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



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Discontinuations due to adverse events

  1. Integrated safety analyses


None provided.
        1. Main/pivotal studies that assessed safety as the sole primary outcome


N/A.
        1. Pivotal and/or main efficacy studies

Combination of palbociclib and fulvestrant – Study 1023

The overall frequency of TEAEs, 68.4% of which were Grade 3/4 severity, associated with permanent discontinuation from treatment was 5.5% in the palbociclib plus fulvestrant arm and 3.5% in the placebo plus fulvestrant arm of Study 1023 as of 31 July 2015 and are summarised in the table below. The sponsor attributed causality of bone pain, drug-induced liver injury and nausea to the fulvestrant component of the treatment.

Comment: As discussed above, palbociclib cannot be excluded from contributing to the drug-induced liver injury6, and with the 6% higher incidence of treatment-emergent nausea in this arm compared with the placebo and fulvestrant arm, nausea cannot be solely attributed to fulvestrant.

Table 30: Study A5481023 Treatment-related discontinuations in patients receiving palbociclib and fulvestrant




Combination with letrozole and palbociclib – Study 1008 top-line summary (no CSR available)

43 (9.7%) patients permanently discontinued from treatment due to treatment-emergent, all-causality AEs in the palbociclib plus letrozole arm versus 13 (5.9%) patients in the placebo plus letrozole arm. Most of those AEs were reported as a single event. In the palbociclib plus letrozole arm, 5 (1.1%), 3 (0.7%), and 3 (0.7%) patients discontinued due to Neutropenia, Alanine aminotransferase increased, and Disease progression, respectively. In the placebo plus letrozole arm, 2 (0.9%) patients discontinued due to fatigue. The all-causality AEs associated with permanent discontinuation for ≥ 2 patients in either treatment arm are summarised in Table 31.

Table 31: Study A5481008 Summary of all-causality treatment-emergent adverse events associated with discontinuation for ≥ 2 patients in either treatment group (As Treated population)



The clinical evaluator reviewed the supporting table for events occurring in one patient that were not reported. The data in that table are MedDRA terms presented by SOC, providing a degree of collation of similar events that is not presented in the top-line summary table above. The following are noted:



  • There were 10 deaths in the palbociclib and letrozole arm with the following causes:

    • 4 were related to cardiac events;

    • 1 was attributed to ‘death’;

    • 2 due to respiratory, thoracic, mediastinal disorders (pulmonary embolism, respiratory failure);

    • 3 were attributed to disease progression.

Overall discontinuations due to AEs when classified by SOC in order of decreasing frequency were:

  • Investigations

    • Hepatic enzyme increased/aspartate transaminase increased/alanine transaminase increased: 6 patients (1.4%) including Grade 4 (2 patients) and Grade 3 (3 patients)

  • Neutropenia/neutrophil count decreased: 7 patients (1.6%)

  • Cardiac disorders: 5 patients (1.1%)

  • Respiratory, thoracic, mediastinal disorders: 5 patients (1.1%) including Grade 3 pneumonitis (1 patient)

  • Renal and urinary disorders: 3 patients (0.7%) including 2 patients with ‘acute kidney injury’

  • Skin and subcutaneous tissue disorders: rash or dermatitis in total of 3 patients (all Grade 1 or 2)

  • Nervous system disorders: 1 patient with cerebral haemorrhage, 1 with cerebrovascular accident

Comment: No narratives to assess these significant events including the deaths and any possible relation to treatment. This requires submission for full evaluation of the CSR for Study 1008. This table provided information on the listing of TEAEs leading to deaths, which have been added to the section above on deaths on study.
Temporary discontinuations
Combination of palbociclib and fulvestrant – Study 1023

There was a 5-fold increase in TEAEs associated with temporary discontinuation from treatment in the palbociclib plus fulvestrant arm (69.3%; 65.4% Grade 3 or 4)) compared with the placebo plus fulvestrant arm (12.8%; 6.4% Grade 3 and 0 Grade 4)) as of that data cutoff date. There was a 10-fold increased risk of developing a Grade 3 or 4 toxicity in the experimental arm compared with the comparator arm. The conditions leading to a temporary discontinuation are similar to those listed for all-causality TEAEs, and include laboratory test abnormalities, nausea, vomiting diarrhea, fatigue, pain, thrombosis and a range of infections (9 different types recorded). Treatment for ten patients (2.9%), either at that time or subsequently, was discontinued permanently due to AEs.

Comment: The significance of the toxicity of the addition of palbociclib to fulvestrant becomes apparent with the figures of dose interruption, adjustment and discontinuation. Furthermore the severity is clearly indicated by the observed 10-fold increased risk of a Grade 3 or 4 toxicity (in fact no Grade 4 toxicities were observed in the placebo and fulvestrant arm). While most of these are due to haematological abnormalities and may be without symptoms, many of the remaining adverse events are associated with significant morbidity and severity.
Combination with letrozole and palbociclib – Study 1008 top-line summary (no CSR available)

The only information provided was in the top-line summary where temporary discontinuations due to an AE were listed as 9.9% in the palbociclib and letrozole arm compared with 4.1% in the placebo and letrozole arm.

Comment: No supporting data or analyses were presented and no evaluation of, or comment on the very limited information provided can be made.
Dose reductions due to TEAEs
Combination of palbociclib and fulvestrant –Study 1023

128 patients (37.1%) in the palbociclib plus fulvestrant arm had their palbociclib dose reduced as of 31 July 2015:

  • 118 patients (34.2%) had their dose reduced from 125 mg QD to 100 mg QD, and

  • 41 patients (11.9%) had their dose reduced from 125 mg to 100 mg QD and further to 75 mg QD. Palbociclib dose was reduced at least twice for 31 patients (9.0%) in that treatment arm.

In addition, 13 patients (3.8%) had their palbociclib dose regimen changed from Schedule 3/1 to Schedule 2/2 (2 weeks on palbociclib treatment followed by 2 weeks off treatment).

In the placebo plus fulvestrant arm, only 3 patients (1.7%) had their placebo dose reduced as of 31 July 2015.

TEAEs of neutropenia, febrile neutropenia, leukopenia, thrombocytopenia, stomatitis and fatigue accounted for 124/128 of palbociclib dose reductions/modifications as of 31 July 2015. A total of patients (35.9%) in the palbociclib plus fulvestrant arm and 3 patients (1.7%) in the placebo plus fulvestrant arm experienced these TEAEs as of that data cutoff date. SAEs leading to dose reduction/modification in the palbociclib plus fulvestrant arm included neutropenia (2 patients [0.6%]) as well as febrile neutropenia, pericarditis, gastro-oesophageal reflux disease, intestinal obstruction, pyrexia, otitis media acute, pharyngitis, electrocardiogram QT prolonged, neutrophil count decreased, and rash maculo-papular (1 [0.3%] each).

As of the 31 July 2015 cut-off date, the median time to first dose reduction was 57 days (range 27-459) on the palbociclib and fulvestrant arm. For the 9% of patients requiring a further dose reduction to 75 mg, the median time on the 100 mg dose was 197 days (range 56-450).



Comment: This is clinically relevant information as the range indicates that continuous monitoring is required as dose reductions may be required after the first cycle or many months after commencement or dose reduction. This also supports the advice that a full blood count should be obtained prior to each cycle. This monitoring information is currently in the Precautions section but should also be included in the Dosage and Administration section, together with the information about the median times to dose reduction.

