SUMMARY OF CHANGES
Amendment #4 Version Date: April 21, 2006
RTOG 0411, "A Phase II Study of Bevacizumab with Concurrent Capecitabine and Radiation Followed by Maintenance Gemcitabine and Bevacizumab for Locally Advanced Pancreatic Cancer"
Study Chair: Christopher Crane, MD, Phone: 713-563-2340, ccrane@mdanderson.org
RTOG 0411 was amended as follows:
Section 1.4: Last paragraph was added to describe the potential adverse events of Reversible Posterior Leukoencephalopathy Syndrome (RPLS) or similar leukoencephalopathy syndrome per NCI's request.
Section 3.1.9: The creatinine clearance formula for females was corrected; and has been provided in a more user-friendly format. For males, the creatinine clearance was correct; and it has been provided in a more user-friendly format as well.
Section 7.3.9: The Comprehensive Adverse Events and Potential Risks List (CAEPR) for Bevacizumab (NSC 704865) was updated per NCI's request.
Section 7.4: "Bevacizumab should be held in patients with symptoms/signs suggestive of RPLS (reversible posterior leukoencephalopathy syndrome), pending work-up and management, including control of blood pressure. Bevacizumab should be discontinued upon diagnosis of RPLS" was added to the beginning of the treatment section per NCI's request.
Consent Form: Under Risks Associated with Bevacizumab, Rare But Serious, "Posterior Leukoencephalopathy Syndrome (RPLS) or similar leukoencephalopathy syndrome: RPLS is a medical condition related to the leakiness of blood vessels in the brain and can cause confusion, blindness or vision changes, seizure or other symptoms, as well as changes in brain scans. This condition is usually reversible, but in rare cases, it is potentially life-threatening and may have long-term effects on brain function" was added to inform patients of the risk of potential adverse events of RPLS per NCI's request.
An amended protocol is available (password required) on the RTOG Web site, http://www.rtog.org/
SUMMARY OF CHANGES
Update Date: November 29, 2005
RTOG 0411, "A Phase II Study of Bevacizumab with Concurrent Capecitabine and Radiation Followed by Maintenance Gemcitabine and Bevacizumab for Locally Advanced Pancreatic Cancer"
Study Chair: Christopher Crane, MD, Phone: 713-563-2340, ccrane@mdanderson.org
RTOG 0411 has been updated as follows:
Section 5.0: "Pre-Registration Requirements" (Section 5.1) was removed because capecitabine (Xeloda®) will only be commercially available. Subsequent sections were renumbered as 5.1 and 5.2 as a result.
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 on the RTOG website: http://www.rtog.org/
SUMMARY OF CHANGES
Update Date: November 17, 2005
RTOG 0411, "A Phase II Study of Bevacizumab with Concurrent Capecitabine and Radiation Followed by Maintenance Gemcitabine and Bevacizumab for Locally Advanced Pancreatic Cancer"
Study Chair: Christopher Crane, MD, Phone: 713-563-2340, ccrane@mdanderson.org
RTOG 0411 has been updated as follows:
Index: "Appendix VII Study Agent Shipment Form (SASF)" was removed because capecitabine (Xeloda®) will only be commercially available.
Section 7.1.7: The procedure for obtaining capecitabine (Xeloda®), from Roche Laboratories, Inc, for use during protocol treatment was removed because the drug will only be commercially available.
Sample Informed Consent, under Will my medical information be kept private?: "Qualified representatives of Roche Laboratories, Inc." was removed from the list of "Organizations that may look at and/or copy your medical records for research, quality assurance and data analysis" because Roche will not be supplying capecitabine (Xeloda®).
Appendix VII Study Agent Shipment Form (SASF) was removed because capecitabine (Xeloda®) will only be commercially available.
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 on the RTOG website: http://www.rtog.org/
SUMMARY OF CHANGES
Amendment #3 Version Date: October 20, 2005
RTOG 0411, "A PHASE II STUDY OF BEVACIZUMAB WITH CONCURRENT CAPECITABINE AND RADIATION FOLLOWED BY MAINTENANCE GEMCITABINE AND BEVACIZUMAB FOR LOCALLY ADVANCED PANCREATIC CANCER"
Study Chair: Christopher Crane, MD; Phone: 713-563-2340; ccrane@mdanderson.org
RTOG 0411 has been updated as follows:
Section 3.2.1: was changed to clarify that patients are ineligible for the study if they have evidence of duodenal invasion on CT scan or if they have evidence of gastric outlet obstruction.
