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 pharmacokinetics

  1. ADME


  • It is proposed that a single oral IR capsule dose of 125 mg dose of palbociclib be taken QD with food.

  • Following a single oral dose of 125 mg of the formulation proposed for marketing to healthy males the Tmax, Cmax, AUCinf, t1/2, Vz/F and CL/F values of palbociclib were 8.1 h, 59.6 ng/mL, 1864 ng.h/mL, 22.1 h, 2114 L and 67.1 L/h.

  • The absolute oral BA of a 125 mg IR capsule, which contained the initial Phase III freebase, under fasted conditions relative to a 50 mg IV infusion was 45.69% (90% CI: 39.25%, 53.19%).

  • The dose-normalised GMRs (50 mg dose of an oral solution/125 mg dose of the isethionate hard capsule) for AUCinf and Cmax were 92.78% (90% CI: 85.65%, 100.50%) and 85.68% (90% CI: 75.42%, 97.34%), respectively.

  • The final Phase III formulation of palbociclib 125 mg IR capsule, which is the formulation proposed for marketing, is bioequivalent to the initial Phase III formulation 125 mg IR capsule.

  • Although the final Phase III formulation of palbociclib was bioequivalent in regards to AUCinf to the isethionate salt, the lower bound of 90% CIs for Cmax was below the lower bound of the BE limit (i.e. 80%, 125%).

  • Following administration of 125 mg palbociclib (final Phase III form) with a high fat, low fat or moderate fat meal compared to fasted conditions, the GMRs (90% CIs) of palbociclib AUCinf were 120.59% (112.61%, 129.14%), 111.81% (104.29%, 119.87%) and 113.13% (105.60%, 121.19%), respectively. For Cmax, the GMRs (90% CIs) were 137.78% (120.55%, 157.47%), 127.08% (110.92%, 145.60%) and 124.04% (108.43%, 141.88%) for the high fat, low fat and moderate fat conditions, respectively.

  • Following doses of 75mg, 100 mg, 125 mg or 150 – 200 mg of the final Phase III capsule palbociclib AUCinf and Cmax increased with increasing dose from 75 mg to 150 mg with the increases appearing to be dose-proportional.

  • Following administration of a single oral dose of 125 mg of the final Phase III capsule with a high fat, high-calorie breakfast in healthy subjects the Vz/F (%CV) was 2114 L (17) indicating that that palbociclib is highly distributed to the tissues.

  • Palbociclib is moderately bound to plasma proteins with an average protein binding of 85%. By contrast, binding of palbociclib to human serum albumin and α1-acid glycoprotein was low, with mean values of 37.8% and 35.4%, respectively.

  • The human blood-to-plasma concentration ratio for palbociclib was 1.63, suggesting a modest preferential distribution into blood cells relative to the plasma compartments.

  • In human hepatocytes, palbociclib was primarily metabolised via oxidation, sulphonation, glucuronidation, and reduction mediated by CYP3A and SULT2A1.

  • The major metabolite in faeces was M11 (PF-06754233), which accounted for 25.8% of the radioactive dose. Other relatively abundant metabolites (≥ 5%) in the faeces included M16 and M20. Unchanged parent was also present in the faeces of 5 of 6 subjects at levels ranging from 0.5% to 5.1% (with a mean of 2.3%).

  • Palbociclib was the primary drug-related material in circulation, accounting for 23.3% of the plasma radioactivity, whereas, the most abundant metabolite (M22) was responsible for 14.8% of radioactivity. Other metabolites identified in the circulation at levels of <5% of circulating radioactivity included M11, M26, M12, M16, PF-05089326, M24 and M25.

  • PF-05089326 was shown to have comparable potency with that of palbociclib for inhibiting CDK 4 (IC50=5.4 nM or 2.4 ng/mL) and CDK 6 (IC50=16.2 nM or 7.3 ng/mL).