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 suggests 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).


Combination with letrozole and palbociclib – Study 1008 top-line summary (no CSR available)

The only information provided was in [Table 9] of the top-line summary where dose reductions due to an AE were listed as 35.6% in the palbociclib and letrozole arm compared with 0.9% in the placebo and letrozole arm.

Comment: There is a substantial difference between the toxicities of the two arms as indicated by the dose reductions required. It is not possible to determine what the precipitating events were which led to the dose reductions nor whether the rechallenge was tolerated and these dose reductions were effective. In particular, significant toxicities were apparent in this study requiring discontinuation (for example, acute kidney injury, elevated liver enzymes, pulmonary fibrosis) and it is not possible to determine the rates of these, whether they were treatment-related and whether dose reduction strategies were effective.

Without the appropriate supporting data, analyses and narratives, it is not possible to evaluate this information, or comment on the very limited information provided can be made. Significantly, no comment can be included in the PI as to how best to manage the adverse events listed in the TEAE section.


        1. Other efficacy studies

Study 1003
Phase II

As of 2 January 2015 cutoff, 13 patients (15.7%) in the palbociclib plus letrozole arm and 2 patients (2.6%) in the letrozole alone arm experienced TEAEs associated with permanent discontinuation from treatment. The only TEAEs associated with permanent discontinuation of more than 1 patient in the palbociclib plus letrozole arm were neutropenia (6.0%]) and fatigue (2.4%), although other notable TEAEs resulting in discontinuation included pulmonary embolism (2 other patients discontinued temporarily due to pulmonary embolisms), ischaemic colitis, weight loss and asthenia (all 1 patient each). The only TEAEs associated with permanent discontinuation from treatment in the letrozole alone arm were arthralgia and nausea (1.3% each).

Dose reductions and temporary discontinuations

31 of the 83 patients (37.3%) in the palbociclib plus letrozole arm experienced TEAEs associated with palbociclib dose reduction in this portion of the study. Most frequently reported TEAEs (≥ 2 patients [2.4%]) leading to dose reduction in that treatment arm included neutropenia (28.9%), leukopenia (7.2%), thrombocytopenia/platelet count decreased (3.6%), and fatigue (2.4%). Overall, a total of 27 patients (32.5%) experienced haematological TEAEs associated with palbociclib dose reduction.

Comments:



  1. Granulocytopenia and neutropenia are the same events, as are thrombocytopenia and platelet count decreases and have been collated by the evaluator.

  2. Adverse events included petechiae and the sponsor has been requested to provide data on the platelet count for this patient at that time, as well as a correlation between the risks of bleeding, bruising etc particularly and low platelet counts for all patients who have received palbociclib in the trials presented in the dossier. (Clinical Question)

5 of the 31 patients (6.0%) in the palbociclib plus letrozole arm in the Phase II portion of the study who had experienced TEAEs associated with dose reduction experienced later treatment-related AEs associated with permanent discontinuation from treatment.

Temporary discontinuations due to TEAEs in the palbociclib and letrozole arm were very common (63.9%), with 49.4% of these due to Grade 3 events, 7.2% due to Grade 4 events. Most of these were haematological toxicities, particularly neutropenia (53% including all MedDRA related terms) but prominent also were stomatitis/mucosal inflammation (4.8%), vomiting (2.4%) and fatigue (2.4%). 5 of the 53 patients (6.0%) in the palbociclib plus letrozole arm in the Phase II portion of the study who had experienced TEAEs associated with temporary discontinuation from treatment experienced later treatment-related AEs associated with permanent discontinuation from treatment. In comparison only one patient (1.3%) required a temporary discontinuation in the letrozole alone arm.

Phase I

11/12 patients in the Phase I arm required a treatment interruption and dose reduction but none discontinued permanently.


Study 1010

In the Ph1P2 portion of Study 1010, 1 patient (16.7%) experienced Neutrophil count decreased associated with permanent discontinuation from treatment.

In addition, TEAEs associated with permanent discontinuation from treatment were experienced by 1 patient (16.7%) in the Ph1P1 portion of Study 1010.


Study 1001

11 patients experienced TEAEs associated with permanent discontinuation.

No updated data are provided in the 90-day safety update for either Study 1001 or 1010.


      1. Adverse events of special interest


The events of special clinical interest summarised in this section include myelosuppression (neutropenia-related and thrombocytopenia-related events), prolongation of time from beginning of the QRS complex to the end of the T wave as shown on the ECG (QT interval), eye disorders with a focus on cataracts, respiratory disorders with a focus on interstitial lung disease and pneumonitis, and venous thromboembolic disorders.

Data, analyses and discussion were only presented for Study 1023. No specific information was available, nor was there any discussion of these key adverse events identified in the top-line summary from Study 1008.



Comment: This is a significant omission of key safety data and analyses which require evaluation prior to the evaluator making any recommendations about registration for the proposed usage with letrozole and which are also required to inform the PI.
        1. Integrated safety analyses


None provided.
        1. Main/pivotal studies that assessed safety as the sole primary outcome


N/A
        1. Pivotal and/or main efficacy studies

Neutropenia

The SCS states for Studies 1003 and 1023 that the cluster term of NEUTROPENIA comprise MedDRA preferred terms for AEs of neutropenia and neutrophil count decreased.

Comment: These underreport events of low neutrophils due to the abnormal laboratory findings not being required by the protocol to be defined as AEs, as well as granulocytopenia, which may be low neutrophils. This approach has led to underreporting of the frequency and severity of adverse events in both trials, Study 1023 and 1003. Analyses of events provided in the 90-day update for neutropenia for Study 1023 for example, time to first event of neutropenic and duration etc have been presented variously based on the cluster term or abnormal laboratory term. Any presentation of the data in the PI should present the total numbers of events of the abnormal laboratory terms, and use analyses based on these figures in any representations in the PI to minimise the impact of this reporting bias.
Combination of palbociclib and fulvestrant – Study 1023 (as of July 31 2015)

Consistent with the pharmacological activity of palbociclib (that is, cell cycle inhibition), one of the potential primary target organ systems for palbociclib identified from nonclinical studies is the haematolymphopoietic system. Myelosuppression is also observed in clinical studies of palbociclib.

Patients could have more than one episode and only the highest grade was reported.



From [Table 21] 90-day safety update, TEAEs coding to either PT Neutropenia or PT Neutrophil count decreased in the All Treated (AT) set:

  • palbociclib plus fulvestrant arm

    • 287/345 patients (83.2%)

      • 228 or 240 patients with Grade 3/4 severity (66.1% as proportion of AT set); 47 patients with Grade 1/2 severity (13.6% AT set)

  • placebo plus fulvestrant arm

    • 7/172 patients (4.1%)

      • 1 patient with Grade 3 severity, 0 Grade 4 (0.6% as proportion of AT set)

Comments:

  1. Was a patient able to be recorded as having both neutrophil count decreased and neutropenia by MedDRA PT? If so, the sponsor is requested to provide the number of patients where this has occurred and revise the figures collating any potential double reporting for these patients for these 2 events.(Clinical Question)

  2. The figures do not appear to tally between Tables 7 and 21 compared with Table 22 for the number of patients reported to have Grade 3/4 events as defined by the cluster term NEUTROPENIA (Table 21 and subsequent text). 287 patients were reported to have NEUTROPENIA events of any severity (based on figures from Table 7); with the text following Table 21 stating 240 of these patients had Grade 3/4 severity (citing Table 7). However, Table 22 demonstrates that the number of patients with maximum grade of 3 was 191 patients and with a maximum of Grade 4 was 37 and this equals 228 patients. The sponsor is requested to state which are the correct figures and explain how these differences were arrived at. (Clinical Question).

