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14.3 sample size and duration

Based on the PALOMA 3 study results, a conservative estimated of PFS for the control arm (125 mg daily, 3/ 4 weeks) is 10 months (Turner 2015).  
ADMIN UPDATE \#1: 2017-JUL-05 The objective of this trial is to estimate the relative efficacy between the two arms. It will not include a test of superiority or non-inferiority between the two arms. The sample size is based on estimating the hazard ratio (HR) of two arms (experimental vs. control) within a 90% confidence interval (CI). For a 1:1 randomization with 1 year accrual and one-year additional follow-up. If we observe approximately 58 PFS events in each arm, the upper bound of the 90% CI will be 1.36 times the estimated HR and the lower bound will be 0.74 times the estimated HR. Assuming a median PFS of approximately 10 months for both treatment arms, and duration of accrual and follow-up both at 1 year, and a dropout rate of 10%, the study would need to enroll approximately 90 subjects in each arm. If the observed hazard ratio is 0.736 or less, then the upper bound of the 90% confidence interval will be less than 1.
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14.4 safety monitoring

Adverse events and their frequencies will be monitored on an ongoing basis by the CCTG Statistics and Operations Office personnel and reviewed by the independent Data Safety and Monitoring Committee on a 6 monthly basis with more frequent evaluation as required. This data will also be presented to the Study Chair, Trial Committee and investigator network at annual investigator meetings.  
In addition a detailed safety evaluation will be performed after the initial 12 patients on both arms are enrolled and followed for 8 weeks to assess safety, tolerability and compliance with therapy, including dose reductions and dose discontinuations. Adverse events of importance will include grade 3 or 4 neutropenia, febrile neutropenia, infections and death. Accrual will continue during this safety assessment.
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14.6. quality of life analyses

The EORTC QLQ-C30 and the Trial Specific Checklist will be mandatory. Scoring of questionnaires will be conducted by the central office of CCTG according to the scoring manual of the EORTC QLQ-C30. The Trial Specific Checklist items will be scored individually. QOL results will be described and exploratory analysis will be conducted to compare the QOL between the 2 groups.  
15.0 PUBLICATION POLICY
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15.1 authorship of papers meeting

15.1.1 The results of this study will be published. Prior to trial activation, the chair will decide whether to publish the trial under a group title, or with naming of individual authors. If the latter approach is taken, the following rules will apply: - The first author will generally be the chair of the study. - A limited number of the members of the Canadian Cancer Trials Group and Pfizer may be credited as authors depending upon their level of involvement in the study.  
- Additional authors, up to a maximum of 15, will be those who have made the most significant contribution to the overall success of the study. This contribution will be assessed, in part but not entirely, in terms of patients enrolled and will be reviewed at the end of the trial by the study chair.  
- In the event of a separate paper dealing with the quality of life outcomes, the first author will generally be the Quality of Life Coordinator on the trial committee.  
- In the event of a separate paper dealing with the correlative studies outcomes, the first author will generally be the Correlative Sciences Coordinator on the trial committee.  
15.1.2 In an appropriate footnote, or at the end of the article, the following statement will be made:
"A study coordinated by the Canadian Cancer Trials Group. Participating investigators included: (a list of the individuals who have contributed patients and their institutions)."
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15.2 responsibility for publication

It will be the responsibility of the Study Chair to write up the results of the study within a reasonable time of its completion. If after a period of six months following study closure the manuscript has not been submitted, the central office reserves the right to make other arrangements to ensure timely publication.
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dissemination of trial results

CCTG will inform participating investigators of the primary publication of this trial. The complete journal reference and, if where publicly available, the direct link to the article will be posted on the Clinical Trial Results public site of the CCTG web site (http://www.ctg.queensu.ca).
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15.3 submission of material for

Material may not be submitted for presentation or publication without prior review by Pfizer, the CCTG Senior Investigator, Senior Biostatistician, Study Coordinator, and approval of the Study Chair. Individual participating centres may not present outcome results from their own centres separately. Supporting groups and agencies will be acknowledged.  
ADMIN UPDATE \#1: 2017-JUL-05 16.0 ETHICAL, REGULATORY AND ADMINISTRATIVE ISSUES
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16.1 regulatory considerations

All institutions in Canada must conduct this trial in accordance with International Conference on Harmonization-Good Clinical Practice (ICH-GCP) Guidelines.  
This trial is being conducted under a Clinical Trial Application (CTA) with Health Canada. As a result, the conduct of this trial must comply with Division 5 of the Canadian Regulations Respecting Food and Drugs (Food and Drugs Act).
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16.2 inclusivity in research

CCTG does not exclude individuals from participation in clinical trials on the basis of attributes such as culture, religion, race, national or ethnic origin, colour, mental or physical disability (except incapacity), sexual orientation, sex/gender, occupation, ethnicity, income, or criminal record, unless there is a valid reason (i.e. safety) for the exclusion. In accordance with the Declaration of Helsinki and the Tri-Council Policy Statement (TCPS), it is the policy of CCTG that vulnerable persons or groups will not be automatically excluded from a clinical trial (except for incompetent persons) if participation in the trial may benefit the patient or a group to which the person belongs. However, extra protections may be necessary for vulnerable persons or groups. It is the responsibility of the local investigator and research ethics board (REB) to ensure that appropriate mechanisms are in place to protect vulnerable persons/groups. In accordance with TCPS, researchers and REBs should provide special protections for those who are vulnerable to abuse, exploitation or discrimination. As vulnerable populations may be susceptible to coercion or undue influence, it is especially important that informed consent be obtained appropriately.  
Centres are expected to ensure compliance with local REB or institutional policy regarding participation of vulnerable persons/groups. For example, if a vulnerable person/group would be eligible for participation in a CCTG clinical trial under this policy but excluded by local policy, it is expected that they would not be enrolled in the trial. It is the centre's responsibility to ensure compliance with all local SOPs. It is CCTG's policy that persons who cannot give informed consent (i.e. mentally incompetent persons, or those physically incapacitated such as comatose persons) are not to be recruited into CCTG studies. It is the responsibility of the local investigator to determine the subject's competency, in accordance with applicable local policies and in conjunction with the local REB (if applicable). Subjects who were competent at the time of enrolment in the clinical trial but become incompetent during their participation do not automatically have to be removed from the study. When re-consent of the patient is required, investigators must follow applicable local policies when determining if it is acceptable for a substitute decision maker to be used. CCTG will accept re-consent from a substitute decision maker. If this patient subsequently regains capacity, the patient should be reconsented as a condition of continuing participation.
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16.3 obtaining informed consent

