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9.0 subject withdrawal and trial

Subjects may be withdrawn from the study treatment for the following reasons:
- Subject completes all protocol defined therapy- 6 cycles
- Progressive neoplastic disease - Subject or guardian withdraws consent to continue study drug - Subject develops an intercurrent illness that precludes further participation, or requires a prohibited concomitant treatment
- The Investigator withdraws the subject in the subject's best interests - Subject is lost to follow-up (defined as the inability to contact the subject on 3 separate occasions over a period of 2 weeks)
- Administrative reasons (e.g., the subject is transferred to hospice care) - An adverse event, which in the opinion of the Investigator, precludes further trial participation or fulfills the protocol requirements for withdrawal (e.g., the development of dose limiting toxicity despite a reduction in protocol therapy for a previous episode of dose limiting toxicity)
- Death 9.2 **Criteria for Subject Off-Study**
Subjects may be withdrawn from the study completely which includes withdrawal from survival follow-up for the following reasons:
- Subject or guardian withdraws consent to continue in the trial - Subject is lost to follow-up (defined as the inability to contact the subject on 3 separate occasions over a period of 2 weeks)
- Subject completes all protocol defined therapy including all follow-up time points. - Death
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9.3 trial discontinuation

The lead site may discontinue the trial as a whole or at an individual investigational site at any time. Reasons for early trial discontinuation may include, but are not limited to, unacceptable toxicity of study drug, a request to discontinue the trial from a regulatory authority, protocol violations at an investigational site, violations of good clinical practice at an investigational site, or poor enrollment. The lead site will promptly inform all Investigators in the event of premature study discontinuation and provide all Investigators with instructions regarding the disposition of subjects still on study. Should the study be terminated prematurely, all unused study drug, case report forms and any other study material will be returned to the lead site.
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10.0 data analysis 10.1 data

Electronic case report forms (CRF) will be checked for correctness against source document data by the monitor. If any entries into the CRF are incorrect, incomplete or illegible, the monitor will ask the Investigator or the study site staff to make appropriate corrections.
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10.2 statistical analysis

This is an open label, single agent, multicenter, study for subjects with relapsed or refractory neuroblastoma. The following data sets will be used in this study:  
- All enrolled and eligible subjects (ITT) population: All eligible subjects who have a signed informed consent form.  
- All treated and eligible subjects (Safety evaluable) population: All subjects who received at least one dose of study drug
- All eligible subjects treated to first evaluable time point with evaluation completed (generally 2 cycles) (as Treatment Efficacy) population, unless subjects have reached the study endpoint of progression of disease at an earlier time point.
Efficacy analyses will be performed on the Treatment evaluable population. Safety analysis will be performed on the Safety and Efficacy evaluable population. All baseline patient characteristics will be summarized in a tabular format. Safety data will be described for all subjects receiving at least one dose of DFMO. Safety data will include values for hematology, serum chemistry, vital signs, and adverse events. The proportion of subjects experiencing adverse events, serious adverse events, dose limiting toxicities and treatment delays will be summarized. Enrollment to study will not pause at interim analysis time points.
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sample size and analysis