By clinical laboratory findings - abnormal neutrophil counts (not defined as increase or decrease in table 37, 90-day safety update so conservatively taken as all neutropenia by evaluator)

  • palbociclib plus fulvestrant arm

    • 326/339 patients (94.4%) - 2254 events (any severity)

      • 225 patients with Grade 3/4 severity, all as shift from Grade ≤2 at baseline to Grade ≥ 3 postbaseline that is, treatment-emergent (66.4% of AT set)

  • placebo plus fulvestrant arm

    • 23/167 patients (13.8%) – 30 events (any severity)

      • 0 patients had Grade 3 decreases and 2 had Grade 4 decreases (1.2% of AT set - both were a shift from baseline so treatment-emergent)

Comment:

  1. 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:

  1. 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);

  2. 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).

The sponsor attributed causality to palbociclib and fulvestrant in 98.7% of cases reported for TEAEs but no attribution is made for clinical laboratory abnormalities although this is likely to be similar.
Febrile neutropenia

The sponsor states that 3 events of febrile neutropenia occurred in the palbociclib and fulvestrant arm (1 Grade 3 neutropenia and 2 Grade 4) and one event in the comparator arm but no events of neutropenic sepsis or neutropenic infection were reported until a report in November 2015 (after cut-off date) of a patient ([information redacted]) whom the investigator described as the ‘Reported cause of death were neutropenic sepsis, multiple organ failure and disease progression’ with the CIOMS recording the investigator attribution as ‘unrelated to blinded therapy, fulvestrant, concomitant drugs or to a clinical trial procedure’. The sponsor states this SAE to be unrelated to treatment. Palbociclib had been discontinued 22 days earlier and the last dose of fulvestrant was 46 days prior to presentation. The CIOMS records that the neutrophils were 0.35 x 103/mm3 on the day of presentation. Two days later it had increased to 1.61 x 103/mm3, and blood cultures were declared positive for Escherichia coli indicating neutropenic sepsis. The patient died 3 days later. No post mortem was performed.

Comment: The evaluator disagrees with the sponsor regarding this case. The patient was neutropenic and had a documented bacterial infection to account for the presentation with septic shock (neutropenic sepsis), within the Protocol-defined safety period defined as within 28 days of taking palbociclib. There was an accompanying low platelet count and anaemia, which would be consistent with residual toxicities after the recent discontinuation of palbociclib with its known profound myelosuppressive effects (as well as very commonly causing anaemia). The median duration of neutropenia reported for those experiencing > Grade 3 neutropenic events (21 days; range: 1-167) indicate that this may well have contributed to this presentation and a causative effect of treatment cannot be excluded as is stated by the sponsor. The investigator’s narrative was not provided (just a draft CIOMS) and it is to be noted that the investigator would not have had this information about duration of neutropenia when making the attribution of causality and may be unaware of the potentially very long duration of neutropenia associated with palbociclib; this differs significantly from the neutropenia associated with chemotherapy which could reasonably have been expected to have resolved within a 22 day timeframe. This is considered important clinical information and the range (1-42) should be included in the information about median duration for Grade 3 neutropenia in the Neutropenia section in the Precautions in the PI. 90-day Safety Update attests further this with 40.5% of patients experiencing a TEAE of Infection while neutropenic. On balance, the evaluator considers this patient’s cause of death should be considered treatment-related and the PI should include in the Precautions statement that infections, sometimes fatal, have been observed in patients on palbociclib. Sepsis, chronic disease, bone marrow infiltration cannot be ruled out as a contributing factor to the observed pancytopenia, but the most likely cause is palbociclib treatment.

Actions for sponsor: Include fatalities in descriptions of infection in the Precautions section. Add neutropenic sepsis, sometimes fatal and median durations of neutropenia to Precautions section of PI.

Febrile neutropenia experienced by 3 patients in the palbociclib plus fulvestrant arm of

Study 1023 (Cycle 1 Week 3, Cycle 5 Week 4, and Cycle 5 Week 5) was of Grade 3 severity and was considered treatment-related; while febrile neutropenia experienced by 1 patient in the placebo plus fulvestrant arm of this study was of Grade 4 severity but not considered related to treatment.

Neutropenia was almost universally detected in the palbociclib and fulvestrant arm: 326/339 patients (96.2%), including 189 patients (55.8%) with Grade 3 decreases and 36 patients (10.6%) with Grade 4 decreases in these counts compared with 23/167 patients (13.8%) in the placebo plus fulvestrant arm with any abnormal absolute neutrophil count (0 Grade 3, 2 (1.2%) Grade 4).



Comment: The hyperlinks to the Summary of Clinical Safety from the 90-day safety update are all incorrect and direct the evaluator to an unrelated section of that summary document. It appears the discussion of additional events and data in the 90-day safety summary is not referring to the same Summary of Clinical Safety data presented to the TGA.

The sponsor presented data analysing the baseline characteristics of those developing Grade 3/4 neutropenia, and reports no clear predictive factors. While a high percentage of patients developing Grade 3 neutropenia went on to develop Grade 4 neutropenia at a later treatment time point, there was no clear pattern and this was also observed in those with lower grade earlier neutropenic AEs. Dose reduction strategies were effective but events of high-grade neutropenia were still observed in some patients despite this.



Comment: The onset of significant and severe neutropenia is not predictable and requires ongoing monitoring throughout the treatment period.

Time to onset of neutropenia (based on Clinical laboratory findings)

The median time from first dose to the >Grade 3 neutrophil count was shorter in the palbociclib plus fulvestrant arm (30.5 [13 – 587] days) than in the placebo plus fulvestrant arm (214 [15 – 538] days).

In the palbociclib plus fulvestrant arm, the median time from first dose to onset of first neutropenia episode of any severity grade (15 days), Grade >2 (15 days), Grade >3 (16 days), or Grade 4 (19 days) was shorter than 1 treatment cycle.



Comment: The PI figures for this do not reflect the 31 July cut-off data and require updating (PI Comments), as the updated data with its much higher upper limit of the range (from 140 days to 317 days) indicate clearly that an episode of neutropenia can occur for the first time at any time during treatment. There are appropriate recommendations for monitoring on day 14 of the first 2 cycles and prior to the commencement of each cycle in the PI.

Median duration of neutropenia (based on Clinical laboratory abnormalities)

The median duration of any grade neutropenia by patient (that is, duration of all episodes combined) reported in the palbociclib plus fulvestrant arm was 179 (3 – 573) days across all cycles, while the median duration of Grade >3 neutropenia and Grade 4 neutropenia across all cycles was 21 (1 – 167) days and 10.5 (2 – 28) days, respectively.

Neutropenia and infections (based on Clinical laboratory abnormalities)

The sponsor reported that 40.5% of patients who had a laboratory finding of neutropenia (any severity grade) in the palbociclib plus fulvestrant arm experienced concomitant TEAEs within the MedDRA SOC Infections and infestations as follows:

  • 8 patients (2.5%) with any severity grade neutropenia experienced a concomitant Grade 3/4 TEAE within this SOC;

  • 3 patients (1.3%) with Grade 3/4 neutropenia had a concomitant Grade 3/4 TEAE within this SOC (Grade 3 Erysipelas, Grade 3 Upper respiratory tract infection, and Grade 4 Cellulitis (1 patient each).