It is expected that consent will be appropriately obtained for each participant/potential participant in an CCTG trial, in accordance with ICH-GCP section 4.8. The centre is responsible for ensuring that all local policies are followed. Additionally, in accordance with GCP 4.8.2, CCTG may require that participants/potential participants be informed of any new information may impact a participant's/potential participant's willingness to participate in the study. Based upon applicable guidelines and regulations (Declaration of Helsinki, ICH-GCP), a participating investigator (as defined on the participants list) is ultimately responsible, in terms of liability and compliance, for ensuring informed consent has been appropriately obtained. CCTG recognizes that in many centres other personnel (as designated on the participants list) also play an important role in this process. In accordance with GCP 4.8.5, it is acceptable for the Qualified Investigator to delegate the responsibility for conducting the consent discussion. CCTG requires that each participant sign a consent form prior to their enrollment in the study to document his/her willingness to take part. CCTG may also require, as indicated above, that participants/potential participants be informed of new information if it becomes available during the course of the study. In conjunction with GCP 4.8.2, the communication of this information should be documented.  
CCTG allows the use of translators in obtaining informed consent. Provision of translators is the responsibility of the local centre. Centres should follow applicable local policies when procuring or using a translator for the purpose of obtaining informed consent to participate in a clinical trial.  
In accordance with ICH-GCP 4.8.9, if a subject is unable to read then informed consent may be obtained by having the consent form read and explained to the subject.
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16.3.1 obtaining consent for pregnancy/exposure

Information from and/or about the subject (i.e. the pregnant female, the newborn infant, male partner, exposed individual) should not be collected about or from them unless or until they are a willing participant in the research. The rights and protections offered to participants in research apply and consent must be obtained prior to collecting any information about or from them. If the main consent form adequately addresses the collection of information regarding the outcome of a pregnancy of a trial participant, a "Pregnancy Follow-up consent form will not be required by CCTG.  
Trial-specific consent forms for "Pregnancy Follow-up" and "Exposure Follow-up" can be found on the trial webpage. The appropriate consent form must be used to obtain consent from any nontrial participant (such as the pregnant partner or exposed individual).  
Participants will not be withdrawn from the main trial as a result of refusing or withdrawing permission to provide information related to the pregnancy*/exposure*. Similarly, male participants will not be withdrawn from the main study should their partner refuse/withdraw permission.
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obtaining consent for research on

In the case of collecting information about a child (i.e. the child resulting from a pregnant participant/partner or an exposed child), consent must be obtained from the parent/guardian.  
For reporting an exposure, the parent/guardian is required to sign an "Exposure Follow-up" consent form (even if they are a participant in the main study) prior to collecting information about the child.
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16.4 discontinuation of the trial

If this trial is discontinued for any reason by the CCTG all centres will be notified in writing of the discontinuance and the reason(s) why. If the reason(s) for discontinuance involve any potential risks to the health of patients participating on the trial or other persons, the CCTG will provide this information to centres as well.  
If this trial is discontinued at any time by the centre (prior to closure of the trial by the CCTG), it is the responsibility of the qualified investigator to notify the CCTG of the discontinuation and the reason(s) why. Whether the trial is discontinued by the CCTG or locally by the centre, it is the responsibility of the qualified investigator to notify the local Research Ethics Board and all clinical trials subjects of the discontinuance and any potential risks to the subjects or other persons.
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16.5 retention of patient records

All essential documents must be maintained as per C.05.012 and in accordance with ICH-GCP. The Qualified Investigator must ensure compliance with the Regulations and the GCP Guideline from every person involved in the conduct of the clinical trial at the site. Essential documents must be retained for 25 years following the completion of the trial at the centre
(25 years post final analysis, last data collected, or closure notification to REB, whichever is later),
or until notified by CCTG that documents no longer need to be retained. In accordance with GCP 4.9.7, upon request by the monitor, auditor, REB or regulatory authority, the investigator/institution must make all required trial-related records available for direct access. CCTG will inform the investigator/institution as to when the essential documents no longer need to be retained.
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16.6 centre performance monitoring

This study is eligible for inclusion in the Centre Performance Index (CPI). Forms are to be submitted according to the schedule in the protocol. There are minimum standards for performance.
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16.7 on-site monitoring/auditing

CCTG site monitoring/auditing will be conducted at participating centres in the course of the study as part of the overall quality assurance program. The monitors/auditors will require access to patient medical records to verify the data, as well as essential documents, standard operating procedures
(including electronic information), ethics and pharmacy documentation (if applicable).  
As this trial is conducted under a CTA with Health Canada, your site may be subject to an inspection by the Health Canada Inspectorate.
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16.8 case report forms

A list of forms to be submitted, as well as expectation dates, are to be found in Appendix IV.  
This trial will use a web-based Electronic Data Capture (EDC) system for all data collection except.  
For details of accessing the EDC system and completing the on-line Case Report Forms please refer to the "Registration/Randomization and Data Management Guidebook" posted on the MA.38 area of the CCTG web-site (www.ctg.queensu.ca).
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17.0 references

