see separate pd flow sheet
sample collection for day 1

| Studies for Cycle 1 - Page 2 of 4                                                                                                                            |                             |              |              |        |    |          |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------|--------------|--------------|--------|----|----------|
| Cycle 1, Day 1:                                                                                                                                              | Patient ID ________________ |              |              |        |    |          |
| Date                                                                                                                                                         | Hr:Min                      | Sample       | Planned Time | Actual | RN | Comments |
| Time                                                                                                                                                         | Init.                       |              |              |        |    |          |
| ______ (Day 1, Cont.)                                                                                                                                        | Important - Record time     | :            | ______       |        |    |          |
| infusion started                                                                                                                                             |                             |              |              |        |    |          |
| :                                                                                                                                                            | #5                          | 15 Minutes - |              |        |    |          |
| (P2)                                                                                                                                                         | 3 mL of blood in a greentopped tube with ZEB                             | :            | ______       |        |    |          |
| :                                                                                                                                                            | #6                          | 30 Minutes - |              |        |    |          |
| (P3)                                                                                                                                                         | 3 mL of blood in a greentopped tube with ZEB                             | :            | ______       |        |    |          |
| :                                                                                                                                                            | #7                          | 1 Hour -     |              |        |    |          |
| (P4)                                                                                                                                                         | 3 mL of blood in a greentopped tube with ZEB                             | :            | ______       |        |    |          |
| :                                                                                                                                                            | #8                          | 2 Hours -    |              |        |    |          |
| (P5)                                                                                                                                                         | 3 mL of blood in a greentopped tube with ZEB                             | :            | ______       |        |    |          |
| :                                                                                                                                                            | #9                          | 2.5 Hours -  |              |        |    |          |
| (P6)                                                                                                                                                         | 3 mL of blood in a greentopped tube with ZEB                             | :            | ______       |        |    |          |
| ______ (Day 1, Cont.)                                                                                                                                        | Important - Record time     | :            | ______       |        |    |          |
| infusion ended                                                                                                                                               |                             |              |              |        |    |          |
| :                                                                                                                                                            | #10                         | 15 Minutes - |              |        |    |          |
| (P7)                                                                                                                                                         | 3 mL of blood in a greentopped tube with ZEB                             | :            | ______       |        |    |          |
| :                                                                                                                                                            | #11                         | 30 Minutes - |              |        |    |          |
| (P8)                                                                                                                                                         | 3 mL of blood in a greentopped tube with ZEB                             | :            | ______       |        |    |          |
| :                                                                                                                                                            | #12                         | 1 Hour -     |              |        |    |          |
| (P9)                                                                                                                                                         | 3 mL of blood in a greentopped tube with ZEB                             | :            | ______       |        |    |          |
| :                                                                                                                                                            | #13                         | 2 Hours -    |              |        |    |          |
| (P10)                                                                                                                                                        | 3 mL of blood in a greentopped tube with ZEB                             | :            | ______       |        |    |          |
| :                                                                                                                                                            | #14                         | 4 Hours -    |              |        |    |          |
| (P11)                                                                                                                                                        | 3 mL of blood in a greentopped tube with ZEB                             | :            | ______       |        |    |          |
| :                                                                                                                                                            | #15                         | 6 Hours -    |              |        |    |          |
| (P12)                                                                                                                                                        | 3 mL of blood in a greentopped tube with ZEB                             | :            | ______       |        |    |          |
| Send each sample when drawn to local lab for processing and interim storage according to Appendix E. Sample Collection for Days 2-5 begins on the next page. |                             |              |              |        |    |          |  
| Studies for Cycle 1 - Page 3 of 4                                                                       |                                                    |                               |                      |        |    |          |
|---------------------------------------------------------------------------------------------------------|----------------------------------------------------|-------------------------------|----------------------|--------|----|----------|
| Cycle 1, Days 2-5:                                                                                      | Patient ID _______________                         |                               |                      |        |    |          |
| Date                                                                                                    | Hr:Min                                             | Sample                        | Planned Time         | Actual | RN | Comments |
| Time                                                                                                    | Init.                                              |                               |                      |        |    |          |
| Ask patient to void just before ending urine collection.                                                |                                                    |                               |                      |        |    |          |
| ______                                                                                                  | :                                                  | #16                           | Before Day 2 Chemo - |        |    |          |
| (Day 2)                                                                                                 | (U2)                                               | End of 24-Hr urine collection | :                    | _____  |    |          |
| :                                                                                                       | #17                                                | Before Day 2 Chemo -          |                      |        |    |          |
| (P13)                                                                                                   | 3 mL of blood in a greentopped tube with ZEB                                                    | :                             | _____                |        |    |          |
| ______ (Day 2, Cont.)                                                                                   | Important - Record time                            | :                             | _____                |        |    |          |
| infusion started                                                                                        |                                                    |                               |                      |        |    |          |
| ______ (Day 2, Cont.)                                                                                   | Important - Record time                            | :                             | _____                |        |    |          |
| infusion ended                                                                                          |                                                    |                               |                      |        |    |          |
| :                                                                                                       | #18                                                | After Day 2 Chemo (up         |                      |        |    |          |
| (B3)                                                                                                    | to 24 Hours) - 7.5 mL of blood in a  CellSave tube | :                             | _____                |        |    |          |
| ______                                                                                                  | :                                                  | #19                           | Before Day 3 Chemo - |        |    |          |
| (Day 3)                                                                                                 | (P14)                                              | 3 mL of blood in a greentopped tube with ZEB                               | :                    | _____  |    |          |
| ______                                                                                                  | :                                                  | #20                           | Before Day 4 Chemo - |        |    |          |
| (Day 4)                                                                                                 | (P15)                                              | 3 mL of blood in a greentopped tube with ZEB                               | :                    | _____  |    |          |
| ______                                                                                                  | :                                                  | #21                           | Before Day 5 Chemo - |        |    |          |
| (Day 5)                                                                                                 | (P16)                                              | 3 mL of blood in a greentopped tube with ZEB                               | :                    | _____  |    |          |
| Send each sample when drawn to local lab for processing and interim storage according to Appendix E for |                                                    |                               |                      |        |    |          |  
Send each sample when drawn to local lab for processing and interim storage according to Appendix E for Pharmacokinetic (green-top) samples and Appendix F for Pharmacodynamic (lavender-top) and CTC
(CellSave) samples.
(see separate pd flow sheet
sample collection for day 12