Comment: The evaluator considers that the patient described above who died of neutropenic sepsis 24 days after discontinuing palbociclib should be included in this analysis and also in the PI. The Precautions section ought to state that neutropenia and neutropenic sepsis were observed in patients receiving palbociclib and fulvestrant in the Neutropenia Section. Severe infections including fatal infections have been observed in patients receiving palbociclib and fulvestrant should be included in the Infections section in the Precautions.
Infections

TEAEs within the MedDRA SOC Infections and infestations were more common in patients in the palbociclib plus fulvestrant arm (47.0%) than in the placebo plus fulvestrant arm (30.8%); however, the frequency of Grade 3/4 TEAEs was similar between the 2 treatment arms (3.2% and 2.9%, respectively).

The most frequently reported infections or infestations (that is, >2% of patients) for the palbociclib plus fulvestrant arm were:



  • nasopharyngitis (13.0%);

  • upper respiratory tract infection (9.3%);

  • urinary tract infection (7.5%);

  • bronchitis (3.2%);

  • rhinitis (2.9%);

  • influenza (2.6%);

  • sinusitis (2.3% each);

  • conjunctivitis (2.3% each).

There was a background rate of nasopharyngitis (8.1%), upper respiratory tract infection (7.0%), urinary tract infection (6.4%), and influenza (4.7%) in the placebo plus fulvestrant arm (pneumonia [2.3%] was also reported most commonly for that treatment arm.)
Exposure and neutropenia

Comment: This would be consistent with the observed effect of fewer episodes of neutropenia when the dose is reduced.
Combination of palbociclib with letrozole - 1008 top-line summary

No data were presented for evaluation
        1. Other efficacy studies

Combination of palbociclib and letrozole –Study 1003, Study 1010

(Study 1027 does not provide evaluable data due to ongoing blinding of treatment allocation).
Study 1003

As of 2 January 2015 as reported in the SCS, TEAEs of neutropenia occurred in:

  • 75.9% of those receiving palbociclib and letrozole in the Phase II part of the study

    • 42 patients (50.6%) Grade 3 severity – 3 patients discontinued permanently

    • 5 patients (6.0%) Grade 4 severity – 2 discontinued permanently

  • 91.7% of patients in the Phase I part of the study

    • 8 patients (66.7%) Grade 3, 2 patients (25%) Grade 4 – none discontinued permanently

Based on laboratory abnormalities data, 3 patients had Grade 4 events in the Phase I part yet the MedDRA PT of neutropenia indicates only 2 patients.

Comment: Neutropenia is established by a blood test and clinical laboratory measurement, regardless of MedDRA PT. The sponsor’s protocol did not require laboratory abnormalities of Grade 4 to be considered AEs, unless accompanied by symptoms or some specific change in the study drugs or concomitant therapy. Consequently, no accounts of any treatment discontinuations or other outcomes are presented for the 3rd patient with laboratory findings of Grade 4 neutropenia (Clinical Question).
Phase II

NEUTROPENIA was reported most frequently (63 patients [75.9%]), and considered treatment-related in 62/63 patients.

Grade 1 2 patients (2.4%);

Grade 2 14 patients (16.9%);

Grade 3 42 patients (50.6%) - 41 patients Neutropenia,1 Neutrophil count decreased;

Grade 4 5 patients (6.0%)

NEUTROPENIA was experienced by 4 patients (5.2%) in the letrozole alone arm and considered related to treatment in 2 patients:

Grade 1: 1 patient; Grade 2: 2 patients; Grade 3: 1 patient.

Comment: Letrozole is not normally associated with neutropenia, particularly Grade 3 events.

By contrast, in the Phase II study, clinical laboratory measurements identified 77/82 (93.9%) patients with abnormal neutrophil counts including 47 patients with Grade 3 events (57.3%) and 5 patients (6.1%) with Grade 4 events, all of which occurred after commencing treatment that is, treatment-emergent (shift from <Grade 2 to >Grade 3 from baseline was the same 63.4%).

In the letrozole alone arm, 13/77 patients (16.9%) had abnormal laboratory findings of absolute neutrophil counts of whom 2 (2.6%) had Grade 3 abnormal results and none had Grade 4 abnormal results.

The use of laboratory abnormalities rather than AEs meant 14 patients (18% of the As Treated safety set) more than the use of MedDRA terms which define the TEAEs were reported including 5 more patients with Grade 3 events.



Comment:

  1. Overall, the protocol-defined approach to recording adverse events has meant 20% of this Phase I/II study population who experienced an event of neutropenia including 6.3% (6/95) patients experiencing Grade 3 and 4 events were not captured by the MedDRA terms and are thus excluded from analyses that report TEAEs.

  2. All the Grade 3 and 4 events were treatment-emergent but not recorded as such and add an additional 6/95 patients with severe neutropenia to the palbociclib and letrozole arm across this entire trial that is, 6.3% of the very small population in this trial.

Comments: The evaluator considers these laboratory-determined events to be more accurate as treatment-related events and that these figures should be used in any tables in the proposed draft PI for this usage when Study 1008 is submitted (PI Comments). Throughout the analyses, the evaluator considers there is underreporting of events of neutropenia against which to record the total number of actions taken as a result (dose reductions, discontinuations etc), and no classification of these as related to treatment. Reporting of these events is included in this subanalysis for events of special interest but not elsewhere in the CSR when neutropenia is discussed or presented.

Such data collection and underreporting is of concern, and particularly for less common or rare events - a specific request for clinical laboratory data abnormalities from all the trials where it is not explicitly stated, will be sought for renal function and hepatic function abnormalities.


Dose interruptions, reductions (by cluster NEUTROPENIA)

All 42 patients with Grade 3 NEUTROPENIA in the palbociclib plus letrozole arm had their dose reduced/interrupted or had their treatment cycle delayed, while 3 of the 5 patients with Grade 4 NEUTROPENIA had their dose reduced/interrupted or had their treatment cycle delayed. (The remaining 2 of the 5 patients with Grade 4 Neutropenia were permanently discontinued from treatment). Discontinuations due to clinical laboratory abnormality of neutropenia could not be located by the evaluator.

No baseline or demographic characteristics were predictive of who might develop neutropenia.



Comment: No information is presented regarding actions taken for those 5 additional patients who had Grade 3 abnormal neutrophil counts by laboratory findings. It would not be standard clinical practice not to respond to such events, especially in a clinical trial setting, and the sponsor is invited to comment.
Time to onset, median duration (clinical laboratory findings)

Based on clinical laboratory findings, the median time to first onset was 15 days (range: 13-141), but first Grade >3 episodes were recorded up to 798 days after starting and the longest time to develop the lowest neutrophil counts was 1066 days. The median duration of neutropenia of any grade was 292 days (range: 6-1440) for the palbociclib and letrozole arm but for Grade 3 was 43 days (range: 1-254) and for Grade 4 was 7 days (range 4-33). The median time to recovery (that is, >1500 absolute neutrophil count) from lowest neutrophil count among patients with Grade ≥ 3 neutropenia in that treatment arm was 99 days.