Aaronson NK, Ahmedzai S, Bergman B, et. al. The European Organization for Research and Treatment of Cancer QLQ-C30: A quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst 85:365-376, 1993. Bergh J, Jönsson PE, Lidbrink EK, et al. FACT: an open-label randomized phase III study of fulvestrant and anastrozole in combination compared with anastrozole alone as fi rst-line therapy for patients with receptorpositive postmenopausal breast cancer. Clin Oncol 2012; 30 : 1919–25. Bottomley A, Biganzoli L, Cufer T, et al. Randomized, controlled trial investigating short-term health-related quality of life with doxorubicin and paclitaxel versus doxorubicin and cyclophosphamide as first-line chemotherapy in patients with metastatic breast cancer: European Organization for Research and Treatment of Cancer Breast Cancer Group, Investigational Drug Branch for Breast Cancer and the New Drug Development Goup study. J Clin Oncol. 1;22(13):2576-86, 2004. Caldon CE, Daly RJ, Sutherland RL, Musgrove EA. Cell cycle control in breast cancer cells. J Cell Biochem 2006; 97: 261–74. Chia S, Gradishar W, Mauriac L, et al. Double-blind, randomized placebo controlled trial of fulvestrant compared with exemestane after prior nonsteroidal aromatase inhibitor therapy in postmenopausal women with hormone receptor-positive, advanced breast cancer: results from EFECT. J Clin Oncol 2008; 26 : 1664–70. Conroy T, Mercier M, Bonneterre J, et al. French version of FACT-G: validation and comparison with other cancer-specific instruments. Eur J Cancer. 40(15) :2243-52, 2004. Cristofanilli M, Turner NC, Bondarenko I, et al. Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3) : final analysis of the multicentre, double-blind, phase 3 randomised controlled trial. Lancet Oncol; 17(4) April 2016 : 425-439. Dean JL, McClendon AK, Hickey TE, et al. Therapeutic response to CDK4/6 inhibition in breast cancer defi ned by ex vivo analyses of human tumors. Cell Cycle 2012; 11: 2756–61. Eisenhauer E, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J. New response evaluation criteria in solid tumors: Revised RECIST guideline version 1.1. Eur J Can 45: 228-47, 2009. Finn R, Crown J, Lang I, et al. Overall survival results from the randomized phase II study of palbociclib (P) in combination with letrozole (L) vs letrozole alone for frontline treatment of ER+/HER2– advanced breast cancer (PALOMA-1; TRIO-18). J Clin Oncol 35, 2017 (suppl; abstr 1001) Finn R, Dieras V, Rugo H, et al. Palbociclib (PAL) + letrozole (L) as first-line (1L) therapy (tx) in estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2−) advanced breast cancer (ABC): Efficacy and safety across patient (pt) subgroups. J Clin Oncol 35, 2017 (suppl; abstr 1039)
Finn RS, Crown JP, Lang I, et al. The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as fi rstline treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 study. Lancet Oncol 2014; published online Dec 16. http://dx.doi.org/10.1016/S1470-2045(14)71159-3.  
Finn RS, Dering J, Conklin D, et al. PD 0332991, a selective cyclin D kinase 4/6 inhibitor, preferentially inhibits proliferation of luminal estrogen receptor-positive human breast cancer cell lines in vitro. Breast Cancer Res 2009; 11: R77. Finn RS, Martin M, Rugo RS, et al. Palbociclib and Letrozole in advanced breast cancer. N Engl J Med 2016; 375:1925-1936.
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admin update #1 2017-jul-05

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. 2012; 18:568-76. Fulvestrant Product Label (US FDA). Harbeck N, Lyer S, Turner N, et al. Quality of life with palbociclib plus fulvestrant in previously treated hormone receptor-positive, HER2-negative metastatic breast cancer: patient-reported outcomes from the PALOMA-3 trial. Ann Oncol 2016; 27(6):1047-1054. Hjermstad M, Fossa S, Bjordal K and Kaasa S. Test/retest study of the European Organization for Research and Treatment of Cancer core quality-of-life questionnaire. J Clin Oncol. 13(5):1249-54, 1995. Howell A, Robertson JF, Quaresma Albano J, et al. Fulvestrant, formerly ICI 182,780, is as effective as anastrozole in postmenopausal women with advanced breast cancer progressing after prior endocrine treatment.  
J Clin Oncol 2002; 20: 3396–403.  
Huschka M, Mandrekar S, Schaefer P, Jett J and Sloan J. A pooled analysis of quality of life measures and adverse events data in North Central Cancer Treatment Group lung cancer clinical trials. Cancer. 109(4):78795, 2007.  
Jiang 2014 Citation: Annals of Oncology (2014) 25 (suppl_4): iv146-iv164. 10.1093/annonc/mdu331 Lemieux J, Beaton D, Hogg-Johnson S, Bordeleau L, Hunter J and Goodwin P. Responsiveness to change due to supportive-expressive group therapy, improvement in mood and disease progression in women with metastatic breast cancer. Qual Life Res. 16(6):1007-17, 2007.  
McLachlan S, Devins G and Goodwin P. Validation of the European Organization for Research and Treatment of Cancer quality of life questionnaire (QLQ-C30) as a measure of psychosocial function in breast cancer patients. Eur J Cancer. 34(4):510-7, 1998. Osborne CK, Shou J, Massarweh S, Schiff R. Crosstalk between estrogen receptor and growth factor receptor pathways as a cause for endocrine therapy resistance in breast cancer. Clin Cancer Res 2005; 11 (suppl): 865– 70s. Osoba D, Rodrigues G, Myles J, Zee B and Pater J. Interpreting the significance of changes in health-related quality-of-life scores. J Clin Oncol16(1):139-44, 1998.  
Paul N, Pater J, Whitehead M and Sadura A. Methods of toxicity data collection: an evaluation of the relative effectiveness of the case report flow sheet (fs), the patient symptom diary (sd), and the quality of life questionnaire (qlq). Control Clin Trials. 2(5):648, 1991.  
Pfizer Inc. and Affiliates. Investigator's Brochure, Pembrolizumab (PD-0332991), 2015. Tamoxifen Product Label (US FDA). Turner N et al. J Clin Oncol 33, 2015 (suppl; abstr LBA502)
Verma S, Huang Bartlett C, Schnell P, et al. Palbociclib in combination with fulvestrant in women with hormone receptor-positive/HER2-negative advanced metastatic breast cancer : detailed safety analysis from a multicenter, randomized, placebo-controlled, phase III study (PALOMA-3). The Oncologist July 2016 : theoncologist.20160097.  
| APPENDIX I - PATIENT EVALUATION FLOW SHEET Pre-study (within 14 days  prior to  randomization  - unless  otherwise  specified)   | End of  Treatment  (4 week  follow-up  visit)   | Subsequent  Follow-Up  Visit (prior  to Disease  progression   | Follow-up  (following  disease  progression)   |     |                             |
|----------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------|----------------------------------------------------------------|------------------------------------------------|-----|-----------------------------|
| Medical History and Physical History                                                                                             | X                                               | X                                                              | X                                              | X   | X                           |
| Concurrent Illnesses                                                                                                             | X                                               | X                                                              | X                                              |     |                             |
| Concomitant Medication                                                                                                           | X                                               | X                                                              | X                                              |     |                             |
| Physical exam (height, Weight,  Blood Pressure, Pulse and ECOG                                                                   | X                                               | X                                                              | X                                              | X   |                             |
| Performance Status)                                                                                                              | On                                              |                                                                |                                                |     |                             |
| Treatment  (Day 1 of  each cycle)                                                                                                | On                                              |                                                                |                                                |     |                             |
| Treatment  (every 12  weeks)                                                                                                     | At time of  disease  progression                |                                                                |                                                |     |                             |
| Required Investigations                                                                                                          |                                                 |                                                                |                                                |     |                             |
| Hematology5 CBC                                                                                                                  | X                                               | X4                                                             | X                                              |     |                             |
| Differential                                                                                                                     | X                                               | X4                                                             | X                                              |     |                             |
| HBA1c                                                                                                                            | X                                               | X4                                                             | X                                              |     |                             |
| Biochemistry5 Serum Creatinine                                                                                                   | X                                               | X                                                              | X                                              |     |                             |
| Bilirubin (total)                                                                                                                | X                                               | X                                                              | X                                              |     |                             |
| Radiology6 CT/MRI of the chest, abdomen  and pelvis                                                                              | X2                                              | X                                                              | X                                              | X   |                             |
| Bone Scan or PET1                                                                                                                | X2                                              | As Clinically Indicated                                        |                                                |     |                             |
| Other imaging as necessary to  document all sites of disease                                                                     | X2                                              | As Clinically Indicated                                        |                                                |     |                             |
| Other Investigations Pregnancy Test                                                                                              | X3                                              | As Clinically Indicated                                        |                                                |     |                             |
| ECG                                                                                                                              | X                                               | As Clinically Indicated                                        |                                                |     |                             |
| Urinalysis                                                                                                                       | X                                               | As Clinically Indicated                                        |                                                |     |                             |
| Ophthalmology Exam                                                                                                               | As Clinically Indicated                         |                                                                |                                                |     |                             |
| Adverse Events Continuously graded and recorded  according to CTCAE v4.0                                                         | X                                               | X                                                              | X11                                            | X11 | X11                         |
| Correlative Studies Archival tissue blocks                                                                                       | X                                               | X10                                                            |                                                |     |                             |
| Whole blood for cell-free DNA                                                                                                    | X7                                              | X7                                                             | X7                                             | X   |                             |
| Whole blood for lymphocytes                                                                                                      | X                                               |                                                                |                                                |     |                             |
| Whole blood for banking                                                                                                          | X8                                              |                                                                |                                                |     |                             |
| Serum and plasma for banking                                                                                                     | X7                                              | X7                                                             | X7                                             | X   |                             |
| Quality of Life EORTC QLQ-C30                                                                                                    | X                                               | X9                                                             | X9                                             | X9  | X9                          |
| Trial Specific Checklist                                                                                                         | X                                               | X9                                                             | X9                                             | X9  | X9 footnotes on next page … |  
1 Per Institutional Standard (mandatory for patients with bone only disease at baseline and every 12 weeks from randomization - schedule must be maintained).  
2 Within 28 days prior to randomization. 3 Pregnancy test (in women of childbearing potential), as part of Pre-Study Evaluation, may include an ultrasound to rule-out pregnancy.  
4 CBC and differential required every 2 weeks for the first two cycles, and then on day 1 of each cycle thereafter. HBA1c is required day 1 every 3rd cycle (i.e. cycle 3, 6, 9, 12, etc.).  
5 Bloodwork Timing: Pre-treatment blood draws may be done the day prior to treatment if necessary, and when treatment is to begin on a Monday, may be done on the previous Friday (maximum 72 hours prior to treatment). In order to ensure that nadir counts are not missed, every effort should be made to do interim blood draws within 24 hours of the day specified in the protocol.  
6 Every 12 weeks from randomization until progression (CT schedule must be maintained). 7 Mandatory whole blood samples for cell free DNA and optional serum and plasma banking for consenting patients are required to be obtained at the following time points; Baseline and then every 12 weeks from randomization.  
8 Optional whole blood banking for consenting patients only. Only required to be obtained at baseline.  
9 Required At 4, 8 and 12 weeks and then every 12 weeks until progressive disease.  
10 If feasible. 11 Only Adverse Events deemed related to protocol therapy (Palbociclib, Fulvestrant or Tamoxifen or AI).
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appendix ii - performance status