  • Following a 125 mg dose of the initial Phase III, to healthy males, the Cmax and AUCinf values for PF-05089326 were 7.03 ng/mL and 110.8 ng.h/mL, respectively.

  • The overall median mass balance of the radioactive dose excreted was 91.6%, with 17.5% recovered in urine and 74.1% recovered in faeces.

  • Palbociclib, 2 isomeric mono-hydroxylated metabolites of palbociclib (M23a, M23b), the glucuronide of palbociclib (M22) and two other unidentified radiochemical peaks were identified in the urine at levels of < 5% of radioactive dose.

  • The inter-subject variability on CL/F, V2/F, Q/F and Ka were estimated to be approximately 36.2%, 30.2%, 126.1% and 83.6%, respectively, whereas, intra-subject variability was estimated to be 0.317.
      1. Pharmacokinetics in the target population


  • Following QD dosing with 125 mg isethionate capsules in postmenopausal women with ER-positive, HER2-negative advanced breast cancer, palbociclib appeared to reach steady-state exposure on or before Day 8 and the steady-state GM CL/F and Vz/F of palbociclib were 63.08 L/h and 2583 L, respectively. The mean palbociclib Cmax, AUC24, t1/2 and Tmax values were 115.8 ng/mL 1982 ng.h/mL, 28.8 h and 7.9 h, respectively.

  • In patients with advanced solid tumours, including some with breast cancer, the median Tmax , mean t1/2, Vz/F and CL/F values were 4 h, 26.5 h, 3103 L and 86.1 L/h, respectively and the accumulation ratio following multiple dosing was 2.4.
      1. Pharmacokinetics in special populations


  • Based on the PopPK analysis, liver enzymes including baseline alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, and total bilirubin values were not significant covariates of palbociclib CL/F. Therefore the sponsor recommends that no dose adjustment is necessary for patients with mild hepatic impairment as defined based on the NCI scale.

  • Given that renal clearance is responsible for approximately 6.9% of palbociclib excretion over a 192 h period and PopPK analysis identified that creatinine clearance (range: 29-185 mL/min) was not a significant covariate on palbociclib CL/F, mild or moderate renal impairment is not likely affect the PKs of palbociclib.

  • In healthy Japanese and matched healthy non-Asians administered 125 mg palbociclib under fed conditions, the median Tmax (6.05 h and 6.02 h) and mean t1/2 values (22.8 h and 23.9 h) were similar. By contrast, palbociclib GM AUCinf and Cmax values were 30% and 35% higher, respectively, in Japanese.

  • The PopPK analysis indicated that although baseline body weight (range: 37.9-123 kg) and age (range: 22-89 years) were significant covariates on CL/F, and baseline body weight was a significant covariate on V2/F, these covariates were not considered clinically significant.

  • The popPK analysis identified that in patients with cancer, palbociclib PK was reasonably well characterised by a 2-compartment model and for a typical patient (i.e. body weight of 73.7 kg at age of 61 years old) CL/F and V2/F were estimated to be 60.2 L/h and 2710 L, respectively.
      1. Pharmacokinetic interactions


  • Compared to administration of 125 mg palbociclib alone, co-administration with steady-state itraconazole, a CYP3A4 inhibitor, resulted in increases in palbociclib t1/2 (from 22.1 h to 33.9 h), AUCinf (+87%) and Cmax (+34%), whereas, palbociclib CL/F decreased from 67.09 L/h to 36.18 L/h.

  • Compared to administration of 125 mg palbociclib alone, co-administration with steady-state rifampin, a potent CYP3A4 inducer, resulted in decreases in palbociclib Tmax (8.0 h to 3.0 h), t1/2 (22.6 h to 7.8 h), AUCinf (-84.5%) and Cmax (-69.8%), whereas, palbociclib CL/F was approximately 6.3-fold higher.

  • Compared to administration of 125 mg palbociclib alone, co-administration with steady-state modafinil, a moderate CYP3A inducer, resulted in decreases in palbociclib t1/2 (22.8 h to 19.4 h), AUCinf (-31.8%) and Cmax (-11.5%), whereas, palbociclib CL/F increased from 69.48 L/h to 102.5 L/h.