Comment: Essentially, neutropenia can occur at any time, tends to resolve quite slowly and the PI should include these figures to ensure this information is available to clinicians as this is different from cytotoxic-induced neutropenia. Dose reduction decreases the likelihood of further events but these still occur. The shorter duration for Grade 4 events is likely to be due to the strict withholding and dose reduction that occurs, whereas prolonged lower grade neutropenia is likely to be associated with continuation of the treatment.
Infections (based on Clinical laboratory findings)

As of January 2015, infections were reported more commonly in the palbociclib and letrozole arm (59% all grades; 6% Grade 3/4) compared with 33.8% in the letrozole alone arm (no Grade 3/4). These events included a range of bacterial, viral and fungal infections, none of which led to treatment discontinuation. The Phase II part of the study, 42.9% of patients with neutropenia (as defined by clinical laboratory abnormality) of any severity developed an infection or infestation, and 2.6% had a Grade 3/4 event. 26.9% with Grade 3/4 neutropenia developed an infection.

No TEAEs of febrile neutropenia, neutropenic sepsis, or neutropenic infection were reported in this Phase I/II study. Infections occurred in 7 patients, all Grade 1 or 2.



Comment: The use of concomitant granulocyte colony stimulating factor support in any of the studies to reduce the risk of infection has not been discussed and the sponsor is requested to present the proportion of patients in each study treated with colony stimulating factors, and any effect on the duration of neutropenia. It is important to include this information and to include a statement as to whether GCSF use is appropriate in the PI (Clinical Question), noting that absence of its use may be as informative of indicating how often it was used.
Study 1010
Phase I

Palbociclib as monotherapy (100 mg and 125 mg daily dosing) in patients with solid tumours was associated with neutropenia in 83.3% and 67.7% patients at the dose levels, respectively. Infections were observed but not considered related to palbociclib treatment. Given the limited relevance to the proposed usage, causality has not been evaluated further by the evaluator.
Phase I Part 2

Neutrophil count decreased was experienced by all 6 patients (100%) participating in this portion of the study as of 31 March 2015 (Grade 2 in severity in 1 patient, Grade 3 in 3 patients, and Grade 4 in 2 patients) by MedDRA term or clinical laboratory findings. All changes were considered treatment-related. 33.3% experienced infections but none was considered related to treatment by the sponsor.

Comment: Narratives were not available and the causality for these events was not evaluated. It is considered already established that patients receiving palbociclib are at an increased risk of infection (statement in the PI).

As with the Ph1P1 portion of the study, the sponsor indicates that no reports of febrile neutropenia were received in the Ph1P2 portion of the study (90-day safety update).

The SCS summary of febrile neutropenia across studies in malignant disease is out of date and thus was not evaluated.7

        1. Thrombocytopenia

Combination of palbociclib with fulvestrant Study 1023

This was presented in 2 ways: as laboratory findings or as TEAEs in Study 1023 as of 31 July 2015, based on a cluster term THROMBOCYTOPENIA comprising the MedDRA PTs of Thrombocytopenia and Platelet count decreased. TEAEs coding to PT Thrombocytopenia (13.0%) or PT Platelet count decreased (10.1%) were experienced by patients receiving palbociclib plus fulvestrant but not the comparator arm in this study. 8 patients (2.3%) experienced a Grade 3 (6 patients) or Grade 4 (2 patients) event and a single patient with Grade 3 toxicity discontinued permanently due to this AE, while 3 others with Grade 3 and 1 with a Grade 4 event had their dose reduced or treatment interrupted. The sponsor reports that ‘(based on Haemorrhage terms, excluding laboratory terms, within Standardized MedDRA Queries [Narrow])’, there were no bleeding episodes.

Clinical laboratory findings indicated 210 patients (61.8%) in the palbociclib plus fulvestrant arm had abnormal platelet counts as of 31 July 2015, including 5 patients (1.5%) with Grade 3 decreases and 3 patients (0.9%) with Grade 4 decreases in these counts. In comparison, 17 patients (10.1%) in the placebo plus fulvestrant arm had abnormal platelet counts, all of Grade 1 severity. A shift in platelet counts from Grade ≤2 at baseline to Grade ≥ 3 post baseline was observed for 8/340 patients (2.4%) in the palbociclib plus fulvestrant arm No such shifts in platelet counts were observed in the placebo plus fulvestrant arm.

Comments:


  1. The definition in the Protocol of an AE with respect to an abnormal test finding is the same as Study 1003 and has once more led to a level of under-reporting of the events for the population as a whole, especially for lower grade AEs of thrombocytopenia. The comparator arm provides the expected baseline rates and this is much higher in the experimental arm. The total number with Grade 3 or 4 TEAEs or laboratory abnormal results is the same although the distribution is different. The sponsor is requested to provide an explanation. Are the TEAEs a subset of the laboratory test abnormalities?

  2. The rate of epistaxis is noted to be increased in Study 1008 for the palbociclib arm and sponsor is requested for Study 1023, to state whether searching using any other MedDRA terms that covers any event of bleeding that is, captures events including but not limited to haemorrhage, bleeding, epistaxis or bruising, yields any events absolutely, and whether these were associated with the events of thrombocytopenia. (Clinical Questions).
Combination with letrozole and palbociclib – Study 1008 top-line summary (no CSR available)

No specific data, analyses or discussion is presented and the CSR is required to evaluate this risk.
Combination with letrozole and palbociclib – Study 1003

The cluster term THROMBOCYTOPENIA used PTs coding to thrombocytopenia and platelet count decreased. The MedDRA PT of thrombocytopenia reported in the TEAE tables did not capture all the events of significant decrease in platelets related to treatment.

As of January 2 2015:

Phase I


  • 3 patients in the (25%) had developed thrombocytopenia – no events of platelet count decreased; 2 Grade 2, 1 Grade 1

  • Based on clinical laboratory tests, 8/12 patients (66.7%) had abnormal platelet counts, although no Grade 3 or Grade 4 decreased counts were reported;

Phase II

  • 19 patients (22.9%) in the part developed thrombocytopaenia/platelet count decreased with palbociclib and letrozole compared with 2 patients on letrozole alone (2.6%);

    • 2 were Grade 3 events, 0 Grade 4 events

      • 2 patients had a dose reduction/interruption/delay but none discontinued permanently;

  • Based on clinical laboratory tests, 53/82 patients (64.6%) had abnormal platelet counts

    • 3 (3.7%) Grade 3 events, no Grade 4;

      • shift from Grade ≤2 to Grade ≥ 3 occurred in 3 patients;

      • 12/77 (15.6%) on letrozole alone had an abnormal result;

      • 1 Grade 3 events, no Grade 4 ;

The sponsor reports that there were no associated events of bleeding using the term ‘haemorrhage’.

Comment: An appropriate statement should be included in the PI to reflect the nearly 4-fold and almost 50% absolute increase in rates of all grades of thrombocytopenia with palbociclib; these changes should be recorded as very common with a percentage in any ADR table of a draft PI when the CSR for Study 1008 is submitted (PI Comments).

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 events or any other bleeding events were associated with thrombocytopenia/platelet count decreased is not discussed and the sponsor is requested to state the platelet count at the time of each event of epistaxis for these patients as well as for any patients in either treatment arm experiencing an event of bleeding or haemorrhage in any organ system (Clinical Questions).



