2. approval signatures
13. study procedure - assessments

Every effort should be made to ensure that the protocol required tests and procedures are completed as described. However, it is anticipated that from time to time there may be circumstances, outside of the control of the investigator that may make it unfeasible to perform the test. In these cases, the investigator will take all steps necessary to ensure the safety and well-being of the patient. When a protocol required test cannot be performed the investigator will document the reason for this and any corrective and preventive actions which he/she has taken to ensure that normal processes are adhered to as soon as possible. The monitor should be informed of these incidents in a timely fashion. Safety assessment will consist of monitoring of all adverse events (AEs), including serious adverse events (SAEs), regular monitoring of hematology, serum chemistry, and routine monitoring of ECGs, physical examinations, vital signs, and ECOG performance status. Adverse event assessment will include type, incidence, severity (graded by the National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE], Version 4.0, see Severity Assessment section), timing, seriousness, and relatedness.  
| Timing                                                                                                                                                                                                                                                                                                                                                                                                                                                                 |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  |                                         |           |        |           |     |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------|-----------|--------|-----------|-----|
| Investigations prior to study entry to any protocol  investigations or procedures - Prescreening (within days prior to  randomization) - Breast ultrasound (<13 months) and either                                                                                                                                                                                                                                                                                     |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  |                                         |           |        |           |     |
| Imaging tests  **                                                                                                                                                                                                                                                                                                                                                                                                                                                      | Bilateral mammography (< 13 months) OR bilateral  breast MRI (<13 months). For women treated with  mastectomy only imaging data of contralateral breast  is required ; for women with bilateral mastectomy  an imaging assessment as recommended per  national guidelines should be available. Other instrumental examinations only in case of symptoms suspicious for locoregional or distant  relapse. Reports of these examinations < 13 month  prior to enrollment must be available then. Bone scan,  CT, MRI, and/or PET-CT scans may be performed as  clinically indicated according to the investigator. | •Imaging tests for  staging < 13 Months |           |        |           |     |
| Data                                                                                                                                                                                                                                                                                                                                                                                                                                                                   | including                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        | imaging                                 | from      | intial | results   | for |
| calculation of clinical score of CPS-EG needs to be  available as source data.                                                                                                                                                                                                                                                                                                                                                                                         |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  |                                         |           |        |           |     |
| Surgery                                                                                                                                                                                                                                                                                                                                                                                                                                                                | Surgery (breast-conserving surgery or ablation)                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  |                                         |           |        |           |     |
| excising the initial tumor bed. Subsequent  secondary surgical interventions do not count  regarding this time interval. All surgery reports and all pre- and postneoadjuvant histopathology reports including information on the components of  residual cancer burden (RCB) (primary tumor bed area, overall cancer cellularity (%), percentage of  cancer that is in situ disease, number of positive  nodes, diameter of largest metastases) have to be  provided. | less than 16 weeks  prior to  randomization                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      |                                         |           |        |           |     |
| Radiotherapy                                                                                                                                                                                                                                                                                                                                                                                                                                                           | Completed adiotherapy after surgery according                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    |                                         |           |        |           |     |
| to                                                                                                                                                                                                                                                                                                                                                                                                                                                                     | guidelines                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       | if                                      | indicated | (IORT  | allowed). |     |
| Radiotherapy reports including information of time  period of radiotherapy, irradiated region and dose per  region, dose per day have to be provided                                                                                                                                                                                                                                                                                                                   | less than 10 weeks  prior to  randomization                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      |                                         |           |        |           |     |  
| Timing                                                                                                                                                                                                                                                                                                                                                                                                                                             | (within days                                                 |                       |                                                      |           |        |        |         |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------|-----------------------|------------------------------------------------------|-----------|--------|--------|---------|
| Investigations with Screening                                                                                                                                                                                                                                                                                                                                                                                                                      | prior                                                        | to                    |                                                      |           |        |        |         |
| randomization)                                                                                                                                                                                                                                                                                                                                                                                                                                     |                                                              |                       |                                                      |           |        |        |         |
| Patient  informed  consent                                                                                                                                                                                                                                                                                                                                                                                                                         |                                                             | Obtained              | Prior to any protocol  investigations or  procedures |           |        |        |         |
| History and  physical  exam                                                                                                                                                                                                                                                                                                                                                                                                                        | History                                                      | -                     | including:                                           | diagnosis | of     | breast | cancer, |
| menopausal status, general medical history including  cardiac history and allergy, concurrent illnesss,  response to neoadjuvant chemotherapy (assessed  according to Appendix1 21.1)  Concomitant medications, and their indication,  used within one month prior to study entry  Physical exam - including: height and weight,  ECOG for performance status according to  Appendix 2, 21.2) / vital signs, heart rate (pulse),  blood pressure | < 30 days                                                    |                       |                                                      |           |        |        |         |
|                                                                                                                                                                                                                                                                                                                                                                                                                                                   | Palpation                                                    | of                    | breasts,                                             | axillae,  | supra- | and    |         |
| infraclavicular region                                                                                                                                                                                                                                                                                                                                                                                                                             |                                                              |                       |                                                      |           |        |        |         |
|                                                                                                                                                                                                                                                                                                                                                                                                                                                   | Preexisting signs and symptoms                               |                       |                                                      |           |        |        |         |
|                                                                                                                                                                                                                                                                                                                                                                                                                                                   | Check FSH and E2                                             | in patients aged <55  | and                                                  |           |        |        |         |
| history of hysterectomy.                                                                                                                                                                                                                                                                                                                                                                                                                           |                                                              |                       |                                                      |           |        |        |         |
| Hematology *                                                                                                                                                                                                                                                                                                                                                                                                                                       |                                                             | Hemoglobin            |                                                      |           |        |        |         |
|                                                                                                                                                                                                                                                                                                                                                                                                                                                   | White blood cells (WBC) and absolute neutrophil  count (ANC) | < 8 days              |                                                      |           |        |        |         |
|                                                                                                                                                                                                                                                                                                                                                                                                                                                   | Platelet count                                               |                       |                                                      |           |        |        |         |
| Pregnancy                                                                                                                                                                                                                                                                                                                                                                                                                                          |                                                             | Serum (if applicable) |                                                      |           |        |        |         |
| Test                                                                                                                                                                                                                                                                                                                                                                                                                                               | <                                                            | 14                    | days                                                 | (if       |        |        |         |
| applicable)                                                                                                                                                                                                                                                                                                                                                                                                                                        |                                                              |                       |                                                      |           |        |        |         |
| Highly                                                                                                                                                                                                                                                                                                                                                                                                                                             | effective                                                    | non-hormonal          | contraceptive                                        |           |        |        |         |
| methods, (barrier methods, intrauterine contraceptive  devices, sterilization) ; sexual abstinence or  vasectomized partne                                                                                                                                                                                                                                                                                                                         |                                                              |                       |                                                      |           |        |        |         |
2. approval signatures
13.1 study procedures at screening

| Timing                        | (within days                                                                                                                              |                                                                                                                                                                                                                                                                                                                                                                     |           |     |
|-------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------|-----|
| Investigations with Screening | prior                                                                                                                                     | to                                                                                                                                                                                                                                                                                                                                                                  |           |     |
| randomization)                |                                                                                                                                           |                                                                                                                                                                                                                                                                                                                                                                     |           |     |
| Biochemistry                  |                                                                                                                                          | Sodium, Potassium , total calcium, magnesium                                                                                                                                                                                                                                                                                                                        |           |     |
| *                             |                                                                                                                                          | Albumin                                                                                                                                                                                                                                                                                                                                                             |           |     |
|                              | Alkaline phosphatase                                                                                                                      | < 8 days                                                                                                                                                                                                                                                                                                                                                            |           |     |
|                              | ASAT (SGOT), ALAT (SGPT)                                                                                                                  |                                                                                                                                                                                                                                                                                                                                                                     |           |     |
|                              | Total bilirubin                                                                                                                           |                                                                                                                                                                                                                                                                                                                                                                     |           |     |
|                              | Serum creatinine                                                                                                                          |                                                                                                                                                                                                                                                                                                                                                                     |           |     |
| Biochemistry                  |                                                                                                                                          | HbA1C                                                                                                                                                                                                                                                                                                                                                               | < 30 days |     |
| * Cardiac                     |                                                                                                                                          | 12-lead ECG including automated calculation of                                                                                                                                                                                                                                                                                                                      |           |     |
| Monitoring                    | PR interval, QT interval, RR interval, and QRS                                                                                            | < 30 days                                                                                                                                                                                                                                                                                                                                                           |           |     |
| complex                       |                                                                                                                                           |                                                                                                                                                                                                                                                                                                                                                                     |           |     |
| Biomaterials                  |                                                                                                                                          | Formalin-fixed paraffin-embedded (FFPE) tumor  tissue block from post-neoadjuvant surgically  removed tissue or if not available, involved lymph  nodes (mandatory). After ICF signature Formalin-fixed paraffin-embedded (FFPE) tumor  tissue block from pre-neoadjuvant core biopsies  for further exploratory analysis or to confirm  luminal status (mandatory) |           |     |
|                              | 10 mL full blood for serum (mandatory) needs to  be provided before 1 st dosing with IP                                                   | < 30 days but  latest before                                                                                                                                                                                                                                                                                                                                        | 1st       |     |
| dosing with IP                |                                                                                                                                           |                                                                                                                                                                                                                                                                                                                                                                     |           |     |
|                              | 10 ml full blood for plasma (mandatory) needs to  be provided before 1st dosing with IP                                                   |                                                                                                                                                                                                                                                                                                                                                                     |           |     |
|                              | 10 mL full blood for SNP analysis (mandatory) (can  also be taken any time after randomization) < 30 days but latest before EoT < 30 days |                                                                                                                                                                                                                                                                                                                                                                     |           |     |
|                              | 20 ml full blood for detection of ctDNA (optional)                                                                                        | latest                                                                                                                                                                                                                                                                                                                                                              | before    | 1st |
| dosing with IP                |                                                                                                                                           |                                                                                                                                                                                                                                                                                                                                                                     |           |     |  
| Timing                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  | (within days                                                                                  |                         |           |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------|-------------------------|-----------|
| Investigations with Screening                                                                                                                                                                                                                                                                                                                                                                                                                                                           | prior                                                                                         | to                      |           |
| randomization)                                                                                                                                                                                                                                                                                                                                                                                                                                                                          |                                                                                               |                         |           |
| Patient  reported  outcome /  Health  economics                                                                                                                                                                                                                                                                                                                                                                                                                                         |                                                                                              | EORTC QLQ C30,          |           |
|                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        | EORTC QLQ BR-23,                                                                              |                         |           |
|                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        | EORTC QLQ FA-13 Fatigue,                                                                      |                         |           |
|                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        | GAD7 patient self-rating mood scale                                                           | < 14 days               |           |
|                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        | EQ-5D. See Appendix 5-8 (21.5 - 21.8)                                                         |                         |           |
|                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        | Use of medical resources related to breast cancer  and that may differ between trial arms**** |                         |           |
| Other  Investigations                                                                                                                                                                                                                                                                                                                                                                                                                                                                   |                                                                                              | as clinically indicated | < 30 days |
| * Laboratory assessments will be performed whenever possible by the same laboratory  throughout the study.  **Every effort will be made to use the same instrumental examination from baseline  through follow-up. **** Medical resource use at the treating center should be recorded by study staff without  involving the patient. Assessment of medical resource use by other health care providers  and of lost resources (days of work etc.) should be based on patient interview |                                                                                               |                         |           |
2. approval signatures
13.2 evaluation during active treatment

