7.1 comprehensive adverse events and
9.4.2 discipline review neuro-imaging

Local review of MR imaging studies at each site and central review of the MR imaging studies will be conducted through the PBTC Neuroimaging Center (NIC). The director and one Neuroradiologist of NIC will review the imaging studies at study completion. If the local and central review are not in agreement the NIC neuroradiologist will confer with the participating site to determine why there is a discrepancy via conference call. NIC review will include assessment of response to therapy (as feasible). All patients with a documented PR/CR at any time point will have central review of the scan showing response, the confirmation scan obtained approximately 8 weeks later, as well as the corresponding baseline scan conducted for confirmation.
7.1 comprehensive adverse events and
10 study calendar

| Completion/                                                                                                                                                        |                         |                     |    |    |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------|---------------------|----|----|
| Discontinuation Of Treatment                                                                                                                                       |                         |                     |    |    |
| PHYSICAL ASSESSMENTS Medical history                                                                                                                               | X                       | Weekly              | X  | X  |
| Physical exam /height/weight                                                                                                                                       | X                       | Weekly              | X  | X  |
| Vital signs                                                                                                                                                        | X                       | Weekly              | X  | X  |
| Performance status                                                                                                                                                 | X                       | Weekly              | X  | X  |
| Neurologic exam                                                                                                                                                    | X                       | Weekly              | X  | X  |
| LABORATORY EVALUATIONS CBC - WBC, HgB, Hct, Platelets, ANC,                                                                                                        | WeeklyA                 | WeeklyA, B          | X  |    |
| ALC                                                                                                                                                                | X Pre                         |                     |    |    |
| therapy                                                                                                                                                            | Course 1                | Course 2- Course 26 |    |    |
| Serum Chemistry - Sodium, Potassium,  Bicarbonate, Chloride, Calcium, BUN,  Creatinine, Glucose, Phosphorous,  Magnesium, Albumin, Total Protein                   | X                       | Weekly              | XB | X  |
| SGPT (ALT), SGOT (AST), Alkaline  phosphatase, Total Bilirubin                                                                                                     | X                       | Weekly              | XB | X  |
| Serum pregnancy test (for females of  childbearing potential)                                                                                                      | X                       | XB                  | XB |    |
| CSF cytology (if clinically indicated)                                                                                                                             | X                       |                     |    |    |
| OTHER ASSESSMENT 12-lead EKG                                                                                                                                       | X                       | XC                  | XC | XC |
| Ophthalmology Examination (including slit  lamp)                                                                                                                   | X                       | XD                  |    |    |
| IMAGING ASSESSMENTS Brain MRI (standard)                                                                                                                           | X                       | XE                  | X  |    |
| Spine MRI (if clinically indicated)                                                                                                                                | X                       | XF                  | X  |    |
| CORRELATIVE STUDIES Screening Pre-trial tumor materials for Rb1  testing (required for patients with all types  of CNS tumors except DIPG,  medulloblastoma, ATRT) | XG                      |                     |    |    |
| Pharmacogenetic Studies (if consented)                                                                                                                             | XH                      |                     |    |    |
| Plasma Pharmacokinetic Studies (required)                                                                                                                          | XI                      | XI                  |    |    |
| Plasma PK after discontinuation of                                                                                                                                 | Any time after stopping |                     |    |    |
| dexamethasone (if consented)                                                                                                                                       | dexamethasone I         |                     |    |    |
| Pre-trial tumor materials for Genomics (if  consented)                                                                                                             | XJ                      |                     |    |    |
| Tumor Tissue and blood for Biorepository  (if consented)                                                                                                           | XK                      |                     |    |    |  
| Completion/                  |    |
|------------------------------|----|
| Discontinuation Of Treatment |    |
| A.                           | CBC with differential at baseline and q weekly during each cycle for the first 3 cycles; consideration can be given  Pretherapy Course 1 Course 2- Course 26    |  
Completion/
Discontinuation Of Treatment A. CBC with differential at baseline and q weekly during each cycle for the first 3 cycles; consideration can be given to increase interval to q 2 weeks from course 4 onwards if the patient has no DLT in the previous cycle. If patient develops Grade 4 neutropenia or thrombocytopenia, then CBCs should be checked every 3-4 days until recovery to Grade 3.  
B. Within 48 hours of beginning protocol therapy and each course (see 5.3).  
C. 12-lead EKG at baseline, and 3 hours post dose on days 1, 8, and 15 of cycle 1 and on day 1 of cycles 2 and 3.  
Thereafter, EKG should be done prior to the start of every 3 rd cycle (prior to 6, 9, 12, 15, 18, 21, 24 and end of treatment).  
D. Eye exam is to be done at baseline, and every 3 months (after courses 3, 6, 9, 12, 15, 18, 21, 24). The ophthalmology exam report should clearly specify the presence or absence of cataracts and data must be recorded in Rave database.  
E. Standard imaging is to be done every 8 weeks (after courses 2, 4, 6) and then every 12 weeks thereafter through the 26 courses and at the completion of treatment.  
F. MRI Spine should be done at the same time points as the standard MRI brain, if clinically indicated. G. 2 unstained slides from FFPE block and 1 H&E slide required to be submitted for Rb testing (see 9.1.1)
H. Obtain 5 mL of whole blood prior to 1st dose if consented (See section 9.2.1 for details)
I. Plasma PK (required) - D1 Course 1: pre-dose, 0.5, 1, 2, 4, 8, 10, 24, 48 hrs after dose D21 Course 1: pre-dose, 1, 2, 4, 8, 10, 24 after dose (See section 9.2.2 for details of Plasma PK)
Plasma PK after discontinuation of dexamethasone (if consented) - see section 9.2.2 J. 10 unstained slides from FFPE block or FFPE tissue block [See section 9.3.3 for details of Pre-trial tumor materials for Genomics (if consented)]
K. Biorepository samples (if consented) - 20 unstained FFPE slides and blood. Obtain 2-5 mL of whole blood at baseline. If unable to collect at baseline, it can be collected any time during protocol therapy. See section 9.3.1 for details.
7.1 comprehensive adverse events and
11 measurement of effect 11.1

