2. approval signatures
informed consent

25. Participation by individuals capable of giving informed consent as subjects in medical research must be voluntary. Although it may be appropriate to consult family members or community leaders, no individual capable of giving informed consent may be enrolled in a research study unless he or she freely agrees. 26. In medical research involving human subjects capable of giving informed consent, each potential subject must be adequately informed of the aims, methods, sources of funding, any possible conflicts of interest, institutional affiliations of the researcher, the anticipated benefits and potential risks of the study and the discomfort it may entail, poststudy provisions and any other relevant aspects of the study. The potential subject must be informed of the right to refuse to participate in the study or to withdraw consent to participate at any time without reprisal. Special attention should be given to the specific information needs of individual potential subjects as well as to the methods used to deliver the information. After ensuring that the potential subject has understood the information, the physician or another appropriately qualified individual must then seek the potential subject's freelygiven informed consent, preferably in writing. If the consent cannot be expressed in writing, the non-written consent must be formally documented and witnessed. All medical research subjects should be given the option of being informed about the general outcome and results of the study. 27. When seeking informed consent for participation in a research study the physician must be particularly cautious if the potential subject is in a dependent relationship with the physician or may consent under duress. In such situations the informed consent must be sought by an appropriately qualified individual who is completely independent of this relationship. 28. For a potential research subject who is incapable of giving informed consent, the physician must seek informed consent from the legally authorised representative. These individuals must not be included in a research study that has no likelihood of benefit for them unless it is intended to promote the health of the group represented by the potential subject, the research cannot instead be performed with persons capable of providing informed consent, and the research entails only minimal risk and minimal burden. 29. When a potential research subject who is deemed incapable of giving informed consent is able to give assent to decisions about participation in research, the physician must seek that assent in addition to the consent of the legally authorised representative. The potential subject's dissent should be respected. 30. Research involving subjects who are physically or mentally incapable of giving consent, for example, unconscious patients, may be done only if the physical or mental condition that prevents giving informed consent is a necessary characteristic of the research group. In such circumstances the physician must seek informed consent from the legally authorised representative. If no such representative is available and if the research cannot be delayed, the study may proceed without informed consent provided that the specific reasons for involving subjects with a condition that renders them unable to give informed consent have been stated in the research protocol and the study has been approved by a research ethics committee. Consent to remain in the research must be obtained as soon as possible from the subject or a legally authorised representative. 31. The physician must fully inform the patient which aspects of their care are related to the research. The refusal of a patient to participate in a study or the patient's decision to withdraw from the study must never adversely affect the patient-physician relationship. 32. For medical research using identifiable human material or data, such as research on material or data contained in biobanks or similar repositories, physicians must seek informed consent for its collection, storage and/or reuse. There may be exceptional situations where consent would be impossible or impracticable to obtain for such research. In such situations the research may be done only after consideration and approval of a research ethics committee. Use of Placebo 33. The benefits, risks, burdens and effectiveness of a new intervention must be tested against those of the best proven intervention(s), except in the following circumstances: Where no proven intervention exists, the use of placebo, or no intervention, is acceptable; or Where for compelling and scientifically sound methodological reasons the use of any intervention less effective than the best proven one, the use of placebo, or no intervention is necessary to determine the efficacy or safety of an intervention and the patients who receive any intervention less effective than the best proven one, placebo, or no intervention will not be subject to additional risks of serious or irreversible harm as a result of not receiving the best proven intervention. Extreme care must be taken to avoid abuse of this option.
2. approval signatures
post-trial provisions

