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

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A5481008 ‘PALOMA-2’ hereafter referred to as Study 1008.

The top-line summary report dated 21 April 2016 using a data cut-off date of 26 February 2016 was provided from this randomised, multicentre, double-blind Phase III study of palbociclib plus letrozole versus placebo plus letrozole for the treatment of postmenopausal women with ER-positive, HER2- breast cancer who have not received any prior systemic anticancer treatment for advanced disease.

The sponsor provided 12 pdf documents for evaluation of Study A5481008:

  1. 1 with Serious adverse event narratives (with some hyperlinks to CIOMS narratives watermarked with ‘DRAFT’; others with no hyperlinks which appear to be the cases from 08 May 2015) dated 16 Dec 2015 – this appears to supersede the 08 May 2015 document – this information is blinded as to treatment group so not evaluable to inform regarding safety of palbociclib.

  2. 1 with serious adverse event narratives (no hyperlinks) dated 08 May 2015 – this information is stated to be blinded as to treatment group and superseded by pdf dated 16 Dec 2015. The absence of hyperlinks prevented any checks of the CIOMS provided to confirm this.

  3. 1 with CIOMS watermarked ‘DRAFT’ labeled ‘Death Narratives’ with each blinded as to treatment group dated 16 Dec 2015.

  4. 1 with CIOMS watermarked ‘DRAFT’ labeled Death Narratives; with each blinded as to treatment group and superseded by pdf dated 29 July 2015.

  5. 1 with CIOMS watermarked ‘DRAFT’ labeled ‘Other Serious Adverse Event’ blinded as to treatment group dated 16 Dec 2015.

  6. 1 with CIOMS watermarked ‘DRAFT’ labeled ‘Other Serious Adverse Event’ dated 29 July 2015 blinded as to treatment group and superseded by document dated 16 Dec 2015.

  7. Final Protocol, Amendment 5, 02 December 2014

  8. Final Protocol, Amendment 6, 07 April 2015

  9. Final Protocol, Amendment 7, 15 October 2015

  10. Statistical Analysis Plan, 2 December, 2014 (not finalized and not incorporating Protocol Amendments 6 and & 7)

  11. 130-page document labeled ‘Topline Summary Tables’ dated 19 April 2016

  12. 38-page document labeled Study A5481008 – ‘Topline summary of safety and efficacy’ dated 21 April 2016

Notably, the following information is not included:

  • results from the blinded independent central review assessments for all efficacy endpoints

  • Results for 7/11 planned secondary objectives, that is, there were no results presented for OS (data immature), quality of life, QTc, PK/PD and there was a limited presentation of biomarker studies undertaken.

Comment: The documents highlighted in red are those considered to provide evaluable efficacy and safety data. Three of the first 6 documents include duplicated information, and the information in all 6 documents is blinded with respect to study treatment allocation and therefore not evaluable. The SAP has been evaluated but is stated not to be a finalized version and does not incorporate Amendments 6 and 7, which occurred after the date of this document. The Protocol Amendments 5 and 6 have been reviewed but are superseded by the later version with Amendment 7 (see below). Given this is in effect, the pivotal study in support of the proposed first line indication this is not considered sufficient to satisfactorily demonstrate safety and efficacy for registration purposes. It is reiterated that Australia does not have a provisional registration process.
        1. Study design, objectives, locations and dates

The study design is as follows:

This is an ongoing international, multi centre, randomised, double-blind, placebo-controlled parallel-group Phase III trial comparing the efficacy and safety of PD-0332991 in combination with letrozole versus placebo plus letrozole in postmenopausal women with ER-positive/HER2- advanced breast cancer, not amenable to curative treatments. Eligible patients will have histologically or cytologically proven diagnosis of adenocarcinoma of the breast with evidence of locoregionally recurrent or metastatic disease and will be candidates to receive letrozole as first-line treatment for their advanced disease. Crossover is not permitted.

This study had the following objectives:

Primary Objective:

  • To demonstrate that the combination of PD-0332991 with letrozole is superior to placebo plus letrozole in prolonging progression-free survival (PFS) in postmenopausal women with ER-positive/HER2-negative advanced breast cancer who have not received any prior systemic anti-cancer therapies for their advanced disease.

