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



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Evaluator’s overall conclusions on pharmacodynamics

  1. Mechanism of action


Palbociclib selectively inhibits CDK 4/CCND1, which are important components of the cell cycle.
        1. Primary pharmacodynamic effects


  • Following 125 mg palbociclib QD for 21 days to patients with MCL, all subjects who had percent phospho-Rb positive measurements available had ≥ 50% change from baseline in phospho-Rb percent positive cells, while 90% of these subjects had ≥ 60% change from baseline and the mean (SD) percent change from baseline was -89.49 (14.80). Paired t-test results for phospho-Rb percent positive cells, Ki-67 composite score, and cyclin D1 composite score (baseline versus Day 21) indicated that there were clinically significant decreases in mean phospho-Rb percent positive cells and Ki-67 composite score at baseline versus Cycle 1 Day 21, but not for cyclin D1.

  • In terms of PET response for FLT, 15 patients were considered partial responders to treatment, 2 patients had stable disease and no patients had disease progression, whereas, for FDG, 7 patients were considered partial responders, 10 patients had stable disease and as for FLT no patients had progressive disease.

  • PET response determined at Cycle 1 Day 21 showed a trend towards decreased uptake post treatment with anti-tumour activity. However, the relationship between PET response on Day 21 and objective response at the end of the study was not significant.

  • There was correlation between the PET SUVmax values and phospho-Rb percent positive cells, Ki-67 composite score or cyclin D1 composite score.

  • In terms of RECIST, 3 subjects achieved a best response of PR (2 subjects [12.5%]) or CR (1 subject [6.3%]). The overall ORR was 18.8% (95% CI: 4.0% to 45.6%). Seven subjects (43.8%) had a best response of stable disease/no response. Both median TTP and PFS were 5.5 months (95% CI: 2.0 to 18.6 months). The probability of being event-free at Month 12 was 36.4% (95% CI: 11.1 to 61.6%).

  • Following treatment with QD doses of 25 mg to 225 mg palbociclib in patients with advanced solid tumours, included six diagnosed with breast cancer, one patient (who had testicular cancer and was on the 14/21 day dosing schedule) had a confirmed PR during the study.

  • Thirty-five percent of patients on the 21/28 day schedule and 29% of patients on the 14/21 day schedule had StD for two or more cycles of treatment; 27% of patients on the 21/28 day schedule and 19% of patients on the 14/21 day schedule had StD for 4 or more cycles; and 16% of patients on the 21/28 day schedule and 10% of patients on the 14/21 day schedule had StD for 10 or more cycles.

  • There were no notable differences in response between the 14/21 day and 21/28 day dosing schedules.

  • Following 3 weeks of QD dosing with 100 mg or 125 mg palbociclib in 12 Japanese patients with advanced solid tumours, including 3 patients with breast cancer, no objective responses (CR/PR) were reported.
        1. Secondary pharmacodynamic effects


  • The estimated EC50 for the inhibition of ANC count was 37.7 ng/mL, which was much lower than the mean average concentration at steady state with 125 mg daily dosing, 86.5 ng/mL, derived from the population typical value of CL/F 60.2 L/h in patients.

  • A relationship between plasma palbociclib concentration and thrombocyte levels in plasma was identified with higher doses of palbociclib being associated with lower ATC time profiles. Baseline albumin value (range: 2.4-4.89 g/dL) was a statistically significant covariate on CIRC0 with higher baseline albumin concentration associated with lower CIRC0 value.

  • A slightly positive linear relationship was identified between palbociclib concentration and increased QTcS and following therapeutic doses (125 mg QD) in cancer patients the mean (90% CI) QTcS increase as compared with baseline at the mean and median palbociclib c were 5.60 (2.48-8.72) msec and 5.88 (2.61-9.16) msec, respectively.
        1. Relationship between drug concentration and pharmacodynamic effects


  • There is some evidence to suggest that PFS was improved in patients with higher levels of palbociclib exposure.

  • Although, for phospho-Rb there appeared to be a trend towards larger changes from baseline at higher plasma concentrations, no clinically significant correlations were identified between palbociclib plasma concentration and the following biomarkers of cell proliferation: Ki-67; cyclin D1; phospho-Rb; FLT-PET SUVmax; or FDG-PET SUVmax.
        1. Genetic, gender and age related differences in pharmacodynamic response


Gender was not identified as a covariate of baseline QTc.
        1. Pharmacodynamic interactions


When palbociclib was co-administered with letrozole QD in Japanese patients with advanced solid tumours, improvements in objective response were identified, which were not seen when palbociclib was administered alone.
        1. Limitations of the PD studies


No dedicated PD studies examined the primary PD effects of palbociclib in the target population of patients with HR-positive, HER2-negative advanced or metastatic breast cancer.
        1. Questions regarding the PD studies