Complete disappearance on MR of all enhancing tumor and mass effect, on a stable or decreasing dose of corticosteroids (or receiving only adrenal replacement doses), accompanied by a stable or improving neurologic examination, and maintained for at least 8 weeks. If CSF was positive for malignant cells, it must be negative.
7.1 comprehensive adverse events and
11.1.2 partial response (pr)

Greater than or equal to 50% reduction in tumor size by bi-dimensional measurement, as compared with the baseline measurements, on a stable or decreasing dose of corticosteroids, accompanied by a stable or improving neurologic examination, and maintained for at least 8 weeks. If CSF was positive for malignant cells, it must be negative.
7.1 comprehensive adverse events and
11.1.3 stable disease (sd)

Neurologic exam is at least stable and maintenance corticosteroid dose not increased, and MR/CT imaging meets neither the criteria for PR nor PD. CSF can be positive or negative for malignant cells. If this category is to be reported as of possible clinical benefit, Stable Disease status must be maintained for at least 4 courses.
7.1 comprehensive adverse events and
11.1.4 progressive disease (pd)

Progressive Disease (PD): Progressive neurologic abnormalities or worsening neurologic status not explained by causes unrelated to tumor progression (e.g., anticonvulsant or corticosteroid toxicity, electrolyte disturbances, sepsis, hyperglycemia, etc.), OR a greater than 25% increase in the bi-dimensional measurement, taking as a reference the smallest disease measurement recorded since the start of protocol therapy, OR the appearance of a new lesion (including new appearance of malignant cells in the CSF), OR increasing doses of corticosteroids required to maintain stable neurological status or imaging.
7.1 comprehensive adverse events and
12 data reporting/ regulatory requirements

Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.
7.1 comprehensive adverse events and
12.1 data reporting 12.1.1 responsibility

Data collection for this study will be done exclusively through the Medidata Rave clinical data management system. Access to the trial in Rave is granted through the iMedidata application to all persons with the appropriate roles assigned in Regulatory Support System (RSS). To access Rave via iMedidata, the site user must have an active CTEP-IAM account (check at <https://ctepcore.nci.nih.gov/iam>) and the appropriate Rave role (Rave CRA, Read-Only, CRA (Lab Admin, SLA or Site Investigator) on either the LPO or participating organization roster at the enrolling site. To the hold Rave CRA role or CRA Lab Admin role, the user must hold a minimum of an AP registration type. To hold the Rave Site Investigator role, the individual must be registered as an NPIVR or IVR. Associates can hold read-only roles in Rave. Upon initial site registration approval for the study in RSS, all persons with Rave roles assigned on the appropriate roster will be sent a study invitation e-mail from iMedidata. To accept the invitation, site users must log into the Select Login (https://login.imedidata.com/selectlogin) using their CTEP-IAM user name and password, and click on the "accept" link in the upper right-corner of the iMedidata page. Please note, site users will not be able to access the study in Rave until all required Medidata and study specific trainings are completed. Trainings will be in the form of electronic learnings (eLearnings), and can be accessed by clicking on the link in the upper right pane of the iMedidata screen. Users that have not previously activated their iMedidata/Rave account at the time of initial site registration approval for the study in RSS will also receive a separate invitation from iMedidata to activate their account. Account activation instructions are located on the CTSU website, Rave tab under the Rave resource materials (Medidata Account Activation and Study Invitation Acceptance). Additional information on iMedidata/Rave is available on the CTSU members' website under the Rave tab at www.ctsu.org/RAVE/ or by contacting the CTSU Help Desk at 1888-823-5923 or by e-mail at ctsucontact@westat.com. Users may also contact OBDMC to get help with study specific issues including clinical forms, data entry, data query, data sign-offs and/or uploading of regulatory and other required documents. For complete OBDMC contact details, click on the OBDMC Contact Information link that is available in the Members' Area of the PBTC website (http://www.pbtc.org/).
7.1 comprehensive adverse events and
12.1.2 method

This study will be monitored by the Clinical Data Update System (CDUS) Version 3.0. A protocol and subject-specific CDUS "Abbreviated" data set will be submitted electronically to CTEP on a quarterly basis via CDUS OPEN (Oncology Patient Enrollment Network). 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 website (http://ctep.cancer.gov/reporting/cdus.html). 12.2 **Collaborative Agreements Language** Not applicable. 12.3 **Participant and Data Confidentiality** Participant confidentiality is strictly held in trust by the participating investigators, their staff and the sponsor(s) and their agents. This confidentiality is extended to cover testing of biological samples and genetic tests in addition to the clinical information relating to participants. Therefore, the study protocol, documentation, data and all other information generated will be held in strict confidence. No information concerning the study and the data will be released to an unauthorized third party without the prior written approval of the Pediatric Brain Tumor Consortium (PBTC). The PBTC protocol coordinators, other authorized representatives of the sponsor, regulatory representatives, PBTC auditors, representatives of the IRB or the pharmaceutical collaborator supplying study product may inspect all documents and records required to be maintained by the investigator, including but not limited to, medical records (office, clinic, or hospital) and pharmacy records for the participants in this study. The clinical study site will permit access to such records. Source documents which are the original records of clinical findings, observations or activities in a clinical trial are to be maintained at each participating site. Sites must upload all source documentation which supports the eligibility of the participant to the PBTC via the RAVE database. In the event the patient experiences unexpected events, additional source documentation may be requested to complete the event review. These documents may include but are not limited to, hospital records, clinical and office charts, laboratory notes, memoranda and radiographic images. Study participant study related data, which is for purposes of statistical analysis and scientific reporting will be transmitted to the Pediatric Brain Tumor Consortium electronically via the RAVE database. This will not include the participant's contact or identifying information. Rather, research participants and their research data will be identified by a unique study identification number assigned at the time of screening or registration. The study participant's contact information will be securely stored at each clinical site for internal use during the study. At the end of the study, all records will continue to be kept in a secure location for as long a period as dictated by local IRB and institutional regulations.  
The study data entry and study management systems used by clinical sites and by the PBTC will be secured and password protected. At the end of the study, all study data is maintained on a secure server. After the study is completed, the data collected will be maintained on a server and may be used by other investigators, including those outside the study. With the participant's approval and as approved by local IRBs, biological samples labeled only with the participant's protocol specific identification number will be stored at the PBTC Central Review and Biorepository and could be made available to other investigators for future unspecified research. Investigators conducting future studies will not have access to the key for stored data collected while the participant is on study. Clinical data will be de-identified before it is shared with other investigators. If the participant agrees to submit a repository sample, those samples contain genetic information that may be used for research related to brain tumors and their treatment. They may also be used to develop tests/assays to improve diagnosis and treatment of these diseases in the future. Genetic research may consist of the analysis of one or more genes or the analysis of genetic markers throughout the genome.
7.1 comprehensive adverse events and
13 statistical considerations 13.1 evaluability

