phase ii study of cediranib
11.1.4 response criteria

11.1.4.1 Evaluation of Target Lesions Complete Response (CR): Disappearance of all target lesions Partial Response (PR): At least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD. Progressive Disease (PD): At least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started.  
11.1.4.2 Evaluation of Non-Target Lesions Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor marker level Note: If tumor markers are initially above the upper normal limit, they must normalize for a patient to be considered in complete clinical response. Incomplete Response/ Stable Disease (SD): Persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level above the normal limits. Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions Although a clear progression of "non-target" lesions only is exceptional, the opinion of the treating physician should prevail in such circumstances, and the progression status should be confirmed at a later time by the review panel (or Principal Investigator).  
| Target                                                                                                                                                                                                                                                                | Non-Target   | New        | Overall   | Best Response for This                           |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------|------------|-----------|--------------------------------------------------|
| Lesions                                                                                                                                                                                                                                                               | Lesions      | Lesions    | Response  | Category Also Requires*:                         |
| CR                                                                                                                                                                                                                                                                    | CR           | No         | CR        | >4 weeks confirmation                            |
| CR                                                                                                                                                                                                                                                                    | NonCR/Non-PD              | No         | PR        | >4 weeks confirmation                            |
| PR                                                                                                                                                                                                                                                                    | Non-PD       | No         | PR        |                                                  |
| SD                                                                                                                                                                                                                                                                    | Non-PD       | No         | SD        | documented at least once  >4 weeks from baseline |
| PD                                                                                                                                                                                                                                                                    | Any          | Yes or  No | PD        | no prior SD, PR or CR                            |
| Any                                                                                                                                                                                                                                                                   | PD*          | Yes or  No | PD        |                                                  |
| Any                                                                                                                                                                                                                                                                   | Any          | Yes        | PD        |                                                  |
| * See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. In exceptional circumstances, unequivocal progression in non-target lesions may be  accepted as disease progression. Note: Patients with a global deterioration of health status |              |            |           |                                                  |  
11.1.4.3 Evaluation of Best Overall Response The best overall response is the best response recorded from the start of the treatment until disease progression/recurrence (taking as reference for progressive disease the smallest measurements recorded since the treatment started). The patient's best response assignment will depend on the achievement of both measurement and confirmation criteria.  
11.1.4.4 Duration of Response Duration of overall response: The duration of overall response is measured from the time measurement criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since the treatment started). The duration of overall CR is measured from the time measurement criteria are first met for CR until the first date that recurrent disease is objectively documented. Duration of stable disease: Stable disease is measured from the start of the treatment until the criteria for progression are met, taking as reference the smallest measurements recorded since the treatment started.
phase ii study of cediranib
12 data reporting / regulatory

Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.
phase ii study of cediranib
12.1 data reporting 12.1.1 method

This study will be monitored by the Clinical Data Update System (CDUS) version 3.0. Cumulative CDUS data will be submitted quarterly to CTEP by electronic means. Reports are due January 31, April 30, July 31, and October 31. Instructions for submitting data using the CDUS can be found on the CTEP Web site (http://ctep.cancer.gov).  
Note: All adverse events that have occurred on the study, including those reported through CTEP-AERS, must be reported via the monitoring method identified above.  
12.1.2 *Responsibility for Submission* Study participants are responsible for submitting CDUS data and/or data forms to the Coordinating Center quarterly to allow time for Coordinating Center compilation, Principal Investigator review, and timely submission to CTEP (see Section 12.1.1). The Coordinating Center is responsible for compiling and submitting CDUS data to CTEP for all participants and for providing the data to the Principal Investigator for review.
phase ii study of cediranib
12.2 data safety and monitoring

All data will be collected in a timely manner and reviewed by the principal investigator and/or protocol chairpersons every 2 weeks. In addition, there will be weekly meetings with the investigators, research nurse, protocol chairpersons, and principal investigator to discuss patient issues, as well as important adverse events and trends in the data. Confidentiality will be maintained as much as possible, consistent with applicable regulations. Names of participants or identifying material will not be released without patient permission, except when such release is required by law. No patient's name or identifying information will be released in any publication or presentation. Records are maintained according to current legal requirements, and are made available for review according to the requirements of the FDA or other authorized user, only under guidelines established by the Federal Privacy Act.
phase ii study of cediranib
12.3 cooperative research and development

The agent(s), supplied by CTEP, DCTD, NCI, used in this protocol is/are provided to the NCI under a Collaborative Agreement (CTA) between the Pharmaceutical Company [hereinafter referred to as "Collaborator"] and the NCI Division of Cancer Treatment and Diagnosis. Therefore, the following obligations/guidelines, in addition to the provisions in the "Intellectual Property Option to Collaborator" contained within the terms of award, apply to the use of Agent(s) in this study:
1. Agent(s) may not be used for any purpose outside the scope of this protocol, nor can Agent(s) be transferred or licensed to any party not participating in the clinical study. Collaborator(s) data for Agent(s) are confidential and proprietary to Collaborator(s) and shall be maintained as such by the investigators. The protocol documents for studies utilizing investigational agents contain confidential information and should not be shared or distributed without the permission of the NCI. If a copy of this protocol is requested by a patient participating on the study or patient's family member, the individual should sign a confidentiality agreement. A suitable model agreement can be downloaded from http://ctep.cancer.gov.  
2. For a clinical protocol where there is an investigational Agent used in combination with (an)other investigational Agent(s), each the subject of different collaborative agreements, the access to and use of data by each Collaborator shall be as follows (data pertaining to such combination use shall hereinafter be referred to as "Multi-Party Data."):
a. NCI must provide all Collaborators with prior written notice regarding the existence and nature of any agreements governing their collaboration with NIH, the design of the proposed combination protocol, and the existence of any obligations that would tend to restrict NCI's participation in the proposed combination protocol.  
b. Each Collaborator shall agree to permit use of the Multi-Party Data from the clinical trial by any other Collaborator solely to the extent necessary to allow said other Collaborator to develop, obtain regulatory approval, or commercialize its own investigational agent.  
c. Any Collaborator having the right to use the Multi-Party Data from these trials must agree in writing prior to the commencement of the trials that it will use the Multi-Party Data solely for development, regulatory approval, and commercialization of its own investigational agent.  
3. Clinical Trial Data and Results and Raw Data developed under a collaborative agreement will be made available exclusively to Collaborator(s), the NCI, and the
FDA, as appropriate. All data made available will comply with HIPAA regulations.  
4. When a Collaborator wishes to initiate a data request, the request should first be sent to the NCI, who will then notify the appropriate investigators (Group Chair for Cooperative Group studies, or Principal Investigator for other studies) of Collaborator's wish to contact them.  
5. Any data provided to Collaborator(s) for phase 3 studies must be in accordance with the guidelines and policies of the responsible Data Monitoring Committee (DMC), if there is a DMC for this clinical trial.  
6. Any manuscripts reporting the results of this clinical trial must be provided to CTEP for immediate delivery to Collaborator(s) for advisory review and comment prior to submission for publication. Collaborator(s) will have 30 days from the date of receipt for review. Collaborator shall have the right to request that publication be delayed for up to an additional 30 days in order to ensure that Collaborator's confidential and proprietary data, in addition to Collaborator(s)'s intellectual property rights, are protected. Copies of abstracts must be provided to CTEP for forwarding to Collaborator(s) for courtesy review as soon as possible and preferably at least three (3) days prior to submission, but in any case, prior to presentation at the meeting or publication in the proceedings. Press releases and other media presentations must also be forwarded to CTEP prior to release. Copies of any manuscript, abstract, and/or press release/ media presentation should be sent to:
Regulatory Affairs Branch, CTEP, DCTD, NCI
9609 Medical Center Dr Rockville, MD 20850 FAX 240-276-7894 E-mail: anshers@mail.nih.gov The Regulatory Affairs Branch will then distribute them to Collaborator(s). No publication, manuscript or other form of public disclosure shall contain any of Collaborator's confidential/proprietary information.
phase ii study of cediranib
13 statistical considerations

