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Revised 4/08, Addendum #5 Revised 8/10, Addendum #8 Revised 9/10, Addendum #9 Eastern Cooperative Oncology Group A Phase III Randomized Trial of Adjuvant Chemotherapy With or Without Bevacizumab for Patients With Completely Resected Stage IB (> 4 cm) - IIIA Non-Small Cell Lung Cancer (NSCLC) Heather Wakelee, M.D.
Alan Sandler, M.D. THORACIC SURGERY CO-CHAIR: Steven Keller, M.D. PATHOLOGY CO-CHAIR: Seena Aisner, M.D. LABORATORY CO-CHAIR: Jill M. Kolesar, Pharm. D. David Carbone, M.D., Ph.D. Suzanne Dahlberg, Ph.D. THORACIC COMMITTEE CHAIR: Joan Schiller, M.D. COMMUNITY CO-CHAIR: Christian Adonizio, M.D. Alex Adjei, M.D. NCCTG SURGICAL CO-CHAIR: Dennis Wigle, M.D., Ph.D. David Gandara, M.D. SWOG SURGICAL CO-CHAIR: Eric Vallieres, M.D. Stephen Graziano, M.D. CALGB SURGICAL CO-CHAIR: Richard Battafarano, M.D. NCIC CTG CO-CHAIRS: Charles Butts, M.D. Natasha Leighl, M.D. NCI Supplied Agent: Bevacizumab (NSC 704865, BB-IND 7921)
This is an FDA registration trial.
Version Date: September 15, 2010
NCI Update Date: September 15, 2010
STUDY PARTICIPANTS
ACTIVATION DATE
ECOG Entire Group Addendum #1-3 – Incorporated prior to activation NCCTG Entire Group* SWOG Entire Group* Update #1 and 2 – Incorporated prior to activation CALGB Entire Group* Addendum #4 – 8/07 NCIC CTG Entire Group* Addendum #5 – 4/08 Addendum #6 – 4/09 * This study is supported by the NCI Cancer Trials Addendum #7 – 5/09
Support Unit (CTSU). Institutions not aligned Addendum #8 – 8/10 with ECOG will participate through the CTSU Addendum #9 – 9/10 Update #3 – 9/10 Eastern Cooperative
Oncology Group
Revised 7/07, Addendum #4 Revised 4/08, Addendum #5 Revised 4/09, Addendum #6 Revised 5/09, Addendum #7 Revised 8/10, Addendum #8 Revised 9/10, Addendum #9 Selection of Patients
Each of the criteria in the checklist that follows must be met in order for a patient to be considered
eligible for this study. Use the checklist to confirm a patient’s eligibility. The checklist must be
completed for each patient and must be signed and dated by the treating physician. Please submit
the completed eligibility checklist as outlined in the Forms Submission Schedule, which is
posted on the ECOG website with the protocol (www.ecog.org). A copy of the completed
checklist should also be maintained in the patient’s chart.
In calculating days of tests and measurements, the day a test or measurement is done is
considered Day 0. Therefore, if a test is done on a Monday, the Monday four weeks later
would be considered Day 28.
ECOG Patient No.
