CIBMTR 13-TLEC PBMTC LTE1401 Natural History and Biology of Long-Term Late Effects Following Hematopoietic Cell Transplant for Childhood Hematologic.

CIBMTR 13-TLEC PBMTC LTE1401 Natural History and Biology of Long-Term Late Effects Following Hematopoietic Cell Transplant for Childhood Hematologic Malignancies Thank you for joining us today. We’re exciting to welcome you to the training for the Natural History and Biology of Long-Term Late Effects Following Hematopoietic Cell Transplant for Childhood Hematologic Malignancies study – also known by its short name of “13-TLEC.” As you know, this study just recently opened and the first three patients were enrolled in March 2015.

Study Sponsors Collaborative Effort
Center for International Blood & Marrow Transplant Research (CIBMTR) And Pediatric Blood and Marrow Transplant Consortium (PBMTC) Michael Pulsipher, MD – Current Chairperson This study is a collaboration between the CIBMTR and the PBMTC – of which Dr. Michael Pulsipher is the current Chairperson.

13-TLEC Key Study Personnel
Study Chairpersons Christine Duncan, MD Dana-Farber K.Scott Baker, MD Fred Hutchinson Cancer Center CIBMTR Protocol Coordinators Sue Flesch RaeAnne Besser Sr. Clinical Research Specialist Clinical Research Specialist CIBMTR Protocol Monitors Ashley Birch Kari Reilly Sr. Clinical Research Associate Clinical Research Associate This slide lists the key personnel involved on the study. Christine Duncan from Dana-Farber and Scott Baker from Fred Hutch are the PIs. The protocol coordinators at the CIBMTR are Sue Flesch and RaeAnne Besser. These are the people to contact with any questions pertaining to such things as the protocol, study procedures and FormsNet. The study monitors are Kari Reilly and Ashley Birch. They should be contacted with any questions or concerns pertaining to the monitoring process for the study including preparing for a monitoring visit and responding to any monitoring findings.

13-TLEC Protocol Team Lynette Anderson, NP Children’s Hospital of Wisconsin Christopher Dvorak, MD University of California, San Francisco Jerelyn Moffet, MSN, C-PNP Duke Children’s Hospital & Health Center Jeffrey Auletta, MD Nationwide Children’s Hospital Sangeeta Hingorani, MD Fred Hutchinson Cancer Research Center Michael Nieder, MD Moffitt Cancer Center K. Scott Baker, MD * David Jacobsohn, MD Children’s National Medical Center Michael Pulsipher, MD Primary Children’s Hospital Kristen Barbieri, PA-C Childrens National Karina Danner-Koptik, APN,CNS Ann and Robert H. Lurie Children’s Hospital of Chicago Angela R. Smith, MD, MS University of Minnesota Kristen Beebe, PAC Mayo Clinic Arizona – Phoenix Children’s Hospital Robert Krance, MD Texas Children’s Cancer and Hematology Centers Andrew Dietz, MD Morris Kletzel, MD * Study Principal Investigators Christine Duncan, MD * Dana Farber Cancer Institute Paul Martin, MD And this table lists the members of the protocol team that developed the 13-TLEC protocol.

13-TLEC Study Design Prospective, non-therapeutic study to assess long-term toxicity of pediatric hematopoietic stem cell transplant (HCT) for hematologic malignancies. Study examines the hypothesis that survivors of pediatric HCT: Are at risk for late organ toxicity Will have identifiable biomarkers present within first two years following HCT Biomarkers will be predictive for late adverse outcomes allowing for early identification of patients at risk So to begin, we will start off by talking a bit about the design of the TLEC study. This is a prospective, non-therapeutic study looking at the long-term toxicity of pediatric hematopoietic stem cell transplant for hematologic malignancies. The study examines the hypothesis that survivors of pediatric stem cell transplant: Are at risk for late organ toxicity Will have identifiable biomarkers present within the first two years following transplant And These biomarkers will be predictive for late adverse outcomes which will allow for early identification of those patients at risk.

13-TLEC Study Design (continued)
Background/Rationale Lifelong risk for transplant-related late effects in survivors of childhood HCT Burden of late effects disproportionately borne by children with highly resistant hematopoietic malignancies Findings of The Bone Marrow Transplant Survivor Study First International Consensus Conference on Late Effects after Pediatric HCT (NCI/NHLBI; April 2011) Formation of Late Effects Strategy Group by PBMTC A little bit about the background and rationale for this study…. The Bone Marrow Transplant Survivor Study reported that adult patients who survived at least 2 years from allogeneic transplant were at 9.9-fold-increased risk of death compared to the general population. Even 15 years from transplant, the mortality rates of HCT patients remained higher than those of the general population and approximately 25% of these deaths were attributed to late transplant-related toxicities. In recognition of the growing number of HCT survivors, the importance of post-HCT long-term health, and the absence of data regarding late effects in children, the National Cancer Institute and the National Heart, Lung, and Blood Institute sponsored the First International Consensus Conference on Late Effects after Pediatric HCT in April The conference brought together experts in the area of pediatric HCT late effects and resulted in 7 summary articles that outlined key research needs calling for multi-center studies. In response to the mandate the Pediatric Blood and Marrow Transplant Consortium (PBMTC) formed the Late Effects Strategy Group. This multi-center proposal from the PBMTC Late Effects Strategy Group is a comprehensive study of the late toxicities of pediatric HCT for hematologic malignancy and is in direct response to the research priorities outlined at the consensus conference.

