SUMMARY OF CHANGES
Update Date: February 27, 2007

RTOG 0424, A PHASE II STUDY OF TEMOZOLOMIDE-BASED CHEMORADIOTHERAPY REGIMEN FOR HIGH RISK LOW-GRADE GLIOMAS

Study Chair: Barbara J. Fisher, MD; (519) 685-8600 x53347; Barbara.fisher@lhsc.on.ca


RTOG 0424 has been updated as follows:

Section 3.1.1: The following sentence was added to the end of this section for clarification: "Patients who have only had a stereotactic biopsy are not eligible." Per Amendment #1 (version January 5, 2006) of this protocol, stereotactic biopsies were no longer acceptable for diagnosis because of the requirement for tissue for MGMT analysis.

Section 10.2.5: The contact information for LDS was updated.

NOTE: These are editorial/administrative changes to the protocol. NCI now requires that these changes be documented on the protocol title page with the date of the update noted as "Update Date," not as a revision. An updated protocol is available on the RTOG website: http://www.rtog.org







SUMMARY OF CHANGES
Amendment # 2 Version Date: June 2, 2006

RTOG 0424, A PHASE II STUDY OF TEMOZOLOMIDE-BASED CHEMORADIOTHERAPY REGIMEN FOR HIGH RISK LOW-GRADE GLIOMAS

Study Chair: Barbara J. Fisher, MD; (519) 685-8600 x53347; Barbara.fisher@lhsc.on.ca


RTOG 0424 has been amended to clarify submission of tissue and to incorporate NCI requirements regarding adverse events and reporting of these events as follows:

Title Page: Dr. Fisher's email address has been updated.

Index: Appendix VIII, "Specimen Plug Kit" was added to the Index as it was added to the protocol.

Eligibility Checklist, page 1: In Question # 14, "block" was deleted for consistency with the change to Section 3.1.11.

Section 3.1.11: "Block" was deleted as punches are also acceptable.

Section 6.10: The original section was deleted and replaced with "See Sections 7.5 and 7.6 for adverse event reporting."

Sections 7.5 and 7.6: Section 7.5 was rewritten and a new Section 7.6 was added to update the protocol to current RTOG standards and NCI requirements regarding adverse events and the reporting of these events.

Section 10.2: In the first sentence of the first paragraph, "in the form of a tissue block or tumor core punch biopsy" was added.

Section 10.2.1: A second paragraph was added regarding submission of tissue punched with a skin punch.

Section 10.2.2: A new sentence was added at the end to address submission of a tissue punch.

Section 10.2.5: The email addresses for LDS were updated.

Section 10.2.6: "or tissue punch" was added after "block" in the first sentence.

Section 10.3: "or punch" was added to the first sentence.

Section 11.5.2: Under the fifth bullet, "46-item" was corrected to "50-item."

Appendix VII: Frozen Tissue Kit Instructions were updated.





SUMMARY OF CHANGES
Update Date: February 23, 2006

RTOG 0424, A PHASE II STUDY OF TEMOZOLOMIDE-BASED CHEMORADIOTHERAPY REGIMEN FOR HIGH RISK LOW-GRADE GLIOMAS

Study Chair: Barbara J. Fisher, MD; (519) 685-8600 x53347; Barb.fisher@lrcc.on.ca


RTOG 0424 has been updated as follows:

Appendix IV: Corrected the fax number for the CTSU Regulatory Office.

The last two pages of the protocol were renumbered.

NOTE: These are editorial/administrative changes to the protocol. NCI now requires that these changes be documented on the protocol title page with the date of the update noted as "Update Date," not as a revision.

An updated protocol is available (no password required) on the RTOG website: www.rtog.org



SUMMARY OF CHANGES
Amendment # 1 Version Date: January 5, 2006

RTOG 0424, A PHASE II STUDY OF TEMOZOLOMIDE-BASED CHEMORADIOTHERAPY REGIMEN FOR HIGH RISK LOW-GRADE GLIOMAS

Study Chair: Barbara J. Fisher, MD; (519) 685-8600 x53347; Barb.fisher@lrcc.on.ca


RTOG 0424 has been amended to add quality of life and neurocognitive assessment and submission of tissue for analysis of MGMT methylation status as follows:

Title Page: Three new study chairs have been added for Quality of Life/Neuropsychological Assessments and TRP. "Principal Investigator" has been added next to Dr. Fisher's name.

Index: Appendices V, VI, and VII were added as these were added to the protocol. "Recommended" was deleted from the title of Section 4.0.

Schema Page: The required sample size was increased by an amount equal to the study accrual as of the date of the submission of this amendment (25) to 97. The rationale for this is in the new paragraph added at the end of Section 13.3.

Eligibility Checklist, page 1: Questions # 13 and # 14 were added for consistency with the addition of Sections 3.1.10, 3.1.11, and 3.2.11.

Section 1.8: Two new paragraphs were added to the end of this section to provide the rationale for the addition of Quality of Life (QOL) and neurocognitive evaluation and MGMT methylation analysis to this study.

Sections 1.9 and 1.10: These new sections describe the feasibility of studying cognitive function and quality of life in this patient population.

Sections 2.3, 2.4, 2.5, and 2.6: These new sections define the objectives of the addition of quality of life and neurocognitive assessments and MGMT methylation status to this study.

Section 3.1.1: The second to last sentence was deleted. In Section 3.1.6, the third sentence was deleted. In Section 6.4, the parenthetical text in the first sentence was deleted. These changes were all made because stereotactic biopsy will no longer be acceptable for diagnosis because of the requirement for tissue for MGMT analysis.