The primary objective of this study is to determine if AZD2171 will be associated with a modest response rate in patients with alveolar soft cell carcinoma. In addition, this study will determine whether pediatric patients with ASPS will experience at least a minimal response rate when treated with AZD2171. Data from a very limited number of patients with this disease suggest that this agent may have a potentially useful level of activity in this population [27, 28]. The study in adults will be conducted as an optimal two-stage Phase II trial (Simon R, Controlled Clinical Trials 10:1-10, 1989), to rule out an unacceptably low 5% clinical response rate (PR+CR; p0=0.05) in favor of a modestly high response rate of 25% (p1=0.25). With alpha=0.10 (probability of accepting a poor treatment=0.10) and beta = 0.10 (probability of rejecting a good treatment=0.10), the study will initially enroll 9 evaluable patients. If there are 0/9 responses, accrual stops. If there are one or more responses in the initial 9 patients, then accrual continues to a total of 24 patients. As it may take several weeks to determine if a patient has experienced a clinical response, a temporary pause in the accrual to the trial may be necessary to ensure that enrollment to the second stage is warranted. If 1 or 2 of the 24 patients respond, then this is inadequate; if 3 or more of the 24 patients respond, then this is favorable. Under the null hypothesis (5% response rate), the probability of early termination is 63%. Following completion of the initial cohort of 24 evaluable patients, the primary objective of the study will be to enroll patients onto a replicate cohort using the identical therapy as that administered to the initial 24 patients. This cohort will consist of 30 evaluable patients. The overall clinical response rate in these 30 patients will be determined. If the response rate is approximately 50%, the maximum confidence interval width will be +/- 19%. Following the enrollment of the 30 patients in the replicate cohort, the response rates from the original 24 evaluable patients will be compared to that of the replicate cohort. If the two cohorts have similar results, that is, if they do not differ with a Fisher's exact p-value of <0.30, then the results from both cohorts will also be combined and reported together as well as separately.  
The maximum confidence interval width with 54 patients would be +/- 14%.  
Biopsies will be obtained from as many patients as possible in the replicate cohort. The specimens will be subjected to gene expression profiling, with the analyses conducted under the direction of Dr. Richard Simon, Chief, Biometric Research Branch, DCTD. VEGFR pathway analysis will also be undertaken. If there are up to 3 independent outcome measures evaluated, and if 15 patients are able to provide biopsy specimens pre-treatment as well as at one or two times following treatment, then there would be 85% power for each difference from baseline equal to 1.0 SD of the difference (effect size =1) to be detected, using a 0.017 alpha level paired t-test for each evaluation. The 0.017 level for each of three comparisons will permit the overall family of tests to be performed at the 0.05 level, using an assumption of a very conservative Bonferroni adjustment for multiple comparisons. If there are up to 6 comparisons, there would be 76% power for each comparison, as a minimum. In practice, comparisons may be made using a Hochberg adjustment, which is not as overly conservative as the Bonferroni adjustment. Also, a Wilcoxon signed rank test may be used instead of a paired t-test if the differences from pre-treatment are not normally distributed (p<0.05 by a Shapiro-Wilks test). The portion of the study in pediatric patients will be conducted as a small, optimal two-stage phase II trial (Simon R, Controlled Clinical Trials 10:1-10, 1989), in order to rule out an unacceptably low 5% overall response rate (ORR; p0=0.05), in favor of a higher response rate of 35% (p1=0.35). With alpha=0.10 (probability of accepting a poor treatment=0.10) and beta = 0.10 (probability of rejecting a good treatment=0.10), the study will initially enroll 6 evaluable patients and if 0 of the 6 have a response, then no further patients will be accrued. If 1 or more the first 6 evaluable patients (16.7% or more) have a response, then accrual would continue until a total of 12 evaluable patients have enrolled. As it may take several weeks to months to determine if a patient has experienced a response, a temporary pause in the accrual to the trial may be necessary to ensure that enrollment to the second stage is warranted. If there is 1 response in 12 patients, this would be an uninterestingly low response rate, while if there were 2 or more responses in 12 (16.7% or more) patients, then this would be sufficiently interesting to warrant further study in later trials. Under the null hypothesis (5% response rate), the probability of early termination is 74%. It is anticipated that 6 pediatric patients per year will enroll on this trial. Thus, it will take up to two years to complete enrollment of pediatric subjects. At the present time, approximately 40 adult patients have been enrolled in slightly greater than 2 years. The former accrual ceiling, based on two cohorts of adult patients, was 60 patients, and accrual of adult patients is expected to be completed within 2 years as well. To account for these additional evaluable pediatric patients, the accrual ceiling will be increased by 13 (12 + an allowance for 1 inevaluable patient). Thus, the accrual ceiling will be set at 73.
phase ii study of cediranib
14 references

