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



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List of common abbreviations


Abbreviation

Meaning

%CV

Percent Coefficient of Variation

%RE

Percent Relative Error

ABC

advanced breast cancer

ADI

average dose intensity

ADME

Absorption, distribution, metabolism and elimination

AE

Adverse Event

ALP

Alkaline Phosphatase

ALT

Alanine Aminotransferase

ANC

Absolute Neutrophil Count

ANOVA

Analysis of Variance

AST

Aspartate Aminotransferase

AT

All Treated As Treated Set

ATC

Absolute thrombocyte count

AUCextrap%

The Area Under The Plasma Concentration-Time Curve From The Time of Last Measurable Concentration To Infinity Divided By AUCinf

AUCinf

Area Under The Plasma Concentration-Time Curve From Time 0 To Infinity

AUClast

Area Under The Plasma Concentration-Time Curve From Time 0 To Time Of Last Measurable Concentration

AUC24

Area Under The Plasma Concentration-Time Curve From Time 0 To 24 Hours

BALB

Baseline albumin

BALK

Baseline alkaline phosphatase

BAST

Baseline Alanine Aminotransferase

BAST

Baseline Aspartate Aminotransferase

BICR

Blinded Independent Central Review

BLQ

Below The Lower Limit of Quantification

BMI

Body Mass Index

BP

Blood Pressure

BUN

Blood Urea Nitrogen

CBR

Clinical Benefit Response

CCND1

Cyclin D1

CDKN2A

Cyclin-Dependent Kinase Inhibitor 2A (also known as ‘p16INK4A’)

CDK

Cyclin-Dependent Kinase

CI

Confidence Interval

CIOMS

Council for International Organizations of Medical Sciences

CL/F

Apparent Clearance

Cmax

Maximum Observed Plasma Concentration

CR

Complete Response

CRF

Case Report Form

CRO

Contract Research Organization

CSP

Clinical Study Protocol

CSR

Clinical Study Report

CT

Computed Tomography

CTCAE

Common Terminology Criteria for Adverse Events

Ctrough

Predose Concentration

CYP

CytochromeP450

DDI

Drug-Drug Interaction

DILI

Drug-Induced Liver Injury

DLT

Dose-Limiting Toxicity

DOR

Duration of Response

ECG

Electrocardiogram

ECOG

Eastern Cooperative Oncology Group

EDTA

Ethylenediaminetetraacetic Acid

EIA

Enzyme-Linked Immunosorbent Assay

eNCA

Electronic Noncompartmental Analysis

EOT

End Of Treatment

ER

Estrogen Receptor

ER positive

Oestrogen receptor postivie

FISH

Fluorescence In Situ Hybridization

FSH

Follicle Stimulating Hormone

GCP

Good Clinical Practice

GCSF

Granulocyte Colony-Stimulating Factor

GGT

Gamma Glutamyltransferase

H3

Tritium

HER2

Human Epidermal Growth Factor Receptor 2 (ErbB2)

HPLC/MS/MS

High Pressure Liquid Chromatography Tandem Mass Spectrometry

HR

Hazard Ratio

IB

Investigator’s Brochure

IC50

Half-Maximal Inhibitory Concentration

ICH

International Conference on Harmonization

IEC

Independent Ethics Committee

IF

Immunofluorescence

IHC

Immunohistochemistry

IND

Indeterminate

IOBU-SDMC

Internal Oncology Business Unit-Safety Data Monitoring Committee

IRB

Institutional Review Board

IRT

Interactive response technology

ITT

Intent-to-Treat

IWRS

Interactive Web Response System

Ki

Concentration for half-maximal inactivation

Ki67

Nuclear protein identified by the Ki67 monoclonal antibody

LDH

Lactate Dehydrogenase

LLOQ

Lower Limit of Quantification

mBPI-sf

Modified Brief Pain Inventory–Short Form

MCF

Michigan Cancer Foundation

MedDRA

Medical Dictionary For Regulatory Activities

MRAUCinf

metabolite to parent ratio AUCinf

MRAUClas

metabolite to parent ratio AUClast

MRCmax

metabolite to parent ratio of Cmax

MRI

Magnetic Resonance Imaging

mRNA

Messenger Ribonucleic Acid

MTD

Maximum Tolerated Dose

NCBI

National Center For Biotechnology Information

NC

Not Calculated

NCI

National Cancer Institute

NR

Not Reached

OR

Objective Response

ORR

Objective Response Rate

OS

Overall Survival

p16INK4A

Cyclin-Dependent Kinase Inhibitor 2A

PALOMA

Palbociclib Ongoing trials in the Management of Breast Cancer

PD

Progressive Disease

PFS

Progression-Free Survival

Ph2P1

Phase II Part 1

Ph2P1+Ph2P2

Phase II Combined

Ph2P2

Phase II Part 2

PK

Pharmacokinetic(s)