PERFORMANCE STATUS CRITERIA  
Karnofsky and Lansky performance scores are intended to be multiples of 10.  
| Karnofsky 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  evidence of disease.                                                                         | 100                                                                    | Fully active, normal.                                              |                                                                    |                                                |
| Fully active, able to carry on all                                                                                                                            |                                                                                                                         |                                                                        |                                                                    |                                                                    |                                                |
| 0                                                                                                                                                             | pre-disease performance  without restriction.                                                                           | Able to carry on normal activity;                                      | 90                                                                 | Minor restrictions in physically                                   |                                                |
| 90                                                                                                                                                            | minor signs or symptoms of                                                                                              | strenuous activity.                                                    |                                                                    |                                                                    |                                                |
| disease.                                                                                                                                                      |                                                                                                                         |                                                                        |                                                                    |                                                                    |                                                |
| Restricted in physically  strenuous activity but  ambulatory and able to carry  out work of a light or sedentary  nature, e.g. light housework,  office work. | 80                                                                                                                      | Normal activity with effort; some  signs or symptoms of disease.       | 80                                                                 | Active, but tires more quickly.                                    |                                                |
| 1                                                                                                                                                             | 70                                                                                                                      | Cares for self, unable to carry on  normal activity or do active work. | 70                                                                 | Both greater restriction of and  less time spent in play activity. |                                                |
| Requires occasional assistance, but                                                                                                                           | Up and around, but minimal                                                                                              |                                                                        |                                                                    |                                                                    |                                                |
| 60                                                                                                                                                            | is able to care for most of his/her                                                                                     | 60                                                                     | active play; keeps busy with                                       |                                                                    |                                                |
| needs.                                                                                                                                                        | quieter activities.                                                                                                     |                                                                        |                                                                    |                                                                    |                                                |
| Ambulatory and capable of all  selfcare but unable to carry out  any work activities. Up and  about more than 50% of waking  hours.                           |                                                                                                                         |                                                                        |                                                                    |                                                                    |                                                |
| 2                                                                                                                                                             | Gets dressed, but lies around  much of the day; no active play;  able to participate in all quiet  play and activities. |                                                                        |                                                                    |                                                                    |                                                |
| 50                                                                                                                                                            | Requires considerable assistance  and frequent medical care.                                                            | 50                                                                     |                                                                    |                                                                    |                                                |
| 40                                                                                                                                                            | Disabled, requires special care and  assistance.                                                                        | 40                                                                     | Mostly in bed; participates in  quiet activities.                  |                                                                    |                                                |
| Capable of only limited  selfcare; confined to bed or                                                                                                         |                                                                                                                         |                                                                        |                                                                    |                                                                    |                                                |
| 3                                                                                                                                                             | chair more than 50% of waking  hours.                                                                                   | 30                                                                     | Severely disabled, hospitalization  indicated. Death not imminent. | 30                                                                 | In bed; needs assistance even for  quiet play. |
| 20                                                                                                                                                            | Very sick, hospitalization  indicated. Death not imminent.                                                              | 20                                                                     | Often sleeping; play entirely  limited to very passive activities. |                                                                    |                                                |
| Completely disabled. Cannot                                                                                                                                   |                                                                                                                         |                                                                        |                                                                    |                                                                    |                                                |
| 4                                                                                                                                                             | carry on any selfcare. Totally  confined to bed or chair.                                                               | 10                                                                     | Moribund, fatal processes  progressing rapidly.                    | 10                                                                 | No play; does not get out of bed.              |
| * The conversion of the Lansky to ECOG scales is intended for NCI reporting purposes only.                                                                    |                                                                                                                         |                                                                        |                                                                    |                                                                    |                                                |  
APPENDIX III - DRUG DISTRIBUTION, SUPPLY AND CONTROL
ADMIN UPDATE \#1: 2017-JUL-05 Distribution Palbociclib will be supplied by Pfizer Inc. and distributed by Bay Area Research Logistics (BARL) to participating centres.  
Fulvestrant will be supplied for this study, and distributed by Bay Area Logistics (BARL) to participating centres. All other drugs for this protocol are commercially available and sourced from the Canadian market.
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drug labelling

