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hypertension

The dose of bevacizumab should be held for resting SBP > 150 or resting DBP > 100 at the time of infusion. Dose should also be held for symptomatic hypertension regardless of grade or blood pressure level. Dose may be held for up to 4 weeks.  
| regardless of grade or blood pressure level. Dose may be held for up to 4 weeks.  No dose modifications for Grade 1-2 events. Grade 3 Medications should be used for blood pressure control. Ideal  goal for blood pressure is < 140/80. If a new anti-hypertensive  is to be added, the choice of drug is at the discretion of treating  physician. Prior experience with bevacizumab-associated  hypertension among carcinoid patients suggested  dihydrophyridine calcium channel blockers and alpha adrenergic  vasodilators were effective. In general, the dose of agents  should be maximized prior to changing or adding new agents.  Record any new anti-hypertensive added and whether blood  pressure was adequately controlled.  Recommended anti-hypertensives:   nifidipine (Procardia XL®, Adalat CC®) 30 to 90 mg q day   nicardipine (Cardine SR®) 30 to 60 mg BID   terazosin (Hytrin®) 2 to 10 mg per day   doxazosin (Cardura®) 1 to 2 mg q day  If HTN cannot be controlled with medications, remove patient  from protocol treatment.  Grade 4 e patient from protocol treatment Proteinuria [Proteinuria should be monitored by urine analysis for urine  protein creatinine (UPC) ratio prior to every other dose of  bevacizumab.]  UPC ratio < 3.5 Continue bevacizumab  UPC ratio ≥ 3.5 Hold bevacizumab until UPC recovers to <  3.5. If bevacizumab is held for > 8 weeks due  to proteinuria, discontinue bevacizumab.  Grade 4 or  nephrotic  syndrome Discontinue bevacizumab  Wound dehiscence requiring medical  Discontinue bevacizumab  or surgical intervention GI perforation, GI leak or fistula Discontinue bevacizumab  Hemoptysis ≥ Grade 2 Discontinue bevacizumab   |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
| Hemorrhage                                                                                            | Grade 3                                                                                                                                                                                                                                                                                                                                           |                                                                        | Patients receiving full-dose  anticoagulation should discontinue  bevacizumab.   |
|-------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------|----------------------------------------------------------------------------------|
|                                                                                                      | For patients not on full-dose  anticoagulation, hold bevacizumab until  ALL of the following criteria are met:  - the bleeding has resolved and Hb is  stable  - there is no bleeding diathesis that  would increase the risk of therapy  - there is no anatomic or pathologic  condition that could increase the risk  of hemorrhage recurrence. |                                                                         |                                                                                  |
|                                                                                                      | Patients who experience recurrence of  Grade 3 hemorrhage should discontinue  bevacizumab.                                                                                                                                                                                                                                                        |                                                                         |                                                                                  |
| Grade 4                                                                                               | Discontinue bevacizumab                                                                                                                                                                                                                                                                                                                           |                                                                         |                                                                                  |
| Other clinically  significant AEs  attributable to  bevacizumab  (except controlled  nausea/vomiting) | Grade 3                                                                                                                                                                                                                                                                                                                                           | Hold bevacizumab for up to 4 weeks until  symptoms resolve to ≤ Grade 1 |                                                                                  |
| Grade 4                                                                                               |                                                                                                                                                                                                                                                                                                                                                  | Discontinue bevacizumab                                                 |                                                                                  |
|                                                                                                      | Upon consultation with the Study  Coordinator, resumption of bevacizumab  may be considered if a patient is benefiting  from therapy, and the Grade 4 toxicity is  transient, has recovered to ≤ Grade 1  within 4 weeks and is unlikely to recur with  retreatment.                                                                              |                                                                         |                                                                                  |
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8.6 g-csf usage

G-CSF (Amgen) has been licensed by the Food and Drug Administration for the prevention of chemotherapy induced neutropenia and may be used according to clinical practice guidelines. It may be used for patients who develop Grade 3 - 4 neutropenia. For patients who experience Grade 3 or 4 neutropenia or develop neutropenic fever between cycles of chemotherapy, G-CSF may be added to all subsequent cycles of chemotherapy. G-CSF is commercially available and should be purchased through third party mechanisms. The NCI will not provide G-CSF for this study. If G-CSF is used, it is recommended that it be used in the following manner:
If a patient develops neutropenia following chemotherapy, all dose modifications outlined in the protocol will be followed according to the original protocol. However, G-CSF will be added to all subsequent cycles of chemotherapy, unless there is clinical suspicion that the neutropenia was due to an unrelated medical condition and not due to the chemotherapy.  
If the patient maintains an ANC of ≥ 1,000/mm3 throughout the initial cycle of G-CSF
supported chemotherapy, then the next cycle of chemotherapy may be increased back to the original dose level with the continued support of the G-CSF. **No dose escalations**
above the original dose level should be performed on patients taking G-CSF.  
G-CSF will be given at a dose of 5 mcg/kg/d subcutaneously beginning 24 hours after completion of chemotherapy and continuing until the ANC exceeds 1,000/mcl on two successive determinations. Doses may be rounded off to the nearest vial size (300 mcg and 480 mcg vials). G-CSF should be discontinued at least 24 hours before the next chemotherapy dose. While the patient is receiving G-CSF, the CBC should be monitored at least twice a week (more frequently if clinically indicated). NOTE: Neulasta™ (pegfilgrastim) is allowed in the place of G-CSF. The dose is 6 mg given once, 24 hours after chemotherapy. While the patient is receiving Neulasta™, the CBC should be monitored weekly. The use of G-CSF or pegfilgrastim must be documented on the **S0819** Treatment Form.  
8.7 G-CSF Dose Modifications
Dose adjustments for toxicities associated with G-CSF (bone pain, splenomegaly, abnormalities in uric acid concentrations, LDH and alkaline phosphatase, transient elevations of serum creatinine and aminotransferase activity) Dose modifications for G-CSF toxicity should only be initiated if symptomatic control of the toxicity fails (i.e., analgesics such as acetaminophen or acetaminophen with codeine for myalgias or bone pain, etc.).  
| Toxicity Grade   | Dose Adjustment              |
|------------------|------------------------------|
| Grade 0 - 1      | No change                    |
| Grade 2          | Decrease G-CSF to 3 mcg/kg/d |
| Grade 3 - 4      | Discontinue G-CSF            |
|                  |                              |  
8.8 Dose Modifications for Non-Hematologic Toxicity In the event of any other (except nausea and vomiting) Grade 3 or 4 non-hematologic toxicity not discussed above, **hold all protocol treatment and discuss** with one of the Study Coordinators listed in Section 8.9.  
8.9 Dose Modification Contacts
For treatment or dose modification related questions, please contact any of the following Study Coordinators: Dr. Herbst at 203/785-6879 or roy.herbst@yale.edu, Dr. Kim at 980/442-3105 or edward.kim@carolinashealthcare.org or Dr. Semrad at 916/734-3771 or thomas.semrad@ucdmc.ucdavis.edu.
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8.10 adverse event reporting

Toxicities (including suspected reactions) that meet the expedited reporting criteria as outlined in Section 16.0 of the protocol must be reported to the Operations Office, Study Coordinator and NCI via CTEP-AERS, and to the IRB per local IRB requirements.
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9.0 study calendar

9.1 Study Calendar - ARM 1a - Chemotherapy plus Bevacizumab without Cetuximab  
|                                         | Off TX F/U Prior to Prog ƒ ¶   | Off TX F/U After Prog  ƒ   |         |         |           |               |    |     |       |     |          |       |    |       |    |    |
|-----------------------------------------|--------------------------------|----------------------------|---------|---------|-----------|---------------|----|-----|-------|-----|----------|-------|----|-------|----|----|
| Cycle 1                                 | Cycle 2                        | Cycle 3                    | Cycle 4 | Cycle 5 | Cycle 6 √ | Cont'd TX √ ≠ |    |     |       |     |          |       |    |       |    |    |
| REQUIRED STUDIES                        | PRE                            | W W W                      | W       | W W     | W         | W W           | W  | W   | W     | W   | W W W    | W     | W  | W     | W  | W  |
| STUDY 1 2                               | 3                              | 4                          | 5       | 6       | 7         | 8             | 9  | 10  | 11 12 | 13  | 14 15 16 | 17 18 | 19 | 20 21 |    |    |
| PHYSICAL                                |                                |                            |         |         |           |               |    |     |       |     |          |       |    |       |    |    |
| H&P                                     | X                              | X ß                        |         | X ß     |           | X ß           |    | X ß |       | X ß |          | X ß   |    | X     | X  |    |
| Wt & PS                                 | X                              | X ß                        |         | X ß     |           | X ß           |    | X ß |       | X ß |          | X ß   |    | X     | X  |    |
| Disease  Assessment ¶                   | X                              | X ß                        |         | X ß     |           | X ß           |    | X   |       |     |          |       |    |       |    |    |
| Toxicity  Notation                      | X                              |                            | X       |         | X         |               | X  |     | X     |     | X        |       | X  | X     |    |    |
| LABORATORY                              |                                |                            |         |         |           |               |    |     |       |     |          |       |    |       |    |    |
| CBC/Diff/Platelets £                    | X                              | X                          |         | X       |           | X             |    | X   |       | X   |          | X     |    | X     | X  |    |
| Serum Creatinine ¤                      | X                              | X                          |         | X       |           | X             |    | X   |       | X   |          | X     |    | X     | X  |    |
| Calc or Meas CrCL ¤                     | X                              | X                          |         | X       |           | X             |    | X   |       | X   |          | X     | X  |       |    |    |
| UPC (Urine Protein  Creatinine) Ratio π | X                              | X                          |         | X       |           | X             |    | X   |       |     |          |       |    |       |    |    |
| Total Bilirubin §                       | X                              | X                          |         | X       |           | X             |    | X   |       | X   |          | X     |    | X     | X  |    |
| SGOT or SGPT §                          | X                              | X                          |         | X       |           | X             |    | X   |       | X   |          | X     |    | X     | X  |    |
| Alk Phos ∞                              | X                              | X                          |         | X       |           | X             |    | X   |       | X   |          | X     |    | X     | X  |    |
| INR                                     | X                              |                            |         |         |           |               |    |     |       |     |          |       |    |       |    |    |
| Albumin ∞                               | X                              | X                          |         | X       |           | X             |    | X   |       | X   |          | X     |    | X     | X  |    |
| LDH ∞                                   | X                              | X                          |         | X       |           | X             |    | X   |       | X   |          | X     |    | X     | X  |    |
| Serum Sodium, Calcium                   |                                |                            |         |         |           |               |    | X   | X     |     |          |       |    |       |    |    |
| & Magnesium † ∞                         | X                              | X                          | X       | X       | X         | X             | X  |     |       |     |          |       |    |       |    |    |
| SPECIMEN/IMAGE  SUBMISSION              |                                |                            |         |         |           |               |    |     |       |     |          |       |    |       |    |    |
| Plasma Submission *                     | X                              | X                          |         | X       | X         |               |    |     |       |     |          |       |    |       |    |    |
| Tissue Submission *                     | X                              |                            |         |         |           |               |    |     |       |     |          |       |    |       |    |    |
| Image Submission &                      | X                              | X                          |         | X       |           | X             |    | X   |       |     |          |       |    |       |    |    |  
Calendar continued on next page. Click here for footnotes.  
| Off TX F/U After Prog  ƒ            |         |             |         |         |         |           |               |    |             |       |     |       |                              |    |
|-------------------------------------|---------|-------------|---------|---------|---------|-----------|---------------|----|-------------|-------|-----|-------|------------------------------|----|
| REQUIRED STUDIES                    | PRE     | W W W W W W | W       | W W     | W       | W         | W             | W  | W           | W W W | W   | W     | W                            | W  |
| STUDY 1 2 3                         | 4       | 5           | 6       | 7       | 8       | 9         | 10 11 12      | 13 | 14 15 16 17 | 18    | 19  | 20 21 |                              |    |
| SCANS                               |         |             |         |         |         |           |               |    |             |       |     |       |                              |    |
| CT or MRI for Disease  Assessment ¶ | X       | X ß         |         | X ß     |         | X ß       |               | X  |             |       |     |       |                              |    |
| Brain CT/MRI                        | X       |             |         |         |         |           |               |    |             |       |     |       |                              |    |
| Bone Scan Ω                         | X       |             |         |         |         |           |               |    |             |       |     |       |                              |    |
| EKG ¥                               | X       |             |         |         |         |           |               |    |             |       |     |       |                              |    |
| TREATMENT ∆                         |         |             |         |         |         |           |               |    |             |       |     |       |                              |    |
| Carboplatin                         | X       | X           |         | X       |         | X         |               | X  |             | X     |     |       |                              |    |
| Paclitaxel                          | X       | X           |         | X       |         | X         |               | X  |             | X     |     |       |                              |    |
| Bevacizumab √ %                     | X       | X           |         | X       |         | X         |               | X  |             | X     | X √ |       | Off TX F/U Prior to Prog ƒ ¶ |    |
| 9.1 (contd.)                        | Cycle 1 | Cycle 2     | Cycle 3 | Cycle 4 | Cycle 5 | Cycle 6 √ | Cont'd TX √ ≠ |    |             |       |     |       |                              |    |  
Note: Forms are found on the protocol abstract page of the SWOG website (www.swog.org). Forms submission guidelines are found in Section 14.0.  
∞ Results of these tests do not determine eligibility but are recommended prior to registration, during treatment and throughout follow-up in accordance with Good Medical Practice (see Section 7.1).  
† In the event of hypomagnesemia, more frequent monitoring and magnesium repletion should be instituted as per routine clinical practice. ¶ CT or MRI (the same method used at prestudy to meet the eligibility criteria in Section 5.1b must be repeated every 6 weeks until disease progression. After 9 months from registration, the frequency of this scan may be reduced to every 3 months until disease progression.  
¤ Calculated CrCl based on creatinine level obtained within 3 days prior to each dose is required to determine carboplatin dose. * See Section 15.0. & Submit scans to QARC as outlined in Sections 15.4 and Appendix 18.6. § SGOT or SGPT and bilirubin is required within 7 days prior to each dose of paclitaxel/carboplatin. Ω This test is required prestudy for Good Medical Practice only if clinically indicated. It is recommended to be performed during treatment if clinically indicated. £ CBC should be obtained more frequently if patient is on G-CSF, per Section 8.6. √ After completion of Cycle 6 and if the patient has not met criteria outlined in Section 7.8, bevacizumab will be continued until one of the criteria in Section 7.8 is met. Patients who are bevacizumab inappropriate are removed from protocol treatment at this time.  
ƒ After off treatment, patients should be followed by repeating indicated laboratory tests every 3 months for the first year, then every 6 months for up to 3 years from the date of registration.  
∆ See Sections 7.2 and 7.3. % Bevacizumab will be given only if patient is determined to be bevacizumab-appropriate. π After beginning treatment, UPC ratio required with alternate cycles only for patients who are receiving bevacizumab. ß To be performed within 7 days prior to starting cycle. ¥ This test is required prestudy for Good Medical Practice (see Section 7.1 for guidance on timing and interpretation of these test results). ≠ During continued treatment, items marked under physical and laboratory should be performed at every subsequent bevacizumab treatment (every 3 weeks).  
Disease assessments and image submission are to take place every 6 weeks.  
9.2 ARM 1b - Chemotherapy without Cetuximab  
  