| Cycle 1, Continued:                                         | Patient ID __________________   |        |                         |        |        |          |
|-------------------------------------------------------------|---------------------------------|--------|-------------------------|--------|--------|----------|
| Date                                                        | Hr:Min                          | Sample | Planned Time            | Actual | RN     | Comments |
| Time                                                        | Init.                           |        |                         |        |        |          |
| Cycle 1, Day 12 +/- 1 day: ______ (Day 12  +/- 1 day) : #22 | 7.5 mL of blood in a            | :      | ______                  |        |        |          |
| (B4)                                                        | CellSave tube                   |        |                         |        |        |          |
| ______ (Day 12  +/- 1 day)                                  | :                               | #23    | 2 lavender-topped tubes | :      | ______ |          |
| (B5)                                                        | with 4 mL of blood each         |        |                         |        |        |          |  
Combined Specimen Collection Form **(PK/PD Flow Sheet)** for Pharmacokinetic and Pharmacodynamic Studies **for Cycle 1 - Page 4 of 4**
Send each sample when drawn to local lab for processing and interim storage according to Appendix E for Pharmacokinetic (green-top) samples and Appendix F for Pharmacodynamic (lavender-top) and CTC (CellSave) samples.  
The processed samples for Cycle 1 should be shipped according to Appendix E for Pharmacokinetic (greentop) samples and Appendix F for Pharmacodynamic (lavender-top) and CTC (CellSave) samples.  
Sample Collection for Cycle 2 and beyond begins on the next page.  
$=\;\mathrm{m}^2$.
$\mathbf{v}_{\rm f}=\mathbf{v}_{\rm f}\mathbf{v}_{\rm f}$ (10.10)
$\mathbf{a}=\mathbf{a}\cdot\mathbf{a}$.  
Flow Sheet for Cycle 2 and Beyond (See combined PK/PD flow sheet for cycle 1.)
Specimen Collection Form for Pharmacodynamic Studies  
Patient ID____________________ Institution: NCI / COH / USC / UCD /PENN  
  
Height ________ cm Weight: ____ . __ kg BSA __ . __ __ m2  
  
Cycle \# ________ Start of current treatment cycle (Day 1): Date ________  
| Sample                                                                                                                                                                                                                                                                                                                  | Date   | Time   | RN   | Comment   |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------|--------|------|-----------|
| Initials                                                                                                                                                                                                                                                                                                                |        |        |      |           |
| #1 - Cycles 2 and 4 Pretreatment  (Day 1) 2 lavender-topped tubes with 4 mL of  blood each #2 - Cycles 2, 4, 6 Day 1 7.5 mL of blood in CellSave tube #3 - Cycles 2 and 4 Day 12 (+/- 1 day)  2 lavender-topped tubes with 4 mL of  blood each #4 - Cycles 2, 4, 6 Day 12 (+/- 1 day)  7.5 mL of blood in CellSave tube |        |        |      |           |  
Send each sample when drawn to local lab for processing and interim storage according to Appendix E for Pharmacokinetic (green-top) samples and Appendix F for Pharmacodynamic (lavender-top) and CTC
(CellSave) samples.  
The processed samples should be shipped according to Appendix E for Pharmacokinetic (green-top)
samples and Appendix F for Pharmacodynamic (lavender-top) and CTC (CellSave) samples.  
$$\mathrm{me)}$$  
  
