rtog 1114 phase ii randomized
13.5 analyses plans (07-aug-2018) 13.5.1

OS and PFS rates will be estimated using the Kaplan-Meier method (Kaplan 1958), and differences between treatment arms will be tested by the log rank test (Mantel 1966). OS will be measured from the date of randomization to the date of death or, otherwise, the last follow-up date on which the patient was reported alive. PFS will be measured from the date of randomization to the date of first progression or death or, otherwise, the last follow-up date on which the patient was reported alive. Differences in observed severities of toxicities (grade 3+) between groups will be tested using a chi square test.  
Multivariate analyses with the Cox proportional hazard model (Cox 1972) for OS and PFS
will be performed with the stratification variables as fixed variables to assess the treatment effect adjusting patient-specific risk factors. The covariates evaluated for the multivariate models are: assigned protocol treatment, RPA risk class, and other prognostic factors.  
Proportional hazard assumptions will be checked using different graphical or time-varying coefficients testing methods. If the data clearly do not follow proportional hazards, other statistical models will be used to fit the data instead. Possible alternatives are to use the stratified Cox proportional hazard model, to use the accelerated failure model, or to partition the time axis into sections where proportional hazard assumption holds.  
Analysis of Neurotoxicity and Impact on Cognitive Function and QOL
Evaluation of neurotoxicity will occur at two levels: formal evaluation of cognitive function through neuropsychological and QOL evaluation, as well as evaluation of neurotoxicity as clinically defined by the treating physician.  
- Neuropsychological and QOL evaluation: In both arms, the cumulative incidence approach will be used to estimate the median time to neurocognitive failure to account for the competing risks of death. To that end, neurocognitive failure will be defined as the first cognitive failure on 2 or more of the following tests: the HVLT-R for Free Recall, Delayed Recall and Delayed Recognition; the COWA; and the Trail Making Test Part A or B. Cognitive failure for each test is defined as a change in a score that meets or exceeds the Reliable Change Index (RCI) value for each test indicating a performance that is worse than the patient's personal baseline score. In addition, the standardized test score will also be calculated for each test and to determine which tests are most sensitive to detect cognitive impairment/change. The cut-offs for standardized scores will be determined through receiver operating characteristic (ROC) methods. Gray's test will be used to test for a statistically significant difference in the distribution of neurocognitive failure times (e.g. neurocognitive failure at 3-year, 5-year) at the alpha=0.05 level (Gray RJ. 1988). Fine and Gray's proportional subdistribution hazard regression model (Fine and Gray, 1999) will be used to assess the effects of covariates on the progression. A similar approach will be used for symptom and HRQOL data. For the EORTC
QLQ30/BN20, differences of at least 10 points will be classified as the minimum clinically meaningful change in a HRQOL measure. For example, an increase of 10 points or more on a functional scale would mean a moderate improvement, whereas a decrease of 10 points or more would be interpreted as moderate worsening. Furthermore, a rise in a symptom score means deterioration. Changes of less than 10 points will be regarded as no change or as clinically irrelevant, and changes of more than 20 points will be considered large effects.  
For the quality of life, symptom and neurocognitive function endpoints, the longitudinal data analysis will also be performed to assess if there exists difference over time across the two treatment arms using hierarchical formulation of the linear mixed model.  
Participation in the quality of life/neurocognitive function component is not mandatory in this study. However, if patients agree to participate in this component, adherence to the component assessment schedule will be encouraged through reminders from participating institutions. Completion of all scheduled assessment is part of the routine delinquency assessment for participating institutions. The Statistics and Data Management Center staff will monitor proportions of missing quality of life/neurocognitive function information in each treatment arm at different assessment points. In spite of these efforts, missing data is to a certain extent expected. The information from patients with missing data will be reviewed in to determine whether the data analyses will be biased. Patients with missing data will be reviewed for the distributions of treatment arms and patient characteristics. Mean scores on the primary items will be compared for patients with and without missing data at different assessment points to identify whether missing data was preceded by a significant decline in the scores. Mean scores by assessment time for cohorts stratified by baseline score quartile will also be compared to investigate if the missingness is consistent with an ignorable missing data process (missing at random). If no missing data mechanism can be detected, the data will be analyzed assuming missing data is at random and the appropriate imputation for missing values will be conducted. The imputation methods may include: the missing value can be imputed from the variable mean of the completed cases, or it can be imputed from the mean conditional on observed values of other variables, or multiple imputation. If the missing data mechanism appears to be present, we will use appropriate analytic strategies to control for the potential bias and, if possible, to impute the missing data. The possible strategies for imputation and analyses will depend on the severity of the missing data problem and missing pattern. The imputation methods may include: worse-case scenario, use of mean response for individuals who withdraw from the trial from either all or similar (matched) patients remaining in the trial, last observation carry forward, or multiple imputation. The data can also are analyzed using pattern mixture models to estimate separate estimates for the outcome within strata based on the missing data pattern, and then combining estimates in a specialized way to yield appropriate an overall effect estimate (Little R and Rubin D. 2002). Sensitivity analyses based on the varying assumptions about the missing data mechanisms will also be conducted.  
- Evaluation of clinically defined neurotoxicity: In addition to the formal evaluation of cognitive function and QOL as described above, information on the incidence of neurotoxicity as per the investigator's assessment will be collected in this study. The purpose of this analysis is to provide an estimate of neurotoxicity rate that can be compared to historical controls on the utilization of full-doses of WBRT, which have not included neuropsychological evaluation. In those studies, neurotoxicity was qualitatively defined by treating physicians. For a comparable assessment, in this study physicians will be asked to determine whether the patient is experiencing neurotoxicity at each clinical assessment throughout the 5 year followup. For this purpose, neurotoxicity will be defined as severe cognitive deterioration in comparison to post-treatment baseline, accompanied by psychomotor slowness and gait ataxia, and that cannot be accounted for by disease recurrence. Analysis will be descriptive, and the 3y and 5y cumulative incidence of neurotoxicity in each arm will be reported, accounting for death as a competing risk (as described above).  
13.5.2 Interim Analysis to Monitor Study Progress Interim reports with statistical analyses will be prepared every 6 months until the initial manuscript reporting the treatment results has been submitted. The reports will contain:
the patient accrual rate with a projected accrual completion date; accrual by institution; the pretreatment characteristics of accrued patients; the frequency and severity of toxicities; and the results of any completed study chair modality reviews.  
The interim reports will not contain the results from the treatment comparisons with respect to the efficacy endpoints (OS, PFS, treatment response). The NRG Oncology Data Monitoring Committee (DMC) will review the accrual to the study and the rate of adverse events on the study at least twice per year until the initial results of the study have been presented to the scientific community.  
13.5.3 Interim Futility Analysis The interim futility analysis will be performed when 50% of the required events (34 death or progression) are reported. The analysis will be performed on an intent-to-treat basis, with all eligible cases included in the treatment arm to which they were randomized regardless of what treatment the patients actually received. The primary endpoint progression-free survival will be tested. The responsible statistician may recommend early reporting of the results and/or stopping accrual (if applicable) of the trial if the estimated hazard ratio favors the control arm (by any amount). The accrual rate, treatment compliance, safety of the treatments, and the importance of the study are also considered in making such a recommendation. The results will be reported to the NRG Oncology DMC with the treatment blinded. The DMC will then make a recommendation about the trial to the NRG Oncology Group Co-Chairs.  