| Investigations during Treatment                                                                                                                                                                                                                                                                                      | Timing                                                                                                    |                    |         |     |             |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------|--------------------|---------|-----|-------------|
| History                                                                                                                                                                                                                                                                                                              | and                                                                                                       |                    |         |     |             |
| physical  exam**                                                                                                                                                                                                                                                                                                     | since                                                                                                     |                    |         |     |             |
| previous visit                                                                                                                                                                                                                                                                                                       |                                                                                                          | Clinical           | history | and | concomitant |
| medication                                                                                                                                                                                                                                                                                                           | Days 1 (+/-2) and 14 during  cycles 1 and 2,                                                              |                    |         |     |             |
|                                                                                                                                                                                                                                                                                                                     | Physical exam -                                                                                           | including: weight, |         |     |             |
| ECOG performance status (Appendix  2, 21.2), heart rate , blood pressure Day 1 (+3) at cycle 3, 4, 5, 7, 9,  11, 13 and at EOT.  SAEs must be reported within  24 hours. For all randomized  patients SAEs must be  reported until 30 days after  last intake of IMP once they  received initial dose of study  drug |                                                                                                           |                    |         |     |             |
|                                                                                                                                                                                                                                                                                                                     | Adverse events*                                                                                           |                    |         |     |             |
|                                                                                                                                                                                                                                                                                                                     | Information on external hematology  lab results or from site lab taken on  day 1 of cycles 6,8,10,12 only |                    |         |     |             |  
| Investigations during Treatment                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         | Timing                                                       |            |               |               |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------|------------|---------------|---------------|
| Hematology**                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            |                                                             | Hemoglobin | Days 1 (+/-2) | and 14 (+/-2) |
| during cycles 1 and 2, Day 1  (+3) of 3, 4, 5, 6, 7,8, 9,10, 11,  12, 13 and at EOT, and clinically indicated.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          |                                                              |            |               |               |
|                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        | White blood cells (WBC) and absolute  neutrophil count (ANC) |            |               |               |
|                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        | Platelet count                                               |            |               |               |
| Laboratory assessments will be performed whenever possible by the same laboratory ("site  lab"). The exception are hematology labs on Day 1 of Cycles 6, 8, 10 and 12 which can be  done at any laboratory conveniently located for the patient and if accepted per local EC/IRB  with protocol approval. Results have to be sent immediately to the site for review. Abnormal  external lab results (neutropenia <1000/mm³, thrombocytopenia <50.000/mm³ or anemia  grade >=3) obtained on those dates and at a lab different from the site lab, must be  repeated at the site lab within 2 days (=extra, but clinically indicated hematology lab), and  the Investigator must immediately determine the impact on study drug dosing and further  medical management of the patient based on site lab results (See Table 3 Dose  modifications). Biochemistry**  Sodium, Potassium , total calcium, magnesium  Albumin Day 1 (+/-2) Cycles 1, 2, Day 1  (+3) of Cycle 3, 7, 11, and  EOT, and as clinically  indicated  Alkaline phosphatase   ASAT (SGOT), ALAT (SGPT)  Total bilirubin  Serum creatinine HbA1C Day 1 (+3) of Cycle 3, 7, 11,  and EOT Drug  compliance and  dispensing  Palbociclib/placebo bottles including  any unused medication will be  returned to the clinic for drug  accountability. Drug accountability  will be performed on Day 1 of each  cycle prior to dispensing drug supply  for the next cycle(s). Day 1 (+/-2) at cycle 1, 2, Day  1 (+3) of Cycle 3, 4, 5, 7, 9, 11,  13 |                                                              |            |               |               |  
| Investigations during Treatment                                                                                                                                                                                                                        | Timing                                                                                                                                         |                    |       |           |           |           |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------|--------------------|-------|-----------|-----------|-----------|
| Pharmacokinetics                                                                                                                                                                                                                                                        |                                                                                                                                               | Plasma             | pk    | samples   | for       | drug-drug |
| interaction(DDI)  (sites not being prepared to collect pk  samples will only be allowed to  include patients planned for  treatment with letrozole until these f  24 patient of a respective cohort are  being included) - sampling  completed         | Several samples in cycle 1  and/or cycle 2 [only for the24  patients each receiving  tamoxifen, and goserelin plus  tamoxifen, or anastrozole] |                    |       |           |           |           |
|                                                                                                                                                                                                                                                       | plasma pk samples for drug exposure. (sampling ongoing since mandatory  for all patients) pre-dose Day 14 of cycle 1  and 2 [all patients]     |                    |       |           |           |           |
| Clinical disease                                                                                                                                                                                                                                       | Clinical disease assessment, relapse                                                                                                           |                    |       |           |           |           |
| assessment                                                                                                                                                                                                                                             | and survival status.                                                                                                                           | cycle 7 and at EOT |       |           |           |           |
| Imaging                                                                                                                                                                                                                                                | (mammograph                                                                                                                                    | or                 | MRI): |           |           |           |
| Imaging should be performed at Cycle  7 and EOT.. In patients with  mastectomy only contralateral  mammography / MRI is required;  patients with bilateral mastectomy  should be assessed as per national  guidelines recommended imaging examination. |                                                                                                                                                |                    |       |           |           |           |
|                                                                                                                                                                                                                                                       | Thoracic or abdominal CT / MRI, bone                                                                                                           |                    |       |           |           |           |
| Other                                                                                                                                                                                                                                                  | in case of symptoms suspect                                                                                                                    |                    |       |           |           |           |
| Investigations                                                                                                                                                                                                                                         | for disease progression or as                                                                                                                  |                    |       |           |           |           |
| scans, x-rays, biopsies and others***                                                                                                                                                                                                                  | clinically indicated                                                                                                                           |                    |       |           |           |           |
| Cardiac                                                                                                                                                                                                                                                |                                                                                                                                               | 12-lead            | ECG   | including | automated |           |
| monitoring**                                                                                                                                                                                                                                           | calculation of PR interval, QT interval,  RR interval, and QRS complex Day                                                                     | 14                 | Cycle | 1         | and       | as        |
| clinically indicated                                                                                                                                                                                                                                   |                                                                                                                                                |                    |       |           |           |           |  
| Investigations during Treatment                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                | Timing                                              |                                        |                                                                                                                                                       |       |     |        |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------|----------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------|-------|-----|--------|
| Biomaterials                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   |                                                    | 10 mL full blood for serum (mandatory) | Before cycle 7 and at EOT                                                                                                                             |       |     |        |
|                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               | 10                                                  | mL                                     | full                                                                                                                                                  | blood | for | plasma |
| (mandatory)                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    |                                                     |                                        |                                                                                                                                                       |       |     |        |
|                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               | 20 ml full blood for detection of ctDNA  (optional) |                                        |                                                                                                                                                       |       |     |        |
|                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               | Formalin-fixed                                      | paraffin-embedded                      |                                                                                                                                                       |       |     |        |
| (FFPE) tumor tissue from metastasis in  case of recurrence - upon occurance                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    |                                                     |                                        |                                                                                                                                                       |       |     |        |
| Patient  reported  outcome and health economics -                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              |                                                    | EORTC QLQ C30,                         | Day 1 or (+/-2 days) of Cycle  1, 3, Day 1 or (+/ -7 days) of  Cycle 5, 7, 9, 11, and EOT, and  every 6 months until final  primary endpoint analysis |       |     |        |
|                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               | EORTC QLQ BR-23,                                    |                                        |                                                                                                                                                       |       |     |        |
|                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               | EORTC QLQ FA13 (Fatigue),                           |                                        |                                                                                                                                                       |       |     |        |
|                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               | GAD7 patient self-rating mood scale                 |                                        |                                                                                                                                                       |       |     |        |
|                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               | EQ-5D                                               |                                        |                                                                                                                                                       |       |     |        |
| See Appendix 5-8 (21.5 - 21.8)  Use of medical resources related to breast  cancer and that may differ between trial  arms****                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 |                                                     |                                        |                                                                                                                                                       |       |     |        |
| * Toxicities will be recorded according to NCI-CTCAE v4 criteria with the maximum grade per  cycle.  ** Laboratory assessments will be performed whenever possible by the same laboratory  throughout the study. Cycle 1/Day 1: Blood chemistry, hematology, 12-lead ECG and physical  examination not required if acceptable screening assessment was performed within 7 days  prior to randomization ***Every effort will be made to use the same instrumental examination from baseline until  end of study treatment. **** Medical resource use at the treating center should be recorded by study staff without  involving the patient. Assessment of medical resource use by other health care providers  and of lost resources (days of work etc.) should be based on patient interview |                                                     |                                        |                                                                                                                                                       |       |     |        |
2. approval signatures
13.3 pharmacokinetic measurements all groups

Trough concentrations of palbociclib will be collected pre-dose on Day 14 of cycle 1 and 2 for all patients. These samples will be used for exposure/response analysis for safety and efficacy findings. If these PK samples are not collected during the planned nominal visit/time, "make-up" samples can be drawn within the same cycle on Days 15 to 21, or in a later cycle on Days 14 to 21 providing that all planned doses of palbociclib in that cycle have been administered (ie no missed samples or dose interruptions) up until the PK collection day. The actual date and time of palbociclib administration for the most recent palbociclib dose before and the most recent dose after collection of the PK samples must be recorded in the study CRF.
2. approval signatures
note pk-ddi sampling as descbribed

In subsets of at least 24 evaluable patients each starting with the combination of tamoxifen and palbociclib/placebo, anastrozole and palbociclib/placebo, goserelin and tamoxifen and palbociclib/placebo plasma PK samples will be collected to explore DDI between palbociclib and the combination drug. Patients enrolled as a part of the DDI assessment subset who dropout of the study prior to completion of all planned PK collections for their respective treatment combination DDI assessment, may be replaced at the discretion of the Sponsor/Investigator to ensure that evaluable PK data is available from 24 patients within each endocrine treatment group. The PK sample handling and processing instructions are at the end of this section and further details can be found in the biomaterial management manual.
2. approval signatures
tamoxifen together with palbociclib/placebo patients

In 24 patients receiving tamoxifen together with palbociclib/placebo plasma PK samples will be drawn on Cycle 2 Day 14 pre-dose and 2, 4, 6, 8, and 24 hours post-dose for DDI assessment. These samples will be analyzed for palbociclib, tamoxifen, 4-hydroxy-tamoxifen, N-desmethyltamoxifen, and endoxifen. The Cmax, Cmin, and AUC(0-24) of tamoxifen and its active metabolites will be compared between the palbociclip and placebo subgroups. The Cmax, Cmin, and AUC(0-24) of palbociclib will be compared with historical data. These data will be used to explore the potential two-way DDI between tamoxifen and palbociclib and the result will be used to inform dose adjustment if necessary after IDMC review of the DDI analysis. If the planned PK samples are not collected during the planned nominal visit on Cycle 2 Day 14, then "make-up" samples can be drawn within the same cycle on Days 15 to 21, or in a later cycle on Days 14 to 21 providing that all planned doses of palbociclib and tamoxifen in that cycle have been administered (ie no missed samples or dose interruptions) up until the PK collection day. The actual date and time of administration for the most recent palbociclib and tamoxifen doses before and the most recent dose after collection of their respective PK samples must be recorded in the study CRF. Of note, the samples should be collected from the same dosing interval (ie if PK sampling starts with a pre-dose PK sample on Cycle 2 Day 18, then the 24hr post-dose sample should be drawn on Cycle 2 Day 19 and all planned samples drawn in between), and the 24 hours post-dose samples should be drawn prior to administration of the next dose.
2. approval signatures
anastrozole together with palbociclib/placebo patients

In 24 patients receiving anastrozole together with palbociclib/placebo plasma PK samples will be drawn on Cycle 1 Day 14 pre-dose and 1, 2, 4, 6, 8, and 24 hours post-dose for DDI
assessment. These samples will be analyzed for palbociclib and anastrozole. The Cmax, Cmin, and AUC(0-24) of anastrozole will be compared between the palbociclib and placebo subgroups. The Cmax, Cmin, and AUC(0-24) of palbociclib will be compared with historical data.  
These data will be used to explore the potential two-way DDI between anastrozole and palbociclib and the result will be used to inform dose adjustment if necessary after IDMC review of the DDI analysis. . If the planned PK samples are not collected during the planned nominal visit on Cycle 1 Day 14, then "make-up" samples can be drawn within the same cycle on Days 15 to 21, or in a later cycle on Days 14 to 21 providing that all planned doses of palbociclib and anastrozole in that cycle have been administered (ie no missed samples or dose interruptions) up until the PK collection day. The actual date and time of administration for the most recent palbociclib and anastrozole doses before and the most recent dose after collection of their respective PK samples must be recorded in the study CRF. Of note, the samples should be collected from the same dosing interval (ie if PK sampling starts with a pre-dose PK sample on Cycle 1 Day 18, then the 24hr post-dose sample should be drawn on Cycle 1 Day 19 and all planned samples drawn in between), and the 24 hours post-dose samples should be drawn prior to administration of the next dose.
2. approval signatures
goserelin and tamoxifen together with

In 24 patients receiving goserelin and tamoxifen together with palbociclib/placebo, plasma PK samples will be drawn on Cycle 2 and Cycle 3 Days 1 and Day 14 pre-dose for DDI assessment. These samples will be analyzed for palbociclib, goserelin and tamoxifen. Concentrations of Goserelin and tamoxifen will be compared between the palbociclib and placebo subgroups. The concentrations of palbociclib will be compared with historical data. These data will be used to explore the potential two-way DDI between goserelin and palbociclib and the result will be used to inform dose adjustment if necessary after IDMC
review of the DDI analysis.  
If the planned PK samples are not collected during the planned nominal visit, then "make-up" samples can be drawn in a later cycle on the same planned cycle Day (ie a Cycle 3 Day 1 sample can be made-up on Cycle 4 Day 1, and a Cycle 3 Day 14 sample can be made-up on Cycle 4 Day 14) providing that all planned doses of palbociclib, tamoxifen, and goserelin in that cycle (or the previous cycle in the case of Day 1 PK samples) have been administered (ie no missed samples or dose interruptions) up until the PK collection day. The actual date and time of administration for the most recent palbociclib, tamoxifen, and goserelin doses before and the most recent dose after collection of their respective PK samples must be recorded in the study CRF.
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pk sample handling and processing

