0615 Revision

SUMMARY OF CHANGES Amendment 3, Version Date: April 21, 2008 (Broadcast 4/28/08)
RTOG 0615, "A Phase II Study of Concurrent Chemoradiotherapy Using Three-Dimensional Conformal Radiotherapy (3D-CRT) or Intensity-Modulated Radiation Therapy (IMRT) + Bevacizumab (BV) [NSC 708865; IND 7921] for Locally or Regionally Advanced Nasopharyngeal Cancer"

Study Chair: Nancy Lee, MD; 212-639-3341; Leen2@mskcc.org

The following changes were made to RTOG 0615:

A conventional fraction size of 1.8 Gy should be utilized for areas at high risk for microscopic disease to minimize the risk of recurrence. Therefore, the radiation dose to the high risk subclinical region has been amended from 56-59.4 Gy to 59.4 Gy, 1.8 Gy per day. The following sections were changed accordingly: the Schema page in the table, under "Concurrent Phase, 3D-CRT or IMRT" and in Sections 6.1.2, 6.1.6, 6.4.2, 6.4.2.2, 6.4.2.3, and 6.4.3.

At NCI's request, information indicating that the bevacizumab supplied for the study is intended for clinical use only and is not the commercially available Avastin™ was deleted from the following sections: Sections 7.5, 7.5.2, and in Appendix I, the sample consent, the first paragraph under "Risks Associated with Bevacizumab".

Other Changes

Title page: The name and contact information of the study statistician was added to update the protocol to current RTOG standard.

Section 2.2.1 was amended to be consistent with changes made in Section 13.1.2 (see details below).

Section 3.1.8: The second sentence was amended to clarify in what instances a 24-hour urine protein should be obtained.

Section 3.1.10: The phrase, "X UNL" was deleted after "(INR) < 1.5", as sites do not have an upper normal level for patients not already on anti-coagulant therapy (and these patients are excluded from the study according to Section 3.2.13).

Section 5.3 was updated to the current RTOG standard text for "Regulatory Pre-Registration Requirements".

Section 6.7.4: In the table, under "Minor Variation", the 5^th item was amended to "Mean dose < 76 Gy" (vs. 74 Gy). According to the Medical Physics Co-Chair, Dr. Mechalakos: The mean dose constraint for PTV₇₀ for the case of "No Variation" is reasonable; however, based on an informal survey of recent IMRT head and neck cases at our institution, there are a limited number of cases for which the mean dose may exceed 74Gy despite the planner's best efforts. This may occur when the PTV₇₀ structure has an unusually high volume, for example. It does not seem reasonable to exclude such cases on the basis of the mean dose constraint when all other constraints are met. Therefore, the mean dose constraint for PTV₇₀ has been amended for "Minor Variation" to 76 Gy.

Section 7.2.2.2: The second sentence was added to clarify that sites may follow their standard guidelines for 5-FU administration at the dose specified in the study.

Section 7.6.5: In the third table, the dose reduction for an AGC < 1,000 and/or platelets < 50,000 was amended to "Decrease 2 dose levels*" and, the statement referred to with the asterisk was amended to be consistent with this change. In addition, a sentence was added above the "Note" to provide instruction to sites regarding continuing dose reductions made in cycle 1 of adjuvant treatment.

Sections 7.6.6 and 7.6.7: An instruction to sites regarding weight loss was added.

Section 7.8: The MedDRA version for this study was added in the first sentence.

Section 10.0:

The RTOG Tissue Bank has been renamed the "RTOG Biospecimen Resource". This section was amended to include this name and to include the new location of and the contact information for the Biospecimen Resource. These changes also were made in Appendices VI and VII.
In the last paragraph, RTOG 0514 was amended to the "Head and Neck Cancer Tissue/Specimen Repository", the current title of the study.

Section 10.4, "Reimbursement", was amended to current RTOG standard.

Section 11.2.2: In the first bulleted item, the required timeframe for history/physical, CBC, differential and platelets was specified to "within 24 hours prior to each treatment".