13.5.4 Interim Efficacy Analysis In July 2017, the result of the interim futility analysis mentioned in the section above was presented to the NRG Oncology DMC. At the request of the DMC, it was agreed upon that an interim efficacy analysis would be added at a later stage of the trial. This section addresses the method to be used for this interim analysis. An interim efficacy analysis will be performed when 67% of the required events (45 deaths or progression events) are observed. At that time, if the PFS hazard ratio is in favor of the experimental arm with an estimated value of 0.50 or less, then the responsible statistician may recommend early reporting of the results. At 45 events, a hazd ratio of 0.50 corresponds to a Haybittle-Peto interim monitoring boundary p-value of 0.01. The results will be reported to the NRG Oncology DMC. The DMC will then render the final recommendation about the trial to the NRG Oncology Group Co-Chairs.  
13.5.5 Analysis for Reporting the Initial Treatment Results The final analysis will be performed on an intent-to-treat basis, such that all eligible cases on the study will be included in the arm to which they were randomized regardless of what treatment the patients actually received. The analysis to report the final results of treatment comparison between the experimental arm and the control arm will be undertaken when 67 events (death or progression) have been reported. A one-sided log-rank test at the 0.15 significance level will be performed to test the difference in PFS between the two treatment arms. If the P value is less than protocol-specified 0.15 (one-sided), the study statistician will reject the null hypothesis and conclude that the experimental arm has a better PFS than the standard arm, thereby supporting the development of a phase III trial comparing this regimen to the current standard at that time. All information reported in the interim analyses to monitor the study progress (Section 13.5.2) and treatment compliance with respect to radiation and chemotherapy will also be included in the final report.  
13.5.6 CDUS Tracking This study will be monitored by the Clinical Data Update System (CDUS) version 3.0.  
Cumulative CDUS data will be submitted quarterly by electronic means. Reports are due January 31, April 30, July 31, and October 31.  
13.6 **Gender and Minorities**
In conformance with the National Institutes of Health (NIH) Revitalization Act of 1993 with regard to inclusion of women and minorities in clinical research, we address this issue here; both men and women of all races and ethnic groups are eligible for this study. The following table lists the projected accrual for each racial and ethnic group based upon previous RTOG PCNSL trials.  
| Gender                                    |         |       |       |
|-------------------------------------------|---------|-------|-------|
| Ethnic Category                           | Females | Males | Total |
| Hispanic or Latino                        | 1       | 3     | 4     |
| Not Hispanic or Latino                    | 43      | 42    | 85    |
| Ethnic Category: Total of all subjects    | 44      | 45    | 89    |
| Gender                                    |         |       |       |
| Racial Category                           | Females | Males | Total |
| American Indian or Alaskan Native         | 0       | 0     | 0     |
| Asian                                     | 1       | 1     | 2     |
| Black or African American                 | 1       | 2     | 3     |
| Native Hawaiian or other Pacific Islander | 0       | 1     | 1     |
| White                                     | 42      | 41    | 83    |  
| Gender                                 |         |       |       |
|----------------------------------------|---------|-------|-------|
| Ethnic Category                        | Females | Males | Total |
| Racial Category: Total of all subjects | 44      | 45    | 89    |  
Abrey LE, Yahalom J, DeAngelis LM: Treatment for primary CNS lymphoma: the next step. J Clin Oncol 18:31443150, 2000 Abrey LE, Batchelor TT, Ferreri AJM, et al: Report of an international workshop to standardize baseline evaluation and response criteria for primary CNS lymphoma. J Clin Oncol 23:5034-5043, 2005 Abrey LE, Benporat L, Panageas KS, et al. Prognostic model for primary CNS lymphoma (PCNSL): Recursive partitioning analysis (RPA) of the MSKCC PCNSL population. J Clin Oncol, 2006 ASCO Annual Meeting Proceedings Part I. Vol 24, No. 18S (June 20 Supplement): 1531, 2006 Benedict RHB, Schretlen D, Groninger L, et al. Hopkins Verbal Learning Test - Revised: Normative data and analysis of inter-form and test-retest reliability. Clin Neuropsychologist. 12:43-55,1998.  
Benton AL, Hamsher KdeS. Multilingual Aphasia Examination. Iowa City, IA: AJA Associates; 1989.  
Batchelor T, Carson K, O'Neill A, et al: Treatment of primary CNS lymphoma with methotrexate and deferred radiotherapy: a report of NABTT 96-07. J Clin Oncol 21:1044-1049, 2003 Camilleri-Broet S, Criniere E, Broet P, et al: A uniform activated B-cell-like immunophenotype might explain the poor prognosis of primary central nervous system lymphomas: analysis of 83 cases. Blood 107:190-6, 2006 Correa DD, Rocco-Donovan M, DeAngelis LM, et al: Prospective cognitive follow-up in primary CNS lymphoma patients treated with chemotherapy and reduced-dose radiotherapy. J Neurooncol 91:315-21, 2009 Cox DR: Regression models and life tables. J Royal Stat Soc, Series B, 34:187-229, 1972 DeAngelis LM, Seiferheld W, Schold SC, et al: Combination chemotherapy and radiotherapy for primary central nervous system lymphoma: Radiation Therapy Oncology Group Study 93-10. J Clin Oncol 20:4643-8, 2002 Fine, J. and Gray, R. A proportional hazards model for the subdistribution of a competing risk. J Am Stat Assoc 94:496-509, 1999.  
Gray R.J. A class of K-sample tests for comparing the cumulative incidence of a competing risk. Ann Statist. 16:1141-1154, 1988.  
Groves MD, Maor MH, Meyers C, et al. A phase II trial of high-dose bromodeoxyuridine with accelerated fractionation radiotherapy followed by procarbazine, lomustine, and vincristine for glioblastoma multiforme. Int J Radiat Oncol Biol Phys 45:127-35, 1999. Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Amer Statist Assoc 53:457-481, 1958 Levin VA, Yung WK, Bruner J, et al. Phase II study of accelerated fractionation radiation therapy with carboplatin followed by PCV chemotherapy for the treatment of anaplastic gliomas. Int J Radiat Oncol Biol Phys 53:58-66, 2002.  
Levy O, Deangelis LM, Filippa DA, et al: Bcl-6 predicts improved prognosis in primary central nervous system lymphoma. Cancer 112:151-6, 2008 Linnebank M, Moskau S, Jurgens A, et al: Association of genetic variants of methionine metabolism with methotrexate-induced CNS white matter changes in patients with primary CNS lymphoma. Neuro Oncol 11:2-8, 2009 Mantel N: Evaluation of survival data and two new rank order statistics rising in its consideration. Cancer Chemotherapy Rep 50:163-170, 1966 Meyers CA, Smith JA, Bezjak A, et al. Neurocognitive function and progression in patients with brain metastases treated with whole-brain radiation and motexafin gadolinium: results of a randomized phase III trial. J Clin Oncol. 22:157-65, 2004.  
Omuro AM, Ben-Porat LS, Panageas KS, et al: Delayed neurotoxicity in primary central nervous system lymphoma. Arch Neurol 62:1595-600, 2005 Omuro A, Taillandier L, Chinot O, et al: Primary CNS lymphoma in patients younger than 60: can whole-brain radiotherapy be deferred? J Neurooncol, 2010 Osoba D, Aaronson NK, Muller M, et al. The development and psychometric validation of a brain cancer qualityof-life questionnaire for use in combination with general cancer-specific questionnaires. Qual Life Res 5:139-50, 1996.  
Pels H, Schmidt-Wolf IGH, Glasmacher A, et al: Primary central nervous system lymphoma: results of a pilot and phase II study of systemic and intraventricular chemotherapy with deferred radiotherapy. J Clin Oncol 21:44894495, 2003 Pels H, Juergens A, Glasmacher A, et al: Early relapses in primary CNS lymphoma after response to polychemotherapy without intraventricular treatment: results of a phase II study. J Neurooncol 91:299-305, 2009 Reitan RM. Trail Making Test. Manual for Administration and Scoring. Reitan Neuropsychology Laboratory; Tucson, Arizona, 1992 Rubinstein LV, Korn EL, Freidlin B, et al. Design issues of randomized phase II trials and a proposal for phase II
screening trial. J Clin Oncol 22:7199-7206, 2005. Rubenstein JL, Fridlyand J, Shen A, et al: Gene expression and angiotropism in primary CNS lymphoma. Blood 107:3716-23, 2006 Shah GD, Yahalom J, Correa DD, et al: Combined immunochemotherapy with reduced whole-brain radiotherapy for newly diagnosed primary CNS lymphoma. J Clin Oncol 25:4730-5, 2007 Thiel E, Korfel A, Martus P, et al: High-dose methotrexate with or without whole brain radiotherapy for primary CNS lymphoma (G-PCNSL-SG-1): a phase 3, randomised, non-inferiority trial. Lancet Oncol 11:1036-47, 2010 Yung WK, Albright RE, Olson J, et al. A phase II study of temozolomide vs. procarbazine in patients with glioblastoma multiforme at first relapse. Br J Cancer 83:588-93, 2000. Zelen M. The randomization and stratification of patients to clinical trials. J Chronic Dis 27:365-375, 1974.  
APPENDIX I (8/25/15)  
STUDY PARAMETER TABLES  
| STUDY PARAMETER TABLES Pretreatment Assessments ≤6 wks prior to  ≤2 wks prior to                                  | ≤2 wks prior to                                      |                    |
|-------------------------------------------------------------------------------------------------------------------|------------------------------------------------------|--------------------|
| registration                                                                                                      | registration                                         | start of treatment |
| Histology confirmation                                                                                            | X                                                    |                    |
| See section 3.1.1 for details History/physical                                                                    | X                                                    | X                  |