Patient’s Initials (L, F, M)
NOTE: All questions regarding eligibility should be directed to the Study Chair or Study Chair
NOTE: Institutions may use the eligibility checklist as source documentation if it has been reviewed,
signed, and dated prior to registration/randomization by the treating physician. A copy of the eligibility checklist must be submitted to ECOG attached to a source document coversheet. NOTE: Patients going on Chemotherapy Regimen 4 (pemetrexed/cisplatin) must meet all eligibility
criteria (3.1-3.23) as well as eligibility criteria 3.24 (“Pemetrexed/Cisplatin Therapy”). In order to be eligible for this trial, patients must have undergone complete resection of their non-small cell lung cancer (NSCLC) [stage IB (> 4 cm)] – [IIIA (T2-3N0, T1-3N1, T1-3N2] prior to enrollment. (Refer to Appendix X for staging guidelines per AJCC 6th edition). Accepted types of resection will consist of lobectomy, sleeve lobectomy, bi-lobectomy or pneumonectomy. Resections by segmentectomy or wedge resection will not be accepted. Mediastinal lymph node sampling at specified levels is required pre-operatively (mediastinoscopy) or intraoperatively (level 7 and 4 for right sided tumors or level 7 and 5 and/or 6 for left sided tumors). Please refer to Section 5 for specific details on lymph node level sampling requirements and resection criteria. If patient’s tumor is stage IB, it must be > 4 cm in size. Is patient’s tumor stage IB? (Yes or No) If ‘yes’, is tumor > 4 cm? _ (Yes or No) Patients must be no less than 6 weeks (42 days) and no more than 12 weeks (84 days) post-thoracotomy at the time of randomization and must be adequately recovered from surgery. Date of surgery: Planned date of randomization: [Deleted in Addendum #4] Age > 18 years. ECOG performance status 0 or 1. Patients must not have received the following: Prior systemic chemotherapy at any time. Methotrexate (MTX) given in low doses for non-malignant conditions with last dose at least 2 weeks prior to date of registration will be allowed. Other low dose chemotherapeutics for non-malignant conditions will be considered, but review by the study chair is required. Eastern Cooperative
Oncology Group
Revised 8/10, Addendum #8 Hormonal cancer therapy or radiation therapy as prior cancer treatment within 5 years of randomization. (Prior surgery, biologic therapy, hormonal therapy, or radiation therapy for a malignancy over 5 years prior to enrollment that is now considered cured is acceptable.) Patients must not have any history of cancer within 5 years from randomization, with the exception of in-situ carcinoma of the cervix or completely resected non-melanoma skin cancer. Required laboratory values obtained within two weeks of randomization: ANC: _ Date of Test: Platelets 100,000/mm3 Platelet count: Date of Test: Prothrombin time/INR 1.5 Or, if patient is on therapeutic anticoagulation, prothrombin time/INR < 3.0 Prothrombin time/INR: Date of Test: Is patient on therapeutic anticoagulation? _ (Yes or No) institutional upper limit of normal (ULN) OR, if patient is on therapeutic anticoagulation, PTT must be < 1.5 x ULN. PTT: _ULN: _ Date of Test: Is patient on therapeutic anticoagulation? _ (Yes or No) PTT: Date of Test: Total Bilirubin 1.5 mg/dL Total Bilirubin: Date of Test: SGOT (AST) < 5 x upper limit of normal (ULN): Institutional Upper Limit of Normal: _ SGPT (ALT) < 5 x upper limit of normal (ULN): Institutional Upper Limit of Normal: _ Patients must have adequate renal function as determined by the following tests within 2 weeks prior to randomization: Serum Creatinine 1.5 x institutional upper limit of normal (ULN) Serum Creatinine: _ Urine protein should be screened by urine analysis for Urine Protein Creatinine (UPC) ratio. For UPC ratio > 0.5, 24-hour urine protein must be obtained and the level must be < 1000 mg for patient enrollment. Eastern Cooperative
Oncology Group
Revised 8/10, Addendum #8 NOTE: UPC ratio of spot urine is an estimation of the 24 urine protein excretion – a UPC
ratio of 1 is roughly equivalent to a 24-hour urine protein of 1 g. UPC ratio is calculated using one of the following formulas: [urine protein]/[urine creatinine] – if both protein and creatinine are reported in mg/dL [(urine protein) x 0.088]/[urine creatinine] – if urine creatinine is reported in mmol/L UPC ratio: _ Date of calculation: Eastern Cooperative
Oncology Group
Revised 4/08, Addendum #5 Revised 4/09, Addendum #6 Revised 5/09, Addendum #7 Revised 8/10, Addendum #8 If necessary, 24-hour urine protein: _ Date of test: _ Patients with a known history of myocardial infarction or other evidence of arterial thrombotic disease (angina) will be allowed on study only if they have had no evidence of active disease for at least 12 months prior to randomization. Patients with any history of cerebral vascular accident (CVA) or transient ischemic attack (TIA) will not be allowed on trial. Women must not be pregnant or breast-feeding due to potential harm to the fetus or infant from cytotoxic chemotherapy and the unknown risk from bevacizumab. It is also unknown if these agents are excreted into breast milk. All females of childbearing potential must have a blood or urine test within 2 weeks prior to randomization to rule out pregnancy. Female of child-bearing potential? _ (Yes or No) Date of blood or urine test: Both fertile men and women must agree to use adequate contraceptive measures during study treatment and for at least 6 months after completion of bevacizumab. Patients must not have any clinically significant ongoing, active or serious infection, symptomatic or uncontrolled congestive heart failure, symptomatic or uncontrolled cardiac arrhythmia or any other