  
|                                        | Cycle 1   | Cycle 2   | Cycle 3   | Cycle 4   | Cycle 5   | Cycle 6   | Off TX F/U   | Off TX F/U   |     |       |       |          |    |       |
|----------------------------------------|-----------|-----------|-----------|-----------|-----------|-----------|--------------|--------------|-----|-------|-------|----------|----|-------|
| Prior to Prog ƒ ¶ After Prog ƒ         |           |           |           |           |           |           |              |              |     |       |       |          |    |       |
| REQUIRED STUDIES                       | PRE       | W W W     | W         | W W       | W         | W W       | W            | W            | W   | W W W | W     | W        | W  |       |
| STUDY                                  | 1         | 2         | 3         | 4         | 5         | 6         | 7            | 8            | 9   | 10    | 11 12 | 13 14 15 | 16 | 17 18 |
| PHYSICAL                               |           |           |           |           |           |           |              |              |     |       |       |          |    |       |
| H&P                                    | X         | X ß       |           | X ß       |           | X ß       |              | X ß          | X ß |       | X     | X        |    |       |
| Wt & PS                                | X         | X ß       |           | X ß       |           | X ß       |              | X ß          | X ß |       | X     | X        |    |       |
| Disease  Assessment ¶                  | X         | X ß       |           | X ß       | X         |           |              |              |     |       |       |          |    |       |
| Toxicity  Notation                     | X         |           | X         |           | X         |           | X            | X            |     | X     | X     |          |    |       |
| LABORATORY                             |           |           |           |           |           |           |              |              |     |       |       |          |    |       |
| CBC/Diff/Platelets £                   | X         | X         |           | X         |           | X         |              | X            | X   |       | X     | X        |    |       |
| Serum Creatinine ¤                     | X         | X         |           | X         |           | X         |              | X            | X   |       | X     | X        |    |       |
| Calc or Meas CrCL ¤                    | X         | X         |           | X         |           | X         |              | X            | X   |       | X     | X        |    |       |
| Total Bilirubin §                      | X         | X         | X         | X         | X         | X         | X            | X            |     |       |       |          |    |       |
| SGOT or SGPT §                         | X         | X         | X         | X         | X         | X         | X            | X            |     |       |       |          |    |       |
| Alk Phos ∞                             | X         | X         | X         | X         | X         | X         | X            | X            |     |       |       |          |    |       |
| INR                                    | X         |           |           |           |           |           |              |              |     |       |       |          |    |       |
| Albumin ∞                              | X         | X         |           | X         |           | X         |              | X            | X   |       | X     | X        |    |       |
| LDH ∞                                  | X         | X         |           | X         |           | X         |              | X            | X   |       | X     | X        |    |       |
| Serum Sodium, Calcium  & Magnesium † ∞ | X         | X         |           | X         |           | X         |              | X            | X   |       | X     | X        |    |       |
| SPECIMEN/IMAGE  SUBMISSION             |           |           |           |           |           |           |              |              |     |       |       |          |    |       |
| Plasma Submission *                    | X         | X         |           | X         | X         |           |              |              |     |       |       |          |    |       |
| Tissue Submission *                    | X         |           |           |           |           |           |              |              |     |       |       |          |    |       |
| Image Submission &                     | X         | X         |           | X         | X         |           |              |              |     |       |       |          |    |       |  
Calendar continued on next page. Click here for footnotes S0819 Page 66 Version Date 10/3/16  
| 9.2 (contd.)                   | Cycle 1   | Cycle 2     | Cycle 3   | Cycle 4   | Cycle 5   | Cycle 6 √   | Off TX F/U   | Off TX F/U   |    |          |                   |
|--------------------------------|-----------|-------------|-----------|-----------|-----------|-------------|--------------|--------------|----|----------|-------------------|
| Prior to Prog ƒ ¶ After Prog ƒ |           |             |           |           |           |             |              |              |    |          |                   |
| REQUIRED STUDIES               | PRE       | W W W W W W | W         | W W W     | W         | W           | W W W        | W            | W  | W        |                   |
| STUDY                          | 1         | 2           | 3         | 4         | 5         | 6           | 7            | 8            | 9  | 10 11 12 | 13 14 15 16 17 18 |
| SCANS                          |           |             |           |           |           |             |              |              |    |          |                   |
| CT or MRI for Disease          | X         | X ß         |           | X ß       |           |             |              |              |    |          |                   |
| Assessment ¶                   | X         |             |           |           |           |             |              |              |    |          |                   |
| Brain CT/MRI                   | X         |             |           |           |           |             |              |              |    |          |                   |
| Bone Scan Ω                    | X         |             |           |           |           |             |              |              |    |          |                   |
| EKG ¥                          | X         |             |           |           |           |             |              |              |    |          |                   |
| TREATMENT ∆                    |           |             |           |           |           |             |              |              |    |          |                   |
| Carboplatin                    | X         | X           | X         | X         | X         | X           |              |              |    |          |                   |
| Paclitaxel                     | X         | X           | X         | X         | X         | X           |              |              |    |          |                   |  
Note: Forms are found on the protocol abstract page of the SWOG website (www.swog.org). Forms submission guidelines are found in Section 14.0. ∞ Results of these tests do not determine eligibility but are recommended prior to registration, during treatment and throughout follow-up in accordance with Good Medical Practice (see Section 7.1).  
† In the event of hypomagnesemia, more frequent monitoring and magnesium repletion should be instituted as per routine clinical practice. ¶ CT or MRI (the same method used at prestudy to meet the eligibility criteria in Section 5.1b must be repeated every 6 weeks until disease progression.  
After 9 months from registration, the frequency of this scan may be reduced to every 3 months until disease progression.  
¤ Calculated CrCl based on creatinine level obtained within 3 days prior to each dose is required to determine carboplatin dose. * See Section 15.0. & Submit scans to QARC as outlined in Sections 15.4 and Appendix 18.6. § SGOT or SGPT and bilirubin are required within 7 days prior to each dose of paclitaxel/carboplatin. Ω This test is required prestudy for Good Medical Practice only if clinically indicated. It is recommended to be performed during treatment if clinically indicated.  
£ CBC should be obtained more frequently if patient is on G-CSF, per Section 8.6. ƒ After off treatment, patients should be followed by repeating indicated laboratory tests every 3 months for the first year, then every 6 months for up to 3 years from the date of registration.  
∆ See Sections 7.2 and 7.3. ß To be performed within 7 days prior to starting cycle. ¥ This test is required prestudy for Good Medical Practice (see Section 7.1 for guidance on timing and interpretation of these test results).  
  
9.3 ARM 2a - Chemotherapy plus Bevacizumab with Cetuximab  
|                                                            | Cycle 1                      | Cycle 2   | Cycle 3   | Cycle 4   | Cycle 5   | Cycle 6 √   | Cont'd TX   | Off TX F/U   | Off TX F/U   |     |          |       |    |       |    |    |    |    |    |    |    |    |
|------------------------------------------------------------|------------------------------|-----------|-----------|-----------|-----------|-------------|-------------|--------------|--------------|-----|----------|-------|----|-------|----|----|----|----|----|----|----|----|
| √ ≠                                                        | Prior to Prog ƒ After Prog ƒ |           |           |           |           |             |             |              |              |     |          |       |    |       |    |    |    |    |    |    |    |    |
| REQUIRED STUDIES                                           | PRE                          | W W W     | W         | W W       | W         | W W         | W           | W            | W            | W   | W W W    | W     | W  | W     | W  | W  |    |    |    |    |    |    |
| STUDY 1 2                                                  | 3                            | 4         | 5         | 6         | 7         | 8           | 9           | 10           | 11 12        | 13  | 14 15 16 | 17 18 | 19 | 20 21 |    |    |    |    |    |    |    |    |
| PHYSICAL                                                   |                              |           |           |           |           |             |             |              |              |     |          |       |    |       |    |    |    |    |    |    |    |    |
| H&P                                                        | X                            | X ß       |           | X ß       |           | X ß         |             | X ß          |              | X ß |          | X ß   |    | X     | X  |    |    |    |    |    |    |    |
| Vital Signs Only $                                         | X X                          | X         | X         | X         | X         | X           | X           | X            | X            | X   | X        | X     | X  | X     | X  | X  | X  | X  | X  | X  | X  | X  |
| Wt & PS                                                    | X                            | X ß       | X ß       | X ß       | X ß       |             | X ß         | X ß          | X            | X   |          |       |    |       |    |    |    |    |    |    |    |    |
| Disease  Assessment ¶                                      | X                            | X ß       |           | X ß       |           | X ß         |             | X            |              |     |          |       |    |       |    |    |    |    |    |    |    |    |
| Toxicity  Notation $                                       | X                            |           | X         |           | X         |             | X           |              | X            |     | X        |       | X  | X     |    |    |    |    |    |    |    |    |
| LABORATORY                                                 |                              |           |           |           |           |             |             |              |              |     |          |       |    |       |    |    |    |    |    |    |    |    |
| CBC/Diff/Platelets £                                       | X                            | X         |           | X         |           | X           |             | X            |              | X   |          | X     |    | X     | X  |    |    |    |    |    |    |    |
| Serum Creatinine ¤                                         | X                            | X         |           | X         |           | X           |             | X            |              | X   |          | X     |    | X     | X  |    |    |    |    |    |    |    |
| Calc or Meas CrCL ¤                                        | X                            | X         | X         | X         | X         |             | X           | X            | X            |     |          |       |    |       |    |    |    |    |    |    |    |    |
| UPC (Urine Protein  Creatinine) Ratio π                    | X                            | X         |           | X         |           | X           |             | X            |              |     |          |       |    |       |    |    |    |    |    |    |    |    |
| Total Bilirubin §                                          | X                            | X         |           | X         |           | X           |             | X            |              | X   |          | X     |    | X     | X  |    |    |    |    |    |    |    |
| SGOT or SGPT §                                             | X                            | X         | X         | X         | X         |             | X           | X            | X            | X   |          |       |    |       |    |    |    |    |    |    |    |    |
| Alk Phos ∞                                                 | X                            |           | X         | X         | X         | X           |             | X            | X            | X   | X        |       |    |       |    |    |    |    |    |    |    |    |
| INR                                                        | X                            |           |           |           |           |             |             |              |              |     |          |       |    |       |    |    |    |    |    |    |    |    |
| Albumin ∞                                                  | X                            | X         |           | X         |           | X           |             | X            |              | X   |          | X     |    | X     | X  |    |    |    |    |    |    |    |
| LDH ∞                                                      | X                            | X         |           | X         |           | X           |             | X            |              | X   |          | X     |    | X     | X  |    |    |    |    |    |    |    |
| Serum Sodium, Calcium  & Magnesium † ∞                     |                              |           |           |           |           |             |             | X            | X            |     |          |       |    |       |    |    |    |    |    |    |    |    |
| X                                                          | X                            | X         | X         | X         | X         | X           |             |              |              |     |          |       |    |       |    |    |    |    |    |    |    |    |
| SPECIMEN/IMAGE  SUBMISSION                                 |                              |           |           |           |           |             |             |              |              |     |          |       |    |       |    |    |    |    |    |    |    |    |
| Plasma Submission *                                        | X                            | X         |           | X         | X         |             |             |              |              |     |          |       |    |       |    |    |    |    |    |    |    |    |
| Tissue Submission *                                        | X                            |           |           |           |           |             |             |              |              |     |          |       |    |       |    |    |    |    |    |    |    |    |
| Image Submission &                                         | X                            | X         | X         |           | X         | X           |             |              |              |     |          |       |    |       |    |    |    |    |    |    |    |    |
| Calendar continued on next page. Click here for footnotes. |                              |           |           |           |           |             |             |              |              |     |          |       |    |       |    |    |    |    |    |    |    |    |  
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| 9.3 (contd.)                        | Cycle 1                        | Cycle 2     | Cycle 3   | Cycle 4   | Cycle 5   | Cycle 6 √   | Cont'd TX   | Off TX F/U   | Off TX F/U   |                |    |       |    |    |    |    |    |    |    |    |
|-------------------------------------|--------------------------------|-------------|-----------|-----------|-----------|-------------|-------------|--------------|--------------|----------------|----|-------|----|----|----|----|----|----|----|----|
| √ ≠                                 | Prior to Prog ƒ ¶ After Prog ƒ |             |           |           |           |             |             |              |              |                |    |       |    |    |    |    |    |    |    |    |
| REQUIRED STUDIES                    | PRE                            | W W W W W W | W         | W W W     | W         | W           | W           | W            | W W W        | W              | W  | W     | W  |    |    |    |    |    |    |    |
| STUDY 1 2                           | 3                              | 4           | 5         | 6         | 7         | 8           | 9           | 10 11 12     | 13           | 14 15 16 17 18 | 19 | 20 21 |    |    |    |    |    |    |    |    |
| SCANS                               |                                |             |           |           |           |             |             |              |              |                |    |       |    |    |    |    |    |    |    |    |
| CT or MRI for Disease  Assessment ¶ | X                              | X ß         |           | X ß       |           | X ß         |             | X            |              |                |    |       |    |    |    |    |    |    |    |    |
| Brain CT/MRI                        | X                              |             |           |           |           |             |             |              |              |                |    |       |    |    |    |    |    |    |    |    |
| Bone Scan Ω                         | X                              |             |           |           |           |             |             |              |              |                |    |       |    |    |    |    |    |    |    |    |
| EKG ¥                               | X                              |             |           |           |           |             |             |              |              |                |    |       |    |    |    |    |    |    |    |    |
| TREATMENT ∆                         |                                |             |           |           |           |             |             |              |              |                |    |       |    |    |    |    |    |    |    |    |
| Carboplatin                         | X                              | X           |           | X         |           | X           |             | X            |              | X              |    |       |    |    |    |    |    |    |    |    |
| Paclitaxel                          | X                              | X           | X         | X         | X         |             | X           |              |              |                |    |       |    |    |    |    |    |    |    |    |
| Cetuximab √                         | X X                            | X           | X         | X         | X         | X           | X           | X            | X            | X              | X  | X     | X  | X  | X  | X  | X  | X√ | X  | X  |
| Bevacizumab √ %                     | X                              | X           | X         | X         | X         |             | X           | X √          |              |                |    |       |    |    |    |    |    |    |    |    |  
NOTE: Forms are found on the protocol abstract page of the SWOG website (www.swog.org). Forms submission guidelines are found in Section 14.0.  
Click here for footnotes.
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calendar 9.3 footnotes