Secondary Objectives:

  • To compare measures of tumour control duration and overall survival between the treatment arms;

  • To compare safety and tolerability between the treatment arms;

  • To compare health-related quality of life between the treatment arms;

  • To characterize the effects of PD-0332991 at therapeutic doses in combination with letrozole on QT interval in this patient population;

  • To determine trough PD-0332991 plasma concentration in this patient population and explore the correlations between exposure and response and/or safety findings;

  • To characterize alterations in genes, proteins, and ribononucleic acids (RNAs) relevant to the cell cycle (for example, CCND1 amplification, CDKN2A deletion), drug targets (such as CDK 4/6), and tumor sensitivity and/or resistance (Ki67, pRb) in tumour tissues.

The study will use an External Data Monitoring Committee (E-DMC).

The following amendments are presented as they are considered key changes to the study design:

Amendment 2, 03 Jan 3014

Preliminary results from two clinical pharmacology studies A5481018 and A5481021 suggested that palbociclib exposure may be decreased when administered in a minimally fasted state or concomitantly with proton-pump inhibitors. Therefore the protocol was amended to revise the study drug administration instructions from administration in a minimally fasted state to administration with food and also to prohibit the concomitant use of proton-pump inhibitors.

Amendment 3, 21 March 2014

Taking into account the preliminary results from studies A5481018 and A5481021, it was assumed that drug exposures before and after implementation of Amendment 2 might be different in patients who took palbociclib in a minimally fasted state (fast from 1 hour before to 2 hours after dosing) and/or concomitantly with proton-pump inhibitors compared to those patients who did not. This difference could potentially reduce the statistical power to detect the true treatment effect of palbociclib in the intent to treat (ITT) population under the current study design. As a result, the protocol is being amended prior to the interim analysis to increase the sample size from 450 patients to 650 patients to preserve the desired statistical power.

This amendment included the requirement for ophthalomological examinations based on an interim identification of a potential risk of cataracts.

Comment: Cataract formation should be included as a potential identified risk in the safety specification of the RMP.

Amendment 5, 02 December 2014

In the current study design, an interim analysis will be performed after approximately 266 PFS events have occurred (about 65% of total PFS events needed for final analysis) using O’Brien-Fleming efficacy boundary (Lan-DeMets procedure). Under these conditions, the study could be stopped for efficacy if z ≥ 2.5469 which would equate to a hazard ratio (HR) ≤ 0.6979, or about 4 months improvement in median PFS if the median PFS of the control arm is exactly 9 months as the study design assumed. In this instance, the interim efficacy boundary, while reaching statistical significance, may not represent a clinically meaningful improvement. The interim analysis is being revised in this protocol amendment to ensure that the study would only be stopped at the interim analysis if the primary analysis (PFS) results are statistically significant and clinically meaningful. This amendment also included the requirement for measuring baseline and subsequent based on an interim identification of a potential risk of hyperglycaemia.

Comment: Hyperglycaemia should be included as a potential identified risk in the safety specification of the RMP.

Amendment 7, 15 October 2015

In order to better understand the potential influence of palbociclib on response to subsequent anti-cancer treatments, the study is being amended to collect the date of disease progression while on subsequent anti-cancer therapy in addition to the follow-up anti-cancer therapy details already collected (regimen number, name of therapy, and start/stop dates).

        1. Inclusion and exclusion criteria

Inclusion criteria

  1. Adult women (>18 years of age) with proven diagnosis of adenocarcinoma of the breast with evidence of locoregionally recurrent or metastatic disease not amenable to resection or radiation therapy with curative intent and for whom chemotherapy is not clinically indicated.

  2. Histologically or cytologically confirmed diagnosis of oestrogen-receptor positive (ER-positive) breast cancer based on local laboratory results.

  3. Previously untreated with any systemic anti-cancer therapy for their locoregionally recurrent or metastatic ER-positive disease.

  4. Postmenopausal women defined as women with:

    • Prior bilateral surgical oophorectomy, or

    • Medically confirmed post-menopausal status defined as spontaneous cessation of regular menses for at least 12 consecutive months or follicle-stimulating hormone (FSH) and estradiol blood levels in their respective postmenopausal ranges with no alternative pathological or physiological cause.

  1. Measurable disease as defined per RECIST v.1.1 or bone-only disease (with bone lesions confirmed by CT, MRI or bone X-ray). Tumour lesions previously irradiated or subjected to other locoregional therapy will only be deemed measurable if disease progression at the treated site after completion of therapy is clearly documented.

  2. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-2

  3. Adequate organ and marrow function defined as follows:

ANC≥ 1,500/mm3 (1.5 x 109 /L);

Platelets≥ 100,000/mm3 (100 x 109 /L);

Hemoglobin9 g/dL (90 g/L);

Serum creatinine≤1.5 x ULN or estimated creatinine clearance ≥ 60 mL/min as calculated using the method standard for the institution;

Total serum bilirubin ≤1.5 x ULN (<3.0 x ULN if Gilbert’s disease);

AST and/or ALT ≤3 x ULN (≤5.0 x ULN if liver metastases present);

Alkaline phosphatase ≤2.5 x ULN (≤5.0 x ULN if bone or liver metastases present).