  • Compared to administration of 2 mg midazolam, a CYP3A4 substrate, alone, co-administration with steady-state palbociclib (125 mg QD), resulted in increases in midazolam Cmax and AUCinf of 37.5% and 61.1%, respectively.

  • Co-administration of palbociclib with steady-state tamoxifen, a CYP2D6 and CYP3A4 substrate, had little effect on palbociclib exposure.

  • Co-administration of palbociclib with letrozole had no effect on the PKs of palbociclib at steady-state, compared to when palbociclib was administered alone. Similarly, co-administration of letrozole with palbociclib had no effect on letrozole exposure.

  • Under fed conditions, co-administration of palbociclib with famotidine, an H2-receptor antagonist, or the antacid Mi-Acid Maximum Strength Liquid did not affect palbociclib exposure, whereas, co-administration with multiple doses of the PPI, rabeprazole sodium, decreased palbociclib AUCinf and Cmax by 13.1% and 40.8%, respectively. Under fasted conditions, the PPI decreased palbociclib AUCinf and Cmax by approximately 56% and 75%, respectively.

Clinical implications of in vitro findings

  • In vitro studies identified that palbociclib and PF-05089326 time-dependently inhibited CYP3A, whereas, clinically relevant interactions were unlikely to occur with drug substrates of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or CYP2A6. Additionally, palbociclib did not induce CYP1A2, CYP2B6, CYP2C8, or CYP3A4 in human hepatocytes and also displayed low potential for inhibiting the activities of selected UGT enzymes (UGT1A1, UGT1A4, UGT1A6, UGT1A9 and UGT2B7) and transporters (P-gp, BCRP, OATP1B1, OATP1B3, BSEP, OAT1, OAT3 and OCT2).
      1. Limitations of the clinical pharmacology studies


  • The current application is for the registration of 3 dosage strengths of IR capsules, which contain 75 mg, 100 mg or 125 mg of the final Phase III formulation of palbociclib. No studies have been provided that examine the BE of these 3 dosage strengths nor has the Sponsor applied for a waiver of the requisite studies.

  • No study data, other than the PopPK analysis, has been provided regarding effects of hepatic or renal impairment on the PKs of palbociclib.

  • Although Study A5481012 examined the effect of palbociclib on midazolam PKs, it did not evaluate the effect of midazolam on palbociclib PKs.

  • Although Study A5481026 examined the effect of tamoxifen on palbociclib PKs, it did not evaluate the effect of palbociclib on tamoxifen PKs.

  • Many of the PK studies were undertaken in predominantly Black males. As palbociclib is indicated for the treatment of breast cancer and the Australian population is predominantly white it could be argued that the PK study population group is not representative of the target population in Australia.
      1. Questions related to the PK studies


  • Although Study A5481032 examined dose proportionality between 4 single dose levels of palbociclib (75mg, 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?

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

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


Although, in general, the studies providing information regarding the PKs of palbociclib appear to have been undertaken according to TGA guidelines there were a number of notable shortcomings in the methodology or the populations examined. Most notably in 11 of the 21 PK studies provided the populations were solely Black or predominantly Black and very few if any female subjects were enrolled. As stated previously, as palbociclib is indicated for the treatment of breast cancer and the Australian population is predominantly white it could be argued that the PK study populations examined in these 11 trials are not representative of the drug’s target population in Australia. In addition, the relative BE of the three proposed dose strengths of palbociclib have not been examined and no Biowaiver has been provided by the sponsor. Moreover, the summary report and results for the study which examined the PKs of palbociclib in hepatically impaired subjects have not been provided and crossover drug-drug interaction studies examining the effect of the midazolam on palbociclib PKs and palbociclib on tamoxifen PKs have not been undertaken.
  1. Pharmacodynamics

    1. Studies providing pharmacodynamic information


Note: Only the studies that have not been previously described in Table 4 (included PK data) have been summarised in Table 5.