∞ Results of these tests do not determine eligibility but are recommended prior to registration, during treatment and throughout follow-up in accordance with Good Medical Practice (see Section 7.1).  
† In the event of hypomagnesemia, more frequent monitoring and magnesium repletion should be instituted as per routine clinical practice. ¶ CT or MRI (the same method used at prestudy to meet the eligibility criteria in Section 5.1b must be repeated every 6 weeks until disease progression. After 9 months from registration, the frequency of this scan may be reduced to every 3 months until disease progression.  
¤ Calculated CrCl based on creatinine level obtained within 3 days prior to each dose is required to determine carboplatin dose. * See Section 15.0. & Submit scans to QARC as outlined in Sections 15.4 and Appendix 18.6. § SGOT or SGPT and bilirubin are required within 7 days prior to each dose of paclitaxel/carboplatin. Ω This test is required prestudy for Good Medical Practice only if clinically indicated. It is recommended to be performed during treatment if clinically indicated. £ CBC should be obtained more frequently if patient is on G-CSF, per Section 8.6. √ After completion of Cycle 6 and if the patient has not met criteria outlined in Section 7.8, bevacizumab and cetuximab will be continued until one of the criteria in Section 7.8 is met.  
ƒ After off treatment, patients should be followed by repeating indicated laboratory tests every 3 months for the first year, then every 6 months for up to 3 years from the date of registration.  
∆ See Sections 7.2 and 7.3. $ Patients will have vital signs taken (before, during and after treatment) and will be evaluated for toxicities at each visit during cetuximab treatment (see Section 3.3c - "Administration of Cetuximab").  
% Bevacizumab will be given only if patient is determined to be bevacizumab-appropriate. π After beginning treatment, UPC ratio required with alternate cycles only for patients who are receiving bevacizumab. ß To be performed within 7 days prior to starting cycle. ¥ This test is required prestudy for Good Medical Practice (see Section 7.1 for guidance on timing and interpretation of these test results). ≠ During continued treatment, items marked under physical and laboratory should be performed at every subsequent bevacizumab treatment (every 3 weeks).  
Vital signs and toxicity notation should still be continued on a weekly basis according to the footnote labeled "$". Disease assessments and image submission are to take place every 6 weeks.  
| 9.4                                                        | ARM 2b - Chemotherapy with Cetuximab   | Off Tx  F/U Prior  To Prog ƒ   | Off Tx  F/U After   |         |         |           |                |        |       |    |                            |    |    |    |    |    |    |    |    |    |    |    |    |
|------------------------------------------------------------|----------------------------------------|--------------------------------|---------------------|---------|---------|-----------|----------------|--------|-------|----|----------------------------|----|----|----|----|----|----|----|----|----|----|----|----|
|                                                            | Cycle 1                                | Cycle 2                        | Cycle 3             | Cycle 4 | Cycle 5 | Cycle 6 √ | Continued Tx √ | Prog ƒ |       |    |                            |    |    |    |    |    |    |    |    |    |    |    |    |
| REQUIRED STUDIES                                           | PRE                                    | W W W                          | W                   | W W     | W       | W W       | W              | W      | W W W | W  | W                          | W  | W  | W  | W  | W  |    |    |    |    |    |    |    |
|                                                            | STUDY                                  | 1                              | 2                   | 3       | 4       | 5         | 6              | 7      | 8     | 9  | 10 11 12 13 14 15 16 17 18 | 19 | 20 | 21 |    |    |    |    |    |    |    |    |    |
| PHYSICAL                                                   |                                        |                                |                     |         |         |           |                |        |       |    |                            |    |    |    |    |    |    |    |    |    |    |    |    |
| History and Physical                                       | X                                      | Xß                             |                     | Xß      |         | Xß        |                | Xß     | Xß    |    | Xß                         |    | X  | X  |    |    |    |    |    |    |    |    |    |
| Vital Signs  Only $                                        | X                                      | X                              | X                   | X       | X       | X         | X              | X      | X     | X  | X                          | X  | X  | X  | X  | X  | X  | X  | X  | X  | X  | X  | X  |
| Weight and Performance Status                              | X                                      | Xß                             |                     | Xß      |         | Xß        |                | Xß     | Xß    |    | Xß                         |    | X  | X  |    |    |    |    |    |    |    |    |    |
| Disease Assessment ¶                                       | X                                      | X                              |                     | X       | X       | X         |                |        |       |    |                            |    |    |    |    |    |    |    |    |    |    |    |    |
| Toxicity  Notation $                                       | X                                      | X                              | X                   | X       | X       | X         | X              | X      | X     | X  | X                          | X  | X  | X  | X  | X  | X  | X  | X  | X  | X  | X  | X  |
| LABORATORY                                                 |                                        |                                |                     |         |         |           |                |        |       |    |                            |    |    |    |    |    |    |    |    |    |    |    |    |
| CBC/Differential/                                          | Platelets £                            | X                              | X                   |         | X       |           | X              |        | X     | X  |                            | X  | X  | X  |    |    |    |    |    |    |    |    |    |
| Serum Creatinine ¤                                         | X                                      | X                              |                     | X       |         | X         |                | X      | X     |    | X                          | X  | X  |    |    |    |    |    |    |    |    |    |    |
| Calc or Meas CrCL ¤                                        | X                                      | X                              |                     | X       |         | X         |                | X      | X     |    | X                          | X  |    |    |    |    |    |    |    |    |    |    |    |
| Total Bilirubin §                                          | X                                      | X                              |                     | X       |         | X         |                | X      | X     |    | X                          | X  | X  |    |    |    |    |    |    |    |    |    |    |
| SGOT or  SGPT §                                            | X                                      | X                              |                     | X       |         | X         |                | X      | X     |    | X                          | X  | X  |    |    |    |    |    |    |    |    |    |    |
| Alkaline Phosphatase ∞                                     | X                                      | X                              |                     | X       |         | X         |                | X      | X     |    | X                          | X  | X  |    |    |    |    |    |    |    |    |    |    |
| INR                                                        | X                                      |                                |                     |         |         |           |                |        |       |    |                            |    |    |    |    |    |    |    |    |    |    |    |    |
| Albumin ∞                                                  | X                                      | X                              |                     | X       |         | X         |                | X      | X     |    | X                          | X  | X  |    |    |    |    |    |    |    |    |    |    |
| LDH ∞                                                      | X                                      | X                              |                     | X       |         | X         |                | X      | X     |    | X                          | X  | X  |    |    |    |    |    |    |    |    |    |    |
| Serum Sodium , Calcium and  Magnesium †∞                   | X                                      | X                              |                     | X       |         | X         |                | X      | X     |    | X                          | X  | X  |    |    |    |    |    |    |    |    |    |    |
| Calendar continued on next page. Click here for footnotes. |                                        |                                |                     |         |         |           |                |        |       |    |                            |    |    |    |    |    |    |    |    |    |    |    |    |  
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| 9.4 (contd.)                                                                                                                                                            |         | Off Tx  F/U After   |         |         |         |           |                |        |    |    |                            |    |    |    |    |    |    |    |    |    |    |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------|---------------------|---------|---------|---------|-----------|----------------|--------|----|----|----------------------------|----|----|----|----|----|----|----|----|----|----|
|                                                                                                                                                                         | Cycle 1 | Cycle 2             | Cycle 3 | Cycle 4 | Cycle 5 | Cycle 6 √ | Continued Tx √ | Prog ƒ |    |    |                            |    |    |    |    |    |    |    |    |    |    |
| Off Tx  F/U Prior  To Prog ƒ                                                                                                                                            |         |                     |         |         |         |           |                |        |    |    |                            |    |    |    |    |    |    |    |    |    |    |
| REQUIRED STUDIES                                                                                                                                                        | PRE     | W W W W W W         | W       | W W W   | W       | W         | W W W          | W      | W  | W  | W                          | W  | W  |    |    |    |    |    |    |    |    |
|                                                                                                                                                                         | STUDY   | 1                   | 2       | 3       | 4       | 5         | 6              | 7      | 8  | 9  | 10 11 12 13 14 15 16 17 18 | 19 | 20 | 21 |    |    |    |    |    |    |    |
| SPECIMEN/                                                                                                                                                               |         |                     |         |         |         |           |                |        |    |    |                            |    |    |    |    |    |    |    |    |    |    |
| IMAGE SUBMISSION                                                                                                                                                        |         |                     |         |         |         |           |                |        |    |    |                            |    |    |    |    |    |    |    |    |    |    |
| Plasma Submission *                                                                                                                                                     | X       | X                   |         | X       | X       |           |                |        |    |    |                            |    |    |    |    |    |    |    |    |    |    |
| Tissue  Submission *                                                                                                                                                    | X       |                     |         |         |         |           |                |        |    |    |                            |    |    |    |    |    |    |    |    |    |    |
| Image  Submission &                                                                                                                                                     | X       | X                   |         | X       | X       | X         |                |        |    |    |                            |    |    |    |    |    |    |    |    |    |    |
| SCANS                                                                                                                                                                   |         |                     |         |         |         |           |                |        |    |    |                            |    |    |    |    |    |    |    |    |    |    |
| CT or MRI for disease assessment ¶                                                                                                                                      | X       | Xß                  |         | Xß      | Xß      |           | X              |        |    |    |                            |    |    |    |    |    |    |    |    |    |    |
| Brain CT/MRI                                                                                                                                                            | X       |                     |         |         |         |           |                |        |    |    |                            |    |    |    |    |    |    |    |    |    |    |
| Bone Scan                                                                                                                                                               | Ω       | X                   |         |         |         |           |                |        |    |    |                            |    |    |    |    |    |    |    |    |    |    |
| EKG                                                                                                                                                                     | ¥       | X                   |         |         |         |           |                |        |    |    |                            |    |    |    |    |    |    |    |    |    |    |
| TREATMENT ∆                                                                                                                                                             |         |                     |         |         |         |           |                |        |    |    |                            |    |    |    |    |    |    |    |    |    |    |
| Carboplatin                                                                                                                                                             | X       |                     | X       |         | X       |           | X              |        | X  | X  |                            |    |    |    |    |    |    |    |    |    |    |
| Paclitaxel                                                                                                                                                              | X       |                     | X       |         | X       |           | X              |        | X  | X  |                            |    |    |    |    |    |    |    |    |    |    |
| Cetuximab √                                                                                                                                                             | X       | X                   | X       | X       | X       | X         | X              | X      | X  | X  | X                          | X  | X  | X  | X  | X  | X  | X  | X√ | X  | X  |
| NOTE: All forms for this study can be found on the protocol abstract page of the SWOG website (www.swog.org). Form Submission Guidelines can be  found in Section 14.0. |         |                     |         |         |         |           |                |        |    |    |                            |    |    |    |    |    |    |    |    |    |    |  
NOTE: All forms for this study can be found on the protocol abstract page of the SWOG website (www.swog.org). Form Submission Guidelines can be found in Section 14.0.  
Click here for footnotes.
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calendar 9.4 footnotes.

∞ Results of these tests do not determine eligibility but are recommended prior to registration, during treatment and throughout follow-up in accordance with Good Medical Practice (see Section 7.1).  
† In the event of hypomagnesemia, more frequent monitoring and magnesium repletion should be instituted as per routine clinical practice. ¶ CT or MRI (the same method used at prestudy to meet the eligibility criteria in Section 5.1c) must be repeated every 6 weeks until disease progression. After 9 months from registration, the frequency of this scan may be reduced to every 3 months until disease progression.  
¤ Calculated CrCL based on creatinine level obtained within 3 days prior to each dose is required to determine carboplatin dose. * See Section 15.0. & Submit scans to QARC as outlined in Sections 15.4 and Appendix 18.6. § SGOT or SGPT and bilirubin is required within 7 days prior to each dose of paclitaxel/carboplatin. Ω This test is required prestudy for Good Medical Practice only if clinically indicated. It is recommended to be performed during treatment if clinically indicated. £ CBC should be obtained more frequently if patient is on G-CSF, per Section 8.6. √ After completion of Cycle 6 and if the patient has not met criteria outlined in Section 7.8, cetuximab will be continued until one of the criteria in Section 7.8 is met.  
ƒ After off treatment, patients should be followed by repeating indicated laboratory tests every 3 months for the first year, then every 6 months for up to 3 years from the date of registration.  
∆ See Sections 7.2 and 7.3. $ Patients will have vital signs taken (before, during and after treatment) and will be evaluated for toxicities at each visit during cetuximab treatment (see Section 3.3c - "Administration of Cetuximab").  
ß To be performed within 7 days prior to starting cycle. ¥ This test is required prestudy for Good Medical Practice (see Section 7.1 for guidance on timing and interpretation of these test results).
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10.1 measurability of lesions 10.2

a. **Measurable disease**: Lesions that can be accurately measured in at least one dimension by 1) medical photograph (skin or oral lesion), palpation, plain x-ray, CT, MRI or other conventional technique with longest diameter 2 cm or greater in the axial plane (bone lesions not included), or 2) spiral CT with longest diameter 1 cm or greater. Ultrasound is suitable only for superficial disease (superficial palpable nodes, subcutaneous lesions, thyroid nodules). Conventional CT and MRI should be performed with cuts of 10 mm or less in slice thickness contiguously. Spiral CT should be performed using a 5 mm contiguous reconstruction algorithm.  
b. **Non-measurable disease**: All other lesions including lesions too small to be considered measurable, pleural or pericardial effusions, ascites, bone disease, inflammatory breast disease, leptomeningeal disease, lymphangitis, pulmonitis, abdominal masses not confirmed and followed by imaging techniques, cystic lesions or disease documented by indirect evidence only (e.g., by lab values), previously radiated lesions that have not progressed.
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10.0 criteria for evaluation and

Objective status at each evaluation: Objective Status is to be recorded at each evaluation. All measurable lesions up to a maximum of 5 lesions per organ and 10 lesions in total, representative of all involved organs, should be identified as target lesions at baseline. All measurable lesions not identified as target lesions are non-target lesions and are included as non-measurable disease. Measurements must be provided for target measurable lesions, while presence or absence must be noted for non-target measurable and non-measurable disease. a. **Complete Response (CR)**: Complete disappearance of all measurable and non-measurable disease. No new lesions. No disease related symptoms. Normalization of markers and other abnormal lab values. All disease must be assessed using the same technique as baseline.  
b. **Partial Response (PR)**: Applies only to patients with at least one measurable lesion. Greater than or equal to 30% decrease under baseline of the sum of longest diameters of all target measurable lesions. No unequivocal progression of non-measurable disease. No new lesions. All target measurable lesions must be assessed using the same techniques as baseline.  
c. **Stable**: Does not qualify for CR, PR, Progression or Symptomatic Deterioration.  
All target measurable lesions must be assessed using the same techniques as baseline.  
d. **Progression**: One or more of the following must occur: 20% increase in the sum of longest diameters of target measurable lesions over smallest sum observed (over baseline if no decrease during therapy) using the same techniques as baseline. Unequivocal progression of non-measurable disease in the opinion of the treating physician (an explanation must be provided). Appearance of any new lesion/site. Death due to disease without prior documentation of progression and without symptomatic deterioration (see Section 10.2e).  
e. **Symptomatic deterioration**: Global deterioration of health status requiring discontinuation of treatment without objective evidence of progression. Efforts should be made to obtain objective evidence of progression after discontinuation.  
f. **Assessment inadequate, objective status unknown**: Progression or symptomatic deterioration has not been documented, and one or more target measurable lesions have not been assessed or inconsistent assessment methods were used.  
g. Objective status notes:  
1. Non-measurable and non-target measurable disease do not affect objective status except in determination of CR (must be absent--a patient who otherwise has a CR, but who has non-measurable or non-target measurable disease present or not assessed, will be classified as having a PR), and in determination of progression (if new sites of disease develop or if unequivocal progression occurs in the opinion of the treating physician).  
2. An objective status of PR or stable cannot follow one of CR. Stable can follow PR only in the rare case that tumor increases too little to qualify as progression, but enough that a previously documented 30% decrease no longer holds.  
3. In cases for which initial flare reaction is possible (hypercalcemia, increased bone pain, erythema of skin lesions), objective status is not progression unless either symptoms persist beyond 4 weeks or there is additional evidence of progression.  
4. Lesions that appear to increase in size due to presence of necrotic tissue will not be considered to have progressed.  
5. For bone disease documented on bone scan only, increased uptake does not constitute unequivocal progression.  
6. Appearance or worsening of pleural effusions does not constitute unequivocal progression unless cytologically proven of neoplastic origin.  
7. If CR determination depends on a lesion for which the status is unclear by the required tests, it is recommended the residual lesion be investigated with biopsy or fine needle aspirate.
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10.3 best response

This is calculated from the sequence of objective statuses. a. CR: Two or more objective statuses of CR a minimum of four weeks apart documented before progression or symptomatic deterioration.  
b. PR: Two or more objective statuses of PR or better a minimum of four weeks apart documented before progression or symptomatic deterioration, but not qualifying as CR.  
c. Unconfirmed CR: One objective status of CR documented before progression or symptomatic deterioration but not qualifying as CR or PR.  
d. Unconfirmed PR: One objective status of PR documented before progression or symptomatic deterioration but not qualifying as CR, PR or unconfirmed CR.  
e. Stable/no response: At least one objective status of stable/no response documented at least 6 weeks after registration and before progression or symptomatic deterioration, but not qualifying as anything else above.  
f. Increasing disease: Objective status of progression within 12 weeks of registration, not qualifying as anything else above.  
g. Symptomatic deterioration: Objective status of symptomatic deterioration within 12 weeks of registration, not qualifying as anything else above.  
h. Inadequate assessment, response unknown: Progression or symptomatic deterioration greater than 12 weeks after registration and no other response category applies.
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10.4 performance status

Patients will be graded according to the Zubrod Performance Status Scale.
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point description

0 Fully active, able to carry on all pre-disease performance without restriction.  
1 Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light housework, office work.  
2 Ambulatory and capable of self-care but unable to carry out any work activities; up and about more than 50% of waking hours.  
3 Capable of limited self-care, confined to bed or chair more than 50% of waking hours.  
4 Completely disabled; cannot carry on any self-care; totally confined to bed or chair.  
10.5 Progression-Free Survival (Central-Review Based)
From date of randomization (which is the date of registration) to date of first documentation of progression based on Central Radiological Review of the appropriate CT or MRI scans, or symptomatic deterioration (as defined in Section 10.2.e), or development of new lesions or progression (as defined in Section 10.2d) documented by methods other than on CT or MRI, or death due to any cause. Patients who have a local assessment of progression based on CT/MRI imaging, but for whom central review does not concur, will be censored at the last imaging date, unless documentation by subsequent reviewed CT/MRI scans, methods other than CR or MRI, or symptomatic deterioration provides evidence of progression. Patients last known to be alive and progression-free are censored at the date of last contact.  
10.6 Progression-Free Survival
From date of registration to date of first documentation of progression or symptomatic deterioration (as defined in Sections 10.2d and 10.2e), or death due to any cause. Patients last known to be alive and progression-free are censored at date of last contact.
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10.7 time to death

From date of registration to date of death due to any cause. Patients last known to be alive are censored at date of last contact.
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11.0 statistical considerations 11.1 primary

Entire study population: The primary objective in the entire study population is to compare overall survival (OS) in advanced NSCLC patients treated with cetuximab chemotherapy plus bevacizumab (if appropriate) versus chemotherapy and bevacizumab (if appropriate). The addition of cetuximab will be judged to be superior if the true increase in median OS is 20%.  
EGFR FISH-positive cohort: The primary objective for this cohort is to compare progression-free survival (PFS) by institutional review in EGFR FISH-positive patients with advanced NSCLC treated with cetuximab-chemotherapy plus bevacizumab (if appropriate)
versus chemotherapy and bevacizumab (if appropriate). The addition of cetuximab will be judged to be superior if the true increase in median PFS is 33%.
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11.2 secondary endpoints