Section 13.0: The efficacy endpoints as currently defined are slightly different than those reported in the literature and those in RTOG 0225, to which the study results will be compared. Therefore, the following changes were made to allow for a more appropriate comparison with historical results in this patient population:

Sections 13.1.2.5 and 13.1.2.6: The word, "free", was added after "metastases" and "progression", respectively, and Section 13.1.2.8 was deleted.
Section 13.2: In the 1st sentence of the 3^rd paragraph, the reference to Sections 13.1.2.5-13.1.2.9 was amended to Sections 13.1.2.5-13.1.2.8 to be consistent with changes made in Section 13.1.2.
Sections 13.4.1 and 13.4.6 were amended to be consistent with changes made in Section 13.1.2.

Appendix II, Study Parameters: Under "Concurrent Phase", an "X" was added for "Metabolic Panel" to make this appendix consistent with Section 11.2.1.

SUMMARY OF CHANGES Update: November 15, 2007
RTOG 0615, "A Phase II Study of Concurrent Chemoradiotherapy Using Three-Dimensional Conformal Radiotherapy (3D-CRT) or Intensity-Modulated Radiation Therapy (IMRT) + Bevacizumab (BV) [NSC 708865; IND 7921] for Locally or Regionally Advanced Nasopharyngeal Cancer"

Study Chair: Nancy Lee, MD; 212-639-3341; Leen2@mskcc.org

The following changes were made to RTOG 0615:

Eligibility Checklist, page 2:

Question 19 was corrected to be consistent with changes made in Sections 3.2.6 and 4.1.1 in Amendment 2.

Questions 20 and 21 were deleted to be consistent with moving the text of Sections 3.2.7 and 3.2.8 to Sections 4.1.2 and 4.1.3 in Amendment 2. (Subsequent questions were appropriately renumbered).

No changes were made to the eligibility criteria of the study.

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.

SUMMARY OF CHANGES Amendment 2, Version Date: November 7, 2007
RTOG 0615, "A Phase II Study of Concurrent Chemoradiotherapy Using Three-Dimensional Conformal Radiotherapy (3D-CRT) or Intensity-Modulated Radiation Therapy (IMRT) + Bevacizumab (BV) [NSC 708865; IND 7921] for Locally or Regionally Advanced Nasopharyngeal Cancer"

Study Chair: Nancy Lee, MD; 212-639-3341; Leen2@mskcc.org

The following changes were made to RTOG 0615:

Schema page: In both "Concurrent Phase" and "Adjuvant Phase", the word, "day", was added after the doses of cisplatin, bevacizumab, and 5-fluorouracil for clarity. This clarification also was added in Sections 7.1.1 and 7.2.1.

Section 3.1.7: The baseline serum creatinine was amended from < 1.6 mg/dl to < 1.5 mg/dl to be consistent with Section 7.6.6.4. In addition, "24 hr" was deleted prior to "calculated creatinine clearance", as a creatinine estimated via the Cockcroft-Gault formula is not a 24 hour creatinine.

Sections 3.2.6, 3.2.7, and 3.2.8: Required timeframes for biopsies, major surgical procedures, fine needle aspirations, and placement of PEG tubes were moved to Section 4.1, as the timing of these procedures should refer to "prior to treatment" versus "prior to registration". Subsequent sections were appropriately renumbered.

Section 3.2.7 (former Section 3.2.9): The phrase, "or frank clots within minimal or no phlegm" was added to the parenthetical definition of gross hemoptysis or hematemesis to provide further specifics for sites. This addition also was made in the Eligibility Checklist, page 2, question 22.

Section 3.2.10 was amended for clarity.

Section 4.1.3 was amended for clarity.

Section 7.1.1: The last sentence in the section, "Patients will not make up missed doses of chemotherapy or bevacizumab", was deleted, as sites found it inconsistent with the prior sentence about treatment delays.

Sections 7.1.2.1, 7.1.2.2, and 7.2.2.2: REFERENCES to "Dose Modifications" in these sections was corrected from Section 7.7 to Section 7.6.

Sections 7.3.1 and 7.4.2: The descriptions of cisplatin and 5-fluorouracil were updated.