Study Aims Prospectively collect comprehensive information about HCT late effects Particular emphasis on renal, cardio-metabolic, and skeletal toxicities Establish a biologic sample repository from large cohort of childhood HCT survivors - Study Accrual 340 subjects projected Accrual period 3 years; all subjects followed for 2 years post transplant The accrual projection for the study is 340 patients over a three year period – beginning in March Under the current protocol, all subjects enrolled on the study will be followed for 2 years post-transplant. The basic aims of the study are: To prospectively collect comprehensive information about the late effects of stem cell transplant To look at late effects with a particular emphasis on renal, cardio-metabolic, and skeletal toxicities To also establish a biologic sample repository from a large cohort of childhood survivors of stem cell transplant.

Study Aims Prospectively study screening modalities to establish incidence of renal, cardio-metabolic and skeletal late effects. Examine potential biomarkers for prediction of organ specific late toxicities To prospectively study screening modalities to establish the incidence of renal, cardio-metabolic and skeletal late effects AND To examine potential biomarkers for the prediction of organ specific late toxicities

Study Endpoints Primary Assessment of chronic kidney disease, metabolic syndrome, and osteopenia at one and two years post HCT The primary endpoint of the study is the assessment of chronic kidney disease, metabolic syndrome and osteopenia at one and two years after transplant.

Study Endpoints Secondary Hypertension Systolic or diastolic blood pressure ≥ 95th percentile Acute kidney injury Increase in Scr by x 0.3mg/dL (x26.5 Imol/L) within 48 hours OR Increase in Scr to 1.5 x baseline (known or presumed to have occurred within prior 7 days) Urine volume < 0.5 mL/kg/h for 6 hours There are several secondary endpoints for the study. The first of these is hypertension in which the systolic or diastolic blood pressure is greater than or equal to the 95th percentile. Another secondary endpoint is evidence of acute kidney injury as defined by one of the three criteria outlined on this slide. (These criteria are also included in the study protocol.)

Study Endpoints Secondary Proteinuria Presence of protein > 300 mg/g creatinine in a spot urine sample. Adiposity Body fat percent (BF%) > McCarthy’s 85th percentile of body fat reference data. Obesity BMI ≥ 95% for age and sex using 2000 CDC reference data and growth charts. Vitamin D deficiency 25-OH vitamin level < 20 ng/mL (50 nmol/L) Secondary endpoints also include Proteinuria, Adiposity, Obesity and Vitamin D deficiency as defined by the values displayed on this slide. Again, all of this information is detailed in the protocol so I won’t read it here verbatim.

Study Endpoints Secondary Dyslipidemia Trigylycerides > 150 mg/dL LDL cholesterol > 130 mg/dL OR HDL cholesterol < 40 mg/dL and/or use of lipid lowering medications. Osteoporosis Z-score < -2.0 in any area assessed by DXA and/or non-traumatic fracture. Albuminuria Urine albumin to urine creatinine ratio (ACR) between 30 and 299 mg/g creatinine in a spot urine sample. The last three secondary endpoints to be assessed in this study are Dyslipidemia, Osteoporosis and Albuminuria.

Study Endpoints Tertiary BMD Whole body DXA Z-score DXA order needs to specify to read the body composition. BMI Calculated as mass (kg) and height (cm) Reported as kg/m2 in percentile normalized for age and sex. GFR Reported in mL/min/1.73 m2 measured by nuclear medicine GFR or 24 hour creatinine clearance There are also three tertiary study endpoints associated with this study: a measurement of bone mineral density (or BMD), Body Mass Index (or BMI) and Glomerular Filtration Rate (or GFR) as defined on this slide. One note here about ordering the DXA scan – based on the experience of our first site to begin enrolling - be sure to specify that the body composition needs to be read.

Test Your Knowledge Measurement of which of the following is tied to one of the study endpoints? Blood Pressure Obesity Vitamin D deficiency Albuminuria All of the above

Eligibility Criteria Inclusion Age less than 22 years at admission for HCT (no lower limit on age) Planned allogeneic HCT Any donor Any stem cell source No study-specific criteria for HLA-matching There are seven inclusion criteria patients must meet to be eligible to enroll on the TLEC study. First, the patient must be less than 22 years old at the time of admission for his or her transplant. There is no lower limit on age. Secondly, the patient must have a planned allogeneic stem cell transplant. The transplant can be from any donor and from any stem cell source. There are no study-specific criteria for HLA-matching.