| Neurologic exam, KPS                                                                                              | X                                                    |                    |
| MRI of brain, response assessment                                                                                 | X                                                    | X                  |
| History of corticosteroids use                                                                                    | X                                                    |                    |
| CT chest, abdomen, pelvis                                                                                         | X                                                    |                    |
| Chest X-ray                                                                                                       | X                                                    |                    |
| Anti-HIV test                                                                                                     | X                                                    |                    |
| CBC w/ diff & ANC, platelets, Hgb                                                                                 | X                                                    | X                  |
| Bilirubin, AST                                                                                                    | X                                                    | X                  |
| ALT                                                                                                               | X                                                    |                    |
| LDH                                                                                                               | X                                                    |                    |
| Serum creatinine                                                                                                  | X                                                    | X                  |
| Creatinine clearance                                                                                              | X                                                    | X                  |
| Electrolytes, BUN                                                                                                 | X                                                    |                    |
| Urinalysis                                                                                                        | X                                                    |                    |
| Serum or urine pregnancy test (if applicable)                                                                     | X                                                    |                    |
| Complete ophthalmologic exam including slit                                                                       | X                                                    |                    |
| lamp exam Bone marrow biopsy see section 4.1 for                                                                  | Taken pre-treatment (≤ 6 weeks); submitted postregistration (< 1 month after start of treatment)                                                      |                    |
| details Lumbar puncture see section 4.1 for details                                                               | Taken pre-treatment (≤ 6 weeks)                      |                    |
| Hepatitis B screening (recommended): see                                                                          | Recommended (≤ 6 weeks) pre-treatment; results not   |                    |
| section 4.2 for details                                                                                           | needed for patient to start treatment                |                    |
| Informed consent                                                                                                  | X                                                    |                    |
| QOL assessment                                                                                                    | X                                                    |                    |
| (for consenting pts) NCF assessment                                                                               | X                                                    |                    |
| (for consenting pts) Tissue (H&E, immunohistochemistry, tissue  block, unstained slides) for central path  review | Taken pre-treatment; submitted post-registration     |                    |
| Tissue (tumor, bone marrow, +/or eye  biopsy) for banking/correlative studies (for  consenting pts)               | Taken pre-treatment; submitted post-registration     |                    |
| CSF for banking/correlative studies (for                                                                          | Taken pre-treatment; submitted post-registration.    |                    |
| consenting pts)                                                                                                   | Remnant sample from clinical collection can be used. |                    |
| DNA for banking/correlative studies (for                                                                          | Taken pre-treatment; submitted post-registration     |                    |
| consenting pts) Buccal swab (for consenting pts)                                                                  | Taken pre-treatment; submitted post-registration     |                    |  
Assessments During Treatment  
| A window of + 3/- 2 days is acceptable for all on-study treatments and assessments. (It is NOT applicable to pretreatment assessments.) R-MPV (cycles 1, 2, 3, 4) Consolidation  Cytarabine (Cycles 1 &2) History/physical d 1, 15 d 1 Neurologic exam, KPS d 1, 15 d 1 MRI of brain, response assessment Cycle 2, d28  Cycle 1 d 1 (arm B) Cycle 4, d28 History of corticosteroids use Cycle 2, d28  Cycle 1 d 1 (arm B) Cycle 4, d28 CBC w/ diff & ANC, platelets, Hgb d 1, 8, 15, 22 Repeat wkly throughout  cycle Bilirubin, AST d 1, 15 ALT d 1, 15 Serum creatinine d 1, 15 (and then daily until MTX is  d 1 cleared) Creatinine clearance d 1, 15 Electrolytes, BUN d 1, 15 (and then daily until MTX is  d 1 cleared) MTX levels d3, 17 (and then daily until MTX is  cleared Note: the administration of  MTX is on d 2 and 16 (see Section  7.1) Urinalysis D 1, 15 QOL assessment Cycle 4, d28 (for consenting pts) NCF assessment Cycle 4, d28 (for consenting pts)   |
|---|  
Assessments During Follow-Up  
| Q 2 m for 1st 2 yrs (starting 4                                                                                                                | Q 6 m during years 3-5          |                        |
|------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------|------------------------|
| wks after cytarabine cycle 2, d 1)                                                                                                             |                                 |                        |
| History/physical                                                                                                                               | X                               | X                      |
| Neurologic exam, KPS                                                                                                                           | X                               | X                      |
| MRI of brain, response                                                                                                                         | X                               | X                      |
| assessment Lumbar puncture                                                                                                                     | X*                              | X*                     |
| History of corticosteroids use                                                                                                                 | X                               | X                      |
| Complete ophthalmologic exam                                                                                                                   | Repeated if previously positive | Repeated if previously |
| including slit lamp exam                                                                                                                       | positive                        |                        |
| QOL assessment                                                                                                                                 | Q 6 months                      | X                      |
| (for consenting pts) NCF assessment                                                                                                            | Q 6 months                      | X                      |
| (for consenting pts) *Performed at each MRI time point, until the second MRI showing CR (which confirms the CR status if tap still  negative). |                                 |                        |  
NOTE. If a patient experiences disease progression during the study evaluation period, the neurocognitive and QoL assessment should be put on hold until the patient is clinically stable for 3 consecutive months, at which time the follow-up neurocognitive evaluation should be obtained. The next neurocognitive evaluation should be performed according to the next standard/planned protocol follow-up dates (the study calendar is not reset), but no sooner than 3 months from the previous neurocognitive evaluation.  
APPENDIX II
rtog 1114 phase ii randomized
karnofsky performance scale

