Clinical Trial Results:
A randomized, multicenter, open-label, phase II trial to evaluate the efficacy and safety of palbociclib in combination with fulvestrant or letrozole in patients with HER2 negative, ER+ metastatic breast cancer.
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Summary
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EudraCT number |
2014-004698-17 |
Trial protocol |
ES GB IT DE CZ |
Global end of trial date |
31 Jan 2020
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Results information
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Results version number |
v1(current) |
This version publication date |
12 Mar 2022
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First version publication date |
12 Mar 2022
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Other versions |
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Summary report(s) |
PARSIFAL clinical study report |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
MedOPP067
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02491983 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Medica Scientia Innovation Research (MedSIR)
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Sponsor organisation address |
Av Diagonal 211, Torre Glories - 27th floor, Barcelona, Spain, 08018
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Public contact |
Sr Global Project Manager, Medica Scientia Innovation Research (MedSIR), +34 932 214 135, alicia.garcia@medsir.org
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Scientific contact |
Sr Global Project Manager, Medica Scientia Innovation Research (MedSIR), +34 932 214 135, alicia.garcia@medsir.org
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
01 Oct 2020
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
31 Jan 2020
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Global end of trial reached? |
Yes
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Global end of trial date |
31 Jan 2020
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
To assess the efficacy of the combination of palbociclib plus fulvestrant or palbociclib plus letrozole in terms of 1-year progression-free survival (PFS) in patients with hormone-sensitive HER2-negative metastatic or locally advanced breast cancer
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Protection of trial subjects |
Study progress will be monitored by MedSIR or its representative (e.g., a CRO) as frequently as necessary to ensure:
That the rights and well-being of human subjects are protected;
- the reported trial data are accurate, complete, and verifiable from the source documents; and
- the conduct of the trial is in compliance with the current approved protocol/amendment(s), GCP, and applicable regulatory requirements.
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Background therapy |
Palbociclib (PD-0332991) is an oral and selective inhibitor of cyclin dependent kinases 4 and 6 (CDK4/6) with little or no activity against a large panel of 274 other protein kinases. The only known natural substrate for Cdk4/cyclin D1 is the retinoblastoma gene product, Rb. Palbociclib has shown to have no effect in Rb-negative tumor cells. Letrozole (Femara®) is an oral non-steroidal aromatase inhibitor and it is approved worldwide for the first-line treatment of postmenopausal women with hormone receptor-positive advanced breast cancer (ABC). Fulvestrant is a novel estrogen-receptor antagonist that, unlike Tamoxifen, is devoid of any agonist activity. After binding to the ER, Fulvestrant induces a rapid degradation and loss of ER and the PgR. As a result, there is less chance of the estrogen receptor being activated by alternative pathways that are believed to cause resistance. | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
17 Jul 2015
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Spain: 255
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Country: Number of subjects enrolled |
United Kingdom: 54
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Country: Number of subjects enrolled |
Czechia: 14
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Country: Number of subjects enrolled |
France: 70
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Country: Number of subjects enrolled |
Germany: 24
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Country: Number of subjects enrolled |
Italy: 38
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Country: Number of subjects enrolled |
Russian Federation: 31
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Worldwide total number of subjects |
486
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EEA total number of subjects |
401
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
273
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From 65 to 84 years |
209
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85 years and over |
4
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Recruitment
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Recruitment details |
Postmenopausal women and premenopausal women receiving LHRH analogues, aged ≥ 18 years with ER positive and HER2 negative locally advanced or metastatic breast cancer that had not received any therapy for the metastatic disease. | |||||||||||||||||||||
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Pre-assignment
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Screening details |
- Postmenopausal and premenopausal women receiving LHRH analogues, ≥ 18 years. - ECOG score ≤ 2 - Histologically confirmed ER+ and/or PgR+ and HER2- locally advanced or MBC - Not candidates for a local treatment with a radical intention - No prior therapy for metastatic disease. - Evidence of measurable or evaluable metastatic disease | |||||||||||||||||||||
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Pre-assignment period milestones
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Number of subjects started |
486 | |||||||||||||||||||||
Number of subjects completed |
486 | |||||||||||||||||||||
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Period 1
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Period 1 title |
Global (overall period)
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Is this the baseline period? |
Yes | |||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Not blinded | |||||||||||||||||||||
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Palbociclib + Fulvestrant | |||||||||||||||||||||
Arm description |
- | |||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||
Investigational medicinal product name |
Fulvestrant
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Solution for injection
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Routes of administration |
Intramuscular use
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Dosage and administration details |
Fulvestrant will be supplied as two pre-filled syringe (5 ml) that contains each one 250 mg fulvestrant and other ingredients (excipients) like ethanol (96 per cent), benzyl alcohol, benzyl benzoate and castor oil. Fulvestrant is a clear, colourless to yellow, viscous solution in a pre-filled syringe fitted with a tamper-evident closure, containing 5 ml solution for injection. Two syringes must be administered to receive the 500 mg recommended monthly dose.