Table5: Submitted pharmacodynamic studies



PD Topic

Subtopic

Study ID

*

Primary Pharmacology

Effect on biomarkers

A5481002

Compare biomarkers of CDKs 4/6 inhibition in tumour biopsies

Population PD and PK-PD analyses

Patients with advanced cancers

PMAR-EQDD-A548b-DP4-387

To explore the relationship between PFS and palbociclib exposure and attempted to identify potential prognostic factors

PMAR-EQDD-A548b-DP4-271

To describe the effect of palbociclib on absolute neutrophil count

PMAR- EQDD-A548b-DP4-286

To describe the effect of palbociclib on absolute thrombocyte count

PMAR-EQDD-A548b-DP4-287

To characterise the effects of palbociclib exposure on the QT interval

*Indicates the primary PD aim of the study. § Subjects who would be eligible to receive the drug if approved for the proposed indication. ‡ And adolescents if applicable.
    1. Summary of pharmacodynamics

      1. Mechanism of action


Palbociclib is a highly selective inhibitor of cyclin-dependent kinase (CDK) 4/cyclin D1 (CCND1) kinase activity as well as the redundant CDK 6/cyclin D1 kinase. During cell proliferation, the G1 to S transition of the cell cycle is under the control of CDKs which are activated through specific complex formation with regulatory cyclins. CDK 4 and CDK 6 are activated by binding to D-type cyclins in early G1 phase. The only known natural substrate for CDK 4 and CDK 6 activity is retinoblastoma susceptibility gene product (Rb), which mediates G1 arrest through sequestration of transcriptional factors of the heterodimeric transcription factor (E2F-DP) family. Phosphorylation of pRb and other members of the pocket protein family (p107 and p130) by active cyclin-CDK complexes leads to release of E2F and DP transcription factors and transcription of requisite genes for S-phase entry. Therefore, inhibition of CDK 4 and CDK 6 activation prevents cellular DNA synthesis and thus inhibits cell division. Non-clinical data has also indicated that palbociclib may be expected to cause both growth arrest as well as a potential secondary cytoreductive effect.
        1. Assays for primary PD effects

Immunohistochemical identification of biomarkers in tumour biopsies

In order to assess the extent to which palbociclib is pharmacologically active against molecular targets in tumour cells, immunohistochemistry analysis of paired serial tumour biopsy specimens was performed to measure changes in intra-cellular biomarkers associated with cellular growth and division. These biomarkers included: the phosphorylation status of Rb protein, levels of the proliferation marker Ki-67 and levels of the cell cycle associated protein cyclin D1.

The percent reduction in phospho-Rb between the screening and Day 21 tumour biopsies was calculated for each subject and was an endpoint for proof of mechanism. If ≥ 50% reduction in phospho-Rb at the serine-780 site in >30% of the evaluable subjects was seen, proof of mechanism was considered to be achieved. The percentage of subjects with ≥ 60%, ≥ 50%, ≥ 40% and ≥ 30% reduction in phospho-Rb was provided. In addition, the mean change from baseline to Day 21 in percent of cells expressing phospho-Rb was analysed using a paired-differences t-test.

The mean change from baseline to Day 21 in the composite score (sum of each intensity category x percent of cells in that category) for Ki-67 and cyclin D1 were analysed using a paired-differences t-test. If other tumour biopsy biomarkers were collected, they were summarised appropriately (mean change, percent change, etc.).

Identification of biomarkers in in situ lesions using positron emission tomography (PET)

A screening PET was used to determine evaluable index lesions for each subject. Tumour background ratios (TBR) and development of new sites of abnormality were recorded. Whenever possible, both FLT-PET and FDG-PET scanning were performed within the same timeframe, and both assessments were done at screening and then during the first treatment cycle.