100 **Normal; no complaints; no evidence of disease**
0 Dead  
| 90   | Able to carry on normal activity; minor signs or symptoms of disease          |
|------|-------------------------------------------------------------------------------|
| 80   | Normal activity with effort; some sign or symptoms of disease                 |
| 70   | Cares for self; unable to carry on normal activity or do active work          |
| 60   | Requires occasional assistance, but is able to care for most personal  needs  |
| 50   | Requires considerable assistance and frequent medical care                    |
| 40   | Disabled; requires special care and assistance                                |
| 30   | Severely disabled; hospitalization is indicated, although death not  imminent |
| 20   | Very sick; hospitalization necessary; active support treatment is necessary   |
| 10   | Moribund; fatal processes progressing rapidly                                 |  
APPENDICES FOR NRG ONCOLOGY BIOSPECIMEN COLLECTION *(as specified by the protocol)*.  
NRG Oncology FFPE Specimen Plug Kit Collection NRG Oncology Frozen Tissue and Bone Marrow Kit Instructions NRG Oncology Blood Collection Kit Instructions NRG Oncology Buccal Scrapings Specimen Kit Instructions
rtog 1114 phase ii randomized
nrg oncology csf collection kit

U.S. Postal Service Mailing Address: For FFPE or Non-frozen Specimens Only NRG Oncology Biospecimen Bank University of California San Francisco UCSF Box 1800 2340 Sutter St, room S341 San Francisco, CA 94143-1800 Courier Address (FedEx, UPS, etc.): For Frozen or Trackable Specimens NRG Oncology Biospecimen Bank University of California San Francisco 2340 Sutter St, room S341 San Francisco, CA 94115 Include all NRG Oncology paperwork in pocket of biohazard bag. Check that the Specimen Transmittal (ST) Form has the consent boxes checked off.  
Check that all samples are labeled with the NRG Oncology study and case number, and include date of collection as well as collection time point (e.g., pretreatment, post-treatment).
rtog 1114 phase ii randomized
ffpe specimens

o Slides should be shipped in a plastic slide holder/slide box. Place a small wad of padding in top of the container. If you can hear the slides shaking it is likely that they will break during shipping.  
o FFPE Blocks can be wrapped with paper towel, or placed in a cardboard box with padding. Do not wrap blocks with bubble wrap or gauze. Place padding in top of container so that if you shake the container the blocks are not shaking.  
o Slides, Blocks, or Plugs can be shipped ambient or with a cold pack either by United States Postal Service (USPS) to the USPS address (94143) or by Courier to the Street Address (94115). **Do NOT** ship on Dry Ice.
rtog 1114 phase ii randomized
frozen specimens

