79(16):1693- 8, 2012. Pro00054746: RESIST Study Version: 20171011 PT-PhI-II v05.22.12 Duke Cancer Institute Page 54 CONFIDENTIAL 83. Yung WK, Albright RE, Olson J, Fredericks R, Fi nk K, Prados MD, Brada M, Spence A, Hohl RJ, Shapiro W, Glantz M, Greenberg H, Selker RG, Vick NA, Rampling R, Friedman H, Phillips P, Bruner J, Yue N, Osoba D, Zaknoen S, Levin VA. A phase II study of temozolomide vs. procarbazine in patients with glioblastoma multiforme at first relapse. Br J Cancer. 83(5):588- 93, 2000. PMCID: PMC2363506. Pro00054746: RESIST Study Version: 20171011 PT-PhI-II v05.22.12 Duke Cancer Institute Page 55 CONFIDENTIAL 18 APPENDICES 18.1 Protocol Synopsis and Summary Please see separate documents (available upon request). Pro00054746: RESIST Study Version: 20171011 PT-PhI-II v05.22.12 Duke Cancer Institute Page 77 CONFIDENTIAL 18.2 Special or Representative SOPs and FORMs Please see separate document s (available upon request). Pro00054746: RESIST Study Version: 20171011 PT-PhI-II v05.22.12 Duke Cancer Institute Page 78 CONFIDENTIAL 18.3 DSMBplus Monitoring Plan Please see separate document (available upon request). Pro00054746: RESIST Study Version: 20171011 PT-PhI-II v05.22.12 Duke Cancer Institute Page 79 CONFIDENTIAL 18.4 Standard Radiation Therapy Radiotherapy typically begins within ≤ 5 weeks of surgery. One treatment of 1.8- 2.0 Gy/fraction should be given daily 5 days per week for a total of 59.4- 60.0 Gy over <7 weeks. 3D conformal and intensity - modulated RT is permitted. All portals should be treated during each treatment session. Doses are specified as the target dose that shall be to the center of the target volume. The gross target volume (GTV) for both the initial volume (GTV1) and the conedown volume (GTV2) should be based on the postoperat ive CT/MRI (and preferably the MRI; the preoperative scans may be used if postoperative scans are not available). This initial target volume (GTV1) should include the contrast - enhancing lesion (and should include the surgical resection cavity) and surrounding edema (if it exists) demonstrated on CT/MRI plus a 2.0- cm margin (this 2.0- cm margin- extended volume will be considered the initial planning target volume, or PTV1). The initial target volume should be treated to 46 Gy at 2Gy/fraction or 45- 50.4 Gy at 1.8Gy/fraction. If no surrounding edema is present, the initial planning target volume (PTV1) should include the contrast -enhancing lesion (and should include the surgical resection cavity) plus a 2.5- cm margin. Please note that clinical judgment may be us ed to modify PTV1 to exclude sensitive structures such as the optic chiasm, non- cranial contents, or anatomic regions in the brain where natural barriers would likely preclude microscopic tumor extension, such as the cerebellum, the contralateral hemispher e, directly across from the tentorium cerebri, the ventricles, etc. After 46 Gy, the tumor volume (GTV2) for the conedown treatment should include the contrast -enhancing lesion (without edema) on the pre- surgery CT/MRI scan plus a 1.5- 2-cm margin (PTV2). T reat to 14 Gy at 2Gy/fraction or 14.4- 9.0 Gy at 1.8Gy/fraction to a total of 60.0 or 59.4Gy, respectively. Dose is prescribed to the isodose line such that at least 95% of the target volume receives he prescribed dose. The optic apparatus should be limit ed to a maximum of 54Gy and no more than 5% of the volume of the brainstem should receive >54Gy. Radiation should be delayed or interrupted if the platelet count is < 20,000. Radiation should not begin or resume until the platelet count is ≥ 20,000. Hemat ologic toxicities should be rated on a scale of 0- 5 as defined in the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. If radiotherapy has to be temporarily interrupted for technical or medical reasons unrelated to the temozolomide administration, then treatment with daily temozolomide should continue. If radiotherapy has to be permanently interrupted then treatment with daily temozolomide should stop. The following should be recorded at entry into this study: daily treatment record, all isodose distributions (in color), dose volume histograms including the cumulative dose to the target volumes, optic chiasm, optic nerves and brain stem, and the radiotherapy summary. Pro00054746: RESIST Study Version: 20171011 PT-PhI-II v05.22.12 Duke Cancer Institute Page 80 CONFIDENTIAL 18.5 Temozolomide Therapy 18.5.1 Concurrent TMZ and RT For subjects who progr ess to Grade 3 at the time of surgery, TMZ should be administered concomitant with standard external beam RT under the direction of the study Neuro- Oncologists (listed on title page), or their designees, respectively, at Duke University