Secondary objectives include the comparison of OS and PFS by centralized review in the EGFR FISH-positive cohort, PFS (by centralized review and institutional review) in the entire cohort, and response and toxicity in both study populations (entire cohort and EGFR FISH-positive cohort) treated with cetuximab and chemotherapy and bevacizumab (if appropriate) versus chemotherapy and bevacizumab (if appropriate), as well as to compare other purported EGFR-related biomarkers to EGFR IHC and EGFR FISH and to patient outcomes. K-ras mutational testing will be performed and correlated to response and outcome. Analysis for EGFR FISH and KRAS mutational status will be evaluated at each interim analysis.
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11.3 h-score

Based on the FLEX trial, we assume that among patients with an IHC result, 26% will be determined to have a score > 200. Assuming 95% of patients with an EGFR FISH result will have sufficient tissue for IHC, then 20% of patients will be classified as H-score positive (>200), 1174 patients will have an IHC result, and 306 patients will be available for the analysis of the efficacy of cetuximab (as measured by OS and PFS) among patients with an IHC >200. Further, based on the FLEX trial we assume that IHC score is not prognostic for either outcome. It follows that this design has 82% power to detect a 40% improvement in median PFS using a 1-sided 0.025 level stratified log-rank test. This design also has 80% power to detect a 43% improvement in median OS using a 1-sided 0.025 level stratified log-rank test. If approximately 35% of patients positive for EGFR FISH also have an H-score > 200 (or equivalently 67% of H-score positive are EGFR FISH positive), then the expected numbers of patients in each biomarker category are as below:  
| No FISH result    | EGFR FISH -   | EGFR FISH +   | Total     |           |
|-------------------|---------------|---------------|-----------|-----------|
| No IHC result     | 310           | 31            | 31        | 372 (24%) |
| IHC H-score < 200 | --            | 486           | 382       | 868 (56%) |
| IHC H-score > 200 | --            | 101           | 205       | 306 (20%) |
| Total             | 310 (20%)     | 618 (40%)     | 618 (40%) | 1546      |  
11.4 Sample Size With Power Justification This design employs co-primary objectives with OS within the entire study population and PFS by institutional review as the primary outcome in the EGFR FISH-positive group. Interim testing for efficacy is based on both PFS by institutional review and OS in the EGFR FISH-positive group. As the hypothesis within the EGFR FISH-positive group is partially nested (since PFS and OS are correlated) within the entire study hypothesis, (1sided) testing of the EGFR FISH-positive hypothesis at the 0.02 level and the entire study hypothesis at the 0.015 level results in an overall level of 0.025 (determined via simulation).  
Based on published and unpublished data (Fred Hirsch, personal communication), we expect at least 81% of patients will have adequate specimen for testing. The assay failure rate is estimated to be approximately 2% (98% success rate). Finally we assume that the proportion among those with a EGFR FISH assay result determined positive is 50%.  
Therefore, the assumed rate of EGFR FISH-positive patients among all patients enrolled is 40% (= 81% * 98% *50%). We assume for 50% of patients it will be inappropriate to receive bevacizumab, and that the median PFS in this group is less than that in the bevacizumab-appropriate group. The null median PFS is assumed to be 6 months for the bevacizumab-appropriate group, based on data from **E4599**. The null median PFS is assumed to be 4 months, for the bevacizumab-inappropriate group based on data from **S0003**.  
EGFR FISH-positive cohort: A design with 92% power, 4 years accrual, 1 year of followup, requires 618 patients to detect a 33% improvement in median PFS, using a 0.02 1sided logrank test. This would require ~1,546 patients to be enrolled on study. Entire study population: Assuming 50% of patients are bevacizumab inappropriate, a median OS of 10 months in the bevacizumab-inappropriate stratum, and median OS of 12 months in the bevacizumab-appropriate stratum this design has 86% power to detect a 20% improvement in the entire cohort of 1,546 patients in median OS, using a 0.015 1sided level stratified logrank test. In summary: Entire study: 1,546 patients, EGFR FISH-positive: 618.  
11.5 Analysis Plan Including Plans for Formal Interim Analysis  
Primary analyses will be performed on an intent-to-treat basis. A (stratified) log-rank test at the 0.02 level will be used to test the primary hypothesis in the EGFR FISH-positive cohort and at the 0.015 level in the entire study to achieve an overall type I error rate of 0.025. A formal interim analysis will be done after 30% of the expected progression events in the control arm (87 progression events) in the EGFR FISH-positive cohort, approximately 21 months after the study opens, by which time about 266 EGFR FISH-positive patients and overall 665 patients will have entered into the study. Evidence suggesting early termination of the trial for superiority will only be formally assessed in the EGFR FISH
positive cohort and will be based on PFS and OS. Data on PFS and OS in the entire study population will be provided to the SWOG Data and Safety Monitoring Committee (DSMC). As such, in the EGFR FISH-positive cohort, the conclusion that the experimental arm is better than the control arm would be if the hypothesis of no difference in PFS were rejected at the one-sided 0.002 level and OS were rejected at the 0.004 level, or OS alone were rejected at 0.002 level. The level for OS is adjusted upward as the primary hypothesis within the FISH-positive cohort is PFS, but it is desired to establish a benefit in OS should the trial stop early for efficacy. The following table summarizes the conditions that are to be met for early stopping for superiority.  
| Table 1 Conditions for stopping for superiority  Reject null hypothesis:   | PFS        | OS   |    |
|----------------------------------------------------------------------------|------------|------|----|
| EGFR FISH-positive cohort                                                  | (P<  0.002 | and  | P< |
| 0.004)                                                                     |            |      |    |
|                                                                            | or         | P<   |    |
| 0.002                                                                      |            |      |    |
| Entire study cohort                                                        | N/A        | N/A  |    |  
If the conditions in Table 1 are met then the recommendation will be to stop the EGFR
FISH-positive group for efficacy. If at this time futility is not reached in the overall group and the EGFR FISH-positive group has been stopped, then the SWOG DSMC will consider all the evidence to determine if the study should continue in the EGFR FISH nonpositive group.  
Evidence suggesting early termination of the trial for futility will be formally assessed in the EGFR FISH-positive cohort and the entire study population. This assessment will be based on PFS in the EGFR FISH-positive cohort and based on PFS and OS in the entire study population For futility testing, the alternative hypothesis of at least 33% improvement in PFS for the experimental arm in the EGFR FISH-positive cohort will be tested at onesided level 0.002, using an extension of the logrank test that allows for testing a relative risk not equal to 1. Additionally, the alternative hypothesis of at least 20% improvement in PFS and OS for the experimental arm in the entire study population will be tested at onesided level 0.0015, also using the test that allows for testing a relative risk not equal to 1.  
Evidence suggesting early termination of the trial for futility will be that the alternative hypotheses are rejected for PFS in the EGFR FISH-positive cohort and PFS and OS in the entire study population. If the alternative hypotheses are rejected as specified above (PFS
in EGFR FISH-positive, PFS and OS in the entire study), this will be considered evidence suggesting early termination of the trial for futility. The following table summarizing the conditions that are to be met for early stopping for futility.  
| Table 2 Conditions for stopping for futility  Reject alternative hypothesis:   | PFS      | OS   |     |
|--------------------------------------------------------------------------------|----------|------|-----|
| EGFR FISH-positive cohort                                                      | P< 0.002 | and  | N/A |
| Entire study cohort                                                            | (P<      | or   | P<  |
| 0.0015                                                                         | 0.0015)  |      |     |  
Evidence suggesting early termination of the study in the non-EGFR FISH positive cohort will be assessed in the entire study population and the non-positive cohort and will be based on PFS and OS. For futility testing, the alternative hypothesis of at least 20% improvement in PFS and OS for the experimental arm in the entire study population will be tested at one-sided level 0.0025, using a test that allows for testing a relative risk not equal to 1. Also, for futility testing, the alternative hypothesis of at least 10% improvement in PFS and OS for the experimental arm in the EGFR FISH non-positive will be tested at one-sided level 0.0025, using a test that allows for testing a relative risk not equal to 1.  
Evidence suggesting early termination of the trial for futility will be that the alternative hypothesis is rejected for either PFS or OS in the EGFR FISH-positive cohort or the entire study population.  
| Table 3 Conditions for stopping EGFR FISH non-positive cohort for futility  Reject alternative hypothesis: PFS   | OS     |    |     |
|------------------------------------------------------------------------------------------------------------------|--------|----|-----|
| EGFR FISH non-positive cohort                                                                                    | P<     | or | P < |
| 0.0025                                                                                                           | 0.0025 |    |     |
| Entire study cohort                                                                                              | P<     | or | P < |
| 0.025                                                                                                            | 0.0025 |    |     |  
The actual decision to terminate accrual early will be made by the DSMC, and will consider K-ras mutations, response, toxicities and other factors in addition to PFS and OS. A second interim analysis is planned when 2/3 of the expected events in the control arm have occurred, which will be at approximately 39 months after the study opens, with roughly 199 events and an expected 500 accrued in the EGFR FISH-positive cohort and 1,250 overall. Testing of the null and alternative hypotheses will proceed as described for the first interim analysis. A third interim analysis is planned when 85% of the expected events in the control arm have occurred, which will be approximately 48 months after the study opens, with roughly 252 events and accrual to the study completed. Testing of the null and the alternative hypotheses will proceed as described for the first interim analysis. Should a study cohort be stopped at a previous interim analysis, the recommendation will be based on the rules associated with the current study population. If the decision is to continue the study, the final analysis will take place when at least 297 events in EGFR FISH-positive cohort have occurred, approximately 60 months after the study opens. The final analysis in the EGFR FISH-positive cohort will be at level 0.014 (one-sided test) to allow for the effects of interim testing. A modified Haybittle-Peto approach is used to determine alpha spending. The following table summarizes the expected number  
| Table 4 Description of planned interim and final analyses based on events in control arm  Time EGFR FISH-positive Overall Population Percent of:  (mo) # Prog # Deaths # Prog # Deaths Prog Deaths Accrual  21 89 59 223 148 30% 23% 43%  39 199 153 498 383 67% 59% 81%  48 252 207 630 518 85% 80% 100%  60 297 259 743 648 100% 100% 100%   |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
In addition to the EGFR FISH assay, K-ras will be assessed on the patient specimens for each interim analysis and as a planned subgroup analysis upon study completion. Planned analyses to assess the safety of cetuximab in patients with K-ras mutations are a comparison of OS and PFS by treatment arm using a stratified log-rank test. Analyses following the specifications for the entire study cohort will also be performed within the bevacizumab and non-bevacizumab treated patients to assess safety and efficacy/futility at each interim analysis and as a planned subgroup analysis upon study completion. These analyses will be provided to the SWOG DSMC. At each analysis, the design assumptions regarding proportions of EGFR FISH-positive patients, numbers of adequate specimens, and assay performance will be evaluated. The number of enrolled patients may be adjusted if the proportion of enrolled patients determined to be EGFR FISH-positive is different than expected to accrue 618 EGFR FISH-positive patients. Secondary analyses will also be done regarding OS in the EGFR FISH-positive cohort and PFS in the entire study (using a stratified log-rank test), and response and toxicity (using stratified chi-square tests). This design has 87% power to detect a 33% improvement in OS in the EGFR FISH-positive group using a 1-sided 0.02 level log-rank test. Additionally, this design has 91% power to detect a 20% improvement in PFS in the entire study population using a 1-sided 0.015 level log-rank test. With 309 patients per arm in the EGFR FISH-positive group, response and toxicity rates can be estimated to within at worst
± 6% (95% confidence interval). With 773 patients per arm in the entire study, response and toxicity rates can be estimated to within at worst ± 4% (95% confidence interval).  
The predictive effect of EGFR FISH will be assessed by testing an interaction between EGFR FISH status and treatment in the respective regression model among the 1,236 patients with a FISH result (80% of 1,546). Assuming EGFR FISH is not prognostic, this design has 58% power to detect a difference in hazard ratios for PFS (1.1 versus 1.33)
using a 1-sided 0.05 level log-rank test. Analyses will also be performed within the stratification factor grouping to assess treatment effects within each group. Supportive analyses of the effect of baseline characteristics on survival and progression free survival will be performed using Cox proportional hazards regression modeling. Similarly, the effect of baseline characteristics on response rate will be explored with logistic regression analysis. In addition to the stratification factors, other clinical covariates will include (but may not be limited to) age, gender, race and prior weight loss.
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11.6 amendment to design

S0819 was placed in temporary closure to further accrual on June 1, 2014. As of this date, 400 eligible EGFR FISH positive patients had been accrued to the study. Following review of the pre-specified second interim analysis, further accrual to the EGFR FISH nonpositive cohort was terminated upon the recommendation of the DSMC. Prior to this analysis and independent of the study data, the study team had planned to modify the study design with the EGFR FISH positive cohort due to a lower than anticipated percentage of patients defined to be EGFR FISH positive and lower than anticipated total accrual rate. The study design within the EGFR FISH positive cohort has been modified to a design with 80% power to detect a 33% improvement in median PFS. As result of the closure of the EGFR FISH non-positive cohort, the hypothesis within the overall population will not be tested and no type I error will be spent on that hypothesis. An additional specification is to change the overall type I error to 0.025 from 0.02 in the EGFR FISH positive cohort. The final level of testing will be performed at the 0.021 to account for the effects of interim testing (a change from 0.014). Testing will still be performed using a 1sided log-rank test. Given the modified design assumptions, 386 progression events are needed to detect a 33% improvement in median PFS with 80% power at the 1-sided 0.025 level. Due to logistical considerations, the study team determined it would be preferable to extend follow-up among the EGFR FISH positive patients instead of re-opening the study to further accrual in this population. The third interim analysis at 85% information has been dropped, as well. In order to achieve 386 events, the follow-up duration has been extended from 1 year to 2 years. The final analysis will occur upon the observation of 386 progression events in the EGFR FISH positive cohort or by June 2016, whichever comes first. All other analyses will proceed as previously specified. The following table summarizes the changes to the design.  
|                             | Original Design   | Modified Design   |
|-----------------------------|-------------------|-------------------|
| Alternative hypothesis (HR) | 1.33              | Same              |
| Power                       | 92%               | 80%               |
| Overall Type I error        | 0.02              | 0.025             |
| Number of interim analyses  | 3                 | 2                 |
| Final level of testing      | 0.014             | 0.021             |
| Follow-up duration          | 12 months         | 24 months         |
| PFS events at analysis      | 588               | 386               |
| Sample Size (eligible)      | 618               | 400               |  
11.7 Accrual Information Accrual Rate: 35-40 pts/month. **S0003** accrued approximately 240 patients/year and SWOG-9509 accrued approximately 300 patients per year in SWOG alone. This study will be available on the CTSU menu. With intergroup participation we anticipate accrual of approximately 400 patients per year.  
11.8 Data and Safety Monitoring Committee  
A Data and Safety Monitoring Committee will oversee the conduct of the study. The Committee consists of four members from outside of SWOG. Group members, 3 nonvoting representatives from the National Cancer Institute (NCI), and the Group Statistician
(non-voting). The members of this Committee will receive confidential reports every 6 months from the SWOG Statistical Center, and will meet at the Group's bi-annual meetings as necessary. The Committee will be responsible for decisions regarding possible termination and/or early reporting of the study.
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13.0 registration guidelines

13.1 Registration Timing Patients must be registered prior to initiation of treatment (no more than seven working days prior to planned start of treatment).  
13.2 OPEN Registration Requirements The individual registering the patient must have completed the appropriate SWOG
Registration Worksheet. The completed form must be referred to during the registration but should not be submitted as part of the patient data.  
OPEN will also ask additional questions that are not present on the SWOG Registration Worksheet. The individual registering the patient must be prepared to provide answers to the following questions: a. Institution CTEP ID  
b. Protocol Number c. Registration Step d. Treating Investigator e. Cooperative Group Credit f. Credit Investigator g. Patient Initials h. Patient's Date of Birth i. Patient SSN (SSN is desired, but optional. Do not enter invalid numbers.) j. Country of Residence
k. ZIP Code l. Gender (select one):
Female Gender Male Gender m. Ethnicity (select one):
Hispanic or Latino Not Hispanic or Latino Unknown n. Method of Payment (select one):
Private Insurance Medicare Medicare and Private Insurance Medicaid Medicaid and Medicare Military or Veterans Sponsored NOS
Military Sponsored (Including Champus & Tricare) Veterans Sponsored Self Pay (No Insurance)
No Means of Payment (No Insurance)
Other Unknown o. Race (select all that apply):
American Indian or Alaska Native Asian Black or African American Native Hawaiian or other Pacific Islander White Unknown 13.3 Registration Procedures a. All site staff (SWOG and CTSU Sites) will use OPEN to enroll patients to this study. OPEN is a web-based application and can be accessed from the CTSU members' web site OPEN tab, or from the OPEN Patient Registration link on the SWOG CRA Workbench.  
b. Prior to accessing OPEN site staff should verify the following:
All eligibility criteria have been met within the protocol stated timeframes. Site staff should refer to Section 5.0 to verify eligibility.  
All patients have signed an appropriate consent form and HIPAA
authorization form (if applicable).  
c. Access requirements for OPEN:  
Site staff will need to be registered with CTEP and have a valid and active CTEP-IAM account. This is the same account (user ID and password) used for the CTSU members' web site.  
To perform registrations, the site user must have been assigned the
'Registrar' role on the SWOG or CTSU roster:  
1. If you are a SWOG member, to perform registrations on SWOG
protocols you must have an equivalent 'Registrar' role on the SWOG roster. Role assignments are handled through SWOG.  
2. If you are not a SWOG member, to perform registrations on SWOG
protocols you must have the role of Registrar on the CTSU roster. Site and/or Data Administrators can manage CTSU roster roles via the new Site Roles maintenance feature under RSS on the CTSU members' web site. This will allow them to assign staff the "Registrar" role.
Note: The OPEN system will provide the site with a printable confirmation of registration and treatment information. Please print this confirmation for your records.  
d. Further instructional information is provided on the CTSU members' web site OPEN tab or within the OPEN URL. For any additional questions contact the CTSU Help Desk at 1-888-823-5923 or ctsucontact@westat.com.  
13.4 Registration Exceptions
For either method of registration, exceptions to SWOG registration policies will not be permitted. a. Patients must meet all eligibility requirements.  
b. Institutions must be identified as approved for registration.  
c. Registrations may not be cancelled. d. Late registrations (after initiation of treatment) will not be accepted.
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14.0 data submission schedule 14.1