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Investigational medicinal product name |
Pablociclib
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Capsule
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Routes of administration |
Oral use
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Dosage and administration details |
Palbociclib (PD-0332991) will be supplied as capsules containing 75 mg, 100 mg, or 125 mg equivalents of PD-0332991 free base. The sponsor will supply the oral drug formulation to sites in HDPE (High-density polyethylene) bottles containing 75 mg, 100mg, or 125 mg capsules. The capsules can be differentiated by their size and colour.
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Arm title
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Palbociclib + Letrozole | |||||||||||||||||||||
Arm description |
- | |||||||||||||||||||||
Arm type |
Active comparator | |||||||||||||||||||||
Investigational medicinal product name |
Palbociclib
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Capsule
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Routes of administration |
Oral use
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Dosage and administration details |
Palbociclib (PD-0332991) will be supplied as capsules containing 75 mg, 100 mg, or 125 mg equivalents of PD-0332991 free base. The sponsor will supply the oral drug formulation to sites in HDPE (High-density polyethylene) bottles containing 75 mg, 100mg, or 125 mg capsules. The capsules can be differentiated by their size and colour.
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Investigational medicinal product name |
Letrozole
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Film-coated tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Letrozole: Commercially available letrozole 2.5 mg film-coated tablets will be used in the study.
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Baseline characteristics reporting groups
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Reporting group title |
Palbociclib + Fulvestrant
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Reporting group description |
- | ||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Palbociclib + Letrozole
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Reporting group description |
- | ||||||||||||||||||||||||||||||||||||||||||||
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Subject analysis sets
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Subject analysis set title |
ITT
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Subject analysis set type |
Intention-to-treat | ||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
Considering all patients included regardless of whether they received the required study drug exposure and protocol processing
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Subject analysis set title |
Safety
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Subject analysis set type |
Safety analysis | ||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
Considering all patients that receive at least one drug exposure.
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End points reporting groups
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Reporting group title |
Palbociclib + Fulvestrant
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Reporting group description |
- | ||
Reporting group title |
Palbociclib + Letrozole
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Reporting group description |
- | ||
Subject analysis set title |
ITT
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Subject analysis set type |
Intention-to-treat | ||
Subject analysis set description |
Considering all patients included regardless of whether they received the required study drug exposure and protocol processing
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Subject analysis set title |
Safety
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Subject analysis set type |
Safety analysis | ||
Subject analysis set description |
Considering all patients that receive at least one drug exposure.
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End point title |
PFS | |||||||||
End point description |
The progression-free survival will be compared between the two groups using a two-sided stratified log-rank test with site of disease (visceral vs. non-visceral) and by the onset of metastatic disease diagnose (de novo metastatic vs. non de novo patients) as strata. We will test the primary endpoint at a nominal levels of 0.001 and 0.0498 at interim and final analysis, respectively.
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End point type |
Primary
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End point timeframe |
To evaluate the progression-free survival. This is defined as the time from randomization until objective tumor progression or death by any cause.
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Statistical analysis title |
PFS (per investigator's assessment) | |||||||||
Comparison groups |
Palbociclib + Fulvestrant v Palbociclib + Letrozole
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Number of subjects included in analysis |
486
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Analysis specification |
Pre-specified
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Analysis type |
superiority | |||||||||
P-value |
≤ 0.05 | |||||||||
Method |
Logrank | |||||||||
Parameter type |
Hazard ratio (HR) | |||||||||
Point estimate |
1.1
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Confidence interval |
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level |
95% | |||||||||
sides |
2-sided
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lower limit |
0.86 | |||||||||
upper limit |
1.41 | |||||||||
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End point title |
Safety | |||||||||
End point description |
Analysis of safety-related data will be considered at four levels:
• First, the extent of exposure (dose, duration, number of patients) will be examined to determine the degree to which safety can be assessed from the study.
• Second, we will describe and compare clinically relevant test, concomitant medications and adverse events reported in every study group. For adverse events, we will report intensity, causality, body system, action taken, and outcome.
• Third, serious adverse events, deaths and study discontinuations will be described and examined in every study group.
• Finally, patient grade 3 and 4 toxicities in every study group will be classified by MedDRA system organ class and compared between patient baseline characteristics.