34. In advance of a clinical trial, sponsors, researchers and host country governments should make provisions for post-trial access for all participants who still need an intervention identified as beneficial in the trial. This information must also be disclosed to participants during the informed consent process. Research Registration and Publication and Dissemination of Results 35. Every research study involving human subjects must be registered in a publicly accessible database before recruitment of the first subject. 36. Researchers, authors, sponsors, editors and publishers all have ethical obligations with regard to the publication and dissemination of the results of research. Researchers have a duty to make publicly available the results of their research on human subjects and are accountable for the completeness and accuracy of their reports. All parties should adhere to accepted guidelines for ethical reporting. Negative and inconclusive as well as positive results must be published or otherwise made publicly available. Sources of funding, institutional affiliations and conflicts of interest must be declared in the publication. Reports of research not in accordance with the principles of this Declaration should not be accepted for publication. Unproven Interventions in Clinical Practice 37. In the treatment of an individual patient, where proven interventions do not exist or other known interventions have been ineffective, the physician, after seeking expert advice, with informed consent from the patient or a legally authorised representative, may use an unproven intervention if in the physician's judgement it offers hope of saving life, reestablishing health or alleviating suffering. This intervention should subsequently be made the object of research, designed to evaluate its safety and efficacy. In all cases, new information must be recorded and, where appropriate, made publicly available.
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21.11 appendix 11 national cancer

Toxicity grade should reflect the most severe degree occurring during the evaluated period, not an average.  
When 2 criteria are available for similar toxicities, the one resulting in the more severe grade should be used.  
The evaluator must attempt to discriminate between disease / treatment and related signs
/ symptoms.  
An accurate baseline prior to therapy is essential.
Please use the pdf from the following website: http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf
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21.12 appendix 12 assessment of

Definition of response by physical examination and imaging tests Clinical (c) and imaging (i) response will be assessed by physical examination and imaging tests. Sonography or MRI are the preferred examination, however, if sonography appears not to provide valid results or is not performed; other imaging tests will be considered with the following priority: MRI, mammography, computed tomogram. The same imaging method should be considered for the measurement before and after treatment. - Clinical complete response (cCR) - (iCR) Complete disappearance of all tumor signs in the breast as assessed by imaging test. The response of the axillary nodes is not to be considered. - Clinical partial response (cPR) - (iPR) Reduction in the product of the two largest perpendicular diameters of the primary tumor size by 50% or more assessed by palpation or imaging test. In patients with multifocal or multicentric disease, the lesion with the largest diameters should be chosen for follow-up. The response of the axillary nodes is not to be considered. - Clinical stable disease (cNC) - (iNC) No significant change in tumor size during treatment. This category includes no change, an estimated reduction of the tumor area by less than 50%, or an estimated increase in the size of the tumor area lesions of less than 25% measured by palpation or imaging test. - Clinical progressive disease (cPD)
Development of new, previously undetected lesions, or an estimated increase in the size of preexisting lesions by 25% or more after at least two cycles of therapy.  
For all these defined categories of efficacy, the proportion of patients with success will be determined and appropriate confidence intervals will be calculated.  
Patients in whom success cannot be determined (e.g. patients in whom histology is not evaluable) will be included in the denominator, i.e. these patients will affect the success rate in the same way as treatment failures. The clinical tumor response by palpation prior to surgery will also be presented, if applicable
[ADMINISTRATIVE LETTER 1_PENELOPE PROTOCOL]
Study Title: Phase III study evaluating palbociclib (PD-0332991), a Cyclin-Dependent Linase
(CDK) 4/6 Inhibitor in patients with hormon-receptor-positive, Her2-normal primary breast cancer with high relapse risk after neoadJuvant chemotherapy ,,PENELOPE_B*
Study Code: GBG-78, BIG 1-13, NSABP-B-54-I EudraCt No: 2013-001040-62 Dear Investigators, the following summary is provided in regard to the nonclinical data:
Palbociclib has been evaluated in safety pharmacology, genetic toxicity, reproductive and development (fertility and early embryonic development, embryofetal development), and repeat-dose toxicity studies of up to 15-weeks duration in the rat and dog.  Based on the nonclinical safety studies conducted with palbociclib, the primary palbociclib-related systemic toxicities were observed in hematolymphopoietic tissues (decreased cellularity, increased iron pigment, decreases in peripheral leukocytes and RBC parameters) and male reproductive organs
(degeneration of seminiferous tubules, secondary epididymal hypospermia and increased intratubular cellular debris).  Partial to complete reversibility of toxicities was demonstrated following a 4 week recovery period, with the exception of the male reproductive organ findings in the dog.  These toxicities occurred in both rats and dogs, and are consistent with the intended pharmacologic effect of palbociclib (i.e., cell cycle inhibition) (Fink et al. 2001; Arguello et al.  
1998; Bartkova et al, 2003).  Palbociclib was also identified with the potential to cause QT
prolongation (Section 6.3.4 Penelope Protocol), developmental effects, and aneugenicity. Developmental effects that were considered adverse included a decrease in fetal body weights in rats and a low incidence of small phalanges on the forepaws in rabbits.  A no effect level for aneugenicity was observed at approximately 7-fold higher than unbound systemic AUC 24 exposures associated with the human clinical dose of 125 mg QD.  
Palbociclib is being further evaluated for chronic toxicity in a 6-month rat and 9-month dog repeat-dose toxicity study.  
  