Patients who receive at least one dose of the study drug and are taken off treatment for toxicity during the first course (dose-finding period) are evaluable for estimating the MTD. Similarly patients who have to go off treatment due to inability to de-escalate following toxicity because of BSA restrictions are also evaluable for DLT assessment and for estimating the MTD. Patients who receive approximately 85% (17 or more doses) of prescribed therapy during the dose-finding period but who progress prior to completing the course may be considered evaluable for estimating the MTD, as long as no additional anti-cancer therapy or supportive care that would confound the interpretation of any observed toxicity or side effect is given. Patients must have completed all of the clinical and laboratory monitoring requirements specified by the protocol up to the time of disease progression for them to be considered evaluable for MTD. Patients who have completed all therapy during the dose-finding period but who failed to comply with all the specified clinical and laboratory monitoring requirements for the first course will be considered inevaluable for estimating the MTD and replaced. Patients who receive less than 17 doses of the protocol specified therapy and who go off treatment for reasons other than toxicity (e.g. progressive disease, withdrawal of consent etc.) during the dose finding period will be considered inevaluable for estimating the MTD and will be replaced. However as noted above, patients who go off treatment due to inability to deescalate following toxicity as a result of BSA restrictions are evaluable.
7.1 comprehensive adverse events and
13.1.2 evaluability for preliminary evidence

All eligible patients who received at least one dose of the study drug will be evaluable for response assessment.
7.1 comprehensive adverse events and
13.2 study design/endpoints

This is a phase I study and we will use the Rolling-6 design for dose finding. Since myelosuppression is the predominant side effect of this agent, the phase I study will first evaluate the toxicities in children who have not been heavily pre-treated previously. Once MTD has been established in this cohort of patients, consideration will be given to expanding the trial to include those who have received intensive cytotoxic therapy including myeloablative chemotherapy +/- craniospinal irradiation. As of version 4 and following the declaration of MTD in Stratum I, we will initiate enrollment in Stratum II for heavily pre-treated patients. The initial treatment dose for these patients will be one dose level below the MTD in stratum I and escalation to the MTD of stratum I will be pursued, if the initial dose level is well tolerated.
7.1 comprehensive adverse events and
rolling-6 design

A "Rolling-6" Phase I design will be used to estimate the maximum tolerated dose (MTD), where dose escalations are planned in cohorts of two-six patients. No intra-patient escalation will be allowed. The same algorithm will be used in both strata I and II but will proceed independently. The maximum dose to be studied in Stratum II will be the MTD for Stratum I.  
Skolnik et al recently introduced the Rolling-6 design,31 motivated by the observation that most pediatric Phase I trials in oncology have not produced excessive toxicities. A possible explanation for this could be that pediatric studies are often preceded by adult trials and the knowledge gained in the latter is utilized towards ensuring safety in the former. The Rolling-6 design aims to shorten the duration of pediatric Phase I trials by minimizing the time the trial would be closed to accrual for toxicity monitoring. This is achieved by enrolling anywhere from 2 to 6 patients at a dose level without requiring that the DLT status of the patients already assigned to the same dose level are known, reducing the number of patients who would be turned away due to unavailability of open slots. The simulations in Skolnik et al. as well as PBTC's own simulations indicate that this approach decreases the duration of a Phase I trial compared to the traditional method without increasing the overall incidence of toxicity.
7.1 comprehensive adverse events and
dose escalation/de-escalation rules

The Rolling-6 design allows for accrual of two to six patients concurrently onto a dose level. Decisions as to which dose level to enroll a patient are based on the number of patients currently enrolled and evaluable, the number of patients experiencing dose-limiting toxicities (DLT), and the number of patients still at risk of developing a DLT at the time of new patient entry. Dose escalation occurs if 0 of 3-6 or no more than 1 of 6 evaluable patients experience a DLT while being treated at a dose level; otherwise if 2 of 2-6 patients experience DLTs the dose is declared too toxic and thus above the MTD. Once a dose is determined to be too toxic, further dose escalation is not allowed. The MTD is empirically defined as the highest dose level at which six patients have been treated with at most one patient experiencing a DLT and the next higher dose level has been determined to be too toxic. The following table enumerates all possible scenarios and describes escalation/de-escalation rules for a rolling 6 design.  
| Dose Escalation/De-Escalation Rules for the Rolling-6 Design Decision when Next Patient is  Enrolled   |                               |                |            |             |             |
|--------------------------------------------------------------------------------------------------------|-------------------------------|----------------|------------|-------------|-------------|
| # Pts.  with  DLTs                                                                                     | # Pts.                        |                |            |             |             |
| with Toxicity  Data Pending                                                                            | Not at the Highest Dose Level | At the Highest |            |             |             |
| Dose Level                                                                                             |                               |                |            |             |             |
| # Pts.                                                                                                 |                               |                |            |             |             |
| Enrolled                                                                                               | # Pts. w/o  DLT               |                |            |             |             |
| 2                                                                                                      | 0, 1                          | Any            | Any        | Stay        | Stay        |
| 2                                                                                                      | 2                             | 0              | 0          | De-escalate | De-escalate |
| 3                                                                                                      | 0                             | 0, 1, 2        | 3, 2, 1    | Stay        | Stay        |
| 3                                                                                                      | 0                             | 3              | 0          | Escalate    | Stay        |
| 3                                                                                                      | 1                             | 0, 1, 2        | 2, 1, 0    | Stay        | Stay        |
| 3                                                                                                      | ≥ 2                           | Any            | Any        | De-escalate | De-escalate |
| 4                                                                                                      | 0                             | 0, 1, 2, 3     | 4, 3, 2, 1 | Stay        | Stay        |  
| 4   | 0   | 4             | 0             | Escalate    | Stay               |
|-----|-----|---------------|---------------|-------------|--------------------|
| 4   | 1   | 0, 1, 2, 3    | 3, 2, 1, 0    | Stay        | Stay               |
| 4   | ≥ 2 | Any           | Any           | De-escalate | De-escalate        |
| 5   | 0   | 0, 1, 2, 3, 4 | 5, 4, 3, 2, 1 | Stay        | Stay               |
| 5   | 0   | 5             | 0             | Escalate    | Stay               |
| 5   | 1   | 0, 1, 2, 3, 4 | 4, 3, 2, 1, 0 | Stay        | Stay               |
| 5   | ≥ 2 | Any           | Any           | De-escalate | De-escalate        |
| 6   | 0   | 0, 1, 2, 3, 4 | 6, 5, 4, 3, 2 | Suspend     | Suspend            |
| 6   | 0   | 5, 6          | 1, 0          | Escalate    | MTD not determined |
| 6   | 1   | 0, 1, 2, 3, 4 | 5, 4, 3, 2, 1 | Suspend     | Suspend            |
| 6   | 1   | 5             | 0             | Escalate    | MTD not determined |
| 6   | ≥ 2 | Any           | Any           | De-escalate | De-escalate        |  
Based on the above-outlined escalation rules, if dose level 1 is found to be too toxic in either stratum, then accrual to that stratum will be suspended and the merits of amending or closing the stratum permanently will be reconsidered. On the other hand, if the maximum dose level proposed for the study is deemed to be safe, then the MTD will not have been determined and consideration may be given to investigate higher dose levels. Alternatively, the highest dose level may be recommended as the Phase II dose. Once the MTD has been estimated or the recommended Phase II dose has been determined, 6 additional patients will be treated at that dose level to better describe the toxicity profile of the agent. If the number of toxicities observed in the expansion cohort suggests that the initial estimate of the MTD is too toxic then we will consider de-escalating to a lower dose level and treating additional patients at that level including an expansion cohort in an effort to estimate the phase II recommended dose.
7.1 comprehensive adverse events and
13.3 sample size/accrual rate