Data must be submitted according to the protocol requirements for ALL patients registered, whether or not assigned treatment is administered, including patients deemed to be ineligible. Patients for whom documentation is inadequate to determine eligibility will generally be deemed ineligible.
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14.2 master forms

Master forms can be found on the protocol abstract page on the SWOG website (www.swog.org) and (with the exception of the sample consent form and the Registration Form) must be submitted to the Data Operations Center in Seattle. Data from approved SWOG institutions must be submitted on-line via the Web; see Section 14.3a for details. Exceptions to online data submission are patient-completed (e.g. Quality of Life) forms and source documents (e.g. pathology/operative/lab reports).  
14.3 Data Submission Procedures
a. SWOG institutions must submit data electronically via the Web by using the SWOG CRA Workbench. To access the CRA Workbench, go to the SWOG Web site (http://swog.org) and logon to the Members Area. After you have logged on, click on the *CRA Workbench* link to access the home page for CRA Workbench website. Next, click on the *Data Submission* link and follow the instructions. For new users, the link to a "Starter Kit" of help files may be found by clicking on the Starter Kit link at the Members' logon page. To submit data via the web the following must be done (in order):  
1. You are entered into the SWOG Roster and issued a SWOG Roster ID
Number, 2. You are associated as an investigator or CRA/RN at the institution where the patient is being treated or followed, and 3. Your Web User Administrator has added you as a web user and has given you the appropriate system permissions to submit data for that institution.
For assistance with points 1 and 2 call the Operations Office at 210/614-8808.  
For point 3, contact your local Web User Administrator (refer to the "Who is my Web User Administrator?" function on the swog.org Members logon page). For other difficulties with the CRA Workbench, please email technicalquestion@crab.org.  
b. If you need to submit data that are not available for online data submission, the only alternative is via facsimile. Should the need for this occur, institutions may submit data via facsimile to 800/892-4007 or 206/342-1680 locally. Please do not use cover sheet for faxed data.  
14.4 Data Submission Overview and Timepoints
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a. within 7 days of

Submit a copy of the following: S0819 Prestudy Form Baseline Tumor Assessment Form Pathology Report SWOG **S0819** Pathology Review Form (Appendix 18.8) Radiology reports from all scans performed to assess disease at baseline Operative reports from all surgical or biopsy procedures performed within 28 days prior to registration.
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b. within 14 days after

Submit prestudy specimens as outlined in Section 15.1a Submit images for central review as outlined in Appendix 18.6.  
c. WITHIN 7 DAYS AFTER EACH CYCLE (1 CYCLE = 21 DAYS) OF TREATMENT:
Submit a copy of the following:
S0819 Treatment Form S0819 Adverse Event Form.  
d. AT WEEK 7:
Submit blood specimens as outlined in Section 15.1a.  
e. AFTER EVERY TUMOR ASSESSMENT UNTIL DISEASE PROGRESSION (see Section 9.0 for Disease Assessment Schedule): Submit a copy of the following: Follow-Up Tumor Assessment Form Radiology reports from all scans performed to assess disease Submit images for central review as outlined in Appendix 18.6.  
f. WITHIN 14 DAYS OF PROGRESSION OR RELAPSE:
Submit a copy of the following: Lung Carcinoma First Site(s) of Progression or Relapse Form Follow-Up Tumor Assessment Form If the patient is off protocol treatment, submit the Advanced NSCLC Follow Up Form Submit images for central review as outlined in Appendix 18.6.  
g. WITHIN 14 DAYS OF DISCONTINUATION OF ALL PROTOCOL TREATMENT:
Submit a copy of the following: Off Treatment Notice documenting the date of completion of protocol treatment, progression/relapse/other reason, and summarizing inclusive dates of treatment and patient status Final **S0819** Treatment Form Final **S0819** Adverse Event Form Submit plasma and buffy coat as outlined in Section 15.1a.  
h. WITHIN 14 DAYS AFTER DIAGNOSIS OF SECOND MALIGNANCY:
Submit the Advanced NSCLC Follow Up Form.  
Submit the Advanced NSCLC Follow Up Form.
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j. within 4 weeks of

Submit a copy of the Notice of Death. If the patient was off protocol treatment at the time of death, submit a Advanced NSCLC Follow Up Form.
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15.0 special instructions

15.1 Required Tissue Specimens for EGFR FISH and KRAS
Specimens for EGFR FISH and KRAS mutation analysis (submitted to the University of Colorado) (Required):  
a. Specimens must be submitted at the timepoints listed below. Collection instructions are outlined in Section 15.1c and submission instructions are outlined in Section 15.1e.  
b. Specimens must be submitted at the following times (see Section(s) 9.1 - 9.4):
1. Paraffin-embedded tissue/Prestudy  
c. Specimen Collection Instructions
Submit 1-2 paraffin-embedded tissue blocks containing formalin fixed tumor or needle aspirate slides from time of diagnosis (or subsequent, but prior to therapy) must be submitted for evaluation of expression of relevant molecular targets. Paraffin blocks may be processed according to standard institutional protocols. If blocks are unavailable, 10-12 unstained slides are acceptable alternatives.  
Cytology (i.e. fine-needle aspirations) can be accepted only if they are paraffin embedded as cell blocks. Tumor material must be reviewed by a local pathologist to ensure sufficient tumor cells are present in the sample. The local pathologist must review and sign off on the SWOG S0819 **Pathology Review Form**
(Appendix 18.8) noting that there are at least 100 tumor cells present in the sample. The number of cells present in the sample must be entered into the Specimen Tracking System along with copies of the SWOG S0819 **Pathology** Review Form and the pathology report when the specimen is submitted to the SWOG Solid Tumor Repository. Please also fax the **SWOG S0819 Pathology** Review Form to the Data Operations Center at 800/892-4007 or 206/342-1680 locally. These samples must be submitted for expression of relevant integral molecular targets (see Section 15.3).  
d. Specimen collection kits are not being provided for this submission; sites will use institutional supplies.  
e. Shipping Samples 1. SWOG Specimen Tracking System (STS)
All specimen submissions for this study must be entered and tracked using the SWOG online Specimen Tracking system. SWOG members may log on the online system via the CRA Workbench. To access the CRA Workbench, go to the SWOG Web site (http://swog.org) and logon to the Members Area. After you have logged on using your SWOG roster ID
number and password, click on the *CRA Workbench* link to access the home page for CRA Workbench website. First time non- SWOG users must refer to start-up instructions located at https://gill:crab.org/SpecTrack/. A copy of the Shipment Packing List produced by the online Specimen Tracking system should be printed and placed in the pocket of the specimen bag if it has one, or in a separate resealable bag. The Specimen Submission Form is NOT required when the online system is used.  
ALL SPECIMENS MUST BE LOGGED VIA THIS SYSTEM; THERE ARE
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no exceptions.

To report technical problems with Specimen Tracking, such as database errors or connectivity issues, please send an email to technicalquestion@crab.org. For procedural help with logging and shipping specimens, there is an introduction to the system on the Specimen Tracking main page (http://dnet.crab.org/SpecTrack/Documents/Instructions.pdf); or contact the Data Operations Center at 206/667-2267 to be routed to the Data Coordinator for further assistance.  
In the online specimen tracking system, the appropriate SWOG laboratory for submission of paraffin-embedded tissue for EGFR FISH and KRAS
mutation analysis is identified as follows:
Lab \#78: UCD Biorepository Core Facility Department of Pathology RC-1 North, Room P18-5404M
12801 East 17th Avenue Aurora, CO 80045 Contact: Adrie van Bokhoven Phone: 303/724-3908 E-mail: Adrie.vanBokhoven@ucdenver.edu f. The Federal guidelines for shipment are as follows:
1. The specimen must be wrapped in an absorbable material;  
2. The specimen must then be placed in an AIRTIGHT container resealable bag);
3. Pack the resealable bag and specimen in a Styrofoam container;  
4. Pack the styrofoam shipping container in a cardboard box.  
5. The cardboard box must be marked as "BIOHAZARD."
15.2 Required Plasma and Buffy Coat for Translational Medicine and Optional Banking
Specimens for correlative studies and banking (submitted to the SWOG Specimen Repository - Solid Tissue, Myeloma and Lymphoma Division, Lab \#201) (Required): a. Specimens must be collected at the following times and submitted (see Section(s)
9.1 - 9.4):  
1. Draw 10 ml of plasma and buffy coat specimens into two 5 - 10 cc purple top (EDTA) tubes at the following timepoints: a. Prior to treatment (prestudy) b. Week 7
c. At time of removal from protocol treatment. It is important that a blood specimen also be obtained from any patient when he/she is removed from protocol treatment or has disease progression.  
Blood should be processed as soon as possible after venipuncture, preferably within two hours. Samples not processed immediately after blood draw should be refrigerated at 4°C until processing. The **tubes** will be immediately centrifuged at approximately 1,200 rpm for 10 minutes. Buffy coat cells will be removed and placed in labeled cryotubes.  
Plasma will be separately removed and placed in 4 (2 mL)
labeled cryotubes. All tubes are then to be frozen. Store frozen at -80°C until shipped to the SWOG Specimen Repository on dry ice as detailed on the specimen submission webpage (see Section 15.2b). These samples must be submitted for expression of relevant integral molecular targets (see Section 15.3).  
b. Specimen collection and submission instructions can be accessed on the SWOG
Specimen Submission webpage (http://swog.org/Members/ClinicalTrials/Specimens/STSpecimens.asp), or via the link on the **S0819** protocol abstract page on the SWOG website (www.swog.org).  
c. Specimen collection kits may be ordered by calling the SWOG Specimen Repository at 614/722-2865.  
15.3 Integral Translational Medicine Studies The study includes embedded integral translational medicine studies (e.g., tests that must be performed in order to conduct the trial): EGFR FISH and KRAS mutation analysis. Thus, both tissue (EGFR FISH) and blood specimens (KRAS mutations) are mandatory for this study in order to perform the integral correlative studies.  
EGFR FISH: Among enrolled patients, EGFR FISH will be performed on paraffin embedded material and by using the classification system developed by SWOG
investigators, in which the results of the EGFR gene copy number will be reported as either EGFR FISH-positive, which includes patients with a tumor having high polysomy
(>/= 4 copies of the gene in >/= 40% of the cells) or gene amplification
(gene/chromosome ratio > 2, or presence of gene clusters or >/= 15 gene copies in > 10% of the cells) or EGFR FISH-negative, which includes all other patients. This classification has been validated in several previous SWOG studies as well as in several prospective clinical trials. *(8-11, 25)*
The EGFR FISH analysis in this study will be performed in the Dept of Pathology, University of Colorado under the direction of Dr. Marileila Varella-Garcia (CLIA certified laboratorium). KRAS mutation analysis: Retrospective studies, including those by SWOG lung investigators, have found an association between KRAS mutation (codon 12/13) and resistance to EGFR TKIs. Few KRAS data are available for cetuximab in NSCLC, but an association with resistance has been demonstrated in colorectal cancer. KRAS mutations occur in about 30% of lung adenocarcinomas and in 10-15% of non-adenocarcinomas, all together in about 20% of unselected NSCLC patients. We intend to analyze tumor tissue and plasma for KRAS mutation analysis in all patients treated on the **S0819** clinical trial in real time and to incorporate this information into interim analyses, and well as to correlate results with outcomes and with the results of other biomarkers. The KRAS mutation analysis will be performed at UC Davis by Dr. Philip Mack using the DxS Scorpion method as the principle method of analysis and automated SSCP augmented by cold PCR as additional validation. For patients where tissue is not available, or is insufficient for analysis, we will analyze DNA extracted from plasma. These methods are described in the following paragraph. Allele-specific real-time PCR using scorpion primer and the Amplification Refractory Mutations System (Scorpions-ARMS) will be used to detect the presence of KRAS
mutations. *(26-32)* Scorpion primers (produced by DxS LTD, Manchester, UK) are multifunctional molecules composed of a PCR primer, a fluorophore and a quencher (see Figure 1). In the presence of its target sequence (in this case, a WT or mutant KRAS amplicon with a codon 12 or 13 base substitution), the scorpion primer undergoes an internal conformation rearrangement that releases the fluorophore from the quencher, resulting in a detectable light output. Scorpion-ARMS primers recognize the following KRAS point mutations: for codon 12, GGTGCT (GlyAla), GGTGAT (GlyAsp), GGTCGT (GlyArg), GGTTGT (GlyCys), GGTAGT (GlySer), GGTGTT (GlyVal), for codon 13, GGCGAC (GlyAsp). Sensitivity for Scorpions-ARMS, depending upon the quality/quantity of the available source material (tissue or plasma) approaches 1% mutation detection in a wild-type background. A secondary method, single-stranded conformation polymorphism (SSCP) using cold-PCR for mutation enrichment will be used for validation. Cold PCR is a recently described method for mutation enrichment exploiting differential melting temperatures in heterozygous. *(33,34)*
Specimens are run on a GenePhor electrophoresis (GE) unit with automated silver staining. We have established primers and conditions that are sufficient to detect (at a threshold of 2-5%) all mutations obtained by Scorpion-ARMS as well as the following additional mutations; for codon 12, GGTTTT (GlyPhe), and for codon 13 GGCTGC (GlyAsp), with each base substitution resulting in a unique gel migration pattern (see Figure 2). We have also detected additional rare double base-pair mutations, as well as alterations outside of codon 12 and 13 using this technique.  
   
