Clinical Trials /

Analysis of Olaparib Response in Patients With BRCA1 and/or 2 Promoter Methylation Diagnosed of Advanced Breast Cancer

NCT03205761

Description:

This is a multicenter single-arm phase II clinical trial to evaluate the efficacy and safety of olaparib in patients diagnosed of advanced triple negative breast cancer (TNBC) with methylation of BRCA1 and/or BRCA2 promoters assessed in DNA from metastatic lesions and absence of BRCA1 and 2 germline mutations.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Analysis of Olaparib Response in Patients With BRCA1 and/or 2 Promoter Methylation Diagnosed of Advanced Breast Cancer
  • Official Title: 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)

Clinical Trial IDs

  • ORG STUDY ID: GEICAM/2015-06
  • SECONDARY ID: 2016-001407-23
  • SECONDARY ID: ESR-15-11274
  • NCT ID: NCT03205761

Conditions

  • Advanced Breast Cancer

Interventions

DrugSynonymsArms
OlaparibLynparzaolaparib

Purpose

This is a multicenter single-arm phase II clinical trial to evaluate the efficacy and safety of olaparib in patients diagnosed of advanced triple negative breast cancer (TNBC) with methylation of BRCA1 and/or BRCA2 promoters assessed in DNA from metastatic lesions and absence of BRCA1 and 2 germline mutations.

Detailed Description

      Patients must have received at least one previous regimen in the advance disease setting and
      must have at least one measurable lesion that can be accurately assessed according to RECIST
      v.1.1. Potential eligible patients will be screened to assess somatic (s) BRCA promoter
      methylation at an reference central laboratory. Germinal (g) BRCA mutational status will be
      analyzed also centrally at 'Myriad Genetics GmBh' laboratory unless the BRCA mutational
      status is already known based on a Myriad previous report. 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 enrolled in the study and receive
      olaparib.

      Blood and tumor samples collected from all screened patients could be used for the biomarker
      analysis, including the assessment of germline methylation status and gene expression levels
      of BRCA1/2. An early efficacy review will be performed after 12 evaluable patients are
      enrolled; if at least 4 of them show tumour response, additional patients will be included to
      complete a total of 34 patients.
    

Trial Arms

NameTypeDescriptionInterventions
olaparibExperimentalPatients 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.
  • Olaparib

Eligibility Criteria

        Inclusion Criteria: (Any asterisked* are applicable as an inclusion criteria prior to
        perform the BRCA methylation testing via central testing)

          1. *The patient has signed and dated the informed consent document and it has been
             obtained before conducting any procedure specifically for the study.

          2. Female ≥ 18 years of age on day of signing informed consent.

          3. Patient with histological confirmation of breast cancer with evidence of advanced
             disease not amenable to resection or radiation therapy with curative intent.

          4. Documented Triple Negative (TN) disease by immunohistochemistry (IHC) and/or in situ
             hybridization based on local testing (preferably assessed on the most recent tumour
             biopsy available). TN is defined as negative hormone receptor status (< 1% of tumour
             cells with Estrogen Receptor (ER) and Progesterone Receptor (PgR) expression) and
             Human Epidermal growth factor Receptor 2 (HER2) negative status (defined as IHC score
             0/1+ or negative by in situ hybridization defined according to local criteria).

          5. Patient must have received at least one previous regimen in the advance disease
             setting.

          6. Absence of deleterious or suspected deleterious germline mutations in BRCA1 and BRCA2.
             Germinal BRCA mutational status will be centrally assessed in Myriad laboratories to
             check eligibility unless the test has been previously performed at Myriad and absence
             of mutations has been determined.

          7. Availability of a tumour tissue sample from the metastatic lesions (every effort
             should be done to obtain the sample after the previous therapeutic regimen for
             advanced disease) for central testing.

          8. Documented methylation of BRCA1 and/or 2 promoters based on central testing by
             analysis on the most recent tumour from metastatic lesions available.

          9. At least one lesion measurable not previously irradiated, that can be accurately
             measured at baseline as ≥ 10 mm in the longest diameter (except lymph nodes which must
             have short axis ≥ 15 mm) with computed tomography (CT) or magnetic resonance imaging
             (MRI) or clinical examination and which is suitable for accurate repeated measurements
             according to RECIST v.1.1.

         10. Patient must have normal organ and bone marrow function measured within 28 days prior
             to administration of study treatment as defined below:

               -  Haemoglobin ≥ 10.0 g/dL with no blood transfusions in the past 28 days.