Collect 3 mL PK blood samples for each administered drug in the combination at each timepoint specified above and process each sample according to the procedure below: 1. Upon collection of blood samples in 3mL Lavender Top K2EDTA Tube, keep the blood PK
samples on wet ice at all times prior to centrifugation.  
2. Within 1 hour of collection, centrifuge the blood samples in the refrigerated centrifuges at approximately +4°C at about 1700xg for about 10 min.  
3. Using a separate pipette for each time point, transfer the plasma samples into prelabeled amber cryovials polypropylene tubes and stored at the following temperatures per analyte: the tamoxifen, anastrozole and palbociclib samples should be stored at -20°C and the goserelin samples at -80°C .  
4. As much as practical, keep the blood and the plasma samples away from direct sunlight and unfiltered lab light.  
5. Ship the samples on dry ice to the biobank as per study team request. Sites not being prepared to collect PK samples for DDI Assessment will only be allowed to include patients planned for treatment with letrozole until the 24 patients of a respective cohort are being accrued. Inclusion of patients into the study will not be put on hold to wait for the results of these Pk analyses.
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13.4 patient reported outcomes (pro)

Patients reported outcome and health economic analyses: data will be captured using the following questionnaires: the EORTC QLQ-C30, the breast cancer module QLQ-BR23, QLQ fatigue, GAD7 patient self-rating mood scale and the EQ-5d instruments. Summary statistics (mean, standard deviation, median, 25th and 75th percentiles, and range) of absolute scores and their changes from baseline will be summarized at each assessment time point for the 2 treatment arms. Only patients with a baseline assessment and at least one post-baseline assessment will be included in this analysis. Repeated-measures mixed-effects models will be used to explore the treatment effect changes over time and treatment-by-time interaction. Details on distribution, advising patients and analysis will be provided in the statistical analysis plan.
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13.4.1 eortc qlq-c30 eortc qlq-fa13

The EORTC QLQ-C30 is a validated and reliable self-report measure 114 115 116) that consists of 30 questions that assess five aspects of patient functioning (physical, emotional, role, cognitive, and social); three symptom scales (fatigue; nausea, vomiting, and pain; and the global health/quality of life) and six single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). Scale scores can be obtained for the multiitem scales. The fatigue module has been developed for use in all diagnoses, stages of the disease and treatment settings. It is measuring cancer related fatigue based on a multidimensional approach including physical, emotional and cognitive aspects of fatigue. One global item is assessing the interference of fatigue with activities of daily living. FA-13 (reduced version with 13 items to be used in combination with EORTC QLQ-C30, Weis, J. 2009;) The QLQ-BR23 breast cancer module is meant for use among patients varying in disease stage and treatment modality.  
117 The module comprises 23 questions assessing disease symptoms, side effects of treatment (surgery, chemotherapy, radiotherapy, and hormonal treatment), body image, sexual functioning, and future perspective. The breast cancer module incorporates five multiple-item scales to assess systemic therapy side effects, arm symptoms, breast symptoms, body image, and sexual functioning. In addition, single items assess sexual enjoyment, hair loss, and future perspective. The QLQ-C30 and QLQBR23 take 10 to 15 minutes to complete.
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13.4.2 eq-5d

The EQ-5D is a widely used, preference-based measure of health related quality of life (utility) that is frequently used as a basis for calculating quality-adjusted life years (QALY) and for conducting health economic evaluation studies118 119. The EQ-5D measures five dimensions (mobility, self-care, usual activities, pain/discomfort and anxiety/depression),
offering three answer categories for each120 121. Resulting health states are combined with country-specific value sets, derived from population-based studies, to calculate utility. In addition, a visual analogue scale (VAS) allows individuals to directly rate their self-perceived overall health state. It takes about 5 minutes to complete the EQ-5D. Health economics: medical resource use related to breast cancer and that may differ between trial arms will be collected as a basis for cost analysis and health economic evaluation. Medical resource use at the treating center will be recorded by study staff without involving the patient. Assessment of medical resource use accrued with other health care providers and of lost resources (lost days of work etc.) will be based on patient interviews and/or patient diaries. It is estimated that during the treatment period, the additional time requirement will be 15 minutes of patient and staff time per clinical visit. During the follow-up period, the expected time requirement is an 20 minutes per assessment time point. Details of the cost analyses and health economic evaluation will be described in a Health Economic Analysis Plan. In brief, cost differences between treatment strategies will be assessed for the final iDFS (and interim OS) analysis time point (QIV 2018), for the final OS analysis time point (QIV 2021), and with a lifelong time horizon based on extrapolation. Incremental cost-effectiveness, expressed as cost per QALY gained, will be estimated based on the data available at the final iDFS and final OS analysis time points, using a lifelong time horizon. Supporting analyses may be added. Given the specifics of health economic analysis, some points must be noted: Approaches to analysis will follow the health economic state-of-the-art, which may evolve until the analyses are due. Assessments of cost and cost-effectiveness will make use of clinical, utility and medical resource use data collected within the PENELOPE tiral. Unit cost estimates and potentially a limited number of additional parameters will come from external sources. Health economic analysis is always country-specific; countries for which the analyses will be performed, and perspectives of cost assessment, remain to be specified. One option will be to select the largest recruiters into the trial. Consistency of medical resource use across centers and countries will be assessed. If related issues are detected, the use of medical resource use data may need to be restricted to a subset of centers, with an implication of increased statistical uncertainty. If the recording of medical resource use data showed to be only partially feasible (e.g. due to issues with patient compliance), health economic methodology would allow to implement approximate solutions; related limitations of validity would be discussed. Depending on the clinical results of the trial (e.g. if no clinical advantage palbociclib is demonstrated), some of the planned analyses may become obsolete.
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13.4.3 general anxiety disorder-7 (gad-7)

The General Anxiety Disorder-7 (GAD-7) will be collected with baseline and to aid in the identification and severity assessment of potential mood alterations. The GAD-7 are validated (Kroenke 2001, Spitzer 2006, Spitzer 1999), patient self-administered questionnaires developed for use in clinical practices. The GAD-7 is a one-dimensional questionnaire consisting of 7 questions. Patients are asked to indicate how often, over the past 2 weeks, they have been bothered by each of the seven core symptoms of generalized anxiety disorder as referenced in the DSM IV. Response options are ''not at all,'' ''several days,'' ''more than half the days,'' and ''nearly every day,'' scored as 0, 1, 2, and 3, respectively. The sum of all seven questions calculate the total GAD-7 score. Therefore, GAD-7 scores range from 0 to 21.  
Toxicity grading based on anxiety questionnaire scores  
| GD-7 (anxiety)   |          |         |
|------------------|----------|---------|
| Score            | Severity | Grading |
| 0-4              | None     | Normal  |
| 5-9              | Mild     | Grade 1 |
| 10-14            | Moderate | Grade 2 |
| ≥ 15             | Severe   | Grade 3 |
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score severity grading

| More                                              |          |        |    |    |
|---------------------------------------------------|----------|--------|----|----|
| Over the last 2 weeks, how often have you         | Not      | Nearly |    |    |
| Several                                           |          |        |    |    |
| been bothered by the following problems?          | than     |        |    |    |
| at                                                | every    |        |    |    |
| days                                              | half the |        |    |    |
| (Use "✔" to indicate your answer")                | all      | day    |    |    |
| days                                              |          |        |    |    |
| 1. Feeling nervous, anxious or on edge            | 0        | 1      | 2  | 3  |
| 2. Not being able to stop or control worrying     | 2        | 3      |    |    |
| 0                                                 | 1        |        |    |    |
| 3. Worrying too much about different things       | 0        | 2      | 3  |    |
| 1                                                 |          |        |    |    |
| 4. Trouble relaxing                               | 0        | 1      | 2  | 3  |
| 5. Being so restless that it is hard to sit still | o        | 1      | 2  | 3  |
| 6. Becoming easily annoyed or irritable           | 0        | 1      | 2  | 3  |
| 7. Feeling afraid as if something awful might     |          |        |    |    |
| happen                                            | 0        | 1      | 2  | 3  |
| For office coding: Total Score T                  | +        | +      | )  |    |
| =                                                 |          |        |    |    |  
*
Note:
The grading guidance be above may overruled at the discretion of a psychiatrist performing a consult.
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13.5 collection of biomaterials

Collection of formalin-fixed paraffin-embedded (FFPE) tumor tissue block from diagnostic core before start of chemotherapy and at surgery is mandatory. For central review at least 3 cores should be sent to the central pathology laboratory.  
One serum sample (out of 10 mL full blood) should be collected before start study treatment, at day 1 of the 7th cycle and at EOT (mandatory). Serum preparation should be performed as follows: collect 10 ml of peripheral blood in an S-Monovette (Sarstedt; monovette contains granula-bound coagulation agent), invert the tube to mix blood with coagulation agent and leave the sample 20 to 30 min at room temperature. After 20 to 30 min, the clotting of the blood is completed. Please centrifuge the sample for 15 min at 1500g and transfer the clear or yellow supernatant (upper phase/layer =
serum) into the 5 fresh tubes supplied. For tube labeling use adhesive labels provided with the lab kit. The serum samples must be frozen immediately at -20°C to -80°C. The samples frozen at -20°C to -80°C will be stored at the center. Samples will be picked up by a courier service.  
For plasma isolation 10ml of peripheral blood should be collected before start of study treatment, at day 1 of the 7th cycle and at EOT (mandatory). Peripheral blood will be sampled in an EDTA test tube and inverted for several times (5x). After centrifugation for 15 min at 1500g, the plasma can be collected from the supernatant and transferred into 5 fresh tubes. The samples must be frozen immediately at -20oC to -80oC and stored at the center until pick up by a courier service.  
One full blood sample (10 mL) of each patient will be collected preferably before start of study treatment (but can be also collected later) for SNP analysis (mandatory). The samples must be stored frozen at -20°C to -80°C at the center.  
Additional optional full blood sample (20 mL) will be collected before study treatment, at day 1 of the 7th cycle, at EOT and within 4 weeks after confirmation of progressive disease for the analysis circulating DNA (ctDNA).  
All technical and transportation devices (material for blood and serum sampling and packaging) will be provided by the GBG.
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13.6 biomarker analysis

Specific information and guideline on the detection of centrally assessed biomarkers before randomization or exploratory detected biomarkers after randomization are available upon request if required.
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13.7 end of treatment (eot)

The regular end of treatment for a patient is defined as 30 days after the end of the last capsule intake of palbociclib/placebo.
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13.8 follow-up period

Post-Treatment Follow-Up will be assessed according to ASCO-guidelines 122. Patients who discontinue study treatment for any reason other than objective relapse of disease or death will continue to have tumor assessments performed according to ASCO guidelines. See Tumor Assessment Requirements Flowchart for details. For patients who discontinue study treatment due to objective disease progression, survival data (i.e., patient status, onset and type of new anticancer therapy will still be collected approximately every 6 months (+/- 14 days) from the last dose of study treatment. Following the EoT visit, clinical disease assessment will be performed (in patients who have not experienced an iDFS event), and survival status will be collected in all patients (telephone contact or contact in writing with the patient or treating physician is acceptable) twice a year after the last dose of study treatment. Imaging tests have to be performed according to national guidelines for follow up and in case of symptoms suspicious for locoregional or distant relapse but at leaset once a year. Information will be collected on date and site of first non-invasive local recurrence, first invasive local recurrence, first contralateral breast recurrence, first regional recurrence, first distant recurrence, first palliative endocrine, first palliative cytotoxic (+/- targeted) treatment, date and cause of deaths as well as date and diagnosis of secondary malignancies, as well as every serious adverse reaction related to palbociclib/placebo. In case of disease progression it is recommended to confirm diagnosis by histological examination. A FFPE tumor tissue block from the metastatic lesion should be provided to GBG. Newly occurred serious adverse reactions (SARs) have to be documented on the SAE form and have to be sent to the Sponsor within 24 h after becoming aware of the event. Participating patients are recommended to be registered in the GBG self-reporting registry (if allowed by national regulations) that will allow further follow up and long-term efficacy evaluations beyond the end of the study.
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13.9 treatment discontinuation of individual

If a patient shows one of the following reasons palbociclib/placebo treatment has to be discontinued from study treatment:  
Detection of local, regional or distant invasive recurrence breast cancer, Unacceptable toxicity according to investigators decision Detection of any secondary malignancy Patients request or non-compliance.
The reason and date of discontinuation for all patients will be documented on the Case Report Form (e.g. progressive disease, death, adverse event, withdrawal of consent, lost to follow-up, etc.). The investigator will attempt to complete all discharge procedures at the time of discontinuation of palbociclib/placebo treatment. The procedures have to be documented in the CRF.
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13.10 end of study (eos)

No interventional procedures after final iDFS (and interim OS) analysis. All patients will be contacted by telephone before the database lock. The end of study is defined with evaluation of the primary objective. Planned end of study is QIII 2020. Survival and Relapse assessments will continue post study.  
13.10.2 *Premature Termination of Study* The study may be terminated prematurely for safety reasons, slow accrual, or upcoming new data impairing the relevance of the study objective by the GBG Forschungs GmbH as the sponsor or the protocol board. The Independent Data Monitoring Committee will provide advice. The sponsor is allowed to close the trial for any reason at any time. A decision to prematurely terminate the study is binding to all investigators of all study sites. Responsible ethics committees and regulatory authorities will be informed about the reason(s) and time of termination according to the applicable laws and regulations. If the study is terminated prematurely, all investigators have to inform their patients and take care of appropriate follow-up and further treatment of the patients.
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13.10.3 premature termination of study