Study 1010 in Japanese Patients with Advanced Malignant Solid Tumours, Including Breast Cancer, Receiving Palbociclib Alone (Phase I Part 1) or in Combination with Letrozole (Phase I Part 2 and Phase II)

Phase I


Two events: 1Grade 2 (100 mg QD) cohort and 2 events in the 125 mg cohort (1 Grade 1 and 1 Grade 4) events of thrombocytopenia by TEAE or laboratory finding were observed.

Comment: The report is inconsistent with the 125 mg cohort being stated to be Grade 1 and Grade 4 events in paragraph 1 (p196, SCS) then Grade 3 and Grade 4 in the second paragraph. The management was of temporary discontinuations and dose reduction, respectively.

Phase I Part 2

Grade 1 or 2 events were reported as TEAEs in 4/6 patients and 5/6 patients using laboratory findings. No action was required.

No report was included in the SCS for thrombocytopenia in the Phase II part of this Study although the 90-day safety update refers to safety events for 32 patients being included in this SCS.


        1. QT prolongation


A potential of palbociclib for QT prolongation and hemodynamic effects was identified from in vitro assays and/or in vivo cardiovascular dog studies. Palbociclib caused a small but statistically significant increase of action potential duration at 90% repolarization at 10 µM (4475 ng/mL) in the dog Purkinje fiber assay and had a concentration associated with 50% inhibition (IC50) at 3.2 µM (1432 ng/mL) in a human ether-à-go-go related gene assay.
Combination of palbociclib and fulvestrant Study 1023

As of 31 July 2015, evaluations of QTc were based on the data reported for 150 patients in the palbociclib plus fulvestrant arm and 109 patients in the placebo plus fulvestrant arm who had both baseline and postbaseline ECG data. Twelve-lead triplicate ECG recordings were performed in patients with advanced breast cancer receiving palbociclib plus fulvestrant or placebo plus fulvestrant in Study 1023 at screening and end of treatment.

Comment:

  1. This approach lacks the rigour necessary to characterise ECG abnormalities or determine the potential for palbociclib to cause QT prolongation; as such, this study provides only very limited information regarding potential ECG abnormalities that may be observed while on treatment.

  2. The denominator changed for this update (and therefore the rate of events recorded) from that reported in the SCS as more patients had completed the trial and had their final recording.

One patient in the palbociclib plus fulvestrant arm and 1 other patient in the placebo plus fulvestrant arm had a post baseline QTcF of ≥ 500 msec (90-day safety update). The proportion of patients with a post baseline QTcB of ≥ 500 msec was higher in the palbociclib plus fulvestrant arm (3.3%) than in the placebo plus fulvestrant arm (1.8%). The proportions of patients who had a >60 msec maximum increase from baseline in QTcF and QTcB were also higher in the palbociclib plus fulvestrant arm (2.0% and 2.7%, respectively) than in the placebo plus fulvestrant arm (0.9% for each QTc measurement).

One patient in the palbociclib plus fulvestrant arm of Study 1023 experienced an SAE of Grade 3 Electrocardiogram QT prolonged (resolved within 2 days) as of 31 July 2015, which coincided with a Grade 2 SAE of pericarditis. Palbociclib therapy was temporarily discontinued in response to these events and was subsequently restarted, although at a reduced dose of 100 mg QD; the events did not reoccur thereafter. No new SAEs of Electrocardiogram QT prolonged were reported in this study as of 31 July 2015.



Comment: After reviewing the details of this SAE, the evaluator agrees with the investigator who ‘considered there was a reasonable possibility that the events pericarditis and QTc prolongation were related to the blinded therapy and not related to fulvestrant, to a concomitant medication or to a clinical trial procedure’ and also with the sponsor that there is still uncertainty about attribution of causality to the treatment received given the clinical events surrounding the admission with pericarditis. A dose-reduction was made, and no further abnormalities were recorded on rechallenge. It is appropriate, given the preclinical findings and this case, that QT prolongation is investigated further and reported. It was a secondary endpoint of Study 1008, but not included in top line summary in this application so remains an important, outstanding issue needing evaluation. It is appropriately listed as an important potential risk in the safety specification of the RMP.

The following relevant TEAEs were experienced by patients in that treatment arm: Tachycardia (9 patients [2.6%]), Presyncope (5 patients [1.4%]), Bradycardia and Palpitations (3 [0.9%] each), Atrial fibrillation and Sinus tachycardia (2 [0.6%] each), as well as Electrocardiogram QT prolonged, Extrasystoles, Syncope, Ventricular extrasystoles, and Ventricular tachycardia (1 [0.3%] each). Among these relevant TEAEs, Electrocardiogram QT prolonged (Grade 3 in severity) along with Atrial fibrillation, Bradycardia, Tachycardia, Ventricular extrasystoles, and Ventricular tachycardia (all ‘Grade 1’ in severity – see evaluator comment below) experienced by 1 patient each were considered to be related to treatment.



Comment: The Study protocol states that CTCAE v 4.0 was used to grade events. There is no classification of Grade 1 for ventricular tachycardia, as this arrhythmia necessarily requires medical attention and potentially intervention. Similarly, there are no CTCAE terms for ‘bradycardia’, ‘tachycardia’ or ‘ventricular extrasystoles’ to which the term Grade 1 could be attached. The sponsor is requested to comment on which grading system was used for these assessments and to provide updated details and classifications regarding these adverse events as per the protocol, and the clinical details surrounding the event of ventricular tachycardia (Clinical Question).
Combination with letrozole and palbociclib – Study 1008 top-line summary (no CSR available)

Although a secondary endpoint, no data were presented on the outcome of the ECG substudy in 60 patients in this study. An event of Grade 3 QT prolongation is included in the summary of Grade 3-5 TEAEs in the palbociclib and letrozole arm but no further information is provided.

Comment: The full CSR is required and no comment or recommendation can be made on the limited information provided.
Combination with letrozole and palbociclib Study 1003

One of 12 patients had a maximum increase from baseline in QTcF interval of ≥ 30 and <60 msec (Grade 2) in the Phase I part of this study and no patients had a QTcF value of >500 msec.

In the Phase II part, cardiac events were infrequent with 3 in the palbociclib and letrozole arm and 4 in the letrozole arm. There were no reports of the following preferred terms in the palbociclib and letrozole arm during the Phase II portion of the study: syncope, cardiac arrest, convulsion, electrocardiogram QT prolonged, sudden death, torsade de pointes, ventricular fibrillation, ventricular flutter, or ventricular tachycardia.



Comment: QT prolongation was noted in the preclinical studies, and there has been one case reported in Study 1023 and one in Study 1008. Other cardiac adverse events were infrequent in patients receiving palbociclib.
Study 1010

As of 31 March 2015 (SCS), none of the patients with ECG data available for evaluation had postbaseline QTc values of >500 msec in this portion of the study, and none had increases from baseline in QTc values of ≥ 30 msec (Study 1010). No data are provided for the Phase II part of the study in the SCS.

The 90-day safety update reports that as of 31 July 2015, no patients had an on-study post baseline QTcS, QTcF, and/or QTcB value longer than 500 msec in completed Studies 1003, 1010 Phase I, 1001, 1002, and 1004. A single patient in Study 1001 had a maximum baseline change >60 msec but was able to carry on treatment.



Comment: A review of the CSR for Study 1001 PK/safety study included a patient in the ‘Summary of ECG outlier analysis’ with a QTcB ≥ 500msec in the 75mg dose level group but no reports where QTcF≥ 500msec .