Projected Accrual Rages and Study Duration Though it is difficult to come up with a precise estimate for recurrent pediatric brain tumor patients, we are estimating that up to 30% of patients screened will be Rb1 negative as measured by IHC and thus will not be eligible for this trial. The maximum sample size for stratum I is 24 eligible and evaluable patients if all 3 dose levels are studied and taking into account the expansion cohort at the MTD (barring excessive toxicities at the expansion cohort). Hence we may need to screen up to 35 patients in order to enroll 24 eligible patients in stratum I. Based on the available information as of version 4.0, dose level 3 will not be studied in Stratum II and thus with two possible dose levels to be studied, the maximum number of patients to be enrolled on Stratum II is 18 (barring excessive toxicities at the expansion cohort). Though less information is available about the potential patient cohort for stratum II, if we assume that 30% of patients screened will be Rb1 negative as measured by IHC, then we may have to screen 25 patients in order to be able to enroll 18 eligible and evaluable patients. As of version 8.0, 25 patients had been enrolled on this study; 21 in stratum I and 4 in stratum II.  
For stratum I, the MTD has been determined as dose level 2 (75 mg/m2/day) and this stratum has been closed to accrual. Accrual for stratum II was recently initiated at 50 mg/m2/day, which is one dose level below the stratum I MTD. Four patients have been enrolled at this dose level to date. The intent is to either determine a new MTD for this stratum which is lower than 75 mg/m2/day or establish that the stratum I MTD is also safe in this patient cohort. The accrual to the trial is ongoing. Considering that there are always patients who enroll on Phase I trials but are not evaluable for dose finding we may need to screen as many as 55 patients in total for both strata. The accrual rate for most of our Phase I trials open to all recurrent patients is typically 2-3 patients/month. Considering that eligibility to this study will be limited to patients with available tissue for IHC analysis and among those only to patients with Rb1 + tumors, accrual rate is estimated to be 1-2 eligible patients per month per stratum. Hence we expect to complete accrual to each stratum within 1-2 years of initiating enrollment.  
| Accrual Targets                           |            |       |    |    |    |
|-------------------------------------------|------------|-------|----|----|----|
| Ethnic Category                           | Sex/Gender |       |    |    |    |
| Females                                   | Males      | Total |    |    |    |
| Hispanic or Latino                        | 5          | +     | 6  | =  | 11 |
| Not Hispanic or Latino                    | 22         | +     | 22 | =  | 44 |
| Ethnic Category: Total of all subjects    | 27         | +     | 28 | =  | 55 |
| Racial Category                           |            |       |    |    |    |
| American Indian or Alaskan Native         | 0          | +     | 0  | =  | 0  |
| Asian                                     | 3          | +     | 3  | =  | 6  |
| Black or African American                 | 6          | +     | 7  | =  | 13 |
| Native Hawaiian or other Pacific Islander | 0          | +     | 0  | =  | 0  |
| White                                     | 18         | +     | 18 | =  | 36 |
| Racial Category: Total of all subjects    | 27         | +     | 28 | =  | 55 |
7.1 comprehensive adverse events and
13.4 analysis of the adverse

All patients who receive at least 1 dose of protocol therapy will be included in the safety analyses. Adverse event data will be summarized in stratum specific tables which will incorporate dose, attribution as well as grade information.
7.1 comprehensive adverse events and
13.5 data analysis plan for

Any objective responses (PR+CR) which may be observed in this trial will be described by dose and by histology. We will also report prolonged disease stabilizations in a descriptive fashion. The biology and PD/PG studies are optional in this trial and thus data will be available only from a subset of patients who are likely to represent a variety of histologies. The data generated as part of these correlative studies will be described and summarized in an exploratory fashion via summary statistics and frequency tables as appropriate.
7.1 comprehensive adverse events and
13.6 statistical analysis of pharmacokinetics