The GBG Forschungs GmbH as the sponsor reserves the right to discontinue the study at a particular study site at any time. The reasons will be discussed with the investigator. The GBG Forschungs GmbH may terminate this study in one particular study site for one of the following reasons: Non-compliance with GCP and/or regulatory requirements. Insufficient number of recruited patients. False documentation in the CRF due to carelessness or deliberately. Inadequate co-operation with GBG Forschungs GmbH or its representatives. The Investigator request to close of his/her study site. If the study is prematurely terminated in a study site, the responsible investigators have to inform their patients and take care of appropriate follow-up and further treatment of the patients. The responsible ethics committee and regulatory authorities will be informed about the reason and time of termination according to the applicable laws and regulations.
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14. data quality assurance 14.1

Data management and monitoring will be carried out by the GBG Forschungs GmbH. Data management refers to eCRF design, database and application hosting and data validation. All CRF data will be entered into the trial database using the MedCODES® application, which will perform automated plausibility and value range checks before committing the data to the database. As soon as a Case Report Form is committed to the database it can no longer be edited or deleted by the investigator. Committed data, other than baseline, can be changed by the investigator as long as it is not monitored. Any changes made by the investigator are reviewed by data management. Once data is monitored, the investigator is not allowed to make any changes without a query. CRF data will be reviewed by a data entry clerk and queries created for every data field that do not match the trial guidelines. These queries will be forwarded to be resolved (within the MedCODES® application) to the center. Resolved queries will be checked by a data entry clerk and closed or if necessary requeried. The patient baseline and registration eCRFs will be checked for eligibility manually and using programmed checks. Visual and computerized methods of data validation are applied in order to ensure accurate, consistent and reliable data for the subsequent statistical analysis. These procedures detect out-of-range values, contradictory data, and abnormal changes over time, and possible protocol violations. As soon as all data is stored in the trial database and all queries are closed, patient data entry in MedCODES® is stopped, all patients (CRF) are set to "End Status", any data changes in MedCODES® are stopped. The database is locked to any kind of manipulation and then handed over to the Statistics Department. Prior to statistical analysis, concomitant medications entered into the database will be coded using the WHO Drug Dictionary,. Medical history, adverse events, cause of death, antineoplastic surgeries, procedures or nondrug therapies will be coded using the Medical dictionary for regulatory activities (MedDRA) terminology.
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pseudonymisation

In order to keep patient data confidential and for safeguarding the privileged doctor patient relationship, each participating patient will be assigned a unique GBG reference number. This reference number consists of a trial specific prefix and a unique randomization number from a prepared block of numbers. The pseudonym, instead of the true patient identity, is used in all communication between the trial site and the GBG Forschungs GmbH.
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user access control

Every user is provided with a personal user name and password. Every user is assigned to a user group, which represents their role in the MedCODES® application. Access control is based on user name, group and place of work (e.g. center or the GBG Headquarters). Users can only access those datasets necessary for them to fulfill their role in the CRF workflow ("need to know basis").
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14.2 monitoring and source data

All source data verification (SDV) is conducted according to GBG monitoring standard operations procedures (SOP). The investigator must permit the monitor, the sponsor's internal auditors and representatives from the regulatory authorities to inspect all study-related documents and pertinent hospital or medical records for confirmation of data contained within the CRFs. After logging in to the MedCODES® application, the monitor chooses a trial center (their current location) and a trial. Source data verification is then performed by consulting the patient file. In case of discrepancies the monitor creates queries which must be solved by the center.
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14.3 computer systems

All data are collected and stored using the MedCODES® application. The MedCODES® application is based on an Apache 2.4 / PHP 5.5 application server and a MySQL 5.6 database backend. Due to the nature of the MedCODES® application, the trial centers must be equipped with computer terminals with online access and current versions of Microsoft Internet Explorer, Mozilla Firefox or Apple Safari. JavaScript execution must be enabled with the web browser.
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15. statistics

The statistical analysis of the present study is performed in accordance with the principles stated in the Consensus Guideline E9 (Statistical Principles for Clinical Trials) of the International Conference on Harmonization (ICH).
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15.1 disposition of patient

Screened patients are defined as any patient who met the inclusion criteria and signed the informed consent. Randomized patients consist of all patients, who have been allocated to treatment with palbociclib or placebo of palbociclib based on the randomization process. It will consist of all patients with randomization number and recorded in the computerized system database and regardless of whether the treatment was used or not. Patients treated without being randomized will not be considered as randomized and will not be included in any population. For any patient randomized more than once, only the data associated with the first randomization will be used in any analysis population. The safety experience associated with any later randomization will be assessed separately. The safety experience of patients treated and not randomized will be reported separately, and these patients will not be in the All randomized and treated patients **(SP)** population. For patient study status, the total number of patients for each one of the following categories will be presented: Screened patients Randomized patients Randomized and treated patients Patients who discontinued study treatment by main reason for permanent treatment discontinuation.
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15.2 analysis populations

Randomized patients consist of all patients who have given their written informed consent and for whom there is confirmation of successful allocation of a randomization number through the web-based data collection interface. Intent to treat (ITT) efficacy population: all randomized patients (including those not starting treatment). This population provides the basis for the main efficacy analyses. Patients will be analyzed according to the treatment group they were randomized to. Evaluable patients (EP) efficacy population: subset of the ITT population, this population includes all treated patients with at least 80% of the planned number of doses of palbociclib/placebo. This population is for supportive efficacy analyses. Patients will be analyzed according to the treatment group they were randomized to. All randomized and treated patients safety (SP) population: all randomized patients (excluding those not starting treatment). Patients will be analyzed according to the treatment actually received. This is the only population for all safety analyses. In addition: Not randomized but treated patients will not be part of the safety population, but their safety data will be presented separately. Randomized patients for whom it is unclear whether they took the study medication will be included in the safety population as randomized. For patients receiving palbociclib and placebo during the trial, the treatment group allocation for as-treated analysis will be the palbociclib arm. Translational Research sub-study population: a subset of randomized and treated patients with available molecular-biological parameters before first study drug administration. All analyses using this population will be based on the treatment received. Major protocol violations according to the sponsor guideline are applicable and made available to sites for referencing Major protocol violations leading to exclusions from the available subset will be defined in the statistical analysis plan.
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15.3 sample size determination

Sample size was determined based on the analysis of the primary endpoint, iDFS. The sample size was calculated based on the following assumptions:  
Time to iDFS event follows an exponential distribution. 3-year iDFS rates for placebo arm and for the palbociclib arm are 0.77 and 0.836, respectively. The rates are equivalent to a HR (palbociclib/ placebo) of 0.685.
Based on these assumptions, a minimal number of 255 iDFS events will be required to give 85% power to detect a HR (palbociclib/ placebo) of 0.685 at the 0.05 significance level (2sided) on iDFS using a stratified log-rank test. Assuming time to dropout follows exponential distribution with a common hazard rate (0.04383 subjects per year) for both arms. Applying a 1:1 randomization and a non-uniform enrollment rate of 40 subjects per month at the peak, it was estimated that 1100 subjects will need to be enrolled. The total enrollment period is estimated to be 3.6 years. The final analysis will take place when 255 iDFS events are observed which is estimated to occur about 6.5 years after first patient. Power calculation is also done for the secondary endpoint of iDFS excluding second primary of non-breast cancer. Assuming that not more than 15% of iDFS events are second primary of non-breast cancer, there is 79% power to detect statistical significance between the 2 arms with a 2-sided significance level of 0.05.
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rationale of assumptions on sample

Estimation of 3-year iDFS rate was performed on the basis of a metadatabase containing 2659 HR+/Her2- patients who received neoadjuvant therapy (about 18-24 weeks), surgery (average period of around 6 weeks after last cycle of chemotherapy) and radiation (about 6 weeks). In the PENELOPEBstudy patients will be randomized after radiation or rehabilitation, if applicable, which is estimated to be approximately 9 months after start of neoadjuvant chemotherapy. Given these assumptions a 3-year iDFS rate of 0.77 was estimated for the control arm of patients with CPS-EG score >= 3 or CPS-EG score = 2 and ypN+. The assumption of exponential distribution on time-to-iDFS event for the control arm may affect the duration of study. This assumption cannot be assessed due to lack of patient-level data on surgery date.
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15.4 treatment stratification

Randomization will be stratified using block randomization by:
histological lymph node status at surgery (ypN 0-1 vs ypN2-3)
age at first diagnosis (<=50 vs >50 yrs)
Ki-67 measured (>15% vs <=15%)
global region of participating site (Asian vs non Asian)
risk status (CPS-EG Score >=3 vs CPS-EG Score = 2 and ypN+)
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15.5 statistical analyses 15.5.1 analyses

Primary efficacy endpoint is invasive disease-free survival (iDFS) which is defined according to Hudis as the time period between randomization and first event (ipsi- or contralateral invasive in-breast or loco-regional recurrence, distant recurrence, death from breast cancer, death from non-breast cancer cause, death from unknown cause, invasive contralateral breast cancer, second primary invasive cancer (non-breast)). The primary analysis for iDFS will be the comparison between treatment arms in the ITT population with a 2-sided stratified log-rank test at the overall significance level 0.05. The factors used in the stratified log-rank test will be histological lymphnode status at surgery (ypN 0-1 vs ypN 2-3), age at first diagnosis (<=50 vs >50 yrs), Ki-67 (>15% vs <=15%), and risk status (CPS-EG score >= 3 vs. CPS-EG score = 2 and ypN+). Global region will not be included. The nominal significance level for the final analysis of iDFS is 0.0463 because of the two planned interim analyses. In addition, iDFS curve will be estimated in each treatment arm using the Kaplan-Meier method. Cox regression model stratified by the factors used in the stratified log-rank test will be used to estimate the treatment hazard ratio. The iDFS rates at 3 years will also be estimated for each arm.
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final efficacy analysis

Final analysis of the primary endpoint and secondary efficacy endpoints (except for OS) will be conducted when the target number of iDFS events for the final analysis have been observed. The minimum number of iDFS events is 255. Due to the adaptive design of the trial this number can be increased to a maximum of 290 iDFS events depending on the result of the efficacy interim analysis. The final analysis is estimated to be performed approximately 6.5 years after first patient randomized.
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analysis of secondary efficacy endpoints

Secondary efficacy endpoints are:
iDFS excluding second primary of non-breast cancers overall survival (OS)
distant disease free survival (DDFS)
locoregional recurrences-free (LRRFS) survival iDFS per treatment group in patients with luminal-B tumors as determined by PAM50.  
Overall survival (OS) is defined as the time period between randomization and death of any cause. An interim OS analysis will be conducted at the time of final iDFS analysis and final OS analysis will be conducted at a later time after the final analysis for iDFS endpoint. Details will be described in Statistical Analysis Plan.  
Locoregional recurrences-free survival (LRRFS) is defined as the time period between randomization and diagnosis of any loco-regional (ipsilateral breast (invasive or DCIS), local/regional lymph nodes) recurrence of disease, any invasive contralateral breast cancer or death due to any cause whichever occurs first. Distant disease free survival (DDFS) is defined as the time period between randomization and diagnosis of any distant recurrence of disease, any second primary invasive cancer (non-breast) or death due to any cause whichever occurs first. LRRFS and DDFS will be analyzed at the time of final iDFS analysis. Time-to-event curves will be estimated using the Kaplan-Meier method and compared between 2 arms with a two-sided stratified log-rank test. Univariate Cox-proportional hazards model will be used to calculate hazard ratios for the overall population as well as for subgroups predefined by the stratification factors. Multivariate Cox-proportional hazards model will be performed for event free data, to adjust for all stratification factors, as well as clinical stage before neoadjuvant chemotherapy, pathological stage after neoadjuvant chemotherapy, and grade.
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analysis of other endpoints

Tolerability and Safety: Descriptive statistics for the 2 treatments will be given on the number of patients whose treatment had to be reduced, delayed or permanently stopped. The reason for termination includes aspects of efficacy (e.g. termination due to tumor progression), safety (e.g. termination due to adverse events) and compliance (e.g. termination due to patient's withdrawal of consent). Reasons for premature termination will be categorized according to the main reason and will be presented in frequency tables. Safety by toxicity grades will be defined by the NCI-CTCAE v4.0. Patients reported outcome and health economic analyses: data will be captured using the following questionnaires: the EORTC QLQ-C30, the breast cancer module QLQ-BR23, QLQ fatigue, GAD7 patient self-rating mood scale and the EQ-5d instruments. Summary statistics (mean, standard deviation, median, 25th and 75th percentiles, and range) of absolute scores and their changes from baseline will be summarized at each assessment time point for the 2 treatment arms. Only patients with a baseline assessment and at least one post-baseline assessment will be included in this analysis. Repeated-measures mixed-effects models will be used to explore the treatment effect changes over time and treatment-by-time interaction. Translational research: Exploratory analyses will be performed to identify possible relationships between biomarkers and iDFS and OS. Patients with missing biomarker data will not be included in the respective analysis 15.5.2 *Extent of study treatment exposure and compliance* The extent of study treatment exposure and compliance will be assessed and summarized by actual treatment received within the *All randomized and treated patients population.*
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15.5.3 extent of investigational medicinal