               -  Absolute neutrophil count (ANC) ≥ 1.5 x 109/L

               -  Platelet count ≥ 100 x 109/L

               -  Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN)

               -  Aspartate aminotransferase (AST) (Serum Glutamic Oxaloacetic Transaminase, SGOT)
                  /Alanine aminotransferase (ALT) (Serum Glutamic Pyruvate Transaminase, SGPT) ] ≤
                  2.5 x institutional upper limit of normal unless liver metastases are present in
                  which case they must be ≤ 5 x ULN

               -  Patients must have creatinine clearance estimated using the Cockcroft-Gault
                  equation of ≥51 mL/min:

             Estimated creatinine clearance = (140-age [years]) x weight (kg) (x F)/ serum
             creatinine (mg/dL) x 72; where F=0.85 for females.

         11. *Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1 (see protocol
             attachment 2)

         12. *Patient must have a life expectancy ≥ 16 weeks

         13. *Postmenopausal or evidence of non-childbearing status for women of childbearing
             potential: negative urine or serum pregnancy test within 28 days of study treatment
             and confirmed prior to treatment on day 1.

             Postmenopausal patient is defined as a woman fulfilling any one of the following
             criteria (based on the National Comprehensive Cancer Network (NCCN) definition of
             menopause 2008):

               -  Prior bilateral oophorectomy.

               -  Age > 60 years.

               -  Age ≤ 60 years and with amenorrhea for 12 or more months in the absence of
                  chemotherapy, tamoxifen, toremifene, or ovarian suppression and follicle
                  stimulating hormone and estradiol in the postmenopausal range.

         14. Olaparib is regarded as a compound with medium/high foetal risk, patients of
             childbearing potential and their partners, who are sexually active, must agree to the
             use of 2 highly effective forms of contraception in combination as listed below. This
             should be started from the signing of the informed consent and continue throughout
             period of taking study treatment and for at least 1 month after last dose of study
             drug or they must totally/truly abstain from any form of sexual intercourse (see
             below).

             Acceptable non-hormonal birth control methods include:

               -  Total sexual abstinence. Abstinence must continue for the total duration of the
                  study treatment and for at least 1 month after one dose. Periodic abstinence
                  (e.g., calendar ovulation, symptothermal, post-ovulation methods) and withdrawal
                  are not acceptable methods of contraception.

               -  Vasectomised sexual partner plus male condom. With participant assurance that
                  partner received post-vasectomy confirmation of azoospermia.

               -  Tubal occlusion plus male condom.

               -  Intrauterine Device (IUD) plus male condom. Provided coils are copper-banded.

             Acceptable hormonal methods:

               -  Normal and low dose combined oral pills plus male condom.

               -  Cerazette (desogestrel) plus male condom. Cerazette is currently the only highly
                  efficacious progesterone based pill.

               -  Hormonal shot or injection (e.g., Depo-Provera) plus male condom.

               -  Etonogestrel implants (e.g. Implanon or Norplan) plus male condom.

               -  Norelgestromin/ethinyl estradiol (EE) transdermal system plus male condom.

               -  Intrauterine system (IUS) device (e.g., levonorgestrel releasing IUS -Mirena®)
                  plus male condom.

               -  Intravaginal device plus male condom (e.g. EE and etonogestrel).

         15. *Patient is willing and able to comply with the protocol for the duration of the study
             including undergoing treatment and scheduled visits, laboratory tests and examinations
             and other study procedures including follow up.

        Exclusion Criteria: (Any asterisked* are applicable as an inclusion criteria prior to
        perform the BRCA methylation testing via central testing)

          1. Involvement in the planning and/or conduct of the study (applies to the sponsor and/or
             study site staff).

          2. Previous enrolment in the present study.

          3. Participation in another clinical study with an investigational product during the
             last 4 weeks.

          4. *Any previous treatment with a Poly Adenosine diphosphate-Ribose Polymerase (PARP)
             inhibitor, including olaparib.

          5. *Patients with other malignancy within the last 5 years, except: adequately treated
             non-melanoma skin cancer (basal cell or squamous cell carcinoma), curatively treated
             in-situ cancer of the cervix, ductal carcinoma in situ (DCIS), stage 1, grade 1
             endometrial carcinoma, or other solid tumours including lymphomas (without bone marrow
             involvement) curatively treated with no evidence of disease for ≥ 5 years prior to
             study inclusion. Patients with a history of localised breast cancer with a tumor
             histology different to TN, with no evidence of disease for ≥ 5 years since they
             completed their adjuvant treatment.

          6. Patients receiving any systemic chemotherapy or radiotherapy (except for palliative
             reasons), within 3 weeks prior to study treatment (or a longer period depending on the
             defined characteristics of the agents used).

          7. Resting ECG with corrected QT interval (QTc) > 470 msec on 2 or more time points
             within a 24 hour period or family history of long QT syndrome.