FDG-PET can be used to identify hotspots of cellular metabolism, which provides information about possible cellular proliferation and cell death; however, FDG does not convey an actual measurement of cancer cell proliferation. In regards to FLT-PET, the primary mechanism for its specificity for cell proliferation is in its relationship to thymidine kinase 1, which sequesters FLT for phosphorylation and is hyper-expressed in multiplying cells. This relationship has been demonstrated in studies involving brain, breast and lung tumours.



The repeated measures hierarchical model was used to analyse the mean change from baseline to Cycle 1 Day 21 in the natural log of the maximum standard uptake value (SUVmax) for [18F]-FDG-PET and [18F]-FLT-PET. If, for either parameter, the upper end of individual 60% CIs were below 0 and at least 30% of the CIs achieved this criteria, the primary endpoint for proof of mechanism using PET was considered to be achieved. All paired baseline and Cycle 1 Day 21 SUVmax measurements were used where baseline FLT-PET SUVmax ≥ 2.0, and FDG-PET SUVmax ≥ 5.0 for liver lesions and ≥ 3.5 for other lesions.
Efficacy - Response Evaluation Criteria In Solid Tumours (RECIST)

Disease and response assessments were defined by RECIST, which is a set of guidelines that define when tumours in cancer patients improve (‘respond’), stay the same (‘stabilize’), or worsen (‘progress’) during treatment. Changes in tumour size were categorised as complete response (CR), partial response (PR), stable disease (StD) or progressive disease (PrD); the latter incorporating the appearance of new lesions. Confirmation of responses was to be done no less than 4 weeks after the response was initially documented. Bone marrow assessments were to be completed to confirm CRs in NHL patients.
    1. Pharmacodynamic effects

      1. Primary pharmacodynamic effects


Comment: 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. Biomarker analysis of tumour biopsies


Study A5481002 evaluated and compared biomarkers of CDKs 4/6 inhibition in tumour biopsies with [18F]-FDG-PET, [18F]-FLT-PET, and anti-tumour activity following 125 mg palbociclib QD in subjects with mantle cell lymphoma (MCL). The results indicated that all 10 subjects who had percent phospho-Rb positive measurements available at baseline and following 21 days treatment with palbociclib (Cycle 1) had ≥ 50% change from baseline, while 9 (90%) of these subjects had ≥ 60% change from baseline and mean (SD) percent change from baseline was -89.49 (14.80). There was also a reduction in mean total Rb percent positive cells between baseline (87.8%) and Cycle 1 Day 21 (75.5%). The small magnitude of change, while statistically significant (p=0.0142), does not account for the large and significant decrease seen in the mean phospho-Rb percent positive cells seen at baseline versus Cycle 1 Day 21. Paired t-test results for phospho-Rb percent positive cells, Ki-67 composite score, and cyclin D1 composite score (baseline versus Cycle 1 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 cyclin D1.
        1. PET screening of lesions


As part of Study A5481002, PET studies were undertaken to determine levels of tumour biomarkers prior to and after 21 days treatment with palbociclib. The results indicated that FLT-PET and FDG-PET SUVmax were correlated at both baseline and Cycle 1 Day 21, with r=0.615 and 0.766, respectively (p≤0.0001 for both). The correlation between FLT-PET and FDG-PET SUVmax percent change from baseline to Cycle 1 Day 21 was 0.406 (p=<0.0001).

For FLT-PET, 15/17 (88.2%) had a 60% CI below 0. For FDG-PET, 14/17 (82.4%) had a 60% CI below 0. 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. 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 Cycle 1 Day 21 and objective response at the end of the study was not significant (Kappa=0.0638 and 0.1864 for FLT-PET and FDG-PET, respectively).