$$\mathrm{BSA}\,\_\,\_\,\_\,\_\,\_\,\mathrm{m}^{2}$$  
  
Flow Sheet for Cycle 1 and Beyond (after patients in each cohort have completed PK requirements)
Specimen Collection Form for Pharmacodynamic Studies Patient ID____________________ Institution: NCI / COH / USC / UCD / PENN
(circle one)  
Height ________ cm Weight: ____ . __ kg BSA __ . __ __ m2  
| THU ___________mg/day rapid IV infusion (bolus) THU ___________mg/day continuous IV infusion over 3 hrs, with FdCyd ___________mg/day continuous IV infusion over 3 hrs. Cycle # ________ Start of current treatment cycle (Day 1): Date ________  Sample Date Time RN Initials Comment #1 - Cycles 1, 2 & 4 Pretreatment Day 1 2 lavender-topped tubes with 4 mL  of blood each #2 - Cycles 1, 2, 4, & 6 Pretreatment Day 1 7.5 mL of blood in CellSave tube #3 - Cycle 1, Day 2 after treatment  (up to 24 hours after end of infusion) 7.5 mL of blood in CellSave tube #4 - Cycles 1, 2 & 4 Day 12 (+/- 1 day)  2 lavender-topped tubes with 4 mL  of blood each #5 - Cycles 1, 2, 4, & 6 Day 12 (+/- 1 day)  7.5 mL of blood in CellSave tube   |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
Send each sample when drawn to local lab for processing and interim storage according to Appendix F for Pharmacodynamic (lavender-top) and CTC (CellSave) samples. The processed samples should be shipped according to Appendix F for Pharmacodynamic (lavender-top) and CTC (CellSave) samples.  
Appendix H: Eligibility/Pre-Registration Worksheet  
  
A Multi-Histology Phase II Study of 5-Fluoro-2-Deoxycytidine with Tetrahydrouridine
(FdCyd + THU)
Coordinating Center: NCI Protocol Chair: Bethesda, MD 20892 James H. Doroshow, MD Contact: Jennifer Zlott National Cancer Institute Tel: 301-594-5664 Tel: 301-496-4291 Fax: 301-480-7281 doroshoj@mail.nih.gov zlottjh@mail.nih.gov Lead Associate Investigator: A. P. Chen, MD National Cancer Institute Tel: 301-496 4291 chenali@mail.nih.gov  
| Patient's Name: (FML)                                                                       | Institution:                     |                                    |
|---------------------------------------------------------------------------------------------|----------------------------------|------------------------------------|
| Medical Record Number:                                                                      | Investigator:                    |                                    |
| Patient's Birth date:                                                                       | Signature of Treating  Physician |                                    |
| Sex: ______male ______female                                                                | Date Informed Consent was        |                                    |
| IRB approval valid until (date):                                                            | signed:                          |                                    |
| Race:                                                                                       | Ethnicity:                       | Projected start date of treatment: |
| _____ Black                                                                                 | ___Hispanic                      |                                    |
| _____ Caucasian                                                                             | ___Non-Hispanic                  |                                    |
| _____ Asian                                                                                 | ___Other:______                  |                                    |
| _____ American Indian  _____ Native Hawaiian/Pacific Islander _____ Other _________________ |                                  |                                    |  
INCLUSION CRITERIA: All responses must be YES. A NO response will make the subject
(see separate pd flow sheet
ineligible.

| Histologically documented (confirmed by the department of pathology at  the institution where the patient is enrolled prior to patient enrollment)  metastatic or unresectable non-small cell lung cancer, head and neck cancer, urothelial transitional cell carcinoma, or breast cancer, whose  disease has progressed after at least one line of standard therapy.   | Yes   | No   | N/A   |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------|------|-------|
| Patients with solid tumors (non-small cell lung cancer, head and neck cancer, urothelial transitional cell carcinoma, and breast cancer) must  have measurable disease, defined as at least one lesion that can be  accurately measured in at least one dimension (longest diameter to be  UHFRUGHGDV• PP ZLWKFRQYHQWLRQDOWHFKQLTXHV RUDV• 10 mm with  spiral CT scan. Patients with head and neck cancer whose disease is  limited to the skin are eligible at the discretion of the PI and must have a  physical exam with documentation of skin lesion(s) by color  photography, including a ruler to estimate the size of the lesion(s). $Q\ SULRUWKHUDS\PXVW KDYHEHHQFRPSOHWHG•ZHHNVSULRUWR enrollment on protocol, and the participant must have recovered to eligibility levels from prior toxicity. Patients should be at least six weeks  out from nitrosoureas and mitomycin C. Prior radiation should have  EHHQFRPSOHWHG•ZHHNVSULRUWRVWXG\ HQUROOPHQWDQGDOODVVRFLDWHG toxicities should have resolved to eligibility levels. 3DWLHQWVPXVW EH• weeks since any investigational agent administered as part of a Phase 0  study, and should have recovered to eligibility levels from any toxicities. Age - 18 years? Karnofsky score______see Appendix A? Life expectancy > 3 months? Women of childbearing potential and men must agree to use adequate  birth control Has a signed informed consent/assent been obtained by the patient or  parent/legal guardian?                                                                                                                                                                                                                                                                                                                                                                         |       |      |       |
(see separate pd flow sheet
exclusion criteria responses should be