1. Daigeler, A., et al., Alveolar soft part sarcoma: clinicopathological findings in a series of 11 cases. World J Surg Oncol, 2008. 6: p. 71.  
2. Brennan, M.F., K.M. Alektiar, and R.G. Maki, *Sarcomas of the soft tissue and bone*, in Cancer, principles and practice of oncology, V.T. DeVita, S. Hellman, and S.A.  
Rosenberg, Editors. 2001, Lippincott, Williams & Wilkins: Philadelphia. p. 1841-1891.  
3. Reichardt, P., et al., *Chemotherapy in alveolar soft part sarcomas. What do we know?*
Eur J Cancer, 2003. 39(11): p. 1511-6.  
4. Stockwin, L.H., et al., Gene expression profil*ing of alveolar soft-part sarcoma (ASPS).*
BMC Cancer, 2009. 9: p. 22.  
5. Casanova, M., et al., Alveolar soft part sarcoma in children and adolescents: A report from the Soft-*Tissue Sarcoma Italian Cooperative Group.* Ann Oncol, 2000. 11(11): p.  
1445-9.  
6. Ogose, A., et al., Alveolar soft part sarcoma in Japan: multi*-institutional study of 57* patients from the Japanese Musculoskeletal Oncology Group. Oncology, 2003. 65(1): p.  
7-13.  
7. Kayton, M.L., et al., *Clinical presentation, treatment, and outcome of alveolar soft part* sarcoma in children, adolescents, and young adults. J Pediatr Surg, 2006. 41(1): p. 18793.  
8. Anderson, M.E., et al., *Alveolar soft part sarcoma: a rare and enigmatic entity.* Clin Orthop Relat Res, 2005. 438: p. 144-8.  
9. Bisogno, G., A. Rosolen, and M. Carli, *Interferon alpha for alveolar soft part sarcoma.*
Pediatr Blood Cancer, 2005. 44(7): p. 687-8.  
10. Kuriyama, K., et al., *Alveolar soft part sarcoma with lung metastases. Response to* interferon alpha-2a? Med Pediatr Oncol, 2001. 37(5): p. 482-3.  
11. Roozendaal, K.J., et al., *Alveolar soft-part sarcoma responding to interferon alpha-2b.* Br J Cancer, 2003. 89(2): p. 243-5.  
12. Azizi, A.A., et al., Vascular-endothelial-growth-*factor (VEGF) expression and possible* response to angiogenesis inhibitor bevacizumab in metastatic alveolar soft part sarcoma.  
Lancet Oncol, 2006. 7(6): p. 521-3.  
13. Hennequin, L.F., et al., *Design and structure-activity relationship of a new class of potent* VEGF receptor tyrosine kinase inhibitors. J Med Chem, 1999. 42(26): p. 5369-89.  
14. Wedge, S.R., et al., *ZD6474 inhibits vascular endothelial growth factor signaling,*
angiogenesis, and tumor growth following oral administration. Cancer Res, 2002. 62(16): p. 4645-55.  
15. Wedge, S.R., et al., ZD4190: an orally active inhibitor of vascular endothelial growth factor signaling with broad-spectrum antitumor efficacy. Cancer Res, 2000. 60(4): p.  
970-5.  
16. Ogilvie, D.J., et al., *AZD2171, a highly potent inhibitor of VEGF receptor signaling in* primary human endothelial cells, exhibits broad-spectrum activity in tumor xenograft models. AACR Meeting Abstracts, 2004. **2004**(1): p. 1051-b-.  
17. Bradley, D.P., et al., *The VEGF signaling inhibitors ZD6474 and AZD2171 compromise* hemodynamic parameters in an SW620 human colon tumor model: An analysis using perfusion-permeability dynamic contrast-enhanced magnetic resonance imaging (ppDCE-MRI). AACR Meeting Abstracts, 2004. **2004**(1): p. 1051-a-.  
18. Drevs, J., et al., Effect of AZD2171, a highly potent VEGF receptor *tyrosine kinase* inhibitor, on primary tumor growth, metastasis and vessel density in murine renal cell carcinoma. AACR Meeting Abstracts, 2004. **2004**(1): p. 1051-c-1052.  
19. Klinowska, T.C., et al., AZD2171, a highly potent inhibitor of VEGF receptor tyrosine kinase activity, inhibits the growth of spontaneous mammary tumors in the MMTV-neu transgenic mouse. AACR Meeting Abstracts, 2004. **2004**(1): p. 1048-a-.  
20. Drevs, J., et al., *Phase I Clinical Study of AZD2171, an Oral Vascular Endothelial* Growth Factor *Signaling Inhibitor, in Patients With Advanced Solid Tumors.* J Clin Oncol, 2007. 25(21): p. 3045-3054.  
21. Lindsay, C.R., I.R. MacPherson, and J. Cassidy, *Current status of cediranib: the rapid* development of a novel anti-angiogenic therapy. Future Oncol, 2009. 5(4): p. 421-32.  
22. Matulonis, U.A., et al., Cediranib (AZD2171) is an active agent in recurrent epithelial ovarian cancer. ASCO Meeting Abstracts, 2008. 26(15_suppl): p. 5501-.  
23. Hirte, H.W., et al., *A phase II study of cediranib (AZD2171) in recurrent or persistent* ovarian, peritoneal or fallopian tube cancer: Final results of a PMH, Chicago and California consortia trial. J Clin Oncol (Meeting Abstracts), 2008. 26(15_suppl): p.  
5521-.  
24. Ramalingam, S.S., et al., Cediranib (AZD2171) for the treatment of recurrent small cell lung cancer (SCLC): A California Consortium phase II study (NCI \# 7097). J Clin Oncol
(Meeting Abstracts), 2008. 26(15_suppl): p. 8078-.  
25. Ryan, C.J., et al., Phase I dose escalation and pharmacokinetic study of AZD2171, an inhibitor of the vascular endothelial growth factor receptor tyrosine kinase, in patients with hormone refractory prostate cancer (HRPC). Invest New Drugs, 2007. 25(5): p.  
445-51.  
26. Langenberg, M., et al., Optimal management of emergent hypertension during treatment with a V*EGF signaling inhibitor: A randomized phase II study of cediranib.* J Clin Oncol
(Meeting Abstracts), 2008. 26(15_suppl): p. 3555-.  
27. Gardner, K., et al., *Activity of the VEGF/KIT tyrosine kinase inhibitor Cediranib (AZD 2171) in* alveolar soft part sarcoma, Abstract \# 34936, in Connective Tissue Oncology Society 14th Annual Meeting2008: London, United Kingdom.  
28. Fox, E., et al., A Phase 1 Trial and Pharmacokinetic Study of Cediranib, an Orally Bioavailable Pan-Vascular Endothelial G*rowth Factor Receptor Inhibitor, in Children* and Adolescents With Refractory Solid Tumors. Journal of Clinical Oncology, 2010.  
28(35): p. 5174-5181.  
29. Wedge, S.R., et al., *The VEGF receptor tyrosine kinase inhibitor AZD2171 inhibits* VEGF signaling, angio*genesis, and tumor growth in vivo.* AACR Meeting Abstracts, 2004. **2004**(1): p. 1052-.  
30. Lazar, A.J.F., et al., Angiogenesis-*Promoting Gene Patterns in Alveolar Soft Part* Sarcoma. Clinical Cancer Research, 2007. 13(24): p. 7314-7321.  
31. Therasse, P., et al., *New guidelines to evaluate the response to treatment in solid tumors.*
European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst, 2000.  
92(3): p. 205-16.  
32. Portera, C., et al., Alveolar soft part sarcoma: clinical course and patterns of metastasis in 70 patients treated at a single institution. Cancer, 2001. 91(3): p. 585-91.  
33. Smith, A.D., M.L. Lieber, and S.N. Shah, Assessing Tumor Response and Detecting Recurrence in Metastatic Renal Cell Carcinoma on Targeted Therapy: Importance of Size and Attenuation on Contrast-Enhanced CT. American Journal of Roentgenology, 2010. 194(1): p. 157-165.  
34. Smith, A.D., et al., *Morphology, Attenuation, Size, and Structure (MASS) Criteria:*
Assessing Response and Predicting Clinical Outcome in Metastatic Renal Cell Carcinoma on Antiangiogenic Targeted Therapy. American Journal of Roentgenology, 2010. 194(6): p. 1470-1478.  
35. Choi, H., et al., *Correlation of Computed Tomography and Positron Emission* Tomography in Patients With Metastatic Gastrointestinal Stromal Tumor Treated at a Single Institution With Imatinib Mesylate: Proposal of New Computed Tomography Response Criteria. Journal of Clinical Oncology, 2007. 25(13): p. 1753-1759.  
36. vanSonnenberg, E., et al., *Image-guided 25-gauge needle biopsy for thoracic lesions:*
diagnostic feasibility and safety. Radiology, 2003. 227(2): p. 414-8.
appendix a performance status criteria
14 references

