Date of first round report: 1 September 2016 Date of second round report: 30 January 2017

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Clinical questions

  1. Efficacy

  1. Many patients required a dose reduction or delay. It is not discussed whether the clinical benefit for those on a lower dose is comparable with those who manage to stay on the starting dose. The sponsor is requested to provide an analysis of the efficacy outcomes and a forest plot of PFS and ORR to demonstrate the effect by dose received for Study 1023 (with the lowest dose received to be used for any who have had dose reductions).

  1. Study 1003: Please provide the breakdown of the operations as to whether they were breast versus non-breast surgery for each treatment arm. For those who underwent breast surgery, please state the number and percentage going on to receive adjuvant therapy, by treatment arm.

  2. Study 1003: Please provide a breakdown of the numbers of the 17.9 % patients for each arm who received no endocrine therapy following an earlier ER-positive breast cancer diagnosis.

  3. Study 1003: The data presented in [Tables 27 and 28] of the CSR for investigator and BICR censoring respectively, differ from those data presented for the BICR censoring in Table 26 and Table 27 of the FDA report (publicly available on the website) for Study A5481003. The sponsor is requested to provide an explanation for all differences in the data presented in the dossier versus the tables in the FDA report, including but not limited to, the higher AE rates, clinical progression, withdrawal of consent reported in the FDA report- noting that the FDA table was generated in response to an FDA query on 28 Feb 2014.

  4. For Study 1003, the sponsor is requested to provide a breakdown for both the control and experimental arms of the numbers and percentage where BICR was performed prospectively versus retrospectively.

  5. For Study 1003, the sponsor is requested to provide concordance rates between the investigator and BICR by imaging modality eg bone scan, CT, MRI for each lesion type that is, bone lesions, visceral, other.

  6. For Study A5481008, the sponsor is requested to state whether the CRF or Impala data was used to define populations for the primary efficacy analysis of the data, and how such discrepancies are handled in the statistical analysis. Noting that the 2016 ASCO meeting presentation of the latest results for Study 1008 (including BICR-reviewed data) by Dr Richard Finn used the CRF data, the sponsor is requested to provide a comment on the choice of this dataset over that presented for the primary analyses in this top-line summary.

  7. For Study A5481008, what subgroups were prespecified for efficacy analyses?

  8. How many patients ‘in follow up for progression’ in Study A5481008 were still on study drug in each arm?

  9. When submitting the CSR for Study A5481008, the sponsor is requested to provide details of the deaths of each patient who died without evidence of disease progression if not already included in that document. This is recommended to be done as a second NCE application.

  10. Uncertainty exists as to whether there is a benefit for those with de novo metastatic disease. Whether this represents an increased responsiveness to the control arm which generally did better than in other subgroup analyses cannot be checked against the group who had received no prior systemic treatment for their disease (irrespective of stage of presentation) as these data could not be located in the Tables or Topline summary. Provision of these data is requested to be included when the CSR is lodged with the TGA (second NCE application recommended).

  11. For Study 1023, the anticipated dropout rate was high at 25%, particularly for those with metastatic disease and a high degree of motivation to continue treatment if their disease is not progressing. The sponsor is requested to provide a rationale for this high rate. Was this to anticipate side effects related to the use of fulvestrant, the administration of which is associated with significant discomfort?

  12. In the update report using an earlier cut-off date of 16 March 2015, discontinuations due to withdrawal of consent occurred in 1.2 % (4 patients) in the palbociclib and fulvestrant arm but are now reported as 0.9% (3 patients) with a later cut-off date - the sponsor is requested to explain why there are now fewer presented (Clinical Questions).

  13. The sponsor included an updated PFS analysis for Study 1023, which also included updated OR, DoR and clinical benefit rate. None of these analyses were supported by BICR-derived analyses; the sponsor is requested to provide the BICR analyses for these endpoints for evaluation or state that none was done.

  14. CSR for Study A5481023 includes data about the recurrence type. This includes ‘newly diagnosed’ as a significant category (17.7% of total population) amongst breakdown by anatomical site which makes it difficult to establish how many in the study had local or locoregional disease only. The sponsor is requested to provide:

  15. A breakdown of numbers in each arm this is a population identified in the indication;

  16. The following efficacy outcomes for those in each arm with local or locoregional disease: median PFS, OR, DoR, CBR.

  17. This question only needs to be addressed in the response if the sponsor wishes to retain the PI statements about quality of life in the Clinical trials section:

  18. a justification of the clinical significance of the presented results against the prespecified criteria in the SAP;

  19. to indicate meaningful completion rates, please provide the number and percentage of patients who completed all questions of the EORTC-QLQ-C30 out of the PRO analysis in each arm;

  20. please provide the number / percentage of patients for whom pro-rating was undertaken due to missing data in each arm.

