SUMMARY OF CHANGES
Update Date: June 29, 2005

RTOG 0211, A PHASE I/II STUDY OF AN ORAL EPIDERMAL GROWTH FACTOR RECEPTOR TYROSINE KINASE INHIBITOR (EGFR-TKI), ZD 1839 (IRESSA), [NSC# 715055] WITH RADIATION THERAPY IN GLIOBLASTOMA MULTIFORME

Study Chair: Arnab Chakravarti, M.D. (617) 724-1548 achakravarti@partners.org


RTOG 0211 was updated as follows:

Section 6.7.4: This section, which had been erroneously numbered 6.7.2, is now correctly numbered 6.7.4.





SUMMARY OF CHANGES
Amendment 7, Version Date: June 16, 2005

RTOG 0211, A PHASE I/II STUDY OF AN ORAL EPIDERMAL GROWTH FACTOR RECEPTOR TYROSINE KINASE INHIBITOR (EGFR-TKI), ZD 1839 (IRESSA), [NSC# 715055] WITH RADIATION THERAPY IN GLIOBLASTOMA MULTIFORME

Study Chair: Arnab Chakravarti, M.D. (617) 724-1548 achakravarti@partners.org


RTOG 0211 was amended to incorporate the NCI Adverse Events Reporting Guidelines Revision as follows:

Index/Appendices: Original Appendix IV was deleted in the index because Appendix IV, “Adverse Reaction Reporting Guidelines” was deleted and replaced by new text within the protocol. As a result, original Appendix V has been renumbered as Appendix IV.

Section 6.7.4: “See Section 7.5 for Adverse Event Reporting.” This new section was added for Radiation Therapy.

Section 7.2.3: The reference to Appendix V was changed to Appendix IV due to the renumbering of Appendices.

Section 7.5: This section was rewritten in accordance with the revised NCI Adverse Events Reporting Guidelines.

Section 10.2.5: The email contact information for LDS Hospital was updated.

Section 12.0: The RTOG HQ address was updated.





SUMMARY OF CHANGES
Amendment #6, Version Date: January 13, 2005

RTOG 0211, “A Phase I/II Study of an Oral Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor (EGFR-TKI), ZD 1839 (Iressa), [NSC# 715055] With Radiation Therapy in Glioblastoma Multiforme”

Study Chair: Arnab Chakravarti, M.D., (617) 724-1548, achakravarti@partners.org


RTOG 0211 has been amended as follows to include the Comprehensive Adverse Event and Potential Risks (CAEPR) list and related information:

Index: Reference to the addition of Appendix V was added.

Section 7.2.3: The first two paragraphs of this section were deleted and replaced with a reference to see Appendix V.

Appendix I: Under “What Are the Risks of the Study?” / ”Risks Associated With ZD 1839”” Appendix V: Added.

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






SUMMARY OF CHANGES
Amendment #5, Version Date: December 29, 2004

RTOG 0211, “A Phase I/II Study of an Oral Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor (EGFR-TKI), ZD 1839 (Iressa), [NSC# 715055] With Radiation Therapy in Glioblastoma Multiforme”

Study Chair: Arnab Chakravarti, M.D., (617) 724-1548, achakravarti@partners.org


In response to a memo distributed by CTEP regarding non-clinical carcinogenicity studies, RTOG 0211 has been amended as follows:

Section 1.5.2: The last paragraph of this section was added.

Appendix IA/Sample Consent: Under “Risks Associated With ZD 1839,” the last paragraph (“Additional Risk Information”) was added.

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





SUMMARY OF CHANGES
Revision 4, Version Date: September 3, 2003

RTOG 0211, A Phase I/II Study Of An Oral Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor (EGFRr-TKI), ZD 1839 (Iressa), [NSC# 715055] With Radiation Therapy In Glioblastoma Multiforme

Study Chair: Arnab Chakravarti, M.D., (617) 724-1548; FAX # (617) 726-2098; achakravarti@partners.org

IRB Review Requirements:
(   ) Full board review required
(X) Expedited review allowed, site IRB requirements take precedence
(   ) No review required


This amendment is in response to the memo from Dr. Janet Dancey (danceyj@ctep.nci.nih.gov phone 301-496-1196) regarding the development of CNS hemorrhage.

