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6.1.2 azd6244 hyd-sulfate

Table 8: AZD6244 Monotherapy Dose Level Reductions  
| Dose Level            | AZD6244 Dose  I   |
|-----------------------|-------------------|
| Starting Dose         | 75 mg BID         |
| First Dose Reduction  | 50 mg BID         |
| Second Dose Reduction | 50 mg once daily  |  
Table 9: Dosage Modification Criteria for AZD6244–related Toxicities  
| D                                    |                                                                                                           |                   |
|--------------------------------------|-----------------------------------------------------------------------------------------------------------|-------------------|
| Event                                | AE Grade or Observation                                                                                   | Dose modification |
| Grade 1 or 2                         | Maintain dose Hold AZD6244 until < tolerable grade 2,  then reduce 1 dose level and resume  treatment 1 . |                   |
| Grade 3 or 4 or intolerable  grade 2 |                                                                                                           |                   |
| Dermatology/Skin                     | Hold AZD6244 until < tolerable grade 2,  then reduce 1 additional dose level and  resume treatment 1 .    |                   |
| Recurrent Grade 3                    |                                                                                                           |                   |  
| Recurrent Grade 3 after 2 dose                     | Remove patient from study arm.                                                                                                                                              |               |
|----------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------|
| reductions                                         | Patients with grade 4 rash (i.e. life  threatening generalized exfoliative  ulceration; erythemia multiforme/toxic  epidermal necrolysis should be removed  from study arm. |               |
| Grade 4                                            |                                                                                                                                                                             |               |
| V                                                  | Maintain dose; continue anti-diarrheal  treatment. Loperamide (4 mg at first onset,  followed by 2 mg every 2–4 hrs until  diarrhea free for 12 hrs)                        |               |
| Grade 1 or 2                                       |                                                                                                                                                                             |               |
| Diarrhea                                           | Hold AZD6244 until < tolerable grade 2,                                                                                                                                     |               |
| Grade 3 or 4                                       | loperamide; reduce 1 dose level and resume  treatment 1 .                                                                                                                   |               |
| (if anti-diarrheal  treatment is  ineffective)     | Hold AZD6244 until < tolerable grade 2,  loperamide; reduce 1 additional dose level  and resume treatment 1 .                                                               |               |
| Recurrent Grade 3 or 4 after 2 dose                | Remove patient from study arm.                                                                                                                                              |               |
| reductions  O Recurrent Grade 3 or 4  Grade 1 or 2 | Maintain dose                                                                                                                                                               |               |
| Grade 3 or 4                                       | Hold AZD6244 until < grade 2, then reduce  1 dose level and resume treatment.                                                                                               |               |
| Hematologic                                        | I Hold AZD6244 until < grade 2, then reduce  1 additional dose level and resume  treatment.                                                                                 |               |
| Recurrent Grade 3 or 4 after 2 dose                | Remove patient from study arm.                                                                                                                                              |               |
| reductions  Recurrent Grade 3 or 4                 |                                                                                                                                                                             |               |
| (neutrophils,  platelets,  hemoglobin)             | Grade 1 or 2                                                                                                                                                                | Maintain dose |
| Grade 3 or 4                                       | Hold AZD6244 until < grade 2, then reduce  1 dose level and resume treatment  D                                                                                             |               |
| Liver Function                                     | Hold AZD6244 until < grade 2, then reduce  1 additional dose level and resume  treatment                                                                                    |               |
| Recurrent Grade 3 or 4 after 2 dose                | Remove patient from study arm.                                                                                                                                              |               |
| reductions  Recurrent Grade 3 or 4                 |                                                                                                                                                                             |               |
| (serum bilirubin,  AST, or ALT) Other non-         | Grade 1 or 2                                                                                                                                                                | Maintain dose |  
| hematological                                                                                                                               | Any Grade 2 of concern                                                                               |                                                                                                                       |
|---------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------|
| toxicity                                                                                                                                    | (e.g., prolonged cardiac,  pulmonary, or  neurotoxicity, intolerable  stomatitis)                    | Hold AZD6244 until < grade 1, then reduce  1 dose level and resume treatment  Hold AZD6244 until < tolerable grade 2, |
| Grade 3 or 4                                                                                                                                | then reduce 1 dose level and resume  treatment 2                                                     |                                                                                                                       |
| V                                                                                                                                           | Hold AZD6244 until < tolerable grade 2,  then reduce 1 additional dose level and  resume treatment 2 |                                                                                                                       |
| 1                                                                                                                                           | If event has not improved to < tolerable grade 2 or baseline within < 21 days, patient               |                                                                                                                       |
| should be removed from the study.  2 Patients with medically concerning grade 3 or 4 AEs related to AZD 6244 may be  Recurrent Grade 3 or 4 |                                                                                                      |                                                                                                                       |  
6.1.2 MK2206 Table 10: MK2206 Monotherapy Dose Level Reductions  
| O                     |             |
|-----------------------|-------------|
| Dose Level            | MK2206 Dose |
| Starting Dose         | 200 mg QW   |
| First Dose Reduction  | 135 mg QW   |
| Second Dose Reduction | 90 mg QW    |  
Table 11: Dosage Modification Criteria for MK2206–related Toxicities  
I  
| Event                          | AE Grade or  Observation                                                                                                                             | Dose modification                                                                                |
|--------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------|
| Grade 1 or 2                   | Maintain dose                                                                                                                                        |                                                                                                  |
| Grade 3 or 4 or intolerable    | Hold MK2206 until < tolerable grade 2, then                                                                                                          |                                                                                                  |
| grade 2                        | reduce 1 dose level and resume treatment 1 .  DHold MK2206 until < tolerable grade 2, then  reduce 1 additional dose level and resume  treatment 1 . |                                                                                                  |
| Recurrent Grade 3 after 2 dose | Remove patient from study arm.                                                                                                                       |                                                                                                  |
| reductions  Recurrent Grade 3  |                                                                                                                                                      |                                                                                                  |
| Dermatology/Skin               | Grade 4                                                                                                                                              | Patients with grade 4 rash (i.e. life threatening  generalized exfoliative ulceration; erythemia |  
| Version Date: 01/07/2020                                                                                  | multiforme/toxic epidermal necrolysis should  be removed from study arm.  Maintain dose; continue anti-diarrheal  treatment. Loperamide (4 mg at first onset,  followed by 2 mg every 2–4 hrs until diarrhea  free for 12 hrs)   |                                                                                         |
|-----------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------|
| Grade 1 or 2                                                                                              |                                                                                                                                                                                                                                  |                                                                                         |
| Diarrhea                                                                                                  | Hold MK2206 until < tolerable grade 2,                                                                                                                                                                                           |                                                                                         |
| Grade 3 or 4                                                                                              | loperamide; reduce 1 dose level and resume  treatment 1 .                                                                                                                                                                        |                                                                                         |
| V                                                                                                         |                                                                                                                                                                                                                                  |                                                                                         |
| (if anti-diarrheal  treatment is  ineffective)                                                            | Hold MK2206 until < tolerable grade 2,  loperamide; reduce 1 additional dose level and  resume treatment 1 .                                                                                                                     |                                                                                         |
| Recurrent Grade 3 or 4 after 2 dose                                                                       | Remove patient from study arm.                                                                                                                                                                                                   |                                                                                         |
| reductions  Recurrent Grade 3 or 4  Grade 1 or 2                                                          | Maintain dose                                                                                                                                                                                                                    |                                                                                         |
| O                                                                                                         |                                                                                                                                                                                                                                  |                                                                                         |
| Grade 3 or 4                                                                                              | Hold MK2206 until < grade 2, then reduce 1  dose level and resume treatment.                                                                                                                                                     |                                                                                         |
| Recurrent                                                                                                 | Hold MK2206 until < grade 2, then reduce 1                                                                                                                                                                                       |                                                                                         |
| Grade 3 or 4                                                                                              | additional dose level and resume treatment.                                                                                                                                                                                      |                                                                                         |
| Hematologic (neutrophils,  platelets,  hemoglobin)                                                        | Recurrent Grade 3 or 4 after 2 dose                                                                                                                                                                                              | Remove patient from study arm.                                                          |
| reductions  Grade 1 or 2                                                                                  | Maintain dose                                                                                                                                                                                                                    |                                                                                         |
| I                                                                                                         |                                                                                                                                                                                                                                  |                                                                                         |
| Grade 3 or 4                                                                                              | Hold MK2206 until < grade 2, then reduce 1  dose level and resume treatment                                                                                                                                                      |                                                                                         |
| Recurrent                                                                                                 | Hold MK2206 until < grade 2, then reduce 1  additional dose level and resume treatment                                                                                                                                           |                                                                                         |
| Grade 3 or 4                                                                                              |                                                                                                                                                                                                                                  |                                                                                         |
| Liver Function  (serum bilirubin,  AST, or ALT)                                                           | Recurrent Grade 3 or 4 after 2 dose                                                                                                                                                                                              | Remove patient from study arm.                                                          |
| reductions                                                                                                | D                                                                                                                                                                                                                                |                                                                                         |
| Grade 1 or 2                                                                                              | Maintain dose                                                                                                                                                                                                                    |                                                                                         |
| Any Grade 2 of concern  (e.g., prolonged cardiac,  pulmonary, or  neurotoxicity, intolerable  stomatitis) | Hold MK2206 until < grade 1, then reduce 1  dose level and resume treatment                                                                                                                                                      |                                                                                         |
| Other nonhematological  toxicity                                                                                                           | Grade 3 or 4                                                                                                                                                                                                                     | Hold MK2206 until < tolerable grade 2, then  reduce 1 dose level and resume treatment 2 |
| Recurrent                                                                                                 | Hold MK2206 until < tolerable grade 2, then  reduce 1 additional dose level and resume                                                                                                                                           |                                                                                         |
| 60                                                                                                        |                                                                                                                                                                                                                                  |                                                                                         |  
| Grade 3 or 4                                                                                                                                                     | treatment 2                                                                            |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------|
| 1                                                                                                                                                                | If event has not improved to < tolerable grade 2 or baseline within < 21 days, patient |
| should be removed from the study.  2 Patients with medically concerning grade 3 or 4 AEs related to MK2206 may be taken off  study at investigator's discretion. |                                                                                        |  
In the event of Grade 3 hyperglycemic events (>250 mg/dL) consult with an endocrinologist or other specialist. If glucose levels do not return to grade 1 or lower within one week of appropriate therapy, patients should be considered to have a DLT (dose modification, etc.). Appropriate therapy will usually involve oral antihyperglycemic agents, since the inhibition of glucose transport into the cell by AKT/mTOR inhibitors may render insulin ineffective. The goal of therapy is to keep fasting glucose <150 mg/dL, random blood glucose levels <180 mg/dL, and Hemoglobin A1c <8%. Glucose monitoring should be performed weekly, during the first cycle of therapy, and on day 1 of subsequent cycles, prior to drug administration. Hemoglobin A1c monitoring, for patients requiring treatment of hyperglycemia, should be performed with each cycle of MK-2206 therapy.  
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6.1.3 Lapatinib Table 12: Lapatinib Monotherapy Dose Level Reductions  
| O                     |                |
|-----------------------|----------------|
| Dose Level            | Lapatinib Dose |
| Starting Dose         | 1500 mg daily  |
| First Dose Reduction  | 1250 mg daily  |
| Second Dose Reduction | 1000 mg daily  |  
Table 13: Dosage Modification Criteria for Lapatinib –related Toxicities  
I  
| Event                          | AE Grade or Observation                                                                                                                                 | Dose modification   |
|--------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------|
| Grade 1 or 2                   | Maintain dose                                                                                                                                           |                     |
| Grade 3 or 4 or intolerable    | Hold Lapatinib until < tolerable grade 2, then                                                                                                          |                     |
| grade 2                        | reduce 1 dose level and resume treatment 1 .  DHold Lapatinib until < tolerable grade 2, then  reduce 1 additional dose level and resume  treatment 1 . |                     |
| Recurrent Grade 3 after 2 dose | Remove patient from study arm.                                                                                                                          |                     |
| reductions  Recurrent Grade 3  |                                                                                                                                                         |                     |
| Dermatology/Skin               | Patients with grade 4 rash (i.e. life threatening                                                                                                       |                     |
| Grade 4                        | generalized exfoliative ulceration; erythemia  multiforme/toxic epidermal necrolysis should                                                             |                     |  
| be removed from study arm. Maintain dose; continue anti-diarrheal  treatment. Loperamide (4 mg at first onset,  followed by 2 mg every 2–4 hrs until diarrhea  free for 12 hrs)   |                                                                                                                                |                                                                                            |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------|
| Grade 1 or 2                                                                                                                                                                      | Hold Lapatinib until < tolerable grade 2,                                                                                      |                                                                                            |
| Grade 3 or 4                                                                                                                                                                      | loperamide; reduce 1 dose level and resume  treatment 1 .                                                                      |                                                                                            |
| Diarrhea V (if anti-diarrheal  treatment is  ineffective)                                                                                                                         | Hold Lapatinib until < tolerable grade 2,  loperamide; reduce 1 additional dose level  and resume treatment 1 .                |                                                                                            |
| Recurrent Grade 3 or 4 after 2 dose                                                                                                                                               | Remove patient from study arm.                                                                                                 |                                                                                            |
| reductions  Recurrent Grade 3 or 4  Grade 1 or 2                                                                                                                                  | Maintain dose                                                                                                                  |                                                                                            |
| O                                                                                                                                                                                 |                                                                                                                                |                                                                                            |
| Grade 3 or 4                                                                                                                                                                      | Hold Lapatinib until < grade 2, then reduce 1  dose level and resume treatment.  Hold Lapatinib until < grade 2, then reduce 1 |                                                                                            |
| Recurrent                                                                                                                                                                         | additional dose level and resume treatment.                                                                                    |                                                                                            |
| Grade 3 or 4                                                                                                                                                                      |                                                                                                                                |                                                                                            |
| Hematologic (neutrophils,  platelets,  hemoglobin)                                                                                                                                | Recurrent Grade 3 or 4 after 2 dose                                                                                            | Remove patient from study arm.                                                             |
| reductions  Grade 1 or 2                                                                                                                                                          | Maintain dose                                                                                                                  |                                                                                            |
| I                                                                                                                                                                                 |                                                                                                                                |                                                                                            |
| Grade 3 or 4                                                                                                                                                                      | Hold Lapatinib until < grade 2, then reduce 1  dose level and resume treatment                                                 |                                                                                            |
| Recurrent                                                                                                                                                                         | Hold Lapatinib until < grade 2, then reduce 1                                                                                  |                                                                                            |
| Grade 3 or 4                                                                                                                                                                      | additional dose level and resume treatment                                                                                     |                                                                                            |
| Liver Function  (serum bilirubin,  AST, or ALT)                                                                                                                                   | Recurrent Grade 3 or 4 after 2 dose                                                                                            | Remove patient from study arm.                                                             |
| reductions  Grade 1 or 2                                                                                                                                                          | Maintain dose                                                                                                                  |                                                                                            |
| Any Grade 2 of concern  (e.g., prolonged cardiac,  pulmonary, or  neurotoxicity, intolerable  stomatitis)                                                                         | D                                                                                                                              |                                                                                            |
| Hold Lapatinib until < grade 1, then reduce 1  dose level and resume treatment                                                                                                    |                                                                                                                                |                                                                                            |
| Other nonhematological  toxicity                                                                                                                                                                                   | Grade 3 or 4                                                                                                                   | Hold Lapatinib until < tolerable grade 2, then  reduce 1 dose level and resume treatment 2 |
| Recurrent                                                                                                                                                                         | Hold Lapatinib until < tolerable grade 2, then                                                                                 |                                                                                            |
| Grade 3 or 4                                                                                                                                                                      | reduce 1 additional dose level and resume                                                                                      |                                                                                            |  
| treatment 2                                                                                                                                                         |                                                                                        |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------|
| 1                                                                                                                                                                   | If event has not improved to < tolerable grade 2 or baseline within < 21 days, patient |
| should be removed from the study.  2 Patients with medically concerning grade 3 or 4 AEs related to Lapatinib may be taken  off study at investigator's discretion. |                                                                                        |
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6.1.4 criteria for evaluating cardiac