Summary: QT prolongation and VT were observed in Study 1023 in the experimental arm. QTcF prolongation from baseline >60msec occurred more commonly in the palbociclib and fulvestrant arm compared with the placebo and fulvestrant arm. The responses to the clinical questions should provide some clarification surrounding the event of VT.
        1. Eye disorders with a focus on cataracts

Combination of palbociclib and fulvestrant Study 1023

Eye disorders were more frequently experienced by patients in the palbociclib plus fulvestrant arm (TEAEs: 22.3%; treatment-related AEs: 10.7%) than in the placebo plus fulvestrant arm (TEAEs: 10.5%; treatment-related AEs: 2.9%).
Cataracts

3 patients developed cataracts in the palbociclib and fulvestrant arm compared with none in the comparator arm. For 2 of the cases reported and where the safety update/clinical summary include a brief review, the two respective investigators clearly considered the cataract development or rate of development to be related to palbociclib, and the sponsor disagreed and does not consider them treatment-related.

Clinical evaluator comments on cataracts:



  1. The clinical evaluator was able to locate the CIOMS for [information redacted] and notes the investigator has remained adamant this is treatment-related.

  2. No narrative was available for [information redacted], and for the first case reported, the reference hyperlink in the 90-day safety update (as with all but one tried by the evaluator), identified an unrelated table; therefore it is not possible to evaluate this adverse event.

  3. This remains an important identified risk as it would appear both investigators consider this related. This should be listed as such in the RMP.

Overall, the frequencies of any TEAEs (22.3%) and any treatment-related AEs (10.7%) within the MedDRA SOC Eye disorders were reported more frequently in the palbociclib plus fulvestrant arm of Study 1023 as of 31 July 2015 were (90-day safety update). There was a substantial increase in these events reported between the previous cut-off date of 5 December 2014, of 5.2% more TEAEs and 3.2% more treatment-related events. No CTCAE grading is provided for these and there were no narratives to determine the severity or action required with respect to the study drugs.

These TEAEs and treatment-related TEAEs in the palbociclib arm include a more frequent occurrence of conditions which threaten visual acuity as well as events describing visual impairment:



  • Vision blurred, visual impairment, visual acuity reduced, myopia;

  • retinal degeneration, macular fibrosis, cataract, panophthalmitis;

Comments:

  1. No narratives or supporting data was provided for evaluation of how relation to treatment was determined from the baseline TEAEs.

  2. Nonetheless, the clinical evaluator notes the much higher rate of treatment-related events which will cause visual impairment, with consequent impairment of function and quality of life. This warrants a Precaution given:

  1. the frequency is high

  2. they have been designated as treatment-related

  3. some of the events described above are not reversible

  4. many are likely to cause significant local discomfort without threatening vision.

  5. PI does not currently have up to date data on these events and the frequency and the reporting of ‘vision blurred’, ‘lacrimation increased’, ‘dry eyes’ does not accurately or adequately reflect the incidence nor the severity of the events observed in this latest safety update.

  6. The CMI should clear identify these risks.

  7. The RMP should include terms that capture visual impairment in addition to the specific adverse event of cataracts for targeted pharmacovigilance.

  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 in the palbociclib and fulvestrant arm. 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.
Study 1008

No data, analyses and discussion as an event of special interest is provided from Study 1008, and the reported rates in the ‘Adverse Drug Reaction’ table cannot be evaluated due to there being no data or analyses provided.
Study 1003

In Phase II (Ph2P1+Ph2P2), a higher percentage of patients in the palbociclib plus letrozole arm (17 patients, 20.5% [treatment-related 10.8%]) had at least 1 TEAE in the SOC of Eye disorders compared with the letrozole alone arm (4 patients, 5.2% [treatment-related 1.3%]). Treatment emergent events of vision blurred, cataract (1).

Significant treatment-emergent adverse events, by MedDRA preferred term, which threaten vision in the palbociclib and letrozole arm and letrozole alone arm were:



    • Cataract 1.2% versus 0

    • Vision blurred 2.4% versus 0

    • Visual acuity reduced 2.4% versus 0

    • Visual impairment 3.6% versus 3.0%

    • Blindness 1.2% versus 0% (this was due to cerebral metastases)

The narrative for the 83 year old who developed a cataract indicates this was considered age-related. The episode of blindness occurred with brain metastases so is central blindness rather than an eye disorder per se.

A further case of bilateral cataracts was reported in the Phase I population as of the 2 January 2015 cut-off (SCS). Events of lacrimation, visual impairment and dry eye were reported to be treatment-related in the SCS.


Study 1010

Phase I

No AEs of Cataracts was reported in the Phase I portion of Study 1010. In the Ph1P2 portion of the study, 1 patient (16.7%) experienced Grade 1 Conjunctival haemorrhage and the other patient experienced Grade 1 Vision blurred within the MedDRA SOC Eye disorders. These TEAE were considered to be unrelated to study treatment.

No information on the rates of visual disorders or cataracts could be located in the 90-day safety update for the Phase II part of the study.

Study 1001

No information was provided about cataract formation or visual adverse events for Study 1001 and no events were located in a search of the CSR by the evaluator.

Comments:

  1. Cataracts are diagnosed commonly in the older age group, who will form a significant proportion of patients in the proposed target population. An acceleration of the rate of cataract formation by palbociclib cannot be excluded and this needs to be a prespecified adverse event of interest in ongoing randomised clinical trial as routine pharmacovigilance will not be able to differentiate between background rates and a treatment effect.

  2. Although there was a link postulated from the preclinical models between cataract formation and hyperglycaemia, this should not be presumed to be the mechanism and the absence of hyperglycaemia should not discount the risk of cataract formation.

  3. The increased frequency of adverse events affecting vision by terms that are not actual diagnoses means the potential for cataracts to be the cause is not excluded. In any case, the excess of these events supports the need for a Precaution as above.
        1. Hyperglycaemia-related events


As of 31 July 2015, a total of 5 patients (1.4%) in the palbociclib plus fulvestrant arm and 4 patients (2.3%) in the placebo plus fulvestrant arm experienced hyperglycaemia.

In each treatment arm, all but 1 of the TEAEs of Hyperglycaemia was of Grade 1 severity. The remaining patients (one in each treatment arm) experienced Grade 3 hyperglycaemia. In addition, diabetes mellitus (Grade 1) was experienced by 1 patient (0.3%) in the palbociclib plus fulvestrant arm and glycosylated haemoglobin increased (Grade 1) was experienced by 1 patient (0.6%) in the placebo plus fulvestrant arm. As stated earlier in this section, none of the 3 patients who experienced cataracts in the palbociclib plus fulvestrant arm of the study experienced any hyperglycemia-related events as of 31 July 2015.

No data were submitted on this for evaluation from Study 1008.

Comment: These rates appear to be very low, but given this was a significant signal in the preclinical studies, and it is also readily monitored as part of routine investigations, it is appropriate that it remains in the RMP as an important potential risk for palbociclib.

Study 1003

Phase I/II Study

One patient in the Phase I part had a TEAE of hyperglycaemia (Grade 2) and one patient in the palbociclib and letrozole arm had a TEAE of diabetes mellitus (Grade 2). Neither was considered treatment-related but it is not possible to evaluate causality for either as no details are provided.

Details of eye disorders were provided (as above) for consideration of hyperglycaemia-related events. Cataracts occurred in both parts of the study (1 patient in each Phase) but neither had hyperglycaemia-related events.