medical condition or psychiatric illness/social situations that would limit compliance with study requirements. Patients must have no history of bleeding diathesis or coagulopathy. All patients must have a documented BP with systolic < 150 and diastolic < 90 within 28 days of registration. Patients with known hypertension must be on a stable regimen of anti-hypertensive therapy. Patients receiving daily treatment with aspirin or non-steroidal anti-inflammatory agents (NSAIDS) are eligible. Treatment with dipyridamole (Persantine), ticlopine (Ticlid), clopidogrel (Plavix) and/or cilostazol (Pletal) is not allowed. Patients must have stopped taking any of these agents at least 7 days prior to randomization. Patients must not have serious non-healing wound, ulcer, bone fracture, or have undergone a major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to randomization OR core biopsy within 7 days prior to randomization. Patients must not have a history of abdominal fistula, gastrointestinal perforation or intra-abdominal abscess within 28 days prior to randomization. Patients must not have any anticipated major surgical procedure(s) during the course of the study. Patients must not have known hypersensitivity to Chinese hamster ovary cell products or other recombinant human antibodies. Patients may be on a stable regimen of therapeutic anticoagulation or may be receiving prophylactic anticoagulation of venous access devices, provided that coagulation studies meet entry criteria 3.8. Caution must be exercised for patients requiring anticoagulation, including treatment with low dose heparin or low molecular weight heparin for DVT prophylaxis while on study due to an increased risk of bleeding with bevacizumab. Patients with ongoing post-operative hemoptysis (defined as bright red blood of ½ teaspoon or more) are not eligible. Patients with pre-operative hemoptysis that has resolved post-operatively are eligible. Pemetrexed/Cisplatin Therapy Patients who will receive pemetrexed/cisplatin therapy must meet all eligibility criteria (3.1-3.23) as well as 3.24.1 and 3.24.2. Eastern Cooperative
Oncology Group
Revised 4/09, Addendum #6 3.24.1 Patients assigned to pemetrexed/Cisplatin therapy must NOT have squamous cell Does patient have squamous cell histology? No _ Yes _ (ineligible to receive pemetrexed/cisplatin therapy) 3.24.2 Calculated Creatinine Clearance must be obtained within 2 weeks of randomization and calculated CrCl must be > 45mL/min using the standard Cockcroft and Gault formula (See Appendix XIII), or the measured glomerular filtration rate (GFR) using the appropriate radiolabeled method (51-CrEDTA or Tc99m-DTPA) must be used to calculate CrCl . Is Calculated CrCl >/= 45mL/min? Yes No _ (if No, ineligible to receive pemetrexed/cisplatin therapy) Date of Test Does patient receiving pemetrexed/cisplatin meet all requirements? Yes _ No _ (patient ineligible to receive pemetrexed/cisplatin therapy) Physician Signature OPTIONAL:
This signature line is provided for use by institutions wishing to use the eligibility checklist as source documentation. Eastern Cooperative
Oncology Group
Revised 4/08, Addendum #5 Revised 5/09, Addendum #7 Revised 8/10, Addendum #8 Study Parameters
Pre-Study/ Eligibility Therapeutic Parameters Prior to surgical resection patients must have had adequate staging to rule out metastatic disease. (CT or equivalent scan of the thorax, CT/MRI of the brain as clinically indicated (strongly encouraged for all patients with IIIA disease), CT/US of liver/abdomen as clinically indicated, positron emission scanning (PET) as clinically indicated). These studies do not need to be repeated post-operatively unless this is clinically indicated. Prestudy CBC (with differential and platelet count) must be done 2 weeks before All required prestudy chemistries, as outlined in Section 3, must be done 2 weeks before randomization. Tests and Procedures cycle until end of Medical history/ Performance Status Toxicity Assessment9 Weight, blood pressure Serum Chemistries4 Calculation of Urine Creatinine Protein Smoking Status Survey Pathology and Surgical Biological Sample See Sections 7.2 and 10 Eastern Cooperative
Oncology Group
Revised 4/08, Addendum #5 Revised 4/09, Addendum #6 Revised 5/09, Addendum #7 Revised 8/10, Addendum #8 1. Pre-study evaluations that should be completed no earlier than 14 days prior to randomization include: CBC with Diff and Platelet Count; Serum Chemistries; Physical Exam*; Weight; B-HCG (as needed); Medical History/Concurrent Meds; UPC ratio; CXR; EKG**; INR,PT/PTT. Pre-reg BP must be done within 28 days of randomization and must be < 150/90. * PE may be done by PA/NP if included as sub-investigator. ** EKG should be obtained within 14 days of randomization if clinically indicated or if pre-operative test results are abnormal. If pre-operative EKG was normal and there is no indication of a change in cardiac condition a repeat EKG within 14 days is not mandatory. 2. Mandatory smoking status surveys (see Appendix V) are to be performed pre-study and every 3 months post- registration up to 12 months (optional urine dipstick tests may also be performed at these times). Refer to section 5.6 for additional information. 3. Serum or urine pregnancy test. Women of childbearing potential only drawn within 2 weeks of randomization to rule out pregnancy. 4. To include, at a minimum, sodium, potassium, chloride, BUN, creatinine, AST (SGOT) and/or ALT (SGPT), total bilirubin, alkaline phosphatase. Patients receiving pemetrexed should have creatinine clearance calculated with
these chemistry values (Cockroft/Gault formula [see Appendix XIII]) or should have a more definitive creatine
clearance test.