Eligibility Criteria Inclusion Disease and disease status criteria Acute lymphoblastic leukemia/lymphoma in complete morphologic remission defined as M1 marrow (<5% blasts) with no evidence of active extramedullary disease within 30 days of the start of the conditioning regimen; OR Myelodysplasia (regardless of subtype) with less than 10% marrow blasts within 30 days of the start of the conditioning regimen; OR Acute myelogenous leukemia in complete morphologic remission defined as an M1 marrow (<5% blasts) with no evidence of extramedullary disease within 30 days of the start of the conditioning regimen; OR Juvenile myelomonocytic leukemia; OR Chronic myelogenous leukemia excluding refractory blast crisis Acceptable definition of blast crisis is the persistence of circulating blasts despite therapy. Patients must also meet one of the disease and disease status criteria categories as defined on this slide. This same information is also outlined in the study protocol as well. With respect to Chronic myelogenous leukemia – the last disease listed on this slide – an acceptable definition for “blast crisis” is persistence of circulating blasts despite therapy.

Eligibility Criteria Inclusion Planned myeloablative conditioning regimen which includes one of the following as backbone agent Busulfan ≥ 12.8 mg/kg total dose (IV or PO) PK-based dosing allowed, if intent is total overall dose of 12 mg/kg OR Total Body Irradiation ≥ 1200 cGy fractionated Treosulfan ≥ 30 g/m2 total dose IV Regimens may include other agents as long as at least one of above criterion met. The study inclusion criteria also mandates that patients have a planned myeloablative conditioning regimen which includes one of the three agents and doses outlined on this slide as a backbone agent. Regimens may include other agents as well, but at least one of the above mentioned criteria must be met.

Eligibility Criteria Inclusion Co-enrollment on following NMDP research protocols Protocol for a Research Database for Hematopoietic Cell Transplantation, Other Cellular Therapies and Marrow Toxicity Injuries Protocol for a Research Sample Repository for Allogeneic Hematopoietic Stem Cell Transplantation and Marrow Toxic Injuries Written informed consent Signed by patient if developmentally able and equal to or greater than age 18 Signed by parent or legal guardian if patient developmentally unable or less than age 18 To be eligible for enrollment on the TLEC study, co-enrollment on two NMDP research protocols: the research database and the research sample repository is also required. Finally, of course, written informed consent is also required of any patient enrolling on the study. If the patient is 18 years old or older and developmentally able, he or she would sign the consent. In those instances where the patient is under the age of 18 and/or is developmentally unable, a parent or legal guardian must sign on his or her behalf.

Eligibility Criteria Exclusion Prior allogeneic or autologous HCT Renal disease prior to start of HCT conditioning requiring use of dialysis at time of enrollment and/or GFR < 60 mL/min/1.73 m2 Osteopenia or osteoporosis treated with bisphosphonate medication any time prior to enrollment Pre-existing diabetes or hyperglycemia treated with insulin or oral hypoglycemic medication at time of enrollment The following criteria would exclude a patient from being eligible for participation on the TLEC study. These include: Having had a prior allogeneic or autologous stem cell transplant Having renal disease prior to the start of conditioning which required the use of dialysis at the time of enrollment and/or a GFR of less than 60 mL/min/1.73 m2 Osteopenia or osteoporosis treated with bisphosphonate medication any time prior to enrollment Pre-existing diabetes or hyperglycemia treated with insulin or an oral hypoglycemic medication at the time of enrollment

Eligibility Criteria Exclusion Uncontrolled viral, bacterial, fungal or protozoal infection at time of study enrollment Karnofsky performance score or Lansky Play-Performance Scale Score < 60 at time of study enrollment Known inherited or constitutional predisposition to cancer Including (but not limited to) Down Syndrome, Li-Fraumeni Syndrome, Fanconi Anemia, BRCA1 and BRCA2 mutations An uncontrolled viral, bacterial, fungal or protozoal infection at the time of enrollment A Karnofsky performance score or a Lansky Play-Performance Scale Score of less than 60 at the time of enrollment And lastly, any known inherited or constitutional predisposition to cancer. This includes, but is not limited to, those conditions you see listed at the bottom of this slide.

Subject Consent and Enrollment Confirm all eligibility criteria met Must have signed study consent NOTE: Patient must be successfully enrolled prior to collection of any data, performance or protocol specific diagnostic studies Written informed consent Signed by patient If greater than or equal to 18 years of age Patient is developmentally able Signed by parent or legal guardian Patient less than 18 years of age OR Greater than or equal to 18 years of age but developmentally unable to provide consent Assent Obtained according to guidelines of patient’s transplant institution. Prior to enrolling a patient onto the study, it must be confirmed that all eligibility criteria have been met and consent and assent if applicable must be obtained. Again, if the patient is 18 years old or older and developmentally able, he or she would sign the consent. And again, in those instances where the patient is under the age of 18 and/or is developmentally unable, a parent or legal guardian must sign on his or her behalf. Please refer to your institution’s guidelines regarding when assent should be obtained.