The correlations between mean change from baseline to Cycle 1 Day 21 in FLT-PET and FDG-PET SUVmax versus mean change from baseline to Cycle 1 Day 21 in phospho-Rb percent positive cells were -0.250 and 0.136, respectively (p=0.4854 and p=0.7090, respectively). The correlations between mean change from baseline to Cycle 1 Day 21 in FLT-PET and FDG-PET SUVmax versus mean change from baseline to Cycle 1 Day 21 in Ki-67 composite score were 0.562 and -0.265, respectively (p=0.2454 and p=0.6112, respectively). The correlations between mean change from baseline to Cycle 1 Day 21 in FLT-PET and FDG-PET SUVmax versus mean change from baseline to Cycle 1 Day 21 in cyclin D1 composite score were -0.083 and 0.435, respectively (p=0.8756 and p=0.3891, respectively).


        1. Efficacy - RECIST


In terms of RECIST, Study A5481002 indicated that a total of 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 (Study A5481001) in 74 patients with advanced solid tumours, including 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. At the time of data cut off for this report, 5 patients (2 on the 21/28 day schedule and 3 on the 14/21 day schedule) had StD (having received between 20 and 39 cycles of treatment) and were continuing to receive study drug. No patient achieved a complete response. There were no notable differences in response between the 14/21 day and 21/28 day dosing schedules. The numbers of patients in the different tumour-type subgroups are too small to comment on any potential differences in efficacy.

Following 3 weeks of QD dosing with 100 mg or 125 mg palbociclib (Study A5481010) in 12 Japanese patients with advanced solid tumours, including 3 patients with breast cancer, no objective responses (CR/PR) were reported. The best overall tumour response was stable disease in 3 patients in the palbociclib 100 mg group and 1 patient in the palbociclib 125 mg group. Among them, StD ≥ 24 weeks was observed in 1 patient with rectal cancer in the palbociclib 100 mg group and 1 patient with oesophageal carcinoma in the palbociclib 125 mg group. The best overall tumour response was indeterminate (discontinued the study for the reasons other than disease progression) in 1 patient in the palbociclib 100 mg group.

        1. Progression free survival (PFS)


PopPK-PD analysis PMAR-EQDD-A548b-DP4-387 explored the relationship between PFS and palbociclib exposure and attempted to identify potential prognostic factors (covariates) for PFS. The dataset for this analysis was taken from Study A5481003 which examined the PKs and efficacy of palbociclib when given alone and in combination with letrozole in postmenopausal women with ER-positive, HER2-negative advanced breast cancer. The subsequent exposure response analyses were conducted using 2 datasets: one included the data from both the letrozole alone (control arm) and the palbociclib plus letrozole arm (test arm) and one included data from only the palbociclib plus letrozole arm (test arm). A stronger ER relationship was found when data from both arms (control and test arms) were used, while a weaker relationship was found when the data from only the test arm were used. It should be pointed out that by using the data from only the palbociclib plus letrozole arm, the effect of drug exposure on PFS could not be adequately characterized due to the issues of the confounding effects of other prognostic factors and the small sample size.

Subject data were then divided into two groups according to low and high palbociclib exposure with the high exposure group receiving ~18.5% higher daily doses than the low exposure group. CL/F was also ~34.5% lower in the high exposure group compared to the low exposure group, whereas, the mean (SD) Cavg values in the low and the high groups were 47.7 (9.71) and 85.2 (30.0) ng/mL, respectively. As a result of both the higher dose intensity and a lower CL/F in the high exposure group, the mean Cavg in the high exposure group was 78.7% higher than that in the low exposure group.

Overall, the baseline demographic and other clinical characteristics (laboratory values, tumour size, etc.) were similar between the two exposure groups; however, the baseline tumour size was higher and the lymphocyte counts were lower in patients within the low exposure group and it should be noted that these differences may influence estimation of the drug exposure effect on PFS.

The median survival time obtained from Kaplan Meier analysis in the letrozole alone, the low, and the high palbociclib exposure group was 10.2, 17.3, and 24.4 months, respectively, which not only suggested that PFS improved as palbociclib exposure increased, but also that PFS was improved in both the low- and high-exposure groups compared to the group receiving letrozole alone.