Definition of KRAS positivity: The cycle threshold (CT) is defined as the fractional cycle number at which the fluorescence passes the fixed threshold, set above baseline, as determined by the software. For each probe set specific to a KRAS codon 12 or 13 base substitution, a cut-off deltaCT, defined as the CT of the mutant minus the CT of the wild type control, has been established by the manufacturer as the point at which a positive signal could be due to background fluorescence of the primer on wild-type DNA. For our purposes, any specimen where the control probe has a CT value of >/= 40 will be repeated and/or disqualified as insufficient material. For a patient specimen to be considered positive for mutation it must have: 1) a mutation CT < 45, 2) a deltaCT lower than the cut-off for that probe and 3) a smooth amplification curve in the log phase parallel to the control probe. In addition, an independent validation assay will be conducted for each specimen using SSCP. Due to formalin-induced DNA artifacts in archival tumor specimens, mutant positivity will likely be skewed slightly at the lower threshold. *(32)* As such, all tissue specimens will be compared, based upon sample size and quality of DNA, to determine the appropriate threshold below which any positivity will be determined to result from background artifacts. In addition, differentially migrating bands in the SSCP gel can be isolated, extracted and sequenced to confirm mutations. Divergent results between the DxS Scorpion-ARMS method and SSCP will result in re-analysis from, if at all possible, an additional tumor specimen and repeat of assays. Microdissection and sequencing can be used to resolve any further discrepancies, if required. Plasma analysis is expected to generate cleaner results due to lack of formalin-induced artifact formation, however the quantity of total DNA and mutant DNA extracted may vary tremendously on a patient-to-patient basis. *(29, 30)* Therefore, while plasma DNA may confirm the presence of a mutation in a tissue specimen, any discrepancy between tissue and plasma will be resolved in favor of the tissue results. Results from plasma analysis will be used as a back-up for patients where tumor tissue is insufficient or not available. If the mutation status remains ambiguous after the rigorous testing outlined above has been completed and no additional specimens are available for analysis, the KRAS status for that patient will be considered undeterminable. Our experience is that this will occur in less than 3% of cases.  
In order to compare the results of the FISH assay with other EGFR-related markers, other markers also be assessed in specimens from this trial as integrated translational medicine studies (e.g., tests that are clearly identified as part of the clinical trial from the beginning and intended to identify or validate assays or markers planned for future studies, see Section 18.5).
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15.4 radiology review

PET/CT, CT and MRI images will be initially interpreted by the local site radiologist.  
Imaging exams will then be forwarded to the Quality Assurance Review Center (QARC) for central review.
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all ct and/or mri images

All study participants will have a PET/CT, CT or MRI exam prior to study entry.  
Participants will then undergo additional imaging every 6 weeks until progression of disease. The same imaging modality used for the pre-treatment exam must be used for the post-treatment exams (i.e., patients with a pre-study PET/CT are to receive follow-up PET/CT scans throughout the trial for assessment of progression; patients with a prestudy CT are to receive follow-up CT scans throughout the trial for assessment of progression; patients with a pre-study MRI are to receive follow-up MRI scans throughout the trial for assessment of progression). Each exam should be performed per Appendix 18.6. QARC will facilitate a central/expert review per RECIST criteria; the central reviewbased PFS is the basis for the assessment of objectives (see Section1.2a and 1.2b. Clinical management and treatment decisions will be made by the treating physician based on local site assessments and other clinically appropriate considerations. Results of the central review will be reported only to the DSMC. A detailed description of the central radiology PFS review, including image acquisition parameters and image submission instructions, can be found in Appendix 18.6.
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16.0 ethical and regulatory considerations

The following must be observed to comply with Food and Drug Administration regulations for the conduct and monitoring of clinical investigations; they also represent sound research practice:
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informed consent

The principles of informed consent are described by Federal Regulatory Guidelines (Federal Register Vol. 46, No. 17, January 27, 1981, part 50) and the Office for Protection from Research Risks Reports: Protection of Human Subjects (Code of Federal Regulations 45 CFR 46). They must be followed to comply with FDA regulations for the conduct and monitoring of clinical investigations.
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institutional review

This study must be approved by an appropriate institutional review committee as defined by Federal Regulatory Guidelines (Ref. Federal Register Vol. 46, No. 17, January 27, 1981, part 56) and the Office for Protection from Research Risks Reports: Protection of Human Subjects (Code of Federal Regulations 45 CFR 46).
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monitoring

This study will be monitored by the Clinical Data Update System (CDUS) Version 3.0. Cumulative CDUS data will be submitted quarterly to CTEP by electronic means. Reports are due January 31, April 30, July 31 and October 31. 16.1 Adverse Event Reporting Requirements
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a. purpose

Adverse event data collection and reporting, which are required as part of every clinical trial, are done to ensure the safety of patients enrolled in the studies as well as those who will enroll in future studies using similar agents. Adverse events are reported in a routine manner at scheduled times during a trial. (Directions for routine reporting are provided in Section 14.0.) Additionally, certain adverse events must be reported in an expedited manner to allow for more timely monitoring of patient safety and care. The following guidelines prescribe expedited adverse event reporting for this protocol. See also Appendix 18.1 for general and background information about expedited reporting.
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b. reporting methods

This study requires that expedited adverse event reporting use the NCI's Adverse Event Reporting System (CTEP-AERS). The NCI's guidelines for CTEP-AERS can be found at http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_even ts.htm. In the rare event when internet connectivity is disrupted an electronic report MUST be submitted immediately upon re-establishment of internet connection. Please note that all paper CTEP-AERS forms have been removed from the CTEP
website and will NO LONGER be accepted.  
c. When to report an event in an expedited manner When the adverse event requires expedited reporting, submit the report within 10 calendar days of learning of the event.
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d. other recipients of adverse

The SWOG Operations Office will forward reports and documentation to the appropriate regulatory agencies and drug companies as required.  
Adverse events determined to be reportable to the Institutional Review Board responsible for oversight of the patient must also be reported according to local policy and procedures.
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e. expedited reporting for commercial

Commercial reporting requirements are provided in Table 16.1. If there is any question about the reportability of an adverse event or if on-line CTEP-AERS cannot be used, please telephone or email the SAE Program at the Operations Office, 210/614-8808 or adr@swog.org, before preparing the report. Table 16.1. Expedited reporting requirements for adverse events experienced by patients who have received commercial drugs on this study. All of the agents used in this study are commercial agents.  
| Attribution                                             | Grade 4   | Grade 5 a   |           |
|---------------------------------------------------------|-----------|-------------|-----------|
| Unexpected                                              | Expected  | Unexpected  | Expected  |
| Unrelated or  Unlikely                                  | CTEP-AERS | CTEP-AERS   |           |
| Possible, Probable,  Definite                           | CTEP-AERS | CTEP-AERS   | CTEP-AERS |
| CTEP-AERS:                                              | Indicates an expedited report is to be submitted via NCI CTEP           |             |           |
| AERS within 10 calendar days of learning of the eventb. |           |             |           |  
a This includes all deaths within 30 days of the last dose of treatment with a commercial agent(s), regardless of attribution. Any death that occurs more than 30 days after the last dose of treatment with a commercial agent(s) and is attributed (possibly, probably, or definitely) to the agent(s) and is not due to cancer recurrence must be reported according to the instructions above.  
b Submission of the on-line CTEP-AERS report plus any necessary amendments generally completes the reporting requirements. You may, however, be asked to submit supporting clinical data to the Operations Office in order to complete the evaluation of the event. If requested, the specified data should be sent by fax to 210-614-0006.  
1. Shepherd FA, Rodrigues Pereira J, Ciuleanu T, et al; National Cancer Institute of Canada Clinical Trials Group. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med.  
353:123-32, 2005.  
2. Tsao M-S, Sakurada A, Cutz J-C: Erlotinib in lung cancer- molecular and clinical predictors of outcome. N Engl J Med 353: 133-144. 2005.  
3. Zhu C-Q, da Cunha Santos G, Ding K et al: Role of KRAS and EGFR as biomarkers of response to erlotinib in national Cancer Institute of Canada Clinical Trials Group study BR-21.  
J Clin Oncol 26 (E pub, July 14. 2008):  
4. Hirsch FR, Varella-Garcia M, Bunn PA, Jr., et al. Molecular predictors of outcome with gefitinib in a phase III placebo-controlled study in advanced non-small-cell lung cancer. J Clin Oncol 24:5034-5042, 2006.
5. Eberhard DA, Johnson BE, Amler LC, et al. Mutations in the epidermal growth factor receptor and in KRAS are predictive and prognostic indicators in patients with non-small-cell lung cancer treated with chemotherapy alone and in combination with erlotinib. J Clin Oncol 23:5900-5909, 2005.  
6. Mukohara T, Engelman J, Hanna N et al. Differential effects of gefitinib and cetuximab on non-small-cell lung cancers bearing epidermal growth factor receptor mutations. J Natl Cancer Inst. 97:1185-94, 2005.
7. Meert AP, Martin B, Delmotte P, et al. The role of EGF-R expression on patient survival in lung cancer: a systematic review with meta-analysis. Eur Respir J 20:975-981, 2002.  
17.0 BIBLIOGRAPHY 8. Hirsch FR, Varella-Garcia M, McCoy J, et al. Increased epidermal growth factor receptor gene copy number detected by fluorescence in situ hybridization associates with increased sensitivity to gefitinib in patients with bronchioloalveolar carcinoma subtypes: a Southwest Oncology Group Study. J Clin Oncol 23:6838-6845, 2005.  
9. Hirsch FR, Varella-Garcia M, Bunn PA, Jr., et al. Epidermal growth factor receptor in nonsmall-cell lung carcinomas: correlation between gene copy number and protein expression and impact on prognosis. J Clin Oncol 21:3798-3807, 2003.  
10. Cappuzzo F, Hirsch FR, Rossi E, et al. Epidermal growth factor receptor gene and protein and gefitinib sensitivity in non-small-cell lung cancer. J Natl Cancer Inst 97:643-655, 2005.  
11. Hirsch FR, Herbst RS, Olsen C, et al. Increased EGFR gene copy number detected by FISH
predicts outcome in non-small cell lung cancer patients treated with cetuximab and chemotherapy. J Clin Oncol 26: 3351-3357, 2008.  
12. Jeon YK, Sung SW, Chung JH, Park WS, Seo JW, Kim CW, Chung DH. Clinicopathologic features and prognostic implications of epidermal growth factor receptor (EGFR) gene copy number and protein expression in non-small cell lung cancer. Lung Cancer 54:387-98, 2006.  
13. Chung CH, Ely K, McGavran L, Varella-Garcia M, Parker J, Parker N, Jarrett C, Carter J,
Murphy BA, Netterville J, Burkey BB, Sinard R, Cmelak A, Levy S, Yarbrough WG, Slebos RJ, Hirsch FR. Increased epidermal growth factor receptor gene copy number is associated with poor prognosis in head and neck squamous cell carcinomas. J Clin Oncol 24:4170-6, 2006.  
14. Dziadziuszko R, Holm B, Skov BG, Osterlind K, Sellers MV, Franklin WA, Bunn PA Jr, Varella-Garcia M, Hirsch FR. Epidermal growth factor receptor gene copy number and protein level are not associated with outcome of non-small-cell lung cancer patients treated with chemotherapy. Ann Oncol 18:447-52, 2007.  
15. Douillard JY, Kim E, Hirsch V, et al. Gefitinib (IRESSA) versus docetaxel in patients with locally advanced or metastatic non-small-cell lung cancer pre-treated with platinum-based chemotherapy: a randomized, open-label phase III study (INTEREST). J Thorac Oncol 2: S305, 2007.  
16. Van Cutsem E, Lang I, D'haens G, Moiseyenko V, Zaluski J, Folprecht G, Tejpar S, Kisker O,
Stroh C, Rougier P. KRAS status and efficacy in the first-line treatment of patients with metastatic colorectal cancer (mCRC) treated with FOLFIRI with or without cetuximab: The CRYSTAL experience. J Clin Oncol 26: 2008 (May 20 suppl; abstr 2)
17. Gandara DR, Gumerlock PH. Epidermal growth factor receptor tyrosine kinase inhibitors plus chemotherapy: case closed or is the jury still out? J Clin Oncol. 23:5856-8, 2005.  
18. Lynch TJ, Patel T, Dreisbach L, et al. A randomized multicenter phase III study of cetuximab
(Erbitux) in combination with Taxane/Carboplatin versus Taxane/Carboplatin alone as firstline treatment for patients with advanced/metastatic Non-small cell lung cancer (NSCLC).  
IASLC 12th World Conference on Lung Cancer, 2007.  
19. Pirker R, Szczesna A, von Pawel J, et al. FLEX: A randomized, multicenter, phase III study of cetuximab in combination with cisplatin/vinorelbine (CV) versus CV alone in the first-line treatment of patients with advanced non-small cell lung cancer. J Clin Oncol 26: 1006s, 2008.  
20. Taguchi F, Solomon B, Grecorg V, et al. Mass spectrometry to classify non-small cell lung cancer patients for clinical outcome after treatment with epidermal growth factor receptor tyrosine kinase inhibitors: a multicohort cross-institutional study. J Natl Cancer Inst 99: 838846, 2007.  
21. Eberhard DA, Giaccone G, Johnson BE. Biomarkers of response to epidermal growth factor receptor inhibitors in non-small-cell lung cancer working group: standardization for use in the clinical trials setting. J Clin Oncol 26: 983-994, 2008.  
22. Pocock SJ, Simon R. Sequential treatment assignment with balancing for prognostic factors in controlled clinical trials. Biometrics 31:103-115, 1975.  
23. Tsao MS, Aviel-Ronen S, Ding K, et al. Prognostic and predictive importance of p53 and RAS for adjuvant chemotherapy in non-small cell lung cancer. J Clin Oncol 25(33):5240-47, 2007.  
24. Punt CJ, Tol J, Rodenburg CJ, et al. Randomized phase III study of capecitabine, oxaliplatin and bevacizumab with or without cetuximab in advanced colorectal cancer (ACC), the CAIRO2 study of the Dutch colorectal cancer group (DCCG). J Clin Oncol 26 (May 20 suppl; abstr LBA4011), 2008.  
25. Hirsch FR, Varella-Garcia M, Bunn PA, et al, Fluorescence in situ hybridization (FISH)
subgroup analysis of TRIBUTE, a phase III trial of erlotinib plus carboplatin and paclitaxel in NSCLC. J Clin Oncol 25(18S) (June 20 suppl:abstr 7570), 2007.  
26. Whitcombe D, Theaker J, Guy SP, et al. Detection of PCR products using self-probing amplicons and fluorescence. Nature Biotech 17:804-807, 1999.
Page 97 Version Date 10/3/16 28. Clayton SJ, Scott F, Walker J, et al. K-ras point detection mutation in lung cancer. Clinical Chemistry 46(12):1929-1938, 2000 29. Kuang Y, Rogers A, Yeap BY, et al. Noninvasive detection of EGFR T790M in gefitinib or erlotinib resistant non-small cell lung cancer. Clin Cancer Res 15:2630-6, 2009  
27. Thelwell N, Millington S, Solinas A, et al. Mode of action and application of scorpion primers to mutation detection. Nucleic Acids Research 28(19):3752-3761, 2000.  
30. Mack PC, Holland WS, Burich RA, et al. Predictive value of EGFR and KRAS mutations detected in plasma from non-small cell lung cancer (NSCLC) patients treated with docetaxel and intermittent erlotinib. JCO Vol 26, No 15S (May 20 Supplement): 8062, 2008.  
31. Amado RG, Wolf M, Peeters M, et al. Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. JCO Vol 26:1626-1634, 2008.  
32. Jimeno A, Messersmith WA, Hirsch FR, et al. KRAS mutations and sensitivity to epidermal growth factor receptor inhibitors in colorectal cancer: practical application of patient selection. JCO Vol 27, No 7: pp. 1130-1136, 2009.  
33. Li J, Wang L, Mamon H, et al. Replacing PCR with COLD-PCR enriches variant DNA
sequences and redefines the sensitivity of genetic testing. Nat Med 14:579-84, 2008.  
34. Zuo Z, Chen SS, Chandra PK, et al. Application of COLD-PCR for improved detection of KRAS mutations in clinical samples. Mod Pathol 2009 May 8. [Epub ahead of print].
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18.0 appendix