Subject Consent and Enrollment Informed consent must be obtained within 60 days of the start of the conditioning regimen. If transplant delayed and more than 60 days passes, patient should be re-assessed to ensure still meets all eligibility criteria, but does NOT need to be re-consented. Enrollment assessments and Baseline assessments considered standard of care permissible prior to consent Any research specific baseline assessments (including collection of plasms and urine samples) may NOT be initiated prior to consent. Pre-HCT Assessment Must occur within 30 days of the start of the conditioning regimen If HCT delayed, contact CIBMTR coordinator The consent must be obtained within 60 days of the start of the condition regimen. If something happens and the transplant is delayed outside of this 60 day window, the patient should be re-assessed to make sure that they still qualify for the study. Any enrollment and/or baseline assessments are acceptable to occur prior to consent only if they are part of the patient’s standard of care. This also means that any research specific assessments (including blood and urine collections) cannot happen prior to consent. All pre-HCT assessments must occur within 30 days of the condition regimen starting. If the HCT is delayed; Contact CIBMTR Coordinator to determine, which, if any assessments should be repeated.

Test Your Knowledge 2) Which of the following is a true statement?
A subject must be at least 12 months old to be considered eligible for enrollment on the 13-TLEC study. 13-TLEC study subjects must also co-enroll on NMDP’s Protocol for a Research Database for Hematopoietic Cell Transplantation, Other Cellular Therapies and Marrow Toxicity Injuries. It is permissible to collect the pre-HCT study plasma sample prior to the subject signing the 13-TLEC study consent form. A legal guardian may not sign a consent on behalf of a subject over the age of 18 even if he/she is developmentally unable to do so. It is not permissible to conduct any standard of care Baseline assessments prior to the subject consenting to the study.

13-TLEC Critical Study Logistics
All data collection in FormsNet CIBMTR Recipient Forms (FN3) 13-TLEC study-specific forms (FN2) Separate FormsNet training module Completion of both CIBMTR and study-specific forms Timely submission of data important!! All data for the TLEC study will be captured in the FormsNet system. Most of you are already familiar with FormsNet- particularly FormsNet3 which you access to complete the CIBMTR outcomes data forms on your patients. As you’ll see in an upcoming slide, information collected from a number of these outcomes forms will be utilized in this study. All patients taking part in the TLEC study must be put on the Comprehensive Research Form (CRF) track. Please remember to indicate, on question 6 of the Pre-TED (Form 2400) that these patients are participating on the RCI BMT TLEC study. All study-specific information for TLEC will be collected on Case Report Forms housed within the Clinical Trials module in FormsNet2. Specific instruction on the completion of these forms is detailed in a separate TLEC FormsNet Training module now available on the NMDP’s new Learning Center. One important thing to remember when accessing FormsNet - the browser you use does make a difference whether using FormsNet2 or FormsNet3. As many of you are probably already aware, when accessing FormsNet3 to complete the CIBMTR forms, it is best to use a browser such as Chrome. For FormsNet2, on the other hand, a browser of IE8 works best. We want to stress the importance of timely submission of both the CIBMTR and the study-specific data. Especially in the case of the later, it’s also to your advantage to submit the forms as soon as you are able since doing so is tied into your study reimbursement. We will be monitoring data submission regularly and will be contacting you to ensure this data is submitted as soon as possible.

Recommended Standard of Care
Pre-HCT Day 30 (+/- 7 days) Day 100 (+/- 14 days) Day 180 (+/- 21 days) 1 Year (+/- 30 days) 2 Year (+/- 60 days) Baseline morbidity X Late effects assessment Noncorticosteroid medication and therapeutic intervention assessment X Corticosteroid assessment Weight, height, and waist circumference Blood pressure 24-hour blood pressure (Seattle only) Urine Protein & Albumin GFR or creatinine clearance Cystatin C , BUN (for calculation of eGFR) Serum & urine creatinine Fasting TG, HDL, and LDL Fasting insulin & glucose DXA or chest radiograph Vitamin D, PTH & calcium Study-Specific Repository plasma Urine elafin Osteocalcin, bone specific alkaline phosphatase, urine N-telopeptide This next slide is an illustration of what is also found in Table 4.2 in the protocol. It is a summary of all TLEC activities and the time points when they are scheduled. As you can see, activities are also separated by those considered “standard of care” and those which are being done as part of the study only. To assist you in keeping track of all the requirements for each of your patients, we’ve created a worksheet – which looks exactly like this – with checkboxes. This worksheet is available in the Study Materials section in FormsNet2 for you to print off and use if you wish. A few important things of note here…… First you will note in the table the required collection of cystatin c and BUN to be used later in the collection of eGFR. This is a change which will be reflected in the upcoming protocol amendment. CRFs currently being modified to capture this values Likely not implemented until August 2015 Will be required to go back into FN at a later date to enter Also, in terms of measuring the GFR at pre-HCT, 1 and 2 years this may be done using nuclear medicine, or either 12 or 24 hour creatinine clearance – but whatever method you use to measure, it must be consistent at all three timepoints.