or another institut ion at the standard dose per discretion of the treating neuro- oncologist. During standard RT, s ubjects will receive 75mg/m2/day TMZ for 42 days (6 weeks). Per the new NCI Temozolomide (NSC 362856) Action Letter: o Liver function tests (or CMP) should be performed:  prior to treatment initiation. If abnormal, the decision to initiate temozolomide treatment should carefully consider the benefits and risks for the individual patient;  after each treatment cycle. o For patients on a 42 day treatment cycle, liver function tests should be repeated midway during this cycle; o For patients with significant liver function abnormalities the benefits and risks of continuing treatment should be carefully considered. If any interruption occurs or dose reduction is required, TMZ may be resumed when re- treatment criteria are met as outlined in Table 5 and Table 6. Dose reduction or alteration during this period due to toxicity is standardly performed as outlined in Table 5. Table 5: Temozolomide Dosing Interruption or Discontinuation during Concomitant Radiotherapy Toxicity TMZ Interruptiona TMZ Discontinuation Absolute Neutrophil Count >0.5 and <1.0 x 109/L <0.5 x 109/L Platelet Count >10 and <100 x 109/L <10 x 109/L Common toxicity criteria (CTC2) Non - hematological Toxicity (except for alopecia, nausea, vomiting) CTC Grade 2 CTC Grade 3 or 4 a: Treatment with concomitant TMZ can be continued when all of the following conditions are met: absolute neutrophil count >1.0 x 109/L; platelet count > 100 x 109/L; CTC non- hematological toxicity <Grade 1 (except for alopecia, nausea, vomiting). The dose may be modified as outlined in Table 6 at the discretion of the treating oncologist. Table 6. Dose Modifications of Temozolomide during Radiation Therapy Dose at Toxicity Modified Dose 75 mg/m2 (during XRT) 60 mg/m2 60 mg/m2 (during XRT) 50 mg/m2 18.5.2 Guidelines for 21-day TMZ Therapy Subjects with stable histologic grade at time of surgery (Grade 2) will be treated with adjuvant TMZ at a targeted dose of 50- 100mg/m2/day for 21 days every 28 days for up to 12 cycles . Subjects that progress to Grade 3 at the time of surgery will recei ve SOC RT with TMZ x 6 weeks following surgery. Once RT is complete, subjects that progressed to Grade 3 at the time of surgery will have a 3 ± 1 week break before 2 CTC, common toxicity criteria (NCI) Pro00054746: RESIST Study Version: 20171011 PT-PhI-II v05.22.12 Duke Cancer Institute Page 81 CONFIDENTIAL resum ing TMZ ( Table 7). Then, subjects should receive TMZ at a target ed dose of 50-100 mg/m2/day for 21 days every 28 days for up to 12 cycles . A CBC with auto differential (Lab Code 2010300) should be obtained at the end of each cycle for all subjects receiving 21-day TMZ . Table 7. Criteria to Resume Temozolomide after Radiation Absolute Neutrophil Count ≥ 1.0 x 109/L Platelet Count ≥ 100 x 109/L Resolution of CTC Non -hematologic toxicities to Grade 2 or less. Because of the risk of opportunistic infections in patients receiving TMZ, patients may receive antibiotic prophylaxis at the discretion of the primary Neuro- Oncologist, consisting of inhaled pentamidine or oral levofloxacin. Antiemetic prophylaxis with m etoclopramide or a 5- hydroxytryptamine3 antagonist will also be recommended before the initial doses of concomitant TMZ and may be used during the adjuvant 21- day course of TMZ. All subjects will start 21- day TMZ cycle 1 at a dose of 50mg/m2/day, and the dose may be increased up to 100mg/m2/day in subsequent cycles at the discretion of the treating physician. During 21-day TMZ treatment (28 day cycles ), dose adjustments to TMZ, if needed, may be conducted as outlined below: Table 8. Temozolomide Dose Delay, Reduction , or Discontinuation During 21-day Treatment Toxicity Delay TMZ Dose a Reduce TMZ by 25% (down to minimum of 50 mg/m2) b Discontinue TMZ Absolute Neutrophil Count >0.5 and <1.0 x 109/L >0.5 and <1.0 x 109/L <0.5 x 109/L Platelet Count >10 and <100 x 109/L >10 and <100 x 109/L <10 x 109/L CTC Non -hematological Toxicity (except for alopecia, nausea, vomiting) CTC Grade 3 CTC Grade 3 CTC Grade 4 c a: If dose is delayed, treatment with TMZ can resume when the following conditions are met: absolute neutrophil count >1.0 x 109/L; platelet count >100 x 109/L; CTC non- hematological toxicity resolved to baseline (except for alopecia, nausea, vomiting). b: For subjects whose dose was escalated above 50 mg/m2 at the discretion of treating physician c: TMZ is to be discontinued if dose reduction to < 50 mg/m2 is required or if the same Grade 3 non- hematological toxicity (except for alopecia, nausea, vomiting) recurs after dose reduction or delay .