Clinical Trial Results:
A Phase II Clinical Trial to analyse Olaparib Response in patients with BRCA1 and/or 2 Promoter Methylation Diagnosed of Advanced Breast Cancer (COMETA-Breast study).
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Summary
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EudraCT number |
2016-001407-23 |
Trial protocol |
ES |
Global end of trial date |
08 Mar 2022
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Results information
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Results version number |
v1(current) |
This version publication date |
11 Nov 2023
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First version publication date |
11 Nov 2023
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Other versions |
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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 |
GEICAM/2015-06
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT03205761 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
GEICAM (FUNDACIÓN GRUPO ESPAÑOL DE INVESTIGACIÓN EN CÁNCER DE MAMA)
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Sponsor organisation address |
Avenida de los Pirineos 7, San Sebastián de los Reyes / Madrid, Spain, 28703
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Public contact |
Clinical Operations Department, GEICAM (Fundación Grupo Español de Investigación en Cáncer de Mama), +34 916592870, inicio_ensayos@geicam.org
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Scientific contact |
Clinical Operations Department, GEICAM (Fundación Grupo Español de Investigación en Cáncer de Mama), +34 916592870, inicio_ensayos@geicam.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 |
13 May 2022
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
12 Jan 2022
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Global end of trial reached? |
Yes
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Global end of trial date |
08 Mar 2022
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Was the trial ended prematurely? |
Yes
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General information about the trial
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Main objective of the trial |
To analyse the olaparib efficacy in the treatment of patients diagnosed of advanced triple negative breast cancer (TNBC) with BRCA1 and/or BRCA2 promoter methylation assessed in somatic DNA.
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Protection of trial subjects |
Not applicable. It was not necessary to applied extra measures for protection of the subjects out of the good clinical practice environment.
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Background therapy |
Epigenetic silencing by aberrant BRCA1/2 promoters’ methylation can be responsible for a dysfunctional BRCA protein. BRCA1/2 promoters’ methylation occurs in 15-57% of triple negative breast cancer patients. BRCA1/2 promoters’ methylation breast cancer display pathologic features and genetic profiles like germline BRCA1/2-mutated (gBRCA1/2m) carriers. Olaparib is a PARP inhibitor approved for treating gBRCAm HER2-negative advanced breast cancer patients. These are the results of a phase II study assessing the Olaparib efficacy in advanced triple negative breast cancer patients with BRCA1/2 promoters’ methylation. | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
23 Oct 2017
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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: 11
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Worldwide total number of subjects |
11
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EEA total number of subjects |
11
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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) |
11
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
Eleven patients were registered in eight Spanish sites. | ||||||||||||
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Pre-assignment
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Screening details |
Eleven patients were registered in eight Spanish sites. | ||||||||||||
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Period 1
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Period 1 title |
Overall trial (overall period)
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Is this the baseline period? |
Yes | ||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||||
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Arms
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Arm title
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Olaparib | ||||||||||||
Arm description |
Patients with a positive methylation status on at least one of the two genes and lacking of known deleterious or suspected deleterious mutations in both genes could be included in the study to receive olaparib tablet formulation at 600 mg total daily dose (given in two oral administrations of 300 mg every 12 hours approximately). Patients will continue to receive their treatment until objective disease progression, symptomatic deterioration, unacceptable toxicity, death or withdrawal of consent, whichever occurs first. | ||||||||||||
Arm type |
Experimental | ||||||||||||
Investigational medicinal product name |
Olaparib
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Investigational medicinal product code |
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Other name |
Lynparza
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Olaparib as single agent at a continuous daily dose of 600 mg (tablet formulation), given in two oral administrations of 300 mg with a dosing interval of about 12 h with a window interval of 2 hours before and after the scheduled time.
Olaparib is for oral use. Olaparib tablets should be taken with one glass of water and swallowed whole and not chewed, crushed, dissolved or divided. Olaparib tablets can be taken with or without food.