The primary outcome measure is the Overall Response Rate (ORR). A two-stage minimax test for a single binomial population using a directional 5% Type I error level of the null hypothesis that the Overall Response Rate is <=1% versus the alternative hypothesis of the Overall Response Rate being 10% will require 32 evaluable subjects to achieve an 80% power for each of the subject stratum.. The two-stage decision rule for each strata is as follows: Stage 1- When 20 evaluable subjects have been entered into the study and observed for Overall Response, the study will terminate and accept the null hypothesis of a <=1% Overall Response Rate if none (0) of these 20 subjects show a Complete Response or Partial Response (i.e. stop due to futility). If 1 or more of the 20 evaluable subjects show an Overall Response, then the study will continue to Stage 2. Stage 2- When the full 32 evaluable subjects have been entered into the study and observed for an Overall Response, the study would terminate and accept the null hypothesis of an Overall Response Rate <=1% if 1 or fewer of the 32 subjects show a Complete Response or Partial Response. If 2 or more of the 32 evaluable subjects show an Overall Response, the study will terminate and will result in the rejection of the null hypothesis and conclude that the 10% Overall Response Rate is more likely. Total subjects: Assuming that approximately 10% of subjects will be non-evaluable, the actual sample size needed will be n =35 per stratum. The secondary outcome measure is Progression Free Survival (PFS) at 100 days. The sample size discussion that follows mimics the two-stage design approach used for the primary outcome measure, ORR. However, since this sample size and decision rule description relate to PFS at 100 days, this section is illustrative only and will not be used to impact on study accrual. Assuming an exponential model with the null hypothesis median Progression Free Survival of 42 days and an alternative median Progression Free Survival of 82 days, then one would expect the proportion of subjects who are progression free at 100 days of follow-up to be19.2% under the null value of 42 days and 42.9% under the alternative value of 82 days. Shorter follow-up time frames would increase the proportion of progression free subjects while a longer follow-up would decrease these proportions. Rationale for the null hypothesis effect size is derived from recent Children's Oncology Group reports in multiply relapsed NB patients. Forty-two days was selected as the standard for comparison because it is the median time to progression for a control population of NB patients recently treated on other Phase I and II trials (CCG-8607, ANBL00321, NANT-0103, CCG0926, and CCG-0961).  
Progression Free Survival (PFS) is defined as the period from the first day of administration of study drug (DFMO) until the criteria for progression are met taking as reference the screening measurements. The definition of "progression" as applied to this control population will include deaths from any cause. From the control patients in the COG study (n=136), the 42 day PFS rate was 50% ± 4%. Day 42 corresponds to the time at which most patients will have completed 2 courses of study therapy (assuming no delays, 21 days per course for 2 courses is 42 days). An assessment of disease will be required after the completion of 2 courses. Therefore, the standard for comparison, which DFMO/Velcade is anticipated to exceed, has been set at a median time to progression of 42 days. Using a one sample exact binomial test of the 19.2% versus the 42.9% progression free survival values at 100 days, the overall sample size would be n = 23 using a two-stage minimax test with directional 5% Type I error level and 80% power The two-stage decision rule is as follows: Stage 1- When 18 evaluable subjects have been entered into the study and observed for at least 100 days, the study will terminate and accept the null hypothesis of 19.2% progression free survival if 5 or fewer of the 18 subjects are progression free at 100 days of follow-up (i.e. stop due to futility). If 6 or more of the 18 evaluable subjects are progression free, then the study will continue to Stage 2. Stage 2- When 23 evaluable subjects have been entered into the study and observed for at least 100 days, the study would terminate and accept the null hypothesis of 19.2% progression free survival if 7 or fewer of the 23 subjects are progression free at 100 days of follow-up. If 8 or more of the 23 evaluable subjects are progression free, the study will terminate and will result in the rejection of the null hypothesis and conclude that the 42.9% progression free survival at 100 days is more likely. It is thus clear that the analysis of PFS will be able to progress without difficulty if the full sample size of 32 evaluable subjects per stratum is achieved for the ORR primary outcome evaluation. It is also clear that even with an early termination for futility for the ORR outcome at n = 20 subjects at Stage I in either of the subject strata, that the PFS secondary outcome should be testable although with slightly lower power.
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11.0 administrative procedures 11.1 patient

No study related procedures will be performed until a patient or a patient's legal representative has given written informed consent. The lead site will provide to the site Investigators a sample informed consent document that conforms to all the requirements for informed consent according to ICH GCP and US FDA guidelines (21 CFR 50). However, it is up to each site Investigator to provide a final informed consent that may include additional elements required by the Investigator's institution or local regulatory authorities. The IRB/EC for each investigational site must approve the consent form document prior to study activation; changes to the consent form during the course of the study may also require IRB/EC approval. The informed consent document must clearly describe the potential risks and benefits of the trial, and each prospective participant must be given adequate time to discuss the trial with the Investigator or site staff and to decide whether or not to participate. Each patient who agrees to participate in the trial and who signs the informed consent will be given a copy of the signed dated and witnessed document. The original copy of the signed, dated, and witnessed informed consent document will be retained by the Investigator in the study files. The Investigator must also obtain authorization from the patient to use and/or disclose protected health information in compliance with the Health Insurance Portability and Accountability Act (HIPAA). Written HIPAA authorization may be obtained as part of the informed consent process.
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11.2 ethical conduct of the