| PERFORMANCE STATUS CRITERIA Karnofsky and Lansky performance scores are intended to be multiples of 10.   |                                         |                                 |                                  |                                       |                       |
|-----------------------------------------------------------------------------------------------------------|-----------------------------------------|---------------------------------|----------------------------------|---------------------------------------|-----------------------|
| ECOG (Zubrod)                                                                                             | Karnofskv                               | Lansky                          |                                  |                                       |                       |
| Description                                                                                               | Description                             | Description                     |                                  |                                       |                       |
| Score                                                                                                     | Score                                   | Score                           |                                  |                                       |                       |
| o                                                                                                         | Fully active, able to carry on all pre- | 100%                            | Normal, no complaints, no        | 100%                                  | Fully active, normal. |
| disease performance without restriction.                                                                  | evidence of disease.                    |                                 |                                  |                                       |                       |
| 90%                                                                                                       | Able to carry on normal                 | 90%                             | Minor restrictions in physically |                                       |                       |
| activity; minor sighs of                                                                                  | strenuous activity.                     |                                 |                                  |                                       |                       |
| symptoms of disease                                                                                       |                                         |                                 |                                  |                                       |                       |
| Restricted in physically strenuous activity                                                               | 80%                                     | Able to carry on normal         | 80%                              | Active, but tires more quickly.       |                       |
| but ambulatory, able to carry out light or                                                                | activity with effort; some              |                                 |                                  |                                       |                       |
| sedentary work, e.g., light housework,                                                                    | signs or symptoms of disease.           |                                 |                                  |                                       |                       |
| office work.                                                                                              | 70%                                     | Cares for self, unable to carry | 70%                              | Both greater restriction of, and less |                       |
| on normal activity or do                                                                                  | time spent in, play activities.         |                                 |                                  |                                       |                       |
| active work.                                                                                              |                                         |                                 |                                  |                                       |                       |
| Ambulatory and capable of all self-care                                                                   | 60%                                     | Requires occasional             | 60%                              | Up and around, but minimal active     |                       |
| but unable to carry out any work.                                                                         | assistance but is able to care          | play; keeps busy with quieter   |                                  |                                       |                       |
| activities. Up and about more than 50%                                                                    | for most of own needs.                  | activities.                     |                                  |                                       |                       |
| of waking hours.                                                                                          | 50%                                     | Requires considerable           | 50%                              | Gets dressed, but lies around much    |                       |
| assistance and frequent                                                                                   | of the day; no active play; able to     |                                 |                                  |                                       |                       |
| medical care.                                                                                             | participate in quiet play and           |                                 |                                  |                                       |                       |
| activities.                                                                                               |                                         |                                 |                                  |                                       |                       |
| Capable of only limited self-care,                                                                        | 40%                                     | Disabled; requires special      | 40%                              | Mostly in bed; participates in quiet  |                       |
| confined to bed or chair more than 50%                                                                    | care and assistance.                    | activities.                     |                                  |                                       |                       |
| of waking hours                                                                                           | 30%                                     | Severely disabled;              | 30%                              | In bed; needs assistance even for     |                       |
| hospitalization indicated,                                                                                | quiet play.                             |                                 |                                  |                                       |                       |
| although death not imminent.                                                                              |                                         |                                 |                                  |                                       |                       |
| Completely disabled.  Cannot carry on                                                                     | 20%                                     | Very ill; hospitalization       | 20%                              |                                       |                       |
| 4                                                                                                         | Often sleeping; play entirely limited   |                                 |                                  |                                       |                       |
| any self-care. Totally confined to a bed on                                                               | necessary;  active supportive;          | to very passive activities.     |                                  |                                       |                       |
| chair                                                                                                     | treatment required.                     |                                 |                                  |                                       |                       |
| 10%                                                                                                       | 10%                                     |                                 |                                  |                                       |                       |
| Moribund, fatal process                                                                                   | No play; does not get out of bed        |                                 |                                  |                                       |                       |
| progressing rapidly                                                                                       |                                         |                                 |                                  |                                       |                       |
| Dead                                                                                                      | 0%                                      | Patient expired                 | 0%                               | Unresponsive; Dead                    |                       |
appendix b enzyme-inducing anticonvulsant drugs
14 references

| For drugs not listed, please contact the Study Chair   |                    |
|--------------------------------------------------------|--------------------|
| Anticonvulsants with little or no enzyme induction     |                    |
| Generic Name                                           | Trade Name         |
| Ethosuximide                                           | Zarontin           |
| Gabapentin                                             | Neurontin          |
| Lamotrigine                                            | Lamictal           |
| Levetiracetam                                          | Keppra             |
| Tigabine                                               | Gabitril           |
| Topiramate                                             | Topamax            |
| Valproic Acid                                          | Depakote, Depakene |
| Zonisamide                                             | Zonegran           |  
For drugs not listed, please contact the Study Chair Enzyme inducing anticonvulsant drugs (EIACD)  
| Generic Name   | Trade Name    |
|----------------|---------------|
| Carbamazepine  | Tegretol      |
| Felbamate      | Felbatol      |
| Phenobarbital  | Phenobarbital |
| Phenytoin      | Dilantin      |
| Primidone      | Mysoline      |
| Oxcarbazepine  | Trileptal     |
appendix c study diary page
14 references

Today's date ________________________________ Patient Name________________________________ Patient Study ID____________________ (*initials acceptable)*  
INSTRUCTIONS TO THE PATIENT:  
1. Complete one form for each cycle. 2. You will take ___ pills (15mg) and___ pills (20 mg) each day. Please take the pill(s) on an empty stomach  
either 1 hour before or 2 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.  
5. Please bring your pill bottle and this form to your physician when you go for your next appointment.  
| 4.                                                                                                                                                                                                                                                                                                                                                                                                                                                | If you have any comments or notice any side effects, please record them in the Comments column.              |                 |                |          |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------|-----------------|----------------|----------|
| 5.                                                                                                                                                                                                                                                                                                                                                                                                                                                | Please bring your pill bottle and this form to your physician when you go for your next appointment. # pills |                 |                |          |
| Date                                                                                                                                                                                                                                                                                                                                                                                                                                              | Day                                                                                                          | and when  taken | Blood Pressure | Symptoms |
| morning                                                                                                                                                                                                                                                                                                                                                                                                                                           | evening                                                                                                      |                 |                |          |
| 1 2  3 4 5 6 7 8  9  10 11 12 13 14                                                                                                                                                                                                                                                                                                                                                                                                               |                                                                                                              |                 |                |          |
| Patient's Signature: _____________________________________________ Date:_______________________ Physician's Office will complete this section: 1. Date patient started protocol treatment___________ Date patient was removed from study____________ 2. Patient's planned daily dose________________________ Total number of pills taken this cycle _____ Physician/Nurse/Data Manager's Signature ______________________________________________ |                                                                                                              |                 |                |          |
appendix c study diary page
14 references

Today's date ________________________________ Patient Name________________________________ Patient Study ID____________________ (*initials acceptable)*  
INSTRUCTIONS TO THE PATIENT:  
1. Complete one form for each cycle.  
2. You will take ___ pills (15 mg) and ___pills (20 mg) each day. Please take the pill(s) on an empty stomach  
either 1 hour before or 2 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.  
5. Please bring your pill bottle and this form to your physician when you go for your next appointment.  
| 4.                                                                                                                                                                                                                                                                                                                                                                                                                                                      | If you have any comments or notice any side effects, please record them in the Comments column.              |                 |                |          |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------|-----------------|----------------|----------|
| 5.                                                                                                                                                                                                                                                                                                                                                                                                                                                      | Please bring your pill bottle and this form to your physician when you go for your next appointment. # pills |                 |                |          |
| Date                                                                                                                                                                                                                                                                                                                                                                                                                                                    | Day                                                                                                          | and when  taken | Blood Pressure | Symptoms |
| morning                                                                                                                                                                                                                                                                                                                                                                                                                                                 | evening                                                                                                      |                 |                |          |
| 15  16 17 18 19 20 21 22 23 24 25 26 27 28                                                                                                                                                                                                                                                                                                                                                                                                              |                                                                                                              |                 |                |          |
| Patient's Signature: _____________________________________________ Date:______________________ Physician's Office will complete this section: 1. Date patient started protocol treatment____________ Date patient was removed from study__________ 2. Patient's planned daily dose_____________________ Total number of pills taken this cycle_________ Physician/Nurse/Data Manager's Signature ______________________________________________________ |                                                                                                              |                 |                |          |
appendix d patient drug interactions
14 references

Information for Patients, Their Caregivers and Non-Study Healthcare Team on Possible Interactions with Other Drugs and Herbal Supplements  
|          | Diagnosis:   | Trial #:   |       |           |
|----------|--------------|------------|-------|-----------|
|          | Study Doctor |            | Study | Cediranib |
| Phone #: | Drug(s):     | (AZD2171)  |       |           |  
Please show this paper to all your healthcare providers (doctors, physician assistants, nurse  
 practitioners, pharmacists), and tell them you are taking part in a clinical trial sponsored by the National Cancer Institute. These are the things that your healthcare providers need to know: Cediranib (AZD2171) interacts with certain enzymes in the liver and certain transport proteins that help move drugs in and out of cells.
appendix d patient drug interactions
explanation