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Baseline characteristics reporting groups
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Reporting group title |
Olaparib
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Reporting group description |
Patients with a positive methylation status on at least one of the two genes and lacking of known deleterious or suspected deleterious mutations in both genes could be included in the study to receive olaparib tablet formulation at 600 mg total daily dose (given in two oral administrations of 300 mg every 12 hours approximately). Patients will continue to receive their treatment until objective disease progression, symptomatic deterioration, unacceptable toxicity, death or withdrawal of consent, whichever occurs first. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Olaparib
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Reporting group description |
Patients with a positive methylation status on at least one of the two genes and lacking of known deleterious or suspected deleterious mutations in both genes could be included in the study to receive olaparib tablet formulation at 600 mg total daily dose (given in two oral administrations of 300 mg every 12 hours approximately). Patients will continue to receive their treatment until objective disease progression, symptomatic deterioration, unacceptable toxicity, death or withdrawal of consent, whichever occurs first. | ||
Subject analysis set title |
Arm to report statistical analysis
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
Arm to report statistical analysis for the ORR endpoint definition section in a single arm trial.
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End point title |
Overall Response Rate (ORR) | |||||||||
End point description |
ORR is defined as the percentage of patients with a Complete Response (CR) or Partial Response (PR) out of the patients from the efficacy population. Per RECIST, CR is defined as the disappearance of all target lesions; PR is defined as an >=30% decrease in the sum of the longest diameter of target lesions.
Tumor response will be assessed using Response Evaluation Criteria In Solid Tumors Criteria (RECIST 1.1). Efficacy population is a subset of the intend to treat population that has received at least one dose of study medication and has performed at least one tumor response assessment according to RECIST v.1.1 (unless a progression, death or unacceptable toxicity is seen before the first tumor response assessment).
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End point type |
Primary
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End point timeframe |
Through study treatment, and average of 8 weeks
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| Notes [1] - Arm to report statistical analysis for the ORR endpoint definition section in a single arm trial. |
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Statistical analysis title |
ORR analysis | |||||||||
Statistical analysis description |
ORR will be estimated by dividing the number of patients with objective response (CR or PR) by the Efficacy population (“response rate”).
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Comparison groups |
Olaparib v Arm to report statistical analysis
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Number of subjects included in analysis |
12
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Analysis specification |
Pre-specified
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Analysis type |
other [2] | |||||||||
Method |
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Parameter type |
Percentage | |||||||||
Point estimate |
9.1
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Confidence interval |
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95% | |||||||||
sides |
2-sided
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lower limit |
0.2 | |||||||||
upper limit |
41.3 | |||||||||
| Notes [2] - The rate of OR and confidence interval. |
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End point title |
Clinical Benefit Rate (CBR) | ||||||
End point description |
Tumor response was assessed using Response Evaluation Criteria In Solid Tumors Criteria (RECIST 1.1) criteria. CBR was defined as the percentage of patients with a Complete Response (CR) or Partial Response (PR) plus stable disease (SD) ≥ 24 weeks out of the efficacy population. Per RECIST, CR is defined as the disappearance of all target lesions; PR is defined as an >=30% decrease in the sum of the longest diameter of target lesions; SD is defined as a failure to meet criteria for CR or PR in the absence of progressive disease. Overall Response (OR) = CR + PR.
Efficacy population is a subset of the intend to treat population that has received at least one dose of study medication and has performed at least one tumor response assessment according to RECIST v.1.1 (unless a progression, death or unacceptable toxicity is seen before the first tumor response assessment).
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End point type |
Secondary
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End point timeframe |
Through study treatment, and average of 8 weeks
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| No statistical analyses for this end point | |||||||
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End point title |
Progression Free Survival (PFS) | ||||||||
End point description |
Tumor response was assessed using Response Evaluation Criteria In Solid Tumors Criteria (RECIST 1.1). PFS is defined as the time from enrollment to the first documented progression disease (PD), or death from any cause, whichever occurs first. PD is defined using RECIST, as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.
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End point type |
Secondary
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End point timeframe |
Through study treatment, and average of 8 weeks
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| No statistical analyses for this end point | |||||||||
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End point title |
Overall Survival (OS) | ||||||||
End point description |
Overall Survival (OS) defined as the time from the date of study enrollment to the date of death from any cause.
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End point type |
Secondary
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End point timeframe |
Up to 14 months
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| No statistical analyses for this end point | |||||||||
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End point title |
Correlation Value Between BRCA1 Methylation Status and Efficacy Outcome Data | ||||||||||||||
End point description |
To evaluate the effect of methylation status with time to event variables (e.g. PFS, OS) it will be used a univariate Cox Regression model.