V
A patient who has a >20% decrease in the left ventricular cardiac ejection fraction (as a % of baseline) that is asymptomatic, and the ejection fraction is below the institution's lower limit of normal, should have a repeat evaluation of ejection fraction 1-2 weeks later while still receiving therapy with lapatinib. If the repeat ejection fraction evaluation confirms a > 20% decrease in left ventricular cardiac ejection fraction (as a % of baseline), and the ejection fraction is below the institution's lower limit of normal, then the CTEP medical monitor should be consulted to help determine if therapy should be temporarily discontinued. If therapy is interrupted and the left ventricular ejection fraction recovers during the next 3 weeks, in consultation with the CTEP medical monitor, the patient may be restarted on therapy with lapatinib at a reduced dose. For such patients, monitoring of left ventricular ejection fraction will then be performed 2 weeks and 4 weeks after re-challenge and then every 4 weeks therafter for at least 16 weeks or until resolution. If repeat ejection fraction evaluation still shows a decrease >20% in left ventricular ejection fraction (as a % of baseline), and the value is below the insitution's lower limit of normal, then the patient should be withdrawn from therapy with lapatinib.  
O
Patients with and NCI-CTCAE grade 3 (LVEF less than 40% and symptomatic) or grade 4 (LVEF less than 20%) left ventricular systolic dysfunction or interstitial pneumonitis must be withdrawn from lapatinib therapy.
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6.2 other agents

6.2.1 Sunitinib Table 14: Sunitinib Monotherapy Dose Level Reductions  
I  
  
| Table 14: Sunitinib Monotherapy Dose Level Reductions Dose Level Sunitinib Dose Starting Dose 50 mg daily   First Dose Reduction 37.5 mg daily   Second Dose Reduction 25 mg daily   |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
  
Table 15. Management of Treatment-Emergent Hypertension  
| (BP in mmHg) Grade                                                                                                                                                | Antihypertensive                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     | Blood Pressure                                                      | Sunitinib         |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------|-------------------|
| (CTCAE v4)                                                                                                                                                        | Therapy                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              | Monitoring                                                          | Dose Modification |
| Persistent Grade 1 Pre-hypertension  Systolic 120-139  Diastolic 80-90                                                                                            | No change except as                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  |                                                                     |                   |
| V                                                                                                                                                                 | described in step 4                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  |                                                                     |                   |
| Standard                                                                                                                                                          | No change                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            |                                                                     |                   |
| Persistent Grade 2- Moderate Systolic 140-159  Diastolic 90-99    Protocol-specific  guidance  supersedes any  other management  guidelines,  including CTCAE  v4 | Step 1) Initiate LA DHP CCB  treatment and if needed, after  24-48 hr Rx, increase dose in  stepwise fashion every 24-48  hours until BP is controlled or  at max dose of Rx Step 2) If BP still not  controlled, add another  antihypertensive Rx, a BB,  ACE1, ARB, or ABB;  increase dose of this drug as  described in step 1  Step 3) If BP still not  controlled, add 3rd drug from  the list of antihypertensives in  step 2; increase dose of this  drug as described in step 1  Step 4) If BP still not  controlled, consider either 1  dose reduction of sunitinib or  stopping sunitinib  NOTE: Stopping or reducing  the dose of sunitinib is  expected to cause a decrease  in BP. The treating physician  should monitor the patient for  hypotension and adjust the  number and dose of  antihypertensive  medication(s) accordingly. | BP should be  monitored as  recommended by  the treating  physician |                   |
| O                                                                                                                                                                 | I                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    | D                                                                   |                   |  
| Version Date: 01/07/2020 Persistent Grade 3  Severe  Systolic >160  Diastolic >100  HOLD sunitinib until systolic  BP <159 and diastolic BP  <99.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             | BP should be  monitored as  recommended by  the treating  physician unless  the patient is  symptomatic with  systolic BP >180  or diastolic BP  >110 in which  case, monitoring  should be  intensive.   | HOLD sunitinib until  systolic BP <159 and  diastolic BP  <99.  In most circumstances,  if BP cannot be  controlled after an  optimal trial of antihypertensive  medications, consider  either 1 dose reduction  of sunitinib or  stopping sunitinib.  HOWEVER, if the patient requires  hospitalization for  management of  symptomatic systolic  BP >180 or diastolic  BP >110,permanently  discontinue sunitinib  or if BP is controlled,  re-start sunitinib at 1  lower dose level after  consultation with the  study Principal  Investigator                                                                                                                                                                    |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| BP management is identical to  that for Grade 2 (see steps 1-4  above) with 2 major  exceptions:  1) If systolic BP >180 or  diastolic BP >110 and the  patient is symptomatic:  optimal management with  intensive IV support in ICU;  STOP sunitinib and notify  hospital staff that stopping  sunitinib may result in a  decrease in BP  and  2) If systolic BP >180 or  diastolic BP >110 and the  patient is asymptomatic, 2 new anti-hypertensives must  be given together in step 1  (and dose escalated  appropriately as in step 1).  NOTE: Stopping or reducing  the dose of sunitinib is  expected to cause a decrease  in BP. The treating physician  should monitor the patient for  hypotension and adjust the  number and dose of  antihypertensive  medication(s) accordingly |                                                                                                                                                                                                           |                                                                                                                                                                    |
| Protocol-specific  guidance  supersedes any  other management  guidelines,  including CTCAE  v4  V                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            | O                                                                                                                                                                                                         | I                                                                                                                                                                  |
| Grade 4 Life-threatening  consequences of  hypertension                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       | Intensive                                                                                                                                                                                                 | Permanently  discontinue sunitinib  or if BP is controlled,  re-start sunitinib at 1  lower dose level after  consultation with the  study Principal  Investigator |
| Abbreviations: dihydropyridine calcium-channel blockers (DHP-CCB), selective beta blockers  (BB), angiotensin converting enzyme inhibitors (ACEI), angiotensin II receptor blockers (ARB),  alpha beta blocker (ABB) Optimal management with  intensive IV support in ICU;  STOP sunitinib and notify  hospital staff that stopping  sunitinib may result in a  decrease in BP D                                                                                                                                                                                                                                                                                                                                                                                                              |                                                                                                                                                                                                           |                                                                                                                                                                    |  
If patients require a delay of >2 weeks for management of hypertension, discontinue protocol therapy If patients require >2 dose reductions, discontinue protocol therapy Patients may have up to 2 drugs for management of hypertension prior to any dose reduction in sunitinib 24-48 hours should elapse between modifications of anti-hypertensive therapy Hypertension should be graded using CTCAE v4. Increases in blood pressure (BP) and cases of hypertension have been associated with many drugs acting on the VEGF pathway. The proposed mechanism for this increase is through inhibition of VEGF-induced peripheral vasodilation. Hypertension following sunitinib treatment has rarely been seen in animal studies or clinical trials. Specific guidelines for management of this adverse event and a table of various antihypertensive medications are provided in **Appendix H**. In addition, guidance on the collection and recording of BP information is also provided.  
V  
| O                                      |                                                                                                                      |                   |
|----------------------------------------|----------------------------------------------------------------------------------------------------------------------|-------------------|
| Event                                  | AE Grade or Observation                                                                                              | Dose modification |
| Grades 1 and 2                         | Maintain dose                                                                                                        |                   |
| Grade 3*                               | Hold sunitinib until < grade 2, then resume  at same dose level                                                      |                   |
| Grade 4                                | Hold sunitinib until < grade 2, then reduce  1 dose level and resume treatment                                       |                   |
| Neutropenia                            | Grades 1 and 2                                                                                                       | Maintain dose     |
| Grade 3*                               | Hold sunitinib until < grade 2, then reduce  1 dose level and resume treatment                                       |                   |
| Grade 4                                | Hold sunitinib until < grade 2, then reduce  1 dose level and resume treatment                                       |                   |
| Fever or flu-like                      | Grades 1-4                                                                                                           | Maintain dose     |
| symptoms                               | I                                                                                                                    |                   |
| Thrombocytopenia                       | Grades 1 and 2                                                                                                       | Maintain dose     |
| Grade 3*                               | Hold sunitinib until < grade 2, then reduce  1 dose level and resume treatment                                       |                   |
| >450 but                               | Review patient's concomitant medications                                                                             |                   |
| < 550 msec                             | for QT interval-prolonging agents. Correct  any electrolyte abnormalities. Continue sunitinib at current dose level. |                   |
| Fatigue (lethargy,  malaise, asthenia) | D                                                                                                                    |                   |  
Table 16. Dosage Modification Criteria for Sunitinib –related Toxicities  
| > 550 msec                                                      | Stop sunitinib and any other QT-interval  prolonging agents immediately. Correct  any electrolyte abnormalities, then If there is a plausible explanation for AE  other than sunitinib treatment, resume  sunitinib at current dose level. If sunitinib may have contributed to the  AE: Reduce 2 dose levels and restart sunitinib.  If QTc remains <500 msec after 14 days at  reduced dose, increase one dose level and  continue sunitinib.  If QTc remains <500 msec after 14 days,  original dose of sunitinib may be resumed.   |
|-----------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| QTc prolongation  Do not use  CTCAE v4 grades  V Grades 1 and 2 | Maintain dose                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          |
| Grade 3*                                                        | Hold sunitinib until < grade 1, then resume  treatment at same dose or reduce 1 dose  level                                                                                                                                                                                                                                                                                                                                                                                                                                            |
| AST and/or ALT  elevation (SGOT, SGPT) Hand-foot  syndrome      | O                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      |
| Grades 1-4                                                      | Maintain dose *                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        |
|                                                                 | *Recurrent grade 3 events require dose reduction.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      |  
Table 17. Management of Other Clinically Significant Sunitinib-related AEs  
| I                                                                                                                                                     |                                                |    |
|-------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------|----|
| (not specifically addressed above)                                                                                                                    |                                                |    |
| Observation                                                                                                                                           | Action                                         |    |
| AE resolves promptly with supportive care                                                                                                             | Maintain dose level                            |    |
| 1.                                                                                                                                                    | Grade 3 or higher (non-hematologic or grade 4  |    |
| (hematologic) AE related to sunitinib and lasting >5  days that does not resolve to grade 2 or below despite  maximum supportive care for < 48 hours. | Reduce one dose level                          |    |
| 2.                                                                                                                                                    | Lower grade but related AEs (e.g., creatinine) | D  |
| AE does not resolve to grade 2 or below after treating  patient at the lowest (i.e., 25* mg or 12.5* daily)  reduced dose level.                      | In general, remove patient from study**        |    |  
* 25 mg if the patients start dosing at 50 mg on a 4/2 schedule (solid tumors) or 12.5 mg if patients start dosing at 37.5 mg ** After consultation with study sponsor (DCTD, NCI), a dose of 25 mg daily may be considered for patients on study > 3 months who are benefiting from the agent.
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6.3 treatment delays and modifications

Brief interruptions and delays may occasionally be required due to travel delays, airport closure, inclement weather, family responsibilities, security alerts, and government holidays, etc. These delays will not be considered protocol deviations, and will not be separately reported. A patient that interrupts therapy for more than 21 days will be taken off treatment.
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6.4 treatment delays and modifications

V
Patients experiencing complications of their disease or other medical illness not attributable to disease progression, or protocol therapy may also require brief interruptions and delays that will not be considered protocol deviations, and will not be separately reported. A patient that interrupts therapy for more than 21 days will be taken off treatment.
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7 adverse events list and