Duration of palbociclib/Placebo exposure is defined as: last dose date - first dose date + 7 days regardless of unplanned intermittent discontinuations. The overall extent of exposure will be assessed for each patient as:  
Duration of exposure Total number of cycles (K)
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dose information

The actual dose received Cumulative dose (mg) defined at cycle k as the sum of all doses from cycle 1 to and including cycle k, where k is based on Investigator's report.  
The actual dose intensity (ADI) is defined as the cumulative dose divided by the number of weeks on treatment (mg/week) including delays. The relative dose intensity (RDI) is defined as the ratio of the actual dose intensity to the planned dose intensity. RDI, as an indicator of the feasibility of the chosen schedule of administration. Dose reduction and reason for dose reduction: Dose reduction will be derived using the definition provided in the protocol compared to the previous dose. For the second and subsequent cycles, a dose is deemed to have been reduced if the dose level a patient receives is lower than the previous actual dose level. Dose delays: A cycle is deemed to have been delayed if start date of the current cycle - start date of previous cycle > 3.
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15.5.4 analysis of adverse events

The summary of safety results will be presented by treatment group. All safety analyses will be performed on the randomized and treated patient populations. The grade will be taken into account in the summaries. For patients with multiple occurrences of the same event, the maximum grade is used. Sorting within tables should ensure same presentation for the set of all AEs within the observation period. Adverse event incidence tables will be presented by system organ class (SOC) (sorted by internationally agreed order), high-level group term (HLGT), high level term (HLT) and preferred term (PT) sorted in alphabetical order for each treatment group, the number (n) and percentage (%) of patients experiencing an AE. Multiple occurrences of the same event in the same patient will be counted only once in the tables within a treatment phase. The denominator for computation of percentages is the All randomized and treated patients population within each treatment group.
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15.5.5 analyses of laboratory variables

The baseline value is defined as the last available value before randomization. Hematological and clinical biochemistry toxicities will be assessed from laboratory test parameters. Each test result will be graded by NCI-common terminology criteria (version 4.0). The number of patients with abnormal laboratory tests at baseline (grade ≥1) will be presented by grade. The frequency of patients in each grade of laboratory test during treatment will be summarized. For patients with multiple occurrences of the same laboratory variable during the treatment, the maximum grade (worst) per patient will be used. When appropriate, the summary table will present the frequency of patients with any grade of abnormal laboratory tests and with grade 3-4 of abnormal laboratory tests. For the non-NCI gradable parameters, out-of-normal laboratory range value analyses will be performed.  
15.5.6 *Translational research analyses* The analyses will be defined in the separate Statistical Analysis Plan.
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15.5.7 interim analysis for safety

Safety interim analysis (SIA) reviewed by the IDMC have a special focus on safety and reasons for treatment discontinuations (including progressive disease) and are scheduled regarding the number of patients having completed 2 cycles of treatment or discontinued study treatment prematurely: after the first 25 patients, two more SIA after approximately further 50 patients each, then after further 50 patients and whenever the next 300 patients have completed 2 cycles or discontinued study treatment prematurely. SIA frequency may be adjusted due to the IDMCs recommendations. Ad-hoc IDMC meetings may also be held if a significant safety issue or issue deemed important for discussion arise on this or any other palbociclib study. After each meeting, the IDMC will advise the and the Sponsor's representative on the further conduct of the trial. In subsets of 24 at least evaluable patients each starting with the combination of palbociclib/placebo and tamoxifen, palbociclib and anastrozole, and palbociclib/placebo and goserelin and tamoxifen plasma PK samples will be collected to explore DDI between palbociclib and the combination drug. No significant DDI between Palbociclib and Letrozole were observed and no samples need to be collected to explore DDI for the Letrozole combination. A PK unblinding plan will allow for review of the PK data prior to completion of the trial without unblinding the trial. The PK unblinding will be applied once all planned PK samples from at least 24 evaluable patients of each assessed combination have been collected. PK parameter analysis will proceed according to the PK analysis plan with results provided to the IDMC for review. The study will continue while PK analysis and data review are ongoing. Details of the analysis (along with other safety data included in the early safety review) will be provided in the IDMC charter.
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15.5.8 interim analysis for efficacy

Two efficacy interim analyses (EIA) will be performed in the study. O'Brien - Fleming type stopping boundaries based on the Lan-DeMets spending function will be applied. Futility criteria are not used to calculate the nominal alphas (non-binding method) in order to control the overall Type-I-error.  
The objectives of the first EIA will be:
To re-estimate the sample size.  
To assess safety, including any unexpected toxicity.  
To allow for early stopping of the trial due to futility.
The objectives of the second EIA will be:  
To assess safety, including any unexpected toxicity.  
To allow for early stopping of the trial due to futility.  
To allow for early stopping of the trial due to overwhelming efficacy.
The first EIA was originally planned to be performed after the first 85 events (1/3 of the total events) have occurred or prior to the last patient randomized to allow for the continuation of the enrollment in case of SSR. According to an estimation in February 2017 the planned fraction of events would have occurred one month after last patient randomized. It was estimated that approximately two months are required to perform the EIA and to implement potential changes. Therefore, the EIA is scheduled to be performed in April 2017. The second EIA will be performed on the basis of 2/3 of the total events. It was estimated that 2/3 of 255 events (170 events) will have occurred <5 years from the first patient randomized. In case of sample size re-estimation, 2/3 of 290 events (194 events) must have been documented, which is estimated to have occurred 5.1 years from first patient randomized. The unblinded results of the EIA will be provided to the IDMC to receive recommendation regarding the efficacy interim analysis' objectives. All staff at GBG will remain blinded to the treatment allocation of the patients with exception of the independent statistician (unblinded statistician). The following table displays the decision rules regarding the objectives of the two EIA and the final analysis.  
| Number  of events     | Futility   | Sample size   | Efficacy  (-level)   |     |         |
|-----------------------|------------|---------------|-----------------------|-----|---------|
| min/max               | (HR)       | re-estimation |                       |     |         |
| 1 st EIA              | April 2017 | 67            | ≥1.0                  | Yes | <0.0002 |
| 2 nd EIA              | 2/3        | 170/194       | ≥0.90                 | No  | <0.0120 |
| FA*                   | 3/3        | 255/290       | N/A                   | N/A | <0.0463 |
| Time /                |            |               |                       |     |         |
| Information  Fraction |            |               |                       |     |         |
| Analysis              |            |               |                       |     |         |  
* Final Analysis The actual nominal  levels for the EIA and for the final analysis will depend on the fraction of total events occurred at the time of analysis, in order to control the overall type I error for the endpoint of iDFS.  
At EIA statistical hypothesis tests will be performed only for the primary efficacy parameter, iDFS. The secondary endpoint of iDFS excluding second primary of non-breast cancer will also be taken into consideration when performing sample size re-estimation (SSR). Cui, Hung and Wang method will be used for adaptive sample size modification. The decision about SSR will be made on the basis of the favorable zone concept by Mehta and Pocock. In case the conditional power calculated on the basis of the efficacy interim analysis' treatment effect fell in the favorable zone, increase of sample size to the maximum of 1250 patients and increase of the number of iDFS events to the maximum of 290 events is planned. The definition of the favorable zone is only laid down in the addendum to the IDMC charter and must be kept secret to avoid "reverse engineering" of the treatment effect.
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15.5.9 further analysis after the

Final survival will be analyzed 3 years after the final analysis on iDFS. Survival time in each treatment group will be estimated with the Kaplan-Meier product-limit method and will be reported together with the two-sided 95% confidence interval. The log-rank test will be performed to compare overall survival between the two treatment groups. The multivariate Cox proportional hazards model will be used for all efficacy endpoints in order to adjust for the major prognostic factors.
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16. independent data monitoring committee

In addition to the Protocol Board, the Independent Data Monitoring Committee (IDMC) of the GBG reviews and monitors the conduct of the trial. The IDMC consists of five members, three medical oncologists, one biometrician and a patients advocate. An ad hoc member experienced in CDK inhibitors will join each meeting via telefon conference support the IDMC. The members are independent of the trial and familiar with the methodology of oncology trials. They are aware of the dangers of conclusions based on immature data and have agreed with the design and the goals of this protocol. IDMC meetings are held at least every six months or as stated in section 15.5.4. The mission of the IDMC is to ensure the ethical conduct of the trial and to protect patients' safety interests in this study. The work of the IDMC will further specified in a separate charter.
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16.2 recommendations of the idmc

After each meeting, the IDMC will provide the Protocol Board with a written recommendation to either modify the trial (with reasons), or discontinue the trial (with reasons), or make the interim safety and efficacy results of the trial public (with reasons), or continue the trial unchanged. The final decision to amend the protocol or to discontinue the trial will be taken only by the International Steering Committee.
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16.3 early termination of the

Early termination of the trial will be considered by the International Steering Committee based on suggestion of the IDMC if less than 50 patients are recruited within 12 months, unsatisfactory toxicity or compliance.
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17. adverse events

Patients will be instructed by the investigator to report the occurrence of any adverse event.
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17.1 adverse event

An adverse event is any untoward medical occurrence in a patient administered a medicinal product and which does not necessarily have a causal relationship with this treatment. It also includes any undesirable clinical or laboratory changes which does not commonly occur in the patient. The study Investigator will rate the severity of each adverse event according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE Version 4.0) Hematological and clinical biochemistry toxicities will be assessed from laboratory test parameters. Each test result will be graded by NCI-common terminology criteria (version 4.0). (see section 15.5.5) . In case serum creatinine increase fulfills criteria to be reported as AE, the cause of the renal function impairment should be reported and the renal function impairment should be considered in the grade of the reported AE according to NCI-CTCAE version 4.0. If no cause can be identified and creatinine increase is considered serious or has an action taken on study treatment (dose reduction, dose delay, dose interruption or permanent discontinuation), the "creatinine increase" term should be preferred rather than the "renal failure" term. Any case of renal function impairment should be documented at least by a creatinine value and creatinine clearance. Tests will be repeated until recovery or stabilization and all results will be recorded in the e-CRF. Any complementary exams made to explore renal function or the cause of renal failure should be reported in the e-CRF and product contrast administration for CT scan should be recorded in concomitant medication.
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17.2 adverse reaction

Adverse reactions are all untoward and unintended responses to a medicinal product related to any dose administered. All expected Adverse Reactions are listed in the Investigator's Brochure (IB). If the nature or the severity of an adverse reaction is not consistent with the applicable product information, the adverse reaction is defined as unexpected. The basis for the decision is the current version of the corresponding reference document that has been submitted and approved by the competent authority and the ethics committees. Pfizer has agreed to inform GBG in an expedited manner of any Suspected, Unexpected and Serious Adverse Reactions (SUSAR) for the product, observed at any time after a subject has received the study drug. The impact of any report on the benefit/risk profile of the Pfizer product is evaluated as part of Pfizer procedures for safety evaluation, including the review and analysis of aggregate data for adverse events. Any safety concern identified as part of this review (including, but not limited to, an increase in the frequency of expected serious adverse effects, events in connection with the study execution or the development of the study drug that can potentially affect the safety of the affected persons, significant safety findings from animal or in vitro studies), as well as any appropriate action in response, will be promptly notified to GBG.
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17.3 serious adverse event/serious adverse

A serious adverse event (SAE) is any untoward medical occurrence or effect that at any dose results in death, is life-threatening, requires or prolongs hospitalization, results in persistent or significant disability or incapacity, a congenital anomaly or birth defect, or an important medical event from the time the patient signs the informed consent. Important medical events are those which may not be immediately life-threatening, but are clearly of major clinical significance. Pregnancy and AEs of special interest (see Section 17.5) must also be documented on the serious adverse event form. Exceptions: Progression of the malignancy during study (including signs and symptoms of progression) should not be reported as an SAE unless the outcome is fatal and death occurred before EOT. Thereafter death due to disease progression has not to be reported as SAE. Hospitalization due to signs and symptoms of disease progression should not be reported as an SAE. Hospitalization which is due solely to a planned study visit and without prolongation does not constitute a Serious Adverse Event.  
An overnight stay in the hospital that is only due to transportation, organization or accommodation problems and without medical background does not need to be handled/documented as a Serious Adverse Event.
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17.4 suspected unexpected serious adverse

All unexpected serious adverse events judged by either the investigator or the GBG Forschungs GmbH as the sponsor to have a reasonable suspected causal relationship to an investigational or an accompanying medicinal product qualify as suspected unexpected serious adverse reactions (SUSAR). Adverse event reporting, including suspected serious unexpected adverse reactions, will be carried out in accordance with applicable local regulations. All Suspected Serious Adverse Reactions (SAR) must be reported to the GBG Forschungs GmbH as the sponsor regardless of the time which has elapsed during the clinical trial (treatment and follow-up phase).
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17.5 adverse events of special

For AESIs the Sponsor will be informed immediately (ie, within 1 working day), as per the SAE notification instructions described in Section 17.7, even if not fulfilling a seriousness criterion, using the corresponding pages in the CRF (to be sent) or screens in the e-CRF.
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17.5.1 pregnancy

Pregnancy occurring in a female patient included in the clinical trial. Pregnancy will be recorded as an AESI with immediate notification in all cases. It will be qualified as an SAE only if it fulfills the SAE criteria.  
In the event of pregnancy, IMP must be discontinued.  
Follow-up of the pregnancy is mandatory until the outcome has been determined.
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17.5.2 relevant overdose with imp