To evaluate the effect of methylation status with efficacy rate parameters it will be used chi-square test if both of them are quantitative, and will be used an ANOVA analysis if one variable is quantitative and the other one is qualitative
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End point type |
Secondary
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End point timeframe |
Through study treatment, and average of 8 weeks
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| Notes [3] - Only 4 patients with Partial Response or Stable Disease |
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| No statistical analyses for this end point | |||||||||||||||
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End point title |
Correlation Value Between BRCA2 Methylation Status and Efficacy Outcome Data | ||||||||||||||
End point description |
To evaluate the effect of methylation status with time to event variables (e.g. PFS, OS) it will be used a univariate Cox Regression model.
To evaluate the effect of methylation status with efficacy rate parameters it will be used chi-square test if both of them are quantitative, and will be used an ANOVA analysis if one variable is quantitative and the other one is qualitative.
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End point type |
Secondary
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End point timeframe |
Through study treatment, and average of 8 weeks
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| Notes [4] - Only 4 patients with Partial Response or Stable Disease |
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| No statistical analyses for this end point | |||||||||||||||
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End point title |
Response Duration (RD) | ||||||
End point description |
Tumor response was assessed using Response Evaluation Criteria In Solid Tumors Criteria (RECIST 1.1) criteria. RD was defined as the time from the first documentation of objective tumor response (complete response (CR) or partial response (PR)) to the first documented progressive disease (PD), or to death due to any cause, whichever occurs first.
Per RECIST, CR is defined as the disappearance of all target lesions; PR is defined as an >=30% decrease in the sum of the longest diameter of target lesions; PD is defined as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.
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End point type |
Secondary
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End point timeframe |
Through study treatment, and average of 8 weeks
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| Notes [5] - There was only 1 Partial Response. |
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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 |
AE were reported after Informed Consent Document (ICD) and before study drugs until approximately 30 days following the discontinuation of study treatment.
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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 |
24.1
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Reporting groups
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Reporting group title |
Olaparib
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Reporting group description |
Patients with a positive methylation status on at least one of the two genes and lacking of known deleterious or suspected deleterious mutations in both genes could be included in the study to receive olaparib tablet formulation at 600 mg total daily dose (given in two oral administrations of 300 mg every 12 hours approximately). Patients will continue to receive their treatment until objective disease progression, symptomatic deterioration, unacceptable toxicity, death or withdrawal of consent, whichever occurs first. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 0% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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07 Jun 2017 |
INTRODUCTION: Pharmacokinetics and safety information has been updated according to the most recent version of the Investigator Brochure (IB) (V.14 March 10, 2017).
PROCEDURES FOR PATIENT SELECTION:
It is emphasized that every effort should be made to obtain the sample for methylation analysis after the last treatment.
It is specified that the analysis of germline BRCA1/2 mutations in blood can be carried out in the prior treatment line in those patients who are future candidates for inclusion in the trial. A specific HIP-ICF has been generated for this analysis.
The timeframe for methylation analysis is changed from 10 to 8 working days, unless justified.
It has been specified that plasma samples are required for all registered patients who send sample for methylation analysis.
MANAGEMENT OF ADVERSE EVENTS AND CONCOMITANT MEDICATION:
Olaparib dose adjustment instructions after anemia grade 3 have been updated (Section 5.4.1 Management of haematological toxicity).
The instructions for concomitant medication are updated if 1) co-administration of moderate inhibitors of CYP3A is required, the olaparib dose should be reduced to 150 mg twice daily for the duration of treatment with the inhibitor and continue for 3 half-lives; 2) concomitant anticoagulant treatments it is updated that the administration of low molecular weight heparin is allowed and that if the patient is being treated with warfarin is should be follow-up the parameter APTT (5.5 "General Concomitant Medication and supportive care”
REPORTING OF ADVERSE EVENTS AND PREGNANCIES
The fax number for SAE and pregnancy reporting has been updated.
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10 Jun 2019 |
INTRODUCTION: Pharmacokinetics and safety information has been updated according to the most recent versions of the Investigator Brochure (IB) ((ver. 15 _08 March 2016, ver.16 _29 Jan 2019 and ver. 17_ 02 May 2019).
Investigational Plan: Early efficacy review was changed by Step 1 analysis of the optimal two-stage Simon model.
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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. | |||
| In this proof-of-concept study, Olaparib did not show clinically nor statistically significant antitumor activity. The statistical assumptions for the first Simon’s model stage were not met so the recruitment did not proceed onto the second stage | |||