Adverse event monitoring and reporting is a routine part of every clinical trial. The following list of adverse events (Section 7.3) and the characteristics of an observed adverse event (Section 7.4) will determine whether the event requires expedited (via CTEP-AERS; Section 7.5) or routine (via CTMS or CDUS; Section 7.6) reporting.  
O
The following sections related to adverse event monitoring and reporting apply only to patients receiving treatment under one of the experimental arms (Erlotinib, AZD6244, MK2206, Lapatinib and Sunitinib). No toxicity data will be reported to CTEP for patients being followed under the NOS arm or individuals enrolled for germline mutation testing and follow-up only; applicable side effects occurring in these participants will be reported to the IRB.
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7.1 comprehensive adverse events and

I
The Comprehensive Adverse Event and Potential Risks list (CAEPR) was developed to provide a single, complete list of reported and/or potential adverse events associated with an agent using a uniform presentation of adverse events by body system. In addition to the comprehensive list, the subset of those events that are "expected" [i.e., the Agent Specific Adverse Event List (ASAEL)] is presented in a separate column and identified with bold and italicized text. This subset is used to guide expedited reporting requirements. 7.1.1 CAEPRs for CTEP-Supplied Investigational Agent(s) 7.1.1.1 Erlotinib (OSI-774, NSC 718781)
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for erlotinib (tarceva nsc 718781)

The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of reported and/or potential adverse events (AE) associated with an agent using a uniform presentation of events by body system. In addition to the comprehensive list, a subset, the Specific Protocol Exceptions to Expedited Reporting (SPEER), appears in a separate column and is identified with bold and italicized  
text. This subset of AEs (SPEER) is a list of events that are protocol specific exceptions to expedited reporting to NCI (except as noted below). Refer to the 'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf for further clarification. *Frequency is provided based on 3622 patients.* Below is the CAEPR for erlotinib
(Tarceva®).  
NOTE: Report AEs on the SPEER **ONLY IF** they exceed the grade noted in parentheses next to the AE in the SPEER. If this CAEPR is part of a combination protocol using multiple investigational agents and has an AE listed on different SPEERs, use the lower of the grades to determine if expedited reporting is required.  
| V                                                                | 2015( 77)                                                                                                                  |                        |    |
|------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------|------------------------|----|
| Adverse Events with Possible                                     |                                                                                                                            |                        |    |
| Relationship to Erlotinib (Tarceva®)  (CTCAE 4.0 Term) [n= 3622] | Specific Protocol                                                                                                          |                        |    |
| Exceptions to Expedited  Reporting (SPEER)                       |                                                                                                                            |                        |    |
| Likely (>20%)                                                    | Less Likely (<=20%)                                                                                                        | Rare but Serious (<3%) |    |
| BLOOD AND LYMPHATIC SYSTEM DISORDERS                             | Disseminated intravascular  coagulation( 104)  Hemolytic uremic syndrome( 104)  Thrombotic thrombocytopenic  purpura( 104) |                        |    |
| CARDIAC DISORDERS                                                | Myocardial infarction( 104)                                                                                                |                        |    |
| EYE DISORDERS                                                    | Conjunctivitis                                                                                                             | Conjunctivitis (Gr 2)  |    |
| Dry eye                                                          | Dry eye (Gr 2)                                                                                                             |                        |    |
| Eye disorders - Other (corneal  perforation)                     |                                                                                                                            |                        |    |
| Eye disorders - Other (eyelash ingrowth and/or thickening)                                                                  | Keratitis                                                                                                                  |                        |    |
| GASTROINTESTINAL DISORDERS Abdominal pain                        | Abdominal pain (Gr 3)                                                                                                      |                        |    |
| Diarrhea                                                         | Diarrhea (Gr 3)                                                                                                            |                        |    |
| Dry mouth                                                        | Dry mouth (Gr 2)                                                                                                           |                        |    |
| Dyspepsia                                                        | Dyspepsia (Gr 2)                                                                                                           |                        |    |
| Gastrointestinal hemorrhage( 105)                                | Gastrointestinal perforation( 106)                                                                                         |                        |    |
| Mucositis oral                                                   | Mucositis oral (Gr 3)                                                                                                      |                        |    |
| Nausea                                                           | Nausea (Gr 3)                                                                                                              |                        |    |
| Vomiting                                                         | Vomiting (Gr 3)                                                                                                            |                        |    |
| GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS Fatigue     | Fatigue (Gr 3)                                                                                                             |                        |    |
| HEPATOBILIARY DISORDERS                                          | Hepatic failure                                                                                                            |                        |    |
| INFECTIONS AND INFESTATIONS Skin infection( 107)                 | Skin infection( 107) (Gr 2)                                                                                                |                        |    |
| INVESTIGATIONS                                                   | O                                                                                                                          | I                      | D  |  
  
| Adverse Events with Possible                                                                                    |                                            |                        |
|-----------------------------------------------------------------------------------------------------------------|--------------------------------------------|------------------------|
| Relationship to Erlotinib (Tarceva®)  (CTCAE 4.0 Term) [n= 3622]                                                | Specific Protocol                          |                        |
| Exceptions to Expedited  Reporting (SPEER)                                                                      |                                            |                        |
| Likely (>20%)                                                                                                   | Less Likely (<=20%)                        | Rare but Serious (<3%) |
| Alanine aminotransferase increased                                                                              | Alanine aminotransferase  increased (Gr 3) |                        |
| Alkaline phosphatase increased Aspartate aminotransferase                                                       | Aspartate aminotransferase                 |                        |
| increased                                                                                                       | increased (Gr 3)                           |                        |
| Blood bilirubin increased                                                                                       | Blood bilirubin increased (Gr  3)          |                        |
| METABOLISM AND NUTRITION DISORDERS Anorexia                                                                     | Anorexia (Gr 3)                            |                        |
| Dehydration                                                                                                     | Dehydration (Gr 3)                         |                        |
| NERVOUS SYSTEM DISORDERS Dysgeusia                                                                              | Dysgeusia (Gr 2)                           |                        |
| Headache                                                                                                        | Headache (Gr 2)                            |                        |
| Intracranial hemorrhage Ischemia cerebrovascular( 104)                                                          |                                            |                        |
| RENAL AND URINARY DISORDERS                                                                                     | Acute kidney injury                        |                        |
| RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS Cough                                                           | Cough (Gr 2)                               |                        |
| Dyspnea                                                                                                         | Dyspnea (Gr 3)                             |                        |
| Epistaxis Pneumonitis                                                                                           | Pneumonitis (Gr 3)                         |                        |
| SKIN AND SUBCUTANEOUS TISSUE DISORDERS Alopecia                                                                 | Alopecia (Gr 2)                            |                        |
| Dry skin                                                                                                        | Dry skin (Gr 2)                            |                        |
| Erythema multiforme                                                                                             |                                            |                        |
| Nail loss                                                                                                       | Nail loss (Gr 2)                           |                        |
| Palmar-plantar  erythrodysesthesia syndrome                                                                     |                                            |                        |
| Pruritus                                                                                                        | Pruritus (Gr 2)                            |                        |
| Rash acneiform                                                                                                  | Rash acneiform (Gr 2)                      |                        |
| Rash maculo-papular                                                                                             | Rash maculo-papular (Gr 3)                 |                        |
| Stevens-Johnson syndrome Toxic epidermal necrolysis                                                             |                                            |                        |
| V                                                                                                               | O                                          | I                      |
| 1This table will be updated as the toxicity profile of the agent is revised. Updates will be distributed to all |                                            |                        |  
1This table will be updated as the toxicity profile of the agent is revised. Updates will be distributed to all Principal Investigators at the time of revision. The current version can be obtained by contacting PIO@CTEP.NCI.NIH.GOV. Your name, the name of the investigator, the protocol and the agent should be included in the e-mail.  
2The risk of myocardial infarction, cerebrovascular accident, and microangiopathic hemolytic anemia is increased in patients with pancreatic cancer who were treated concomitantly with gemcitabine.  
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3Gastrointestinal hemorrhage includes Anal hemorrhage, Cecal hemorrhage, Colonic hemorrhage, Duodenal hemorrhage, Esophageal hemorrhage, Esophageal varices hemorrhage, Gastric hemorrhage, Hemorrhoidal hemorrhage, Ileal hemorrhage, Intra-abdominal hemorrhage, Jejunal hemorrhage, Lower gastrointestinal hemorrhage, Oral hemorrhage, Pancreatic hemorrhage, Rectal hemorrhage, Retroperitoneal hemorrhage, and Upper gastrointestinal hemorrhage under the GASTROINTESTINAL DISORDERS SOC.  
4Gastrointestinal perforation includes Colonic perforation, Duodenal perforation, Esophageal perforation, Gastric perforation, Ileal perforation, Jejunal perforation, Rectal perforation, and Small intestinal perforation under the GASTROINTESTINAL DISORDERS SOC.  
5Includes infection of the skin (folliculitis or cellulitis) as complications of rash.  
Adverse events reported on erlotinib (Tarceva®) **trials, but for which there is insufficient evidence** to suggest that there was a reasonable possibility that erlotinib (Tarceva®) caused the adverse event:
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EYE DISORDERS - Blurred vision; Eye disorders - Other (orbital cellulitis); Uveitis; Watering eyes GASTROINTESTINAL DISORDERS - Colitis; Constipation; Duodenal ulcer; Dysphagia; Esophagitis; Gastric ulcer; Gastritis; Gastrointestinal disorders - Other (pneumatosis intestinalis); Pancreatitis GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Edema limbs HEPATOBILIARY DISORDERS - Cholecystitis INVESTIGATIONS - Creatinine increased; INR increased (in patients taking Coumadin); Lymphocyte count decreased; Platelet count decreased METABOLISM AND NUTRITION DISORDERS - Hyperglycemia; Hyperkalemia; Hypocalcemia; Hypokalemia; Hypomagnesemia; Hyponatremia; Hypophosphatemia MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Generalized muscle weakness NERVOUS SYSTEM DISORDERS - Dizziness; Peripheral sensory neuropathy PSYCHIATRIC DISORDERS - Confusion RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Adult respiratory distress syndrome; Pharyngolaryngeal pain SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Urticaria VASCULAR DISORDERS - Thromboembolic event O
Note: Erlotinib (Tarceva®) in combination with other agents could cause an exacerbation of any adverse event currently known to be caused by the other agent, or the combination may result in events never previously associated with either agent.  
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Note: Erlotinib (Tarceva®)-induced diarrhea and/or vomiting has been associated with dehydration, hyperkalemia; hypocalcemia; hypokalemia; hypomagnesemia; hyponatremia; hypophosphatemia, increased creatinine, and renal failure.  
Note: Cases of hepatic failure and hepatorenal syndrome (including fatalities) have been reported during use of erlotinib (Tarceva®) in patients with or without baseline hepatic impairment.  
7.1.1.2 Comprehensive Adverse Events and Potential Risks list (CAEPR) for Selumetinib
(AZD6244 Free base [NSC 741078], AZD6244 Hydrogen sulfate [NSC 748727])
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The Comprehensive Adverse Event and Potential Risks list (CAEPR) provides a single list of reported and/or potential adverse events (AE) associated with an agent using a uniform presentation of events by body system. In addition to the comprehensive list, a subset, the Specific Protocol Exceptions to Expedited Reporting (SPEER), appears in a separate column and is identified with *bold* and *italicized* text. This subset of AEs (SPEER) is a list of events that are protocol specific exceptions to expedited reporting to NCI via CTEP-AERS (except as noted below). Refer to the 'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf for  
further clarification. *Frequency is provided based on 665 patients.* Below is the CAEPR for Selumetinib (AZD6244).  
NOTE: Report AEs on the SPEER **ONLY IF** they exceed the grade noted in parentheses next to the AE in the SPEER. If this CAEPR is part of a combination protocol using multiple investigational agents and has an AE listed on different SPEERs, use the lower of the grades to determine if expedited reporting is required.  
| V                                                                                                                                                  | Version 2.4, February 26, 20131 Specific Protocol Exceptions  to Expedited Reporting  (SPEER)  (formerly known as ASAEL)   |                           |
|----------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------|---------------------------|
| Likely (>20%)                                                                                                                                      | Less Likely (<=20%)                                                                                                        | Rare but Serious (<3%)    |
| BLOOD AND LYMPHATIC SYSTEM DISORDERS Anemia                                                                                                        | Anemia (Gr 3)                                                                                                              |                           |
| Febrile neutropenia2                                                                                                                               |                                                                                                                            |                           |
| CARDIAC DISORDERS                                                                                                                                  | Left ventricular systolic                                                                                                  | Left ventricular systolic |
| dysfunction                                                                                                                                        | dysfunction (Gr 2)                                                                                                         |                           |
| GASTROINTESTINAL DISORDERS Abdominal pain                                                                                                          | Abdominal pain (Gr 2)                                                                                                      |                           |
| Constipation                                                                                                                                       | Constipation (Gr 2)                                                                                                        |                           |
| Diarrhea3                                                                                                                                          | Diarrhea3 (Gr 3)                                                                                                           |                           |
| Dry mouth Mucositis oral                                                                                                                           | Mucositis oral (Gr 2)                                                                                                      |                           |
| Nausea                                                                                                                                             | Nausea (Gr 3)                                                                                                              |                           |
| Vomiting                                                                                                                                           | Vomiting (Gr 2)                                                                                                            |                           |
| GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS Edema face                                                                                    | Edema face (Gr 2)                                                                                                          |                           |
| Edema limbs                                                                                                                                        | Edema limbs (Gr 2)                                                                                                         |                           |
| Fatigue                                                                                                                                            | Fatigue (Gr 2)                                                                                                             |                           |
| Fever                                                                                                                                              | Fever (Gr 2)                                                                                                               |                           |
| INVESTIGATIONS                                                                                                                                     | Alanine aminotransferase                                                                                                   | Alanine aminotransferase  |
| increased                                                                                                                                          | increased (Gr 3)                                                                                                           |                           |
| Alkaline phosphatase increased Aspartate aminotransferase                                                                                          | Aspartate aminotransferase                                                                                                 |                           |
| increased                                                                                                                                          | increased (Gr 3)                                                                                                           |                           |
| Platelet count decreased                                                                                                                           |                                                                                                                            |                           |
| METABOLISM AND NUTRITION DISORDERS Anorexia                                                                                                        | Anorexia (Gr 2)                                                                                                            |                           |
| Hypoalbuminemia Hypomagnesemia                                                                                                                     |                                                                                                                            |                           |
| NERVOUS SYSTEM DISORDERS Dizziness Headache                                                                                                        | Headache (Gr 2)                                                                                                            |                           |
| PSYCHIATRIC DISORDERS                                                                                                                              | Insomnia                                                                                                                   |                           |
| RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS Adverse Events with Possible  Relationship to Selumetinib (AZD6244)  (CTCAE 4.0 Term) [n= 665] O I | D                                                                                                                          |                           |  
| Cough                                           | Cough (Gr 2)               |
|-------------------------------------------------|----------------------------|
| Dyspnea                                         | Dyspnea (Gr 2)             |
| SKIN AND SUBCUTANEOUS TISSUE DISORDERS Dry skin | Dry skin (Gr 2)            |
| Pruritus                                        |                            |
| Rash acneiform                                  | Rash acneiform (Gr 3)      |
| Rash maculo-papular                             | Rash maculo-papular (Gr 2) |
| VASCULAR DISORDERS                              | Hypertension               |  
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1This table will be updated as the toxicity profile of the agent is revised. Updates will be distributed to all Principal Investigators at the time of revision. The current version can be obtained by contacting PIO@CTEP.NCI.NIH.GOV. Your name, the name of the investigator, the protocol and the agent should be included in the e-mail.  
2Febrile neutropenia/neutropenic infection has been observed primarily in trials combining Selumetinib (AZD6244)
and docetaxel.  
3SBE-CD (Captisol®, vehicle) in the mix and drink formulation is known to cause soft stools and/or diarrhea in rats and dogs; however, it is possible that some of these findings might be related to exacerbation of the vehicle effect by Selumetinib (AZD6244).  
4Infection includes all 75 sites of infection under the INFECTIONS AND INFESTATIONS SOC.  
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Also reported on Selumetinib (AZD6244) trials but with the relationship to Selumetinib (AZD6244) still undetermined: BLOOD AND LYMPHATIC SYSTEM DISORDERS - Blood and lymphatic system disorders - Other (hemorrhagic anemia)
CARDIAC DISORDERS - Acute coronary syndrome; Cardiac disorders - Other (Takatsubo cardiomyopathy syndrome); Chest pain - cardiac; Heart failure; Palpitations; Right ventricular dysfunction; Sinus bradycardia EYE DISORDERS - Blurred vision; Extraocular muscle paresis; Eye disorders - Other (bilateral macular edema);
Eye disorders - Other (black haze in line of vision); Eye disorders - Other (elevated intraocular pressure); Flashing lights; Glaucoma; Retinopathy GASTROINTESTINAL DISORDERS - Abdominal distension; Ascites; Colitis; Dyspepsia; Esophagitis; Flatulence; Gastric hemorrhage; Gastroesophageal reflux disease; Ileal stenosis GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Flu like symptoms; Non-cardiac chest pain HEPATOBILIARY DISORDERS - Hepatic failure; Hepatobiliary disorders - Other (cholangitis)
INFECTIONS AND INFESTATIONS - Infection4 I
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INVESTIGATIONS - CPK increased; Creatinine increased; Electrocardiogram QT corrected interval prolonged; Neutrophil count decreased; Weight gain METABOLISM AND NUTRITION DISORDERS - Dehydration; Hypokalemia; Hyponatremia MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthralgia; Back pain; Generalized muscle weakness; Musculoskeletal and connective tissue disorder - Other (joint swelling); Musculoskeletal and connective tissue disorder - Other (rhabdomyolysis); Myalgia; Myositis; Pain in extremity NERVOUS SYSTEM DISORDERS - Cognitive disturbance; Depressed level of consciousness; Dysgeusia; Dysphasia; Ischemia cerebrovascular; Leukoencephalopathy; Memory impairment; Nervous system disorders -  
Other (numbness); Nervous system disorders - Other (spinal cord compression); Oculomotor nerve disorder; Peripheral sensory neuropathy; Reversible posterior leukoencephalopathy syndrome; Seizure
untitled h1
psychiatric disorders - confusion depression

RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Adult respiratory distress syndrome; Epistaxis; Hypoxia; Pharyngolaryngeal pain; Pleural effusion; Pneumonitis; Sore throat; Voice alteration SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Pain of skin; Palmar-plantar erythrodysesthesia syndrome; Photosensitivity; Scalp pain; Skin and subcutaneous tissue disorders - Other (angular cheilitis, unilateral); Skin and subcutaneous tissue disorders - Other (skin fissures)
VASCULAR DISORDERS - Hypotension; Thromboembolic event Note: Selumetinib (AZD6244) in combination with other agents could cause an exacerbation of any adverse event currently known to be caused by the other agent, or the combination may result in events never previously associated with either agent.  
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7.1.1.3 Comprehensive Adverse Event and Potential Risks list (CAEPR) for MK-2206 (NSC
749607)
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of reported and/or potential adverse events (AE) associated with an agent using a uniform presentation of events by body system. In addition to the comprehensive list, a subset, the Specific Protocol Exceptions to Expedited Reporting (SPEER), appears in a separate column and is identified with bold and italicized text. This subset of AEs (SPEER) is a list of events that are protocol specific exceptions to expedited reporting to NCI (except as noted below). Refer to the 'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf for further clarification. Frequency is provided based on 245 patients. Below is the CAEPR for MK2206.  
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NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses next to  
 the AE in the SPEER. If this CAEPR is part of a combination protocol using multiple investigational agents and has an AE listed on different SPEERs, use the lower of the grades to determine if expedited reporting is required.  
| Version 2.2, June 16, 2015( 77)                                                 |                                                               |                        |
|---------------------------------------------------------------------------------|---------------------------------------------------------------|------------------------|
| Adverse Events with Possible  Relationship to MK-2206 (CTCAE 4.0 Term) [n= 245] | Specific Protocol Exceptions  to Expedited Reporting  (SPEER) |                        |
| D                                                                               |                                                               |                        |
| Likely (>20%)                                                                   | Less Likely (<=20%)                                           | Rare but Serious (<3%) |
| BLOOD AND LYMPHATIC SYSTEM DISORDERS Anemia CARDIAC DISORDERS Sinus bradycardia | Sinus bradycardia (Gr 2)                                      |                        |
| GASTROINTESTINAL DISORDERS Diarrhea                                             | Diarrhea (Gr 3)                                               |                        |
| Mucositis oral                                                                  | Mucositis oral (Gr 3)                                         |                        |
| Nausea                                                                          | Nausea (Gr 2)                                                 |                        |
| Vomiting                                                                        | Vomiting (Gr 3)                                               |                        |  
Version 2.2, June 16, 2015(77)
74  
| Adverse Events with Possible  Relationship to MK-2206 (CTCAE 4.0 Term) [n= 245]   | Specific Protocol Exceptions  to Expedited Reporting  (SPEER)                                                                                                |                                |
|-----------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------|
| Likely (>20%)                                                                     | Less Likely (<=20%)                                                                                                                                          | Rare but Serious (<3%)         |
| GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS Fatigue                      | Fatigue (Gr 3)                                                                                                                                               |                                |
| Fever                                                                             | Fever (Gr 2)                                                                                                                                                 |                                |
| INVESTIGATIONS                                                                    | Alanine aminotransferase  increased Alkaline phosphatase increased Aspartate aminotransferase  increased Creatinine increased Electrocardiogram QT corrected | Electrocardiogram QT corrected |
| interval prolonged                                                                | interval prolonged (Gr 2)                                                                                                                                    |                                |
| Hemoglobin increased Investigations - Other                                       | Investigations - Other                                                                                                                                       |                                |
| (eosinophilia)                                                                    | (eosinophilia) (Gr 2)                                                                                                                                        |                                |
| Investigations - Other (insulin cpeptide increased) Lymphocyte count decreased                                                                                   | Lymphocyte count decreased (Gr  4)                                                                                                                           |                                |
| Neutrophil count decreased                                                        | Neutrophil count decreased (Gr 4)                                                                                                                            |                                |
| Platelet count decreased Weight loss White blood cell decreased                   | White blood cell decreased (Gr 2)                                                                                                                            |                                |
| METABOLISM AND NUTRITION DISORDERS Anorexia                                       | Anorexia (Gr 2)                                                                                                                                              |                                |
| Hyperglycemia                                                                     | Hyperglycemia (Gr 3)                                                                                                                                         |                                |
| Hypocalcemia Hyponatremia                                                         |                                                                                                                                                              |                                |
| NERVOUS SYSTEM DISORDERS Dysgeusia Headache                                       | Headache (Gr 2)                                                                                                                                              |                                |
| SKIN AND SUBCUTANEOUS TISSUE DISORDERS Dry skin                                   | Dry skin (Gr 2)                                                                                                                                              |                                |
| Pruritus                                                                          | Pruritus (Gr 2)                                                                                                                                              |                                |
| Rash maculo-papular                                                               | Rash maculo-papular (Gr 3)                                                                                                                                   |                                |
| V                                                                                 | O                                                                                                                                                            | I                              |  
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1This table will be updated as the toxicity profile of the agent is revised. Updates will be distributed to all Principal Investigators at the time of revision. The current version can be obtained by contacting PIO@CTEP.NCI.NIH.GOV. Your name, the name of the investigator, the protocol and the agent should be included in the e-mail. Adverse events reported on MK-2206 trials, but for which there is insufficient evidence to suggest that there was a reasonable possibility that MK-2206 caused the adverse event: Blood and lymphatic system disorders - Febrile neutropenia; Hemolysis; Hemolytic uremic syndrome; Leukocytosis  
Cardiac disorders - Atrioventricular block complete; Left ventricular systolic dysfunction; Myocardial infarction; Palpitations; Ventricular arrhythmia Ear and labyrinth disorders - Vertigo
untitled h1
endocrine disorders - hypothyroidism