Section 6.1.1: The block margin for treating the primary tumor and enlarged lymph nodes was changed from 2 cm to "as referenced in Section 6.4.1.1." "All four beams will be equally weighted" was changed to "Beam weighting will be optimized to match the doses specified in Section 6.5.1.1."
Section 6.4.1.1: The underlined phrase "Planning target volume (PTV)" was changed to "Treatment field." "The PTV must be digitized or drawn…" was changed to "The GTV must be digitized or drawn…."
Section 6.6.1.1: "radiographs of DRRs designating the PTV…" was changed to "simulation films or DRRs designating the treatment field…."
Section 7.4: A sentence was added under "Maintenance Gemcitabine and Bevacizumab" to specify hematologic parameters that must be met before starting maintenance therapy.
Section 7.4.1.1: A statement was added to clarify that dose modifications for bevacizumab apply to both concurrent and maintenance therapy.
Section 9.1: Neupogen and Neulasta are given as examples of myeloid growth factors.
Section 9.2.2: Neumega was added to the list of prohibited concomitant medications.
Section 11.1: The footnote "c" "Must be done 3-4 weeks following chemoradiation completion" was added to blood draws, proteinurea and chest x-ray for clarity.
An amended protocol is available (password required) on the RTOG Web site, http://www.rtog.org
SUMMARY OF CHANGES
Update Date: September 8, 2005
RTOG 0411, “A Phase II Study of Bevacizumab with Concurrent Capecitabine and Radiation Followed by Maintenance Gemcitabine and Bevacizumab for Locally Advanced Pancreatic Cancer”
Study Chair: Christopher Crane, MD, Phone: 713-563-2340, ccrane@mdanderson.org
RTOG 0411 has been updated as follows:
Section 6.6.1.2: In the sentence: “color DVHs if the treatment planning system provides this out put …” “color” was added for clarity. Also, “and boost films (simulation and portal)” were removed because boost films are not required in this study.
Section 12.1: “Boost Films (simulation and portal) (T8)” was removed because boost films are not required in this 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.
An updated protocol is available on the RTOG website: http://www.rtog.org/
SUMMARY OF CHANGES
Amendment #2 Version Date: July 29, 2005
RTOG 0411, “A PHASE II STUDY OF BEVACIZUMAB WITH CONCURRENT CAPECITABINE AND RADIATION FOLLOWED BY MAINTENANCE GEMCITABINE AND BEVACIZUMAB FOR LOCALLY ADVANCED PANCREATIC CANCER”
Study Chair: Christopher Crane, MD; Phone: 713-563-2340; ccrane@mdanderson.org
RTOG 0411 was amended per FDA request. This amendment also includes the updated AE guidelines; the addition of the Study Agent Shipment Form (SASF) for capecitabine (Xeloda®); and amendments to Patient Selection (Section 3.0), Registration Procedures (5.0), Drug Therapy (7.0), Other Therapy (9.0), Patient Assessments (11.0), Data Collection (12.0), Statistical Considerations (13.0) and the Informed Consent. (See detailed changes below.)
Index/Appendix VII: Study Agent Shipment Form (SASF) was added for treating institutions to obtain capecitabine (Xeloda®), which Roche Laboratories, Inc. will provide per protocol treatment.
Sections 1.3 and 1.4: Seventh paragraph of Section 1.3 and the first and second paragraphs of Section 1.4 were amended to include the final data from a phase I study conducted at MD Anderson Cancer Center; Tables 1 and 2 were updated to include the final data as well per FDA.
Section 3.1.9: The following was added for clarity when calculating creatinine clearance: calculated creatinine clearance > 50 ml/min using Cockcroft-Gault formula:
• Male: Creatinine Clearance = (140 – age) x weight/(72 x serum creatinine)
• Female: Creatinine Clearance = (140 – age) x weight/(72 x serum creatinine x 0.85).
Section 3.2.12: In the first sentence, the phrase, “which could lead to unexpected elevation in the INR. This could further predispose patients to bleeding while on bevacizumab” was added for clarity. Also, “and therapeutic” was removed from the last sentence, “Low molecular weight heparin is allowed at prophylactic dosages at any time during this protocol” per FDA.
Section 3.2.18: “Known or suspected dihydropyrimidine dehydrogenase (DPD) deficiency”, was added for clarity.