Section 7.5.9: NCI's current Comprehensive Adverse Events and Potential Risks List (CAEPR), v. 1.2, June 19, 2007, was added. The risks associated with bevacizumab in Appendix I were amended to be consistent with the v. 1.2 CAEPR.

Section 7.6.3: The second sentence, explaining that dose modifications for chemotherapy are intended to be permanent, was added for clarity.

Section 7.6.5: In the first sentence of the first paragraph (below the tables), the level for platelets was corrected from > 75,000 to > 100,000.

Section 7.6.7.4: In the table under "Hemorrhage/GI Bleeding", the description of and action for grade 2 were deleted, as they were inconsistent with the action for grade 3 adverse events and grade 2 non-CNS or non-pulmonary hemorrhage does not mandate holding bevacizumab.

Sections 7.8, 7.8.1, and 7.8.2 were updated to current RTOG standard.

Section 7.9: The first paragraph was added to update this section to current RTOG standard.

Section 11.2.2: In the third bulleted item, a parenthetical phrase, "no earlier than 24 hours prior to the treatment", was added after "on each bevacizumab treatment date" to provide clarity about the timeframe for the assessments.

Section 12.2: A prompt to submit a copy of the T5 form to RTOG Headquarters and the ITC was added next to the Daily Treatment Record.

Appendix I: Under "What side effects or risks can I expect from being in the study?", the risks associated with feeding tube placement were added to provide that information to patients and sites.

Appendix II: In the "Follow up" column, the liver CT and UPC ratio were deleted as unnecessary.

SUMMARY OF CHANGES Amendment 1, Version Date: May 7, 2007
RTOG 0615, "A Phase II Study of Concurrent Chemoradiotherapy Using Three-Dimensional Conformal Radiotherapy (3D-CRT) or Intensity-Modulated Radiation Therapy (IMRT) + Bevacizumab (BV) [NSC 708865; IND 7921] for Locally or Regionally Advanced Nasopharyngeal Cancer"

Study Chair: Nancy Lee, MD; 212-639-3341; Leen2@mskcc.org

In response to NCI's recent safety report and Action Letter, RTOG 0615 was amended clarify the risks of neutropenia and infection and fistulas associated with bevacizumab. The following changes were made:

Section 1.4, "Bevacizumab Toxicities": Paragraphs titled, "Neutropenia" and "Tracheoesophageal (TE) Fistula" were added at the end of the section.

Section 7.6.4.7, the last table, "Other Bevacizumab Treatment Modifications Non-specific to CTCAE, v. 3.0":

Appendix I, the sample consent: Under Rare but serious risks associated with Bevacizumab, the risks of "ulcer" and "fistula" were added. In addition, a paragraph concerning neutropenia and infection was added under "Risks Associated with Bevacizumab, Chemotherapy, and Radiation Therapy".

In addition, based on the reported fistulas in NCI's Action Letter, which occurred during maintenance bevacizumab, the Study Chairs have deleted the maintenance phase of bevacizumab from 0615 to ensure patient safety. The combination of the bevacizumab with radiation therapy and/or chemotherapy likely delivers greater therapeutic benefit than single agent bevacizumab, and given the adverse events recently reported by the NCI, the potential benefits of the planned maintenance of bevacizumab may not outweigh the risks. The following changes were made:

Schema: The maintenance phase was deleted from the table as was footnote "c", referring to that phase.

Section 1.7: The last sentence, discussing maintenance bevacizumab, was deleted.

Section 1.8: The first sentence of the second paragraph was amended to delete REFERENCES to maintenance bevacizumab.

Section 2.2: The last phrase of Section 2.2.1, "followed by 6 months of maintenance BV", was deleted. In addition, Section 2.2.2, the secondary objective to explore the feasibility of maintenance bevacizumab, was deleted.

Section 7.3, "Maintenance Biologic Therapy", was deleted, and subsequent sections were appropriately renumbered.

Section 10.2.3 was amended to delete REFERENCES to maintenance bevacizumab.