| Uncontrolled intercurrent illness including, but not limited to: active or  uncontrolled infection, immune deficiencies or confirmed diagnosis of HIV  infection, active infection with Hepatitis B or Hepatitis C, uncontrolled  diabetes, uncontrolled hypertension, symptomatic congestive heart failure,  unstable angina pectoris, myocardial infarction within the past 6 months,  uncontrolled cardiac arrhythmia; or psychiatric illness/social situations that  would limit compliance with study requirements.   | Yes                  | No   | N/A   |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------|------|-------|
| Pregnant?                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  | Pregnancy Test Date: |      |       |
| Breastfeeding? History of allergic reactions attributed to compounds of similar composition  to the investigational agents? Receiving any other investigational agents?                                                                                                                                                                                                                                                                                                                                                    |                      |      |       |  
| Pre Study Evaluations:                                                                                                                                                                                                                                                                                                                                                                                                                                                                              | Date  Done:   |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------|
| History and Physical Exam (within 8 days prior to enrollment) Height, Weight, vital signs and performance status (within 8 days prior to  enrollment) CBC, Diff, Plts, Blood Chemistries* (within 1 week) * Na+, K+, Cl- , CO2, Creatinine, BUN, calcium, glucose, albumin, SGPT (ALT), SGOT (AST), LDH,  Alkaline Phos, Bilirubin Send actual lab results CT scan chest/abd/pelvis (within 28 days prior to enrollment) Pregnancy Test (if clinically indicated within 8 days prior to enrollment) |               |
(see separate pd flow sheet
descriptive factors

Primary: ___________________________________ Histology: ____________________
Other Chronic Diseases: Y / N (If yes, please explain):
PRIOR THERAPY (Please specify date, procedure, agent, dose, response. Date of last treatment required.) YES NO ____ ____ 1. **Surgery/Biopsy:** ____ ____ 2. **Chemotherapy:** ____ ____ 3. **Radiotherapy**: ____ ____ 4. **Hormonal Therapy:** ____ ____ 5. **Immunotherapy**: Physician's Signature: _________________________ Date:______________ Printed Name of Physician: ________________________ To be completed by participating center when registering a patient:  
Date Registered with NCI ______/_______/_______ Spoke With: ____________________________________ Study ID:_______________________________________ Eligibility Checklist Completed By: _________________  
Assigned CRA / Data Manager: _____________________  
A confirmation of registration will be sent to you by the NCI.  
Participant Status Updates Form Complete form and send via encrypted email to:
NCI Central Registration Office (HOIS) at ncicentralregistration-l@mail.nih.gov Patient Information:
First name Last name Middle initial ID number:________________________________________ Protocol Number (CC\# preferred):______________________ Off Treatment Date (mm/dd/yy): _____________________ Off Treatment Reason: _____________________________ Off Study Date (mm/dd/yy): _________________________
Choose one of the following off-study reasons:
C: Completed Study L: Lost to follow-up R: Refused Further Treatment T: Toxicity D: Death P: Progressive Disease O: Other Death Date: (mm/dd/yy): ______________________________
Choose one or more of the following DOD Sources:
Social Security Death Index SS\#:____________________ http://ssdi.rootsweb.com/
Obituaries Document:____________________ http://www.legacy.com/washingtonpost/DeathNotices Cause of Death______________________________________________________________ Place of Death:______________________________________________________________ Family/staff member name notifying DOD:________________________________________  
Registrar:  
Name:___________________________________________ Work Phone:_____________________ *Today's Date***: ________________________**  
Comments:
appendix i informed consent form
descriptive factors

Study Title: A Multi-Histology Phase II Study of 5-Fluoro-2-Deoxycytidine with Tetrahydrouridine (FdCyd + THU)
appendix i informed consent form
introduction

We invite you to take part in this research study. First, we want you to know that:
Taking part in this research study is entirely voluntary. You may choose not to take part, or you may withdraw from the study at any time. In either case, you will not lose any benefits to which you are otherwise entitled. You may receive no benefit from taking part. The research may give us knowledge that may help people in the future.  
Second, some people have personal, religious or ethical beliefs that may limit the kinds of medical or research treatments they would want to receive (such as blood transfusions). If you have such beliefs, please discuss them with your doctors or research team before you agree to the study. Now we will describe this research study. Before you decide to take part, please take as much time as you need to ask any questions and discuss this study with family, friends or your personal physician or other health professional.
appendix i informed consent form
why is this study being

This research study includes patients with advanced non-small cell lung cancer, breast cancer, urothelial transitional cell carcinoma, and head and neck cancer. You are being asked to volunteer to take part in this research study because you have advanced cancer that has progressed after receiving standard treatment or for which no effective therapy exists. We are doing this study to try to develop better treatments for cancer. On this study, two experimental drugs, FdCyd (also called 5-fluoro-2'-deoxcytidine), and THU (also called tetrahydrouridine), will be given to you. The purpose of this study is to see if the drugs work together to control your tumor growth. FdCyd is thought to work by changing how genes work in cancer cells. THU does not have any anticancer effects on its own, but it helps keep the other drug, FdCyd, from being broken down by your body. These drugs have been given to more than 170 patients as of February 2016. The two drugs have some side effects that will be reviewed with you by your medical team before you sign the consent form.
appendix i informed consent form
how many people will take