The study will be conducted according to the principles of the 2004 version of the Declaration of Helsinki, the International Conference on Harmonization Guidance on Good Clinical Practice and the requirements of all local regulatory authorities regarding the conduct of clinical trials and the protection of human subjects. The Investigator will submit the protocol, the Investigator's Brochure, the informed consent and any other material used to inform patients about the trial to the local IRB/IEC for approval prior to enrolling any patient into the trial. The IRB/IEC should be duly constituted according to applicable regulatory requirements. Approval must be in the form of a letter signed by the Chairperson of the IRB/IEC or the Chairperson's designee, must be on IRB/IEC stationary and must include the protocol by name and/or designated number. If an Investigator is a member of the IRB/IEC, the approval letter must stipulate that the Investigator did not participate in the final vote, although the Investigator may participate in the discussion of the trial. The Investigator will also inform the IRB/IEC of any serious adverse events that are reported to regulatory authorities and will provide to the IRB/IEC a final summary of the results of the trial at the conclusion of the trial. Any amendments to the protocol will be done at the lead site, and will be submitted to the IRB/IEC for review and written approval before implementation. These approved changes will then be forwarded to sites for review by their local IRB/IEC. Written approval from sites will be forwarded to the lead site.
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11.3 data safety monitoring board

An independent Data Safety and Monitoring Board (DSMB) will oversee the conduct of the study. The members of this Board will receive database summaries, including adverse event reports, and will convene either in person or via teleconference every 6 months or for any study drug related Grade 5 toxicity occurring on study, whichever occurs first. The Board will be responsible for recommendations regarding possible termination and/or early reporting of the study. Study will be on hold for safety monitoring by DSMB review when:  
1. Any deaths deemed related to the study drug by the treating PI while on study or occurring less than 30 days after medications ended or 2 serious adverse events possibly related to protocol within 60 days.  
2. Any Life threatening hemorrhage requiring hospitalization 3. Any intracerebral hemorrhage 4. Any other reason that the NMTRC feels it is in the best safety interest of the subjects.
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11.4 monitoring and auditing

A clinical monitor will make regularly scheduled trips to the investigational site to review the progress of the trial as defined in the Monitoring Plan. The actual frequency of monitoring trips will depend on the enrollment rate and performance at each site. At each visit, the monitor will review various aspects of the trial including, but not limited to, screening and enrollment logs; compliance with the protocol and with the principles of Good Clinical Practice; completion of case report forms; source data verification; study drug accountability and storage; facilities and staff data quality; regulatory documentation; and study integrity. In addition the site may be audited by representatives of KC Pharma and/or government inspectors who must be allowed access to CRFs, source documents and other study files. The site must promptly notify the study chair of any inspections scheduled by regulatory authorities, and also forward copies of the inspection reports to the study chair. The study chair will promptly forward this information to KC Pharma as required. During scheduled monitoring visits, the Investigator and the investigational site staff must be available to meet with the study monitor in order to discuss the progress of the trial, make necessary corrections to case report form entries, respond to data clarification requests and respond to any other trial-related inquiries of the monitor.
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11.5 pre-study documentation

Prior to initiating the trial, the Investigators at each site will provide to the Lead site the following documents:
- A signed FDA Form 1572 - A current curriculum vitae for the Principal Investigator and each sub-investigator listed on the FDA Form 1572
- A copy of the Investigator's medical license from the state in which the study is being conducted
- A letter from the IRB or EC stipulating approval of the protocol, the informed consent document and any other material provided to potential trial participants with information about the trial (e.g., advertisements)
- A copy of the IRB- or EC-approved informed consent document - Current IRB membership list for IRB's without a multiple project assurance number or an IRB organization number under the Federal Wide Assurance program (www.ohrp.osophs.dhhs.gov).  
- A signed Investigator Protocol Agreement - A completed financial disclosure form for each person listed in box 6 of the FDA form 1572.  
- Current laboratory certification for the reference laboratory - A list of current laboratory normal values for the reference laboratory
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11.6 confidentiality

It is the responsibility of the investigator to insure that the confidentiality of all subjects participating in the trial and all of their medical information is maintained. Case report forms and other documents submitted must never contain the name of a trial participant. Each subject in the trial will be identified by a unique identifier that will be used on all CRF's and any other material submitted to the lead site. All case report forms and any identifying information must be kept in a secure location with access limited to the study staff directly participating in the trial. The results of the study may be presented in reports, published in scientific journals or presented at medical meetings; however, subject names will never be used in any reports about the study.
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11.7 source documents