18.1 Determination of Expedited Adverse Event Reporting Requirements 18.2 Carboplatin Dosing Worksheet 18.3 New York Heart Association Class 18.4 Proposed Rash Management Algorithm 18.5 Embedded Translational Medicine Studies 18.6 Central Radiology Review 18.7 Cancer Trials Support Unit (CTSU) Participation Procedures  
| 18.8   | SWOG S0819 Pathology Review Form   |
|--------|------------------------------------|  
18.1 Determination of Expedited Adverse Event Reporting Requirements
Adverse event data collection and reporting, which are required as part of every clinical trial, are done to ensure the safety of patients enrolled in the studies as well as those who will enroll in future studies using similar agents. Adverse events are reported in a routine manner at scheduled times during a trial. (Directions for routine reporting are provided in Section 14.0.) Additionally, certain adverse events must be reported in an expedited manner to allow for more timely monitoring of patient safety and care. Expedited adverse event reporting principles and general guidelines follow; specific guidelines for expedited adverse event reporting on this protocol are found in Section 16.1. All serious adverse events determined to be reportable to the Institutional Review Board responsible for the oversight of the patient must be reported according to local policy and procedures. Documentation of this reporting should be maintained for possible inspection during quality assurance audits.  
Steps to determine if an adverse event is to be reported in an expedited manner
(This includes all events that occur while on treatment or within 30 days of the last dose of protocol treatment.)
Step 1: Determine whether the patient has received an investigational agent, commercial agent, or a combination of investigational and commercial agents. An investigational agent is a protocol drug administered under an Investigational New Drug Submission (IND). In some instances, the investigational agent may be available commercially, but is actually being tested for indications not included in the approved package label.  
Commercial agents are those agents not provided under an IND but obtained instead from a commercial source. The NCI, rather than a commercial distributor, may on some occasions distribute commercial agents for a trial.  
When a study includes both investigational and commercial agents, the following rules apply.  
*Concurrent administration*: When an investigational agent(s) is used in combination with a commercial agent(s), the combination is considered to be investigational and expedited reporting of adverse events would follow the guidelines for investigational agents.  
*Sequential administration*: When a study includes an investigational agent(s)
and a commercial agent(s) on the same study arm with sequential administration all expedited reporting of adverse events should follow the guidelines for the type of agent being given. For example, if the patient begins the study on the investigational agent(s), then all expedited reporting of adverse events should follow guidelines for the investigational agent(s). Once the patient begins receiving the commercial agent(s) then all expedited reporting of adverse events should follow the guidelines for commercial agent(s).
Step 2: Identify the type of event using the NCI Common Terminology Criteria for Adverse Events (CTCAE). The CTCAE provides descriptive terminology and a grading scale for each adverse event listed. A copy of the CTCAE can be downloaded from the CTEP home page (http://ctep.cancer.gov). Additionally, if assistance is needed, the NCI has an Index to the CTCAE that provides help for classifying and locating terms. Step 3: Grade the event using the NCI CTCAE version specified in the protocol for reporting serious adverse events. Step 4: Determine if the adverse event is Expected or an Exception to Expedited Reporting. **Expected** events are those that have been previously identified as resulting from administration of the agent and are listed in one of the following:  
The current NCI SPEER (Specific Protocol Exceptions to Expedited Reporting) for treatments using agents provided under an NCI-held IND, or an equivalent listing for treatments using agents provided under a Non-CTEP-held IND; located in Section 3.0 of the protocol.  
For treatments using commercial agents, the current CAEPR (Comprehensive Adverse Event and Potential Risks), ASAEL (Agent Specific Adverse Event List), or other list of expected toxicities located in Section 3.0 of the protocol, or the drug package insert.  
Exception to Expedited reporting located in Section 16.1 f of the protocol.
An adverse event is considered **unexpected,** for expedited reporting purposes only, when either the type of event or the severity of the event is **not** listed in one of the areas outlined above. Step 5: Determine whether the adverse event involved hospitalization or a prolongation of hospitalization (≥ 24 hours). Step 6: Additionally, for commercial drugs, determine whether the adverse event is related to the protocol therapy. Attribution categories are as follows: Unrelated, Unlikely, Possible, Probable, and Definite. Consult the appropriate table for expedited reporting criteria for commercial agent(s). NOTE: Any event that occurs more than 30 days after the last dose of study agent and is attributed (possible, probable, or definite) to the study agent(s) must be reported according to the instructions above and as outlined in the appropriate table in Section 16.1.  
18.2 Carboplatin Dosing Worksheet PATIENT'S INITIALS MEDICAL RECORD \#  
  
SWOG PATIENT \#
TO CALCULATE Creatinine Clearance (CrCl) from SERUM CREATININE:  
$$\begin{array}{c c c}{{}}&{{}}&{{}}\\ {{}}&{{}}&{{}}\\ {{}}&{{}}&{{}}\end{array}$$
$\underline{\mathrm{Id}}$  
  
CrCl = (140 - age) X wt. in kg.* X 0.85 (if female)  
  
$$\operatorname{CrCl}=$$  
CrCl = (140 - ) X ( ) X 0.85 (if female)  
  
TO CALCULATE CARBOPLATIN DOSE WITH CALVERT FORMULA: USE CALCULATED CREATININE CLEARANCE (AS ABOVE) TO SUBSTITUTE FOR GFR.  
$$0.85{\mathrm{~(if~female)}}$$  
(AUC) (GFR + 25) = CARBOPLATIN DOSE PER CYCLE IN mg (6) ( +25) = mg of carboplatin This is the TOTAL DOSE of carboplatin (not mg/m2).  
  
  
Please note that: GFR should NOT exceed 125 ml/min. Hence, the maximum total carboplatin dose should NOT exceed 900 mg for this study.  
* Use current (actual) weight. This should be actual weight but not exceed 140% of IBW.  
** Carboplatin dose should be calculated using a serum creatinine value obtained within 3 days prior to each course therapy. In patients whose serum creatinine is <
0.8 mg/dl, 0.8 mg/dl must be substituted in the Cockroft-Gault formula to calculate the estimated creatinine clearance for carboplatin dosing.
NOTE: PLEASE RETAIN ORIGINAL WORK SHEET as part of patient's PERMANENT RECORD. COPIES MAY BE MADE FOR PHARMACY and/or NURSING RECORDS.
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18.3 new york heart association

|       | Need for                       | Physical Ability   |                     |                   |
|-------|--------------------------------|--------------------|---------------------|-------------------|
| Class | Cardiac Symptoms               | Limitations        | Additional Rest*    | To Work**         |
| I     | None                           | None               | None                | Full Time         |
| II    | Only moderate                  | Slight             | Usually only slight | Usually full time |
|       | or occasional                  |                    |                     |                   |
| III   | Defined, with less             | Marked             | Usually moderate    | Usually part time |
|       | than ordinary                  |                    |                     |                   |
|       | activity                       |                    |                     |                   |
| IV    | May be present                 | Extreme            | Marked              | Unable to work    |
|       | even at rest, & any            |                    |                     |                   |
|       | activity increases  discomfort |                    |                     |                   |  
* To control or relieve symptoms, as determined by the patient, rather than as advised by the physician.  
** At accustomed occupation or usual tasks.  
Macular Rash Pustular/Papular  
Rash  
Dry Skin Pruritis Ulcerative  
Lesions  
| Macular Rash                                                 | Pustular/Papular  Rash                                    |                                                              |                                                           |
|--------------------------------------------------------------|-----------------------------------------------------------|--------------------------------------------------------------|-----------------------------------------------------------|
| Grade 1                                                      | Hydrocortisone                                            | Cleocin T Gel for                                            |                                                           |
| cream                                                        | limited single areas                                      |                                                              |                                                           |
| Grade 2                                                      | Cutivate Topical  BID Medrol dose  pack                   | Minocin OR Bactrim                                           | Lotion applied                                            |
| DS                                                           | BID                                                       |                                                              |                                                           |
| Grade 3                                                      | Medrol dose pack  Consider  dermatologic  consultation    |                                                              |                                                           |
| Grade 4                                                      | Medrol dose pack  Consider  dermatologic  consultation    | Minocin OR Bactrim  DS  Consider  dermatologic  consultation | Lotion applied  TID  Consider  dermatologic  consultation |
| Minocin OR Bactrim  DS  Consider  dermatologic  consultation | Lotion applied  TID  Consider  dermatologic  consultation |                                                              |                                                           |  
Vaseline or  
Silvadene  
Consider dermatologic  
consultation  
Grade 4 Medrol dose pack  
Consider  
dermatologic consultation  
| Topical or  Benadryl OR  Atarax  Benadryl OR  Atarax  Consider  dermatologic  consultation  Benadryl OR  Atarax  Consider  dermatologic  consultation   |
|---------------------------------------------------------------------------------------------------------------------------------------------------------|  
| Lesions  N/A  Vaseline or  Silvadene  Consider  dermatologic  consultation  Vaseline or  Silvadene  Consider  dermatologic  consultation   |
|--------------------------------------------------------------------------------------------------------------------------------------------|  
18.5 Embedded Translational Medicine Studies-Integrated and Other
In order to compare the results of the FISH and IHC assays outlined in Section 15.3 with other EGFR-related markers, *other* markers also will be assessed in specimens from this trial as *integrated correlative studies*. (e.g., tests that are clearly identified as part of the clinical trial from the beginning and intended to identify or validate assays or markers planned for future studies).
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integrated studies

EGFR Protein Expression by IHC: Diagnostic specimens will be sent to a central lab
(University of Colorado-UCCC-under the direction of Dr. Wilbur Franklin) for assessment of EGFR protein expression by IHC using the DAKO EGFR scoring system (0-3+). EGFR-positive staining is defined as any IHC staining of tumor cell membranes above background level: whether it is complete or incomplete circumferential staining. Based on results from a recently completed prospective randomized Phase II study performed by OSI and UCCC in EGFR positive patients we expect similar properties to that of EGFR
FISH as specified in Section 6.0.  
EGFR mutation analysis: EGFR activating mutations, which occur in 10-15% of unselected NSCLC patients in the USA, have proven to be associated with a high objective response rate (about 60%), but no large studies in the western countries have yet demonstrated a survival prolongation in EGFR mutated NSCLC patients (in contrast to Asian populations). EGFR mutation analysis will be performed in all patients included in this study and compared with EGFR FISH and IHC in an exploratory fashion. EGFR mutation analysis will be performed at UC Davis by Dr. Phil Mack using the DxS Scorpion method.
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other studies

Proteomic analysis: Hirsch and collaborators have identified an "8-peak" serum proteomic classifier which is associated with good clinical outcomes after EGFR TKIs, both in 1st line therapy and 2nd line therapy. *(20)* In this proposal we will collect blood in all patients for further correlative studies and compare with the tissue-based marker analyses in an exploratory fashion.  
EGFR polymorphism studies: analysis to be performed by Dr. Alex Adjei with the North Central Cancer Treatment Group (NCCTG) at Roswell Park Cancer Center.  
Angiogenesis-related markers: analysis will be performed at MD Anderson by Dr. John Heymach.  
1.1 Correlative study design (to include methods for obtaining samples, administering forms, or performing radiologic studies):
All registered and eligible patients will have either paraffin embedded blocks or unstained histological or cytological specimen(s) sent to the University of Colorado Cancer Center for EGFR FISH testing, IHC staining, KRAS and assessment of the other proposed EGFR-related biomarkers. These results will not be disclosed to the treatment sites. Blood (plasma and buffy coat) will be collected at the SWOG specimen bank for future research.  
1.2 Specific hypothesis (include relevant background studies):
Based on studies and data reported above, this correlative science proposal has the following hypotheses:  
1. Cetuximab plus chemotherapy compared to chemotherapy alone will result in an improvement in progression-free survival (PFS) in EGFR FISH-positive patients.  
2. EGFR FISH will identify a cohort of patients deriving the greatest benefit as compared with the unselected population and IHC+ patients.  
3. EGFR FISH will compare favorably in exploratory analyses to other EGFR–
related biomarkers in identifying this cohort.
1.3 Statistical design (for each correlative study - include endpoints, sample size and monthly accrual rate): See above. Based on historical data, we assume that the proportion of IHC-positive patients is 85% and we also assume that there are no EGFR FISH-positive/ IHC-negative patients. Therefore, among 1,236 patients (80% of 1,546) with IHC and FISH results, it is expected that at least 1050 will be IHC positive and 618 will be both FISH positive and IHC positive. The following table states the expected numbers of patients within each grouping:  
|               | FISH/IHC unknown   | IHC-   | IHC+/FISH-   | IHC+/FISH+   |
|---------------|--------------------|--------|--------------|--------------|
| # of patients | 310                | 186    | 432          | 618          |  
The assumed median PFS in each of the prognostic/predictive grouping is included in the following table. For the purpose of the following power calculations we have assumed that IHC status and FISH status are not prognostic.  
| Control arm           | Experimental arm   |            |       |      |
|-----------------------|--------------------|------------|-------|------|
|                       | IHC-/FISH -        | IHC+/FISH- | FISH+ |      |
| Median PFS            | 5.5                | 6.6        | 6.6   | 7.3  |
| HR*                   | --                 | 1.10       | 1.10  | 1.33 |
| * against control arm |                    |            |       |      |  
These values correspond to an improvement in median PFS overall of 20%, and an improvement of 22% in the IHC-positive group. The second hypothesis in the unselected population is tested by an interaction test between EGFR FISH and treatment group. Among the 1,236 patients assumed to have an EGFR result for IHC and FISH, this study has 49% power to detect an interaction between treatment arm and FISH status using a 1-sided 0.05 level test under the assumptions in the table above.  
The second hypothesis in the IHC+ population is tested by an interaction test between FISH and treatment group within the IHC+ population. Among the 1,050 patients assumed to be IHC+ and have a result for FISH, this study has 43%
power to detect an interaction between treatment arm and FISH status using a 1sided 0.05 level test among IHC+ patients.  
Analysis of the other EGFR-related biomarkers will be exploratory in nature with the goal of augmenting the EGFR FISH analyses.  
18.6 Central Radiology Review All participants will undergo serial CT or MRI imaging:  
Baseline/pre-treatment Every 6 weeks until progression of disease (as determined by local site assessment)  
The same imaging modality MUST be used throughout the course of the trial. The pre- and post-treatment CT or MRI images must be submitted to QARC for all study participants. Imaging guidelines and image submission instructions are detailed below. Since real-time assessment and reporting of the central radiology review is not feasible, clinical management and treatment decisions will be made by the treating physician based on local site assessments and other clinically appropriate considerations. NOTE: If a disease assessment is missed and/or delayed, if a scan is not done during a disease assessment for any reason; QARC must be notified of the missed and/or delayed disease assessment and the reason. The notification must be submitted in writing to SWOG@qarc.org or FAXED to 401/753-7601. 1.0 Image Acquisition All study participants will undergo serial CT or MRI imaging to be done at baseline and every 6 weeks until progression of disease (as determined by local site assessment).
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1.1 ct imaging

General CT imaging parameters are outlined below. Additional scanning guidelines, per anatomic location, are detailed in the subsequent sections.  
Helical CT scanning is required; axial scanning cannot be used.  
Multi-detector scanning is preferred whenever possible, but singledetector helical scanning can be used.  
o Single detector scanners: Pitch should be 1-1.5; images should be reconstructed at ≤ 5mm intervals in the axial plane.  
o Multi-detector scanners: It is strongly recommended that reconstruction be performed at the highest resolution possible (2 mm or less), but will accept ≤ 5mm intervals.  
Each anatomic area (chest, abdomen, pelvis), scanner settings (kV,
mAs) should be per institutional routine procedures.  
Choice of contrast agent should be according to local institutional routine.  
Contrast dose should be 100-150 mL. Injection rates should be 2 mL/sec minimum for chest and pelvis imaging and 3-5 mL/sec for abdominal imaging.  
18G IV is preferred for bolus rates of injection, especially for abdominal imaging.  
Central lines should not be used unless absolutely required due to lack of acceptable peripheral IV access. Central lines should not be used with power injector unless specifically approved for that indication.
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a. chest and abdominal ct

Scanning with IV contrast is preferred, but not required. If IV contrast is used, pre-contrast imaging is not required. Chest CT scanning should be performed per institutional standards, as long as slice resolution requirements are met (< 5mm, preferably < 2mm). For contrast-enhanced imaging, a scan delay of approximately 20-30 seconds is recommended. If chest imaging is combined with abdominal (and pelvic) imaging, chest imaging should either be performed prior to abdominal imaging (non-contrast chest) or after abdominal (and pelvic)
imaging. Abdominal imaging should be tailored for multi-phase liver imaging techniques. Pre- and post-IV contrast imaging provides optimal evaluation of liver disease; IV contrast should be used whenever possible. In cases when there is a contraindication to IV contrast, MRI is the preferred imaging modality for liver disease (if available). Recommended scanning protocol: Helical non-contrast imaging through the liver prior to contrast-enhanced imaging, followed by dual-phase
(arterial and portal) contrast enhanced imaging is recommended. Arterial phase scan delay time 20-30 seconds (or via bolus timing techniques per institutional routine). Portal venous scan delay time approximately 60-75 seconds. Each vascular phase scan of the liver must be obtained in a single helical acquisition.
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1.2 mri imaging

General MRI imaging parameters are outlined below.  
Field strength of 1 tesla or greater. Imaging must be performed with a specialized torso array coil or other local coil combinations appropriate for body imaging. Body coil for signal reception is not acceptable.  
Image slice thickness should be ≤ 7 mm.  
For contrast enhanced scanning, standard gadolinium chelates should be used at a dose of 0.1 mmol/kg to a maximum of 20mL.  
Injection rate should be 2cc/sec, and all injections must be followed by a saline flush of at least 20cc. Peripheral 22-20G IV preferred.
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a. chest and abdominal mri

Axial imaging must be performed. Imaging using T1W and T2W techniques is recommended. Specific imaging sequences are per institutional standards. Breath-held imaging is required. Contrast enhanced imaging is not required, but is recommended for T1W
imaging. If chest MRI is performed in combination with abdominal imaging, chest imaging must precede abdominal imaging (i.e.,
non-contrast) or must be performed after abdominal imaging (i.e., delayed post-contrast).
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1.3 pet/ct imaging