Drug supplies for this study will be labelled in accordance with Health Canada regulations.
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initial drug supply

Once a centre is locally activated (following receipt and review of all required documentation), the CCTG will authorize a start-up supply of Palbociclib to be shipped directly to the centre. The drug will be shipped to the centre within 5 working days of local activation. Drug accountability and drug re-order forms will be included with the drug shipment and are also available on the trial website.  
Please note that sites must request their initial supply of palbociclib (and fulvestrant) from BARL directly.
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drug ordering (re-supply)

Fax a copy of the re-order form (available on the trial website) to the distributor.
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drug accountability

The investigational products are to be prescribed only by the investigator and co-investigators on the participants list. Under no circumstances will the investigator allow the drug to be used other than as directed by the protocol. Accurate records must be maintained accounting for the receipt of the investigational product and for the disposition of the product (Drug Accountability Log).
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drug destruction

Expired/used study drug may be destroyed as per local standard operating procedures. Destruction of expired/used drug must be documented on the Drug Accountability Log and a copy of the destruction certificate kept on file in the pharmacy. Instructions for return or destruction of unused drug will be supplied at the time of expiry and at trial closure.  
** PLEASE NOTE **
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drug from this supply is

Study drug shipped to participating centres may be transferred from the main hospital pharmacy to a satellite pharmacy, provided separate drug accountability records are maintained in each pharmacy. However, study drug may NOT be transferred to pharmacies or physicians outside the participating centre.
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appendix iv - documentation for

Follow-up is required for patients from the time of randomization and will apply to all eligible patients.  
This trial will use a web-based Electronic Data Capture (EDC) system for all data collection. For details of accessing the EDC system and completing the on-line Case Report Forms please refer to the "CCTG EDC Generic Data Management Guidebook" posted on the MA.38 area of the CCTG web-site
(www.ctg.queensu.ca).  
| The electronic CRFs to be used in this trial, through the EDC system, are as follows: Supporting Documentation  Electronic Folder Required at To be completed electronically Required* Eligibility Checklist Within 2 weeks of randomization Consent form**, relevant  pathology report(s),  relevant radiology  report(s) Baseline Report Within 2 weeks of randomization Information pertaining to  baseline/pretreatment (i.e. tumour  specimen information and blood collection  for correlative studies) must be completed  within 2 weeks of randomization.  Tissue to be submitted immediately upon  request. Consent form**  Information pertaining to post  randomization tissue and blood collection  samples for correlative studies and  banking should be completed within 2  weeks after collection of final blood  specimen.  Information pertaining to skin/blood  collection for Pharmacokinetics/  Pharmacodynamics must be completed in  EDC in real-time, as soon as the sample is  collected.  Treatment Report Every 28 days Within 2 weeks of the end of the cycle Relevant radiology reports  End of Treatment  Report End of treatment Within 2 weeks of the end of treatment None Relapse/Progression  relapse/progression Within 4 weeks of progression Relevant radiology and  Upon disease  Report pathology reports  4 Week Follow-up  4 weeks from the  end of the last cycle Within 2 weeks of the follow-up visit Relevant radiology reports  Report Follow-up Report Every 12 weeks Within 4 weeks of the follow-up visit Relevant radiology reports  Short Follow-up  Report Every 12 weeks Within 4 weeks of the follow-up visit None Continuous  running-log folder  See sections 6.0 and  9.0 Correlative Studies  Report (Tumour and Blood) Diagnostic pathology  report  (for tumour tissue only) Death Report When patient  dies**** Within 4 weeks of the patient's death Copy of post-mortem  report if performed SAE Report*** At time of event Within 1 working day None * Scan and upload into the EDC Supporting Document Upload Tool ** For Canadian centres, it is acceptable to submit only the signature page(s) of the main consent and only the check box page(s)/signature  page(s) of the optional consent provided that the version date of the consent form is indicated.  *** See section 11.0 Serious Adverse Event Reporting for details. **** It is the investigator's responsibility to investigate and report the date and cause of death of any patient entered into this trial.   |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
APPENDIX V - NCI COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS The descriptions and grading scales found in the NCI Common Terminology Criteria for Adverse Events
(CTCAE) version 4.0 will be utilized for Adverse Event (AE) reporting. All appropriate treatment areas should have access to a copy of the CTCAE version 4.0. A copy of the CTCAE version 4.0 can be downloaded from the CTEP website: http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.
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appendix vi - quality of