Plasma drug concentrations and pharmacokinetic parameters will be presented in tabular and graphical form. Pharmacokinetic parameters of interest, such as apparent volume of the central compartment (Vc/F), elimination rate constant (Ke), half-life (t1/2), apparent oral clearance (CL/F), and area under the plasma concentration time curve (AUC) will be estimated using compartmental methods. Dose proportionality in pharmacokinetic parameters will be investigated by performing one-way analysis of variance (ANOVA) on dose-normalized parameters. In addition to estimating individual pharmacokinetic parameters, we will also estimate the population parameters using nonlinear mixed effects modeling methods (NONMEM). This method estimates the population parameters and both the inter- and intra-subject variability. Once the population parameters and corresponding covariance matrix are estimated, individual estimates can be obtained using post hoc analysis. Because this is a Phase I study, most patients will be treated at very low doses of the agent and will have various diseases; thus, observations of objective responses are expected to be rare. In this setting, correlations of copy number variations of various cell cycle proteins and clinical outcome will be reported descriptively.
7.1 comprehensive adverse events and
14 references

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2. Li M, Lockwood W, Zielenska M, et al. Multiple CDK/CYCLIND genes are amplified in medulloblastoma and supratentorial primitive neuroectodermal brain tumor. *Cancer* genetics. May 2012;205(5):220-231.  
3. Schwartz GK, LoRusso PM, Dickson MA, et al. Phase I study of PD 0332991, a cyclindependent kinase inhibitor, administered in 3-week cycles (Schedule 2/1). *Br J Cancer.*
Jun 7 2011;104(12):1862-1868.  
4. Vaughn DJ, Flaherty K, Lal P, et al. Treatment of growing teratoma syndrome. The New England journal of medicine. Jan 22 2009;360(4):423-424.  
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6. Faria C, Miguéns J, Antunes JL, et al. Pediatric brain tumors: genetics and clinical outcome. *Journal of Neurosurgery: Pediatrics.* 2010;5(3):263-270.  
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Neurosurgery. Mar 2004;54(3):692-699; discussion 699-700.  
8. Cen L, Carlson BL, Schroeder MA, et al. p16-Cdk4-Rb axis controls sensitivity to a cyclin-dependent kinase inhibitor PD0332991 in glioblastoma xenograft cells. Neuro Oncol. Jul 2012;14(7):870-881.  
9. Paugh BS, Broniscer A, Qu C, et al. Genome-wide analyses identify recurrent amplifications of receptor tyrosine kinases and cell-cycle regulatory genes in diffuse intrinsic pontine glioma. *Journal of clinical oncology : official journal of the American* Society of Clinical Oncology. Oct 20 2011;29(30):3999-4006.  
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: official journal of the American Society of Clinical Oncology. Jun 20 2010;28(18):30613068.  
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14. Raabe EH, Lim KS, Kim JM, et al. BRAF Activation Induces Transformation and Then Senescence in Human Neural Stem Cells: A Pilocytic Astrocytoma Model. Clinical Cancer Research. June 1, 2011 2011;17(11):3590-3599.  
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16. Rajaram V, Leuthardt EC, Singh PK, et al. 9p21 and 13q14 dosages in ependymomas. A
clinicopathologic study of 101 cases. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc. Jan 2004;17(1):9-14.  
17. Mendrzyk F, Radlwimmer B, Joos S, et al. Genomic and protein expression profiling identifies CDK6 as novel independent prognostic marker in medulloblastoma. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. Dec 1 2005;23(34):8853-8862.  
18. Parsons DW, Li M, Zhang X, et al. The genetic landscape of the childhood cancer medulloblastoma. *Science.* Jan 28 2011;331(6016):435-439.  
19. Jones DT, Jager N, Kool M, et al. Dissecting the genomic complexity underlying medulloblastoma. *Nature.* Aug 2 2012;488(7409):100-105.  
20. Kieran MW, Roberts CW, Chi SN, et al. Absence of oncogenic canonical pathway mutations in aggressive pediatric rhabdoid tumors. *Pediatr Blood Cancer.* Dec 15 2012;59(7):1155-1157.  
21. Fry DW, Harvey PJ, Keller PR, et al. Specific inhibition of cyclin-dependent kinase 4/6 by PD 0332991 and associated antitumor activity in human tumor xenografts. *Mol* Cancer Ther. Nov 2004;3(11):1427-1438.  
22. Flaherty KT, Lorusso PM, Demichele A, et al. Phase I, dose-escalation trial of the oral cyclin-dependent kinase 4/6 inhibitor PD 0332991, administered using a 21-day schedule in patients with advanced cancer. *Clin Cancer Res.* Jan 15 2012;18(2):568-576.  
23. Dean JL, McClendon AK, Hickey TE, et al. Therapeutic response to CDK4/6 inhibition in breast cancer defined by ex vivo analyses of human tumors. *Cell Cycle.* Jul 15 2012;11(14):2756-2761.  
24. Leonard JP, LaCasce AS, Smith MR, et al. Selective CDK4/6 inhibition with tumor responses by PD0332991 in patients with mantle cell lymphoma. *Blood.* May 17 2012;119(20):4597-4607.  
25. Michaud K, Solomon DA, Oermann E, et al. Pharmacologic inhibition of cyclindependent kinases 4 and 6 arrests the growth of glioblastoma multiforme intracranial xenografts. *Cancer Res.* Apr 15 2010;70(8):3228-3238.  
26. Huillard E, Hashizume R, Phillips JJ, et al. Cooperative interactions of BRAFV600E
kinase and CDKN2A locus deficiency in pediatric malignant astrocytoma as a basis for rational therapy. *Proceedings of the National Academy of Sciences of the United States of* America. May 29 2012;109(22):8710-8715.  
27. Aoki Y, Hashizume R, Ozawa T, et al. An experimental xenograft mouse model of diffuse pontine glioma designed for therapeutic testing. *Journal of neuro-oncology.* May 2012;108(1):29-35.  
28. Finn RS CJ, Lang I, et al. Results of a randomized phase 2 study of PD0332991, a cyclindependent kinase (CDK) 4/6 inhibitor, in combination with letrozole vs. letrozole alone for first-line treatment of ER+/HER2- advanced breast cancer (BC). *Cancer Res.* 2012;72:S1-6.  
29. K. E. Parrish RKM, W. F. Elmquist. Mechanisms Limiting the Brain Distribution of Palbociclib (PD0332991). *AAPS.* 2013.  
30. Goldhoff P, Clarke J, Smirnov I, et al. Clinical stratification of glioblastoma based on alterations in retinoblastoma tumor suppressor protein (RB1) and association with the proneural subtype. *J Neuropathol Exp Neurol.* Jan 2012;71(1):83-89.  
31. Skolnik JM, Barrett JS, Jayaraman B, Patel D, Adamson PC. Shortening the timeline of June *2018* pediatric phase I trials: the rolling six design. *Journal of clinical oncology : official* journal of the American Society of Clinical Oncology. Jan 10 2008;26(2):190-195.
7.1 comprehensive adverse events and
appendix a performance scales modified