Section 4.0: "Recommended" was deleted from the title of this section. The following was added: "Note: This section lists baseline evaluations needed before the initiation of protocol treatment that do not affect eligibility." A new Section 4.1, which includes Sections 4.1.1 and 4.1.2 addressing required evaluations, was added.

Section 5.1: The third sentence was rewritten for consistency with revised instructions for the Temozolomide Shipment Form in Appendix IV.

Section 5.3: This new section was added to be sure institutions are aware of testing certification requirements that have been added as new Section 11.6.

Section 7.1.1: In the first paragraph, the first sentence was changed to: "It is suggested that temozolomide be taken orally 1 hour …." In the next sentence "morning" was changed to "evening" as it may improve patient tolerability.

Section 7.1.7: In the second to last sentence, "or other standard PCP prophylaxis regimen" was added to allow study doctor discretion in the choice of medication to use for PCP prophylaxis.

Section 7.2: The IND number was deleted from the heading as it should not have been included with this study.

Section 7.2.2: The second sentence of the second paragraph was rewritten for consistency with revised instructions for the Temozolomide Shipment Form in Appendix IV. In the first sentence of the third paragraph, "patient-specific drug supply" was replaced with "temozolomide" and in the second sentence, "For" was deleted and "allow 7 to 10 days lead" was replaced with "may require additional."

Section 10.0: The first paragraph was rewritten for clarity and to incorporate tissue submission for MGMT methylation status and other molecular pathways and information about the RTOG Tissue Bank at LDS Hospital.

Section 10.2: The heading was changed to "Specimen Collection for MGMT Methylation Status and Tissue Banking" and new text has replaced the original text in this section.

Sections 10.2.1 and 10.2.2: The original text was deleted and replaced by new text.

Section 10.2.3: In the first sentence, "block, core," "or slides" were deleted; "contain" was changed to "contains."

Section 10.2.5: A second contact email address and telephone number were added to LDS Hospital.

Sections 10.2.6, 10.2.7, and 10.2.8: These new sections contain additional instructions for tissue submission.

Section 10.3: This section was rewritten for clarity and to correspond with other changes to the protocol.

Section 10.5: This new section describes the rationale for examining additional markers.

Section 11.1: The MMSE assessment was deleted as it will no longer be used in this study. QOL and Neuropsychological Test Battery Assessments were added to the table with cross-REFERENCES to a new Section 11.1.1. In footnote b, "axial T2" was corrected to "axial T1" and the last sentence "Post-op MRI not required for patient's undergoing biopsy only" was deleted.

Section 11.1.1: This new section " Quality of Life/Neuropsychological Study Parameters" was added for the assessments added with this amendment.

Section 11.4: The old section "Mental Status Evaluation" was deleted and subsequent Section 11.5 "Documentation of Progression" was renumbered as new Section 11.4.

Sections 11.5, 11.6 and 11.7: These new sections incorporate the neuropsychological/QOL assessments, including certification and instructions.

Section 12.1: "Baseline Mini Mental Status Examination (MS)" and "Mini Mental Status Examination (MS)" were deleted; "Pretreatment: Medical Outcomes (QL), FACT G (PF),FACT Brain Subscales (PQ), Neurocognitive Evaluation Summary Form (CS)" due "Within 2 weeks of study entry" were added; "Medical Outcomes (QL), FACT G (PF), FACT Brain Subscales (PQ), Neurocognitive Evaluation Summary Form (CS)" due "At 6 and 12 months" were added. Under "Final Dosimetry Information," the title of the (TL) was changed to "Treatment calculation data for all fields" from "Dose Calculations.

Sections 13.1.4, 13.1.5, and 13.1.6: These endpoints were added corresponding to changes to the study.

Section 13.3: The REFERENCES were renumbered # 47 and # 48 from # 46 and # 47, in addition to the new paragraph added to the end of the section.

Section 13.4: There was a new table added to address gender, race, and ethnicity projections based on the new accrual target.

Section 13.5: A new paragraph was added at the end of the section.

Section 13.6.2: CDUS version 1.1 was updated to version 3.0.

Section 13.6.3: In the first paragraph, second sentence, the cross-reference to Section 13.7.1 has been corrected to Section 13.6.1.

Sections 13.7 and 13.8: These new sections were added to address the statistical considerations of the addition of the QOL and neurocognitive endpoints.

REFERENCES: New reference # 46 was added; old # 46 and # 47 were renumbered # 47 and # 48; new REFERENCES # 49, # 50, and # 51 were added. REFERENCES within the protocol were renumbered accordingly.

Consent: Appendix IV: The instructions in the first paragraph were updated to correspond with those in the protocol text; the instructions to attach copies of IRB approval and sample consent form were deleted; and the address for the CTSU Regulatory Office was added.

Appendix V: Neuropsychological/QOL Assessments: Instructions and Procedures were added.

Appendix VI: Certification Worksheet for Test Administrator was added.

Appendix VII: Frozen Tissue Kit Instructions were added



SUMMARY OF CHANGES
Update Date: Version: June 3, 2005

RTOG 0424, A PHASE II STUDY OF TEMOZOLOMIDE-BASED CHEMORADIOTHERAPY REGIMEN FOR HIGH RISK LOW-GRADE GLIOMAS

Study Chair: Barbara J. Fisher, MD; (519) 685-8600 x53347; Barb.fisher@lrcc.on.ca


RTOG 0424 has been revised as follows:

Appendix IV: A line for an Email address was added.

NOTE: These are editorial/administrative changes to the protocol. NCI now requires that these changes be documented on the protocol title page with the date of the update noted as “Update Date,” not as a revision.

An updated protocol is available (no password required) on the RTOG website: http://www.rtog.org/