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12. statistical considerations

The primary objective of this study is to determine whether AZD2171, when used to treat metastatic AIPC, is associated with having 30% of patients progression free at 6 months by clinical andradiographic criteria. If this is found to be the case, then this agent will be considered potentially useful when combined with other anticancer agents to be tested in later trials. Data from previous trials of NCI patients with similar eligibility requirements demonstrated a 2.1 month median progression free survival when using thalidomide (n=63). Median progression free survival on ketoconazole alone is expected to be 4 months based on previous trials.  
Ketoconazole is recognized as a standard therapy alterative to cytotoxic chemotherapy in the setting of failure of primary hormonal therapy with GnRH agonists and anti-androgen therapy. The Eastern Cooperative Oncology Group sponsored a phase III clinical trial comparing ketoconazole to the combination of estramustine and docetaxel. (closed recently due to poor accrual). Median progression free survival on ketoconazole alone was expected to be 4 months based on previous trials Based on these results, it would be useful to demonstrate whether AZD2171 is able to induce progression free survival in 30% of patients at the 6 month (approximately day 180 evaluation) time point. The study will be conducted as a two-stage optimal design (Simon 1989). With alpha=0.10 and beta=0.10 as acceptable error probabilities, the trial will target 30% as the desirable proportion of patients who are still without progression by clinical and radiographic criteria by the 6th monthly evaluation (p1=0.30), and will be considered inadequate if only a fraction consistent with 10% are without progression by the same evaluation time (p0=0.10).  
Initially 12 patients will be enrolled and followed for progression. If 0-1 of the 12 is progression free at 6 months, then no further patients will be enrolled. The enrollment will be temporarily halted after the 12th patient unless we know that 2 patients have passed the 6 month point without progression. If 2 or more of the first 12 reach 6 months without progression, then enrollment will continue until a total of 35 evaluable patients have been entered. If 2-5 of 35 are able to get to 6 months without progression, this is not adequate responsiveness to treatment, while if 6 or more of 35 are progression free at 6 months, this will indicate results consistent with an adequate progression free survival probability worthy of further investigation. Under the null hypothesis (10% progression free at 6 months), the probability of early termination after 12 patients have been evaluated at 6 months would be 66%.  
Given the difficulties in interpreting progression free rates in our patients compared to historical data, the response rate will be included as a secondary clinical endpoint. In addition to evaluation of the proportion progression free at 6 months, the progression free survival will also be analyzed via a Kaplan-Meier curve. This will be done for both progression free survival evaluated by clinical, radiographic and PSA criteria, as well as secondarily based only on clinical and radiographic criteria. This latter, secondary, evaluation will be based on all patients who are able to be assessed by these criteria in either the first (retrospectively) or second stage of accrual.
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12.1 sample size/accrual rate

Based on previous efforts in recruiting patients with this disease onto trials at the NCI, it is anticipated that 20-30 patients per year may be able to enroll onto this protocol. To allow for up to 2 inevaluable patients, the accrual ceiling will be set at 37. Thus, it is expected that accrual to this trial can be completed in approximately 1.5 years if all 37 patients are to be enrolled.
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12.3 analysis of secondary endpoints

PSA, pharmacokinetic, and molecular endpoints will be evaluated on the protocol in all available enrolled patients. These will all be considered exploratory analyses, and will not have their statistical results adjusted for multiple comparisons. However, all interesting findings will be carefully interpreted as hypothesis generating.
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12.4 reporting and exclusions 12.4.1

All patients will be evaluable for toxicity from the time of their first treatment with AZD2171.  
12.4.2 Evaluation of response.  
All patients included in the study must be assessed for response to treatment, even if there are major protocol treatment deviations or if they are ineligible. Each patient will be assigned one of the following categories: 1) complete response, 2) partial response, 3) stable disease, 4) progressive disease, 5) early death from malignant disease, 6) early death from toxicity, 7) early death because of other cause, or 9) unknown (not assessable, insufficient data). [Note: By arbitrary convention, category 9 usually designates the "unknown" status of any type of data in a clinical database.] All of the patients who met the eligibility criteria (with the possible exception of those who received no study medication) should be included in the main analysis of the response rate. Patients in response categories 4-9 should be considered as failing to respond to treatment (disease progression). Thus, an incorrect treatment schedule or drug administration does not result in exclusion from the analysis of the response rate.
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12. 5 statistical analysis with