Up to 165 patients will take part in this study across 6 centers in the United States.
appendix i informed consent form
what will happen if i

If you are accepted and you choose to take part, you will begin receiving FdCyd and THU. Please see the Study Chart below for more details. You will also have tests and procedures done because you are in the study to see how FdCyd and THU are affecting your body. This will include repeating some of the imaging studies (e.g., CT scans, a computerized x-ray examination) to find out if your cancer has responded. Descriptions of the tests and procedures that will be performed during the study are listed below. For some study procedures we will need you to come to _______________________________ *[name of center]*. FdCyd and THU will be given in cycles. Each cycle is 28 days long. You will receive FdCyd and THU on days 1-5 and 8-12 of each cycle. You may continue to receive FdCyd and THU if your cancer does not grow, if you do not have too many side effects, and if you are willing to do so. Clinic Visits: FdCyd and THU will be given through a vein each day on days 1-5 and 8-12 of each cycle. We will ask that you come to ________________ *[name of center]* on these days during each cycle. While you are at ________________ *[name of center]* we will perform study tests and procedures to see how the study drugs are affecting your body. So, for each cycle you will be coming to ________________ *[name of center]* for at least 12-14 days. If you develop any side effects, you may be asked to visit more often. Standard procedures being done because you are in this study; these may be done more often because you are in the study:
x **Clinic visit:** to ask how you are feeling and to evaluate you with a physical examination every week during Cycle 1, and then at the beginning of each cycle.  
x **Vital signs and physical examinations:** will be performed during the clinic visits.  
x **Blood tests:** Measurement of your white blood cells, red blood cells, and platelets and measurements of your blood sugar and electrolytes and of how your liver, kidneys, and blood clotting work will be done every week during Cycle 1, and then before treatment on weeks 1 and 2 of all other cycles. Approximately 1 tablespoon (15 mL) of blood will be drawn per visit.  
x **Urine test:** Depending on the results of blood tests, you may be asked to collect your urine for 24 hours for further testing.  
x **CT scans** or other imaging tests such as ultrasound (an examination using sound waves) or MRI (an examination using magnetic field and radio waves) that detect your tumor will be done before the study and every 8 weeks while you are receiving study drugs (less often if you have been on study for more than one year). This is done so that any benefit of the treatment can be determined, and if your cancer is not responding to the treatment, the study team can tell you and discuss other treatment options (discussed further below).
appendix i informed consent form
tests and procedures that are

x **Measurement of FdCyd and THU in your blood:** We will collect blood samples from some patients to measure the amount of study drugs in the blood and to help us find out how the body handles the drugs. Blood will be collected during Cycle 1 only, on day 1 before the drugs are given, at multiple time points while the drugs are being given, at several times  
up to 6 hours after the drugs are given, and then once before treatment on days 2, 3, 4, and 5. The total blood for all these tests will be about 3 tablespoons (45 mL).  
x **Other research blood samples:** We will also be collecting blood samples to find out the effects of the drugs on cells in your blood. Blood samples will be collected on days 1, 2, and 12 in Cycle 1, on day 1 of Cycle 2 and every subsequent cycle, on day 12 in Cycles 2, 4, and 6, and, if your disease comes back, at the time that your disease comes back. The total blood for all these tests will be about 1/2 a cup (about 115 mL).  
x **Measurement of FdCyd and THU in your urine:** We will collect urine samples from some patients to measure the amount of study drugs in the urine. Urine will be collected before the study drugs are given and for 24 hours after the drugs are given on Cycle 1, day 1.  
x **Tumor biopsies:** After you are accepted to take part in the study, you will be asked to have a biopsy of your tumor (removal of a small bit of tissue for examination under a microscope) once before you receive study drugs and a second time on day 12 of Cycle 2. We are collecting biopsy samples to study how the drugs affect your tumor. Biopsies are a very important part of this trial and are done for research purposes. Tumor biopsies are optional, and no more than two biopsy procedures will be performed during the study. You may choose not to have tumor biopsies, and this will not affect your taking part in this study. If you decide not to have tumor biopsies, you will still receive study drugs and have other tests that are part of the study.
Tumor biopsies are only collected by trained personnel. Biopsies are collected using a small bore needle under imaging guidance (CT, MRI, or ultrasound as considered appropriate by the interventional radiologist performing the biopsy). Imaging helps the specialized radiologist know that the needle has been placed into the tumor mass. Typical risks of biopsy collection include, but are not limited to, bleeding, infection, pain, and scarring. If you experience any complications from the biopsy, medical care will be offered to you. The amount of radiation you will receive in this study is ____ [*insert centerspecific dosimetry value for 2 research biopsies*] rem (a measurement of ionizing radiation such as emitted in x-rays), which is below the guideline of 5 rem per year allowed for research subjects by the NIH Radiation Safety Committee. You will be counseled in more detail about biopsies, and you will be asked to sign a separate consent form that will describe the procedures and risks at that time. Your safety is the most important thing at all times. If upon attempting the first biopsy, no tissue can be obtained or it has caused you harm, the second biopsy procedure will not be done. After you are enrolled in this study, if for any reason the biopsies cannot be done safely, you may still receive the study drugs but the biopsies will not be done. I agree to allow biopsies for research purposes Yes___ No____ Initials_________  
x Clinical evaluations, imaging studies, and biopsies will be done at ________________
[name of center].
appendix i informed consent form
study chart