The Investigator will maintain source records separate from the case report forms in the form of clinical charts, medical records, original laboratory, radiology and pathology reports, pharmacy records, etc. The Investigator will document in the clinic chart or medical record the name and number of the trial and the date on which the subject signed informed consent prior to the subject's participation in the trial. Source documents must completely reflect the nature and extent of the patient's medical care, and must be available for source document verification against entries in the case report forms when the monitor visits the investigational site. All information obtained from source documents will be kept in strict confidentiality.
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11.8 record retention

The Investigator will retain the records of the study for 15 years, or for 2 years following the date that a marketing application for the study drug is approved, or if no marketing application is filed, or if such an application is not approved, for 2 years after the IND has been closed. The lead site will notify Investigators when retention of study records is no longer required. All study records must be maintained in a safe and secure location that allows for timely retrieval, if needed. Study records that must be retained include copies of case report forms, signed informed consents, correspondence with the IRB or IEC, study drug dispensing and inventory records, source documents, clinic charts, medical records, laboratory results, radiographic reports) and screening/enrollment logs.  
Should the Investigator relocate or retire, or should there be any changes in the archival arrangements for the study records, the lead site must be notified. The responsibility for maintaining the study records may be transferred to another suitable individual, but the lead site must be notified of the identity of the individual assuming responsibility for maintaining the study records and the location of their storage.
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12.0 biological evaluation

A major challenge in the development of cancer therapeutics is an absence of understanding the relationship of the disease to response to therapy, and the ability to predict which subjects are most likely to respond to any particular agent. Emerging technologies including ability to establish primary tumor cells in culture, evaluate pharmacogenomics and explore biomarkers may provide a way to explore relationships between clinical benefit and treatment.
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urine sample analysis

Decarboxylated S-adenosylmethionine (dcSAM) Performed by Dr. Bachmann (section 12.1.1):
Adenine and its derivatives are known to react with 2-chloroacetaldehyde to form highly fluorescent tricyclic derivatives. This reaction gives a sensitive and specific method for measuring dc-SAM in urine and plasma samples. The reaction mixture will be incubated at 40°C overnight. An aliquot of this mixture will be injected onto an Altex Ultrosphere column for chromatographic separation. Detection will be accomplished using a Perkin-Elmer LS-4 spectrofluorometer, as described by others.[77]
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polyamines performed by dr. bachmann

High performance liquid chromatography (HPLC) and other methods will be used, as per previous studies ([4, 77]), to detect putrescine, spermidine, spermine, monoacetylspermidine and monoacetylspermine and diacetylspermine. Samples will be adjusted to 0.2N perchloric acid and analyzed directly. Acid hydrolysis methods will be employed to remove acetyl groups, and thus measure diacetylated amines. The detection level will be 1-10 pmol. Sources of error associated with these measures in colonic tissue have been previously reported ([78]). Urinary creatinine levels will also be determined, using a commercial kit (Oxford Biochemical Research), to normalize urinary polyamines. In the method, picric acid reacts with creatinine and other urinary components to produce an orange color, which can be quantified spectrophotometrically at 490 nm at alkaline pH. The creatinine reaction degrades rapidly when acidified. The difference in optical density is a direct measure of the creatinine concentration.
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blood and bone marrow samples