The relation between baseline characteristics and severe adverse events (classified in MedDRA SOCs) will be analyzed with chi-squared test followed by multivariate logistic regression with appropriate interaction terms.
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End point type |
Secondary
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End point timeframe |
Patient safety and adverse events will be assessed using the CTCAE. Grade 3 and 4 adverse events and serious adverse events will be assessed to determine the safe and tolerability of the different drug combinations.
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| No statistical analyses for this end point | ||||||||||
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End point title |
Time to progression | |||||||||
End point description |
Secondary objective to compare the time to progression (TTP) of the combination of palbociclib plus fulvestrant with palbociclib plus letrozole.
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End point type |
Secondary
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End point timeframe |
TTP is defined as the time from randomization to disease progression, as assessed by the investigator per RECIST v1.1
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| No statistical analyses for this end point | ||||||||||
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End point title |
Overall survival | |||||||||
End point description |
Compare the overall survival (OS) of the combination of palbociclib plus fulvestrant with palbociclib plus letrozole.
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End point type |
Secondary
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End point timeframe |
Overall survival is defined as the time from randomization until death from any cause
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| No statistical analyses for this end point | ||||||||||
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End point title |
Overall response | |||||||||
End point description |
Secondary objective to compare the clinical response (in terms of clinical benefit and overall response) of the combination of palbociclib plus fulvestrant with palbociclib plus letrozole.
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End point type |
Secondary
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End point timeframe |
The ORR is defined as the proportion of patients with best overall response of confirmed complete response (CR) or partial response (PR) based on local investigator’s assessment according to RECIST criteria guidelines (version 1.1).
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| No statistical analyses for this end point | ||||||||||
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End point title |
Duration of response | |||||||||
End point description |
Secondary objective to compare the duration of response (DoR) of the combination of palbociclib plus fulvestrant with palbociclib plus letrozole.
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End point type |
Secondary
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End point timeframe |
DoR is defined as the time from documentation of tumor response (either CR or PR) to disease progression. An objective response needs to be confirmed at least 4 weeks after the initial response
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| No statistical analyses for this end point | ||||||||||
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End point title |
Time to response | |||||||||
End point description |
Secondary objective to compare time to response (TTR) of the combination of palbociclib plus fulvestrant with palbociclib plus letrozole.
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End point type |
Secondary
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End point timeframe |
TTR is defined as the time from randomization to the first overall tumor response (tumor shrinkage of ≥30%) observed for patients who achieved a CR or PR.
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| No statistical analyses for this end point | ||||||||||
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End point title |
Clinical benefit rate | |||||||||
End point description |
Secondary objective to compare the clinical response (in terms of clinical benefit and overall response) of the combination of palbociclib plus fulvestrant with palbociclib plus letrozole.
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End point type |
Secondary
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End point timeframe |
The CBR is defined as the percentage of patients who experience a CR, PR or stable disease for at least 24 weeks and assessed by modified Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) criteria.
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| No statistical analyses for this end point | ||||||||||
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Adverse events information
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Timeframe for reporting adverse events |
Baseline until 30 days after last study treatment dose
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Adverse event reporting additional description |
All study patients will be carefully monitored for the occurrence of AEs (including SAEs and AESIs) during the above specified adverse event reporting period.
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
20
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Reporting groups
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Reporting group title |
Experimental arm
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Reporting group description |
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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20 Jan 2016 |
Protocol amendment 1:
- List of Steering Committee members.
- Revision of Background and Rationale Information to update clinical data related to fulvestrant and palbociclib, interaction of estrogens and cyclin-dependent kinases (CDK) in breast cancer. Addition of a new sub-section covering the rational for the translational sub-studies.
- Addition of new inclusion criterion (inclusion criterion 2) to extend the study population to pre-menopausal women under treatment with luteinizing hormone releasing hormone (LHRH).
- Clarification on inclusion criterion #6 that patient should have not received either hormonal treatment or chemotherapy in the metastatic setting.
- Clarification on inclusion criterion #9 regarding the required value for ANC at baseline from 1.0 x 109/L to 1.5 x 109/L.
- Replacement of the stratification criterion “prior vs. non-prior hormonal therapy” by “de novo vs. non de novo metastatic disease”.
- Implementation of translational sub-studies to evaluate the prognostic and predictive value of a variety of biomarkers involving blood and tumor sample collections at different time points.
These molecular sub-studies will be implemented in selected centers. Participation of patients will be independent of their participation in the main clinical trial.
- Recommendation for the use of erythropoietin-stimulating agents should be based on National Comprehensive Cancer Network (NCCN) guidelines.
- Update on prohibited treatments and drug interactions.