Comment: The sponsor is requested to provide details of clinical laboratory findings for glucose for the 2 patients with cataracts in this study any elevated HbA1c results as this is more likely to capture events of hyperglycaemia than isolated terms used to identify TEAEs. (Clinical Question)

No information from Study 1010 is provided but a review of the clinical chemistry tables did not reveal any events. A single case of hyperglycaemia is recorded in the Study 1001 CSR.


        1. Interstitial lung disease and pneumonitis

Combination of palbociclib and fulvestrant Study 1023

A summary of TEAEs including those coding to PTs within the MedDRA SOC Respiratory, thoracic and mediastinal disorders and a TEAE of pneumonia within the SOC Infections and infestations experienced by at least 2 patients each in either treatment arm of Study 1023 as of 31 July 2015 is provided in the 90-day safety update. No TEAEs of interstitial lung disease or pneumonitis were reported in this study as of that data cutoff date.

A review of the data tables in this study indicate that one patient in the palbociclib and fulvestrant arm had a present medical history of interstitial lung disease and one in the comparator arm had pneumonitis - both these were listed as ‘present’ suggesting the patients were enrolled with this condition still active but these were not specific exclusion criteria. No new cases were reported using these specific terms.

Respiratory events were experienced more frequently by patients in the palbociclib plus fulvestrant arm (TEAEs: 44.9%; treatment-related AEs: 15.4%) than in the placebo plus fulvestrant arm (TEAEs: 30.2%; treatment-related AEs: 8.1%).

Study 1008

No specific discussion or analyses were provided in the top-line summary document for Study 1008. Review of the TEAE tables reveals a single case of Grade 3 pneumonitis in the palbociclib and letrozole arm, a single Grade 2 event of interstitial lung disease (reported as treatment-related but this remains blinded, and an SAE) and 2 deaths from ‘respiratory failure’ and ‘pulmonary fibrosis’; there is a single, Grade 2 event in the comparator arm. No CIOMS or narratives were available unblinded to assess these events further.
Study 1003

No updated information was included in the 90-day safety update for Study 1003 or 1010. As of 2 January 2015, no cases of pneumonitis, interstitial lung disease, hypoxia or dyspnoea were reported using MedDRA preferred terms in the palbociclib and letrozole arm and a single case of Grade 2 pneumonitis was recorded in Study 1003 in a patient receiving letrozole alone.
Study 1010

No events of interstitial lung disease or pneumonitis were reported in the Phase I part and no details are provided for the Phase II part of this study. In the Ph1P2 portion of Study 1010, 2 patients (33.3%) experienced respiratory disorders, Grade 1 TEAEs of Dysphonia and Upper-airway cough syndrome, of which Dysphonia was considered to be related to study treatment.
Study 1001

A single case of ‘allergic alveolitis’ resulted in permanent discontinuation in a patient receiving 100 mg on a 21/28 days dosing schedule. No narrative or CIOMS could be located for this case.

Comment: The terms ‘interstitial lung disease’ and ‘pneumonitis’ are specific diagnostic terms and it is not possible to exclude that some of those with ‘dyspnoea’, ‘cough’, ‘dyspnoea exertional’, ‘hypoxia’, which are all reported with far higher frequencies in the palbociclib and fulvestrant arm do not have either of these 2 diagnoses. It is appropriately listed as an identified important risk in the RMP, and the Study 1008 CSR when submitted should provide narratives to permit evaluation and assessment of causality of the events in that trial.

The current PI does not adequately capture the increased rate of adverse events of cough, dyspnea and the presentation in the PI of only what the sponsor has determined to be adverse drug reactions (which appear to be a subset of treatment-related AEs) has not been updated and therefore cannot be evaluated for the latest dataset. As such, it currently does not accurately or adequately represent the event rates in this trial.


        1. Venous thromboembolic disorders


The evaluator has broadened the evaluation to include arterial thromboembolic events.
Combination of palbociclib and fulvestrant Study 1023 (as of 31 July 2015)

In table 14.3.1.8.6.1 from Study 1023, 7 events of pulmonary embolism were recorded: 1 Grade 1, 4 Grade 3, 1 Grade 4 and a death. 2 DVTs as well as a single case of subclavian vein thrombosis and vena cava thrombosis were reported in the palbociclib and fulvestrant arm.

As of 31 July 2015, a single case of a pelvic DVT was reported in the placebo and fulvestrant arm.


Combination of letrozole and palbociclib Study 1008 top-line summary (no CSR)

No specific discussion or analyses were provided in the top-line summary document for Study 1008, using terms likely to capture all events of thrombosis and embolism. For those events presented of pulmonary embolisms, treatment allocation was not unmasked and there were no accompanying unblinded narratives.

Comment: The full CSR is required for detailed evaluation and it is not possible to evaluate the data provided, nor provide comments on the serious, potentially life-threatening events.
        1. Other studies

Combination of letrozole and palbociclib Study 1003 (Phase I/II)

As of 31 July 2015, in Study 1003, 2/12 patients in the Phase I part of the study and 5/83 patients in the Phase II part receiving palbociclib and letrozole had an adverse event recorded of pulmonary embolism; 2/83 had a DVT in the Phase II part. Six of these events were recorded as Grade 4. There was also a case in the Phase II part of ischaemic colitis (Grade 3), which was considered treatment-related and treatment was discontinued in a woman receiving palbociclib and letrozole (see SAEs Study 1003). No cases of DVT or PE were recorded in the letrozole alone arm.

In the investigator-initiated research using palbociclib monotherapy, there was a death on-study from ischaemic colitis which the investigator considered related to treatment but the sponsor does not. The narrative could not be located for evaluation and the sponsor is requested to provide a copy in their response (Clinical Questions).8


Study 1010

No venous thromboembolic events have been reported in this study in the SCS or 90-day safety update.

In Study 1001, a patient receiving palbociclib experienced a Grade 4 pulmonary embolism.

Study 1004 conducted in patients with myeloma; there was a report of a deep vein thrombosis.

Comments:


  1. a Precaution with the heading’ Thrombosis and thromboembolism’ should be included in the PI, citing that there have been DVTs, pulmonary embolisms and arterial thromboembolic events including some that have been fatal, given the:

  1. 10 arterial or venous thromboembolic or thrombotic events occurring in those receiving palbociclib and letrozole compared with none in the letrozole alone arm in the small study population (95 patients received palbociclib and letrozole) in Study 1003;

  2. 9 events (including 1 death) in Study 1023 in the palbociclib and fulvestrant compared with one Grade 2 event in the placebo and fulvestrant arm;

  3. the Grade 4 pulmonary embolism in a patient in Study 1001;

  4. The evaluator could not locate the narrative for the fatal event of ischaemic colitis in the investigator-initiated study due to the cross-referencing hyperlink being incorrect; given there have been 2 cases of this otherwise uncommon arterial thrombosis, these arterial events merit inclusion in the PI under the Precautions section ‘Thrombosis and thromboembolism’8.

  5. In Study 1023, the pulmonary embolisms and two cases were listed as treatment-emergent SAEs. It is noted that in Study 1003, the events of pulmonary embolism are not recorded in the CIOMS or narrative as being considered related to the study drug. However, investigators as individuals and collectively, would not have much experience of palbociclib’s adverse event profile and the growing body of evidence indicates that these events are more common in patients receiving palbociclib.
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