o Multiple cases/specimens may be shipped in the same cooler, but make sure each one is in a separate bag and clearly identified.  
o Place specimens and absorbent shipping material in Styrofoam cooler filled with dry ice (at least 7 lbs).  
There should be plenty of dry ice under and above the specimens. If the volume of specimens is greater than the volume of dry ice then ship in a larger Styrofoam box, or two separate boxes. Any Styrofoam box can be used, as long as it is big enough.  
o Specimens received thawed due to insufficient dry ice or shipping delays will be discarded and the site will be notified.  
o Send frozen specimens via overnight courier to the address above. Specimens should only be shipped Monday through Wednesday to prevent thawing due to delivery delays. Saturday or holiday deliveries cannot be accepted. Samples can be stored frozen at -80° C until ready to ship.  
For Questions regarding collection/shipping please contact the NRG Oncology **Biospecimen Bank**
by e-mail: NRGBB@ucsf.edu or phone: 415-476-7864 or Fax: 415-476-5271.
nrg oncology ffpe specimen plug
frozen specimens

This Kit allows sub-sampling of an FFPE block for submission to the NRG Oncology **Biospecimen Bank.**  
  
  
The plug kit contains a shipping tube and a punch tool.  
Step 1 If the block is stored cold, allow it to equilibrate for 30 minutes at room temperature. Place the punch tool on the paraffin block over the selected tumor area. (Ask a pathologist to select area with tumor.) Push the punch into the paraffin block. Twist the punch tool once around to separate the plug from the block. Then pull the punch tool out of the block. The punch should be filled with tissue sample.  
Step 2 Label the punch tool with the proper pathology specimen ID and block ID.  
DON'T remove specimen from the punch. Punches must be accompanied Use a separate punch tool for every specimen. Call or e-mail us if you have any questions or need additional specimen plug kits.  
Step 3 Once punch tool is labeled, place in shipping tube and mail to address below. Please do not mix specimens in the same tube.  
We will remove core specimen from the punch, embed in a paraffin block, and label with specimen ID.  
  
  
*NOTE: If your facility is uncomfortable obtaining the plug but wants to retain the tissue block, please send the entire block to the NRG Oncology Biospecimen Bank and we will sample a plug from the block and return the remaining block to your facility. Please indicate on the submission form the request to perform the plug procedure and return of the block.  
Ship specimen plug kit, specimen in punch tool, and all paperwork to the address below. For Questions regarding collection/shipping or to order an FFPE Specimen Plug Kit, please contact the NRG Oncology Biospecimen Bank by e-mail: NRGBB@ucsf.edu or call 415-476-7864/Fax 415-476-5271.  
U.S. Postal Service Mailing Address: For Non-frozen Specimens Only NRG Oncology **Biospecimen Bank**
University of California San Francisco USCF **Box 1800** 2340 Sutter St, room S341 San Francisco, CA 94143-1800 Courier Address (FedEx, UPS, etc.): For Frozen Specimens or Trackable shipments NRG Oncology **Biospecimen Bank** University of California San Francisco 2340 Sutter St, room S341 San Francisco, CA 94115
nrg oncology ffpe specimen plug
nrg oncology frozen tissue kit

This Kit is for processing and shipping of frozen tissue specimens. Kit contents:
- Biohazard pads/wipes 4" x 4" (orange)
- Five (5) 5-mL cryovials - Disposable scalpel blades
- Disposable forceps
- Biohazard bags - Absorbent shipping material
- Styrofoam container (inner)
- Cardboard shipping (outer) box - Prepaid shipping label - UN 3373 Label
- UN 1895 Dry Ice Sticker
nrg oncology ffpe specimen plug
preparation and processing of fresh

Keep biohazard wipes nearby to keep area clean throughout process. Label cryovials with NRG Oncology study and case numbers Using provided disposable scalpel, evenly cut tissue into 3 to 5 separate pieces (Note: if a frozen core was obtained, do not cut but send it whole).  
Use forceps to place each piece of tissue into individual 5-mL cryovials. Snap freeze tissue samples in liquid nitrogen, a dry ice slurry (dry ice with 95% ethanol or isopentane), or directly on dry ice.  
Once frozen, place all of the cryovials into biohazard bag Use NRG Oncology provided labels to label the bag (provided when patient is registered).
nrg oncology ffpe specimen plug
storage and shipping freezing and

Store at -80°C (-70°C to -90°C) until ready to ship.  
If a -80°C Freezer is not available, Samples can be stored short term in a -20° C Freezer (non-frost free preferred) for up to one week (please ship out Monday-Wednesday only).  
OR:
Samples can be stored in plenty of Dry Ice for up to one week, replenishing daily (please ship out on Monday-Wednesday only).  
OR:
Samples can be stored in liquid nitrogen vapor phase (ship out Monday-Wednesday only).  
Please indicate on Specimen Transmittal (ST) Form the storage conditions used and time stored.
nrg oncology ffpe specimen plug
shipping/mailing

Include all NRG Oncology paperwork in pocket of biohazard bag. Place specimens and the absorbent shipping material in Styrofoam cooler filled with dry ice (at least 7-10 lbs.—if appropriate; double-check temperature sample shipping temperature). Place Styrofoam cooler into outer cardboard box, and attach shipping label to outer cardboard box.  
*Multiple cases may be shipped in the same cooler, but make sure each one is in a separate bag and* clearly identified.  
Send frozen specimens via overnight courier to the address below. Specimens should only be shipped Monday through Wednesday to prevent thawing due to delivery delays.  
Saturday or holiday deliveries cannot be accepted. Samples can be stored frozen until ready to ship. For Questions regarding collection/shipping or to order a Frozen Tissue Kit, please contact the NRG
Oncology Biospecimen Bank by e-mail: NRGBB@ucsf.eduor call 415-476-7864/Fax **415-476-5271**.  
Courier Address (FedEx, UPS, etc.): For all Frozen Specimens NRG Oncology **Biospecimen Bank, University of California San Francisco**
2340 Sutter St, room S341, San Francisco, CA 94115
nrg oncology blood collection kit
shipping/mailing

This Kit is for collection, processing, storage, and shipping of whole blood *(as specified by the protocol)*:
nrg oncology blood collection kit
kit contents