CYP
isoenzymes  
| The enzymes in question are CYP 3A4, 2D6, flavin-containing  monooxygenase (FMO) and UGT1A4. Cediranib (AZD2171) is metabolized  by FMO1, FMO3 and UGT1A4 and may be affected by other drugs that  strongly inhibit or induce these enzymes. Cediranib (AZD2171) weakly  inhibits CYP 2D6 and 3A4 and may increase levels of affected substrates.  Cediranib (AZD2171) may induce gastrointestinal CYP3A and UGT enzymes,  therefore potentially reducing the effectiveness of hormonal contraceptives.   |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
Cediranib (AZD2171) is 95% protein bound (human serum albumin and alpha-1-acid glycoprotein) and may displace other highly protein-bound drugs. Use caution in patients taking concomitant medications with narrow therapeutic ranges.
appendix d patient drug interactions
these are the things that

The study drug cediranib, may interact with other drugs which can cause side effects. For this reason, it is very important to tell your doctors about all your medicines, including: (a) medicines you are taking before this clinical trial, (b) medicines you start or stop taking during this study, (c) medicines you buy without a prescription (over-the-counter remedy), (d) herbals  
| Protein      |
|--------------|
| transporters |  
| The transport proteins in question are P-glycoprotein (P-gp) and breast cancer  resistance protein (BCRP). Cediranib (AZD2171) requires P-gp to move in  and out of cells. Cediranib (AZD2171) inhibits P-gp, BCRP and MATE2-K  which may affect the clearance of other drugs that are dependent on these  transport proteins.   |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
or supplements (e.g. St. John's Wort). It is helpful to bring your medication bottles or an updated medication list with you. Before you enroll onto the clinical trial, your study doctor will work with your regular health care providers to review any medicines and herbal supplements that are considered "strong inducers/inhibitors of FMO1, FMO3, UGT1A4 and P-gp." Cediranib (AZD2171) inhibits enzymes "CYP 2D6 and 3A4, transport proteins P-gp, BCRP and MATE2-K and is highly protein-bound." These characteristics may change how other medicine works in your body.  
- Please be very careful! Over-the-counter drugs (including herbal supplements) may contain ingredients that could interact with your study drug. Speak to your doctors or pharmacist to determine if there could be any side effects.  
- Cediranib (AZD2171) may potentially reduce the effectiveness of hormonal contraceptives. Please check with your study provider about using contraception while on study treatment.  
- Patients receiving Cediranib (AZD2171) are at increased risk of bleeding. If you are receiving anticoagulation therapy, you will be monitored more frequently.  
- Make sure your doctor knows to avoid certain prescription medications.  
- Your regular health care provider should check a frequently updated medical reference or call your study doctor before prescribing any new medicine or discontinuing any medicine.  
Version *DEC 2019*
(Next page: Patient Drug Interaction Wallet Card)
appendix d patient drug interactions
patient drug interaction wallet card

| EMERGENCY INFORMATION                                                                                                                                                                                                                                                                                                  | DRUG INTERACTIONS                                                                                                              |                                                                     |                                 |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------|---------------------------------|
| Show this card to all of your  healthcare providers. Keep it  with you in case you go to  the emergency room.                                                                                                                                                                                                          | Tell your doctors before you  start or stop any medicines. Check with your doctor or                                           |                                                                     |                                 |
| pharmacist if you need to use an  over-the-counter medicine or  herbal supplement!                                                                                                                                                                                                                                     | Carry this card with you at all times                                                                                          |                                                                     |                                 |
| Cediranib interacts with: CYP 3A4, 2D6, FMO and UGT1A4 which are  needed to clear cediranib from the body; transport proteins P-gp,  needed to move cediranib in and out of cells; and P-gp, BCRP and  MATE2-K needed to clear other drugs from the body. Cediranib must  be used very carefully with other medicines. |                                                                                                                                |                                                                     |                                 |
| Patient Name:                                                                                                                                                                                                                                                                                                          | Use caution and avoid the  following drugs if possible:                                                                        | Your healthcare providers should be aware of any medicines that are |                                 |
| Diagnosis:                                                                                                                                                                                                                                                                                                             | "strong inducers/inhibitors of FMO1, FMO3, UGT1A4 and P-gp."  Cediranib (AZD2171) inhibits enzymes "CYP 2D6 and 3A4, transport |                                                                     |                                 |
| Study Doctor:                                                                                                                                                                                                                                                                                                          | protein, P-gp. BCRP and MATE2-K and is highly protein-bound."                                                                  |                                                                     |                                 |
| Study Doctor Phone #:  NCI Trial #:                                                                                                                                                                                                                                                                                    | Before prescribing new medicines, your health care provider should                                                             |                                                                     |                                 |
| Study Drug(S): Cediranib (AZD2171)                                                                                                                                                                                                                                                                                     | check a frequently-updated medical reference for a list of drugs to  avoid or contact your study doctor.                       |                                                                     |                                 |
| Hormonal contraceptives                                                                                                                                                                                                                                                                                                |                                                                                                                                |                                                                     |                                 |
|                                                                                                                                                                                                                                                                                                                        |                                                                                                                                | Version DEC/2019                                                    |                                 |
| For more information: 1-800-4-                                                                                                                                                                                                                                                                                         | For more information: 1-800-4-                                                                                                 | For more information: 1-800-4-                                      | For more information: 1-800-4-  |
| CANCER                                                                                                                                                                                                                                                                                                                 | CANCER                                                                                                                         | CANCER                                                              | CANCER                          |
| cancer.gov | clinicaltrials.gov                                                                                                                                                                                                                                                                                        | cancer.gov | clinicaltrials.gov                                                                                                | cancer.gov | clinicaltrials.gov                                     | cancer.gov | clinicaltrials.gov |  
Fold at dotted lines:
appendix d patient drug interactions
appendix e blood pressure collection

Frequency of monitoring: Blood pressure (BP) should be monitored by a health care provider every 2 weeks for the first two cycles of therapy, and then once each cycle. Patients will be instructed to check their BP at home more frequently. Patients with significant elevation in blood pressure requiring medications will continue to evaluate blood pressure twice a day. If blood pressure elevation occurs requiring drug therapy, the frequency of monitoring blood pressure will be determined by the study doctors and the patient instructed appropriately.  
Data recording: All required data should be recorded in the appropriate eCRF or on the patient's blood pressure monitoring diary, as appropriate. **The following data are required at baseline and at each** subsequent assessment:
- Assessment date and time
- Pulse
- Systolic and diastolic BP
Risk factors for hypertension (assess and record data in eCRF)
- Diabetes (type 1 or type 2)
- Renal disease (specify on CRF)
- Endocrine condition associated with HTN (specify on CRF)
- Use of steroids or NSAIDs (specify all concomitant meds)
- Underlying cardiovascular condition - specify (i.e., ischemic heart disease)
Baseline data collection (at registration)
All patients:
- Current BP - Proteinuria, if present Patients with preexisting hypertension (*i.e.*, those for whom "hypertension" is entered as a concomitant condition at registration, or those who are currently receiving therapy with antihypertensive medication) - also record:
- Date of HTN diagnosis (original) - Type HTN (essential or secondary)
- CTCAE grade of HTN (at time of study entry)
- Trade name, drug class*, dose, dose frequency, start/stop dates/ongoing of the following:
- Antihypertensive agents taken at study entry - Antihypertensive agents taken in past (e.g., discontinued for toxicity, lack of efficacy)
appendix d patient drug interactions
follow up bp data collection