ODC SNP analysis –Performed by Pediatric Oncology Translational Research Laboratory (Section 12.1.2) The ODC G316A single nucleotide polymorphism (SNP) was associated with polyamine contents in prostate and colorectal mucosal biopsies. The lowest levels of polyamines are found in colorectal mucosal tissues from individuals homozygous for the A allele, with highest levels observed among carriers of the GG-genotype. There is no relationship between ODC G316A allele genotype and colorectal content of histamine, an amine not dependent on ODC for its synthesis. We wish to determine the effects of DFMO treatment on polyamine levels in patients with each ODC genotype. Results from our recent clinical trial suggest that ototoxicity associated with DFMO therapy is restricted to a small fraction of people with the ODC 316AA genotype. These clinical trial results are corroborated by clinical translational studies that are based on molecular epidemiology investigations and have been replicated by three independent groups in humans showing that a polymorphism affecting the expression of ODC, the DFMO target protein, is highly associated with metachronous colon adenomas and sporadic breast cancer. In addition, two independent groups have reported that this same polymorphism is associated with prostate cancer progression and colon cancer survival. In order to develop algorithms predicting who will benefit, and who will have side effects of DFMO treatment, we will determine the ODC G263T and G316A types of all study participants, by analyzing DNA obtained from nucleated blood cells using established methods. We will also assess levels of micro RNAs in serum (Gilad S, Meiri E, Yogev Y, Benjamin S, Lebanony D, Yerushalmi N, Benjamin H, Kushnir M, Cholakh H, Melamed N, Bentwich Z, Hod M, Goren Y, Chajut A. Serum microRNAs are promising novel biomarkers PLoS One. 2008 Sep 5;3(9):e3148) as predictive markers of DFMO effect. We have evidence in both human cancer cells and apparently normal rectal tissue from humans that DFMO modulates cell and tissue contents of specific micro RNAs. Neuroblastoma Tumor Cell Analysis –Performed by Pediatric Oncology Translational Research Laboratory (Section 12.1.2) Studies will be performed to determine the dose effect of DFMO on biological correlates. Biological Correlates will include an analysis of neuroblastoma cells isolated from bone marrow and from tumor biopsies. Cells will be grown in culture as well as in mice xenograft models. Research studies will include immunohistochemistry, western blot, qRTPCR of bone marrow tumor cells or tumor to study Let-7, ODC, Lin28, MYCN, OKT-4, BMI1, HMGA2, GLUT-4, p-AKT, NF-kB, SOCS3. Studies will measure thymidine and polyamine levels. In vitro research studies of tumor cells collected above will include: Genomic analysis of cells pre- and post- treatment, cell viability assays to determine subject IC50 and correlation of in vitro response to *in vivo* response.
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12.1 biological correlative studies sample

On Days 1 and 15 of Cycle 1 and on Day 1 of cycles 2-6 urine polyamines will be collected. A. First morning void urines will be collected using a clean catch method in containers and placed at 4oC until transported to the laboratory. Collection of 15ml is ideal, but lab can accept amounts down to a minimum of 1 (one) ml.  
B. Specimens will be transferred to 15ml polypropylene conical tubes
(use multiple 15ml tubes as needed) and stored at -80oC until analysis for the dc-SAM and polyamines. Samples should be kept at 4oC (either in refrigerator or on ice pack during shipping) until frozen and must be frozen within 48 hours from collection time. If unable to freeze within 48 hours please note this on the container along with time before frozen.  
Samples will be batch shipped on a Monday (send after approximately 20 samples are collected) and sent on dry ice to: Ping Zhao Pediatric Oncology Translational Research Laboratory Coopers Landing 1345 Monroe Ave., Suite 121 Grand Rapids, MI 49505 Ph: 616-486-8645 Ping.zhao@helendevoschildrens.org
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12.1.2 optional blood collection

1. Sample One- 5ml of blood in purple-top (EDTA) tube(s) will be
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collected

A. On Days 1 and 15 of Cycle 1 and on Day 1 of cycles 2-6 B. The specimen should be placed on ice immediately upon draw and sent on an ice pack immediately via FED-EX overnight along with sample 2 below. (If Friday collection site may store in refrigerator and ship on Monday)-
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tube(s) will go to ping

Pediatric Oncology Translational Research Laboratory Coopers Landing 1345 Monroe Ave., Suite 121 Grand Rapids, MI 49505 Ph: 616-486-8645 Ping.zhao@helendevoschildrens.org 2. Sample Two- 5ml of blood in purple-top (EDTA) tube(s) will be
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collected

A. On Days 1 and 15 of Cycle 1 and on Day 1 of cycles 2-6 B. The specimen should be placed on ice immediately upon draw and sent on an ice pack immediately via FED-EX overnight. (If Friday collection site may store in refrigerator and ship on Monday)-
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tube(s) will go to ping

Pediatric Oncology Translational Research Laboratory Coopers Landing 1345 Monroe Ave, Suite 121 Grand Rapids, MI 49505 Ph: 616-486-8645 Ping.zhao@helendevoschildrens.org
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12.1.3 optional bone marrow collection

If subject agrees to optional biology portion of study, additional bone marrow samples should be sent at the following time points:
(Please note that if subject has also signed to protocol NMTRC 00B, these samples may **be sent under that study instead)**: All Subjects- At Enrollment, End of cycle 2, 4, and 6, and Early Withdrawal (if indicated).
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sample collection-