A. Normal Range 100 = Fully active 90 = Minor restrictions in physically strenuous play 80 = Restricted in strenuous play, tires more easily, otherwise active B. Mild to moderate restriction 70 = Both greater restrictions of and less time spent in active play 60 = Ambulatory up to 50% of time, limited active play with assistance/supervision 50 = Considerable assistance required for any active play; full able to engage in quiet play C. Moderate to severe restriction 40 = Able to initiate quiet activities 30 = Needs considerable assistance for quiet activity 20 = Limited to very passive activity initiated by others e.g. TV) 10 = Completely disabled, not even passive play 0 = Unresponsive, coma
7.1 comprehensive adverse events and
karnofsky scale

100 = Normal; no complaints 90 = Able to carry on normal activities; minor signs or symptoms of disease 80 = Normal activity with effort 70 = Cares for self. Unable to carry on normal activity or to do active work 60 = Requires occasional assistance but able to care for most of his/her needs 50 = Requires considerable assistance and frequent medical care 40 = Disabled; requires special care and assistance 30 = Severely disabled; hospitalization indicated though death not imminent 20 = Very sick. Hospitalization necessary. Active support treatment necessary.  
10 = Moribund 0 = Dead
7.1 comprehensive adverse events and
appendix b medications that may

The following table presents a list of drugs that may prolong the QTc. Patients on these medications are excluded from the study.  
| Possible                             |                                                                                                            |                                 |                                  |
|--------------------------------------|------------------------------------------------------------------------------------------------------------|---------------------------------|----------------------------------|
| Compound                             | Compound Half Life                                                                                         | Washout  Period - Hours         | Possible  Washout  Period - Days |
| Alfuzocin                            | ~10 hours                                                                                                  | 7                               |                                  |
| Amantadine                           | 17 +/- 4 hours (10-25)                                                                                     | 4                               |                                  |
| Amiodarone (cordarone)               | 58 days (15-142)                                                                                           | 180                             |                                  |
| 36 days (active metabolite)          |                                                                                                            |                                 |                                  |
| Amitriptyline*                       | > 24 hours, wide interpatient variability                                                                  |                                 |                                  |
| Arsenic trioxide                     | Not characterized                                                                                          |                                 |                                  |
| Azithromycin                         | 40 hours                                                                                                   |                                 |                                  |
| Bepridil                             | 42 hr (26-64)                                                                                              | 10                              |                                  |
| Chloral hydrate                      | Readily converted to Trichloroethanol (active                                                              | 48                              |                                  |
| metabolite T1/2=7-10 hour)           |                                                                                                            |                                 |                                  |
| Chloroquine                          | Prolonged (days to weeks)                                                                                  |                                 |                                  |
| Chlorpromazine                       | 30 +/- 7 hours                                                                                             | 7                               |                                  |
| Cisapride                            | 6 - 12 hour, up to 20 hour                                                                                 | 60                              |                                  |
| Clarithromycin                       | -                                                                                                          | Non linear PK3-4 hr (250mg Q12) | 36                               |
| 5-7 hr (500mg Q12)                   |                                                                                                            |                                 |                                  |
| Cloroquine                           | 6 to 60 days; mean 20 days                                                                                 |                                 |                                  |
| Desipramine*                         | > 24 hours, wide interpatient variability                                                                  |                                 |                                  |
| Disopyramide                         | 6.7 hr (4-10)                                                                                              | 36                              |                                  |
| Dofetilide                           | 10 hr                                                                                                      | 48                              |                                  |
| Dolesetron                           | 8.1 hr                                                                                                     |                                 |                                  |
| Domperidone                          | 7-8 hr                                                                                                     | 48                              |                                  |
| Doxepin*                             | > 24 hours, wide interpatient variability                                                                  |                                 |                                  |
| Droperidol                           | 2.2 hours                                                                                                  | 10                              |                                  |
| Erythromycin                         | * Each salt form has different Half life*                                                                  |                                 |                                  |
| Felbamate                            | 20-23 hr                                                                                                   | 5                               |                                  |
| Flecainide                           | 20 hr (12-27)                                                                                              | 5                               |                                  |
| Foscarnet                            | 87.5+/-41.8 hours                                                                                          | 20                              |                                  |
| *distribution and release from bone* |                                                                                                            |                                 |                                  |
| Fosphenytoin                         | 12-29 hr                                                                                                   | 6                               |                                  |
| Gatifloxacin                         | 7-14 hr                                                                                                    | 48                              |                                  |
| Gemifloxacin                         | 7 hours                                                                                                    | 48                              |                                  |
| Grepafloxacin                        | 16 hr                                                                                                      | 3                               |                                  |
| Halofantrine                         | 6-10 days ( variable among individual)                                                                     | 45                              |                                  |
| Haloperidol                          | 18 +/-5 hr                                                                                                 | 5                               |                                  |
| Ibutilide                            | 6 hours (2-12) * variable among subject*                                                                   | 36                              |                                  |
| Imipramine*                          | > 24 hours, wide interpatient variability                                                                  |                                 |                                  |
| Indapamide                           | 14 hours (biphasic elimination)                                                                            | 3                               |                                  |
| Isradipine                           | 8 hours ( multiple metabolites)                                                                            | 48                              |                                  |
| Levofloxacin                         | 6-8 hours                                                                                                  | 48                              |                                  |
| Levomethadyl                         | Multiple compartment PK with active metabolite 2.6 day for LAAM, 2 day for nor-LAAM, 4 day for  dinor-LAAM |                                 |                                  |  
2  
0  
| Possible                                |                                                                                                                                       |                         |                                  |
|-----------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------|-------------------------|----------------------------------|
| Compound                                | Compound Half Life                                                                                                                    | Washout  Period - Hours | Possible  Washout  Period - Days |
| Lithium                                 | 24 hour (10-50)                                                                                                                       | 7                       |                                  |
| Mesoridazine                            | 24-48 hours ( animal study)                                                                                                           | 10                      |                                  |
| Methadone                               | 15-30 hours                                                                                                                           | 7                       |                                  |
| Moexipril/HCTZ                          | 2-9 hour (include active metabolite) for moexipril;                                                                                   | 48                      |                                  |
| 5.6-14.8 hours for HCTZ                 |                                                                                                                                       |                         |                                  |
| Moxifloxacin                            | 12 +/-1.3 hours                                                                                                                       |                        | 7 2                              |
| Naratriptan                             | 6 hours                                                                                                                               | 36                      |                                  |
| Nicardipine                             | ~ 2 hour post IV infusion                                                                                                             | 12                      |                                  |
| Nortriptyline*                          | > 24 hours, wide interpatient variability                                                                                             |                         |                                  |
| Octreotide                              | 1.7 hours                                                                                                                             | 12                      |                                  |
| Ofloxacin                               | 5 to 7.5 hours                                                                                                                        | 2                       |                                  |
| Ondansetron                             | 4 hours (IV/IM); 3 hours (PO)                                                                                                         | 1 to 3                  |                                  |
| Pentamidine                             | 6.4+/-1.3 hours                                                                                                                       | 36                      |                                  |
| Pimozide                                | 55 hours                                                                                                                              | 10                      |                                  |
| Procainamide                            | 3-4 hour for PA and NAPA (active metabolite)                                                                                          | 24                      |                                  |
| Protiptyline*                           | > 24 hours, wide interpatient variability                                                                                             |                         |                                  |
| Quetiapine                              | 6 hours                                                                                                                               | 36                      |                                  |
| Quinidine                               | 6-8 hours in adult; 3-4 hours in children                                                                                             | 36                      |                                  |
| Quinine                                 | 4-5 hours                                                                                                                             |                         |                                  |
| Risperidone                             | 3-20 hours (extensive to poor metabolizer) 9-hydroxyrisperidone (active metabolite) T ½ =21-30  hours (extensive to poor metabolizer) | 4                       |                                  |
| Salmeterol                              | 5.5 hours ( only one datum)                                                                                                           | 36                      |                                  |
| Sotalol                                 | 12 hours                                                                                                                              | 72                      |                                  |
| Sparfloxacin                            | 20 hours (16-30)                                                                                                                      | 4                       |                                  |
| Sumatriptan                             | 2.5 hours                                                                                                                             | 12                      |                                  |
| Tacrolimus                              | ~34 hours in healthy; ~19 hours in Kidney transplant                                                                                  | 7                       |                                  |
| Tamoxifen                               | 5-7 days (biphasic)                                                                                                                   | 30                      |                                  |
| Telithromycin                           | 2-3 hr                                                                                                                                | 24                      |                                  |
| Thioridazine                            | 20-40 hours (Phenothiazines)                                                                                                          | 7                       |                                  |
| Tizanidine                              | 2.5 hours                                                                                                                             | 12                      |                                  |
| Vardenifil                              | 4 to 5 hours                                                                                                                          |                         |                                  |
| Venlaflaxine                            | 5 +/-2 hours for parent comp.                                                                                                         | 60                      |                                  |
| 11+-2 hours for OVD (active metabolite) |                                                                                                                                       |                         |                                  |
| Voriconizole                            | 6 hours; dose dependent                                                                                                               |                         |                                  |
| Ziprasidone                             | 7 hr                                                                                                                                  | 36                      |                                  |
| Zolmitriptan                            | 2.8-3.7 hours (higher in female)                                                                                                      | 18                      |                                  |
7.1 comprehensive adverse events and
appendix c potential drug interactions