Notice for sites: Please file this administrative letter in the protocol section
2. approval signatures
[administrative letter 2penelope protocol]

Study Tille: Phase III study evaluating palbociclib (PD-0332991), a Cyclin-Dependent Kinase (CDK) 4/6 Inhibitor in patients with hormon-receptor-positive, Her2-normal primary breast cancer with high relapse risk after neoadjuvant chemotherapy "PENELOPE_B"
Study Code: GBG-78, BIG 1-13, NSABP-B-54-I
EudraCt No: 2013-001040-62 Cear Investigators, the following summary is provided in regard to the administration of Palbociciib:
Preliminary results from recently performed tood cliect study from Pfizer, AS481021, a Phase 1, open-label 4 sequence 4 period crossover study of palbociclib (PD-0332991) in healthy volunteers to estimate the effect of food on the bioavailability of palbociclib, suggest that the administration of palbociclib with food results in more consistent drug uptake and exposure than administration of palbociclib In a fasted state. The patients In this study are administered Lhe Phase III Yellow/Caramel formu at on which Is or will be supplied for your study.  
Because of these tindings, we request that patients be instructed to take palbocidib with food. This may begin immediately. The dosing instructions for PD-0332991/placebo will be updated in The next Protocol Amendment to read, "Patients should take PD-033299f,/placebo with food." This change does not significantly affect the study's scope, safety, or scientific quality.  
  
Notice for sites: Please file Lhis administrative letter in the protocol section Administrative Letter 2_Penelope Protocol     1
[ADMINISTRATIVE LETTER 3_PENELOPE PROTOCOL]
Study Title: Phase III study evaluating palbociclib (PD-0332991), a Cyclin-Dependent Linase
(CDK) 4/6 Inhibitor in patients with hormon-receptor-positive, Her2-normal primary breast cancer with high relapse risk after neoadjuvant chemotherapy "PENELOPE_B"
Study Code: GBG-78, BIG 1-13, NSABP-B-54-1 EudraCt No: 2013-001040-62 Dear Investigators, In Administrative Letter 1 we informed you, that Palbociclib is being further evaluated for chronic toxicity in a 6-month rat and 9-month dog repeat-dose toxicity study.  
Following Data were released by Pfizer on 27 th Jan 2014 as Special Safety Concern Report:
The study entitled "27-Week Oral Gavage Chronic Toxicity and Toxicokinetic Study with PD- 0332991 in Rats with a 12-Week Recovery Phase (Study 8282224; Sponsor Reference Number 13LJ036)
The identification of cataracts in rats following 27-weeks of intermittent dosing represents a new target organ toxicity. In the previous rat and dog repeat-dose toxicity studies up to 15 weeks duration, the primary target organ findings were observed in the hematolymphopoietic and male reproductive tissues.  
The minimal dose level for cataract formation has not been identified from the 27-week rat toxicity study, based on the histological data (lens degeneration was noted microscopically ).  
Cataracts were identified from ophthalmic evaluations at the lower examined dose of 30 mg/kg/day in males but at no dose in females.  
While the impact of this nonclinical finding is considered to suggest a potential risk to human subjects, the overall benefit-risk for palbociclib remains favorable.  
Secondly Proton Pump inhibitors are not recommended during active treatment with Palbocilib: Preliminary results from the recently performed antacid effect from Pfizer Sponsored study :
A5481018, "a Phase I, open-label fixed-sequence 2-period crossover study of palbociclib in healthy subjects to investigate the potential effect of antacid treatment on the pharmacokinetics of a single oral dose administered under fasted conditions", suggest that the administration of PPIs (such as rabeprazole), when concurrently given with palbociclib may lead to a significant decrease in palbociclib exposure. This study uses the free-base formulation of Palbociclib which is also provided for your study. Final results will be made available to investigators and regulatory bodies once the report is complete As a result of these findings, we request that patients be instructed to refrain from the use.  
of proton pump inhibitors.  
If needed, alternative antacid therapies may be used including H2-receptor antagonists, and locally acting antacids. H2-receptor antagonists should be administered with a staggered dosing regimen (twice daily). The dosing of palbociclib should occur at least 10 hours after H2-receptor antagonist evening dose and 2 hours before the H2-receptor antagonist morning dose. Local antacid should be given at least 2 hours before or after palbociclib administration.  
 Gunter/von Minckwitz, MD Principal Investigator  
  