  • Given that at the mean and median c following QD dosing with 125 mg palbociclib the upper bounds of the 90%CIs for QTcS range from +8.72 to +9.16 msec and therefore are relatively close to the 10 msec threshold, is it possible that co-administered drugs that increase palbociclib exposure even by as little as 20% to 30% will possibly result in major safety concerns?
    1. Clinical Pharmacology questions

      1. Pharmacokinetics


  1. Although Study A5481032 examined dose proportionality between 4 single dose levels of palbociclib (75 mg, 100 mg, 125 mg or 150 – 200 mg final Phase III capsule), no studies have been provided that examine the BE of these 3 dosage strengths nor has the sponsor applied for a waiver for the required studies. Can the sponsor please comment?

  2. As M22 is the most abundant circulating metabolite (responsible for 14.8% of circulating radioactivity), does the sponsor have information regarding its activity?

  3. Can the sponsor please provide the complete clinical trial report for Study A5481013, which examined the effects of hepatic impairment on palbociclib PKs?
      1. Pharmacodynamics


  1. Given that at the mean and median c following QD dosing with 125 mg palbociclib the upper bounds of the 90%CIs for QTcS range from +8.72 to +9.16 msec and therefore are relatively close to the 10 msec threshold, is it possible that co-administered drugs that increase palbociclib exposure even by as little as 20% to 30% will possibly result in major safety concerns?

Second round evaluator comment:

It is noted that palbociclib was initially investigated for the treatment of other malignancies and that as such, initial investigation of the PK/PD may have been in men as well as women. Given this is now solely being indicated for use in women, it is recommended that appropriate consideration is given to whether adequate characterisation has occurred in women, and also that reference to male subjects be removed from the PI as there are no proposed usages in men at this time. This is particularly important given:



  1. breast cancer in men is seldom ER-negative or HER2-positivethat is, almost always ER-positive

  2. no data are presented on the safety and efficacy in men and registration is not being sought

  3. the safety and efficacy of aromatase inhibitors and fulvestrant is unproven in men with breast cancer, therefore the addition of palbociclib to either of these adds further uncertainties
  1. Dosage selection for the pivotal studies

    1. Pharmacokinetics and pharmacodynamics: dose finding studies


Comment: This has not been formally evaluated and is presented to explain the dosing rationale for the proposed usage.

Study 1001 evaluated 2 different dosing schedules of palbociclib in patients with advanced cancer: a 4-week schedule consisting of 21 days of treatment followed by 7 days without treatment (Schedule 3/1) and a 3-week schedule consisting of 14 days of treatment followed by 7 days without treatment (Schedule 2/1). The palbociclib treatment schedules were selected based in part on (1) anticipated toxicities and (2) plans to test palbociclib both as a single agent and in combination with cytotoxic chemotherapy (Study 1001 CSR, Section 3.3). Schedule 3/1 was intended to allow the maximum duration of dosing. It was thought that Schedule 3/1 might not permit as high a daily dose to be achieved, as a shorter Schedule 2/1. Schedule 2/1 is expected to permit incorporation of palbociclib dosing with other chemotherapy agents later in clinical development. The predicted toxicity of reversible myelosuppression observed nonclinically in rats and dogs prompted the inclusion in each schedule of a 1-week treatment interruption in each cycle to allow recovery of hematologic parameters.

The recommended Phase II doses, and MTDs, were determined to be 125 mg QD on Schedule 3/1 and 200 mg on Schedule 2/1.

The safety profiles of Schedule 2/1 and Schedule 3/1 were generally comparable; however, a greater proportion of patients on Schedule 2/1 had treatment-related adverse events than on Schedule 3/1. The safety profiles, along with the suggestion of greater long-term antitumour activity observed on Schedule 3/1, led to the selection of this treatment schedule for the advanced breast cancer study.


    1. Phase II dose finding studies


The combination of letrozole was evaluated for safety and drug interactions in the Phase I part of Study 1003. The final proposed dose for palbociclib was Schedule 3/1 (3 weeks on and 1 week off) in combination with the standard daily dose of letrozole (2.5 mg) given continuously.

Comment: This dose schedule is satisfactory and is used in both Study 1003 and 1008.
    1. Phase III pivotal studies investigating more than one dose regimen


None provided.
  1. Clinical efficacy

    1. Studies providing evaluable efficacy data

      1. Ibrance in combination with letrozole


Study A5481003 (Study 1003) was a Phase I/II, open-label, randomised trial assessing the safety, efficacy and pharmacokinetics of palbociclib and letrozole compared with letrozole alone in postmenopausal women who did not receive previous systemic treatment for their ER positive, HER2-negative advanced breast cancer.