Eye disorders - Blurred vision; Conjunctivitis; Dry eye; Extraocular muscle paresis; Eye disorders - Other
(blepharitis); Eye disorders - Other (eye swelling); Eye disorders - Other (foreign body sensation in eyes); Eye disorders - Other (iritis); Eye disorders - Other (mydriasis); Eye disorders - Other (visual acuity reduced); Eye pain; Floaters; Keratitis; Photophobia; Retinal detachment; Uveitis Gastrointestinal disorders - Abdominal distension; Abdominal pain; Ascites; Cheilitis; Colonic perforation; Constipation; Dry mouth; Dyspepsia; Dysphagia; Gastritis; Gastrointestinal disorders - Other (oropharyngeal pain);
Lip pain; Toothache General disorders and administration site conditions - Chills; Edema face; Edema limbs; Flu like symptoms; General disorders and administration site conditions - Other (throat tightness); Injection site reaction; Irritability; Localized edema; Non-cardiac chest pain; Pain Immune system disorders - Allergic reaction Infections and infestations - Infections and infestations - Other (herpetic vesicular rash [due to herpes zoster infection]); Infections and infestations - Other (oral herpes); Lung infection; Nail infection; Paronychia; Pharyngitis; Rhinitis infective; Sepsis; Sinusitis; Skin infection; Urinary tract infection Injury, poisoning and procedural complications - Fall Investigations - Activated partial thromboplastin time prolonged; Blood bilirubin increased; INR increased; Investigations - Other (blood LDH increased); Investigations - Other (hyperinsulinemia); Lipase increased; Serum amylase increased; Weight gain Metabolism and nutrition disorders - Dehydration; Hypercalcemia; Hyperkalemia; Hypermagnesemia; Hypoalbuminemia; Hypokalemia; Hypomagnesemia; Hypophosphatemia Musculoskeletal and connective tissue disorders - Arthralgia; Back pain; Bone pain; Generalized muscle weakness; Myalgia; Neck pain; Pain in extremity Nervous system disorders - Akathisia; Dizziness; Encephalopathy; Lethargy; Presyncope; Reversible posterior leukoencephalopathy syndrome; Seizure; Syncope; Tremor Psychiatric disorders - Anxiety; Confusion; Depression; Insomnia Renal and urinary disorders - Acute kidney injury; Proteinuria; Renal and urinary disorders - Other (renal tubular necrosis); Renal and urinary disorders - Other (glucose urine present); Urinary incontinence; Urinary tract pain Reproductive system and breast disorders - Gynecomastia; Vaginal hemorrhage; Vaginal perforation Respiratory, thoracic and mediastinal disorders - Bronchial obstruction; Cough; Dyspnea; Epistaxis; Hypoxia; Pneumonitis; Pulmonary edema; Respiratory failure; Sore throat Skin and subcutaneous tissue disorders - Alopecia; Erythema multiforme; Erythroderma; Hyperhidrosis; Palmarplantar erythrodysesthesia syndrome; Photosensitivity; Purpura; Rash acneiform; Skin and subcutaneous tissue disorders - Other (skin irritation); Stevens-Johnson syndrome; Urticaria Vascular disorders - Hematoma; Hypertension; Hypotension; Thromboembolic event Note: MK-2206 in combination with other agents could cause an exacerbation of any adverse event currently known to be caused by the other agent, or the combination may result in events never previously associated with either agent.  
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7.1.1.4 Comprehensive Adverse Event and Potential Risks list (CAEPR) for GW572016
(Lapatinib, Tykerb, NSC 727989)
The Comprehensive Adverse Event and Potential Risks list (CAEPR) provides a single list of reported and/or potential adverse events (AE) associated with an agent using a uniform presentation of events by body system. In addition to the comprehensive list, a subset, the Specific Protocol Exceptions to Expedited Reporting (SPEER), appears in a separate column and is identified with bold and italicized text. This subset of AEs (SPEER) is a list of events that are protocol specific exceptions to expedited reporting to NCI via CTEP-AERS (except as noted below). Refer to the 'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf for further clarification. *Frequency is provided based on 1890 patients.* Below is the CAEPR for GW572016 (lapatinib, Tykerb).  
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NOTE: Report AEs on the SPEER **ONLY IF** they exceed the grade noted in parentheses next to the AE in the SPEER. If this CAEPR is part of a combination protocol using multiple investigational agents and has an AE listed on different SPEERs, use the lower of the grades to determine if expedited reporting is required.  
| O                                                                       | Version 2.6, February 28, 20131    |                           |
|-------------------------------------------------------------------------|------------------------------------|---------------------------|
| Adverse Events with Possible                                            |                                    |                           |
| Relationship to GW572016 (lapatinib, Tykerb) (CTCAE 4.0 Term) [n= 1890] | Specific Protocol                  |                           |
| Exceptions to Expedited  Reporting (SPEER)                              |                                    |                           |
| Likely (>20%)                                                           | Less Likely (<=20%)                | Rare but Serious (<3%)    |
| CARDIAC DISORDERS                                                       | Left ventricular systolic          | Left ventricular systolic |
| dysfunction                                                             | dysfunction (Gr 2)                 |                           |
| GASTROINTESTINAL DISORDERS Abdominal distension                         | Abdominal distension (Gr 2)        |                           |
| Abdominal pain                                                          | Abdominal pain (Gr 2)              |                           |
| Anal mucositis                                                          | Anal mucositis (Gr 2)              |                           |
| Diarrhea                                                                | Diarrhea (Gr 3)                    |                           |
| Dyspepsia                                                               | Dyspepsia (Gr 2)                   |                           |
| Flatulence                                                              | Flatulence (Gr 2)                  |                           |
| Mucositis oral                                                          | Mucositis oral (Gr 2)              |                           |
| Nausea                                                                  | Nausea (Gr 3)                      |                           |
| Rectal mucositis                                                        | Rectal mucositis (Gr 2)            |                           |
| Small intestinal mucositis                                              | Small intestinal mucositis  (Gr 2) |                           |
| Vomiting                                                                | Vomiting (Gr 2)                    |                           |
| GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS Fatigue            | Fatigue (Gr 2)                     |                           |
| Flu like symptoms                                                       | Flu like symptoms (Gr 2)           |                           |
| HEPATOBILIARY DISORDERS                                                 | Hepatic failure                    | Hepatic failure (Gr 2)    |
| IMMUNE SYSTEM DISORDERS                                                 | Allergic reaction I                | D                         |  
| INVESTIGATIONS                                                      | Alanine aminotransferase             | Alanine aminotransferase   |
|---------------------------------------------------------------------|--------------------------------------|----------------------------|
| increased                                                           | increased (Gr 2)                     |                            |
| Aspartate aminotransferase                                          | Aspartate aminotransferase           |                            |
| increased                                                           | increased (Gr 2)                     |                            |
| Blood bilirubin increased                                           | Blood bilirubin increased (Gr  2)    |                            |
| Electrocardiogram QT                                                | Electrocardiogram QT                 |                            |
| corrected interval prolonged                                        | corrected interval prolonged  (Gr 2) |                            |
| METABOLISM AND NUTRITION DISORDERS Anorexia                         | Anorexia (Gr 2)                      |                            |
| Dehydration                                                         | Dehydration (Gr 2)                   |                            |
| NERVOUS SYSTEM DISORDERS Dysgeusia                                  | Dysgeusia (Gr 2)                     |                            |
| Headache                                                            | Headache (Gr 2)                      |                            |
| RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS Laryngeal mucositis | Laryngeal mucositis (Gr 2)           |                            |
| Pharyngeal mucositis                                                | Pharyngeal mucositis (Gr 2)          |                            |
| Pneumonitis                                                         |                                      |                            |
| Tracheal mucositis                                                  | Tracheal mucositis (Gr 2)            |                            |
| SKIN AND SUBCUTANEOUS TISSUE DISORDERS Nail loss Pruritus           | Pruritus (Gr 2)                      |                            |
| Rash acneiform                                                      | Rash acneiform (Gr 2)                |                            |
| Rash maculo-papular                                                 | Rash maculo-papular (Gr 2)           |                            |
| VASCULAR DISORDERS                                                  | Flushing                             | Flushing (Gr 2)            |
| V                                                                   | O                                    |                            |  
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1This table will be updated as the toxicity profile of the agent is revised. Updates will be distributed to all Principal Investigators at the time of revision. The current version can be obtained by contacting PIO@CTEP.NCI.NIH.GOV. Your name, the name of the investigator, the protocol and the agent should be included in the e-mail.  
2Gastrointestinal hemorrhage includes Anal hemorrhage, Cecal hemorrhage, Colonic hemorrhage, Duodenal hemorrhage, Esophageal hemorrhage, Esophageal varices hemorrhage, Gastric hemorrhage, Hemorrhoidal hemorrhage, Ileal hemorrhage, Intra-abdominal hemorrhage, Jejunal hemorrhage, Lower gastrointestinal hemorrhage, Oral hemorrhage, Pancreatic hemorrhage, Rectal hemorrhage, Retroperitoneal hemorrhage, and Upper gastrointestinal hemorrhage under the GASTROINTESTINAL DISORDERS SOC.  
3Gastrointestinal obstruction includes Colonic obstruction, Duodenal obstruction, Esophageal obstruction, Ileal obstruction, Jejunal obstruction, Obstruction gastric, Rectal obstruction, and Small intestinal obstruction under the GASTROINTESTINAL DISORDERS SOC.  
4Infection includes all 75 sites of infection under the INFECTIONS AND INFESTATIONS SOC.  
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Also reported on GW572016 (lapatinib, Tykerb) trials but with the relationship to GW572016 (lapatinib, Tykerb) still undetermined:
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Anemia; Febrile neutropenia CARDIAC DISORDERS - Atrial fibrillation; Restrictive cardiomyopathy
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eye disorders - blurred vision

GASTROINTESTINAL DISORDERS - Constipation; Dysphagia; Gastritis; Gastrointestinal hemorrhage2; Gastrointestinal obstruction3 GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Edema limbs; Fever; Pain INFECTIONS AND INFESTATIONS - Infection4 INVESTIGATIONS - Alkaline phosphatase increased; Creatinine increased; Lymphocyte count decreased; Neutrophil count decreased; Platelet count decreased; Weight loss; White blood cell decreased METABOLISM AND NUTRITION DISORDERS - Hyperglycemia; Hypoalbuminemia; Hypoglycemia; Hypokalemia; Hyponatremia; Hypophosphatemia MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthralgia; Back pain; Myalgia NERVOUS SYSTEM DISORDERS - Cerebrospinal fluid leakage; Depressed level of consciousness; Dizziness; Intracranial hemorrhage PSYCHIATRIC DISORDERS - Insomnia RENAL AND URINARY DISORDERS - Acute kidney injury RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Cough; Dyspnea; Epistaxis; Pleural effusion SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Dry skin; Palmar-plantar erythrodysesthesia syndrome; Skin and subcutaneous tissue disorders - Other (seborrheic dermatitis); Urticaria VASCULAR DISORDERS - Hypotension; Thromboembolic event; Vascular disorders - Other (hypovolemia)
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Note: GW572016 (lapatinib, Tykerb) in combination with other agents could cause an exacerbation of any adverse event currently known to be caused by the other agent, or the combination may result in events never previously associated with either agent.  
7.1.2 Adverse Event List(s) for Commercial Agent(s) 7.1.2.1 Sunitinib Malate (SU011248 L-malate, NSC 736511)
Comprehensive Adverse Events and Potential Risks list (CAEPR)
for
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sunitinib malate (su011248 l-malate nsc