  1. Resolution of all acute toxic effects of prior anti-cancer therapy or surgical procedures to NCI CTCAE version 4.0 Grade ≤1 (except alopecia or other toxicities not considered a safety risk for the patient at investigator's discretion).

  2. Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.

  3. All patients must agree to provide tumour tissues for centralized retrospective confirmation of ER status and to evaluate correlation between genes, proteins, and RNAs relevant to the cell cycle pathways and sensitivity/resistance to the investigational agents. Freshly biopsied, recurrent/metastatic tumour samples must be provided whenever possible. If such a biopsy is not feasible or cannot be safely performed, then an archived tumour sample may be accepted. In either case a formalin fixed, paraffin embedded (FFPE) block or 12 unstained FFPE slides are required for patient participation.

  4. Evidence of a personally signed and dated informed consent document indicating that the patient (or a legal representative) has been informed of all pertinent aspects of the study before any study-specific activity is performed.
Exclusion criteria

  1. HER2-positive tumour

  1. Patients with advanced, symptomatic, visceral spread, that are at risk of life-threatening complications in the short term (including patients with massive uncontrolled effusions [pleural, pericardial, peritoneal], pulmonary lymphangitis, and over 50% liver involvement).

  2. Known active uncontrolled or symptomatic CNS metastases, carcinomatous meningitis, or leptomeningeal disease as indicated by clinical symptoms, cerebral edema, and/or progressive growth. Patients with a history of CNS metastases or cord compression are eligible if they have been definitively treated with local therapy (radiotherapy, stereotactic surgery) and are clinically stable off anticonvulsants and steroids for at least 4 weeks before randomisation.

  3. Prior neoadjuvant or adjuvant treatment with a non-steroidal aromatase inhibitor (anastrozole or letrozole) with disease recurrence while on or within 12 months of completing treatment.

  4. Prior treatment with any CDK4/6 inhibitor.

  5. Patients treated within the last 7 days prior to randomisation with:

    • Food or drugs that are known to be CYP3A4 inhibitors (amprenavir, atazanavir, boceprevir, clarithromycin, conivaptan, delavirdine, diltiazem, erythromycin, fosamprenavir, indinavir, itraconazole, ketoconazole, lopinavir, mibefradil, miconazole, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, verapamil, voriconazole, and grapefruit or grapefruit juice);

    • Drugs that are known to be CYP3A4 inducers (carbamazepine, felbamate, nevirapine, phenobarbital, phenytoin, primidone, rifabutin, rifampin, rifapentin, and St. John’s wort);

    • Drugs that are known to prolong the QT interval;

  1. Major surgery, chemotherapy, radiotherapy, any investigational agents, or other anti-cancer therapy within 2 weeks before randomisation. Patients who received prior radiotherapy to >25% of bone marrow are not eligible independent of when it was received.

  2. Diagnosis of any other malignancy within 3 years prior to randomisation, except for adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ of the cervix.

  3. QTc >480 msec (based on the mean value of the triplicate ECGs), family or personal history of long or short QT syndrome, Brugada syndrome or known history of QTc prolongation, or Torsade de Pointes (TdP).

  4. Uncontrolled electrolyte disorders that can compound the effects of a QTc-prolonging drug (hypocalcemia, hypokalemia, hypomagnesemia).

  5. Any of the following within 6 months of randomisation: myocardial infarction, severe/unstable angina, ongoing cardiac dysrhythmias of NCI CTCAE version 4.0 Grade ≥ 2, atrial fibrillation of any grade, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident including transient ischaemic attack, or symptomatic pulmonary embolism.

  6. Active inflammatory bowel disease or chronic diarrhea, short bowel syndrome, or any upper gastrointestinal surgery including gastric resection.

  7. Known hypersensitivity to letrozole, or any of its excipients, or to any palbociclib/placebo excipients.

  8. Known human immunodeficiency virus infection.

  9. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for entry into this study.

  10. Patients who are investigational site staff members or relatives of those site staff members or patients who are Pfizer employees directly involved in the conduct of the trial.

  11. Participation in other studies involving investigational drug (s) (Phases I-IV) within 2 weeks before randomisation and/or during participation in the active treatment phase of the trial.