  21. In Study A5481023, no information was found by the evaluator as to how many of the biopsy samples used in the central testing were from a biopsy sample taken following their most recent episode of progression to determine ER/PR/HER2 status – the sponsor is requested to provide this information as it has been shown that a discordant rate between primary and secondary breast cancers has been reported to be as high as 25-30%.

  22. Study 1023: The sponsor is requested to provide 3 additional sensitivity analyses, presented as a forest plot with accompanying HRs comparing the ITT PFS:

  23. A sensitivity analysis, removing all those who were ineligible for enrolment due to subsequently determined ER-/PR- or HER2+ disease by central testing, to determine whether there was any effect on the ITT PFS analysis;

  24. A second sensitivity analysis excluding those 118 patients whose data were missing or inadequate for central laboratory testing of ER,PR or HER2 status as well as those who were deemed ineligible by central laboratory testing, is also requested to determine whether there was any effect on the ITT PFS analysis;

  25. A subgroup analysis of those whose results were discordant that is, not ER-positive or they were HER2-positive.

  26. The sponsor is requested to provide the number of patients in each arm whose tumour was ER-negative/PR-positive and the results (PFS, OR, DoR, and CBR) for these patients.

  27. Study A5481023: The change to a different schedule (2 weeks on/2 weeks off) was not described in the Protocol and the benefits of this dose in the 3.8% who switched to this regimen cannot be assured. It is not clear what palbociclib dose was taken in this regimen (please provide this information). It would be apparent to the investigator that the patient was receiving palbociclib due to the AE profile, and this may have introduced a bias in wanting to continue if there was a clinical benefit observed but problematic toxicities. That so many changed to this regimen indicates a degree of unmasking. The sponsor is requested to provide an explanation of whether these non prespecified alterations were included in the protocol deviations and also whether these patients’ outcomes were included in the efficacy analyses, and whether any subgroup efficacy analyses were performed for those on this regimen. (Clinical Questions).

  28. Study A5481023 the sponsor is requested to state whether searching using any other MedDRA terms that might capture events of haemorrhage, bleeding or bruising, yields any events associated with the adverse events of thrombocytopenia. (Clinical Questions).

  29. Study A5481008: Within the study, there was some discordance between the baseline information provided at randomisation which affected the stratification and has had an impact on the efficacy analyses, particularly on the subgroup analyses, depending which dataset is used for the ITT population. The full impact of these cannot be understood and contextualised without presentation of the study protocol deviations. It is not sufficient to provide the analyses for these groups according to the differing information source (that is, randomisation versus CRF). A more rigorous approach should include:

  30. Presentation of the number of patients for whom there was any discordance between the randomisation information and CRF;

  31. Whether these patients were from a single or limited number of investigation centres - it is noted that in Study 1003, the FDA clinical site audit identified a single site as having a significant number of protocol deviations but that analyses with these patients censored were not reported to significantly affect the outcomes;

  32. Presentation of sensitivity analyses for the efficacy outcomes censoring the data from these patients incorrectly classified.
        1. Safety

  1. Clinical evaluator comment: the sponsor is requested to provide a table which integrates from all clinical studies (referencing the source studies) and presents:

  1. the total number of patients treated to date:

  2. at the proposed dose level and regimen (palbociclib 125 md QD 3/1)

      • in combination with fulvestrant

      • in combination with letrozole at the proposed dose

      • in combination with letrozole at any dose level

  1. ii. as monotherapy

      • at the proposed dose and schedule

      • at any other dose

    1. the median duration of treatment for all those patients and an interquartile range

  1. in combination with fulvestrant

  2. in combination with letrozole at the proposed dose

  3. in combination with letrozole at any dose level

  4. The sponsor is requested to explain the rationale behind the exclusion from Study A5481008 of patients with recent or active suicidal ideation or behaviour. In particular, the sponsor is requested to provide case details where palbociclib might have been implicated in patients committing suicide or becoming suicidal that is, while taking or after recently stopping palbociclib. And further to the results in Study A5481023, where 4 patients were reported to have a psychosis, depression or suicide attempts, the sponsor is requested to discuss the potential role of palbociclib in these events.