Section 5.1: This section, “Pre-Registration Requirements”, was added to include instructions for submitting Study Agent Shipment Forms (SASFs). Subsequent sections were renumbered as 5.2 and 5.3 as a result.
Section 7.1: Xeloda® was added in the heading.
Section 7.1.7: This section was amended to clarify the procedure for obtaining capecitabine (Xeloda®) for use during protocol treatment.
Section 7.4:
• “Note: All patients must be on a proton pump inhibitor (lansoprazole, omeprazole, pantoprazole sodium, rabeprazole sodium). If any new epigastric pain develops, ulceration should be expected and sucralfate should be started. Upper endoscopy should be performed as clinically directed” was added for clarity.
• In the Capecitabine and Bevacizumab with Concurrent Radiation table, under the Agent column, “refer to Appendix VI” was added for clarity; and the bevacizumab schedule was changed to read, “On days 1, 15 and 29 of chemoradiation”.
• The Anticoagulant guidelines during concurrent chemotherapy/RT table was added for clarity.
• In the Maintenance Gemcitabine and Bevacizumab table the dose for Gemcitabine was edited from 1 gram/m2 to 1,000 mg/m2 for consistency.
• The Anticoagulant guidelines during maintenance therapy table was added for clarity.
Section 7.4.1.1.1: “Grade 3 or 4: Any patient who experiences grade 3 or 4 bleeding will be removed from protocol treatment.” The word “or” replaced the hyphens “-" to add clarity to the sentence.
Section 7.4.1.1.2:
• Misspelling of the word infarction was corrected.
• First bullet was changed to, “> Grade 2: discontinue bevacizumab” from “> Grade 3.”
• Second bullet, “Grade 2, if new or worsened since bevacizumab therapy: discontinue bevacizumab” was deleted.
Section 7.4.1.1.3:
• First bullet, “Grade 3” was changed from “G3 or asymptomatic G4” for clarity.
• First bullet, “If full-dose anticoagulant is needed during concurrent chemoradiation, hold bevacizumab for two weeks following the last full-dose anticoagulant period” was added per FDA.
• Second bullet, “Symptomatic” was removed for clarity and “Grade” added.
Section 7.4.1.1.9: The word “or” replaced 3 hyphens “-“ where grade 3 or 4 are mentioned to add clarity to the section.
Section 7.4.1.2: The row labeled “Note” in the table was modified to read, “… will not receive any more capecitabine.” The word “more” was added for clarity.
Section 7.4.1.3: Under the Modification heading in the “ANC < 1,000 or platelet < 75,000” row the word, “Hold” has replaced “Omit”; and Restart when ANC > 1,000 and platelets > 75,000 was added for clarity.
Section 7.5: Second bullet – cross-reference was changed to Section 7.4.1 from “Sections 6 and 7”.
Sections 7.7 and 7.8: These sections have been rewritten per the new NCI Adverse Events reporting guidelines.
Section 7.9 (old Section 7.8): The number of this section was changed due to the addition of the revised AE reporting guidelines.
Section 9.2.2:
• Fifth bullet, “(during concurrent chemo/RT)” was added for clarity.
• A sixth bullet, “Therapeutic heparin (during concurrent chemotherapy/RT)” was added for clarity.
Section 11.1: “Creatinine” was changed to “Calculated Creatinine Clearance” for clarity.
Section 12.1:
• Under Adverse Event Form (AE) following (TF), “and chemotherapy” was added to, “(Report radiotherapy and chemotherapy related adverse events on the (AE) from submitted with the (TF) form.)”.
• Under Adverse Event Form (AE) following (SF), “(Report chemotherapy related Adverse Events on the AE form submitted with the (SF) form.)” was added for clarity.
Section 13.1.2: First bullet under Frequency of patients developing “grade 3” was added to > Grade 4 bleeding; the text now reads, > Grade 3 or 4 bleeding. This was changed per FDA.
Section 13.3: The sentence, “In the event that an early stopping rule is met, RTOG will notify both CTEP and the FDA” was added per FDA.
Section 13.3.1:
• In the first sentence, cross reference to Section 13.1.2 was corrected (from 13.2.1).
• Second paragraph, fourth sentence, “accrual will be suspended and” was added per FDA. The sentence now reads, “If this occurs, accrual will be suspended and the study chairs, RTOG Gastrointestinal Cancer Committee Chair …”
Section 13.3.2: Reference to Section 13.1.2 was corrected (from 13.2.1).