The assumption that control of symptoms will automatically improve quality of life is probably true but hasn't yet been tested, especially in determining how certain symptoms may or may not affect quality of life. Current literature reveals interesting things; two in particular are:  
- additional and useful information may be obtained from quality of life measurements - a growing consensus that the goal of medical care today for most patients is the preservation of function and well-being in everyday life.
We have reached the stage where the collection of information about psychological distress, social disruption, emotional trauma and painful side-effects is not only necessary but a routine component in many protocols.  
Quality of life data can be used in a variety of ways:
- to try to achieve the best possible outcome for patients  
- to evaluate the extent of change in the quality of life of an individual or group across time - to evaluate new treatments and technologies - to support approval of new drug applications - to try to provide the best value for health care dollars - to compare costs and benefits of various financial and organizational aspects of health care services
In the future, approval of not only drugs but also new therapies or methods of delivery will most likely be based on a combination of quality of life, survival, response, and adverse event data. Instructions for Administration of a Quality of Life Questionnaire. The instructions below are intended as a guide for the administration of the Quality of Life questionnaire.
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1. preamble

Quality of life data are collected for research purposes, and will usually not be used for the patient's individual medical care. The assessment is in the form of a self report questionnaire. Therefore, it must be completed by the patient only, without translation, coaching or suggestions as to the "correct" answer by relatives or health care personnel. The usual scheduled times to obtain the questionnaires are as follows:
- pre-randomization or pre-registration (baseline)  
- during treatment
- during follow-up
The information provided by the patient in the completed questionnaire is confidential and should not be discussed with or shown to anyone who is NOT mentioned in the consent form signed by the patient. If a particular question has not been answered, please document the reason(s) in the appropriate space on the questionnaire. If the whole questionnaire has not been completed, please document the reason(s) on the appropriate case report forms.
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2. pretreatment assessment

It should be explained to the patient that the purpose of the questionnaire is to assess the impact of treatment on different areas of the patient's life, e.g.: psychological distress, social disruption, sideeffects, et cetera.  
The CRA should collect the questionnaire as soon as it has been completed, check to see that each question has been answered and gently remind the patient to answer any inadvertently omitted questions. If a patient states that s/he prefers not to answer some questions and gives a reason(s), the reason(s) should be noted on the questionnaire. If a specific reason is not given, this also should be noted on the questionnaire.
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3. assessments during treatment

The quality of life questionnaire should be given to the patient before being seen by the doctor, and prior to treatment on the day of treatment, as required by the schedule in the protocol. If the patient does not have a doctor visit scheduled, or if it was not possible for the patient to complete the questionnaire before being seen by the doctor, s/he should still complete the questionnaire prior to treatment.
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4. assessments during follow-up

The quality of life questionnaire should be given to the patient before being seen by the doctor, on follow-up visits as required by the schedule.  
A patient may, on occasion, be reluctant to complete the questionnaire because they feel unwell. In that case, you may express sympathy that things are below par, but state that this is exactly the information we require if we are to understand more about how quality of life is affected. You may also remind them that it takes only a few minutes to complete.
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it defeats the whole purpose

The patient should complete the questionnaires at the clinic. The exception is that the design of some trials may require the patient to take the questionnaire home with them after leaving the clinic, and complete it on the specific day, because a return visit to the clinic is not scheduled. There may be circumstances when the patient does not complete the questionnaire as required in the clinic. Three situations are described below. In these cases, it is beneficial if quality of life data can still be collected.  
A. The patient leaves the clinic before the questionnaire could be administered, or someone forgets to give the questionnaire to the patient.
Contact the patient by phone informing him or her that the questionnaire was not completed. Ask the patient if s/he is willing to complete one:
If yes, mail a blank questionnaire to the patient, and make arrangements for return of the questionnaire in a timely fashion. Record the date it was mailed and the date received on the questionnaire.  
If this is not feasible, then ask the patient if s/he is willing to complete a questionnaire over the phone. If the patient agrees, read out the questions and range of possibilities, and record the answers. Make a note on the questionnaire that the questionnaire was completed over the phone.  
If no, note the reason why the questionnaire was not completed on the appropriate case report form.  
B. The patient goes on an extended vacation for several months and won't attend the clinic for regular visit(s).
Ensure that the patient has a supply of questionnaires, with instructions about when to complete them, and how to return them. If it is known beforehand, give the patient blank questionnaires at the last clinic visit; if the extended absence is not known in advance, mail the blank questionnaires to the patient. Written instructions may help ensure that the patient stays on schedule as much as possible.  
C. The patient does not want to complete the questionnaire in clinic. Should the patient not wish to answer the questionnaire in the clinic but insists on taking it home, and failing to comply with the patient's wishes is likely to result in the questionnaire not being completed at all, then the patient may take the questionnaire home with instructions that it is to be completed the same day. When the questionnaire is returned, the date on which the questionnaire was completed should be noted and a comment made on the questionnaire as to why the patient took it away from the clinic before completion.
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6. waiving the quality of

The only time that we will not require a patient to complete the quality of life questionnaires is if s/he is not literate in either English or French (or other languages that the questionnaire may be available in). In other words, if the assistance of a translator is required to comprehend the questions and reply, the questionnaires should not be completed. Translation of the questions is not acceptable. Please indicate on questionnaire.
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7. unwillingness to complete quality

If a patient speaks and reads English or French (or other languages that the questionnaires may be available in), but does not wish to complete the questionnaires then s/he is NOT eligible and should NOT be put on study.
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8. inability to complete quality

An eligible patient may be willing but physically unable to complete the questionnaires, because of blindness, paralysis, etc. If the patient is completing the QOL assessment in the clinic, the questionnaire should be read to them and the answers recorded by a health care professional (e.g. preferably the clinical research associate assigned to the trial, but another clinic nurse, a doctor or social worker who is familiar with the instructions for administering the questionnaires would be acceptable). If the patient is completing the questionnaire at home, and a telephone interview by the clinical research associate is not possible, then a spouse or friend may read the questions to the patient and record the answers.  
However, this method should be a last resort, and the spouse or friend should be instructed to not coach or suggest answers to the patient. Whichever method is used, it should be recorded on the questionnaire. If these special arrangements are not possible or feasible, then the patient would not be required to complete the questionnaires, and this should be reported on the appropriate case report form.
quality of life questionnaire -
8. inability to complete quality