In order to evaluate the impacts of the confounding factors of tumour size and lymphocyte count on the estimate of palbociclib exposure effect on PFS, the hazard ratios between the high and the low exposure groups were compared by the univariate and the multivariate analyses. After excluding the patients who had missing baseline tumour size values, the estimated hazard ratios of the high exposure to the low exposure group were 0.698 and 0.796 by the univariate and the multivariate analyses, respectively. These results suggest that after accounting for the prognostic factors, a positive trend between palbociclib exposure and PFS was still observed, as evidenced by the fact that the hazard ratio between the high and the low exposure group was less than 1 in the multivariate analysis.

When time-varying Cavg was used in the multivariate analysis, the estimated slopes of the Cavg, the baseline lymphocyte count, the baseline AST value, and the baseline tumour size value were -0.0157 ng/mL, -0.704 106/mL, 0.0152 U/L, and 0.00409 mm, respectively. In addition, the estimate of the palbociclib exposure effect on PFS was slightly stronger (Cavg coefficient -0.0157 vs. -0.0149 ng/mL) when a time-varying Cavg was used rather than when a constant Cavg over treatment duration was used.



Based on the Akaike information criteria (AIC), a log-normal distribution best described the PFS event time and was used for the parametric analysis. The parametric analyses confirmed that Cavg, baseline lymphocyte count, baseline AST value, and baseline tumour size value were significantly associated with the PFS. The intercept, the coefficients for Cavg, baseline lymphocyte count, baseline AST value, and baseline tumour size value were 1.699, 0.0146 ng/mL, 0.613 106/mL, -0.0113 U/L, and -0.00287 mm, respectively.
      1. Secondary pharmacodynamic effects

        1. Effect on white blood cells


PopPK-PD analysis PMAR-EQDD-A548b-DP4-271 was undertaken to establish a popPK-PD model that described the longitudinal observations of absolute neutrophil count (ANC) in patients with advanced cancer on treatment of palbociclib based on pooled data from Studies A5481001, A5481002 and A5481003. The results indicated that longitudinal ANC observations were well described by a sequential linked PK-PD model. In combination with the previously described popPK model, PMAR-EQDD-A548b-DP4-269, it was estimated that the drug concentration required to produce 50% of the maximum effect (EC50) 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. Following administration of 125 mg palbociclib once daily in 3/1 schedule, the population mean of ANC nadir was estimated to be approximately 1.18×109/L for a female patient with BALB value of 3.90 g/dL, and the nadir occurred on Day 22 in Cycle 1. Due to the repeated pattern, the nadir in each cycle happened around the same time with the similar nadir value. The analysis also provided estimates that the baseline ANC value of a typical male patient was 34.9% higher than that of a typical female patient and that baseline albumin levels (BALB) appeared to be inversely correlated with ANC values. For instance, relative to the baseline ANC for a patient with median value 3.90 g/dL of BALB in the study population, the baseline ANC is increased by 68.1% if the BALB value is decreased to 2.4 g/dL.
        1. Effect on platelets


PopPK-PD analysis PMAR- EQDD-A548b-DP4-286 was undertaken to establish a popPK-PD model that described the observed absolute thrombocyte count (ATC) in patients with advanced cancer over the duration of palbociclib treatment in data pooled from Studies A5481001, A5481002 and A5481003. Given the known anti-proliferative action of palbociclib as a cell cycle inhibitor, the model assumed that palbociclib suppressed the proliferation rate of stem cells. Therefore, a semi-mechanistic myelo-suppression model was developed using a linear function that successfully described the thrombocyte time-course following palbociclib therapy. Thrombocytopenia profiles were also well characterised when several treatment cycles were modelled continuously in time, and they were applicable to different schedules of administration. 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. According to the model parameter estimates based on the current analysis data, the lowest thrombocyte counts on Cycle 1 were achieved on Day 21 (167.1 x 109/L) for a patient with baseline albumin concentration value of 3.95 g/dL, whereas nadir was reached on Day 24 of Cycle 2 (161.9 x 109/L) for a patient with the same baseline albumin following administration of 125 mg palbociclib once daily with a schedule of 3 weeks on treatment and 1 week off treatment.
        1. QT