13-TLEC Critical Study Logistics (continued)
CIBMTR FORMS FORM NUMBER FORM DESCRIPTION 2400 Pre-Transplant Essential Data (Pre-TED) 2804 CIBMTR Recipient ID Assignment Form 2000 Recipient Baseline Data 2005 Confirmation of HLA typing 2100 100 Days Post-HCT Data 2200 Six Months to Two Years Post-HSCT Data 2900 Recipient Death Data POST-TRANSPLANT DISEASE-SPECIFIC FORMS 2110 Acute Myelogenous Leukemia Post-HCT Data 2111 Acute Lymphocytic Leukemia Post-HCT Data 2112 Chronic Myelogenous Leukemia Post-HSCT Data 2114 Myelodysplasia / Myeloproliferative Disorders Post-HCT Data 2115 Juvenile Myelomonocytic Leukemia Post-HCT Data Not that you need to memorize this, but what this slide shows are the CIBMTR forms applicable to this study. One thing to note here – we are in the process of creating a short study-specific training designed just for the Data Managers at your centers, but we also want to stress the importance of keeping an open line of communication with them. This will help ensure the timely submission of these forms and also help to quickly identify any issues or concerns that may come up.

13-TLEC Study Specific Forms FORM NUMBER FORM DESCRIPTION SCHEDULED(S) UNSCHEDULED(U) 3181 Enrollment S 3182 Baseline 3183 Transplant 3184 Follow-Up – 30 Day 3185 Follow-Up – 100 Day 3186 Follow-Up – 180 Day 3187 Follow-Up – 1 Year and 2 Year 3188 Protocol Deviation U 3189 Unanticipated Problem 3190 Unanticipated Problem – Medical Monitor 3191 Study Exit S & U 3192 Medication 3193 Medication - corticosteroid Similarly, what is shown on this slide are the TLEC study-specific forms. Again, meant to serve as a reference for you.

Form Assessment Timeframe Submission Timeframe 3183 (Enrollment) Upon clinic visit. Within 14 days of confirming eligibility and obtaining subject consent. 3182 (Baseline) Within 30 days prior to the start of the preparative regimen. Within 30 days of assessment completion. 3183 (Transplant) Day 0 Within 14 days of transplant. 3184 (Follow-Up, Day 30) Day 30 +/- 7 days Within 14 days of Follow-Up completion. 3185 (Follow-Up, Day 100) Day 100 +/- 14 days 3186 (Follow-Up, Day 180) Day 180 +/- 21 days 3187 (Follow-Up, 1 year) 1 year +/- 30 days 3187 (Follow-Up, 2 year) 2 year +/- 60 days 3188 (Protocol Deviation) Unscheduled form At the time of the deviation occurrence, or when the site becomes aware of the deviation. 3189 (UAP) Requires expedited reporting. Due within 3 business days of occurrence. 3191 (Study Exit) As close as possible to the time of the qualifying exit event. 3192 (Medication) Same as for all Follow-Up forms. Same as for all Follow-Up Forms. 3193 (Corticosteroid) Same as Day 1, Day 100, Day 180, Year 1 and Year 2 Follow-Up Forms Within 14 days of associated Follow-Up Form completion. As was mentioned in a previous slide, the timely submission of the TLEC study forms is extremely important. This slide outlines the timeline requirements for submission of each of the study-specific forms.

Adverse Events Not applicable for this study Unanticipated problems include Events which are unexpected New information indicating that research subjects or others are at a greater risk of harm than previously believed prior to awareness of this new information Pregnancy of study subject should be reported as an unanticipated problem for this study Since there are no Adverse Events on the TLEC study, there is no study-specific form for reporting them. It is possible, however, that unanticipated problems may arise during the course of the study. By definition, an “unanticipated problem” is an event which occurs during a study which is unexpected and/or some new information which arises indicating that research subjects or others are at a greater risk of harm than previously believed prior to the awareness of this new information. For this study, one specific example of an unanticipated event would be a study subject who becomes pregnant. Should this happen, a form 3189 would need to be completed.

Sample Collection and Shipment Complete details outlined in Study Laboratory Sample Manual Posted in 13-TLEC Study Materials section in FormsNet2 application Another very critical aspect of the study logistics is the collection and shipment of the various samples required for the study. We’ll give a quick overview here in the next few slides, but complete details can be found in the study’s Lab Sample Manual which will be posted in the Study Materials section in FormsNet2.

Sample Collection and Shipment Overview NMDP Repository Blood Sample Pre-transplant Research Repository Critical Facts Sheet ( As part of this study, three different types of samples will be collected on each study subject. The first of these is the pre-transplant sample collected under the NMDP’s Repository Blood Sample protocol. As you may recall from a previous slide, co-enrollment of this protocol is one of the inclusion criterion for being eligible for participation on the TLEC study. Since specifics around the collection and shipment of this sample is managed outside of this study, we recommend that you follow the detailed instructions outlined in the “Research Repository Critical Facts Sheet.” The location for finding this document is shown here. If related donor – site must also collect and submit this sample as well as the patient sample.

