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table 16.1

Phase 1 and Early Phase 2 Studies: Expedited Reporting Requirements for Adverse events that Occur on Studies under an Non-CTEP IND within 30 Days of the Last Administration of the Investigational Agent/Intervention1 GDC-0032 Arm 1 **or Re-Registration, Arm 3.**  
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 they are considered related to the investigational agent(s)/intervention (21 CFR 312.64)
An adverse event is considered serious if it results in ANY of the following outcomes:
1) Death 2) A life-threatening adverse event 3) An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 hours 4) A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions 5) A congenital anomaly/birth defect.  
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, 21 CFR 312.32; ICH E2A and ICH E6).  
| Hospitalization                                                                                         | Grade 1 and Grade 2 Timeframes   | Grade 3-5 Timeframes   |
|---------------------------------------------------------------------------------------------------------|----------------------------------|------------------------|
| 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 (if applicable) are |                                  |                        |  
NOTE: Protocol specific exceptions to expedited reporting of serious adverse events (if applicable) are  
found in Section 16.1f.  
ALL **SERIOUS** adverse events that meet the above criteria MUST be immediately reported to the NCI via CTEP-AERS within the timeframes detailed in the table below.
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expedited ae reporting timelines are

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.
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 May 5, 2011
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f. additional instructions or exceptions

Supporting Documentation Submission - Within 5 **calendar days**
submit the following to the SWOG Operations Office by fax to 210614-0006 or mail to the address below:
a. Printed copy of the first page of the CTEP-AERS report b. Copies of clinical source documentation of the event c. If applicable, and they have not yet been submitted to the SWOG Data Operations Center, copies of Off Treatment Notice and/or Notice of Death.  
2) **The adverse events listed below are considered to be adverse**
events of special interest (AESIs) and require expedited reporting for this trial:
- Grade ≥ 3 symptomatic hyperglycemia - Grade ≥ 2 colitis or enterocolitis - Grade ≥ 2 diarrhea - Grade ≥ 3 rash - Grade ≥ 2 pneumonitis
- Grade ≥ 3 stomatitis
- Cases of potential drug-induced liver injury that include an elevated ALT or AST in combination with either an elevated bilirubin or clinical jaundice, as defined by Hy's law
- Suspected transmission of an infectious agent by the study drug
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g. expedited reporting for commercial

Commercial reporting requirements are provided in Table 16.2. The commercial agent used in Arm 2 of this study is docetaxel. If there is any question about the reportability of an adverse event or if on-line CTEP-AERS cannot be used, please telephone or email the SAE
Program at the Operations Office, 210/614-8808 or adr@swog.org, before preparing the report.  
Table 16.2. Expedited reporting requirements for adverse events experienced by patients on study Arm 2 who have received the commercial drug listed in Section 16.1g above within 30 days of the last administration of the commercial agent.  
| Attribution                                                                                                                                                                                                                       | Grade 4   | Grade 5a   |          |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------|------------|----------|
| Unexpected                                                                                                                                                                                                                        | Expected  | Unexpected | Expected |
| Unrelated                                                                                                                                                                                                                         | CTEPAERS           | CTEPAERS            |          |
| or Unlikely Possible,                                                                                                                                                                                                             | CTEP-AERS | CTEPAERS            | CTEPAERS          |
| Probable,  Definite CTEP-AERS: Indicates an expedited report is to be submitted via CTEP-AERS  within 10 calendar days of learning of the eventb.  a This includes all deaths within 30 days of the last dose of treatment with a |           |            |          |  
CTEP-AERS: Indicates an expedited report is to be submitted via CTEP-AERS
within 10 calendar days of learning of the eventb.  
a This includes all deaths within 30 days of the last dose of treatment with a commercial agent(s), regardless of attribution. Any death that occurs more than 30 days after the last dose of treatment with a commercial agent(s) and is attributed (possibly, probably, or definitely) to the agent(s) and is not due to cancer recurrence must be reported according to the instructions above.  
b Submission of the on-line CTEP-AERS report plus any necessary amendments  
  
  
generally completes the reporting requirements. You may, however, be asked to submit supporting clinical data to the Operations Office in order to complete the evaluation of the event. If requested, the specified data should be sent within 5 calendar days by fax to 210-614-0006.
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h. reporting secondary malignancy including