Send green top (sodium heparin) tube(s) with a minimum of 2cc and preferably 5cc of bone marrow aspirate in them. The bone marrow samples should be shipped room temperature- but needs to be sent out same day priority overnight (must get there within 24 hours of the draw). Shipments are only accepted Monday through Friday, so Bone Marrow draw needs to be done and shipped out on Monday through Thursday only please. Please contact the lab at the number below to let them know of pending arrival. Bone marrow 2-5cc in green top (sodium heparin) tube(s) at room temperature and will be shipped FED-EX overnight to:
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ping zhao

Pediatric Oncology Translational Research Laboratory Coopers Landing 1345 Monroe Ave, Suite 121 Grand Rapids, MI 49505 Ph: 616-486-8645 Ping.zhao@helendevoschildrens.org
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12.1.4 optional tumor sample collection

If subject agrees to optional biology portion of study, and undergoes a standard of care tumor biopsy, tumor samples should be sent as follows:
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sample collection-

Contact Ping Zhao as below for collection materials (kit). Collection instructions can be found in REDCap. To be shipped out on Monday through Thursday only.  
A. Viable, fresh tumor > 0.2 grams should be placed in tissue culture media using sterile technique for cell line generation- ambient.  
B. Remaining Tumor collected in RNA later- ambient. C. Remaining Tumor flash frozen samples in cryovials on dry ice.  
Record sample information on sample collection form found in REDCap and ship form along with samples (2 packages- one ambient, one on dry ice) via FED-EX overnight to:
Ping Zhao Pediatric Oncology Translational Research Laboratory Coopers Landing 1345 Monroe Ave, Suite 121 Grand Rapids, MI 49505 Ph: 616-486-8645 Ping.zhao@helendevoschildrens.org
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12.2 sample storage and destruction

Samples collected for any studies performed in this protocol may be stored in a safe and confidential laboratory area indefinitely to research future scientific questions related to cancer and/or study drugs. Samples will be frozen and stored in a carefully controlled deep freezer. The samples that are stored for future research may only be used by Dr. Sholler and the other investigators who are participating in this study or other NMTRC studies. There is no way to predict exactly what research tests will be performed with the stored samples at this time. Because these tests are for research only, results will not be shared with the subject or their physician. In the unlikely event that the research testing finds important information about the subject's current or future health, the researchers may contact the primary treating oncologist about what the research test results might mean. Only the primary treating oncologist will be notified and the information will not become part of the subject's medical record. The primary treating oncologist may discuss this unexpected finding with the subject, and may recommend that they see a genetic counselor and/or repeat testing in a clinical (not research) laboratory if needed. Samples will be stored with a unique identifier and date of collection only; samples will not contain names or any other identifying information. No information that identifies the subject will be used for any of the future research tests and studies. Samples will not be traceable from the lab to the subject. Only the enrolling site will hold the key to the sample identification between the unique code and the subject. The subject retains the right to have the sample material destroyed at any time by contacting the principal investigator.
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appendix i performance status/scores