This appendix is a partial list of concomitant medications that should be avoided, if possible. Drugs that are known to be moderate to strong inhibitors and/or inducers of CYP3A and PPIs are listed below. Strong CYP3A inducers/inhibitors are prohibited and moderate inducers/inhibitors are not recommended. PPIs are also prohibited.  
Inhibitors of CYP3A Ketoconazole Miconazole Itraconazole Posaconazole Clarithromycin Erythromycin Tilithromycin Nefazodone Diltiazem Verapamil Indinavir Saquinavir Ritonavir Nelfinavir Lopinavir Atazanavir Amprenavir Fosamprenavir Grapefruit Juice Inducers of CYP3A Phenytoin Carbamazepine Rifabutin Rifapentin Clevidipine Phenobarbital Rifampin St. John's Wort  
| Proton Pump Inhibitors (PPI) Rabeprazole Omeprazole   | Pantoprazole   | Lansoprazole   |
|-------------------------------------------------------|----------------|----------------|
| Esomeprazole                                          |                |                |  
Appendix D Dosing Tables for PD-0332991 **(palbociclib; IBRANCE)**  
Dose Level  
50 mg/m2/day  
Total Daily  
Dose (mg)  
BSA Range Capsules Required  
low high 75 mg 100 mg 125 mg  
75 1.20 1.75 1 0 0  
100 1.76 2.25 0 1 0 125 2.26 2.50 0 0 1  
Dose Level  
95 mg/m2/day  
Total Daily  
Dose (mg)  
BSA Range Capsules Required  
low high 75 mg 100 mg 125 mg  
75 0.70 0.92 1 0 0  
100 0.93 1.16 0 1 0 125 1.17 1.44 0 0 1 150 1.45 1.71 2 0 0 175 1.72 1.97 1 1 0 200 1.98 2.23 0 2 0 225 2.24 2.50 0 1 1  
| Dose Level    | Total Daily   | BSA Range   | Capsules Required   |       |        |        |
|---------------|---------------|-------------|---------------------|-------|--------|--------|
| 75 mg/m2 /day | Dose (mg)     | low         | high                | 75 mg | 100 mg | 125 mg |
| 75            | 0.93          | 1.16        | 1                   | 0     | 0      |        |
| 100           | 1.17          | 1.50        | 0                   | 1     | 0      |        |
| 125           | 1.51          | 1.83        | 0                   | 0     | 1      |        |
| 150           | 1.84          | 2.16        | 2                   | 0     | 0      |        |
| 175           | 2.17          | 2.49        | 1                   | 1     | 0      |        |
| 200           | 2.50          | 2.50        | 0                   | 2     | 0      |        |
appendix e patient's diary
patient's medication diary