CCTG Trial:
This **page** to be completed by the Clinical Research Associate Patient Information CCTG Patient Serial No: ___________ Patient Initials: ____ ____ ____
(first-middle-last)
Institution: ___________________________________________ Investigator: ______________________________
Scheduled time to obtain quality of life assessment: please check ()
Prior to randomization During chemotherapy:
Week 4  Week 8  Week 12  Week 24  Week 36  Week48  Week 60 Week _____
Off Treatment:
Week 4  Week 8  Week 12  Week 24  Week 36  Week48  Week 60 Week ______
* Note: Questionnaire is not required to be completed at time of relapse/new primary malignancy or afterwards. Were ALL questions answered? ___ Yes ___ No If no, reason: ________________________________________
Was assistance required? ___ Yes ___ No If yes, reason: ________________________________________
Where was questionnaire completed:  home  clinic  another centre Comments: ____________________________________________________________________________________
Date Completed: __ __ __ __ - __ __ __ - __ __
yyyy mmm dd PLEASE ENSURE THIS PAGE IS FOLDED BACK BEFORE HANDING
TO THE PATIENT FOR QUESTIONNAIRE COMPLETION.  
CCTG use only  
_____________________________________________________________________________________________  
Logged: _______  
______ - ____ - ____  
Study Coord: _______  
______ - ____ - ____  
Res Assoc: _______  
______ - ____ - ____  
Data Ent'd:  
_________  
Verif:  
_________
quality of life questionnaire -
european organization for research and

We are interested in some things about you and your health. Please answer all the questions **yourself** by circling the number that best applies to you. There are no 'right' or 'wrong' answers. Choose the best **single** response that applies to you. The information that you provide is for research purposes and will remain strictly confidential. The individuals (e.g. doctors, nurses, etc.) directly involved in your care will not usually see your responses to these questions -- if you wish them to know this information, please bring it to their attention.  
| Not                                                                                             | A                                                                                                      | Quite   | Very   |    |    |
|-------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------|---------|--------|----|----|
| At All                                                                                          | Little                                                                                                 | a Bit   | Much   |    |    |
| 1.                                                                                              | Do you have any trouble doing strenuous activities, like  carrying a heavy shopping bag or a suitcase? | 1       | 2      | 3  | 4  |
| 2.                                                                                              | Do you have any trouble taking a long walk?                                                            | 1       | 2      | 3  | 4  |
| 3.                                                                                              | Do you have any trouble taking a short walk outside of  the house?                                     | 1       | 2      | 3  | 4  |
| 4.                                                                                              | Do you need to stay in a bed or a chair during the day?                                                | 1       | 2      | 3  | 4  |
| 5.                                                                                              | Do you need help with eating, dressing, washing  yourself or using the toilet?                         | 1       | 2      | 3  | 4  |
| Not                                                                                             | A                                                                                                      | Quite   | Very   |    |    |
| At All                                                                                          | Little                                                                                                 | a Bit   | Much   |    |    |
| During the past week: 6. Were you limited in doing either your work or other  daily activities? | 1                                                                                                      | 2       | 3      | 4  |    |
| 7.                                                                                              | Were you limited in pursuing your hobbies or other  leisure time activities?                           | 1       | 2      | 3  | 4  |
| 8.                                                                                              | Were you short of breath?                                                                              | 1       | 2      | 3  | 4  |  
| This box to be completed by the clinical research associate:   | Pt. Serial #: _____________                                                                           | Pt. Initials: ____ ____ ____   |      |    |    |
|----------------------------------------------------------------|-------------------------------------------------------------------------------------------------------|--------------------------------|------|----|----|
| Not                                                            | A                                                                                                     | Quite                          | Very |    |    |
| At All                                                         | Little                                                                                                | a Bit                          | Much |    |    |
| During the past week: 9. Have you had pain?                    | 1                                                                                                     | 2                              | 3    | 4  |    |
| 10.                                                            | Did you need to rest?                                                                                 | 1                              | 2    | 3  | 4  |
| 11.                                                            | Have you had trouble sleeping?                                                                        | 1                              | 2    | 3  | 4  |
| 12.                                                            | Have you felt weak?                                                                                   | 1                              | 2    | 3  | 4  |
| 13.                                                            | Have you lacked appetite?                                                                             | 1                              | 2    | 3  | 4  |
| 14.                                                            | Have you felt nauseated?                                                                              | 1                              | 2    | 3  | 4  |
| 15.                                                            | Have you vomited?                                                                                     | 1                              | 2    | 3  | 4  |
| 16.                                                            | Have you been constipated?                                                                            | 1                              | 2    | 3  | 4  |
| 17.                                                            | Have you had diarrhea?                                                                                | 1                              | 2    | 3  | 4  |
| 18.                                                            | Were you tired?                                                                                       | 1                              | 2    | 3  | 4  |
| 19.                                                            | Did pain interfere with your daily activities?                                                        | 1                              | 2    | 3  | 4  |
| 20.                                                            | Have you had difficulty in concentrating on things, like  reading a newspaper or watching television? | 1                              | 2    | 3  | 4  |
| 21.                                                            | Did you feel tense?                                                                                   | 1                              | 2    | 3  | 4  |
| 22.                                                            | Did you worry?                                                                                        | 1                              | 2    | 3  | 4  |  
| This box to be completed by the clinical research associate:                                                                                                                | Pt. Serial #: _____________                                                               | Pt. Initials: ____ ____ ____   |      |    |    |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------|--------------------------------|------|----|----|
| Not                                                                                                                                                                         | A                                                                                         | Quite                          | Very |    |    |
| At All                                                                                                                                                                      | Little                                                                                    | a Bit                          | Much |    |    |
| During the past week: 23. Did you feel irritable?                                                                                                                           | 1                                                                                         | 2                              | 3    | 4  |    |
| 24.                                                                                                                                                                         | Did you feel depressed?                                                                   | 1                              | 2    | 3  | 4  |
| 25.                                                                                                                                                                         | Have you had difficulty remembering things?                                               | 1                              | 2    | 3  | 4  |
| 26.                                                                                                                                                                         | Has your physical condition or medical treatment  interfered with your family life?       | 1                              | 2    | 3  | 4  |
| 27.                                                                                                                                                                         | Has your physical condition or medical treatment  interfered with your social activities? | 1                              | 2    | 3  | 4  |
| 28.                                                                                                                                                                         | Has your physical condition or medical treatment  caused you financial difficulties?      | 1                              | 2    | 3  | 4  |
| For the following questions please circle the number between 1 and 7 that best applies to you. 29. How would you rate your overall health during the past week? 1 2 3 4 5 6 | 7                                                                                         |                                |      |    |    |
| Very Poor                                                                                                                                                                   | Excellent                                                                                 |                                |      |    |    |
| 30.                                                                                                                                                                         | How would you rate your overall quality of life during the past week? 1 2 3 4 5           | 6                              | 7    |    |    |
| Very Poor                                                                                                                                                                   | Excellent                                                                                 |                                |      |    |    |  
Patients sometimes report that they have the following symptoms. Please indicate the extent to which you have experienced these symptoms during the past week.  
| Not                                                  | A                                    | Quite   | Very   |    |    |
|------------------------------------------------------|--------------------------------------|---------|--------|----|----|
| At All                                               | Little                               | a Bit   | Much   |    |    |
| During the past week: 31. Did you have a sore mouth? | 1                                    | 2       | 3      | 4  |    |
| 32.                                                  | Have you had tingling hands or feet? | 1       | 2      | 3  | 4  |  
33. Were your fingers or toes numb (loss of feeling)? 1 2 3 4 Please check to make sure you have answered all the questions.  
Please fill in your initials to indicate that you have completed this questionnaire: ______________
Today's date (Year, Month, Day): ________________________________
Thank you.
quality of life questionnaire -
appendix vii - the tnm