A relevant overdose (accidental or intentional) with the IMP is an event suspected / identified by the Investigator or spontaneously notified by the patient and defined as the intake of more than 23 capsules during a cycle (28 days) or more than 2 capsules within 24h. It has to be reported within one working day as an AESI using the SAE reporting form.
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17.5.3 potential cases of drug-induced

Abnormal values in aspartate transaminase (AST) and/or alanine transaminase (ALT) concurrent with abnormal elevations in total bilirubin that meet the criteria outlined below in the absence of other causes of liver injury are considered potential cases of drug-induced liver injury (potential Hy's Law cases) and should always be considered important medical events. The threshold for laboratory abnormalities in the case of potential drug-induced liver injury depends on the subject's individual baseline values and underlying conditions. Subjects who present with the following laboratory abnormalities should be evaluated further to definitively determine the etiology of the abnormal laboratory values: Patients with AST or ALT and total bilirubin baseline values *within the normal range* who subsequently present with AST or ALT 3 times the upper limit of normal (X ULN) concurrent with a total bilirubin 2 X ULN with no evidence of hemolysis and an alkaline phosphatase 2 X ULN or not available.  
For patients with *preexisting* ALT OR AST OR total bilirubin values *above* the upper limit of normal, the following threshold values should be used in the definition mentioned above:
o For patients with pre-existing AST or ALT baseline values above the normal range: AST or ALT 2 times the baseline values and 3 X ULN, or 8 X ULN
(whichever is smaller).
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concurrent with

o For patients with pre-existing values of total bilirubin above the normal range:
Total bilirubin increased twice the baseline value.  
The subject should return to the investigational site and be evaluated as soon as possible, preferably within 48 hours from awareness of the abnormal results. This evaluation should include laboratory tests, detailed history and physical assessment. In addition to repeating AST and ALT, laboratory tests should include albumin, creatine kinase, total bilirubin, direct and indirect bilirubin, gamma-glutamyl transferase, prothrombin time (PT)/INR, and alkaline phosphatase. A detailed history, including relevant information, such as review of ethanol, acetaminophen, recreational drug and supplement consumption, family history, occupational exposure, sexual history, travel history, history of contact with a jaundiced subject, surgery, blood transfusion, history of liver or allergic disease, and work exposure, should be collected. Further testing for acute hepatitis A, B, or C infection and liver imaging (eg, biliary tract) may be warranted. All cases confirmed on repeat testing as meeting the laboratory criteria defined above, with no other cause for LFT abnormalities identified at the time should be considered potential Hy's Law cases irrespective of availability of all the results of the investigations performed to determine etiology of the abnormal LFTs. Such potential Hy's Law cases should be reported as SAEs.
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17.6 death on study

Any death occurring during the active treatment part of the study and within 30 days following the last treatment must be reported to the GBG Forschungs GmbH as the sponsor within 24 hours, regardless of the relation to study drug(s), and has to be reported on the death report form section of the CRF. The cause of death should be documented (cancer-related, treatment-related, cancer- and treatment-unrelated). Autopsy reports should be collected whenever possible and sent to the GBG Forschungs GmbH. Deaths that occur due to tumor progression do not have to be reported as a SAE unless they occurred before EOT. Deaths after the end of study which are considered to be related to study treatment have to be reported as SARs. To the extent feasible sufficient information including relevant laboratory values, ECG, scan, biopsy or autopsy results must be provided by the investigator in the SAE narrative (even if investigator determines the SAE is not related) so as to permit an independent causality assessment by a Health Authority.
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17.7 sae and aesi reporting

Refer to section 17.3 for the definition of a SAE and section 17.5 for definition of an AESI. All SAEs/AESI from the time the patient had the first dose of the investigational medicinal product (IMP) through 30 days following the last administration of IMP must be reported according to the procedure described below. All SAE regardless of timing must be reported, if considered related to study drug. Likewise, progression of a patient's underlying condition leading to one of the above should also not be reported as a serious adverse event, but documented as primary study endpoint. (See also Section 17.3). Address for reports on SAE/AESI (within 24 hours from documented awareness):  
| GBG Forschungs GmbH                                                                              | Via MedCODES                  |                      |
|--------------------------------------------------------------------------------------------------|-------------------------------|----------------------|
| Martin-Behaim-Straße 12                                                                          | Phone: +49 (0) 6102 / 7480-0  | or alternatively via |
| 63263 Neu-Isenburg                                                                               | Fax: + 49 (0) 6102 / 7480-440 |                      |
| Germany The GBG will report all SAEs and AESIs immediately t to the pharmaceutical manufacturer. |                               |                      |  
All SAEs and AESIs will be followed-up by the investigator until satisfactory resolution. Annually all SARs will be reported as the DSUR to the competent authorities and the leading ethics committee, including all SUSARs. Withdrawal from further treatment shall be at the discretion of the investigator.
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17.8 susar reporting

Expected serious adverse reactions are listed in the Investigator Brochure (IB). All serious unexpected adverse events judged by either the investigator or the GBG Forschungs GmbH as the sponsor will be reported in accordance with applicable local regulations.
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18. administrative execution 18.1 monitoring

On-site visits will be made before the study begins and at regular intervals during the study. Other forms of communication (e.g. by telephone, mail, fax etc.) may be used as needed to supplement visits. The monitor has the responsibility of reviewing the ongoing study with the investigator to verify adherence to the protocol and to deal with any problems if and when they arise. Special items monitored are: patient enrollment, completeness, exactness and plausibility of data entered on the CRFs, verification against source data and occurrence of Adverse Events. At all times, the confidentiality of study documents is maintained. Monitoring is performed by GBG Forschungs GmbH or designee. It is the responsibility of the investigator to ensure that, the dispensing and return/destruction of study medication on the drug accountability forms provided is documented correctly. The investigator should ensure that the investigational product use is documented in such a way as to ensure correct dosage. This documentation should confirm that each subject did receive the product dispensed for her and state the identity, including the dosage, of the product received. Drug reconciliation will be verified by a second responsible person at the close-out visit to the site by the study monitor. All discrepancies are accounted for and documented. The investigator agrees to allow the monitor access to all study materials needed for the monitor to properly review the study progress. The investigator (or deputy) agrees to assist the monitor in resolving any problem that may be detected during the monitoring visit.
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18.2 sponsor's responsibilities the gbg

agrees to provide the investigator with sufficient material and support to permit the investigator to conduct the study according to the agreed protocol.  
reserves the right to request the withdrawal of a patient due to protocol violations, administrative or other reasons.  
reserves the right to terminate the study prematurely due to persistent protocol violations, administrative or other reasons. Should this be necessary, the procedures will be arranged after review and after consultation by both parties to ensure protection of the patients' interests.
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18.3 investigator's responsibilities

The investigator agrees to conduct the study in accordance with the procedures and requirements laid out in this protocol. In particular, the investigator agrees to conduct the study in accordance with strict ethical principles. Any modification to the agreed protocol must be approved in writing by both GBG Forschungs GmbH as the sponsor and, if appropriate, the ethics committee(s) approving the original protocol before any modifications are put into effect. On receipt of study medication, the investigator (or deputy) will conduct an inventory of the supplies and complete a supplies receipt. The investigator will retain a copy of this receipt at the site and return the original receipt to the study monitor. It is the responsibility of the investigator to ensure completeness of the CRFs for each patient in the study, and when a patient completes the study, the investigator must (electronically) sign the complete CRFs for each patient. The investigator must comment on any missing, unused or spurious data on the appropriate CRF. In addition to the CRFs, the investigator will maintain adequate records that fully document the progress of the study. The investigator has to state that the patient has taken part in a study and record the study number in the patient's medical records. The exact dates of the beginning and the end of treatment should be given as well. Copies of these study records (and all study-related documents) shall be kept by the investigator for will 10 years after commercialization and till 2 years if development is halted. All documentation and materials provided by GBG Forschungs GmbH for this study are to be retained in a secure place and treated as confidential material.  
The investigator has the right to request termination of the study for administrative or other reasons. Should this be necessary and agreed upon, the procedures will be arranged after review and after consultation by both parties, to ensure protection of the patients' interests. By signing this document the investigator indicates that he/she has read the protocol, fully understands the requirements and agrees to abide by all protocol requirements. Further obligations of the investigator are agreed on in the investigator's contract with the GBG Forschungs GmbH as the sponsor.
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18.4 patient informed consent

Prior to the beginning of specific protocol procedures, the patient is informed about the nature of the study drug and is given pertinent information as to the intended purpose, possible benefits, and possible adverse experiences. The procedures and possible hazards to which the patient will be exposed are explained. Patient insurance for the compensation of patients for possible study-related injury is provided by the GBG Forschungs GmbH as the sponsor according to local law. An approved informed consent statement will then be read and signed by the patient, and, if required, a witness, and the investigator. The patient will be provided with a copy of the signed informed consent statement. The patient may withdraw from the study at any time without prejudicing future medical treatment. Verification of a signed informed consent statement will be noted on the patient's study Case Report Form. Patients are informed that pseudonymised data from their case may be stored electronically and that such data will not be revealed to any unauthorised third party. Data will be reviewed by the monitor, an independent auditor and possibly by representatives of regulatory authorities and/or ethics committees. The terms of the local data protection legislation will be applied as appropriate.
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18.5 confidential follow-up

The investigator will be responsible for retaining sufficient information about each patient (e.g. informed consent form, name, address, phone number, and identity in the study) so that regulatory agencies or the GBG Forschungs GmbH as the sponsor may access this information should the need to do so arise. These records should be retained in a confidential manner for as long as legally mandated according to local requirements.
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18.6 ethics and regulatory considerations

The study described in this protocol is conducted in compliance with the ICH guideline for Good Clinical Practice and applicable regulations in all aspects of preparation, monitoring, reporting, auditing, and archiving. The final approved protocol and the informed consent statement is reviewed by a properly constituted Ethics Committee (EC) / Institutional Review Board (IRB). The EC/IRB decision concerning the conduct of the study is made in writing to the investigator. The investigator or designee agrees to make required progress reports to the EC/IRB, as well as report any serious adverse reaction (SAR) and suspected unexpected serious adverse reaction (SUSAR). The investigator or designee also informs the EC/IRB of reports of serious adverse reactions (provided to him/her by the GBG Forschungs GmbH) in other clinical studies conducted with the study drug if deemed necessary by the GBG Forschungs GmbH as the sponsor. The EC/IRB must be informed by the sponsor of the termination of the study. The sponsor is responsible for notifying the regulatory authorities of the study.
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18.7 declaration of helsinki

This study is to be performed in accordance with ethical principles that have their origin in the Declaration of Helsinki and are consistent with ICH/Good Clinical Practice (Sommerset West, 1996), (Appendix 10).
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modification of the protocol

Any modifications to the protocol which may impact on the conduct of the study, on the potential benefit of the patient or may affect patient safety, including changes of study objectives, study design, patient population, sample sizes, study procedures, or significant administrative aspects, will require a formal amendment to the protocol. Such an amendment will be agreed upon by the Protocol Board, and approved by the EC/IRB prior to implementation, and reported to the health authorities in accordance with local regulations. Administrative changes of the protocol are minor corrections and/or clarifications that have no effect on the way the study is to be conducted. These administrative changes will be agreed upon by the Protocol Board and will be documented in a memorandum. The EC/IRB may be notified of administrative changes at the discretion of the investigator.
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18.8 study documents

All information concerning the study drug and trial conduction, such as scientific data and material not previously published are considered confidential and shall remain the sole property of GBG Forschungs GmbH. The investigator agrees to use the information provided for the conduct of this study only and to use it for no other purposes unless she/he obtains the written consent of the GBG
Forschungs GmbH as the sponsor.
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18.9 case report forms

All key study information must be recorded in the patient's hospital notes. Study procedures will be fully online documented on the electronic CRFs provided through the GBG own EDCSystem (electronic data capture) MedCODES. The investigator will be prompted with an interface to enter his/her login data to sign the document electronically according to the FDA regulatory known as "21 CFR Part 11". The CRFs, as well as the protocol, are confidential. The CRFs remain the property of the GBG Forschungs GmbH at all times. On the CRFs, patients should be identified by their patient number. Patients' data entries may only be made by the persons registered on the form "Delegation of responsibilities and signature list of investigators and medical staff". For details concerning the CRF submission process, please refer to the application manual and electronic training material.
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18.10 gcp documents

The following documents are collected from the investigator's site: Signed Investigator's Agreement, Curricula vitae of all investigators and medical staff, Name and address of the laboratories, List of laboratory reference ranges and a quality certificate, Form "Delegation of responsibilities and signature list of investigators and medical staff", Any other relevant GCP documents.
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18.11 archiving

After completing the study, the GBG Forschungs GmbH will retain all study documents for at least ten years after the completion of the study. The investigator shall arrange for the retention of the patient identification codes, patient files and other source data until at least ten years after the last approval of a marketing application in an ICH region and until there are no pending or contemplated marketing applications in an ICH region, or until at least two years have elapsed since the formal discontinuation of the clinical development of the product. These documents need to be retained for a longer period of time if required by the competent authorities or by agreement with the GBG Forschungs GmbH as the sponsor.  
Patient files and other source data shall be kept for the maximum period of time permitted by the hospital, institution or private practice. After completion of the study, all documents and data relating to the study will be kept in an orderly manner by the investigator in a secure study file. This file will be available for inspection by the sponsor or their representatives. Essential documents must be retained for 10 years after commercialization and till 2 years if development of palbociclib is halted.. The investigator will appoint individuals responsible for the storage of essential documents and access to the documents will be restricted to those people. Any alterations to essential documents must be traceable. The investigator must contact the sponsor before destroying any study-related documentation.
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18.12 use of information and

To allow for the use of the information derived from this clinical study and to ensure compliance to current regulations, the investigator is obliged to provide the sponsor with complete test results and all data obtained in this study. This information is only made available to physicians and to the competent authorities, unless the sponsor is under legal obligation to pass it on a third party. The final statistical trial report will be prepared by the responsible biostatistician and the final medical report by the coordinating investigator and the sponsor. A publication policy will describe the process of preparation of any publication as well as the selection of authors. No publication is allowed by individual investigators without approval by the ICS. The data are owned by GBG. However, GBG are only allowed to use these for any purposes after approval by International Principal Investigator.
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18.13 finance and insurance

Details on finance and insurance will be outlined in a separate agreement between the investigator and the sponsor.
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19. substudies 19.1 tbd 20.