Patient Name____________________ (*initials acceptable)* **Patient Study ID** ______________
CTEP-assigned Protocol \#_PBTC-042___
Local Protocol \# PBTC-042 Today's date _____________________ **Agent:** PD-0332991 (palbociclib; IBRANCE)
INSTRUCTIONS TO THE PATIENT:
1. Complete one form for each cycle of treatment. 2. You will take PD-0332991 (IBRANCE) capsules by mouth with food and use water to swallow the whole capsule (s).  
Dose: Take ________\# of capsules _____________ daily.  
3. Record the date, the number of capsules that 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 this form and your bottles of PD-0332991 (IBRANCE) when you return for each appointment.  
| appointment.                                                                        | Comments   |               |       |        |        |
|-------------------------------------------------------------------------------------|------------|---------------|-------|--------|--------|
| # of capsules taken                                                                 |            |               |       |        |        |
| Day                                                                                 | Date       | Time of  dose | 75 mg | 100 mg | 125 mg |
| 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21                               |            |               |       |        |        |
| Patient's signature________________________________________________________________ |            |               |       |        |        |  
| Physician's Office will complete this section: 1. Date patient started protocol treatment _______________________________________________________________ 2. Date patient was removed from study________________________________________________________________ 3. Patient's planned total daily dose ___________________________________________________________________ 4. Total number of capsules taken this month ___________________________________________________________ 5. Physician/Nurse/Data Manager's Signature ___________________________________________________________   |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
appendix e patient's diary
appendix f patient drug information

[Note to investigators: This appendix consists of an "information sheet" to be handed to the patient at the time of enrollment. Use or modify the text as appropriate for the study agent, so that the patient is aware of the risks and can communicate with their regular prescriber(s) and pharmacist. A convenient wallet-sized information card is also included for the patient to clip out and retain at all times.] The patient ____________________________ is enrolled on a clinical trial PBTC-042 using PD-0332991 **(IBRANCE)***. This form is addressed to the patient, but includes important* information for others who care for this patient.  
PD-0332991 **(IBRANCE)** interacts with many drugs that are processed by your liver. Because of this, it is very important to tell your study doctors about all of your medicine before you start this study. It is also very important to tell them if you stop taking any regular medicine, or if you start taking a new medicine while you take part in this study. When you talk about your medicine with your study doctor, include medicine you buy without a prescription at the drug store (over-the-counter remedy), or herbal supplements such as St. John's wort. Many health care prescribers can write prescriptions. You must also tell your other prescribers (doctors, physicians' assistants or nurse practitioners) that you are taking part in a clinical trial.  
Bring this paper with you and keep the attached information card in your wallet. These are the things that you and they need to know:
PD-0332991 **(IBRANCE)** interacts with a certain specific enzyme in your liver.  
- The enzyme in question is CYP3A4/5. PD-0332991 **(IBRANCE)** is broken down by this enzyme in order to be cleared from your system. The dose of this drug that you are taking assumes that these enzymes are working normally.  
- Certain drugs may reduce the activity of **CYP3A4/5**, which can increase the amount of active drug in your system. This increases your chances of experiencing harmful side effects. Other drugs might increase the activity of **CYP3A4/5**, reducing the level of active drug in your system and making it less effective.  
- PD-0332991 **(IBRANCE)** must be used very carefully with such drugs; it is therefore vitally important that you provide your study doctor with a complete list of your medications. Before you begin the study, your study doctor will work with your regular prescriber to switch any medicines that are considered "strong inhibitors or inducers of CYP3A4/5."
- Once the study begins, you and your healthcare providers must be very careful about adding or removing any drugs in this category. Your prescribers should look at the web site http://medicine.iupui.edu/clinpharm/ddis/main-table/, consult a medical reference, or contact your study doctor to see if any medicine they want to prescribe is on a list of drugs to avoid.  
- Please be very careful! Over-the-counter drugs have a brand name on the label—it's usually big and catches your eye. They also have a generic name—it's usually small and located above or below the brand name, and printed in the ingredient list. Find the generic name and determine, with the pharmacist's help, whether there could be an adverse interaction.
appendix e patient's diary
be careful

➢ If you take acetaminophen regularly: You should not take more than 4 grams a day if you are an adult or 2.4 grams a day if you are older than 65 years of age. Read labels carefully! Acetaminophen is an ingredient in many medicines for pain, flu, and cold.  
➢ If you drink grapefruit juice or eat grapefruit: Avoid these until the study is over.  
➢ If you take herbal medicine regularly: You should not take St. John's wort while you are taking PD-0332991 **(IBRANCE)**.  
Other medicines can be a problem with your study drug.  
- You should check with your doctor or pharmacist whenever you need to use an over-the-counter medicine or herbal supplement.  
- Your regular prescriber should check a medical reference or call your study doctor before prescribing any new medicine for you. Your study doctor's name is *Physician's name* and he or she can be contacted at Physician's telephone number.  
| INFORMATION ON POSSIBLE DRUG INTERACTIONS   |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           |
|---------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| You are enrolled on a clinical trial PBTC-042 using PD0332991 (IBRANCE).  PD-0332991 (IBRANCE) interacts with drugs that are  processed by your liver. Because of this, it is very important to: ➢ Tell your doctors if you stop taking regular medicine or if you  start taking a new medicine. ➢ Tell all of your prescribers (doctor, physicians' assistant,  nurse practitioner, pharmacist) that you are taking part in a  clinical trial. ➢ Check with your doctor or pharmacist whenever you need to  use an over-the-counter medicine or herbal supplement.                                             | PD- 0332991 (IBRANCE) interacts with a specific liver enzyme  called CYP3A4/5, and must be used very carefully with other  medicines that interact with this enzyme.  ➢ Before you start the study, your study doctor will work with  your regular prescriber to switch any medicines that are  considered "strong inducers or inhibitors of CYP3A4/5". ➢ Before prescribing new medicines, your regular prescribers  should go to  http://medicine.iupui.edu/clinpharm/ddis/main-table/ for  a list of drugs to avoid, or contact your study doctor.  ➢ Your study doctor's name is _________________________ and can be contacted at _________________________ _______________________________________. |