- Clarification on the requirements and time points for tumor assessment throughout the study.
- Changes in the contact details (email and fax number) for expedite safety reporting. Removal of section 7.3 where it was described Sponsor responsibilities for safety updates to study funders and competent authorities. |
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30 Jun 2016 |
Protocol amendment 1b:
- List of Steering Committee members
- Revision of Background and Rationale Information to update clinical data related to fulvestrant and palbociclib, interaction of estrogens and CDK in breast cancer. Addition of a new sub-section covering the rational for the translational sub-studies
- Modification of inclusion criterion 1 to extend the study population to pre-menopausal women under treatment with LHRH
- Clarification on inclusion criterion 6 that patient should have not received either hormonal treatment or chemotherapy in the metastatic setting.
- Clarification on inclusion criterion 9 regarding the required value for ANC at baseline from 1.0 x 109/L to 1.5 x 109/L. Clarification regarding acceptable values for alkaline phosphatase
- Addition of new inclusion criterion (inclusion criterion 13) requiring patients consents to blood sample collection for biomarker research
- Replacement of the stratification criterion “prior vs. non-prior hormonal therapy” by “de novo vs. non de novo metastatic disease”
- Implementation of translational sub-studies to evaluate the prognostic and predictive value of a variety of biomarkers. Participation of patients in tumor tissue collection will be optional to their participation in the main clinical trial
- Recommendation for the use of erythropoietin-stimulating agents should be based on NCCN guidelines
- Update on prohibited treatments and drug interactions
- Restriction of the requirement to perform baseline brain tumor assessment at time of screening only in patients with clinical suspicion of central involvement
- Clarification on the requirements and time points for tumor assessment throughout the study
- Harmonization of the protocol wording regarding timepoints and frequency to perform ECGs during the treatment period
- Requirement for additional hemogram on C1D14 and C2D14
- Changes in the contact details for expedite safety report
- Typographical, format and wording adjustments |
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30 Jun 2016 |
Protocol amendment 2:
- Revision of Background and Rationale as per recent published data and update protocol with new data available
on the IMPs used in the study.
- Clarification on inclusion criterion #9 regarding acceptable values for alkaline phosphatase.
- Addition of new inclusion criterion (inclusion criterion #13) as mandatory procedure the participation of patients in the translational sub-study for blood samples collection.
- Typo correction on treatment schedule for palbociclib for Arm B, treatment period corrected from 28 days to 21 days of a 28-days cycle. |
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20 Dec 2016 |
Protocol amendment 3:
- Revision of background information to include recent published data on palbociclib and fulvestrant on the
treatment of ER+/HER2- metastatic breast cancer patients.
- Revision of statistical assumptions leading to:
• Modification of statistical assumptions regarding expected median PFS and Hazard Ratio for control vs. interventional arm.
• Modification of primary variable from Progression free Survival at 1 year (1y-PFS) to overall PFS.
• Change in sample size from 304 patients to 486 as result of updating the assumptions for its calculation.
- Addition of new secondary end-points: Duration of Response and Time to Response.
- Update on the definition of End of Study, EoS will occur one year after randomization of the last patient or when trial efficacy decision criteria are met, whichever is earlier.
- Switch of analysis of primary end-point from superiority only to non-inferiority analyses, if the superiority criteria cannot be met.
- Re-definition of interim analysis. Interim analysis was initially planned to occur after half of all expected patients have completed one-year follow-up period or have discontinued. Re-defined interim analysis will occur at 22 months after 35% of the total PFS events (89 events) have been observed.
- Extend the justification of translational sub-studies analysis in the statistical section.
- Addition of patient derived xenograft (PDX) models as potential studies to be performed from tumor samples obtained form patients enrolled in the study.
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12 May 2017 |
Protocol amendment 4:
- Revision of inclusion criteria #13 to request as mandatory procedure in the study the consent to provide tumor tissue samples. Patients must consent to provide tumor tissue samples at baseline and at time of progression (if biopsable lesion). For non de novo patients, tumor tissue at the time of metastatic disease diagnose will be requested as preferred option, though at least archived tissue samples from the primary tumor could be acceptable.
- Revision of dose modifications guidelines for palbocilcib
• Main changes affect the management of neutropenia during the first two cycles of treatment: Neutropenia grade 3
does not require immediate palbocilib treatment interruption but only if persists for more than 1 week.
• In addition, dose modifications for QTc prolongations are aligned with the other non-hematologic toxicities based on later data showing that palbociclib does not prolong QTc interval.
- Definition of maximum dose of corticosteroids as below of 10 mg per day of methylprednisolone equivalent. |
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