popPK

population pharmacokinetics

PR

Partial Response

pRb

Retinoblastoma Susceptibility Gene Product

PrD

progressive disease

PRO

Patient Reported Outcome

QC

Quality Control

QD

Once Daily

QT

Time From Beginning Of QRS Complex To End Of T Wave In The Electrocardiogram

QTc

Corrected QT Interval

QTcB

Corrected QT Interval According To Bazett

QTcF

Corrected QT Interval According To Fridericia

QTcS

Corrected QT Interval According To Study-Specific Criteria

r2

Goodness-of-fit statistic from the regression

RANKL

Receptor Activator Of Nuclear Factor Kappa-B Ligand

Rb

Retinoblastoma

RECIST

Response Evaluation Criteria In Solid Tumors

RP2D

Recommended Phase II Dose

SAE

Serious Adverse Event

SAP

Statistical Analysis Plan

SD

Stable Disease

SCLC

small cell lung carcinoma

SNP

Single Nucleotide Polymorphism

SOC

System Organ Class

SOP

Standard Operating Procedure

sSAP

Supplemental Statistical Analysis Plan (for Biomarkers)

SSID

Study Subject Identification Number

Std Dev

Standard Deviation

t½

Terminal Plasma Half-Life

TEAE

Treatment-Emergent Adverse Event

Tmax

Time To Maximum Plasma Concentration

TTP

Time To Progression

ULN

Upper Limit Of Normal

Vz/F

Apparent Volume Of Distribution

VGPR

Very Good Partial Response

WBC

White Blood Cell
  1. Submission details

    1. Identifying information


Submission number

PM 2016-01317-1-4

Sponsor

Pfizer Australia Pty Ltd

Trade name

Ibrance

Active substance

Palbociclib

This is an application to register a new chemical entity.
    1. Drug class and therapeutic indication


This medicine is a first in class and stated to be a reversible, small molecule inhibitor of cyclin-dependent kinases (CDK) CDK4/ (cyclin D1) and CDK6/cyclin D2. CDK4/6 are downstream of multiple signalling pathways which lead to cellular proliferation, and palbociclib is postulated to prevent cellular proliferation by preventing G1 to S phase progression of the cell cycle.

The proposed indications taken from the Draft PI and Letter of Application dated 25 April 2016 are:



Ibrance in combination with endocrine therapy is indicated for the treatment of hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer:

      • with letrozole as initial endocrine-based therapy in postmenopausal women

      • with fulvestrant in women who have received prior therapy
    1. Dosage forms and strengths


The following is taken from the Product Information:

Ibrance is supplied as hard gelatin capsules containing 75 mg, 100 mg or 125 mg of palbociclib as the freebase and the following excipients: microcrystalline cellulose, lactose monohydrate, sodium starch glycolate, silicon dioxide and magnesium stearate.


    1. Dosage and administration


The recommended dose of Ibrance is a 125 mg capsule taken orally once daily for 21 consecutive days followed by 7 days off treatment (Schedule 3/1) to comprise a complete cycle of 28 days.

When coadministered with palbociclib, the recommended dose of letrozole is 2.5 mg taken orally once daily continuously throughout the 28-day cycle. Please refer to the full prescribing information of letrozole.

When coadministered with palbociclib, the recommended dose of fulvestrant is 500 mg administered intramuscularly on Days 1, 15, 29, and once monthly thereafter. Please refer to the full prescribing information of fulvestrant.

Ibrance should be taken with food.

Patients should be encouraged to take their dose at approximately the same time each day. Continue the treatment as long as the patient is deriving clinical benefit from therapy.

If the patient vomits or misses a dose, an additional dose should not be taken. The next prescribed dose should be taken at the usual time. Ibrance capsules should be swallowed whole (do not chew, crush or open them prior to swallowing). No capsule should be ingested if it is broken, cracked, or otherwise not intact.

Prior to the start and throughout treatment with the combination palbociclib plus fulvestrant, pre/perimenopausal women should be treated with luteinizing hormone-releasing hormone (LHRH) agonists according to local clinical practice.

      1. Dose Modifications


Dose modification of Ibrance is recommended based on individual safety and tolerability.

Management of some adverse reactions may require temporary dose interruptions/delays, and/or dose reductions, or permanent discontinuation as per dose reduction schedules provided in Tables 1-3 below (same as Tables 6, 7 and 8 in Precautions and Adverse Effects in PI Attachment 1).



Table 1: Recommended dose modifications



Table 2: Dose modifications and management Haematologic toxicities





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