The drugs are given over 28-day periods of time called cycles. FdCyd and THU are given through a vein for about 3 hours each day on days 1-5 and 8-12 of each cycle. The days you receive study drugs may change by up to 1 day for scheduling reasons (for example, weekends, holidays, or for your convenience), but FdCyd and THU will only be given for 5 days in week 1 and 5 days in week 2. The chart below shows what will happen to you during Cycle 1 and future cycles after you sign the consent and start the study. Each cycle is numbered. The left-hand column shows the day in the cycle, and the right-hand column tells you what will happen on that day.  
| Day                            | What to do and what will happen to you                                                                     |                                                                                                                                                                                                                  |
|--------------------------------|------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Before starting                | x                                                                                                          | Have a history taken of how you feel and undergo a physical                                                                                                                                                      |
| study drug                     | examination by a Health Care Provider (HCP)                                                                |                                                                                                                                                                                                                  |
| x                              | Get routine blood tests                                                                                    |                                                                                                                                                                                                                  |
| x                              | CT scan will be done                                                                                       |                                                                                                                                                                                                                  |
| x                              | Tumor biopsy may be performed (optional, see above)                                                        |                                                                                                                                                                                                                  |
| Cycle 1 onwards,               | x                                                                                                          | Have a history taken of how you feel and undergo a physical                                                                                                                                                      |
| Day 1                          | examination by a HCP                                                                                       |                                                                                                                                                                                                                  |
| x                              | Get routine blood tests                                                                                    |                                                                                                                                                                                                                  |
| x                              | FdCyd and THU will be given through a vein for 3 hours                                                     |                                                                                                                                                                                                                  |
| x                              | Blood draws for research will be obtained                                                                  |                                                                                                                                                                                                                  |
| x                              | Urine samples for research will be obtained over a 24-hour period  (Cycle 1 only)                          |                                                                                                                                                                                                                  |
| Cycle 1 onwards,               | x                                                                                                          | FdCyd and THU will be given through a vein for 3 hours                                                                                                                                                           |
| Day 2, 3, 4, 5                 | x                                                                                                          | Blood draws for research will be obtained (Cycle 1 only)                                                                                                                                                         |
| Cycle 1 onwards,               | x                                                                                                          | No treatment                                                                                                                                                                                                     |
| Day 6, 7 Cycle 1 onwards,      | x                                                                                                          | Have a history taken of how you feel and undergo a physical                                                                                                                                                      |
| Day 8                          | examination by a HCP (Cycles 1 and 2 only)                                                                 |                                                                                                                                                                                                                  |
| x                              | Get routine blood tests                                                                                    |                                                                                                                                                                                                                  |
| x                              | FdCyd and THU will be given through a vein for 3 hours                                                     |                                                                                                                                                                                                                  |
| Cycle 1 onwards,               | x                                                                                                          | FdCyd and THU will be given through a vein for 3 hours                                                                                                                                                           |
| Day 9, 10, 11 Cycle 1 onwards, | x                                                                                                          | FdCyd and THU will be given through a vein for 3 hours                                                                                                                                                           |
| Day 12                         | x                                                                                                          | Blood draws for research will be obtained (Cycles 1, 2, 4, and 6)                                                                                                                                                |
| Cycle 1 onwards,               | x                                                                                                          | No treatment                                                                                                                                                                                                     |
| Day 13-28                      | x                                                                                                          | On approximately days 15 and 21, you will have a physical  examination and blood draws for routine blood tests (Cycle 1 only)                                                                                    |
| Cycle 3 onwards                | x                                                                                                          | CT scans to determine how your tumor is responding to the treatment  will be done every 2 cycles (every 3 cycles if you have been on the  study for more than a year or every 4 cycles if for more than 3 years) |
| x                              | Tumor biopsy may be performed (at the end of Cycle 2/prior to start of  Cycle 3 only; optional, see above) |                                                                                                                                                                                                                  |
| x                              | Blood draw for research will be obtained if your disease comes back                                        |                                                                                                                                                                                                                  |
appendix i informed consent form
are there reasons that my

Your study doctor will be watching you and your cancer while you are receiving FdCyd and THU. If your cancer is worsening, the study doctor will suggest that you stop taking the drugs and she or he will discuss other options with you. Also, if you are having side effects from the drugs which are dangerous to your health or too difficult for you to tolerate, you and the study team may decide that you should stop taking the drugs. The study doctor may stop you from taking part in this study at any time if he or she believes it is not in your best interest, if you do not follow the study rules, or if the study is stopped.
appendix i informed consent form
stopping therapy