All patients (at each clinic visit):
- Current BP
- Proteinuria, if present Patients with treatment-emergent hypertension [defined as BP >95% for age, height, and gender for patients ages 1-16 (see Appendix I) and >140/90 for patients' ≥18 years of age] - record at time of hypertension diagnosis and at all subsequent visits:
- BP changes from baseline (or from previous assessment) (specify grade changes per Table 2)
- Hypertension-related symptoms as reported by patient (e.g., headache) - Other relevant changes associated with development of hypertension (e.g., ECG abnormalities)
- Trade name, drug class*, dose, dose frequency, start/stop dates/ongoing of currently prescribed antihypertensive agents Patients with preexisting hypertension at study entry - record at each visit:
- BP changes from previous clinic visit (specify grade changes per Table 2) - Hypertension-related symptoms reported by patient (e.g., headache)
- Other relevant changes associated with development of hypertension (e.g., ECG abnormalities)
- Changes in antihypertensive medications since last assessment (*e.g.*, dose change, add/discontinue drug)
*Classes of antihypertensive drugs include ACE inhibitors, calcium channel blockers, alpha blockers, beta blockers, diuretics, angiotensin II receptor antagonists.  
| Dihydropyridine calcium-channel blockers (DHP CCB) Agent Initial dose Intermediate dose   | Maximum dose      | Hepatic metabolism   |                    |                                |
|-------------------------------------------------------------------------------------------|-------------------|----------------------|--------------------|--------------------------------|
| Nifedipine XL                                                                             | 30 mg po qd       | 60 mg po qd          | 90 mg po qd        | CYP 3A4 substrate              |
| Amlopidine                                                                                | 2.5 mg po qd      | 5 mg po qd           | 10 mg po qd        | CYP 3A4 substrate              |
| Felodipine                                                                                | 2.5 mg po qd      | 5 mg po qd           | 10 mg po qd        | CYP 3A4 substrate +  inhibitor |
| Selective β blockers (BB) Agent Initial dose                                              | Intermediate dose | Maximum dose         | Hepatic metabolism |                                |
| Metoprolol                                                                                | 25 mg po bid      | 50 mg po bid         | 100 mg po bid      | CYP 2D6 substrate              |
| Atenolol                                                                                  | 25 mg po qd       | 50 mg po qd          | 100 mg po qd       | No                             |
| Acebutolol                                                                                | 100 mg po bid     | 200-300 mg po bid    | 400 mg po bid      | Yes (CYP450 unknown)           |
| Bisoprolol                                                                                | 2.5 mg po qd      | 5-10 mg po bid       | 20 mg po qd        | Yes (CYP450 unknown)           |
| Angiotensin Converting Enzyme Inhibitors (ACEIs)  Agent Initial dose Intermediate dose    | Maximum dose      | Hepatic metabolism   |                    |                                |
| Captopril                                                                                 | 12.5 mg po tid    | 25 mg po tid         | 50 mg po tid       | CYP 2D6 substrate              |
| Enalapril                                                                                 | 5 mg po qd        | 10-20 mg po qd       | 40 mg po qd        | CYP 3A4 substrate              |
| Ramipril                                                                                  | 2.5 mg po qd      | 5 mg po qd           | 10 mg po qd        | Yes (CYP450 unknown)           |
| Lisinopril                                                                                | 5 mg po qd        | 10-20 mg po qd       | 40 mg po qd        | No                             |
| Fosinopril                                                                                | 10 mg po qd       | 20 mg po qd          | 40 mg po qd        | Yes (CYP450 unknown)           |
| Rarely used: Perindopril                                                                  | 4 mg po qd        | none                 | 8 mg po qd         | Yes but not CYP450             |
| Quinapril                                                                                 | 10 mg po qd       | 20 mg po qd          | 40 mg po qd        | No                             |
| Angiotensin II Receptor Blockers (ARBs)  Agent Initial dose Intermediate dose             | Maximum dose      | Hepatic metabolism   |                    |                                |
| Losartan                                                                                  | 25 mg po qd       | 50 mg po qd          | 100 mg po qd       | CYP 3A4 substrate              |
| Candesartan                                                                               | 4 mg po qd        | 8-16 mg po qd        | 32 mg po qd        | CYP 2C9 substrate              |
| Irbesartan                                                                                | 75 mg po qd       | 150 mg po qd         | 300 mg po qd       | CYP 2C9 substrate              |
| Telmisartan                                                                               | 40 mg po qd       | none                 | 80 mg po qd        | Yes but not CYP450             |
| Valsartan                                                                                 | 80 mg po qd       | none                 | 160 mg po qd       | Yes but not CYP450             |
| α and β blocker Agent                                                                     | Initial dose      | Intermediate dose    | Maximum dose       | Hepatic metabolism             |
| Labetolol                                                                                 | 100 mg po bid     | 200 mg po bid        | 400 mg po bid      | CYP 2D6 substrate +  inhibitor |  
The algorithm in Appendix J will be used to grade and manage AZD2171-related hypertension. Should initiation of anti-hypertensive therapy be required, single agent therapy (consider a calcium channel blocker such as amlodipine or nifedipine) should be started, and the blood pressure should be monitored at least twice weekly until BP is within the 95th percentile for age, height, and gender per Appendix I.
appendix g lvef dose modification
follow up bp data collection

Asymptomatic Decrease in LVEF The decision to continue or hold STUDY DRUG is based on the LVEF as it relates to the institutions's lower limit of normal (LLN) and change in ejection fraction from screening (LVEF
as measured at registration) according to the following table:  
| Relationship of  LVEF to institution's  LLN   | LVEF Decrease                                     | LVEF Decrease                                                                                   | LVEF Decrease                                     |
|-----------------------------------------------|---------------------------------------------------|-------------------------------------------------------------------------------------------------|---------------------------------------------------|
| < 10%                                         | 10-15%                                            | ≥ 16%                                                                                           |                                                   |
| Normal                                        | Continue                                          | Continue                                                                                        | Continue and repeat  MUGA/ECHO within  1-2 cycles |
| 1-5% below LLN                                | Continue and repeat  MUGA/ECHO within  1-2 cycles | HOLD and repeat  MUGA/ECHO within  1-2 cycles                                                   |                                                   |
| ≥ 6% below LLN                                | Continue and repeat  MUGA/ECHO within  1-2 cycles | Continue and repeat  MUGA/ECHO within  1-2 cycles HOLD and repeat  MUGA/ECHO within  1-2 cycles | HOLD and repeat  MUGA/ECHO within  1-2 cycles     |  
Discontinue STUDY DRUG if:
- Two consecutive HOLD catagories occur.  
- Three intermittant HOLD catagories occur (at the discretion of the investigator, STUDY
DRUG may also be permanently discontinued prior to the occurance of 3 intermittant HOLD catagories).
If LVEF is maintained at a "Continue and repeat MUGA/ECHO" or improves from a HOLD to a "Continue and repeat MUGA/ECHO" category, additonal MUGA scans/echocardiograms prior to the next scheduled MUGA/ECHO will be at the discretion of the investigator.
appendix g lvef dose modification
symptomatic cardiac events

Discontinue STUDY DRUG if:
- A patient has symptoms of congestive heart failure (CHF) and a diagnosis of CHF is confirmed.  
- A patient has a myocardial infarction.  
| Dose Level   | Dose (mg/m2 /dose)   |      |           |           |        |
|--------------|----------------------|------|-----------|-----------|--------|
| 1            | 12                   | BSA* | 1.04-1.45 | 1.46-2.08 | ≥ 2.09 |
| Dose†        | 15                   | 20   | 30        |           |        |  
* BSA, body surface area in m2. † Actual dose in mg (tablets sizes 15 and 20 mg) administered once daily.  
Note: Dose reductions for patients experiencing dose-limiting toxicities are outlined in Section 5.1.2.  
Appendix H: Pediatric Dosing Nomogram for AZD2171
appendix i blood pressure levels
symptomatic cardiac events