This study included a Phase I portion to confirm safety and tolerability and exclude a drug-drug interaction with the combination (N = 12), followed by a randomised Phase II portion (N = 165) in patients who had no prior or current brain metastases and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

Study A5481008 (Study 1008) is an ongoing international, double-blind, placebo-controlled, multi centre Phase III trial that randomised 666 postmenopausal women 2:1. The purpose of Study 1008 was to confirm the efficacy and safety results from the Phase I/II Study 1003. The full CSR is not available but the data submitted include some information on the study design (unfinalised version of the SAP), information on the patient population, primary and 4/11 secondary efficacy results, limited biomarker analyses, safety analyses (all-causality adverse events [AEs], treatment related AEs, serious AEs, treatment discontinuations and deaths) and supporting data tables.

No data are provided for the blinded review of the primary and secondary efficacy outcomes. All CIOMS or narratives are blinded with respect to treatment allocation.


      1. Ibrance in combination with fulvestrant


Study A5481023 (Study 1023) was a Phase III, multi centre, double-blind, placebo-controlled study in 521 pre/postmenopausal women assessing the safety and efficacy of palbociclib plus fulvestrant or placebo plus fulvestrant in women with HR-positive, HER2-negative advanced breast cancer, whose disease progressed after prior endocrine therapy regardless of their menopausal status. The study was still blinded as of the 23-0ct-15 and updated PFS analyses reports for the 16-Mar-15 and 23-0ct-15 data cut-offs were provided.

Some additional efficacy data supportive of efficacy in solid tumours comes from the dose-finding Phase I Study A5481001 in solid tumours.


    1. Pivotal or main efficacy studies


In support of the proposed indication in combination with letrozole data comes from the dose-finding and proof of concept Phase I/II trial Study 1003 with top line summary results from the ongoing Phase III study, 1008.

Data in support of the proposed indication in combination with fulvestrant comes from the pivotal Study 1023.


      1. A5481003 (‘PALOMA-1’) hereafter referred to as Study 1003

        1. Study design, objectives, locations and dates


This was a randomised, open-label, multi centre, international Phase I/II Study A5481003 (PALOMA-1; Study 1003) to assess the safety, efficacy, and pharmacokinetics of palbociclib (isethionate salt formulation) plus letrozole and letrozole alone administered as initial endocrine-based therapy for ER-positive, HER2-negative advanced breast cancer in postmenopausal women.

Comment: The formulation used in this study was not that now proposed for registration. Inter and intra-patient variability was noted in the absorption.

There were 7 amendments to the study plan (dated 27 March 2008) and there were 3 amendments to the original SAP (dated 19 May 2008). These changes are considered key and were summarised by the sponsor. The study design followed an adaptive course and in the final design (see Figure 2) there were 2 Phases and Phase II consisted of 2 parts:

Phase I: to assess the safety and tolerability of the combination and to exclude a drug-drug interaction (DDI) with the combination.

Randomised, open label Phase II in 2 parts:

Part 1 to assess the efficacy and safety of palbociclib in combination with letrozole and of letrozole alone in the first-line treatment

Part 2: had the same objective but enrolled a prospectively defined population of ER-positive, HER2-negative postmenopausal patients with tumors additionally demonstrating:



  1. CCND1 gene amplification (CCND1/CEP11 ratio ≥ 1.5, from this point forward CCND1 ≥ 1.5 will be used in the text and tables)

  1. and/or loss of CDKN2A/ p16INK4A gene (CDKN2A/CEP9 ratio <0.8, from this point forward CDKN2A <0.8 will be used in the text and tables) by fluorescence in situ hybridization (FISH) analysis

The initial Phase II study design included 150 patients randomised in a 1:1 fashion to receive palbociclib plus letrozole (Arm A) or letrozole alone (Arm B). When preclinical data suggested that the tumours with CCND1 amplification and/or loss of CDKN2A were particularly sensitive to palbociclib, the Phase II portion of the trial was subsequently modified to comprise 2 parts; the Phase II Part 1 (Ph2P1) Cohort was to include 60 patients randomised in a 1:1 fashion to receive palbociclib plus letrozole or letrozole alone, without biomarker selection; and the Phase II Part 2 portion (Ph2P2) was to include approximately 150 similar patients who also expressed biomarker-positive disease (defined as CCND1 gene amplification and/or loss of CDKN2A) and were randomised in the same fashion (1:1) as in Ph2P1. (Amendment #3 July 2010).