Study PMAR-EQDD-A548b-DP4-287 was undertaken in an attempt to characterise the effects of palbociclib exposure on the QT interval (QTc or heart rate-corrected QT) based upon 3593 individual QT records and 1904 concentrations obtained from 185 cancer patients and to assess whether palbociclib exposure affects heart rate (via effect on RR). The analysis identified that individual QT and RR values were strongly correlated, suggesting that RR is a confounding factor on QT change. Therefore, in order to adequately evaluate the drug effect on QT, the correlation between QT and RR needed to be corrected and among the correction factors tested, QTcS was found to be the best in minimising this correlation. PK results from Study A5481003 were then used to determine the maximum palbociclib concentrations at steady state (c) in patients receiving a therapeutic regimen of 125 mg palbociclib QD for 3 weeks on/1 week off and in combination with 2.5 mg letrozole QD. In this study, the median and mean c values were 107 and 112 ng/mL, respectively. Further analysis identified a slightly positive linear relationship between palbociclib concentration and 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. However, as the upper bound of the one-sided 95% confidence interval for the increase in QTcS did not exceed the threshold of 10 msec; therefore, QT prolongation is not a major safety concern for palbociclib at the recommended therapeutic dose. A similar palbociclib concentration dependent QTc effect was also observed when QTcF was used in the analysis.

Question: 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. Time course of pharmacodynamic effects


Please see the preceding PD sections of this report.
      1. Relationship between drug concentration and pharmacodynamic effects

        1. Plasma concentration and PFS


As stated previously in this report there was some evidence to suggest that PFS was improved in patients with higher levels of palbociclib exposure.
        1. Plasma concentration and biomarker expression


Study A5481002, described previously, examined the relationships between palbociclib plasma concentrations and the change from baseline in biomarkers including Ki-67 composite score, cyclin D1 composite score and the number of phospho-Rb positive cells following 21 days of treatment. Although, for phospho-Rb there appeared to be a trend towards larger changes from baseline at higher plasma concentrations (n=10), no clinically significant correlations were identified and the correlation coefficients were 0.277, -0.691 and -0.555 for Ki-67, cyclin D1 and phospho-Rb changes, respectively. Similarly, there was no correlation observed between the palbociclib plasma concentrations on Cycle 1 Day 21 and the mean percent change in FLT-PET SUVmax or FDG-PET SUVmax; the correlation coefficients were 0.288 and -0.185, respectively.
      1. Genetic, gender and age related differences in pharmacodynamic response


Gender was examined as a covariate of baseline QTc as part of Study PMAR-EQDD-A548b-DP4-287 but it was not included in the popPK-PD model based on ANOVA analysis. This Sponsor states that this may have resulted from the unequal number of females and males (136 cf. 48) contained in the dataset.
      1. Pharmacodynamic interactions


Study A5481010 examined the efficacy of palbociclib when given alone and when co-administered with 2.5 mg letrozole QD to 12 Japanese patients with advanced solid tumours, including 3 patients with breast cancer. As stated previously, when 125 mg palbociclib was administered alone QD for 3 weeks no objective response (CR/PR) was reported. By contrast, following administration with letrozole, objective response was reported in 2 (33.3%) patients; both were PR. Two patients had a best overall tumour response of StD ≥ 24 weeks and 2 patients had a best response of indeterminate who discontinued the study for the reasons other than disease progression. At the data cut-off date, PFS was 505 days and duration of response was 421 days in one of the patients with PR, PFS was 582 days and duration of response was 498 days in the other patient with PR. PFS were 582 days and 592 days, respectively in the 2 patients with StD.

Comment: Based on the information provided it is difficult to ascertain whether the improvement in objective response seen in this study results from the co-administration of letrozole and palbociclib or from letrozole alone.
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