The 7th Edition of the TNM Classification of Malignant Tumours has recently been released. To facilitate this process, educational resources have been made available to promote the use of staging (visit http://www.cancerstaging.org). These staging criteria should be used for new trials.  
ADMIN UPDATE \#1: 2017-JUL-05  
| Wash-out                                                                                                                                                                                                                                                                                                                                    |                                                                                                                |         |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------|---------|
| (period of time that the medication  should be discontinued prior to  administration of the first dose of  protocol treatment)*                                                                                                                                                                                                             |                                                                                                                |         |
| Inducers of CYP3A4 Drug class                                                                                                                                                                                                                                                                                                               | Agent                                                                                                          |         |
| Antibiotics                                                                                                                                                                                                                                                                                                                                 | All rifamycin class agents (rifampicin, rifabutin,  rifapentine) 7 days                                        |         |
| Anticonvulsants                                                                                                                                                                                                                                                                                                                             | Phenytoin, carbamazepine, barbiturates  (phenobarbital)                                                        | 7 days  |
| Antiretrovirals                                                                                                                                                                                                                                                                                                                             | Efavirenz, nevirapine, tipranivir, etravirine                                                                  | 7 days  |
| Chronic use of cortisone (> 50mg),  hydrocortisone (> 40 mg), prednisone or  prednisolone (> 10 mg), methylprednisolone or  triamcinolone (> 8 mg), betamethasone or  dexamethasone (> 1.5 mg). Glucocorticoid daily  doses (oral) ≤ 1.5 mg dexamethasone (or  equivalent) are allowed. Short term steroid use  (up to 2 weeks) is allowed. |                                                                                                                |         |
| Glucocorticoids (oral)                                                                                                                                                                                                                                                                                                                      | 7 days                                                                                                         |         |
| Other                                                                                                                                                                                                                                                                                                                                       | St. John's Wort, modafinil                                                                                     | 7 days  |
| Inhibitors of CYP3A4 Antibiotic                                                                                                                                                                                                                                                                                                             | clarithromycin, erythromycin, troleandomycin,  flucloxacillin                                                  | 7 days  |
| Antifungals                                                                                                                                                                                                                                                                                                                                 | itraconazole, ketoconazole, fluconazole (> 150  mg daily), voriconazole                                        | 7 days  |
| Antiretrovirals, Protease                                                                                                                                                                                                                                                                                                                   | delaviridine, nelfinavir, amprenavir, ritonavir,  indinavir, saquinavir, lopinivir, atazanavir                 | 7 days  |
| Inhibitors  Calcium channel blockers                                                                                                                                                                                                                                                                                                        | verapamil, diltiazem                                                                                           | 7 days  |
| Antidepressants                                                                                                                                                                                                                                                                                                                             | nefazodone, fluvoxamine                                                                                        | 7 days  |
| GI Agents                                                                                                                                                                                                                                                                                                                                   | Cimetidine, aprepitant                                                                                         | 7 days  |
| Other                                                                                                                                                                                                                                                                                                                                       | grapefruit, grapefruit juice, seville oranges, star                                                            | 7 days  |
| fruit, papaw, amiodarone                                                                                                                                                                                                                                                                                                                    |                                                                                                                |         |
| Miscellaneous Herbal or dietary  supplements and traditional  Chinese medicines                                                                                                                                                                                                                                                             | Ginkgo biloba, kava, grape seed, valerian,  ginseng, Echinacea, evening primrose oil.                          | 14 days |
| *                                                                                                                                                                                                                                                                                                                                           | All patients must have observed the specified washout period for all prohibited drugs prior to randomization.. |         |  
APPENDIX VIII - PROHIBITED MEDICATIONS
ADMIN UPDATE \#1: 2017-JUL-05  
| Contact                                                                                                   | Tel. #                                                                                                                                             | Fax #        |              |
|-----------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------|--------------|--------------|
| ELIGIBILITY CHECKLIST Must be completed prior to  allocation.                                             | Sue Steacy Clinical Trials Assistant, CCTG                                                                                                         | 613-533-6430 | 613-533-2941 |
| Email: ssteacy@ctg.queensu.ca Available on CCTG Website: http://www.ctg.queensu.ca under: Clinical Trials |                                                                                                                                                    |              |              |
| STUDY SUPPLIES Forms, Protocols                                                                           | Chad Winch Study Coordinator, CCTG Email: cwinch@ctg.queensu.ca or: Dr. Wendy Parulekar Senior Investigator, CCTG Email: wparulekar@ctg.queensu.ca |              |              |
| PRIMARY CONTACTS FOR  GENERAL PROTOCOLRELATED QUERIES (including eligibility questions  and protocol management)                                                                                                           | 613-533-6430                                                                                                                                       | 613-533-2941 |              |
| STUDY CHAIR                                                                                               | Dr. Anil Abraham Joy Email: anil.joy@ahs.ca                                                                                                        | 780-432-8762 | 780-432-8888 |
| SERIOUS ADVERSE EVENT  REPORTING See protocol Section 11.0 for  details of reportable events.             | Chad Winch Study Coordinator, CCTG                                                                                                                 | 613-533-6430 | 613-533-2941 |
| Email: cwinch@ctg.queensu.ca                                                                              |                                                                                                                                                    |              |              |
| DRUG ORDERING See Appendix III for full details.                                                          | See Appendix III and trial website: www.ctg.queensu.ca                                                                                             |              |              |