Section 10.3: In the second part of the table, the timeframe was amended to delete REFERENCES to maintenance bevacizumab.

Section 11.2.3: In the heading, the phrase, "Maintenance Biologic Therapy", was deleted. The first paragraph was amended to delete REFERENCES to maintenance bevacizumab, and the first bulleted item was deleted.

Section 12.1: The timeframe for the Follow-up Form (F1) was amended to delete REFERENCES to maintenance bevacizumab.

Section 13.0: The following sections were amended to delete REFERENCES to maintenance bevacizumab: Sections 13.1.2.1, 13.2 (7^th paragraph), and 13.4.4.

Appendix I, the sample consent: The following sections were amended to delete REFERENCES to maintenance bevacizumab: "What will happen if I take part in this research study"; "Study Plan"; "How long will I be in the study?"; and "About Using Tissue and Blood for Research" (3^rd paragraph). In addition, the total time for treatment was amended from 9-10 months to "15-16 weeks" in "What will happen if I take part in this research study" and in "How long will I be in the study?".

Appendix II, study parameters: In the last column, "Maintenance" was deleted from the heading and the following labs, previously required during maintenance bevacizumab, were deleted: CBC, platelets, Hgb, serum creatinine/creatinine clearance, and metabolic panel.

The collection of serum (highly recommended but not required) has been amended to the collection of serum and plasma. Serum will be used for VEGF and VEGF-R2 assays, and plasma will be used to measure the EBV DNA titer. The following changes were made:

Section 10.2: The heading was amended to read, "Serum/Plasma Collection".

Section 10.2.2: At the beginning of the sentence, the phrase, "and plasma", was added after serum, and the word, "plasma", was substituted for the word, "serum", prior to "EBV DNA titer".

Section 10.2.3: At the beginning of the sentence, the amount of blood collected was amended from 3 mL to 6 mL, and the parenthetical phrase, "3 mL serum and 3 mL EDTA plasma", was added. In the last sentence, the reference to Appendix VI was corrected to Appendix VII.

Section 10.2.4: The heading was amended to read, "Serum and Plasma Collection Instructions". Sections 10.2.4.1 and 10.2.4.2 were reformatted to be specific to "Serum" and "Plasma" respectively, and collection instructions for plasma were added to Section 10.2.4.2.

Section 10.3: In the second part of the table, under "Collected pre-treatment…", the second row was amended from "12 mL of whole blood" to "3 mL of whole blood". In addition, the last row specific to plasma was added.

Appendix I: Under "About Using Tissue and Blood for Research", in the third paragraph, the amount of blood was amended from "About 2 teaspoons" to "About 4 teaspoons".

Appendix VII: Instructions for the collection of plasma were added.

Other Changes

Sections 7.1.1 and 7.1.2.1: A sentence was added to provide instructions to sites regarding the order of administration of cisplatin and bevacizumab.

Section 7.2.1: In the second bullet, "5-fluorouracil: 1,000 mg/m²" was clarified to "5-fluorouracil: 1,000 mg/m²/day".

Section 11.2.3: The timeframe for follow up was amended to "6, 9, and 12 months from start of treatment, every 3 months in year 2, every 6 months in years 3-5; then annually" to make it more consistent with current RTOG standard. This change also was made in the timeframe for the Follow-up Form (F1) in Section 12.1 and in Appendix I under "You will need these test and procedures in follow-up visits" and "How long will I be in the study?".

Section 13.2: In the second paragraph, the sentence, "During the first year, patients will receive all BV per the protocol prescription and will be followed for at least 60 days after the last BV administration," was deleted, as it was felt to be unnecessary.

Section 13.4.4: In the sentence beginning, "If there are 3 or more such patients," the phrase, "out of the first 14 eligible patients", was added for clarity. In addition, in the second to last sentence in the section, CTEP was added as one of the parties to which the study chairs and study statistician will make recommendations regarding adverse events.

Section 13.4.5: In the third paragraph, in the sentence beginning, "If there are 4 or more such patients", the phrase, "out of the first 42 eligible patients", was added for clarity.