5. To include absolute neutrophil count, platelet count, hemoglobin. 6. More frequent testing is indicated if there is any suspicion of elevated values (i.e. patient is on low dose anticoagulation for a venous access device). 7. Urine analysis for calculation of urine protein:creatinine ratio (UPC ratio) should be performed at baseline and
prior to every other course of bevacizumab (or more frequently as indicated). Treatment may proceed if UPC ratio is < 3.5. NOTE: UPC ratio must be obtained prior to treatment. Treatment may proceed if a urine protein dip stick result is
0-1+, however the UPC ratio must still be determined. If results of urine protein dip stick are higher, hold bevacizumab until the UPC ratio is known. UPC ratio of spot urine is an estimation of the 24-hour urine protein excretion: a UPC ratio of 1 is roughly equivalent to a 24-hour urine protein of 1 g. UPC ratio is calculated using one of the following formulas: [urine protein]/[urine creatinine] – if both protein and creatinine are reported in mg/dL [(urine protein) x0.088]/[urine creatinine] – if urine creatinine is reported in mmol/L 8. It is strongly encouraged that disease recurrence be documented by biopsy. If there is a recurrence, it is also strongly encouraged that patients be fully restaged, including a CT scan of the thorax and abdomen, imaging (preferably MRI, but CT is acceptable) of the brain and a radionuclide bone scan or positron emission tomography (PET) scan. Additional scans may be necessary if RPLS is suspected on treatment (see Section 5.4.2.7). 9. After last dose of chemotherapy and/or bevacizumab: patients who experience an on-going study agent-related serious adverse event upon active treatment completion, or at discontinuation from the study, should be contacted by the investigator or his/her designee until the event is resolved or determined to be irreversible. [Refer to forms completion guidelines.] 10. To be completed every reporting period [every 3 months (90 days) if patient is <2 years from date of registration, every 6 months (180 days) if patient is 2-5 years from date of registration, and annually until 10 years from date of registration]. All patients, including those who discontinue protocol therapy early, will be followed for response until recurrence and for survival for 10 years from the date of registration. Chest x-rays are required per protocol at specific intervals. If a chest CT scan is obtained at the same intervals as the required chest x-ray, that chest x-ray may be omitted and the chest CT substituted as the required imaging at that interval. 11. Copies of the pathology and surgical reports with coversheet must be submitted. Refer to E1505 Forms Submission Schedule, which is in the E1505 Case Report Forms Packet. 12. [Deleted in Addendum #7] 13. Forms are required to be submitted for each assessment time-point; consult the forms submission schedule and completion guidelines for details. Rev. 4/08, 5/09, 14. Tests should be obtained within 24 hours prior to day of treatment with results known prior to day of treatment. Refer to section 5.4 for dose modifications. Labs that are drawn within 48 hours prior to treatment that are normal will be acceptable. 15. C1D1: Medical history/Concurrent Meds/Physical Exam/Performance Status is not required to be repeated for C1D1 when pre-registration assessments are within 5 days of C1D1. 16. Clinic visit is required every 6 weeks during 3 month post-treatment follow-up. For the remaining follow-ups (up to 1 year post-treatment), it is recommended that patient be seen every 6 weeks. However, a phone assessment may be substituted for every other 6 week visit.

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