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The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of reported and/or potential adverse events (AE) associated with an agent using a uniform presentation of events by body system. In addition to the comprehensive list, a subset, the Specific Protocol Exceptions to Expedited Reporting (SPEER), appears in a separate column and is identified with bold and italicized text. This subset of AEs (SPEER) is a list of events that are protocol specific exceptions to expedited reporting to NCI (except as noted below). Refer to the 'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf for further clarification. *Frequency is provided based on 7115 patients.* Below is the CAEPR for Sunitinib malate (SU011248 L-malate).  
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NOTE: Report AEs on the SPEER **ONLY IF** they exceed the grade noted in parentheses next to the AE in the SPEER. If this CAEPR is part of a combination protocol using multiple investigational agents and has an AE listed on different SPEERs, use the lower of the grades to determine if expedited reporting is required.  
Version 2.12, January 14,  
2016(108)  
| 2016(108)                                                                       |                                                                                                                        |                        |
|---------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------|------------------------|
| Adverse Events with Possible                                                    |                                                                                                                        |                        |
| Relationship to Sunitinib malate (SU011248 L-malate) (CTCAE 4.0 Term) [n= 7115] | Specific Protocol Exceptions  to Expedited Reporting  (SPEER)                                                          |                        |
| V                                                                               |                                                                                                                        |                        |
| Likely (>20%)                                                                   | Less Likely (<=20%)                                                                                                    | Rare but Serious (<3%) |
| BLOOD AND LYMPHATIC SYSTEM DISORDERS Anemia                                     | Anemia (Gr 3)                                                                                                          |                        |
| Hemolytic uremic  syndrome Thrombotic  thrombocytopenic purpura                 |                                                                                                                        |                        |
| CARDIAC DISORDERS                                                               | Cardiac disorders - Other  (cardiomyopathy) Heart failure Left ventricular systolic  dysfunction Myocardial infarction |                        |
| ENDOCRINE DISORDERS                                                             | Endocrine disorders - Other  (thyroiditis) Hyperthyroidism                                                             |                        |
| Hypothyroidism                                                                  | Hypothyroidism (Gr 2)                                                                                                  |                        |
| EYE DISORDERS                                                                   | Eye disorders - Other                                                                                                  | Eye disorders - Other  |
| (macular edema)                                                                 | (macular edema) (Gr 2)                                                                                                 |                        |
| Eye disorders - Other                                                           | Eye disorders - Other (vision                                                                                          |                        |
| (vision deterioration)                                                          | deterioration) (Gr 2)                                                                                                  |                        |
| Papilledema                                                                     | Papilledema (Gr 2)                                                                                                     |                        |
| GASTROINTESTINAL DISORDERS Abdominal distension                                 | Abdominal distension (Gr 2)                                                                                            |                        |
| Abdominal pain                                                                  | Abdominal pain (Gr 3)                                                                                                  |                        |
| Anal mucositis                                                                  | Anal mucositis (Gr 2)                                                                                                  |                        |
| Constipation                                                                    | Constipation (Gr 2)                                                                                                    |                        |
| Diarrhea                                                                        | Diarrhea (Gr 3)                                                                                                        |                        |
| Dry mouth                                                                       | Dry mouth (Gr 2)                                                                                                       |                        |
| Dyspepsia                                                                       | Dyspepsia (Gr 2)                                                                                                       |                        |
| Esophagitis                                                                     |                                                                                                                        |                        |
| Flatulence                                                                      | Flatulence (Gr 2)                                                                                                      |                        |
| Gastritis                                                                       | Gastritis (Gr 2)                                                                                                       |                        |
| Gastroesophageal reflux  disease                                                | Gastrointestinal  perforation(109)                                                                                     |                        |
| Mucositis oral                                                                  | Mucositis oral (Gr 3)                                                                                                  |                        |
| O                                                                               | I                                                                                                                      | D                      |
| 80                                                                              |                                                                                                                        |                        |  
| Adverse Events with Possible                                                                              |                                                               |                        |    |
|-----------------------------------------------------------------------------------------------------------|---------------------------------------------------------------|------------------------|----|
| Relationship to Sunitinib malate (SU011248 L-malate) (CTCAE 4.0 Term) [n= 7115]                           | Specific Protocol Exceptions  to Expedited Reporting  (SPEER) |                        |    |
| Likely (>20%)                                                                                             | Less Likely (<=20%)                                           | Rare but Serious (<3%) |    |
| Nausea                                                                                                    | Nausea (Gr 3)                                                 |                        |    |
| Oral pain                                                                                                 | Oral pain (Gr 2)                                              |                        |    |
| Pancreatitis                                                                                              |                                                               |                        |    |
| Rectal mucositis                                                                                          | Rectal mucositis (Gr 2)                                       |                        |    |
| Small intestinal                                                                                          | Small intestinal mucositis (Gr                                |                        |    |
| mucositis                                                                                                 | 2)                                                            |                        |    |
| Vomiting                                                                                                  | Vomiting (Gr 3)                                               |                        |    |
| GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS Chills                                               | Chills (Gr 2)                                                 |                        |    |
| Edema limbs                                                                                               | Edema limbs (Gr 2)                                            |                        |    |
| Fatigue                                                                                                   | Fatigue (Gr 3)                                                |                        |    |
| Fever                                                                                                     | Fever (Gr 2)                                                  |                        |    |
| Non-cardiac chest pain                                                                                    | Non-cardiac chest pain (Gr 2)                                 |                        |    |
| HEPATOBILIARY DISORDERS                                                                                   | Cholecystitis Hepatic failure                                 |                        |    |
| IMMUNE SYSTEM DISORDERS                                                                                   | Allergic reaction(110)                                        |                        |    |
| INFECTIONS AND INFESTATIONS                                                                               | Infection and infestations - Other (necrotizing fasciitis)    |                        |    |
| INJURY, POISONING AND PROCEDURAL COMPLICATIONS Wound complication INVESTIGATIONS Alanine aminotransferase | Alanine aminotransferase                                      |                        |    |
| increased                                                                                                 | increased (Gr 3)                                              |                        |    |
| Alkaline phosphatase                                                                                      | Alkaline phosphatase                                          |                        |    |
| increased                                                                                                 | increased  (Gr 2)                                             |                        |    |
| Aspartate aminotransferase                                                                                | Aspartate aminotransferase                                    |                        |    |
| increased                                                                                                 | increased (Gr 3)                                              |                        |    |
| Blood bilirubin increased                                                                                 | Blood bilirubin increased (Gr  2)                             |                        |    |
| CPK increased Creatinine increased                                                                        | Creatinine increased (Gr 3)                                   |                        |    |
| Electrocardiogram QT  corrected interval prolonged                                                        |                                                               |                        |    |
| Lipase increased                                                                                          | Lipase increased (Gr 4)                                       |                        |    |
| Lymphocyte count decreased                                                                                | Lymphocyte count decreased  (Gr 2)                            |                        |    |
| Neutrophil count decreased                                                                                | Neutrophil count decreased  (Gr 4)                            |                        |    |
| Platelet count decreased                                                                                  | Platelet count decreased (Gr  4)                              |                        |    |
| V                                                                                                         | O                                                             | I                      | D  |  
| Adverse Events with Possible                                                    |                                                                                            |                        |    |
|---------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------|------------------------|----|
| Relationship to Sunitinib malate (SU011248 L-malate) (CTCAE 4.0 Term) [n= 7115] | Specific Protocol Exceptions  to Expedited Reporting  (SPEER)                              |                        |    |
| Likely (>20%)                                                                   | Less Likely (<=20%)                                                                        | Rare but Serious (<3%) |    |
| Serum amylase increased                                                         | Serum amylase increased (Gr  2)                                                            |                        |    |
| Weight loss                                                                     | Weight loss (Gr 2)                                                                         |                        |    |
| White blood cell decreased                                                      | White blood cell decreased  (Gr 3)                                                         |                        |    |
| METABOLISM AND NUTRITION DISORDERS Anorexia                                     | Anorexia (Gr 3)                                                                            |                        |    |
| Dehydration                                                                     | Dehydration (Gr 3)                                                                         |                        |    |
| Hyperuricemia                                                                   | Hyperuricemia (Gr 2)                                                                       |                        |    |
| Hypoalbuminemia                                                                 | Hypoalbuminemia (Gr 2)                                                                     |                        |    |
| Hypoglycemia                                                                    |                                                                                            |                        |    |
| Hypophosphatemia                                                                | Hypophosphatemia (Gr 2)                                                                    |                        |    |
| Tumor lysis syndrome                                                            |                                                                                            |                        |    |
| MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS Arthralgia                      | Arthralgia (Gr 2)                                                                          |                        |    |
| Back pain                                                                       | Back pain (Gr 2)                                                                           |                        |    |
| Musculoskeletal and  connective tissue disorder -  Other (rhabdomyolysis)       |                                                                                            |                        |    |
| Myalgia                                                                         | Myalgia (Gr 2)                                                                             |                        |    |
| Osteonecrosis of jaw                                                            |                                                                                            |                        |    |
| Pain in extremity                                                               | Pain in extremity (Gr 2)                                                                   |                        |    |
| NERVOUS SYSTEM DISORDERS Dizziness Dysgeusia                                    | Dysgeusia (Gr 2)                                                                           |                        |    |
| Headache                                                                        | Headache (Gr 3)                                                                            |                        |    |
| Leukoencephalopathy Nervous system disorders - Other (cerebral infarction)      |                                                                                            |                        |    |
| Paresthesia                                                                     | Reversible posterior  leukoencephalopathy  syndrome Transient ischemic attacks             |                        |    |
| PSYCHIATRIC DISORDERS Depression Insomnia                                       | Insomnia (Gr 2)                                                                            |                        |    |
| RENAL AND URINARY DISORDERS                                                     | Acute kidney injury Proteinuria Renal and urinary disorders  - Other (nephrotic  syndrome) |                        |    |
| RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS Cough                           | Cough (Gr 2)                                                                               |                        |    |
| V                                                                               | O                                                                                          | I                      | D  |
| 82                                                                              |                                                                                            |                        |    |  
| Adverse Events with Possible                                                    |                                                                             |                        |
|---------------------------------------------------------------------------------|-----------------------------------------------------------------------------|------------------------|
| Relationship to Sunitinib malate (SU011248 L-malate) (CTCAE 4.0 Term) [n= 7115] | Specific Protocol Exceptions  to Expedited Reporting  (SPEER)               |                        |
| Likely (>20%)                                                                   | Less Likely (<=20%)                                                         | Rare but Serious (<3%) |
| Dyspnea                                                                         | Dyspnea (Gr 3)                                                              |                        |
| Epistaxis                                                                       | Epistaxis Gr 2)                                                             |                        |
| Laryngeal mucositis                                                             | Laryngeal mucositis (Gr 2)                                                  |                        |
| Pharyngeal mucositis                                                            | Pharyngeal mucositis (Gr 2)                                                 |                        |
| Tracheal mucositis                                                              | Tracheal mucositis (Gr 2)                                                   |                        |
| SKIN AND SUBCUTANEOUS TISSUE DISORDERS Alopecia                                 | Alopecia (Gr 2)                                                             |                        |
| Dry skin                                                                        | Dry skin (Gr 2)                                                             |                        |
| Erythema multiforme                                                             |                                                                             |                        |
| Palmar-plantar  erythrodysesthesia  syndrome V                                  | Palmar-plantar  erythrodysesthesia syndrome  (Gr 3)                         |                        |
| Pruritus Rash maculo-papular                                                    | Rash maculo-papular (Gr 3)                                                  |                        |
| Skin and subcutaneous tissue  disorders - Other (hair color  change) O          | Skin and subcutaneous tissue  disorders - Other (hair color  change) (Gr 2) |                        |
| Skin and subcutaneous  tissue disorders - Other  (pyoderma gangrenosum)         |                                                                             |                        |
| Skin hypopigmentation                                                           | Skin hypopigmentation (Gr 2)                                                |                        |
| Stevens-Johnson syndrome Toxic epidermal necrolysis                             |                                                                             |                        |
| VASCULAR DISORDERS Hypertension                                                 | Hypertension (Gr 3)                                                         |                        |
| Vascular disorders - Other  (hemorrhage)(111)                                   |                                                                             |                        |  
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1This table will be updated as the toxicity profile of the agent is revised. Updates will be distributed to all Principal Investigators at the time of revision. The current version can be obtained by contacting PIO@CTEP.NCI.NIH.GOV. Your name, the name of the investigator, the protocol and the agent should be included in the e-mail.  
2Gastrointestinal perforation includes Colonic perforation, Duodenal perforation, Esophageal perforation, Gastric perforation, Ileal perforation, Jejunal perforation, Rectal perforation, and Small intestinal perforation under the GASTROINTESTINAL DISORDERS SOC.  
3Allergic reactions observed include anaphylaxis and angioedema. 4The majority of hemorrhage events were mild. Major events, defined as symptomatic bleeding in a critical area or organ (e.g., eye, GI tract, GU system, respiratory tract, nervous system [including fatal intracranial hemorrhage, and cerebrovascular accident], and tumor site) have been reported.  
Adverse events reported on Sunitinib malate (SU011248 L-malate) trials, but for which there is insufficient evidence to suggest that there was a reasonable possibility that Sunitinib malate (SU011248 L-malate) caused the adverse event:
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blood and lymphatic system disorders

CARDIAC DISORDERS - Atrial fibrillation; Cardiac arrest; Pericardial effusion GASTROINTESTINAL DISORDERS - Ascites; Dysphagia; Gastrointestinal disorders - Other (enteritis); Hemorrhoids; Ileus; Small intestinal obstruction GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Pain INVESTIGATIONS - GGT increased; INR increased METABOLISM AND NUTRITION DISORDERS - Hypercalcemia; Hyperglycemia; Hyperkalemia; Hypocalcemia; Hypokalemia; Hyponatremia MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Bone pain NERVOUS SYSTEM DISORDERS - Cognitive disturbance; Nervous system disorders - Other (spinal cord compression); Peripheral sensory neuropathy; Seizure; Syncope PSYCHIATRIC DISORDERS - Anxiety; Confusion Renal and urinary disorders - Hematuria; Urinary retention REPRODUCTIVE SYSTEMS AND BREAST DISORDERS - Hematosalpinx RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Pharyngolaryngeal pain; Pleural effusion; Pneumothorax VASCULAR DISORDERS - Flushing; Hypotension; Thromboembolic event V
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Note: Sunitinib malate (SU011248 L-malate) in combination with other agents could cause an exacerbation of any adverse event currently known to be caused by the other agent, or the combination may result in events never previously associated with either agent.
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7.2 adverse event characteristics

7.2.1 CTCAE term (Adverse event description) and grade:
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The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for AE reporting. All appropriate treatment areas should have access to a copy of the CTCAE version 4.0. A copy of the CTCAE version 4.0 can be downloaded from the CTEP web site (http://ctep.cancer.gov). "Expectedness": Adverse events can be "Expected" (see Section 7.1) or unexpected. Bold and italicized terms in Section 7.1 identify expected events. See Section 7.5 for guidelines for reporting both types of events. 7.2.2 Attribution of the adverse event: Definite - The adverse event is clearly related to the study treatment. Probable - The adverse event is likely related to the study treatment. Possible - The adverse event may be related to the study treatment. Unlikely - The adverse event is doubtfully related to the study treatment. Unrelated - The adverse event is clearly NOT related to the study treatment.  
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7.3 expedited adverse event reporting

Expedited adverse event reporting for this study is via CTEP-AERS (CTEP Adverse Event Reporting System), accessed via the secure CTEP web site https://eappsctep.nci.nih.gov/ctepaers/pages/task?rand=1397144505895). The reporting procedures to be followed are presented in the "NCI Guidelines: Expedited Adverse Event Reporting Requirements for NCI Investigational Agents" which can be downloaded from the CTEP web site (http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf).  
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In the rare occurrence when Internet connectivity is lost, a 24-hour notification is to be made to CTEP by telephone at 301-897-7497, only when Internet connectivity is disrupted. Once Internet connectivity is restored, a 24-hour notification phoned in must be entered electronically into CTEP-AERS by the original submitter at the site. CTEP-AERS is programmed for automatic electronic distribution of reports to the following individuals: Study Coordinator of the Lead Organization, Principal Investigator, and the local treating physician. CTEP-AERS provides a copy feature for other e-mail recipients. 7.3.1 Phase 1 and Early Phase 2 Studies: Expedited Reporting Requirements for Adverse Events that Occur on Studies under an IND/IDE within 30 Days of the Last Administration of the Investigational Agent/Intervention 1, 2  
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FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312)  
  
NOTE: Investigators **MUST** immediately report to the sponsor (NCI) **ANY** Serious Adverse Events, whether or not  
  
1) Death 3) An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 4) A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions 6) Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization may be considered serious when, based upon medical judgment, they may jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the outcomes listed in this definition. (FDA,  
  
  
  
  
ALL **SERIOUS** adverse events that meet the above criteria MUST be immediately reported to the NCI via CTEPAERS within the timeframes detailed in the table below.  
| Grade 3-5                         |                                |            |
|-----------------------------------|--------------------------------|------------|
| Hospitalization                   | Grade 1 and Grade 2 Timeframes | Timeframes |
| D                                 |                                |            |
| Resulting in  Hospitalization     | 10 Calendar Days               |            |
| ≥ 24 hrs                          | 24-Hour 5 Calendar  Days       |            |
| Not resulting in  Hospitalization | Not required                   |            |
| ≥ 24 hrs                          |                                |            |  
```
NOTE: Protocol specific exceptions to expedited reporting of serious adverse events are found in the Specific
Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR.
Expedited AE reporting timelines are defined as:
o "24-Hour; 5 Calendar Days" - The AE must initially be reported via CTEP-AERS within 24 hours of
learning of the AE, followed by a complete expedited report within 5 calendar days of the initial 24-
hour report.
o "10 Calendar Days" - A complete expedited report on the AE must be submitted within 10 calendar
days of learning of the AE.