  5. The sponsor is requested to provide with a future provision of the CSR for Study 1008, an integrated safety summary for the 2 studies 1003 and 1008, and an updated PI to reflect these data.

  6. For Study A5481023, the remaining events accounting for the 3.5% of Grade 3 or 4 TEAEs for the palbociclib and fulvestrant arm and 1.7% in the comparator arm (90-day safety update) are not presented. The sponsor is requested to provide this information.

  7. An update infection rate/febrile neutropenic rate has not been presented in this safety update for Study 1023 and this is needed, to ensure the figure quoted in the PI is accurate.

  8. Bone marrow suppression occurs resulting in leukopenia and neutropenia. The sponsor is requested to provide the following information, and where cases have occurred, provide the details.

  9. What were the rates of opportunistic infections reported for each of the arms for Study 1003, 1023 and 1008?

  10. Were any cases of Hepatitis B reactivation identified?

  11. Has PML ever been reported in the palbociclib development program? Please provide details of any cases reported.

  12. There needs to be a heading and discussion of the rates of infection and febrile neutropenia (0.6% of patients receiving palbociclib and fulvestrant reported at 5 December 2014 cut-off – but what is it now with the later dataset?) An updated infection rate/febrile neutropenic rate has not been presented in this safety update for Study 1023 and this is needed, to ensure the figure quoted in the PI is accurate (Clinical Questions and PI comments).

  13. Table 5 of the draft PI presents out of date data for Adverse Drug Reactions which is in the SOC format which needs to be updated with the 90-day safety update. Where there are clinical laboratory findings (eg for biochemical and haematological events), these should be included in any data presented as these are more accurate than TEAEs. It must be shown clearly how the figures used in the ADR table were reached and why any treatment-related events were discounted. This is required in the response (clearly indicating how these figures were reached) and to be inserted in the PI (see PI comments and Clinical Questions).

  14. Study A5481023: Without a table providing side-by-side comparison of the adverse events of lower frequency, presented with similar terms collapsed to provide a single figure (as in the SOC presentation with like MedDRA terms collated, it is very difficult to determine whether there have been additional clinically significant adverse events occurring more commonly in the experimental arm. Given the importance of understanding these for both clinicians and patients, the sponsor is requested to present all the adverse events, (including all grades frequency, as well as Grade 3 and Grade 4) that occurred more often in the palbociclib and fulvestrant arm than the placebo and fulvestrant arm (Clinical Questions). These adverse events’ preferred terms should be clustered to capture the same event being classified by a range of different terms.

  15. For Study A5481023: It is difficult to determine whether the difference between the rates of thrombocytopenia from laboratory findings compared with the TEAEs of thrombocytopenia indicates a level of under-reporting of the events for the population as a whole for lower grade AEs of thrombocytopenia as it would be unusual for such a high percentage of patients who have received endocrine therapy as their last treatment to be thrombocytopenic (even Grade 1 or 2) at baseline; however, the reporting of TEAEs appears to match the total number with Grade 3 or 4 TEAEs although the distribution is different (one patient more is reported to be Grade 4 not Grade 3). The sponsor is requested to provide an explanation.

  16. Study A5481023 The rates of epistaxis and thrombocytopenia are both noted to be increased in Study 1008 for the palbociclib arm and sponsor is requested for Study 1023, to state the rates for bleeding events by:

  17. Broadening the search criteria beyond ‘Haemorrhage’ and to use all MedDRA terms that are designed to cover the event of bruising, bleeding in any organ ( including petechiae)

  18. How many of these were associated with the events of thrombocytopenia in Study 1023?

  19. Study A5481003: the sponsor is requested to provide the platelet count for the patient at the time of requiring a dose reduction for petechiae.

  20. Study A5481008: ‘Summary of all-causality treatment-related adverse events’ states that 6.1% and 5.0% of patients permanently discontinued letrozole due to an AE in the experimental and comparator arms, respectively. This figure exceeds that for those permanently discontinuing the study due to an AE for those arms (2.5% and 1.8%, respectively). The sponsor is requested to provide explicit details regarding how these patients were treated and followed up from this point of discontinuation.

  21. Was palbociclib or placebo continued as monotherapy in any patients? If so, how many in each arm?

  22. If both letrozole and the placebo or palbociclib were discontinued, what is the difference between the group who permanently discontinuing the study and those labeled as permanently discontinuing letrozole?