I have read the protocol Phase III study evaluating palbociclib (PD-0332991), a CyclinDependent Kinase (CDK) 4/6 Inhibitor in patients with hormone-receptor-positive, HER2-normal primary breast cancer with high relapse risk after neoadjuvant chemotherapy
"PENELOPEB"
GBG-78 - **BIG 1-13**
EudraCT No.: 2013-001040-62 FDA IND: 123239 Protocol G (Version 11 - 9 th April 2019)
and agree to conduct the study in accordance with the current protocol.  
Principal Investigator's Name **(CAPITAL LETTERS )** Principal Investigator's Signature Date GBG Principal Investigators Site Number 21.
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appendix 1 cps-eg score /

| Point Assignments for the CPS + EG Staging System   | ANATOMIC STAGE/PROGNOSTIC GROUPS   |                                        |       |    |    |
|-----------------------------------------------------|------------------------------------|----------------------------------------|-------|----|----|
| Stage                                               | Points                             | Stage 0                                | Tis   | NO | MO |
| Clinical stage                                      | Stage IA                           | T1*                                    | NO    | MO |    |
| 0                                                   |                                    |                                        |       |    |    |
| l                                                   | Stage IB                           | TO                                     | N1mi  | MO |    |
| IA                                                  | 0                                  | T1*                                    | N1mi  | MO |    |
| Stage IIA                                           | TO                                 | N1**                                   | MO    |    |    |
| IB                                                  | 1                                  | T1                                     | N1**  | MO |    |
| IIA                                                 | 1                                  | T2                                     | NO    | MO |    |
| IIB                                                 | 2                                  | Stage IIB                              | T2    | N1 | MO |
| IC                                                  | 2                                  | T3                                     | NO    | MO |    |
| Stage IIIA                                          | TO                                 | N2                                     | MO    |    |    |
| Pathologic stage                                    | T1*                                | N2                                     | MO    |    |    |
| 0                                                   | 0                                  | T2                                     | N2    | MO |    |
| l                                                   | 0                                  | T3                                     | N1    | MO |    |
| IA                                                  | 1                                  | T3                                     | N2    | MO |    |
| Stage IIIB                                          | T4                                 | NO                                     | MO    |    |    |
| IB                                                  | 1                                  | T4                                     | N1    | MO |    |
| IIA                                                 | 1                                  | T4                                     | N2    | MO |    |
| IB                                                  | 1                                  | Stage IIIC                             | Any T | N3 | MO |
| IIC                                                 | 2                                  | * T1 includes T1mi.                    |       |    |    |
| Tumor marker                                        | **                                 | TO and T1 tumors with nodal            |       |    |    |
| ER negative                                         | 1                                  | micrometastases only are excluded from |       |    |    |
| Nuclear grade 3                                     | 1                                  | Stage IIA and are classified Stage IB. |       |    |    |  
  
Abbreviations: CPS + EG, clinical-pathologic staging system incorporating ER-negative disease and nuclear grade 3 tumor pathology; ER,
estrogen receptor.
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21.2 appendix 2 eastern cooperative

| Description                                                                                                                                        | Grade   |
|----------------------------------------------------------------------------------------------------------------------------------------------------|---------|
| Fully active, able to carry on all pre-disease performance  without restriction.                                                                   | 0       |
| Restricted in physically strenuous activity, but ambulatory  and able to carry out work of a light or sedentary nature, ie,                        | 1       |
| light house work, office work. Ambulatory and capable of all self-care but unable to carry  out any work activities. Up and about more than 50% of | 2       |
| waking hours. Capable of only limited self-care, confined to bed or chair  more than 50% of waking hours.                                          | 3       |
| Completely disabled. Cannot carry on any self-care.  Totally confined to bed or chair.                                                             | 4       |
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21.3 appendix 3 list of

The concurrent use of CYP3A inhibitors, including amprenavir, atazanavir, boceprevir, clarithromycin, conivaptan, delavirdine, diltiazem, erythromycin, fosamprenavir, indinavir, itraconazole, ketoconazole, lopinavir, mibefradil, miconazole, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, verapamil, voriconazole, and grapefruit, grapefruit juice or any product containing grapefruit, are not allowed in the study. The concurrent use of CYP3A inducers, including carbamazepine, felbamate, nevirapine, phenobarbital, phenytoin, primidone, rifabutin, rifampin, rifapentin, and St. John's wort, are not allowed in the study. Please refer additionally to P450 Drug Interaction Table from Indiana University department of medicine: http://medicine.iupui.edu/clinpharm/ddis/main-table
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21.4 appendix 4 list with

No longer applicable.  
Appendix 5a and Appendix5b:EORTC OLQ-30 to be used in combination with 21.5 Cancer Related Fatigue: EORTC QLQ-FA13 http://groups.eortc.be/gol/eortc-glg-c30 A
EORTC QLQ-C30 (version 3)
We are interested in some things about you and your health. Please answer all of the questions yourself by circling the number that best applies to you. There are no "right" or "wrong" suswers. The information that you  
  
  
Cancer Related Fatigue: EORTC QLQ-FA13  will be used http://groups.eortc.be/gol/cancerrelated-fatigue-eortc-glg-fa13
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appendix 6 eortc qlq br-23

| you have experienced these symptoms or problems during the past week.   |                                                      |                                   |       |      |    |    |
|-------------------------------------------------------------------------|------------------------------------------------------|-----------------------------------|-------|------|----|----|
| During the past week:                                                   | Not at                                               | Quite                             |       |      |    |    |
| A                                                                       | Very                                                 |                                   |       |      |    |    |
| AI                                                                      | Little                                               | a Bit                             | Much  |      |    |    |
| Did you have a dry mouth?                                               |                                                      |                                   |       |      |    |    |
| 31.                                                                     | l                                                    | 2                                 | 3     | 4    |    |    |
| drink taste different than usual?                                       |                                                      |                                   |       |      |    |    |
| 32.                                                                     | Did food an                                          | l                                 | 2     | 3    | 4  |    |
| 3.33.                                                                   | W                                                    | eyes painful, imitated or watery? | l     | 2    | 3  | 4  |
| 34.                                                                     | Have you lost any have                               | l                                 | 2     | 3    | 4  |    |
| 35.                                                                     | Answer this odestion only if you had any hair loss:  |                                   |       |      |    |    |
| Were you upset by the loss of your hair!                                | l                                                    | 2                                 | 3     | 4    |    |    |
| 36.                                                                     | Did you feel ill or unwell?                          | l                                 | 2     | 3    | 4  |    |
| 37.                                                                     | Did you have hot flushes?                            |                                   | l     | 2    | 3  | 4  |
| 38.                                                                     | Did you have headaches?                              | l                                 | 2     | 3    | 4  |    |
| 39.                                                                     | Have you felt physically less attractive             |                                   |       |      |    |    |
| as a result of your disease or treatment?                               |                                                      | 1                                 | 2     | 3    | 4  |    |
| 40.                                                                     | Have you been feeling less feminine as a             | 2                                 | 3     | 4    |    |    |
| result of your disease or treatment?                                    |                                                      |                                   |       |      |    |    |
| 41.                                                                     | Did you find it difficult to look at yourself naked? | 2                                 | 3     | 4    |    |    |
| 42.                                                                     | Have you been dissatisfied with your body?           | 2                                 | 3     | 4    |    |    |
| 43.                                                                     | Were you worned about your health in the future?     | 2                                 | 3     | 4    |    |    |
| s                                                                       |                                                      |                                   |       |      |    |    |
| During the past four weeks:                                             | Not at                                               |                                   | Quite | Very |    |    |
| AII                                                                     | Little                                               | a Bit-                            | Aluch |      |    |    |
| 4.                                                                      | To what extent were you interested in sex?           | l                                 | 2     |      |    |    |
| 45.                                                                     | To what extent were you sexually active?             |                                   |       |      |    |    |
| (with or without intercourse)                                           | 1                                                    | 4                                 |       |      |    |    |
| 46.                                                                     | Answer this question only if you have been sexually  |                                   |       |      |    |    |
| active: To what extent was sex enjoyable for you?                       | l                                                    | 2                                 | 3     | 4    |    |    |
| Please go on to the next page                                           |                                                      |                                   |       |      |    |    |  
Patients sometimes report that they have the following symptoms or problems. Please indicate the extent to which you have experienced these symptoms or problems during the past week.  
  
©Copyright 1994 EORTC Quality of Life Group. All rights reserved. Version 1.0
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21.7 appendix 7 gad7

| More                                              |                                   |        |    |    |    |
|---------------------------------------------------|-----------------------------------|--------|----|----|----|
| Over the last 2 weeks, how often have you         | Not                               | Nearly |    |    |    |
| Several                                           | than                              |        |    |    |    |
| been bothered by the following problems?          | at                                | every  |    |    |    |
| days                                              | half the                          |        |    |    |    |
| (Use "✔" to indicate your answer")                | all                               | day    |    |    |    |
| dys                                               |                                   |        |    |    |    |
| 1. Feeling nervous, anxious or on edge            | o                                 | 1      | 2  | 3  |    |
| 2. Not being able to stop or control worrying     | o                                 | 1      | 2  | 3  |    |
| 3. Worrying too much about different things       | 0                                 | 1      | 2  | 3  |    |
| 2                                                 |                                   |        |    |    |    |
| 4. Trouble relaxing                               | 0                                 | 1      | 3  |    |    |
| 5. Being so restless that it is hard to sit still | 0                                 | 1      | 2  | 3  |    |
| 6. Becoming easily annoyed or irritable           | o                                 | 1      | 2  | 3  |    |
| 7. Feeling afraid as if something awful might     | o                                 | 1      | 2  | 3  |    |
| happen                                            | (For office coding: Total Score T | =      | +  | +  | l  |
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http//www.phqscreeners.com/overview.aspx 21.8 appendix 8 eq5d

http://www.euroqol.org/  
  
  
By placing a tick in one box in each group below, please indicate which statements best describe your own health state today.
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mobility

l have no problems in walking about l have some problems in walking about l am confined to bed Self-Care l have no problems with self-care l have some problems washing or dressing myself I am unable to wash or dress myself Usual Activities (e.g. work, study, housework, family or leisure activities)
l have no problems with performing my usual activities I have some problems with performing my usual activities l am unable to perform my usual activities Pain/Discomfort  
  
l have no pain or discomfort l have moderate pain or discomfort l have extreme pain or discomfort Anxiety/Depression l am not anxious or depressed l am moderately anxious or depressed l am extremely anxious or depressed  
  
  
  
D
o  
  
D
D
o D
□
UK (English) © 1990 EuroQol Group EQ-SD™ is a trade mark of the EuroQol Group Rest 100 To help people say how good or bad a health state is, we have drawn a scale (rather like a thermometer) on which the best state you can imagine is marked 100 and the worst state you can imagine is marked 0.  
We would like you to indicate on this scale how good or bad your own health is today, in your opinion.  
Please do this by drawing a line from the box below to whichever point on the scale indicates how good or bad your health state is today.  
  
|| Worst maginable health state UK (English) © 1990 EuroQol Group EQ-SD™ is a trade mark of the EuroQol Group Y OU OWN
health state  
today
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21.9 appendix 9 recist (response

Adapted from 123E.A. Eisenhauer, et al: New response evaluation criteria in solid tumours:
Revised RECIST guideline (version 1.1). European Journal of Cancer 45 (2009) 228–247
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categorizing lesions at baseline measurable

Lesions that can be accurately measured in at least one dimension. Lesions with longest diameter twice the slice thickness and at least 10 mm or greater when assessed by CT or MRI (slice thickness 5-8 mm). Lesions with longest diameter at least 20 mm when assessed by Chest X-ray. Superficial lesions with longest diameter 10 mm or greater when assessed by caliper. Malignant lymph nodes with the short axis 15 mm or greater when assessed by CT. NOTE: The shortest axis is used as the diameter for malignant lymph nodes, longest axis for all other measurable lesions.
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non-measurable disease