  12. Recent or active suicidal ideation or behaviour.

Comment: The inclusion criteria are broader than for Study 1003, including patients with past cerebral metastases or spinal cord compression, and ECOG 2 performance status (although there were relatively few patients with ECOG 2 enrolled).

Active or recent suicidal ideation or behaviour are unusual exclusion criteria and were not exclusion criteria for Study 1003 but were in for Study 1023. This might suggest a signal or issue had emerged. The sponsor is requested to explain the rationale behind this exclusion criterion and provide details of any details where palbociclib might have been implicated in causing patients to commit suicide or become suicidal that is, while taking or after recently stopping palbociclib (Clinical Questions).

        1. Study treatments

Patients randomised to Arm A (experimental arm) will receive:

    • palbociclib 125 mg, orally once daily on Day 1 to Day 21 of every 28-day cycle followed by 7 days off treatment;

    • in combination with

      • Letrozole, 2.5 mg, orally once daily (continuously).

Patients randomised to Arm B (control arm) will receive:

    • Placebo orally once daily on Day 1 to Day 21 of every 28-day cycle followed by 7 days off treatment;

in combination with

      • Letrozole, 2.5 mg, orally once daily (continuously).

Patients are to continue to receive their assigned treatment until objective disease progression, symptomatic deterioration, unacceptable toxicity, death, or withdrawal of consent, whichever occurs first. Patients may continue treatment as assigned at randomisation beyond the time of RECIST-defined disease progression at the discretion of the investigator if that is considered to be in the best interest of the patient and as long as no new anticancer treatment is initiated. In this case, the patient would continue with routine safety assessments as per the Schedule of Activities for the active treatment period.
        1. Efficacy variables and outcomes

Disease assessments will be performed every 12 weeks (7 days) from the date of randomisation. Patients with bone lesions identified at baseline will also have repeat bone scans performed every 24 weeks (±7 days) from the date of randomisation, regardless of any dosing delay to prevent the introduction of bias into the assessment of efficacy. Abnormalities found on subsequent bone scans must also be confirmed by X-ray, CT scan, or MRI.

Specific instructions for bone-only disease are as follows:

  • Treatment outcome will be recorded in the CRF as complete response (CR), stable disease (SD) or progression (PD).

Interpretation will be PD if:

  • The malignant nature of one or more new lesions identified with bone scan is confirmed with X-ray, or CT, or MRI scan,

  • Flare observed in bone scan is followed by confirmation of progression with other imaging modalities,

  • Clinical worsening of the disease is assessed by bone scan and disease progression (that is, new lesion(s)) is confirmed with other imaging modalities.

  • Unequivocal progression of existing bone lesions.

Interpretation will be SD if:

  • The malignant nature of all the new lesions identified with bone scan is not confirmed.

In the following cases the patient will be censored at the date of prior tumor assessment with no PD: 1) on-study fracture; 2) on-study management of pain (palliative radiation therapy, palliative surgery), 3) clinical worsening not objectively confirmed; 4) on-study change of therapy. In all the censored cases (no objectively documented PD) tumour assessment will be performed until PD. Also, it will be at the discretion of the investigator to discontinue the study treatment. It is suggested to institute palliative radiotherapy (for example, lesions at risk for spontaneous micro-fractures or painful lesions) before study initiation as well as palliative surgery if possible and clinically appropriate.
Subjective progression

Patients requiring discontinuation of treatment without objective evidence of disease progression should not be reported as PD on tumour assessment CRFs. This should be indicated on the end of treatment CRF as off treatment due to Global Deterioration of Health Status. Every effort should be made to document objective progression even after discontinuation of treatment.

Comment: This study protocol addresses the challenges in characterizing symptomatic bone lesions likely to indicate disease progression in those with bone-only disease, not accompanied by an objective change in the bonescan. These are critical and seek to avoid the uncertainties arising from the significant censoring of patients who discontinued without objective evidence of PD in Study 1003; this affected the statistical significance of the primary endpoint on blinded independent review assessment in that study. Such patients are an important and substantial subset of those with metastatic ER-positive breast, and form 22.7% of this total study population.

This will require the BICR data to be available to assess the impact of these protocol changes on censoring rates and statistical significance. It has not been included in the top-line summary.

Tumour assessments will be performed until radiographically and/or clinically (that is, for photographed or palpable lesions) documented PD as per RECIST v.1.1, study treatment discontinuation (for patients continuing treatment beyond RECIST-defined disease progression), initiation of new anticancer therapy or discontinuation of patient from overall study participation (for example, death, patient's request, lost to follow-up), whichever occurs first.