  23. Study A5481008: Events rates for TEAEs of thrombocytopenia were not reported as occurring below 10% in Study 1008. This is an artefact of the high cut-off threshold of ≥ 10% in either arm and use of separate MedDRA terms for TEAE reporting; the combination of treatment-related thrombocytopenia/platelet count decreased was 14.9% in the experimental arm and 1.4% in the comparator that is, a 10-fold increase in risk, with the lower cut-off of 5% reporting the treatment-related AEs. Furthermore with the lower threshold in the treatment-related events table, the adverse event of epistaxis also emerges which could be linked to the low platelets (any correlation of these 2 adverse events should be addressed in the clinical overview and safety section when providing the CSR for Study 1008). When submitting the CSR for Study 1008, the sponsor is requested to include a table of TEAEs with a cut-off of 1% in either arm, treatment-related AEs with a cut-off of 1% in either arm to be consistent with the Grade 3/4/5 TEAE reporting provided. This will assist in identification of events that may require inclusion in the PI to inform clinicians and patients. The assessment of attribution of AEs considered treatment-related cannot be made without knowing the baseline percentage listed as treatment-emergent. (Clinical Questions).

  24. Study A5481008: Top-line summary provide frequencies for treatment-related adverse events by frequency of at least 5% in either arm. Given, rare events will be missed by presentation this way, the sponsor is requested to provide a table where the cut-off is 1% in either arm when submitting the CSR for Study 1008. The same threshold should be used for the TEAEs – it would be acceptable to add in a table to capture this rate of events. It is recommended that these issues be addressed when submitting the Study 1008 to facilitate any evaluation.

  25. Investigator-initiated research death on study: The narrative could not be located for evaluation of the case of ischaemic colitis on palbociclib monotherapy, and the sponsor is requested to provide a copy of it in the response.

  26. Study A5481023: The CTCAE grading system does not provide a numeric value for Grade 4 events of anaemia but defines this as ‘Life-threatening consequences; urgent intervention indicated’. The sponsor is requested to provide the number of patients for whom transfusions were required in these circumstances and clinical details for such patients (Clinical Question).

  27. Study A5481023: Study 1023 the CIOMS indicates that for the patient with ‘drug-induced liver injury’ (Subject [information redacted]) there was a substantial improvement in the liver function tests after discontinuing the study drugs, even though there is a background of progressive disease from which she died subsequently just over 2 months after the last dose of palbociclib. The evaluator agrees with the investigator and disagrees entirely with the conclusion of the sponsor who cite a ‘progressive marked deterioration of hepatic function after discontinuation after study drugs’ discontinuation’ as a reason for this not being study related, when quite clearly, there was an improvement in liver function that would not be anticipated if this were solely progressive disease. The sponsor is requested to comment upon the quite dramatic improvement in liver function tests, the imaging results that suggest a new appearance to the liver contour, as these appear to have been overlooked in the causality assessment.

  28. Study A5481023: no information is provided about the case of Grade 4 increase in bilirubin – please provide the clinical details for this patient surrounding this event, including details of all the liver function tests that were performed, any diagnostic imaging, whether the study drug dose was reduced, delayed or discontinued and comment on these.

  29. Study 1003: the remaining CIOMS for the SAEs (acute renal failure) and 2 Grade 3 events (nephropathy and nephrolithiasis) of renal and urinary disorders could not be located and should be provided by the sponsor.

  30. Study 1023: the Study protocol states that CTCAE v 4.0 was used. A review of this reveals no such classification of Grade 1 for ventricular tachycardia (as this necessarily requires medical attention). Similarly, there are no CTCAE terms for ‘bradycardia’, ‘tachycardia’ or ‘ventricular extrasystoles.’ The sponsor is requested to comment and provide updated details and classifications regarding these adverse events, and to provide clinical details surrounding the event of ventricular tachycardia (Clinical Question).

  31. Given the proposed usage is in postmenopausal women and the frequency in older women, the sponsor is requested to provide a breakdown for the events reported in the 90-day safety update for those > 75 years of age and include this in the PI.

  32. Study 1003: The sponsor is requested to explain the unusual dose levels in the range accompanying the median daily dose included in the Phase II part of Study 1003 (stated range: 79.6 mg to 266.7 mg).