As of June 2008, protocol 07-C-0059 has enrolled 28 evaluable patients, of whom 19 have experienced at least grade 2 fatigue, anorexia, and/or weight loss (68%). Since this incidence of constitutional symptoms tends to limit the ability to provide treatment which may be associated with improvement in disease outcome, the protocol will be amended following completion of the initial enrollment of 35 patients to include prednisone in combination with AZD2171.  
This amendment will permit 23 additional evaluable patients to enroll onto this trial and receive prednisone and AZD2171. Using a one-sided 0.05 alpha level Fisher's exact test, 23 patients will provide 80% power to detect a difference between the currently identified 19/28=68% of patients with grade 2 or worse fatigue, anorexia, and/or weight loss and 30% with the same level and type of symptoms. The final comparison will be based on up to 35 evaluable patients from the first part of the trial, and thus this power calculation may remain approximately An event free survival curve based on the initial 28 patients indicated that the 3 month EFS probability was 57% with a lower one-sided 90% CI bound of 43%, and the 6 month EFS probability was 38%, with a lower onesided 90% CI bound of 25%. As a stopping rule, after 10 patients have been enrolled onto the amended protocol and potentially followed for at least 6 months, a Kaplan-Meier probability estimate of EFS will be constructed. If either the 3 month or the 6 month observed probability estimates are less than the corresponding lower one-sided 90% CI bounds (43% or 25% at 3 and 6 months respectively), then no further patients will be enrolled onto this amended version of the trial. Furthermore, at the conclusion of the trial, if final Kaplan-Meier estimated results are below those same lower bounds (43% or 25% at 3 and 6 months respectively), the combination will be considered to be inferior to that of AZD alone and will not be recommended for further consideration, even if constitutional symptoms improve dramatically. It is anticipated that approximately 1 to 1.5 years will be required to enroll 23 additional evaluable patients. In order to allow for a small number of potentially inevaluable patients, the accrual ceiling for the protocol will be revised to be 62 patients (up to 37 for the first portion and 25 for the second).
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13. human subjects protections 13.1

Subjects treated on this study, will be individuals with metastatic prostate cancer, which has recurred (or persisted) after appropriate standard treatment. Individuals of any race or ethnic group will be eligible for this study. Eligibility assessment will be based solely on the patient's medical status. Recruitment of patients onto this study, will be through standard CCR
mechanisms. No special recruitment efforts will be conducted.
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13.2 evaluation of benefits and

The potential benefit to a patient that goes onto study, is a reduction in the bulk of their tumor and improvement in their bony lesions, which may or may not have favorable impact on symptoms and/or survival. Potential risks include the possible occurrence of any of a range of side effects, that are listed in the Consent Document (Please refer to http://ctep.cancer.gov/reporting/adeers.html to review the up-to-date expected adverse event list for AZD2171). The procedure for protecting against or minimizing risks, will be to medically evaluate patients on a regular basis as described in Section 9.
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13.3 consent process

Patients will meet with an associate or principal investigator on the trial in the Prostate Cancer Clinic, during the initial evaluation for this study. During that meeting, the investiagor will inform patients of the purpose, alternatives, treatment plan, research objectives and follow-up of this trial. The investigator will then provide a copy of the IRB-approved informed consent document that is included in this protocol. The patient will be allowed to take as much time as he wishes, in deciding whether or not he wishes to participate. If a prolonged period of time expires during the decision making process (several weeks, as an example), it may be necessary to reassess the patient for protocol eligibility. The original signed consent goes to Medical Records; copy placed in research record (NIH policy).  
All patients must have a signed informed consent form and an on-study (confirmation of eligibility) form filled out and signed by a participating investigator before entering on the study.
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13.4 patient records and quality