Blood pressure (BP) levels for BOYS aged 1-17 years **(only patients under 16 years of age are eligible for this protocol)**  
| Systolic Blood Pressure, mm Hg        | Diastolic Blood Pressure, mm Hg   |                      |                      |      |      |      |      |      |     |      |      |      |      |      |      |
|---------------------------------------|-----------------------------------|----------------------|----------------------|------|------|------|------|------|-----|------|------|------|------|------|------|
| Age                                   | BP                                | Percentile of Height | Percentile of Height |      |      |      |      |      |     |      |      |      |      |      |      |
| (years)                               | Percentile                        | 5th                  | 10th                 | 25th | 50th | 75th | 90th | 95th | 5th | 10th | 25th | 50th | 75th | 90th | 95th |
| 1                                     | 95th                              | 98                   | 99                   | 101  | 103  | 104  | 106  | 106  | 54  | 54   | 55   | 56   | 57   | 58   | 58   |
| 2                                     | 95th                              | 101                  | 102                  | 104  | 106  | 108  | 109  | 110  | 59  | 59   | 60   | 61   | 62   | 63   | 63   |
| 3                                     | 95th                              | 104                  | 105                  | 107  | 109  | 110  | 112  | 113  | 63  | 63   | 64   | 65   | 66   | 67   | 67   |
| 4                                     | 95th                              | 106                  | 107                  | 109  | 111  | 112  | 114  | 115  | 66  | 67   | 68   | 69   | 70   | 71   | 71   |
| 5                                     | 95th                              | 108                  | 109                  | 110  | 112  | 114  | 115  | 116  | 69  | 70   | 71   | 72   | 73   | 74   | 74   |
| 6                                     | 95th                              | 109                  | 110                  | 112  | 114  | 115  | 117  | 117  | 72  | 72   | 73   | 74   | 75   | 76   | 76   |
| 7                                     | 95th                              | 110                  | 111                  | 113  | 115  | 117  | 118  | 119  | 74  | 74   | 75   | 76   | 77   | 78   | 78   |
| 8                                     | 95th                              | 111                  | 112                  | 114  | 116  | 118  | 119  | 120  | 75  | 76   | 77   | 78   | 79   | 79   | 80   |
| 9                                     | 95th                              | 113                  | 114                  | 116  | 118  | 119  | 121  | 121  | 76  | 77   | 78   | 79   | 80   | 81   | 81   |
| 10                                    | 95th                              | 115                  | 116                  | 117  | 119  | 121  | 122  | 123  | 77  | 78   | 79   | 80   | 81   | 81   | 82   |
| 11                                    | 95th                              | 117                  | 118                  | 119  | 121  | 123  | 124  | 125  | 78  | 78   | 79   | 80   | 81   | 82   | 82   |
| 12                                    | 95th                              | 119                  | 120                  | 122  | 123  | 125  | 127  | 127  | 78  | 79   | 80   | 81   | 82   | 82   | 83   |
| 13                                    | 95th                              | 121                  | 122                  | 124  | 126  | 128  | 129  | 130  | 79  | 79   | 80   | 81   | 82   | 83   | 83   |
| 14                                    | 95th                              | 124                  | 125                  | 127  | 128  | 130  | 132  | 132  | 80  | 80   | 81   | 82   | 83   | 84   | 84   |
| 15                                    | 95th                              | 126                  | 127                  | 129  | 131  | 133  | 134  | 135  | 81  | 81   | 82   | 83   | 84   | 85   | 85   |
| 16                                    | 95th                              | 129                  | 130                  | 132  | 134  | 135  | 137  | 137  | 82  | 83   | 83   | 84   | 85   | 86   | 87   |
| 17                                    | 95th                              | 131                  | 132                  | 134  | 136  | 138  | 139  | 140  | 84  | 85   | 86   | 87   | 87   | 88   | 89   |
| Instructions for using this BP Chart: |                                   |                      |                      |      |      |      |      |      |     |      |      |      |      |      |      |  
| Systolic Blood Pressure, mm Hg        | Diastolic Blood Pressure, mm Hg   |                      |                      |      |      |      |      |      |     |      |      |      |      |      |      |
|---------------------------------------|-----------------------------------|----------------------|----------------------|------|------|------|------|------|-----|------|------|------|------|------|------|
| Age                                   | BP                                | Percentile of Height | Percentile of Height |      |      |      |      |      |     |      |      |      |      |      |      |
| (years)                               | Percentile                        | 5th                  | 10th                 | 25th | 50th | 75th | 90th | 95th | 5th | 10th | 25th | 50th | 75th | 90th | 95th |
| 1                                     | 95th                              | 100                  | 101                  | 102  | 104  | 105  | 106  | 107  | 56  | 57   | 57   | 58   | 59   | 59   | 60   |
| 2                                     | 95th                              | 102                  | 103                  | 104  | 105  | 107  | 108  | 109  | 61  | 62   | 62   | 63   | 64   | 65   | 65   |
| 3                                     | 95th                              | 104                  | 104                  | 105  | 107  | 108  | 109  | 110  | 65  | 66   | 66   | 67   | 68   | 68   | 69   |
| 4                                     | 95th                              | 105                  | 106                  | 107  | 108  | 110  | 111  | 112  | 68  | 68   | 69   | 70   | 71   | 71   | 72   |
| 5                                     | 95th                              | 107                  | 107                  | 108  | 110  | 111  | 112  | 113  | 70  | 71   | 71   | 72   | 73   | 73   | 74   |
| 6                                     | 95th                              | 108                  | 109                  | 110  | 111  | 113  | 114  | 115  | 72  | 72   | 73   | 74   | 74   | 75   | 76   |
| 7                                     | 95th                              | 110                  | 111                  | 112  | 113  | 115  | 116  | 116  | 73  | 74   | 74   | 75   | 76   | 76   | 77   |
| 8                                     | 95th                              | 112                  | 112                  | 114  | 115  | 116  | 118  | 118  | 75  | 75   | 75   | 76   | 77   | 78   | 78   |
| 9                                     | 95th                              | 114                  | 114                  | 115  | 117  | 118  | 119  | 120  | 76  | 76   | 76   | 77   | 78   | 79   | 79   |
| 10                                    | 95th                              | 116                  | 116                  | 117  | 119  | 120  | 121  | 122  | 77  | 77   | 77   | 78   | 79   | 80   | 80   |
| 11                                    | 95th                              | 118                  | 118                  | 119  | 121  | 122  | 123  | 124  | 78  | 78   | 78   | 79   | 80   | 81   | 81   |
| 12                                    | 95th                              | 119                  | 120                  | 121  | 123  | 124  | 125  | 126  | 79  | 79   | 79   | 80   | 81   | 82   | 82   |
| 13                                    | 95th                              | 121                  | 122                  | 123  | 124  | 126  | 127  | 128  | 80  | 80   | 80   | 81   | 82   | 83   | 83   |
| 14                                    | 95th                              | 123                  | 123                  | 125  | 126  | 127  | 129  | 129  | 81  | 81   | 81   | 82   | 83   | 84   | 84   |
| 15                                    | 95th                              | 124                  | 125                  | 126  | 127  | 129  | 130  | 131  | 82  | 82   | 82   | 83   | 84   | 85   | 85   |
| 16                                    | 95th                              | 125                  | 126                  | 127  | 128  | 130  | 131  | 132  | 82  | 82   | 83   | 84   | 85   | 85   | 86   |
| 17                                    | 95th                              | 125                  | 126                  | 127  | 129  | 130  | 131  | 132  | 82  | 83   | 83   | 84   | 85   | 85   | 86   |
| Instructions for using this BP Chart: |                                   |                      |                      |      |      |      |      |      |     |      |      |      |      |      |      |  
Blood pressure (BP) levels for GIRLS aged 1-17 years (only patients under 16 years of age are eligible for this protocol)
This table was taken from "The Fourth Report on the Diagnosis, Evaluation, and Treatment of High Blood Pressure in Children and Adolescents" PEDIATRICS Vol. 114 No. 2 August 2004, pp. 555-576.
appendix i blood pressure levels
appendix j blood pressure monitoring