  33. Thrombocytopenia/platelet count decreased was more common (19.3%) with palbociclib and letrozole compared with letrozole alone (1.3%), including Grade 3 events. There was an increased rate of epistaxis (6% versus 1.3%; all Grade 1 events in both arms) in the palbociclib and letrozole arm. Whether these were associated with thrombocytopenia is not discussed and the sponsor is requested to state:

  34. The platelet count at the time of each event of epistaxis for these patients

  35. Provide a breakdown of the events by MedDRA PT of any haemorrhage or bleeding in any organ, by treatment arm with the platelet count at that time for each patient experiencing an event.

  36. Study 1003: The sponsor states: ‘Both patients (2.4%) with Grade 3 Thrombocytopenia in the palbociclib plus letrozole arm had their dose reduced, interrupted or their cycle delayed (due to Grade 3 or lower Thrombocytopenia). No patients in either treatment arm were permanently discontinued due to a TEAE of Grade 3 Thrombocytopenia. No patients in either treatment arm had a TEAE of Grade 4 Thrombocytopenia. None of the events of Thrombocytopenia were serious or led to death’ on page 261 of Study 1003 CSR. The sponsor is requested to provide the same information regarding any adverse events or dose level and schedule adjustments for the 2 cases with Grade 3 platelet count decreased adverse events (Clinical Questions).

  37. Study 1003: No update of Table 68 from the CSR Overview of treatment-emergent adverse events Phase II As treated set, Study A5481003 CSR, cut-off date November 29 2013 was provided, nor text to update this information – the sponsor is requested to provide an updated table containing the latest data.

  38. Investigator-initiated research: the safety update report states that detailed narratives are available in Appendix 2 for all 4 patients where the events were considered treatment-related. The evaluator could not locate them in Appendix 2 and the sponsor is requested to provide these in the response for the two patients:

    1. the patient (Case Number [information redacted]) with dyspnoea and pneumonia who was discontinued from palbociclib on day 232 (why?) and then developed dyspnoea and a nosocomial infection on day 257. Pneumonitis or interstitial lung disease need to be considered.

  1. Investigator-initiated research palbociclib monotherapy for non-breast cancer patients: The 90-day report cites as including 2 patients with fatal SAEs considered treatment-related but the clinical evaluator notes 3 cases are listed here – no detailed narratives could be located for any of these 3 patients are the sponsor is requested to provide these.

  2. Study 1023: Was a single patient able to be recorded as having both neutrophil count decreased and neutropenia by MedDRA PT (that is, 2 terms for the same clinical event)? If so, the sponsor is requested to provide the number of patients with an event of NEUTROPENIA (cluster term) without such double reporting (that is, individual patients should be presented as having only one event recorded).

  3. Study 1023: following on from the question immediately before this one, the figures do not appear to tally for the number of patients reported to have Grade 3/4 events as defined by the cluster term NEUTROPENIA. 287 patients were reported to have NEUTROPENIA events of any severity), with the text following stating 240 of these patients had Grade 3/4 severity. However, demonstrates that the number with maximum grade of 3 was 191 patients and of maximum Grade 4 was 37 and this equals 228 patients. The sponsor is requested to state which are the correct figures and explain why these differences occurred.

  4. Study 1023: The TEAEs should be a subset of the clinical laboratory abnormalities, as this AE grading is based on a blood test. The sponsor is requested to explain how there are discrepancies between the clinical laboratory abnormalities and the MedDRA PT reported AEs including:

  5. More patients are reported to have Grade 3/4 neutropenia or neutrophil count decreased by MedDRA PT compared with those determined by clinical laboratory abnormalities (228 or 240 versus 225);

  6. 2 patients in the comparator arm had Grade 4 events on blood tests which were not recorded as TEAEs. In a blinded study, any Grade 4 events of neutropenia should be reported as AEs but the 2 events in the placebo and fulvestrant arm were not recorded as AEs. (Clinical Question).

  7. The sponsor is requested to provide details of clinical laboratory findings for glucose for the 2 patients with cataracts and any elevated HbA1c results as this is more likely to capture events of hyperglycaemia than isolated terms used to identify TEAEs.

  8. The sponsor is requested to characterise further the nature of the conditions leading to reports of visual impairment and provide a discussion about the increased rate of events affecting vision/visual acuity which would compromise vision in those receiving palbociclib, as seen in Study 1003. Were there any preclinical data which identified visual impairment besides cataract development? The CIOMS and narrative for the patient with ‘blindness’ attributed to cerebral metastases are requested. This would require a significant metastasis or haemorrhage into such a lesion in the occipital region for such blindness to occur and be attributable to metastases.
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