Sample Collection and Shipment Overview Biorepository Plasma Samples Kits/packaging materials shipped to sites from Inmark Cryovials, cryovial boxes, EDTA tubes and FedEx air bills shipped to sites from NMDP Repository Cryovial labels shipped to sites from CIBMTR study coordinators Samples collected at all timepoints (pre HCT – 2 years) except day 180 Current requirement: minimum 7-10 mL to change with upcoming amendment – until approved, protocol deviation required Processing of samples to occur at sites prior to shipment to NMDP repository Must occur within 60 minutes or report as protocol deviation Site to batch ship (frozen) samples to NMDP Repository (schedule to be communicated by CIBMTR) As mentioned earlier in this training, one of the basic aims of this study is to collect pre and post-transplant plasma samples on enrolled subjects to develop a large biologic sample repository. These samples may later be used to identify potential biomarkers which could be predictive for late adverse in survivors of childhood stem cell transplant. These study-specific plasma samples will be collected at each of the various time points illustrated on Table 4.2 with the exception of Day 180. The TLEC Laboratory Sample Manual provides detailed information pertaining to the collection and shipment of these samples, but we’ll cover a few main points here as well. The first thing to be aware of is that, after collection, all sample processing will occur at your site prior to shipment to the NMDP Repository for storage. Once your site is officially activated, you will receive approximately 6-12 months’ worth of supplies necessary for the collection, processing and shipping of samples. Note that you will receive shipment from three places: Everything you need to collect the samples – the EDTA tubes and cryovials - will be shipped to your site from the NMDP Repository upon activation. Once your site is ready to ship samples, the outer shipping boxes and all sample packaging materials required to ship samples to the NMDP Repository will be shipped to your site from a company called Inmark. When your site has an upcoming shipment, you will also receive cryovial boxes and pre-printed FedEx air bills from the NMDP Repository. Any time you are in need of additional supplies, you should notify CIBMTR by sending a message to and we will see they get sent to you. As stated in the Lab Manual, sample processing must occur within 60 minutes after collection. Prior to processing, keep all tubes at ambient temperature. As part of the processing procedure, you will need to complete the Plasma Sample Processing Log to document how the samples were handled and prepared. A visual of this processing log is coming up on the next slide. Also, if the processing were to occur outside of this 60 minute window, a protocol deviation must be completed. The protocol currently states a minimum volume of 7-10 mL be collected at each specified time point. We realize this may be difficult – particularly on some of your smaller patients - so will accept whatever volume you are able to collect. We are working on modifying this language in an upcoming protocol amendment, but until that amendment is approved by the IRB, collection of less than that volume must be reported as a protocol deviation. Samples will be stored at your site and batch shipped to the NMDP Repository. We will work with you on determining shipment dates. Frequency will, of course, be contingent to a large degree on how many and how quickly your site is enrolling patients, but we estimate shipments to occur approximately once a quarter or so. A few more important points about shipping….. (these too are things spelled out in detail in the Lab Manual)….. Frozen plasma samples should only be shipped to the Repository Monday through Wednesday. Prior to shipping, we ask that you please send an electronic copy of the completed Sample Manifest (which you will see on an upcoming slide) pertaining to all samples contained in that shipment to A copy of this same Sample Manifest must also be included with the actual shipment itself.

Sample Processing Log 13-TLEC Sample Processing Log PLASMA
Institution Name: ___________________________CCN: _________________ Subject ID Collection Date Time Sample Collected Volume Collected Sample Processing – Start Time Sample Processing – End Time Time Placed Into Freezer Technician Initials This slide shows you what the Sample Processing Log you will be completing for each sample collected looks like. You can find this document in the Lab Sample Manual as well as in the Study Materials section in FormsNet2. Because it’s important for us to verify the proper collection and processing of all study-specific samples, you should retain a copy of each of these logs at your site as well as a copy of each to at the time the samples are shipped to either the NMDP Repository or the laboratory at Fred Hutchinson.

Sample Shipping Manifest
Appendix A: Laboratory Sample Shipping Manifest Sample Shipping Manifest 13-TLEC Laboratory Sample Shipping Manifest Center Name CCN Total Number of Samples Shipped Date of Shipment FedEx Tracking Number Subject ID Label ID Visit Sample Type Volume Unit of Measure Date Collected Time Collected And here is what the sample shipping manifest looks like. You can find this document in both the Lab Sample Manual and in the Study Materials section in FormsNet2 as well.