Notice for sites: Please file this administrative letter in the protocol section Administrative Letter 3_Penelope Protocol _ 1
2. approval signatures
appendix 16 administrative letter 4

[ADMINISTRATIVE LETTER 4_PENELOPE PROTOCOL]
Study Title: Phase III study evaluating palbociclib (PD-0332991), a Cyclin-Dependent Linase
(CDK) 4/6 Inhibitor in patients with hormon-receptor-positive, Her2-normal primary breast cancer with high relapse risk after neoadjuvant chemotherapy "PENELOPE_B" Study Code: GBG-78, BIG 1-13, NSABP-B-54-I EudraCt No: 2013-001040-62 Dear Investigators, After approval by your competent authority Inclusion criterion number 9 changes: From (Old)
9. Less than 16 weeks interval since the date of final surgery and date of randomization (including the radiotherapy period).  
To (New)  
9. Less than 16 weeks interval since the date of final surgery or less than 10 weeks from completing radiotherapy (whichever occurs last) and date of randomization.
This is not significantly changing the patient population and the scope of the trial.  
  
  
[ADMINISTRATIVE LETTER 5_PENELOPE PROTOCOL]
Study Title: Phase III study evaluating palbociclib (PD-0332991), a Cyclin-Dependent Linase (CDK) 4/6 Inhibitor in patients with hormon-receptor-positive, Her2-normal primary breast cancer with high relapse risk after neoadjuvant chemotherapy "PENELOPE_B" Study Code: GBG-78, BIG 1-13, NSABP-B-54-I
EudraCt No: 2013-001040-62 Dear Investigators, In Administrative Letter 3 (30 th Jan 2014) we informed you about the identification of cataracts in rats following 27-weeks of intermittent dosing with palbociclib (Safety Concern Notification Pfizer 29:" Jan 2014). This is a follow-up to communicate further data that emerged from this toxicity study showing correlation between altered glucose metabolism and the formation of cataracts/lens degeneration. A special safety concern notification was released by Pfizer on 18'' July 2014.  
In Administrative Letter 1 we informed you that palbociclib is being further evaluated in dog Toxicity Study (9-month). In dog toxicity studies (15-week and 39-week), no altered glucose levels and no cataracts/lens degeneration have been observed (lack of lens degeneration not yet confirmed in the 39-week study; histopathology pending).  
Hyperglycemia and diabetes mellitus are currently not considered to be identified clinical risks and are not considered to be adverse drug reactions (ADRs) of palbociclib. According to exclusion Criterion \#10 a severe acute or chronic medical condition that may increase the risk associated with study participation needs to be excluded, which includes uncontrolled diabetes mellitus.  
Before a patient enters the Penelope study please ensure their diabetes is easily controlled medically.  
As an amendment to the protocol we ask you to measure HbA1C-levels with the following visits:
Baseline, Day1 Cycle 3 (9'' week +/- 7days),
Day1 Cycle 7 (192) week +/- 7days)
Day1 Cycle 11 (41** week +/- 7days)
End of Therapy (within 30 days after the last dose).  
These measurements can be done at a local laboratory convenient for the patient. In case of a signal please refer the patient to a diabetologist or a diabetes advisor to easily control the diabetes and enter the concomitant medication in the CRF.
2. approval signatures
22. references

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