An interim analysis of Ph2P1 data was performed and showed that clinical activity of palbociclib in combination with letrozole for the first-line treatment of ER-positive, HER2-negative advanced breast cancer in postmenopausal women was independent of patients’ biomarker (CCND1/CDKN2A) status. Therefore, accrual to Ph2P2 was terminated (99 patients had accrued to Part 2), and the protocol was amended to determine the clinical benefit of the combination in patients randomised in both Ph2P1 and Ph2P2 (Amendment #5, June 2012) combined with secondary subgroup analysis in Ph2P1 and Ph2P2 separately. Additionally, Blinded Independent Central Review (BICR) evaluation was incorporated as a secondary analysis for multiple efficacy endpoints prior to the final analysis (Amendment #6).

All patients were randomised with 2 stratification factors:


  1. Site of disease (visceral1 vs. bone only vs. other 2)

  1. Disease free interval (>12 months from the end of adjuvant treatment to disease recurrence vs. ≤12 months from the end of adjuvant treatment to disease recurrence or de novo advanced disease)

  2. 1 ’Visceral’ refers to lung and/or liver + any other site.

  3. 2 ’Other’ refers to bone with other non-visceral disease site or other disease site alone.

The SAP also states: since the primary analysis of PFS contains patients from both Part 1 and Part 2, that were randomised separately and were enrolled under different selection criteria, the Cohort (Part 1 vs. Part 2) should also be considered as a stratification factor in the stratified analysis.

Comment: This biomarker-selected status was not a prespecified stratification factor and is being applied post hoc; in doing this, the SAP does recognize that there were different selection criteria and therefore potential differences between the two groups. The meaningfulness of any statistical outcomes and treatment effect when the two groups are combined for primary efficacy analysis is uncertain and outcomes require confirmation in a well-designed randomised double-blind trial.

The following is taken from the supplemental SAP: ‘As Phase II Part 1 was originally intended as a pre-proof-of-concept study (pre-POC), the study team had full access to the data, as the study was ongoing, and summary analyses were performed for the first interim analysis. Conversely, Part 2 was originally intended as the POC study for this indication, thus, although open-label, the study-team did not have access to aggregate analyses or summaries by treatment arm. With the most recent amendment to the protocol, the primary analysis set is now all patients randomised in Phase II (Part1 and Part 2). As such, the study team is not to be provided aggregate analyses or summaries by treatment arm for both Part 1 and part 2, outside of the scope of pre-specified interim analyses.’



Patients continued with the assigned study treatment until progression of disease, unacceptable toxicity, or consent withdrawal and underwent study-related safety and efficacy assessments. (Amendment #6, dated November 2012 required that post-study patient survival status will be collected for all patients randomised in the Phase II portion of the study every 2 months until death).

Comments:

  1. The initial open label, proof of concept study design was modified at several points based on investigator assessments and interim data analyses, and to accommodate emerging data about a potential biomarker, resulting in a new eligibility criterion. When an interim analysis indicated that a palbociclib treatment effect was independent of that biomarker status, accrual to the biomarker-positive Phase II Part 2 arm was terminated early (when 99/planned 150 patients were recruited) and the two groups from Part 1 and 2 amalgamated for the final data analysis. Separate analyses were also planned post hoc. This last amalgamation appears to contradict the SAP to treat the 2 as separate cohorts.

  1. The SAP states that the study was originally intended as a pre-proof of concept (Part 1) and Proof of concept (Part 2), and the alterations to the study design, protocol and SAP were driven both by looks at the data, and emerging preclinical results – therefore, it cannot be considered a ‘pivotal trial’ for the purposes of establishing safety and efficacy as required for TGA regulatory approval. As such, it is suitable for generating hypotheses and demonstrating the promise of palbociclib but this requires data from a confirmatory, well-designed Phase III study to be presented for evaluation. The CSR for Study 1008 data is not available for a full evaluation by the TGA at this time.

The clinical trial design has multiple potential sources of bias and limitations:

  1. The open label nature of this study.

  1. The study design was proof of concept, and pre-proof of concept in design with an alpha to reflect this.

  2. The analyses and amendments were based on investigator-reported results.

  3. The ITT population for efficacy is comprised of two groups recruited with differing eligibility criteria – the impact of this is uncertain.

  4. This raises uncertainties about the generalizability of the findings when the majority of patients have a particular profile.

  5. Multiple looks at the data and data-driven amendments, especially in the open label setting

  6. A BICR was only introduced as a secondary analysis for multiple efficacy endpoints prior to the final analysis. In the absence of blinding in the trial design, all trial amendments were made based on investigator assessments.

  7. There were no per protocol analysis sets for those in the Phase II part of the study (v4, 31 July 2013).

Patients in the Phase II part of the study received palbociclib 125 mg daily on Schedule 3/1 (3 weeks on/1week off) in combination with letrozole administered continuously versus letrozole administered continuously.

Figure2: The final study design of A5481003



Figure 3: Biomarker status of Study A5481003 by Part 1 and 2




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