Sample Collection and Shipment Urine Samples (elafin assessment) Shipping boxes/packaging materials shipped to sites from Inmark Cryovials, cryovial boxes, urine collection cups and FedEx air bills shipped to sites from NMDP repository Cryovial labels shipped to sites from CIBMTR coordinators Samples collected at all timepoints (pre HCT – 2 years) Requirements: Minimum 8-10 mL Place immediately on ice Site to batch ship (frozen) aliquoted samples to Fred Hutch laboratory Lastly, you will also be collecting urine samples from all of your patients enrolled on the TLEC study. Urine samples will be collected at ALL time points illustrated on Table 4.2. As for the plasma samples, the TLEC Laboratory Sample Manual provides all the necessary information pertaining to sample collection and shipment, but I just want to point out a few main points here too. Although no processing is required for these samples, your site will be responsible for aliquoting, freezing and maintaining these samples prior to shipment to the laboratory at Fred Hutchinson Cancer Research Center. All the supplies needed for collection and shipping the urine samples will come to your site from either Inmark, or the NMDP Repository as previously described in reference to the plasma samples. As is the case for the plasma sample supplies, you can submit a request for additional supplies through A few important things regarding collection of the urine samples…. -First, whatever volume you’re able to collect should be shipped to the lab, but it’s important to collect the minimum 8-10 mL as specified in the protocol whenever possible. This will help ensure some patients won’t later be excluded from some analyses. If less than the minimum volume is collected, it will need to be reported as a protocol deviation at this time. -Secondly, whenever possible, urine should be collected in the morning – preferably between the hours of 8 and 10 AM. -It’s very important that immediately after collection these samples be placed on ice. -And lastly, aliquoting and freezing the samples must occur within one hour. Just as for the plasma samples, we have a Sample Processing Log for you to complete to document the details around collection and handling of the urine. Like the plasma samples, urine samples will also be stored at your site and batch shipped. In this case, however, the samples will be shipped directly to the study lab at Fred Hutch and NOT the NMDP Repository. You can find the lab’s shipping address in the Lab Sample Manual. Again, we will work with you in determining shipment dates, and many parts of the process will be identical to that used when shipping the plasma samples: Urine samples will be shipped to Fred Hutch Monday through Wednesday only. Prior to shipping, we ask that you please send an electronic copy of the completed Sample Manifest to A copy of this same Sample Manifest must also be included with the actual shipment itself.

Test Your Knowledge 3) Which of the following statements is not true?
a. A DXA scan or chest radiograph is required for all study subjects at days 30,100, and 180. Study-specific plasma and urine samples need to be shipped to two different locations. Completion of the Sample Processing Log is required for both plasma and urine samples. A completed copy of the Sample Shipping Manifest must be ed to the CIBMTR prior to samples being shipped and be included with the actual shipment. Urine samples should immediately be placed on ice upon collection.

Good Clinical Practices (GCP)
An international ethical and scientific quality standard for the design, conduct, performance, recording and reporting of clinical trials. Adherence to GCP provides public assurance that: The rights, safety and well-being of subjects are protected Clinical study data are credible GCP requirements apply to: Sponsor and representatives IRB Investigator and study site personnel The next few slides will provide a brief overview of Good Clinical Practices – or GCP – which, as we all know, is extremely important in the conduct of any clinical trial. By definition, GCP is an international ethical and scientific quality standard for the design, conduct, performance, recording and reporting of clinical trials. Adherence to GCP is important in providing public assurance that the rights, safety and well-being of subjects are protected and that study data from clinical trials is credible. GCP requirements apply to any and everyone involved in a clinical trial. This includes the study sponsor and representatives, IRBs and, of course, the study investigators and study site personnel.

Good Clinical Practices (GCP) in Clinical Research
Overall responsibility for conduct of the trial lies with the Study Investigator at each participating site. Investigators are responsible for ensuring the following: Adequate Resources (staff and facility[s]) are in place to properly and safely conduct the study Medical Care of Subjects (including reporting of any serious adverse events [SAEs] ) on the study Delegation of Responsibilities as appropriate for conduct of the study Protocol Compliance by all site personnel involved with conduct of the study One of the most critical aspects of GCP is the fact that the overall responsibility for any given clinical trial lies with the Study Investigator at a participating site. Your site’s investigator needs to ensure that: There are adequate resources, such as study staff and facilities, There is proper medical care for subjects enrolled on to the study, Study responsibilities are properly delegated to trained study staff, The protocol is accurately followed by all site personnel, and

Good Clinical Practices (GCP) in Clinical Research (continued)
Appropriate treatment of Investigational Product Maintenance of study Source Records and Case Report Forms (CRFs) Maintenance of a study Regulatory Binder Record Retention of study documents Oversight of study sponsor audit, FDA inspection, IRB inspection Study records, including source documents, case report forms, and regulatory documents, are maintained and retained for the appropriate length of time. Your site’s principal investigator will also provide oversight in the event that there is an audit of the study. An audit may be conducted by the study sponsor, the IRB overseeing the study and/or your site, or the FDA.

13-TLEC Study Monitoring
Centralized (remote) monitoring Sites submit required documents for off-site review Focus on critical data elements Intensity: At least 30% of subjects enrolled will be monitored Minimum of one monitoring visit per site Duration: 1-3 days per visit Next, we are going to discuss study monitoring. As a reminder, all monitoring questions should be directed to Kari Reilly or Ashley Birch. Visits are conducted by centralized monitoring methods for this study. This process includes sending all required documentation to the monitor for off-site review. The visit focuses on critical data elements, such as primary and secondary endpoints. Visits are scheduled to ensure 30% of all subjects enrolled are monitored. The number of visits will vary per site; however, each site will be monitored at least once. Typically, visits range from one to three days.