- 2 Purple Top EDTA tubes for Whole Blood
- Ten (10) 1 ml cryovials
- Biohazard bags (1) and Absorbent shipping material (1) - Styrofoam container (inner) and Cardboard shipping (outer) box
- UN1845 DRY Ice Sticker and UN3373 Biological Substance Category B Stickers
- Specimen Transmittal (ST) Form and Kit Instructions
nrg oncology blood collection kit
preparation and processing of whole

Label as many 1ml cryovials (6 to 10) as necessary for the whole blood collected. Label them with 1NRG
Oncology study and case number, collection date/time, and time point, and clearly mark cryovials "blood".
nrg oncology blood collection kit
process

1. After collection, invert tube(s) multiple times to ensure adequate mixing of EDTA. Blood can also be mixed for 5 minutes on a mixer at room temperature.  
2. Carefully pipette and aliquot 1.0 ml blood into as many cryovials as are necessary for the blood collected (6 to 10) labeled with NRG Oncology study and case numbers, collection date/time, time point collected and clearly mark specimen as "blood".  
3. Place cryovials into biohazard bag and freeze immediately at -70 to -80° Celsius.  
4. Store blood samples frozen until ready to ship on dry ice. 5. See below for storage conditions.
nrg oncology blood collection kit
please make sure that every

Freeze Blood samples in a -80°C Freezer or on Dry Ice or snap freeze in liquid nitrogen.  
Store at –80°C (-70°C to -90°C) until ready to ship.  
If a -80°C Freezer is not available, Samples can be stored short term in a -20°C freezer (non-frost free preferred) for up to one week (please ship out Monday-Wednesday only).  
OR:
Samples can be stored in plenty of dry ice for up to one week, replenishing daily (please ship out on Monday-Wednesday only).  
OR:
Samples can be stored in liquid nitrogen vapor phase (ship out Monday-Wednesday only).  
Please indicate on Specimen Transmittal (ST) Form the storage conditions used and time stored.
nrg oncology blood collection kit
shipping/mailing

Ship specimens on Dry Ice overnight **Monday-Wednesday** to prevent thawing due to delivery delays.  
Saturday and holiday deliveries cannot be accepted.  
Include all NRG Oncology paperwork in a sealed plastic bag and tape to the outside top of the Styrofoam box.  
Wrap frozen specimens of same type (i.e., all whole bloods together) in absorbent shipping material and place each specimen type in a separate biohazard bag. Place specimen bags into the Styrofoam cooler and fill with plenty of dry ice (7-10 lbs/3.5kg minimum). Add padding to avoid the dry ice from breaking the tubes.  
Place Styrofoam coolers into outer cardboard box, and attach shipping label and UN3373 and UN1895 stickers to outer cardboard box.  
(continued on next page)
NRG ONCOLOGY **BLOOD COLLECTION KIT INSTRUCTIONS (continued)**  
Multiple cases may be shipped in the same cooler, but make sure each one is in a separate bag and that there is enough room for plenty of dry ice. *Add padding to avoid the dry ice from breaking the tubes.*
**For questions regarding collection, shipping or to order a Blood Collection Kit, please e-mail**
NRGBB@ucsf.edu **or call (415)476-7864.**
nrg oncology blood collection kit
shipping address

Courier Address (FedEx, UPS, etc.): For all Frozen Specimens NRG Oncology **Biospecimen Bank** University of California San Francisco 2340 Sutter St, room S341 San Francisco, CA **94115**
For questions, call 415-476-7864,e-mail: NRGBB@ucsf.edu, or Fax 415-476-5271
nrg oncology buccal scrapings specimen
shipping address

This Kit is for collection, processing, storage, and shipping of Buccal Specimens.
nrg oncology buccal scrapings specimen
kit contents

One screw-top container filled with RNAlater  Styrofoam container (inner) Buccal brush/swab  Cardboard shipping (outer) box Biohazard bags  Return shipping label Absorbent shipping material  Specimen Transmittal (ST) Form Preparation and Processing of Buccal Scrapings:
- Brush or swab the oral mucosa generously to collect cells. - The swab with the specimen will then be placed into a cup/vial with RNAlater solution.  
- Swish the swab in the solution to free the cells. - The handle of the swab may be cut or bent to fit into the container.  
- The specimen should then be stored frozen at -70 º to -80º Celsius until ready to ship.  
PLEASE MAKE SURE THAT EVERY SPECIMEN IS LABELED with NRG Oncology **study and case**
numbers, collection date/time, and time point collected (e.g., pretreatment, post-treatment).
nrg oncology buccal scrapings specimen
storage and shipping

Freezing and Storage:
Store at -80°C (-70°C to -90°C) until ready to ship. If a -80°C freezer is not available:
Samples can be stored short term in a -20° C freezer (non-frost free preferred) for up to one week
(please ship out Monday-Wednesday only).  
OR:
Samples can be stored in plenty of Dry Ice for up to one week, replenishing daily (please ship out on Monday-Wednesday only).  
OR:
Samples can be stored in liquid nitrogen vapor phase (ship out Monday-Wednesday only).  
Please indicate on Specimen Transmittal (ST) Form the storage conditions used and time stored.  
Shipping/Mailing:
Ship specimens on Dry Ice overnight **Monday-Wednesday** to prevent thawing due to delivery delays.  
Saturday and holiday deliveries cannot be accepted.  
Include all NRG Oncology paperwork in a sealed plastic bag and tape to the outside top of the Styrofoam box.  
Place sealed specimen bags into the Styrofoam cooler and fill with plenty of dry ice (7-10 lbs/3.5kg minimum). *Add padding to avoid the dry ice from breaking the tubes.*
Place Styrofoam coolers into outer cardboard box, and attach shipping label and UN3373 and UN1895 stickers to outer cardboard box.  
*Multiple cases may be shipped in the same cooler, but make sure each one is in a separate bag and that* there is enough room for plenty of dry ice. *Add padding to avoid the dry ice from breaking the tubes.*
Samples received thawed will be discarded, and a notification will be sent immediately to the Principal Investigator and Clinical Research Assistant of the submitting institution. The institution should send a subsequent sample, collected as close as possible to the original planned collection date.  
For questions regarding ordering, collection, or shipping of a Buccal Collection Kit, please e-mail NRGBB@ucsf.eduor call 415-476-7864 or Fax 415-476-5271.  
Shipping Address: **FedEx/UPS/Courier address (all courier packages & frozen samples)**
NRG Oncology Biospecimen Bank **at UCSF**
2340 Sutter St, room S341 San Francisco, CA 94115 Contact Phone 415.476.7864/Fax 415-476-5271
nrg oncology buccal scrapings specimen
nrg oncology csfand bone marrow