Non-measurable disease includes lesions too small to be considered measurable (including nodes with short axis between 10 and 14.9 mm) and truly non-measurable disease such as pleural or pericardial effusions, ascites, inflammatory breast disease, leptomeningeal disease, lymphangitic involvement of skin or lung, clinical lesions that cannot be accurately measured with calipers, abdominal masses identified by physical exam that are not measurable by reproducible imaging techniques. Bone disease: Bone disease is non-measurable with the exception of soft tissue components that can be evaluated by CT or MRI and meet the definition of measurability at baseline.  
Previous local treatment: A previously irradiated lesion (or lesion subjected to other local treatment) is non-measurable unless it has progressed since completion of treatment.
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normal sites

Cystic lesions: Simple cysts should not be considered as malignant lesions and should not be recorded either as target or non-target disease. Cystic lesions thought to represent cystic metastases can be measurable lesions, if they meet the specific definition above. If non-cystic lesions are also present, these are preferred as target lesions. Normal nodes: Nodes with short axis <10 mm are considered normal and should not be recorded or followed either as measurable or non-measurable disease. Recording Tumor Assessments All sites of disease must be assessed at baseline. Baseline assessments should be done as close as possible prior to study start. For an adequate baseline assessment, all required scans must be done within 28 days prior to treatment and all disease must be documented appropriately. If baseline assessment is inadequate, subsequent statuses generally should be indeterminate.
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target lesions

All measurable lesions up to a maximum of 2 lesions per organ, 5 lesions in total, representative of all involved organs, should be identified as target lesions at baseline. Target lesions should be selected on the basis of size (longest lesions) and suitability for accurate repeated measurements. Record the longest diameter for each lesion, except in the case of pathological lymph nodes for which the short axis should be recorded. The sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target lesions at baseline will be the basis for comparison to assessments performed on study. If two target lesions coalesce the measurement of the coalesced mass is used. If a large target lesion splits, the sum of the parts is used. Measurements for target lesions that become small should continue to be recorded. If a target lesion becomes too small to measure, 0 mm should be recorded if the lesion is considered to have disappeared; otherwise a default value of 5 mm should be recorded. NOTE: When nodal lesions decrease to <10 mm (normal), the actual measurement should still be recorded.
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non-target disease

All non-measurable disease is non-target. All measurable lesions not identified as target lesions are also included as non-target disease. Measurements are not required but rather assessments will be expressed as ABSENT, INDETERMINATE, PRESENT/NOT INCREASED, INCREASED. Multiple non-target lesions in one organ may be recorded as a single item on the case report form (eg, 'multiple enlarged pelvic lymph nodes' or 'multiple liver metastases').
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objective response status at each

Disease sites must be assessed using the same technique as baseline, including consistent administration of contrast and timing of scanning. If a change needs to be made the case must be discussed with the radiologist to determine if substitution is possible. If not, subsequent objective statuses are indeterminate.
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target disease

Complete Response (CR): Complete disappearance of all target lesions with the exception of nodal disease. All target nodes must decrease to normal size (short axis < 10 mm). All target lesions must be assessed. Partial Response (PR): Greater than or equal to 30% decrease under baseline of the sum of diameters of all target measurable lesions. The short diameter is used in the sum for target nodes, while the longest diameter is used in the sum for all other target lesions. All target lesions must be assessed. Stable: Does not qualify for CR, PR or Progression. All target lesions must be assessed. Stable can follow PR only in the rare case that the sum increases by less than 20% from the nadir, but enough that a previously documented 30% decrease no longer holds. Objective Progression (PD): 20% increase in the sum of diameters of target measurable lesions above the smallest sum observed (over baseline if no decrease in the sum is observed during therapy), with a minimum absolute increase of 5 mm. Indeterminate. Progression has not been documented, and one or more target measurable lesions have not been assessed, or assessment methods used were inconsistent with those used at baseline, or one or more target lesions cannot be measured accurately (eg, poorly visible unless due to being too small to measure), or one or more target lesions were excised or irradiated and have not reappeared or increased.
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non-target disease

CR: Disappearance of all non-target lesions and normalization of tumor marker levels. All lymph nodes must be 'normal' in size (<10 mm short axis). Non-CR/Non-PD: Persistence of any non-target lesions and/or tumor marker level above the normal limits. PD: Unequivocal progression of pre-existing lesions. Generally the overall tumor burden must increase sufficiently to merit discontinuation of therapy. In the presence of SD or PR in target disease, progression due to unequivocal increase in non-target disease should be rare. Indeterminate: Progression has not been determined and one or more non-target sites were not assessed or assessment methods were inconsistent with those used at baseline.
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new lesions

The appearance of any new unequivocal malignant lesion indicates PD. If a new lesion is equivocal, for example due to its small size, continued assessment will clarify the etiology. If repeat assessments confirm the lesion, then progression should be recorded on the date of the initial assessment. A lesion identified in an area not previously scanned will be considered a new lesion.
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supplemental investigations

If CR determination depends on a residual lesion that decreased in size but did not disappear completely, it is recommended the residual lesion be investigated with biopsy or fine needle aspirate. If no disease is identified, objective status is CR. If progression determination depends on a lesion with an increase possibly due to necrosis, the lesion may be investigated with biopsy or fine needle aspirate to clarify status.
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subjective progression

Patients requiring discontinuation of treatment without objective evidence of disease progression should not be reported as PD on tumor assessment CRFs. This should be indicated on the end of treatment CRF as off treatment due to Global Deterioration of Health Status. Every effort should be made to document objective progression even after discontinuation of treatment.  
| Table 1. Objective Response Status at each Evaluation   Target Lesions Non-target Disease       | New Lesions                               | Objective status   |               |
|-------------------------------------------------------------------------------------------------|-------------------------------------------|--------------------|---------------|
| CR                                                                                              | CR                                        | No                 | CR            |
| CR                                                                                              | Non-CR/Non-PD                             | No                 | PR            |
| CR                                                                                              | Indeterminate or Missing                  | No                 | PR            |
| PR                                                                                              | Non-CR/Non-PD,  Indeterminate, or Missing | No                 | PR            |
| SD                                                                                              | Non-CR/Non-PD,  Indeterminate, or Missing | No                 | Stable        |
| Indeterminate or Missing                                                                        | Non-PD                                    | No                 | Indeterminate |
| PD                                                                                              | Any                                       | Yes or No          | PD            |
| Any                                                                                             | PD                                        | Yes or No          | PD            |
| Any                                                                                             | Any                                       | Yes                | PD            |
| If the protocol allows enrollment of patients with only non-target disease, the following table |                                           |                    |               |  
Any Any Yes PD  
If the protocol allows enrollment of patients with only non-target disease, the following table will be used:  
Table 2. Objective Response Status at each Evaluation for Patients with Non-Target Disease Only  
| Non-target Disease      | New Lesions   | Objective status   |
|-------------------------|---------------|--------------------|
| CR                      | No            | CR                 |
| Non-CR/Non-PD           | No            | Non-CR/Non-PD      |
| Indeterminate           | No            | Indeterminate      |
| Unequivocal progression | Yes or No     | PD                 |
| Any                     | Yes           | PD                 |
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21.10 appendix 10 declaration of

Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964, and amended by the: 29th WMA General Assembly, Tokyo, Japan, October 1975 35th WMA General Assembly, Venice, Italy, October 1983 41st WMA General Assembly, Hong Kong, September 1989 48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996 52nd WMA General Assembly, Edinburgh, Scotland, October 2000 53th WMA General Assembly, Washington 2002 55th WMA General Assembly, Tokyo 2004 59th WMA General Assembly, Seoul, October 2008 64th WMA General Assembly, Fortaleza, Brazil, October 2013 Preamble 1. The World Medical Association (WMA) has developed the Declaration of Helsinki as a statement of ethical principles for medical research involving human subjects, including research on identifiable human material and data. The Declaration is intended to be read as a whole and each of its constituent paragraphs should be applied with consideration of all other relevant paragraphs. 2. Consistent with the mandate of the WMA, the Declaration is addressed primarily to physicians. The WMA encourages others who are involved in medical research involving human subjects to adopt these principles.  
General Principles 3. The Declaration of Geneva of the WMA binds the physician with the words, "The health of my patient will be my first consideration," and the International Code of Medical Ethics declares that, "A physician shall act in the patient's best interest when providing medical care." 4. It is the duty of the physician to promote and safeguard the health, well-being and rights of patients, including those who are involved in medical research. The physician's knowledge and conscience are dedicated to the fulfilment of this duty. 5. Medical progress is based on research that ultimately must include studies involving human subjects. 6. The primary purpose of medical research involving human subjects is to understand the causes, development and effects of diseases and improve preventive, diagnostic and therapeutic interventions (methods, procedures and treatments). Even the best proven interventions must be evaluated continually through research for their safety, effectiveness, efficiency, accessibility and quality. 7. Medical research is subject to ethical standards that promote and ensure respect for all human subjects and protect their health and rights. 8. While the primary purpose of medical research is to generate new knowledge, this goal can never take precedence over the rights and interests of individual research subjects. 9. It is the duty of physicians who are involved in medical research to protect the life, health, dignity, integrity, right to self-determination, privacy, and confidentiality of personal information of research subjects. The responsibility for the protection of research subjects must always rest with the physician or other health care professionals and never with the research subjects, even though they have given consent. 10. Physicians must consider the ethical, legal and regulatory norms and standards for research involving human subjects in their own countries as well as applicable international norms and standards. No national or international ethical, legal or regulatory requirement should reduce or eliminate any of the protections for research subjects set forth in this Declaration. 11. Medical research should be conducted in a manner that minimises possible harm to the environment. 12. Medical research involving human subjects must be conducted only by individuals with the appropriate ethics and scientific education, training and qualifications. Research on patients or healthy volunteers requires the supervision of a competent and appropriately qualified physician or other health care professional. 13. Groups that are underrepresented in medical research should be provided appropriate access to participation in research.  
14. Physicians who combine medical research with medical care should involve their patients in research only to the extent that this is justified by its potential preventive, diagnostic or therapeutic value and if the physician has good reason to believe that participation in the research study will not adversely affect the health of the patients who serve as research subjects. 15. Appropriate compensation and treatment for subjects who are harmed as a result of participating in research must be ensured.
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risks burdens and benefits

16. In medical practice and in medical research, most interventions involve risks and burdens. Medical research involving human subjects may only be conducted if the importance of the objective outweighs the risks and burdens to the research subjects.  
17. All medical research involving human subjects must be preceded by careful assessment of predictable risks and burdens to the individuals and groups involved in the research in comparison with foreseeable benefits to them and to other individuals or groups affected by the condition under investigation. Measures to minimise the risks must be implemented. The risks must be continuously monitored, assessed and documented by the researcher. 18. Physicians may not be involved in a research study involving human subjects unless they are confident that the risks have been adequately assessed and can be satisfactorily managed. When the risks are found to outweigh the potential benefits or when there is conclusive proof of definitive outcomes, physicians must assess whether to continue, modify or immediately stop the study. Vulnerable Groups and Individuals 19. Some groups and individuals are particularly vulnerable and may have an increased likelihood of being wronged or of incurring additional harm. All vulnerable groups and individuals should receive specifically considered protection. 20. Medical research with a vulnerable group is only justified if the research is responsive to the health needs or priorities of this group and the research cannot be carried out in a non-vulnerable group. In addition, this group should stand to benefit from the knowledge, practices or interventions that result from the research. Scientific Requirements and Research Protocols 21. Medical research involving human subjects must conform to generally accepted scientific principles, be based on a thorough knowledge of the scientific literature, other relevant sources of information, and adequate laboratory and, as appropriate, animal experimentation. The welfare of animals used for research must be respected. 22. The design and performance of each research study involving human subjects must be clearly described and justified in a research protocol. The protocol should contain a statement of the ethical considerations involved and should indicate how the principles in this Declaration have been addressed. The protocol should include information regarding funding, sponsors, institutional affiliations, potential conflicts of interest, incentives for subjects and information regarding provisions for treating and/or compensating subjects who are harmed as a consequence of participation in the research study.  
In clinical trials, the protocol must also describe appropriate arrangements for posttrial provisions.
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research ethics committees

23. The research protocol must be submitted for consideration, comment, guidance and approval to the concerned research ethics committee before the study begins. This committee must be transparent in its functioning, must be independent of the researcher, the sponsor and any other undue influence and must be duly qualified. It must take into consideration the laws and regulations of the country or countries in which the research is to be performed as well as applicable international norms and standards but these must not be allowed to reduce or eliminate any of the protections for research subjects set forth in this Declaration. The committee must have the right to monitor ongoing studies. The researcher must provide monitoring information to the committee, especially information about any serious adverse events. No amendment to the protocol may be made without consideration and approval by the committee. After the end of the study, the researchers must submit a final report to the committee containing a summary of the study's findings and conclusions. Privacy and Confidentiality 24. Every precaution must be taken to protect the privacy of research subjects and the confidentiality of their personal information.