Patients who discontinue study treatment for reasons other than radiographically and/or clinically (that is, for photographed or palpable lesions) documented PD as per RECIST v.1.1 will continue to have tumour assessment performed during the follow-up visits every 12 weeks (±7 days) and bone scans (as applicable) every 24 weeks (±7 days) until RECIST-defined disease progression, initiation of new anticancer therapy or discontinuation of patient from overall study participation (for example, death, patient's request, lost to follow-up), whichever occurs first.

Comment: It is likely that any patient considered to have progressed after this first line therapy will be treated relatively soon after clinical progression is determined and study treatment discontinued and almost certainly within the 24-week interval proposed for the additional follow-up bonescan.

Patients discontinuing the active treatment phase will enter a follow-up period during which survival and new anti-cancer therapy information will be collected every 6 months from the last dose of investigational product. The follow-up period will conclude at the time of the final OS analysis.

Efficacy analyses will be performed using the local radiologist’s/investigator’s tumour assessments as the primary data source. However, a blinded independent third-party core imaging laboratory will complete a retrospective review of radiographic images and clinical information collected on-study to verify the protocol-defined endpoints of disease response and progression determinations as assessed by the investigator.


Primary Endpoint

  • Progression-Free Survival (PFS).

Secondary Endpoint(s)

  • Overall Survival (OS): date of randomisation to date of death due to any cause;

  • 1-year, 2-year, and 3-year Survival Probabilities;

  • Objective Response (OR: Complete Response or Partial Response by RECIST v1.1);

  • Duration of Response (DR): complete response (CR), partial response (PR), or stable disease (SD) >24 weeks according to the RECIST version 1.1

  • Disease Control (DC: CR + PR + Stable disease ≥ 24 weeks/number of patients in that arm);

  • ECG analysis including corrected QT interval (QTc), PK/PD analysis of QTc;

  • Tumour tissue biomarkers, including genes (for example, copy numbers of CCND1, CDKN2A), proteins (for example, Ki67, pRb), and RNA expression (for example, cdk4, cdk6);

  • Trough plasma concentration of PD-0332991;

  • EuroQol (EQ-5D) Score

  • Functional Assessment of Cancer Therapy - Breast (FACT-B);

  • Type, incidence, severity (as graded by National Cancer Institute Common

  • Terminology Criteria for Adverse Events [NCI CTCAE] version 4.0), seriousness and relationship to study medications of adverse events (AE) and any laboratory abnormalities.

All primary and secondary endpoints based on radiological (and photographical where applicable) assessments of tumour burden (ie PFS, OR, DR, DC) will be derived using the local radiologist’s/investigator’s assessment. Tumour assessments will also be performed in retrospective by a blinded independent third-party core imaging laboratory and the data will be used for secondary supportive analyses.

The primary efficacy analyses will be based on the intent-to-treat (ITT) population, defined as all patients randomised to the study. Some efficacy analyses will also be performed on the as-treated (AT) population, defined as patients who receive at least 1 dose of study treatment (that is, palbociclib/placebo or letrozole), with treatment assignments designated according to actual study treatment received. Time-to-event endpoints, including PFS, DR, and OS will be summarised using Kaplan- Meier methods and displayed graphically. The median event time and 2 sided 95% confidence interval for the median will be provided for each endpoint. Stratified log rank tests will be used to compare PFS and OS between the treatment arms.

The 1-year, 2-year, and 3-year survival probabilities will be estimated using the Kaplan-Meier method and a 2 sided 95% confidence interval for the log [-log(1-year, 2-year or 3-year survival probability)] will be calculated using a normal approximation using the Greenwood’s formula and then back transformed to give a confidence interval for the 1-year, 2-year, and 3-year survival probability itself.

Following the End of Treatment visit, survival status will be collected in all patients (telephone contact is acceptable) every 6 months (±7 days) from the last dose of study treatment. Information on subsequent anti-cancer therapy will also be collected

The objective response rate (ORR) will be summarised by treatment arm along with the corresponding exact 2 sided 95% confidence interval calculated using a method based on the F distribution. Response rate comparisons between the 2 treatment arms as randomised will be assessed using Cochran-Mantel-Haenszel (CMH) test with the same stratification factors as for the PFS analysis.

Patient reported outcomes of health-related quality of life and health status will be assessed using the Functional Assessment of Cancer Therapy-Breast (FACT-B) and EuroQol-5D (EQ-5D) instruments.

Tumour tissue samples were required to confirm ER status, but no other specific biomarkers were prospectively defined.

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