|  Performance Status Criteria                                                             |                                     |                                       |                                 |                                   |                                   |
|------------------------------------------------------------------------------------------|-------------------------------------|---------------------------------------|---------------------------------|-----------------------------------|-----------------------------------|
| Kamofsky and Lansky performance scores are intended to be multiples of 10                |                                     |                                       |                                 |                                   |                                   |
| ECOG (Zubrod)                                                                            | Karnofsky                           | Lansky*                               |                                 |                                   |                                   |
| Score                                                                                    | Description                         | Score                                 | Description                     | Score                             | Description                       |
| 100                                                                                      | Normal, no complaints, no           | 100                                   | Fully active, normal.           |                                   |                                   |
| evidence of disease                                                                      |                                     |                                       |                                 |                                   |                                   |
| Fully active, able to cany on all                                                        |                                     |                                       |                                 |                                   |                                   |
| 0                                                                                        | pre-disease performance             | 90                                    | Able to carry on normal         | 90                                | Minor restrictions in physically  |
| without restriction.                                                                     | activity, minor signs or            | strenuous activity.                   |                                 |                                   |                                   |
| symptoms of disease.                                                                     |                                     |                                       |                                 |                                   |                                   |
| 80                                                                                       | Normal activity with effort;        | SO                                    | Active, but tires more quickly  |                                   |                                   |
| Restricted in physically                                                                 | some signs or symptoms of           |                                       |                                 |                                   |                                   |
| strenuous activity but                                                                   | disease.                            |                                       |                                 |                                   |                                   |
| ambulatory and able to carry                                                             |                                     |                                       |                                 |                                   |                                   |
| !                                                                                        | out work of a light or sedentary    | 70                                    | Cares for self, unable to carry | 70                                | Both greater restriction of and   |
| nature, e.g., light housework,                                                           | on normal activity or do active     | less time spent in play activity.     |                                 |                                   |                                   |
| office work.                                                                             | work.                               |                                       |                                 |                                   |                                   |
| 60                                                                                       | Required occasional                 | 60                                    | Up and around, but minimal      |                                   |                                   |
| assistance, but is able to care                                                          | active play, keeps busy with        |                                       |                                 |                                   |                                   |
| Ambulatory and capable of all                                                            | for most of his/her needs.          | quieter activities.                   |                                 |                                   |                                   |
| self-care but unable to carry out                                                        |                                     |                                       |                                 |                                   |                                   |
| 2                                                                                        | any work activities. Up and         | 50                                    | Requires considerable           | 50                                | Gets dressed, but lies around     |
| about more than 50% of waking                                                            | assistance and frequent             | much of the day; no active play.      |                                 |                                   |                                   |
| hours                                                                                    | medical care.                       | able to participate in all quiet play |                                 |                                   |                                   |
| and activities.                                                                          |                                     |                                       |                                 |                                   |                                   |
| 40                                                                                       | Disabled, requires special care.    | 40                                    | Mostly in bed; participates in  |                                   |                                   |
| Capable of only limited self-                                                            | and assistance.                     | quiet activities.                     |                                 |                                   |                                   |
| care, confined to bed or chain                                                           |                                     |                                       |                                 |                                   |                                   |
| 3                                                                                        | more than 50% of waking             | 30                                    | Severely disabled,              | 30                                | In bed; needs assistance even for |
| hours.                                                                                   | hospitalization indicated.          | quiet play.                           |                                 |                                   |                                   |
| Death not imminent.                                                                      |                                     |                                       |                                 |                                   |                                   |
| 20                                                                                       | Very sick, hospitalization          | 20                                    | Often sleeping; play entirely   |                                   |                                   |
| indicated. Death not                                                                     | limited to very passive activities. |                                       |                                 |                                   |                                   |
| Completely disabled. Cannot                                                              | imminent.                           |                                       |                                 |                                   |                                   |
| 4                                                                                        | cany on any self-care. Totally      |                                       |                                 |                                   |                                   |
| confined to bed or chair.                                                                | 10                                  | Moribund, fatal processes             | 10                              | No play; does not get out of bed. |                                   |
| progressing rapidly.                                                                     |                                     |                                       |                                 |                                   |                                   |
| The conversion of the Lansky to ECOG scales is intended for NCI reporting purposes only. |                                     |                                       |                                 |                                   |                                   |
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appendix ii list of strong

| Strong CYP3A4 Inducers: Generic Name                                                                                                                                                                                                                                                                 | Common Trade Name   |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------|
| Carbamazepine                                                                                                                                                                                                                                                                                        | Tegretol            |
| Phenobarbital                                                                                                                                                                                                                                                                                        | Luminal             |
| Phenytoin                                                                                                                                                                                                                                                                                            | Dilantin            |
| Rifampin                                                                                                                                                                                                                                                                                             | Rifadin             |
| St. John's wart                                                                                                                                                                                                                                                                                      | N/A                 |
| Systemic dexamethasone                                                                                                                                                                                                                                                                               | Decadron            |
| Strong* and clinically relevant moderate CYP3A4 Inhibitors: Generic Name Common Trade Name Aprepitant Emend Clarithromycin* Biaxin Erythromycin Eryc, EryPed Fluconazole Diflucan Grapefruit and its juice N/A Itraconazole* Sporanox Ketoconazole* Nizoral Voriconazole VFend Posaconazole* Noxafil |                     |  
A list of additional, less potent inducers or inhibitors of CYP450 isoenzymes can be found at http://medicine.iupui.edu/clinpharm/ddis/
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references

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