General PET/CT imaging parameters are outlined below:
Only full-ring dedicated PET/CT scanners are acceptable. The CT of the PET/CT is used for attenuation correction of PET data and anatomic localization. CT settings should follow institutional guidelines (usually 120-140kV, at least 60mA).  
A documented daily quality control procedure must be in place and records kept.  
Non-diabetic patients should fast for at least 4 hours prior to the scan.  
Plain (unflavored water) should be taken during the period of fasting and the uptake period to ensure good hydration.  
Diabetic patients should ideally be given a morning appointment.  
They should take their usual antidiabetic medication (oral or insulin) and eat a light meal (lighter than they normally would) on that morning. The time interval between that morning meal and PET/CT scan should be approximately 3-4 hours.  
Blood glucose of all patients should be measured on arrival and consideration given to rescheduling when the blood glucose level is higher than 200 mg/dl. Insulin should not be administered to reduce glucose level when the blood glucose is > 200 mg/dl at the time of arrival in the PET clinic.  
Oral diazepam may be given if desired to reduce brown fat uptake one hour prior to tracer injection.  
Oral diluted contrast (e.g., Gastografin or 2% barium sulfate) may be administered, according to institutional guidelines. Intravenous contrast may also be administered, provided this is done in a technique that avoids deterioration of the CT images by streak artifacts from high-concentration iv. contrast bolus.
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a. scanning

Administer 260 - 555 MBq (7-15mCi) 18F- FDG. Emission part of the scan should start no earlier than 60 and no later than 80 minutes after injection. The exact same period of uptake must be used for staging and response scans - within 15 minutes. Perform attenuation corrected 'half-body' PET-CT scan to cover the area from the base of the skull to mid-thigh. This should be done with the arms above the head. Attenuation correction of PET emission data will be based on the low dose CT from the PET/CT. Acquisition should be performed using the institution's standard protocol, i.e. with regard to time per bed position, 2D or 3D, CTAC
parameters, reconstruction parameters etc. Images should be reconstructed using OSEM or a similar iterative reconstruction algorithm. Both attenuation-corrected and non attenuationcorrected images should be reconstructed.
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2.0 image submission

Baseline scans and follow-up imaging at every 6 weeks for nine months and then every three months until progression or end of follow-up will be submitted via the AG Mednet service to QARC (the Quality Assurance Review Center).
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instructions for electronic submission of

Exams must be submitted electronically via the AG Mednet service provided by SWOG. (Please note that while AG Mednet service is provided by SWOG, SWOG
will not be responsible for the cost of the exams). Specific information about the imaging workflow and instructions can be found at http://www.agmednet.com/doc/TrialUserGuide.pdf. Electronic Submission Set-up All participating sites will be provided with an AG Mednet Desktop Agent. The Desktop Agent can be ordered by e-mailing a request to agmednetadmin@swog.org. AG Mednet will require the AG Mednet Desktop Agent Order Form to be faxed directly to AG Mednet at 617/674-8125 or submitted online at the link provided. After activating your desktop agent, sites will be able to submit images electronically, directly from a scanner or PACS, and also from a CD or file system.
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although ag mednet can accommodate

NOTE: The person responsible for activating the desktop agent should be involved in submitting the exams as the desktop agent requires user specific login verification. All questions regarding AG Mednet agent use should be directed to 888.9AGMEDNET, and hit 2 for the support option. Sites should contact AG Mednet at the time of IRB approval for AG Mednet enrollment to allow time for the Desktop Agent activation prior to patient registration. This contact is needed even if you are using AG Mednet for another SWOG trial. Note that activation of the Desktop Agent may take several weeks. Exam Submission Process When submitting images, you will be required to follow the **S0819** Image Submission protocol, which includes completing a transmittal form and deidentifying the exam. First import the exam from a CD or file system, PACS, or directly from the scanner. Select the exam in your Desktop Agent worklist, assign it to the **S0819** trial. To complete the Transmittal Form, select the form under the tasks column. Instructions for the form will be sent to your site at the time you enroll with AG Mednet. The data from that transmittal form will be automatically integrated with the trial databases. To de-identify the exam, select de-identification in the task list. The Agent will guide you through the proper blind encoding. If sites de-identify exams prior to importing, the AG Mednet Agent de-identification task will ensure the exam has been properly blind encoded.  
The final task in your workflow after completing the transmittal form and deidentification is to upload the exam and associated information to SWOG. This can be completed by selecting upload exam in the task list.  
Note: All questions regarding AG Mednet Agent use, transmittal forms, deidentification or image submission through AG Mednet should be directed to 888.9AGMEDNET, and hit 2 for the support option.
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3.0 central radiology review

After registration, SWOG will provide QARC with the registration date and patient number, along with a blinded code indicating which reviewer will be assigned to each case. This ensures that each reader reviews a balanced number of cases from each study arm. An experienced radiologist will review each image for assessment of progression of disease per RECIST criteria. The same reviewer will read all study images of the study participant. Data from local reviews will not be provided to the central reviewers in order to keep the central reviewers blinded to the results of the local investigator-assessed PFS. The result of this read will constitute the definitive radiographic assessment of progression. If assessment of progression for a participant based on central radiology review is earlier than the local investigator/site assessment progression, the date of central review disease progression will be the date of the exam that documented the progression per the central radiology review. If central radiology review does not verify progression based on local radiographic assessment, QARC will continue to review any subsequent scans (if provided) to determine a later progression.  
The actual progression will be determined at the SWOG Statistical Center, using a composite of the QARC assessment, in conjunction with possible data on progression from other sources or symptomatic deterioration (see Section 10.6). Results of the central review will NOT be communicated to the local site. Decisions regarding clinical management of the patient will be made by the treating physician based on local site assessments/reviews and other clinical considerations.
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4.0 radiology review procedures

Review of CT (or MRI) images will be performed using RECIST criteria.
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4.1 review of pre-treatment ct/mri

The reader will review all anatomic areas (chest, abdomen) imaged and available.  
The target lesions to be evaluated will be defined/determined by the review of the pre-treatment exam. A maximum of 10 target lesions will be defined with a maximum of 5 in a single organ. The 10 target lesions will be chosen with representation from all organs involved with the tumor.  
Additional significant non-target lesions and areas of non-measurable disease will be noted. A screen capture of each target lesion, annotated with a pointer and a lesion reference number assigned to the target lesion, will be generated and archived. This will be used on subsequent reads to ensure concordance of lesions on follow-up/post-treatment exams. Measurements will be made from the axial scan (generally the post contrast scan) that best demonstrates the lesion as distinct from background. All measurements will be made by electronic calipers. A
screen capture of the actual measurement axis with calipers will be saved and archived with the exam permanently at QARC.  
4.2 Review of post-treatment image exam(s) will be performed as follows: The pre-treatment annotated exam and CRF will be reviewed to ensure lesion concordance. Readers will review all images for the current time point prior to making measurements. When performing lesion measurements on a scan from a given time point for a given target lesion, the previous measurement(s) of the specific target lesion will be reviewed to provide the reader with the previous axis and slice location for measurement. Measurements will be made from the axial post-contrast image that best demonstrates the lesion as distinct from background.  
Longest axis diameter will be recorded. Unless there is an obvious change in lesion shape, the reader will identify the slice on the current exam that best matches the lesion anatomy of the slice used for the prior measurement(s) and will choose an axis for diameter measurement that best approximates the axis used on the prior measurement(s). If there is an obvious change in lesion shape, a new axis that corresponds to the longest axis observed in the axial plane will be measured. All measurements will be made by electronic calipers. A screen capture of the actual measurement axis with calipers will be saved and archived with the exam permanently at QARC.
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18.7 cancer trials support unit

Prior to the recruitment of a patient for this study, investigators must be registered members of the CTSU. Each investigator must have an NCI investigator number and must maintain an "active" investigator registration status through the annual submission of a complete investigator registration packet (FDA Form 1572 with original signature, current CV, Supplemental Investigator Data Form with signature, and Financial Disclosure Form with original signature) to the Pharmaceutical Management Branch, CTEP, DCTD, NCI. These forms are available on the CTSU registered member Web site or by calling the PMB at 240/276-6575 Monday through Friday between 8:30 a.m. and 4:30 p.m. Eastern time. Each CTSU investigator or group of investigators at a clinical site must obtain IRB approval for this protocol and submit IRB approval and supporting documentation to the CTSU Regulatory Office before they can enroll patients. Study centers can check the status of their registration packets by querying the Regulatory Support System (RSS) site registration status page of the CTSU member web site at www.ctsu.org All forms and documents associated with this study can be downloaded from the **S0819** Web page on the CTSU registered member Web site (www.ctsu.org). Patients can be registered only after pre-treatment evaluation is complete, all eligibility criteria have been met, and the study site is listed as 'approved' in the CTSU RSS.
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pre-study requirements for patient enrollment

Patient must meet all inclusion criteria, and no exclusion criteria should apply Patient has signed and dated all applicable consents and authorization forms All baseline laboratory tests and prestudy evaluations performed (including tumor and plasma samples) within the time period specified in the protocol.
CTSU Procedures for Patient Enrollment  
All site staff (SWOG and CTSU Sites) will use OPEN to enroll patients to this study. OPEN can be accessed at open.ctsu.org or from the CTSU web site OPEN tab at https://www.ctsu.org. Prior to accessing OPEN site staff should verify the following:  
All eligibility criteria have been met within the protocol stated timeframes. Site staff should use the registration forms provided on the group or CTSU web site as a tool to verify eligibility.  
All patients have signed an appropriate consent form and HIPAA
authorization form (if applicable).  
Access requirements for OPEN:  
Site staff will need to be registered with CTEP and have a valid and active CTEPIAM account. This is the same account (user id and password) used for the CTSU
members' web site.  
To perform registrations, the site user must have been assigned the 'Registrar' role on the relevant Group or CTSU roster.  
To perform registrations on protocols for which you are a member of the Lead Group, you must have an equivalent 'Registrar' role on the Lead Group roster.  
Role assignments are handled through the Groups in which you are a member To perform registrations to trials accessed via the CTSU mechanism (i.e., nonLead Group registrations) you must have the role of Registrar on the CTSU roster.  
Site and/or Data Administrators can manage CTSU roster roles via the new Site Roles maintenance feature under RSS on the CTSU members' web site. This will allow them to assign staff the "Registrar" role.  
Note: The OPEN system will provide the site with a printable confirmation of registration and treatment information. Please print this confirmation for your records. Further instructional information is provided on the CTSU web site OPEN tab or within the OPEN URL. For any additional questions contact the CTSU Help Desk at 1-888-823-5923 or ctsucontact@westat.com.
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data submission and reconciliation

1. All case report forms (CRFs) associated with this study must be downloaded from the **S0819** Web page located on the CTSU registered member Web site (www.ctsu.org). Sites must use the current form versions and adhere to the instructions and submission schedule outlined in the protocol.  
2. Submit all completed CRFs (with the exception of patient enrollment forms),
clinical reports, and transmittals directly to the SWOG Data Operations Center.  
The preferred method of sending data is via fax at 800-892-4007. Do NOT include a cover sheet for faxed data. Do NOT send study data to the CTSU.  
3. The SWOG Data Operations Center will send query notices and delinquency reports directly to the site for reconciliation. Please send query responses and delinquent data to the SWOG Data Operations Center and do not copy the CTSU
Data Operations. When faxing data include the query sheet that was originally sent from SWOG.  
4. Each site should have a designated CTSU Administrator and Data Administrator and **must keep their CTEP IAM account contact information current.** This will ensure timely communication between the clinical site and the SWOG data center.
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special materials or substudies

1. All specimens submitted for this study must be entered and tracked using the SWOG on-line Specimen Tracking System, as specified in protocol Section 15.0.  
2. You can also access the Tracking System from the CTSU Member Web Site. Go to the **S0819** protocol page and click on the link provided under the Case Report Forms header.  
Specimen Collection (Section 15.0)  
Collection and shipment kits will be provided by SWOG. Ordering instructions are listed in protocol Section 15.1.  
**Tumor and plasma specimen submissions are mandatory. Additional**
information for tumor and plasma specimens submissions are outlined in Section 15.0 of the protocol.  
Radiology Review (Section 15.0) Submission of CT and/or MRI images is mandatory for central review. Please refer to Section 15.4 and Appendix 18.6 for more information.
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serious adverse event reporting

1. CTSU sites must comply with the expectations of their local Institutional Review Board (IRB) regarding documentation and submission of adverse events. Local IRBs must be informed of all reportable serious adverse reactions.  
2. CTSU sites will assess and report adverse events according to the guidelines and timelines specified in the protocol. You may navigate to the CTEP Adverse Event Report System (CTEP-AERS) from either the Adverse Events tab of the CTSU member homepage (www.ctsu.org) or by selecting Adverse Event Reporting Forms from the document center drop down list on the protocol number Web page.  
3. Do not send adverse event reports to the CTSU. 4. Secondary AML/MDS/ALL reporting: Report occurrence of secondary AML, MDS,
or ALL via the NCI/CTEP AML-MDS Report Form in lieu of CTEP-AERS. Submit the completed form and supporting documentation as outlined in the protocol.
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drug procurement (section 3.0)

Commercial agents: Bevacizumab (Avastin®), Carboplatin (CBDCA), Paclitaxel (Taxol®),
Cetuximab (Erbitux®)
Bevacizumab, Carboplatin, and Paclitaxel are commercially available and will not be supplied free of charge. Cetuximab will be provided free of charge by ImClone Systems, Inc/Bristol-Myers Squibb (BMS) and distributed by BMS. Ordering instructions can be found in Section 3.3.d of the protocol. A copy of the Cetuximab Drug Request Form is available under Pharmacy Forms on the CTSU members' web site. 1. Information on drug formulation, procurement, storage and accountability, administration, and potential toxicities are outlined in Section 3.0 of the protocol.  
2. You may navigate to the drug forms by selecting Pharmacy under the Document folder on the S0819 Web page.
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regulatory and monitoring study audit

To assure compliance with Federal regulatory requirements [CFR 21 parts 50, 54, 56, 312, 314 and HHS 45 CFR 46] and National Cancer Institute (NCI)/ Cancer Therapy Evaluation Program (CTEP) Clinical Trials Monitoring Branch (CTMB) guidelines for the conduct of clinical trials and study data validity, all protocols approved by NCI/CTEP that have patient enrollment through the CTSU are subject to audit. Responsibility for assignment of the audit will be determined by the site's primary affiliation with a Cooperative Group or CTSU. For Group-aligned sites, the audit of a patient registered through CTSU will become the responsibility of the Group receiving credit for the enrollment. For CTSU
Independent Clinical Research Sites (CICRS), the CTSU will coordinate the entire audit process.  
For patients enrolled through the CTSU, you may request the accrual be credited to any Group for which you have an affiliation provided that Group has an active clinical trials program for the primary disease type being addressed by the protocol. Per capita reimbursement will be issued by the credited Group provided they have endorsed the trial, or by the CTSU if the Group has not endorsed the trial. Details on audit evaluation components, site selection, patient case selection, materials to be reviewed, site preparation, on-site procedures for review and assessment, and results reporting and follow-up can be found in the CTMB Monitoring Guidelines and are available for download from the CTEP web page http://ctep.cancer.gov/monitoring/guidelines.html.  
Health Insurance Portability and Accountability Act of 1996 (HIPAA) The HIPAA Privacy Rule establishes the conditions under which protected health information may be used or disclosed by covered entities for research purposes. Research is defined in the Privacy Rule referenced in HHS 45 CFR 164.501. Templated language addressing NCI-U.S. HIPAA guidelines are provided in the HIPAA Authorization Form located on the CTSU website. The HIPAA Privacy Rule does not affect participants from outside the United States. Authorization to release Protected Health Information is NOT required from patients enrolled in clinical trials at non-US sites.  
Clinical Data System–Web (CDS-Web) Monitoring This study will be monitored by the Clinical Data System (CDS-Web). The sponsoring Group fulfills this reporting obligation by transmitting the CDS data collected from the study-specific case report forms, via the Web to the NCI Center for Biometrics (NCICB). Cumulative CDS data are submitted quarterly. 18.8 SWOG **S0819** Pathology Review Form SWOG **S0819** Pathology Review Form SWOG Solid Tumor Biorepository SWOG ID \#_____________ Patient Initials: ______(L, FM) Protocol of Interest: S0819f Pathology Diagnosis: _______________________________________________ Preliminary Data Specimen Submission:
□Resected Tissue □Fine Needle Aspiration (FNA) □Core Biopsy Specimen Type Submitted:
□Block - Surgical Pathology Number* _______________________________ □Slides - Surgical Pathology Number* _______________________________
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specimen review

Tumor Cells Available **(PLEASE CHECK ONLY ONE)**:
□Adequate (≥100 cells) □Inadequate (< 100 cells)
* This is not the number given to the specimen from the Specimen Tracking System.
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interpreted by date

NOTE: A copy of this form is to be submitted with the pathology report to the SWOG Solid Tumor Specimen Repository as outlined in Section 15.1. This form must also be faxed to the Data Operations Center at 800/892-4007 or 206/342-1680 locally.