The unused AZD2171 (partial bottles, empty bottles, and full bottles) will be returned for drug accountability at each clinic visit. Protocol related data will be entered into the NCI C3D
database. Research records will be maintained to include but not limited to:  
o Signed, Dated Consent Form o Completed Eligibility Checklist o Source documents verifying eligibility criteria o Pre-study lab, radiology, pathology reports, histopathological results o Interim monitoring test results
o Physician notes/progress notes documenting physical evaluations, PS, history, prior therapy o Physician/Nursing notes documenting vital signs, adverse event assessment, o Treatment administration forms-In-patient/Out-patient o PK Collection Forms o Study diary/record of self administered medication schedule/compliance o Response evaluation- results/tumor measurements o Research PET Scan/biologic correlate sample collection/analysis o Off study summary See also the CCR Standard Operating Procedure: *Conducting and Documenting Drug* Accountability for Oral Investigational Agents that are Self Administered by Patients (http://ccrintra.cancer.gov/clin_ops/policies/SOPCLIN1.pdf).  
13.4.2 Patients will use a diary to document daily drug intake, blood pressure, and adverse events  
| ECOG Performance Status Scale                                                                                                                                                              | Karnofsky Performance Scale                                |                                                                                 |                                                                        |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------|---------------------------------------------------------------------------------|------------------------------------------------------------------------|
| Grade                                                                                                                                                                                      | Descriptions                                               | Percent                                                                         | Description                                                            |
| 100                                                                                                                                                                                        | Normal, no complaints, no evidence of  disease.            |                                                                                 |                                                                        |
| Normal activity. Fully active, able to                                                                                                                                                     |                                                            |                                                                                 |                                                                        |
| 0                                                                                                                                                                                          | carry on all pre-disease performance  without restriction. | 90                                                                              | Able to carry on normal activity; minor  signs or symptoms of disease. |
| Symptoms, but ambulatory.  Restricted in physically strenuous  activity, but ambulatory and able to  carry out work of a light or sedentary  nature (e.g., light housework, office  work). | 80                                                         | Normal activity with effort; some signs  or symptoms of disease.                |                                                                        |
| 1                                                                                                                                                                                          | 70                                                         | Cares for self, unable to carry on normal  activity or to do active work.       |                                                                        |
| In bed <50% of the time. Ambulatory  and capable of all self-care, but  unable to carry out any work activities.   Up and about more than 50% of  waking hours.                            | 60                                                         | Requires occasional assistance, but is  able to care for most of his/her needs. |                                                                        |
| 2                                                                                                                                                                                          | Requires considerable assistance and                       |                                                                                 |                                                                        |
| 50                                                                                                                                                                                         | frequent medical care.                                     |                                                                                 |                                                                        |
| 40                                                                                                                                                                                         | Disabled, requires special care and  assistance.           |                                                                                 |                                                                        |
| In bed >50% of the time. Capable of  only limited self-care, confined to bed  or chair more than 50% of waking  hours.                                                                     |                                                            |                                                                                 |                                                                        |
| 3                                                                                                                                                                                          | 30                                                         | Severely disabled, hospitalization  indicated. Death not imminent.              |                                                                        |
| 20                                                                                                                                                                                         | Very sick, hospitalization indicated.  Death not imminent. |                                                                                 |                                                                        |
| 100% bedridden. Completely                                                                                                                                                                 |                                                            |                                                                                 |                                                                        |
| 4                                                                                                                                                                                          | disabled. Cannot carry on any selfcare. Totally confined to bed or chair.                                                            | 10                                                                              | Moribund, fatal processes progressing  rapidly.                        |
| 5                                                                                                                                                                                          | Dead.                                                      | 0                                                                               | Dead.                                                                  |  
Performance Status Criteria APPENDIX B  
CTEP-assigned Protocol # 7395  
  
  
Local Protocol # 07-C-0059
patient's pill diary cycle #
instructions to the patient