This **Kit contains:**
- Five (5) 5mL cryovials
- Parafilm
- Sterile Disposable Pipette - Biohazard bags Cerebrospinal Fluid (CSF) and Bone Marrow **Specimens:**
Preparation for collecting CSF **and Bone Marrow:**
- Sterile CSF and bone marrow specimens will be collected according to individual site protocol.  
Processing
- After CSF specimen has been obtained, use the following instructions:
o Aliquot CSF using a sterile pipette into 5 different 5mL vials, each containing a minimum of 1mL
o If CSF is already frozen, perform a controlled thaw and aliquot specimens according to above instructions. Indicate on paperwork if specimen had to be thawed/refrozen.  
o Bone marrow specimens will be collected following institutional SOPs for collection of frozen bone marrow specimens, and may be shipped in the original vial. While the provided cryovial can be used, specimens should not be aliquotted or thawed.  
- Label the specimens with the NRG Oncology study and case number, collection date and time, and clearly mark specimen as "CSF" or "bone marrow".  
- If available, use parafilm to seal the aliquots and to prevent leakage. - Place CSF and bone marrow samples into biohazard bag and seal the bag.  
- Immediately freeze specimens at -80 ºC
- Store specimens frozen until ready to ship.  
Storage:
Store at –80°C (-70°C to -90°C) until ready to ship.  
If a -80°C Freezer is not available, Samples can be stored short term in a -20° C Freezer (non-frost free preferred) for up to one week (please ship out Monday-Wednesday only).  
- OR:
Samples can be stored in plenty of Dry Ice for up to one week, replenishing daily (please ship out on Monday-Wednesday only).  
- OR:
Samples can be stored in liq. nitrogen vapor phase (ship out Monday-Wednesday only).  
Please indicate on Specimen Transmittal (ST) Form the storage conditions used and time stored.
nrg oncology buccal scrapings specimen
shipping instructions for all specimens

CSF and Bone Marrow Specimens: Specimens should be wrapped in an absorbent material (e.g., paper towels) and placed in an airtight plastic freezer bag (i.e., re-sealable bag). Pack the frozen specimens in a heavy grade Styrofoam box with dry ice (4-5 lbs/2-2.5 kg minimum). Seal the box with plastic tape. All NRG
Oncology paperwork should be placed in a plastic bag, sealed, and taped to the outside of the Styrofoam box. Pack the Styrofoam box in a cardboard box. Note: Specimens requiring specific infectious precautions should be clearly labeled, with specific sources of infectious concerns listed, if known. Mark the outer cardboard box "biohazard".  
Send specimens by overnight express to the address below. Only ship **Monday through Wednesday** to prevent thawing due to delivery delays. Saturday and holiday deliveries cannot be accepted. Samples received thawed will be refrozen and held. A notification will be sent immediately to the Principal Investigator and CRA of the submitting institution. The institution should send a subsequent sample, collected as close as possible to the original planned collection date, if possible.  
Sites must submit the required documentation with specimens. Specimens are shipped on Dry Ice to:
NRG Oncology Biospecimen Bank/University of California San Francisco (FedEx/UPS Courier address) 2340 Sutter Street, rm 341 San Francisco, CA 94115
nrg oncology buccal scrapings specimen
appendix iv (8/25/15) certification and

Institutions with patients participating in the quality of life/neurocognitive function components of this study must meet certification requirements for administering neurocognitive assessments. The healthcare professional (e.g., nurse, psychologist) who is responsible for test administration in this study must be pre-certified by Dr. Correa
(See Section 5.1.4). Examiners who have completed the full certification procedure to perform these tests for RTOG 0525, 0534, 0614, 0834 or 0825 during the past 6 months do not need to complete the full certification procedure again, but the certification worksheet for 1114 must be faxed to Dr. Correa (fax number **646-888-3175)**
for documentation purposes with information regarding the examiners prior certification (protocol number, date of certification). If these criteria are met, each examiner and NRG Oncology will be notified of the examiner's recertification status for 1114. Examiners who have not completed the full certification procedure for RTOG 0525, 0534, 0614, 0834 or 0825 within the past 6 months must complete the full certification procedure to be recertified to ensure continued familiarity with study procedures.  
Prior to registering and/or testing a patient, potential examiners must:
(1) Read Section 11.2 of the protocol (2) Read Appendix IV (Certification and Administration Procedures for the Neurocognitive Test Battery) (3) Go to the NRG Oncology/RTOG web site and use your username and password to access the link entitled,
"Neurocognitive Training Procedure Letter" on the **1114** forms section of the website. This letter will provide you with the web address for the training video.  
(4) Obtain copies of the HVLT-R, TMT and COWA from the NRG Oncology/RTOG website (5) Watch the training video (6) Complete the training video post test
(7) Complete a "practice" assessment
(8) Complete the Certification Worksheet (Appendix V) (9) All materials (i.e., post test, completed practice assessment and scoring forms, certification worksheet) must be faxed to Dr. Correa, who will review it and correct any procedural errors with the trainee. (10) If the trainee demonstrates competency, he/she will be notified of the certification approval to administer the tests to study subjects as part of RTOG 1114. A certification approval notice will be sent to NRG Oncology for the registration process and to ensure that only RTOG 1114-approved examiners are testing subjects on protocol RTOG 1114.  
(11) **After you are certified, please fax all neurocognitive test and summary forms for the first study**
patient you test on RTOG 1114 to Dr. Correa (646-888-3175) for centralized review.
nrg oncology buccal scrapings specimen
step 2 - alternate test