Section 13.4.2: The last sentence in the section, “See section 13.6.3 for possible subgroup analyses” was deleted because there is no section 13.6.3 in the document.
Informed Consent:
• How long will I be in the study? Section: “Treatment with radiation, chemotherapy, and bevacizumab will last approximately five and a half weeks” the treatment was changed from six and a half weeks to five and a half weeks.
• Will my medical information be kept private? Section: “Qualified representatives of Roche Laboratories, Inc.” was added to the list of organizations that may look at and/or copy your medical records for research, quality assurance and data analysis.
SUMMARY OF CHANGES
Amendment #1 Version Date: March 8, 2005
RTOG 0411, “A PHASE II STUDY OF BEVACIZUMAB WITH CONCURRENT CAPECITABINE AND RADIATION FOLLOWED BY MAINTENANCE GEMCITABINE AND BEVACIZUMAB FOR LOCALLY ADVANCED PANCREATIC CANCER”
Study Chair: Christopher Crane, MD; Phone: 713-563-2340; ccrane@mdanderson.org
RTOG 0411 has been amended in response to the memo from Dr. Chen dated 1/04/05 as follows:
- “Avastin” was deleted in the heading title of Section 7.3 and in the clinical agreement in Section 7.8.
- The following text was added to Section 7.3.5: “The bevacizumab to be supplied for this protocol is intended for clinical trial use only and is not the commercially available Avastin. Investigational bevacizumab and commercially available Avastin may be produced at separate facilities and some difference may exist between the two products, although both are required to meet similar product testing criteria and are expected to be very similar in safety and activity. For further details and molecule characterization, see the updated bevacizumab Investigator Brochure.”
- The following text was added also to Section 7.3.5: “It is CTEP’s routine policy that all investigational drugs supplied by the CTEP Pharmaceutical Management Branch for clinical trial use be specifically labeled on each container. For bevacizumab, the label reads “Caution: NEW DRUG – Limited by Federal (U.S.A.) law to investigational use”. The investigational bevacizumab is to be identified and handled as any investigational product. The product must be used only for patients enrolled in the clinical study.
- The following text was added to the end of Section 7.7.4: “(For bevacizumab, the Package Insert was prepared for the commercial Avastin but not the investigational bevacizumab being used in this protocol. The Package Insert should therefore only be used as a reference in combination with the Investigator’s Brochure.)”
- The following text was added to the Consent, in the description of bevacizumab under “Why Is This Study Being Done?”: “Bevacizumab is the common name for the commercial drug Avastin. The bevacizumab used in this trial, however, is for use in research studies only and may be made at locations different from those where Avastin is made. Although some differences may exist, bevacizumab for research use and the commercial drug, Avastin, are manufactured by a similar process, meet similar standards for final product testing, and are expected to be very similar in safety and effectiveness.”
In addition, the following changes have been made to the protocol:
Title Page: At the request of NCI, the IND # for bevacizumab was changed to IND 7921.
Eligibility Checklist, page 1: Question # 17 was amended to “Is the patient’s baseline proteinuria >1+ or urine protein:creatinine ratio > 1.0 ?” to be consistent with Section 3.1.10.
Section 5.1: The web link for the Human Subjects Training was updated.
Section 7.3.9: This entire section was deleted and replaced with the Comprehensive Adverse Events and Potential Risks (CAEPR) list for Bevacizumab (NSC #704865) in response to a memo from Dr. Chen dated January 21, 2005.
Section 7.3.10: The following was added to assist sites in obtaining Investigator’s Brochures: “Investigator's Brochures may be obtained from PMB for investigational agents where CTEP holds the IND. To receive an Investigator's Brochure, you must be an active participant on an NCI sponsored clinical trial and have an active investigator registration status. Contact the IB Coordinator at IBCoordinator@mail.nih.gov <mailto:IBCoordinator@mail.nih.gov> or 301-496-5725, Monday through Friday, from 8:30 a.m. to 4:30 p.m. Eastern time.”
Consent: Under “During the Study…” “while on the study” was deleted on all tests and procedures because it is redundant with the heading “during the study.” For CT/MRI and Chest X-ray, 3 months was corrected to 2 months to be consistent with text of the protocol. ”Under Risks Associated with Bevacizumab,” cough” and “voice change” were added under “Less Likely” to be consistent with the new Section 7.3.9.