1. Complete one form for each Cycle. 2. You will take ___ pills each day. You must take the pills on an empty stomach, one hour before or two hours after meals.  
3. Record the date, the number of pills you took, and when you took them. 4. If you have any comments or notice any side effects, please record them in the Comments column.  
3. Please bring your pill bottle and this form to your physician when you go for your next appointment.  
4.Total dose: ___mg per day. Number of pills each day: ___. Effective date of dosage:___  
| # pills,                                                                            |          |             |         |             |                |          |
|-------------------------------------------------------------------------------------|----------|-------------|---------|-------------|----------------|----------|
| Date                                                                                | Day      | when  taken | # pills | # pills,    |                |          |
| missed                                                                              | Comments | Date        | Day     | when  taken | # pills missed | Comments |
|                                                                                     | 1        | 17          |         |             |                |          |
|                                                                                     | 2        | 18          |         |             |                |          |
|                                                                                     | 3        | 19          |         |             |                |          |
|                                                                                     | 4        | 20          |         |             |                |          |
|                                                                                     | 5        | 21          |         |             |                |          |
|                                                                                     | 6        | 22          |         |             |                |          |
|                                                                                     | 7        | 23          |         |             |                |          |
|                                                                                     | 8        | 24          |         |             |                |          |
|                                                                                     | 9        | 25          |         |             |                |          |
|                                                                                     | 10       | 26          |         |             |                |          |
|                                                                                     | 11       | 27          |         |             |                |          |
|                                                                                     | 12       | 28          |         |             |                |          |
|                                                                                     | 13       |             |         |             |                |          |
|                                                                                     | 14       |             |         |             |                |          |
|                                                                                     | 15       |             |         |             |                |          |
|                                                                                     | 16       |             |         |             |                |          |
| Patient's Signature: ___________________________________ Date: ____________________ |          |             |         |             |                |          |  
APPENDIX C
CTEP-assigned Protocol \# 7395 Local Protocol \#07-C-0059_
patient's pill diary cycle #
instructions to the patient

1. Your blood pressure readings have two numbers. The first number is the pressure in your blood vessels during a heart beat (systolic), and the second number is the pressure in the vessels when the heart rests in between beats (diastolic). These numbers are usually written with a slash in between them (for example, normal blood pressure is 120/80).  
2. Record the date, then record your blood pressure twice each day using a home blood pressure monitor:
x each morning after sitting quietly for 30 minutes or reading (not while you are active: dressing, making breakfast, etc.)
x each evening at bedtime or while you are relaxing during the evening 3. If you take your blood pressure at other times of the day, please record the numbers and time under "Other readings."
4. If your systolic pressure is greater than 150 or your diastolic blood pressure is greater than 90 twice in a row measured several hours apart, please contact your research nurse at NIH for instructions.  
5. Patients should seek medical advice immediately if their BP exceeds 180 mmHg (systolic) or 105 mmHg
(diastolic) at any time and should also be encouraged to contact their physician if they are concerned about any symptoms that may be associated with high blood pressure (*e.g.*, headache).  
6. Please bring this form to every clinic visit or appointment.  
| Date                                                                     | AM             |      |    |
|--------------------------------------------------------------------------|----------------|------|----|
| reading s                                                                | PM             |      |    |
| reading s                                                                | Other readings | Date | AM |
| (include time of day)                                                    | reading s      | PM   |    |
| reading s                                                                | Other readings |      |    |
| (include time of day)                                                    |                |      |    |
| /                                                                        | /              | /    | /  |
| /                                                                        | /              | /    | /  |
| /                                                                        | /              | /    | /  |
| /                                                                        | /              | /    | /  |
| /                                                                        | /              | /    | /  |
| /                                                                        | /              | /    | /  |
| /                                                                        | /              | /    | /  |
| /                                                                        | /              | /    | /  |
| /                                                                        | /              | /    | /  |
| /                                                                        | /              | /    | /  |
| /                                                                        | /              | /    | /  |
| /                                                                        | /              | /    | /  |
| /                                                                        | /              | /    | /  |
| /                                                                        | /              | /    | /  |
| /                                                                        | /              | /    | /  |
| /                                                                        | /              | /    | /  |
| Patient's Signature: _____________________________________________ Date: |                |      |    |
patient's pill diary cycle #
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