Your doctor may decide to stop your therapy for the following reasons:
x if he/she believes that it is in your best interest x if your disease comes back during treatment x if you have side effects from the treatment that your doctor thinks are too severe x if new information shows that another treatment would be better for you In this case, you will be informed of the reason therapy is being stopped. You can stop taking part in the study at any time. However, if you decide to stop taking part in the study, we would like you to talk to the study doctor and your regular doctor first. If you decide at any time to withdraw your consent to participate in the trial, we will not collect any additional medical information about you. However, according to FDA guidelines, information collected on you up to that point may still be provided to the Cancer Therapy Evaluation Program (CTEP) at the National Cancer Institute (NCI) or designated representatives. If you withdraw your consent and leave the trial, any samples of yours that have been obtained for the study and stored at the NCI can be destroyed upon request. However, any samples and data generated from the samples that have already been distributed to other researchers or placed in the research databases cannot be recalled and destroyed.
appendix i informed consent form
what side effects or risks

If you choose to take part in this study, there is a risk that you may:
x Lose time at work or home and spend more time in the hospital or doctor's office than usual x Be asked sensitive or private questions which you normally do not discuss The agents used in this study may affect how different parts of your body work such as your liver, kidneys, heart, and blood. The study doctor will be testing your blood and will let you know if changes occur that may affect your health. There is also a risk that you could have side effects from the study drug(s)/study approach. Here are important points about side effects:
x The study doctors do not know who will or will not have side effects.  
x Some side effects may go away soon, some may last a long time, or some may never go away.  
x Some side effects may interfere with your ability to have children. x Some side effects may be serious and may even result in death.  
Here are important points about how you and the study doctor can make side effects less of a problem:  
x Tell the study doctor if you notice or feel anything different so they can see if you are having a side effect.  
x The study doctor may be able to treat some side effects.  
x The study doctor may adjust the study drugs to try to reduce side effects.
The tables below show the most common and the most serious side effects that researchers know about. There might be other side effects that researchers do not yet know about. If important new side effects are found, the study doctor will discuss these with you. Risks and side effects related to FdCyd and THU may include:  
| COMMON, SOME MAY BE SERIOUS                                             |                                                          |
|-------------------------------------------------------------------------|----------------------------------------------------------|
| In 100 people receiving FdCyd/THU, more than 20 and up to 100 may have: |                                                          |
| x                                                                       | Anemia which may require blood transfusion               |
| x                                                                       | Diarrhea, nausea, vomiting                               |
| x                                                                       | Tiredness                                                |
| x                                                                       | Bruising, bleeding                                       |
| x                                                                       | Infection, especially when white blood cell count is low |
| x                                                                       | Loss of appetite                                         |  
| x   | Abnormal heartbeat                                   |
|-----|------------------------------------------------------|
| x   | Bloating, constipation, heartburn, passing gas       |
| x   | Pain                                                 |
| x   | Dry mouth, skin                                      |
| x   | Sores in mouth which may cause difficulty swallowing |
| x   | Chills, fever                                        |
| x   | Swelling of arms, legs                               |
| x   | Weight loss                                          |
| x   | Dehydration                                          |
| x   | Muscle weakness                                      |
| x   | Dizziness, headache                                  |
| x   | Changes in taste                                     |
| x   | Numbness, tingling or pain of the arms and legs      |
| x   | Cough, shortness of breath                           |
| x   | Nose bleed                                           |
| x   | Hair loss, itching, rash                             |
| x   | Increased sweating                                   |
| x   | Redness, pain or peeling of the palms and soles      |
| x   | Low blood pressure which may cause feeling faint     |  
THU has no expected side effects at the dose used in this study, but THU may make the side effects of FdCyd worse. Blood draws for routine laboratory tests may result in bruising, infection, and minor pain or discomfort comparable with a needle prick. When the medication is put through a vein in your arm, you may experience a moment of pain. In addition, there is the discomfort of having the catheter taped to your arm. Other risks include bleeding, bruising, temporary clotting of the vein, and infection. The removal of tumor tissue for research biopsies can cause pain, bruising, and possibly infection at the site where the biopsy was taken. The biopsy procedure will be discussed in detail with you, including side effects, and we will ask you to sign a separate consent form before to the procedure. Reproductive Risks: Because the drugs in this study can possibly affect unborn babies and infants, you should not become pregnant, father a baby, or breastfeed while you are on this study. Women of childbearing potential will be required to have a pregnancy test. If you are a woman who can become pregnant, or are the partner of a woman who can become pregnant, you will need to practice an effective form of birth control before starting study treatment and for 3 months after you finish study treatment. If you think that you or your partner is pregnant, you should tell your study doctor or nurse at once. Avoiding sexual activity is the only certain method to prevent pregnancy. But, if you choose to be sexually active, you should use an appropriate "double barrier" method of birth control (such as female use of a diaphragm, intrauterine device (IUD), or contraceptive sponge, in addition to male use of a condom) or the female should be using prescribed "birth control" pills, injections, or implants. Male participants must also use adequate contraception. If you choose to be sexually active during this study, you understand that even with use of these birth control measures pregnancy could still result. Some methods might not be approved for use in this study. Ask about counseling and more information about preventing pregnancy. For more information about risks and side effects, ask your study team.
appendix i informed consent form
are there benefits to taking