†  Elevated blood pressure (BP) measurements  should be repeated  on the same  day to confirm the elevation.  Patients with elevated  BP at any time should have BP measurements performed at least twice weekly until BP is within the ULN.  
s ULN (Upper Limit of Normal) is a BP equal to the 95th percentile from age, height, and gender-appropriate normal values (Appendix l)
If BP >25 mm Hg above ULN for age (venfied) or Grade 4 HTN at any time, hold drug.  Study drug should also be held for BP < 25 mm Hg above the ULN age for > 14 days or 35 mmHg above baseline for> 14 days. Antihypertensive agents can be used to control hypertension as clinically indicated after study drug is held.  
^Anti-hypertensive therapy should be prescribed as clinically indicated, including the use of multiple anti-hypertensive agents.  
\# Baseline BP is defined in Section 5.2.3.
appendix i blood pressure levels
directions for algorithm arm 1

- If blood pressure (BP) ≤ 95% for age, height, and gender, continue AZD2171 at the same dose.
appendix i blood pressure levels
arm 2 of algorithm

- If BP ≤ 10 mm Hg above the ULN for age, height, and gender, continue AZD2171 at the same dose and recheck the BP within 72 h.  
o If the BP is ≤ ULN on recheck, continue AZD2171 at the same dose.  
o If the BP remains above the ULN on recheck, then start antihypertensive therapy
(Appendix F) and follow Arm 3 of the algorithm from the point that anti-hypertensive therapy is started.
appendix i blood pressure levels
arm 3 of algorithm

- If BP is 11 to 25 mm Hg above the 95% for age, height, and gender on ≥ 2 of 3 measurements or
> 35 mmHg above baseline on ≥ 2 of 3 measurements, start anti-hypertensive therapy
(Appendix F), continue AZD2171 at the same dose, and monitor BP at least every twice weekly.  
o If the BP returns to ≤ ULN within 14 days, continue AZD2171 at the same dose and continue anti-hypertensive therapy.  
o If the BP remains elevated ≤ 25 mm Hg above the 95% or > 35 mm Hg above baseline for more than 14 days after the institution of anti-hypertensive therapy, hold AZD2171 monitor BP at least every 3 days, and follow Arm 4 of the algorithm from the point that AZD2171 is held. The antihypertensive therapy should be continued until the BP is less than the ULN.  
o If the BP returns to ≤ ULN within 14 days, restart AZD2171 at a reduced dose
(Section 5.1.2).  
o If the BP remains > ULN for more than 14 days, patient is Off Protocol Therapy.  
o If the BP increases to > 25 mm Hg above the ULN despite anti-hypertensive therapy, hold AZD2171, but continue the anti-hypertensive agent(s). Monitor the BP as clinically indicated and follow Arm 4 of the algorithm from the point that AZD2171 is held.  
o If the BP is ≤ ULN within 14 days, AZD217may be restarted at a reduced dose
(Section 5.1.2).  
o If the BP is > ULN for > 14 days, the patient is Off Protocol Therapy (Section 5.4).
appendix i blood pressure levels
arm 4 of algorithm

- If BP is >25 mm Hg above the 95% for age, height, and gender, hold AZD2171, monitor BP and administer anti-hypertensive therapy as clinically indicated.  
o If the BP returns to ≤ ULN within 14 days, AZD2171 may be restarted at a reduced dose
(Section 5.1.2).  
o If the BP is > ULN for >14 days, the patient is Off Protocol Therapy (Section 5.4).
appendix i blood pressure levels
arm 5 of algorithm

- If the participant develops Grade 4 hypertension (CTCAE), discontinue AZD2171, monitor BP
and administer anti-hypertensive therapy as clinically indicated. The patient is Off Protocol Therapy (Section 5.4).  
Patients, who require a dose reduction of cediranib, which results in taking cediranib on days 1-5 followed by 2 days rest, should hold antihypertensive medication on the rest days when they are not taking cediranib.
appendix k protocol for mri
patient id number

Note: Unilateral knee MRI. Right knee preferred over left unless prohibited by contractures, lesions, pain, or hypertrophy. This is done to examine the femoral and tibial growth plates. Only the series outlined below are required for the knee MRI for evaluation of femoral and tibial growth plates and must be performed within protocol specifications as indicated below. Two sequential scans of the knee will be performed per patient. The patient must step off the scanner and be placed back on the scanner between the two scans.  
| T1 Weighted Sagittal   | Protocol       | Actual   | Reason For Change   |
|------------------------|----------------|----------|---------------------|
| Specifications         | Specifications |          |                     |
| Echo Train Length      | 72             |          |                     |
| TR                     | 500-600        |          |                     |
| TE                     | min full       |          |                     |
| Slice Thickness        | 3              |          |                     |
| Bandwidth              | 20 kHz         |          |                     |
| GAP                    | 1.5 mm         |          |                     |
| FOV                    | 18             |          |                     |
| FREQ                   | 512            |          |                     |
| Phase                  | 256            |          |                     |
| NEX                    | 1              |          |                     |
| PHFVO                  | Full           |          |                     |
| Saturation             | no FS          |          |                     |
| OPTIONS                | Fast           |          |                     |  
Date:_________Signature (responsible MRI technician):_____________________________
appendix k protocol for mri
appendix l therapeutic response assessment

Department of Radiology and Imaging Sciences investigator Dr. Les Folio and colleagues will retrospectively evaluate 20 consecutive off-study patients on Protocol 09-C-0192. All measurable lesions (>1.0 cm) will be assessed on baseline and follow-up CT. The specific aims are to:
1. Retrospectively compare TVVT (all lesions; volume/density) vs. pre-determined RECIST
(axial only)
2. Correlate TVVT, RECIST, and treatment response Registration and Lesion Management Application (algorithm/ software): Automated registration and semi-automatic segmentation of all metastatic tumors >1.0 cm will be performed on serial CT scans using PACS (Picture Archiving and Communication System) Lesion Management Algorithm radiology imaging software (Carestream Health 11.3, Rochester, NY). First, the baseline and follow-up CT scans are manually opened and globally registered to align axial planes between the two scans. The global registration algorithm employs a fully automated volumetric voxel-based rigid registration algorithm.1 Second, tumors are manually located, which is performed by singly clicking on tumors, or by extending a measurement markup across conglomerated or abutting lesions. The PACS software then performs a refined registration by modifying the initial global registration dataset to enhance localization of the selected metastatic tumor across serial exams.2 Next, the software automatically segments the target tumor on both CT scans using enhanced tumor edge detection (not necessarily defining separate lesions).3 Finally, the PACS software automatically couples segmentation and tumor measurement, providing longest axial tumor length, perpendicular to longest axial length, short axis, mean HU density, and tumor volume of interest (VOI) in the segmented area. Observers then edit the typical segmentation outline using a freeform segmentation tool to exclude non-tumoral components.  
All volume, size, and volumetric density measurements of the target tumors will be recorded on both the baseline and follow-up CT scans. All measurements will be performed by two observers (college graduates with no formal medical training) under other authors with over 10 years of experience in CT as body radiologists. The radiologists will verify observer segmentations, in consensus, when needed.