```  
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```
1Serious adverse events that occur more than 30 days after the last administration of investigational
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows:
Expedited 24-hour notification followed by complete report within 5 calendar days for:
- All Grade 3, 4, and Grade 5 AEs
Expedited 10 calendar day reports for:
- Grade 2 AEs resulting in hospitalization or prolongation of hospitalization
2 For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives,
rounded UP to the nearest whole day, after the agent/intervention was last administered. Footnote "1" above
applies after this reporting period.
Effective Date: May 5, 2011



```  
Note: All deaths on study require both routine and expedited reporting regardless of causality. Attribution to treatment or other cause must be provided.  
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- Expedited AE reporting timelines defined:
"24 hours; 5 calendar days" - The investigator must initially report the AE
via CTEP-AERS within 24 hours of learning of the event followed by a complete CTEP-AERS report within 5 calendar days of the initial 24-hour report.  
"10 calendar days" - A complete CTEP-AERS report on the AE must be submitted within 10 calendar days of the investigator learning of the event.  
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- Any medical event equivalent to CTCAE grade 3, 4, or 5 that precipitates hospitalization (or prolongation of existing hospitalization) must be reported regardless of attribution and designation as expected or unexpected with the exception of any events identified as protocol-specific expedited adverse event reporting exclusions.  
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- Any event that results in persistent or significant disabilities/incapacities, congenital anomalies, or birth defects must be reported via CTEP-AERS if the event occurs following treatment with an agent under a CTEP IND.  
- Use the NCI protocol number and the protocol-specific patient ID assigned during trial registration on all reports.  
7.3.2 Expedited AE reporting timelines defined:
- "24 hours; 5 calendar days" - The investigator must initially report the AE via CTEPAERS within 24 hours of learning of the event followed by a complete CTEP-AERS
report within 5 calendar days of the initial 24-hour report.  
- "10 calendar days" - A complete CTEP-AERS report on the AE must be submitted within 10 calendar days of the investigator learning of the event.
The Worldwide Product Safety (WPS) department at Merck will receive Adverse Experience reports, which are entered into the CTEP-AERS database, from the CTEP Contractor CTIS at the same time that they are forwarded to the NCI/CTEP.  
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Any medical event equivalent to CTCAE grade 3, 4, or 5 that precipitates hospitalization (or prolongation of existing hospitalization) must be reported regardless of attribution and designation as expected or unexpected with the exception of any events identified as protocolspecific expedited adverse event reporting exclusions.  
Any event that results in persistent or significant disabilities/incapacities, congenital anomalies, or birth defects must be reported via CTEP-AERS if the event occurs following treatment with an agent under a CTEP IND. Use the NCI protocol number and the protocol-specific patient ID assigned during trial registration on all reports. 7.3.3 Protocol-Specific Expedited Adverse Event Reporting Exclusions O
For this protocol only, certain adverse events/grades are exceptions to the Expedited Reporting guidelines and do not require expedited reporting. The following adverse events should be reported through the routine reporting mechanism (Section 7.4):  
| I Hospitalization/          |               |        |                 |          |
|-----------------------------|---------------|--------|-----------------|----------|
| CTCAE Category              | Adverse Event | Grade  | Prolongation of | Comments |
| Hospitalization             |               |        |                 |          |
| GI disorders                | Nausea        | 2 to 3 |                 |          |
| Diarrhea                    | 2 to 3        |        |                 |          |
| Constipation                | 2 to 3        |        |                 |          |
| Vomiting                    | 2 to 3        |        |                 |          |
| Metabolism and              | Electrolyte   | 2 to 4 |                 |          |
| nutrition disorders         | abnormalities | D      |                 |          |
| Nervous system              | Disguesia     | 2      |                 |          |
| disorders  Dermatology/Skin | Rash          | 2 to 3 |                 |          |
| Acne/Acneiform              |               |        |                 |          |  
Events that are clearly consequences of the "main" event (e.g., hypokalemia associated with diarrhea or the arrhythmias, hypotension, hypoxia, etc. that are known to occur concurrently with sepsis) may be noted in the Description of Event in the CTEP-AERS report and do not require separate CTEP-AERS reports. The possibility of the contribution of comorbid conditions to the event should be considered when reporting adverse events. Examples include hyperglycemia in patients with diabetes or headaches and seizures in patients with brain tumors.
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7.4 routine adverse event reporting

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Those adverse events that do not require expedited reporting must be reported in routine (CTMS
or CDUS; see Section 14.1) study data submissions. Adverse events reported through CTEPAERS must also be reported in routine study data submissions.  
NOTE: Grade 1 events are not required to be reported or collected.
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8 nih reporting requirements /

Please refer to definitions provided in Policy 801: Reporting Research Events found here.  
8.2 OHSRP Office of Compliance and Training / IRB Reporting  
8.2.1 Expedited Reporting
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Please refer to the reporting requirements in Policy 801: Reporting Research Events and Policy 802 Non-Compliance Human Subjects Research found here. 8.2.2 IRB Requirements for PI Reporting at Continuing Review Please refer to the reporting requirements in Policy 801: Reporting Research Events found here.  
8.3 NCI Clinical Director Reporting I
Problems expeditiously reported to the OHSRP/IRB in iRIS will also be reported to the NCI Clinical Director. A separate submission is not necessary as reports in iRIS will be available to the Clinical Director. In addition to those reports, all deaths that occur within 30 days after receiving a research intervention should be reported via email to the Clinical Director unless they are due to progressive disease. To report these deaths, please send an email describing the circumstances of the death to Dr. Dahut at NCICCRQA@mail.nih.gov within one business day of learning of the death.NIH Required Data and Safety Monitoring Plan 8.3.1 Principal Investigator/Research Team D
The clinical research team will meet on a weekly basis when patients are being actively treated on the trial to discuss each patient. Decisions about dose level enrollment and dose escalation if applicable will be made based on the toxicity data from prior patients. All data will be collected in a timely manner and reviewed by the principal investigator or a lead associate investigator. Events meeting requirements for expedited reporting as described in section **8.2.1** will be submitted within the appropriate timelines.  
The principal investigator will review adverse event and response data on each patient to ensure safety and data accuracy. The principal investigator will personally conduct or supervise the investigation and provide appropriate delegation of responsibilities to other members of the research staff.
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9 pharmaceutical information 9.1 ctep-supplied

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N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine, monohydrochloride 9.1.1.2 Other Names:
Erlotinib hydrochloride, Tarceva™
9.1.1.3 Classification: 9.1.1.4 Molecular Formula:  
  
Tyrosine kinase Inhibitor (EGFR) C22H23N3O4 HCl M.W.: 393.4 (free base) 429.9 (hydrochloride salt)
9.1.1.5 Mode of Action:
Direct inhibition of EGFR tyrosine kinase 9.1.1.6 How Supplied:
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Erlotinib tablets are provided by Astellas Pharma and distributed by the Pharmaceutical Management Branch, DCTD/NCI as 25 mg, 100 mg, and 150 mg white film-coated immediate-release tablets packaged in high-density polyethylene (HDPE) bottle. Each bottle contains 30 tablets.  
The tablets are round and convex without markings. The 25 mg tablets are 1/4 inches (6 mm); the 100 mg tablets are 11/32 inches (9 mm); and the 150 mg tablets are 13/32 inches (10 mm). Erlotinib excipients include lactose monohydrate, hypromellose, hydroxypropyl cellulose, magnesium stearate, microcrystalline cellulose, sodium starch glycolate, sodium lauryl sulfate, and titanium dioxide. The tablets also contain trace amounts of color additives, including FD&C Yellow No. 6 (25 mg only) for product identification.  
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9.1.1.7 storage

Store at 25○C (77○F) in the original container; excursions permitted to 15○ - 30○C (59○ - 86○F).  
9.1.1.8 Stability:
Current data indicates erlotinib is stable for at least 3 years at room temperature.  
9.1.1.9 Route of Administration:
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oral.

9.1.1.10 Method of Administration:
- Tablets should be taken once daily preferably in the morning with up to 200 mL of water one hour before or two hours after food.  
- Administration through G-tube: Dissolve the dose in 100 mL of sterile water, and shake it vigorously to form a uniform suspension. Draw suspension into a syringe and administer through the G-tube port. Repeat the transfer until the entire volume has been administered. Add small volume (40 mL) of sterile water to the container used to dissolve the tablets. Shake the residual suspension, aspirate it into a syringe, and administer. Repeat this last step to ensure the entire dose is administered. The total volume of delivery/rinse is ~180 mL.  
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9.1.1.11 Potential Drug Interaction:
Erlotinib is highly protein bound (92% to 95% in humans) and metabolizes primarily via CYP3A4 enzymes. Dose erlotinib cautiously with agents that are highly protein bound or potent CYP3A4 inhibitors/inducers enzymes.
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cyp iso-enzymes inhibitors/inducers

o Potent CYP3A4 Inhibitors: Use alternative drug. Alternatively, reduce erlotinib dose in the event of drug interaction (if permitted by the protocol).  
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o Potent CYP3A4 inducers: Use alternative drug. If an alternative treatment is contraindicated, consider increasing the erlotinib dose (if permitted by the protocol).  
o Food-drug interaction: Avoid grapefruit /grapefruit juice (potent CYP3A4) while taking erlotinib.  
o Smoking: Advise smokers to stop smoking while taking erlotinib. Smoking induces CYP1A2 enzymes and alters Erlotinib exposure by 64%.
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Anticoagulant: Concomitant NSAIDs, warfarin or warfarin-derivatives may increase bleeding and prothrombin time (PT) / international normalized ratio (INR). Dose adjustment may be needed. Patients receiving warfarin: Severe and fatal hemorrhage associated with elevated INRs can occur when OSI-774 and warfarin are administered concurrently. Patients taking warfarin or other coumarin-derivative anticoagulants should have more frequent INR/PT determinations (e.g., weekly for the first month and weekly for a minimum of 2 weeks following discontinuation of Erlotinib).  
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Statin: The combination of Erlotinib and a statin may increase the potential for statininduced myopathy, including rhabdomyolysis, which was observed rarely. Proton Pump Inhibitor: Erlotinib's solubility decreases as the pH increases. Coadministration of omeprazole with Erlotinib will increase the AUC and Cmax by 46%
and 61%, respectively.  
H2-antagonist: Avoid concomitant use of Erlotinib with gastric acid reducing agents if possible. When ranitidine 300 mg is given with Erlotinib, Erlotinib AUC and Cmax decrease by 33% and 54%, respectively. Increasing the dose of Erlotinib will not compensate the loss of exposure. However, if an H2-antagonist receptor is needed, take Erlotinib at least 2 hours before or 10 hours following the H2-antagonist administration. Dosing such, Erlotinib loss of exposure is minimized to AUC of 15% and Cmax of 17%.  
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Gastrointestinal perforation: Concomitant use of anti-angiogenic agents, corticosteroids, NSAIDs, and/or taxane based chemotherapy, or patients with prior medical history with peptic ulcers or diverticular disease are at high risk of GI perforation while on Erlotinib treatment. Discontinue Erlotinib if GI perforation manifests.  
Patient Care Implications: If patient vomits after taking the tablets, readminister the dose only if the tablets can actually be seen and counted. Recommend patients use sunscreen protection, and wear hat and long sleeve shirts as sunlight can exacerbate skin reactions. 9.1.1.12 Availability O
Erlotinib is an investigational agent supplied to investigators by the Division of Cancer Treatment and Diagnosis (DCTD), National Cancer Institute (NCI). Erlotinib is provided to the NCI under a Clinical Trials Agreement (CTA) between Astellas Pharma and the DCTD, NCI. 9.1.2 AZD6244 AZD6244 hydrogen sulfate (NSC 748727) 9.1.2.1 Chemical Name:
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6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2hydroxy-ethoxy)-amide hydrogen sulfate Other Names: ARRY-142886; AR00142866; AR-142886-01, AZD6244, AZD6244 HydSulfate, 9.1.2.2 Classification: Mitogen-activated protein kinase (MEK) inhibitor CAS Registry Number: 943332-08-9 9.1.2.3 Molecular Formula: C17H15BrClFN4O3 · H2SO4 M.W.: 555.7 9.1.2.4 Mode of Action:  
$$\mathrm{M.W.}\mathrm{:~}555.7$$  
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The RAS/RAF/MEK/ERK pathway is an important mediator of many cellular processes including proliferation, survival, differentiation, apoptosis, motility, and metabolism. This pathway is often aberrantly activated in human tumors due to the overexpression of mutant KRAS, mutant BRAF, or other growth factor receptors. AZD6244 is a selective mitogenactivated protein kinase (MEK) inhibitor. By inhibiting MEK, AZD6244 inhibits ERK
phosphorylation. Thus, AZD6244 may inhibit oncogenic growth signaling in tumor cells by targeting the RAS/RAF/MEK/ERK pathway. 9.1.2.5 How Supplied:
AZD6244 hydrogen sulfate is supplied as a 25 mg, size 4, plain, white, hydroxypropylmethylcellulose (HPMC) capsule in white high density polyethylene (HDPE) containers with foil-lined, induction-sealed, child-resistant closures. Each bottle contains 60 capsules.  
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Each capsule contains a dispersion of AZD6244 hydrogen sulfate in d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS; a water soluble form of vitamin E). 9.1.2.6 Storage: Store the AZD6244 hydrogen sulfate capsules at room temperature (20°C-25°C). Brief excursions are permitted between 15°C and 30°C. 9.1.2.7 Stability: Stability studies are ongoing. 9.1.2.8 Route of Administration: Oral. Take AZD6244 on an empty stomach (either 1 hour before or 2 hours after meals). AZD6244 capsules should be taken with water only. 9.1.2.9 Potential Drug Interactions:
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AZD6244 is primarily metabolized by CYP1A2 to N-desmethyl AZD6244 which is 3-5 fold more pharmacologically active than AZD6244. *In vitro*, AZD6244 is metabolized to a lesser extent by CYP2C19 and CYP3A4. In vitro, AZD6244 is a weak inhibitor of CYP2C9 and CYP1A2. High vitamin E doses may potentiate warfarin's anticoagulant activity. Monitor PT/INR more frequently in patients receiving both warfarin and AZD6244 hydrogen sulfate capsules. Avoid concomitant intake of Vitamin E in excess of 100% of the recommended daily dose. 9.1.2.10 Availability:
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AZD6244 is an investigational agent supplied to investigators by the Division of Cancer Treatment and Diagnosis (DCTD), NCI. AZD6244 is provided to the NCI under a Collaborative Agreement between AstraZeneca and the DCTD, NCI (see Section 14.3). 9.1.3 MK-2206 MK-2206 (NSC 749607) 9.1.3.1 Chemical Name or Amino Acid Sequence: 8-[4-(1-aminocyclobutyl)phenyl]-9-phenyl-1,2,4-triazolo[3,4-ƒ]-1,6-naphthyridin-3(2H)-one mono-hydrochloride salt 9.1.3.2 Classification: Akt inhibitor 9.1.3.3 Molecular Formula: C25H22N5OCl M.W.: 443.93  
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Approximate Solubility: Soluble in water (7.54 mg/mL; pH = 6.13) but less soluble in acetonitrile (1.4 mg/mL) and ethanol (2 mg/mL). Its mono-hydrochloride salt is slightly hygroscopic (absorbs 1.9 wt% water up to 95% relative humidity).  
9.1.3.4 Mode of Action:
The PI3K-Akt pathway is activated downstream of EGFR, HER2, IGF1R, and cMet, and is a suspected driver of tumor progression in most cancers. Overexpression or activating mutations in receptor tyrosine kinases, PI3K and Ras, inactivation of the tumor suppressor PTEN, or amplification or mutation of Akt can activate Akt protein kinase in most carcinomas. It is believed that Akt inhibitors that target the pathway downstream of the most common mutations have broader utility and provide less resistance in the clinic.  
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9.1.3.5 Description: A highly selective non-ATP competitive allosteric Akt inhibitor. 9.1.3.6 How Supplied: MK-2206 tablets are supplied by Merck and distributed by the DCTD, NCI. The 5 mg, 25 mg, and 200 mg tablets are film coated, packaged in HDPE bottles. The 5 mg and 25 mg bottles contain 10 and 20 tablets, respectively. When inventory allows, the 5 mg and 25 mg bottles also contain 30 tablets each. The 200 mg bottles contain 5 tablets each. The pharmaceutical collaborator does not have stability data to support repackaging MK-2206 tablets in any container other than what is provided.  
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The white film (Opadry® 20A18273) coating consists of hydroxypropyl cellulose, hydroxypropyl methylcellulose and titanium dioxide. Inactive ingredients consist of microcrystalline cellulose (Avicel PH102®), calcium phosphate dibasic anhydrous (ATAB®), croscarmellose sodium, and magnesium stearate. 9.1.3.7 Storage: Store intact bottles at room temperature, not to exceed 30°C. 9.1.3.8 Stability:
Shelf life studies of MK-2206 are on going.  
9.1.3.9 Route(s) of Administration: Oral 9.1.3.10 Method of Administration: Take tablets 2 hours before or after food. 9.1.3.11 Potential Drug Interactions:
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No clinical drug interaction studies have been performed with MK-2206; MK-2206 is not an inducer or inhibitor of major human P450 enzymes (CYP3A4, 2C9 and 2D6). In human hepatocytes, its metabolism involves both oxidation mainly by CYP3A4 and direct glucuronidation. MK-2206 is a substrate for P-glycoprotein (P-gp) mediated transport. Patient Care Implications: In acute overdose, use activated charcoal to reduce the absorption of MK-2206. If additional measures are needed, consider emptying the stomach. Administer specific medical therapy as clinically appropriate.  
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9.1.4 Lapatinib Lapatinib (NSC 727989) 9.1.4.1 Chemical Name: N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methylsulfonyl)ethyl]amino}methyl)-2 furyl]-4-quinazolinamine Other Names: GW572016, Tykerb® 9.1.4.2 Molecular Formula: C29H26ClFN4O4S(C7H8O3S)2H2O Molecular Weight: 943.48 V
Approximate solubility: 0.007 mg/mL in water and 0.001 mg/mL in 0.1 N HCl at 25°C.  
9.1.4.3 Mode of Action: Dual inhibitor of epidermal growth factor receptor (EGFR or ErbB1) and ErbB2 tyrosine kinases. 9.1.4.4 How Supplied:
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Lapatinib is supplied by the NCI/DCTD as 250 mg oval, biconvex, orange film-coated tablets with one side plain and the opposite side debossed with either FG HLS or GS XJG. The tablets contain 405 mg of lapatinib ditosylate monohydrate, equivalent to 250 mg lapatinib free base per tablet. The tablets are packaged into HDPE bottles with child-resistant closures containing 90 tablets per container. Excipients present in the tablet include: Microcrystalline cellulose, povidone, sodium starch glycolate, and magnesium stearate.  
$$\mathbf{\Sigma}\left(15^{\circ}\right)$$  
  
$\blacksquare$
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The film-coat contains: Hydroxypropyl methylcellulose, titanium dioxide, macrogel/PEG 400, Polysorbate 80, FD&C Yellow No. 6, and FCF aluminum lake. 9.1.4.5 Storage: Store intact bottles at controlled room temperature (15°C-30°C). Protect from light. 9.1.4.6 Stability: Shelf life surveillance studies of the intact bottle are on-going. Current data indicates lapatinib is stable for at least 36 months at controlled room temperature (15°C - 30°C). 9.1.4.7 Route of Administration: Oral on an empty stomach (either 1 hour before or 1 hour after meals). 9.1.4.8 Method of Administration:
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administer whole tablets. tablet crushing

9.1.4.9 Potential Drug Interactions: In vitro studies with human liver microsomes indicate that lapatinib is metabolized by CYP3A4 and CYP3A5, and to a lesser extent CYP2C19 and CYP2C8. Co-administration of lapatinib with potent or moderate CYP3A4 inhibitors (including grapefruit juice) and all CYP3A4  
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inducers is prohibited. Assess risk/benefit before co-administering lapatinib with weak CYP3A4 inhibitors. CYP3A4 inhibitors may decrease lapatinib metabolism (increasing levels); while CYP3A4 inducers may increase lapatinib metabolism (decreasing levels).  
In human subjects, lapatinib inhibited CYP3A4 and CYP2C8 at clinically relevant concentrations. Avoid co-administration of lapatinib with drugs that are substrates of CYP3A4 or CYP2C8 and have narrow therapeutic windows. Lapatinib potentially interacts with warfarin and quinazoline derivatives to increase INR and bleeding. Collect INR/PT determinations more frequently (e.g. weekly for the first month and weekly for a minimum of 2 weeks following lapatinib discontinuation).  
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9.2 **Other Agent(s)** 9.2.1 Sunitinib Sunitinib malate (NSC 736511) 9.2.1.1 Chemical Name: 5-(5-fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic acid(2-diethylamino-ethyl)-amide; compound with (S)-2-hydroxy-succinic acid. Other names: SU011248 L-Malate salt; SU010398; PHA-290940AD; Sutent; SU011248 9.2.1.2 Classification:  
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Receptor tyrosine kinase inhibitor (RTK) 9.2.1.3 Molecular formula: C22H27FN4O2.C4H6O5 M.W.: 532.56 Daltons 9.2.1.4 Physical description: Yellow to orange powder Cas registry number: 341031-54-7  
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| Aqueous solubility:  Solvent             | Solubility (mg/mL)   |    |
|------------------------------------------|----------------------|----|
| 0.1 M HCl                                | 59.1                 |    |
| pH 4.5 buffer                            | 25.4                 |    |
| pH 6.8 buffer                            | 37.8                 |    |
| pH 7.5 buffer                            | 0.05                 |    |
| in water                                 | 1.6                  | D  |
| Solubility in various solvents:  Solvent | Solubility (mg/mL)   |    |
| Acetonitrile                             | 0.1                  |    |
| Dimethyl sulfoxide                       | 92.9                 |    |
| Tetrahydrofuran                          | 0.2                  |    |
| Methanol                                 | 1.5                  |    |
| Ethanol                                  | 0.3                  |    |
| 1-Butanol                                | 0.1                  |    |  
| 1-Butano:Water (80/20 v/v)   | 6.2   |
|------------------------------|-------|
| N,N-Dimethylacetamide        | 37    |
| N,N-Dimethylformamide        | 18.4  |
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9.2.1.5 mode of action

Sunitinib malate is a receptor tyrosine kinase inhibitor involved in tumor proliferation and angiogenesis, specifically inhibiting platelet derived growth factor receptor, vascular endothelial growth factor receptor, stem cell factor receptor, Fms-like tyrosine kinase-3 receptor, and ret proto-oncogene. 9.2.1.6 How Supplied:
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Sunitinib malate capsule is commercially available through Pfizer, Inc. and will be purchased by the participating institutions in the following strengths: Capsules: 12.5 mg, 25 mg, and 50 mg capsules with mannitol, croscarmellose sodium, povidone, and magnesium stearate. Each opaque plastic bottle contains 30 capsules.  
| Capsule strength                                                           |                                                       | Description   |
|----------------------------------------------------------------------------|-------------------------------------------------------|---------------|
| 12.5 mg                                                                    | Swedish Orange, Size 4 hard gelatin capsule           |               |
| 25 mg                                                                      | Swedish Orange/Caramel, Size 3 hard gelatin  capsule. |               |
| 50 mg                                                                      | Caramel, Size 2 hard gelatin capsule                  |               |
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| Store at controlled room temperature (15 to 30°C), and protect from light. |                                                       |               |  
9.2.1.7 Storage: Store at controlled room temperature (15 to 30°C), and protect from light. 9.2.1.8 Stability: The expiration date can be found on the commercially available supplies. 9.2.1.9 Route of Administration: Oral. Sunitinib malate may be administered without regard to meals. 9.2.1.10 Potential Drug Interaction:
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Sunitinib malate is metabolized primarily by liver enzymes, particularly CYP3A4. Dose reduction with the CYP3A4 inhibitors is recommended, based on clinical symptoms. Concomitant treatment with dysrhythmic drugs, i.e., terfenadine, quinidine, procainamide, sotalol, probucol, bepridil, haloperidol, risperidone, and indapamide, is not recommended. Patients Care Implications: A yellow discoloration of the skin area may result following direct contact with the capsules. Wash the exposed area with soap and water immediately.
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9.3 agent ordering

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NCI supplied agents may be requested by the Principal Investigator (or their authorized designee) at each participating institution. Pharmaceutical Management Branch (PMB) policy requires that agent be shipped directly to the institution where the patient is to be treated. PMB does not permit the transfer of agents between institutions (unless prior approval from PMB is obtained.) The CTEP assigned protocol number must be used for ordering all CTEP supplied investigational agents. The responsible investigator at each participating institution must be registered with CTEP, DCTD through an annual submission of FDA Form 1572 (Statement of Investigator), Curriculum Vitae, Supplemental Investigator Data Form (IDF), and Financial Disclosure Form (FDF). If there are several participating investigators at one institution, CTEP supplied investigational agents for the study should be ordered under the name of one lead investigator at that institution. Active CTEP-registered investigators and investigator-designated shipping designees and ordering designees can submit agent requests through the PMB Online Agent Order Processing (OAOP) application < https://eapps-ctep.nci.nih.gov/OAOP/pages/login.jspx >. Access to OAOP requires the establishment of a CTEP Identity and Access Management (IAM) account < https://eapps-ctep.nci.nih.gov/iam/ > and the maintenance of an "active" account status and a "current" password. For questions about drug orders, transfers, returns, or accountability, call (240) 276-6575 Monday through Friday between 8:30 am and 4:30 pm (ET) or email PMBAfterHours@mail.nih.gov anytime.  
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9.4 agent accountability

Agent Inventory Records - The investigator, or a responsible party designated by the investigator, must maintain a careful record of the inventory and disposition of all agents received from DCTD using the NCI Drug Accountability Record Form (DARF). (See the CTEP home page at http://ctep.cancer.gov for the Procedures for Drug Accountability and Storage and to obtain a copy of the DARF and Clinical Drug Request form.)
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10 correlative / special studies

If enough material is available (after the molecular profiling analyses described in Section 5 have been performed), and the patient provides consent, the remainder paraffin embedded tissue and / or frozen samples or tumor DNA will be used for further molecular analysis.
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10.1 sample storage tracking and

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All research samples will be numerically coded prior to storage to maintain patient confidentiality. Subject identity is not provided to research laboratory personnel; i.e., samples are analyzed in a blinded fashion. Subjects will be given the option of consenting to future use of their research samples per the informed consent process with their option declared in the consent document. Biospecimens will be collected and processed using validated SOPs that will ensure both specimen quality and patient confidentiality pursuant to informed consent provisions. Using a computerized inventory system and a backup hardcopy process, all specimen collection and processing steps will be documented and the specific location of each specimen will be tracked. Each new specimen collected will be assigned a unique barcode identifier that can be linked to the original specimen collected and other relevant information within the inventory system. To ensure patient confidentiality, only containers used for the initial specimen collections will be labeled with patient identifiers. Coded, linked labels will be applied to all subsequent specimen containers. When specimens are processed and aliquoted, no patient information will be included on the new containers. Original specimen containers will be discarded. Only de-linked specimens will be shipped for analysis and/or storage. De-linked specimen labels will indicate: protocol number, order in which the patient was enrolled in the trial, type of sample, collection time, and total volume collected, as appropriate.  
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The inventory process contains other security provisions sufficient to safeguard patient privacy and confidentiality. Access to the inventory system and associated documents will be restricted to appropriate personnel only. The only patient information available in the inventory system will be the patient sex, diagnosis, and level of informed consent provided. SOPs ensure that any changes in the informed consent made by a patient and relayed to the PI will be reflected in the inventory system to ensure that specimens are destroyed as appropriate. All laboratory personnel will be trained to adhere to SOPs and will be monitored for high-quality performance.  
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If, at any time, a patient withdraws from the study and does not wish for their existing samples to be utilized, the individual must provide a written request. Following receipt of this request, the samples will be destroyed (or returned to the patient, if so requested). The PI will record any loss or unanticipated destruction of samples as a deviation. Reporting will be per the requirements of section 8.2.
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10.2 large scale detection of

The remainder paraffin embedded tissue and / or frozen samples or tumor DNA, will be sent to one of the two following laboratories for large scale detection of mutations in candidate genes using next generation sequencing technologies:
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Dr. Paul Meltzer Attn. Dr. Keith Killian Clinical Molecular Profiling Core lab National Cancer Institute Building 37, Room 6144 37 Convent Drive Bethesda, MD 20892 Phone: 301-496-0999 E-Mail: killianj@mail.nih.gov I
Dr. Robert Searless Massively Parallel Sequencing Shared Resource Oregon Health & Science University Mailcode CH14G 3303 SW Bond Ave Portland, OR 97239