Taking part in this study may or may not make your health better. While doctors hope the combination of FdCyd and THU will be useful against your cancer, there is no proof of this yet. You should discuss other treatment options with the study team and your home doctor before deciding to take part in this study. We do know that information from this study will help doctors learn more about the combination of FdCyd and THU as a treatment for cancer. This information will also help future cancer patients.
appendix i informed consent form
what other choices do i

Talk to your doctor about your choices before you decide if you will take part in this study. Your other choices may include:  
x Getting other therapies that, although might not improve survival, may have other benefits, such as delaying disease progression.  
x Taking part in another study. x Getting no treatment.  
x Getting comfort care, also called palliative care. This type of care helps reduce pain, tiredness, appetite problems, and other problems caused by cancer. It does not treat the cancer directly, but instead tries to improve how you feel. Comfort care tries to keep you as active and comfortable as possible.
appendix i informed consent form
will my medical information be

We will do our best to make sure that the personal information in your medical record will be kept private. However, we cannot guarantee total privacy. Your personal information may be given out if required by law. If information from this study is published or presented at scientific meetings, your name and other personal information will not be used.  
Organizations that may look at and/or copy your medical records for research, quality assurance, and data analysis include:
x The National Cancer Institute (NCI) and other government agencies, like the Food and Drug Administration (FDA), involved in keeping research safe for people.  
x Designated investigators from other cancer centers participating in this study, including the City of Hope National Medical Center; the City of Hope Medical Group, Pasadena; the University of Southern California/Norris Comprehensive Cancer Center; the University of California, Davis Cancer Center, and the Penn State Cancer Institute.
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. [Note to Informed Consent Authors: the above paragraph complies with the new FDA regulation found at 21 CFR 50.25(c) and must be included verbatim in all informed consent documents. The text in this paragraph cannot be revised.] [Note to Local Investigators: The NCI has recommended that HIPAA regulations be addressed by the local institution. The regulations may or may not be included in the informed consent form depending on local institutional policy.]
appendix i informed consent form
what are the costs of

You and/or your health plan/ insurance company will need to pay for some or all of the costs of treating your cancer in this study. Some health plans will not pay these costs for people taking part in studies. Check with your health plan or insurance company to find out what they will pay for. Taking part in this study may or may not cost your insurance company more than the cost of getting regular cancer treatment. The study agents, FdCyd and THU, will be provided free of charge while you are participating in this study. Even though it is unlikely, there is a possibility that at some point the supply of study agent may run out necessitating taking you off-study. [If applicable, inform the patient of any tests, procedures or agents for which there is no charge. The explanation, when applicable, should clearly state that there are charges resulting from performance of the test or drug administration that will be billed to the patient and/or health plan. For example, "The NCI is supplying (drug) at no cost to you. However, you or your health plan may need to pay for costs of the supplies and personnel who give you the (drug)."]
appendix i informed consent form
you will not be paid

For more information on clinical trials and insurance coverage, you can visit the National Cancer Institute's Web site at http://cancer.gov/clinicaltrials/understanding/insurance-coverage. You can print a copy of the "Clinical Trials and Insurance Coverage" information from this Web site. Another way to get the information is to call 1-800-4-CANCER (1-800-422-6237) and ask them to send you a free copy.
appendix i informed consent form
what happens if i am

It is important that you tell your study doctor, __________________ *[investigator's name(s)],* if you feel that you have been injured because of taking part in this study. You can tell the doctor in person or call him/her at __________________ *[telephone number].* You will get medical treatment if you are injured as a result of taking part in this study. You and/or your health plan will be charged for this treatment. The study will not pay for medical treatment.
appendix i informed consent form
what are my rights if

Taking part in this study is your choice. You may choose either to take part or not to take part in this study. If you decide to participate, you may leave the study at any time. No matter what decision you make, there will be no penalty to you, and you will not lose any of your regular benefits. Leaving the study will not affect your medical care. You can still get your medical care from our center. We will tell you about new information or changes in the study that may affect your health or your willingness to continue in the study. In the case of injury resulting from this study, you do not lose any of your legal rights to seek payment by signing this form.
appendix i informed consent form
who can answer my questions

You can talk to your study doctor about any questions or concerns you have about this study. Contact your study doctor __________________ *[name(s)]* at __________________ [telephone number]. For questions about your rights while taking part in this study, call the ________________________ *[name of center]* Institutional Review Board (a group of people who review the research to protect your rights) at __________________ *(telephone number). [Note to* Local Investigator: Contact information for patient representatives or other individuals in a local institution who are not on the IRB or research team but take calls regarding clinical trial questions can be listed here.]
appendix i informed consent form
where can i get more

You may call the National Cancer Institute's Cancer Information Service at: 1-800-4-CANCER (1800-422-6237). You may also visit the NCI Web site at http://cancer.gov/.  
x For NCI's clinical trials information, go to: http://cancer.gov/clinicaltrials/ x For NCI's general information about cancer, go to http://cancer.gov/cancerinfo/
You will get a copy of this form. If you want more information about this study, ask your study doctor.
appendix i informed consent form
signature

I have been given a copy of all _____ *[insert total of number of pages]* pages of this form. I have read it or it has been read to me. I understand the information and have had my questions answered. I agree to take part in this study.