1. A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., treatment with investigational agent/intervention, radiation or chemotherapy). A secondary malignancy is not considered a metastasis of the initial neoplasm.  
SWOG requires all secondary malignancies that occur following treatment with an agent under a Non-NCI IND to be reported via CTEP-AERS. Three options are available to describe the event.  
- Leukemia secondary to oncology chemotherapy (e.g.,
Acute Myelocytic Leukemia [AML])
- Myelodysplastic syndrome (MDS)
- Treatment-related secondary malignancy Any malignancy possibly related to cancer treatment (including AML/MDS) should also be reported via the routine reporting mechanisms outlined in each protocol.  
Second Malignancy: A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT a metastasis from the initial malignancy). Second malignancies require ONLY routine reporting via CDUS unless otherwise specified.  
http://ctep.cancer.gov/protocolDevelopment/electronic_applicatio ns/docs/aeguidelines.pdf 2. Any supporting documentation should be submitted to CTEP per NCI guidelines for AE reporting located at http://ctep.cancer.gov/protocolDevelopment/electronic_applicatio ns/docs/aeguidelines.pdf.  
A copy of the report and the following supporting documentation must also be submitted to SWOG Operations Office within 30 days by fax to 210-614-0006 or mail to the address below:
- a copy of the pathology report confirming the AML/ALL /MDS
diagnosis
- (if available) a copy of the cytogenetics report SWOG ATTN: SAE Program 4201 Medical Drive, Suite 250 San Antonio, Texas 78229 NOTE: If a patient has been enrolled in more than one NCIsponsored study, the report must be submitted for the most recent trial.
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i. reporting pregnancy fetal death

1. **Pregnancy** Study participants who become pregnant while on study; that pregnancy should be reported in an expedited manner via CTEP-AERS as Grade 3 "Pregnancy, puerperium and perinatal conditions - Other (pregnancy)" under the Pregnancy, puerperium and perinatal conditions SOC.  
Additionally, the pregnancy outcome for patients on study should be reported via CTEP-AERS at the time the outcome becomes known, accompanied by the same Pregnancy Report Form used for the initial report.  
2. **Fetal Death** Fetal Death defined in CTCAE as "A disorder characterized by death in utero; failure of the product of conception to show evidence of respiration, heartbeat, or definite movement of a voluntary muscle after expulsion from the uterus, without possibility of resuscitation" should be reported expeditiously as **Grade 4 "pregnancy, puerperium and**
perinatal conditions - Other (pregnancy loss)" under the Pregnancy, puerperium and perinatal conditions SOC.  
3. **Death Neonatal** Neonatal death, defined in CTCAE as "A
disorder characterized by cessation of life occurring during the first 28 days of life" that is felt by the investigator to be at least possibly due to the investigational agent/intervention should be reported expeditiously.  
A neonatal death should be reported expeditiously as **Grade 4**
"General disorders and administration - Other (neonatal loss)" under the **General disorders and administration** SOC.  
Fetal death and neonatal death should NOT *be reported as a* Grade 5 event. If reported as such, the CTEP-AERS interprets this as a death of the patient being treated.  
NOTE: When submitting CTEP-AERS reports for "Pregnancy,
"Pregnancy loss", or "Neonatal loss", the Pregnancy Information Form should also be completed and faxed with any additional medical information to 301-230-0159. The potential risk of exposure of the fetus to the investigational agent(s) or chemotherapy agent(s) should be documented in the "Description of Event" section of the CTEP-AERS report.  
The Pregnancy Information Form is available at:
http://ctep.cancer.gov/protocolDevelopment/adverse_effects.htm
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17.0 bibliography

1 Cantley LC. The phosphoinositide 3-kinase pathway. Science 296(5573):1655−7, 2002.  
2 Guertin DA, Sabatini DM. Defining the role of mTOR in cancer. Cancer Cell 12:9-22, 2007.  
3 Cantley LC. The phosphoinositide 3-kinase pathway. Science 296(5573):1655−7, 2002.  
4 Shayesteh L, Lu Y, Kuo WL, et al. PIK3CA is implicated as an oncogene in ovarian cancer. Nat Genet 21:99−102, 1999.  
5 Massion PP, Taflan PM, Shyr Y, et al. Early involvement of the phosphatidylinositol 3-Kinase/AKT
pathway in lung cancer progression. Am J Resp Crit Care Med 170:1088−94, 2004.  
6 Wu G, Xing M, Mabbo E, et al. Somatic mutation and gain of copy number of PIK3CA in human breast cancer. Breast Cancer Res 7:R609−16, 2005.
7 Cantley LC. The phosphoinositide 3-kinase pathway. Science 296(5573):1655−7, 2002.  
8 Ward S, Sotsios Y, Dowden J, et al. Therapeutic potential of phosphoinositide 3-kinase inhibitors.  
Chem Biol 10:207−13, 2003.  
9 Cantley LC. The role of phosphoinositide 3-kinase in human disease. In: The Harvey Lectures, Series 100, 2004−2005. Hoboken: John Wiley and Sons Inc 103−22, 2006.  
10 Bachman KE, Argani P, Samuels Y, et al. The PIK3CA gene is mutated with high frequency in human breast cancers. Cancer Biol Ther 3:772–5, 2004.  
11 Samuels Y, Wang Z, Bardelli A, et al. High frequency of mutations of the PIK3CA gene in human cancers. Science 304:554, 2004.  
12 Karakas B, Bachman KE, Park BH. Mutation of the PIK3CA oncogene in human cancers. Br J
Cancer 94:455−9, 2006.  
13 Jia S, Liu Z, Zhang S, et al. Essential roles of PI(3)K-p110β in cell growth, metabolism and tumorigenesis. Nature 454:776−9, 2008.