RTOG 0211 has been revised as follows:

Section 7.2.3: This was added as the last paragraph in this section:

There have been a total of 12 incidences of CNS hemorrhage reported among patients on NCI sponsored studies of ZD 1839. There have been five reports of CNS hemorrhage of the 48 patients enrolled in the pediatric studies, four events, including one fatality, occurred among 33 patients enrolled on a study of concurrent ZD 1839 and radiation followed by continued ZD 1839 and one event occurred in a patient with ependymoma receiving single agent ZD 1839. There have been 7 patients with CNS hemorrhages into primary or metatstatic tumors reported among 1355 patients enrolled in the adult studies. Four adult patients with hemorrhage had gliomas out of a total of 290 patients enrolled in the glioma studies.

Appendix IA, Sample Consent: This was added to Risks Associated with ZD 1839, under Infrequent Side Effects:

In a study testing the combination of ZD 1839 (gefitinib, Iressa) and radiation in children with brain tumors (called gliomas), 4 of 33 patients had bleeding into the tumors while receiving ZD 1839 with radiation or while continuing to take ZD 1839 after finishing radiation. At present, while the frequency of bleeding into tumors does not appear to be increased in adults, it is unclear whether the risk of bleeding into cancers in children, into gliomas or into cancers getting radiation is higher with ZD 1839.

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





SUMMARY OF CHANGES
Update Date: July 14, 2003

RTOG 0211, “A Phase I/II Study of an Oral Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor (EGFR-TKI), ZD 1839 (IRESSA), [NSC# 715055] with Radiation Therapy in Glioblastoma Multiforme”

Study Chair: Arnab Chakravarti, M.D., (617) 724-1548, achakravarti@partners.org


RTOG 0211 has been updated as follows:

Title Page: Dr. Arnab Chakravarti’s fax number has been updated to 617-726-2098.

NOTE: This is an editorial/administrative change 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/





SUMMARY OF CHANGES
Revision 3, Version Date: November 15, 2002

RTOG 0211, A Phase I/II Study Of An Oral Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor (EGFRr-TKI), ZD 1839 (Iressa), [NSC# 715055] With Radiation Therapy In Glioblastoma Multiforme

Study Chair: Arnab Chakravarti, M.D., (617) 724-1155; FAX # (617) 726-5637; achakravarti@partners.org

IRB Review Requirements:

(X) Full board review required; patients currently on study must be re-consented.
(   ) Expedited review allowed
(   ) No review required


RTOG 0211 has been revised as follows:
As required by CTEP, information regarding the rare side effect associated with ZD 1839 of interstitial pneumonitis/pneumonia has been added to Sections 7.2.3, 7.2.4, and Appendix I, the sample consent.

Other Changes
Schema page, Eligibility list — Exclusion of patients with known Acquired Immune Deficiency and pregnant or lactating women was added to correspond to Sections 3.2.8 and 3.2.10; this is a clarification and not a change to study eligibility.

Section 3.1.5 was revised to clarify the start dates of radiotherapy and Iressa; this clarification also was made in the third item of the Eligibility list on the Schema page and in Question 16, page 1 of the Eligibility Checklist.

Section 3.2.9 was added to exclude patients with known multiple sclerosis, as these patients may have decreased tolerance for radiation therapy to the brain; subsequent sections were appropriately renumbered. This addition also was made to the Eligibility list on the Schema page and as Question 13 on page 1 of the Eligibility Checklist (subsequent questions were appropriately renumbered).

Section 6.0 — In the first sentence, the timeframe was corrected from 4 to 5 weeks to correspond to Section 3.1.5.

Section 7.2.4 — The first and second paragraphs were revised for clarity; in item #1, the last sentence was deleted.