Two of the tests to be administered have alternate forms or versions in order to reduce the effects of practice. See the table below for the versions to be administered at each session. The forms should continue to be alternated in this order for the duration of the study. The forms packet will contain alternate versions of these neuropsychological tests.
nrg oncology buccal scrapings specimen
time table for cognitive evaluations

| TEST                                                                                                         | ≤2 wks prior to start of                                | R-MPV (Cycle 4, d28)   | Every 6 months up to   |
|--------------------------------------------------------------------------------------------------------------|---------------------------------------------------------|------------------------|------------------------|
| treatment                                                                                                    | year 5 (starting 4 wks  after cytarabine cycle 2,  d 1) |                        |                        |
| HVLT-R                                                                                                       | Form 1                                                  | Form 2                 | Form 3 **              |
| COWA                                                                                                         | "C-F-L"                                                 | "P-R-W"                | "C-F-L" ***            |
| ** HVLT-R: Continue to alternate order at subsequent 6-month intervals: Form 4. Form 5, Form 6, Form 1, Form |                                                         |                        |                        |  
***COWA: Continue to alternate order at subsequent 6-month intervals: 'P-R-W', 'C-F-L', 'P-R-W','C-F-L', 'P-RW','C-F-L','P-R-W','C-F-L', 'P-R-W'.
nrg oncology buccal scrapings specimen
step 3 - test instructions

1. Testing must be completed in one session. Test instructions must be followed verbatim with every patient at every study visit. All tests should be completed in black pen. 2. Tests should be administered in the following order to every patient and at every study visit:
HVLT-R Part A (Learning Trials); Trail Making Test Part A; Trail Making Test Part B; COWA; HVLT-R Part B (Delayed Recall); and the HVLT-R Part C (Delayed Recognition).  
3. You may fill the delay interval between COWA and HVLT-R Part B (Delayed Recall) with EORTC QLQC30/BCM20 questionnaire.  
4. Follow the instructions on the Forms Packet Index before submission of forms to NRG Oncology.  
5. Please keep all original test forms. In the event of questions, contact Dr. Correa. Copies of the test forms and summary sheets for the first case from each certified examiner must be faxed for review to Dr. Correa (646-8883175 Additional test forms are not submitted to Dr. Correa nor to NRG Oncology. Results remain on file at the institution as source documentation pending request for submission by NRG Oncology or a study chair. 6. All test results are recorded on the Neurocognitive Evaluation Summary Form (CS), which is found in the Forms Packet. Study/case-specific labels must be applied to all forms.  
7. Patients should not be given copies of their tests to avoid learning the material between test administrations.  
8. Before dismissing the patient, thank the patient for his/her cooperation. 9. In the event that a patient cannot complete a given test, please write the reason(s) on the test form AND the Neurocognitive Evaluation Summary Form (CS).
nrg oncology buccal scrapings specimen
1. hopkins verbal learning test

2. TRAIL MAKING TEST [Timed Test]  
  
  
  
NCF/QOL ENDPOINT FLOW DIAGRAM  
  
| ≤2 wks prior to start of treatment   | R-MPV (Cycle 4, d28)   | Every 6 months up to year 5  (starting 4 wks after cytarabine  cycle 2, d 1)   |
|--------------------------------------|------------------------|--------------------------------------------------------------------------------|
| NCF/QOL                              | NCF/QOL                | NCF/QOL                                                                        |  
NCF/QOL= neurocognitive function and quality of life battery NOTE. If a patient experiences disease progression during the study evaluation period, the neurocognitive and QoL assessment should be put on hold until the patient is clinically stable for 3 consecutive months, at which time the follow-up neurocognitive evaluation should be obtained. The next neurocognitive evaluation should be performed according to the next standard/planned protocol follow-up dates (the study calendar is not reset), but no sooner than 3 months from the previous neurocognitive evaluation.
nrg oncology buccal scrapings specimen
appendix v certification worksheet for

This worksheet must be completed and signed by the person requesting certification and submitted to Dr. Correa prior to the registration of any patients to RTOG 1114. Refer to Appendix IV for details.  
(Y) 1. Have you reviewed the Administration Procedures for the Neurocognitive Test Battery in Appendix IV of the protocol?  
(Y/N) 2. Have you completed the full certification to perform the Neurocognitive Battery for RTOG
0525, 0534, 0614, 0834, or 0825 during the past 6 months?  
(Y) 3. Have you watched the Neuropsychological Test Administration video?  
(Y) 4. Have you completed and submitted the post test associated with the training video and a
"practice" Neuropsychological Assessment?
nrg oncology buccal scrapings specimen
please print

Name of test administrator:
NRG institution number/name:
NCI code:
Telephone number of test administrator Fax number of test administrator:
E-mail address of test administrator: ____________________________________________ ___________________ Signature of test administrator Date (person who read Appendix IV, watched video and completed a "practice" Assessment)
If you have any questions regarding the certification, please contact Dr. Correa. Once you have completed this form, please attach both the Neuropsychological Assessment forms from the "practice" subject and the training video post test and submit to:
Denise Correa, PhD; Phone 646-888-3177; FAX 646-888-3175; corread@mskcc.org
nrg oncology buccal scrapings specimen
for drs. correa's/ wefel's use

(Y/N)The above individual has been certified for administering the neurocognitive assessments for this study. Signature Date
appendix vi patient's medication diary
for drs. correa's/ wefel's use

CTEP-assigned Protocol \#___________ Local Protocol \# ___________________
Today's date _____________________ Agent: Procarbazine Patient Name___________________(*initials acceptable)* **Patient Study ID** __________________________
INSTRUCTIONS TO THE PATIENT:
1. Complete one form for each cycle of treatment. 2. You will take procarbazine tablets for 7 days. You should take the tablets on an empty stomach at approximately the same time each day.  
Dose (each tablet contains 50 mg):
Day 1: take ___ tablets.  
Day 2: take ___ tablets. Day 3: take ___ tablets.  
Day 4: take ___ tablets.  
Day 5: take ___ tablets.  
Day 6: take ___ tablets. Day 7: take ___ tablets. 3. Record the date, the number of tablets of each size of tablet that you took, and when you took them.  
4. If you have any comments or notice any side effects, please record them in the Comments column.  
5. Please bring this form and your bottles of procarbazine tablets when you return for each appointment.  
_________________________________________________________________________
appendix vi patient's medication diary
patient's signature

| Comments      |      |               |                          |
|---------------|------|---------------|--------------------------|
| Day           | Date | Time of  dose | # of 50 mg tablets taken |
| 1 2 3 4 5 6 7 |      |               |                          |  
| Physician's Office will complete this section: 1. Date patient started protocol treatment ________________________________________________ 2. Date patient was removed from study _________________________________________________ 3.Patient's planned total dose during this cycle____________________________________________ 4. Total number of tablets taken this cycle _______________________________________________ 5.Physician/Nurse/Data Manager's Signature ____________________________________________   |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|