13-TLEC Study Monitoring (continued)
Frequency Initial Visit After 5 subjects have enrolled and the Day 180 from has been submitted for the first enrolled subject If a site has not enrolled 5 subjects, within 1 year of the first enrollment at the site Subsequent Visit(s) Dependent on site enrollment to ensure at least 30% of all study subjects are monitored The first visit occurs when one of the following criteria are met: After 5 subjects have enrolled and the Day 180 form has been submitted for the first enrolled subject; or If a site has not enrolled 5 subjects, within one year of the first enrollment at the site Subsequent visits depend on site enrollment to ensure at least 30% of all study subjects are monitored.

Additional monitoring visits may be warranted if data quality issues are identified. Examples include: Excessive protocol deviations Unresolved corrective action items Systemic issues requiring additional training Additional monitoring visits may be scheduled if data quality issues are identified. Examples include: excessive protocol deviations, unresolved corrective action items, or systemic issues requiring additional training.

Visit Timeline Timeframe Action Pre-Visit > 8 weeks Schedule visit 6-8 weeks Monitoring materials sent to site 3 days Site returns agenda, study file verification form, and source documents Visit Visit Date(s) Study file review, subject record review, and closing discussion Post-Visit Monitoring report sent 10-12 weeks Site completes required action Next, we are going to discuss the monitoring timeline. There are three important timeframes to consider: prior to the visit, during the visit, and after the visit.

Pre-Visit Monitoring Materials Description Monitoring Letter Provides general information regarding the monitoring visit Agenda Provides an outline of the visit and the site documents availability Study File Verification Form Provides a list of study file documents required for review and the site documents study file content Source Documentation Checklist Provides a list of source documents required for each subject A scheduling is sent to the study coordinator approximately two months prior to the proposed visit dates. Once the visit is confirmed, the monitoring materials are sent to the study coordinator. The materials include a monitoring letter, agenda, study file verification form, and source documentation checklist. The monitoring letter provides general information regarding the visit and discusses the process for submitting source documents. The agenda provides an outline of the visit. Additionally, the study coordinator documents their availability during the visit and a time for the closing discussion with the monitor. The study file verification form provides a list of regulatory documents that must be submitted. Additionally, the site is required to verify that all essential documents are maintained in the study file. Finally, the source documentation checklist provides a detailed list of all source documents that must be submitted prior to the visit.

Submitting Source Documents CIBMTR is a public health authority (PHA) Centers are allowed to disclose protected health information to the CIBMTR without the written consent or authorization of the patient Public Health Authority Status Not required to be de-identified If de-identified, 13-TLEC study ID must be documented on each page submitted Do not de-identify consent forms Subject Records Since the CIBMTR is a recognized public health authority, documents submitted to monitor do not be de-identified. If it is the center’s policy to de-identify the documents, the 13-TLEC study ID must be present on each page submitted. Also, it is important to note that consent forms must not be de-identified. The completed agenda, study file verification form, and all required source documents must be submitted to the monitor 3 days prior to the visit.

Visit Process Monitor reviews documents submitted Monitor will contact the site with questions or request additional source documents A closing discussion outlines preliminary findings During the visit, the monitor reviews the completed study file verification form, select study file documents, and all subject specific source documents. If there are questions or additional source documents are needed, the monitor will contact the study coordinator. Also, a closing discussion is held to outline the preliminary findings of the visit.

Post-Visit Provides a summary of visit observations and outstanding action items Report Letter Site returns documentation to confirm completion of action items Required Action After the site visit, a monitoring report is sent electronically to the study coordinator and the principal investigator. The report includes a summary of the findings and the outstanding required action items. Lastly, the site completes all required action and submits documentation to verify all items are complete.

Test Your Knowledge 4) Which of the following is a true statement?
GCP requirements typically only apply to the Principal Investigator at any given study site. Monitoring of the 13-TLEC study will occur remotely (vs “on site”) All study subject records to be monitored must be de-identified. The initial 13-TLEC monitoring visit for a site will be scheduled after a site enrolls their first 7 patients.

Thank You for Your Participation in 13-TLEC
Thank you for completing the 13-TLEC protocol training. We look forward to working with your and your site on this important study.

CIBMTR 13-TLEC PBMTC LTE1401 Natural History and Biology of Long-Term Late Effects Following Hematopoietic Cell Transplant for Childhood Hematologic.

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CIBMTR 13-TLEC PBMTC LTE1401 Natural History and Biology of Long-Term Late Effects Following Hematopoietic Cell Transplant for Childhood Hematologic.

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Presentation on theme: "CIBMTR 13-TLEC PBMTC LTE1401 Natural History and Biology of Long-Term Late Effects Following Hematopoietic Cell Transplant for Childhood Hematologic."— Presentation transcript:

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