Section 13.3.1 — The second sentence, defining a dose limiting toxicity (DLT), was revised; grade 3 nausea/vomiting, fatigue, and skin toxicity (as defined in CTC, v. 2) were excluded as DLTs, with some noted exceptions. The RTOG Brain Committee feels that a substantial percentage of these patients, given a drug holiday, will have amelioration of their symptoms and can resume treatment. In consideration of the almost certain mortality of the glioblastoma multiforme population, the RTOG wishes to very carefully establish the maximum tolerated dose of Iressa when administered with radiation, without shortchanging the potential benefits of this combination approach. Inclusion of these grade 3 toxicities as DLTs has the potential of prematurely halting dose escalation of Iressa before the true MTD is reached, potentially endangering the benefits that can be safely achieved.

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







SUMMARY OF CHANGES
Revision 2, October 4, 2002

RTOG 0211, A PHASE I/II STUDY OF AN ORAL EPIDERMAL GROWTH FACTOR RECEPTOR TYROSINE KINASE INHIBITOR (EGFR-TKI), ZD 1839 (IRESSA), [NSC# 715055] WITH RADIATION THERAPY IN GLIOBLASTOMA MULTIFORME

Study Chair: Arnab Chakravarti, M.D., (617) 724-1155; FAX # (617) 726-5637; achakravarti@partners.org

IRB Review Requirements:

(   ) Full board review required
(X) Expedited review allowed
(   ) No review required


RTOG 0211 has been revised as follows:
Information has been added in the event that patients must be taken off enzyme-inducing anticonvulsants or started on enzyme-inducing anticonvulsants during study treatment. The following sections were added: Section 7.1.1, 3rd paragraph; Appendix I, sample consent, under “What Is Involved In The Study”, Part 1.

The timeframe for administration of the Mini-Mental Status Exam has been changed to every 12 weeks post-RT. The following sections were revised for this change: Sections 11.1, 11.2.4, 12.1, and Appendix I, under “What Is Involved In The Study”.

Other Changes
Title Page — The study chair’s contact information has been updated.

Eligibility Checklist, page 2 — The question, “Tissue/blood for research in current study?” was

added as question #23 to this operational/demographic portion of the checklist to correspond to the updated Tissue Consent (Appendix IB), and the subsequent question was appropriately re-numbered.

Section 12.1 — A follow-up CT/MRI scan and report were added with reference to Section 12.2 to clarify submission of scans.

Section 13.3.2: In the sentence beginning, “At a given dose level…”, the phrase “when the true toxicity is 50%” has been corrected (50% has replaced 30%).

Appendix IA — The consent form has been updated to RTOG standard under “Signature”: the patient’s name (as well as signature) is required as is the name and signature of the person obtaining the consent.

Appendix IB — The tissue consent has been revised as follows: The consent form was updated to RTOG standard with the “Participant statement” and “Witness statement”.

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





SUMMARY OF CHANGES
Revision 1, June 27, 2002

RTOG 0211, A PHASE I/II STUDY OF AN ORAL EPIDERMAL GROWTH FACTOR RECEPTOR TYROSINE KINASE INHIBITOR (EGFR-TKI), ZD 1839 (IRESSA), [NSC# 715055] WITH RADIATION THERAPY IN GLIOBLASTOMA MULTIFORME

Study Chair: Arnab Chakravarti, M.D., (617) 724-1155; FAX # (617) 726-5637; achakravarti@partners.org

IRB Review Requirements:
(Ö) Full board review required

(  ) Expedited review allowed

(  ) No review required


RTOG 0211 has been revised as follows:

Tissue submission has been made mandatory. The RTOG Brain Committee, the study chairs, The American College of Radiology’s IRB, and NCI have discussed this issue and agree that mandatory tissue submission is appropriate in selected studies, particularly in studies, such as 0211, that involve molecularly targeted therapy. The following sections have been revised to reflect this change: Schema page eligibility list; the Eligibility Checklist, page 1, question 15; Sections 3.1.11 and 10.1.

The timeframe for the start of therapy after surgery has been revised from 4 weeks to 5 weeks. The following sections have been revised to reflect this change: Schema page eligibility list; the Eligibility Checklist, page 1, question 16; Section 3.1.5.

Section 11.1 — In the last row, “CYP34A” has been corrected to “CYP3A4”.

Section 12.1 — An initial Follow-up Form (FS) and the timeframe for this form has been added; the timeframe for the Follow-up Form (F1) has been revised.