          8. *Concomitant use of known strong Cytochrome P3A (CYP3A) inhibitors (e.g. itraconazole,
             telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or
             cobicistat, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) or moderate
             CYP3A inhibitors (e.g. ciprofloxacin, erythromycin, diltiazem, fluconazole,
             verapamil). The required washout period prior to starting olaparib is 2 weeks. Please
             refer to section 5.5.2.1 about strong and moderate CYP3A inhibitors.

          9. *Concomitant use of known strong CYP3A inducers (e.g. phenobarbital, enzalutamide,
             phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John's
             Wort) or moderate CYP3A inducers (eg. bosentan, efavirenz, modafinil). The required
             washout period prior to starting olaparib is 5 weeks for enzalutamide or phenobarbital
             and 3 weeks for other agents. Please refer to section 5.5.2.2 about strong and
             moderate CYP3A inducers.

         10. *Persistent toxicities (> NCI-CTCAE grade 2) caused by previous cancer therapy (except
             alopecia or other toxicities not considered a safety risk for the patient at
             investigator´s discretion).

         11. *Patients with myelodysplastic syndrome/acute myeloid leukaemia (MDS/AML) or with
             features suggestive of MDS/AML.

         12. *Patients with symptomatic uncontrolled brain metastases. A scan to confirm the
             absence of brain metastases is not required. Patients with brain metastases may be
             eligible for the study only if more than 4 weeks from treatment completion for these
             metastases (including radiation and/or surgery), are clinically stable at the time of
             study entry. The patient can receive a stable dose of corticosteroids before and
             during the study as long as these were started at least 4 weeks prior to treatment.
             Patients with spinal cord compression unless considered to have received definitive
             treatment for this and evidence of clinically stable disease for 28 days.

         13. Major surgery within 2 weeks of starting study treatment and patients must have
             recovered from any effects of any major surgery.

         14. *Patients unable to swallow orally administered medication and patients with
             gastrointestinal disorders likely to interfere with absorption of the study
             medication.

         15. *Breast feeding women.

         16. *Immunocompromised patients, e.g. patients who are known to be serologically positive
             for human immunodeficiency virus (HIV).

         17. *Patients with known active hepatitis (i.e., Hepatitis B or C) due to risk of
             transmitting the infection through blood or other body fluids.

         18. *Patients with a known hypersensitivity to olaparib or any of the excipients of the
             product.

         19. *Patients considered a poor medical risk due to a serious, uncontrolled medical
             disorder, non-malignant systemic disease or active, uncontrolled infection or
             laboratory abnormality that may increase the risk associated with study participation
             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. Examples
             include, but are not limited to, uncontrolled ventricular arrhythmia, recent (within 3
             months) myocardial infarction, uncontrolled major seizure disorder, unstable spinal
             cord compression, superior vena cava syndrome, moderate or severe hepatic impairment
             (according to Child-Pugh classification), an extensive interstitial bilateral lung
             disease on High Resolution Computed Tomography (HRCT) or any psychiatric disorder that
             prohibits obtaining informed consent.

         20. *Previous allogenic bone marrow transplant or double umbilical cord blood
             transplantation (dUCBT).

         21. *Whole blood transfusions in the last 120 days prior to entry to the study (packed red
             blood cells and platelet transfusions are acceptable, for timing refer to inclusion
             criteria no 10).
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure:Overall Response Rate to olaparib defined as the percentage of patients with a complete or partial response out of the total of patients of the efficacy population
Time Frame:Estimated median of 6 months (until disease progression is confirmed)
Safety Issue:
Description:Tumor response will be assessed using RECIST v.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).

Secondary Outcome Measures

Measure:Clinical Benefit Rate (CBR) to olaparib defined as the percentage of patients with a complete response (CR), partial response (PR), or stable disease (SD) ≥ 24 weeks according to the RECIST version 1.1. out of the efficacy population
Time Frame:Estimated median of 6 months (until disease progression is confirmed)
Safety Issue:
Description: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). It could be performed sensitivity analysis using the Intended to treat population.
Measure:Response Duration (RD) to olaparib defined as the time from the first documentation of objective tumour response (CR or PR) to the first documented progressive disease using RECIST version 1.1, or to death due to any cause, whichever occurs first.
Time Frame:Estimated median of 6 months (until disease progression is confirmed)
Safety Issue:
Description:The efficacy population will be the primary population for the efficacy analysis. It will be performed a sensitivity analysis using the intend to treat population.
Measure:Progression Free Survival (PFS)defined as the time from study enrolment to the first documented progressive disease, using RECIST version 1.1., or death from any cause, whichever occurs first.
Time Frame:Estimated median of 6 months (until disease progression is confirmed)
Safety Issue:
Description:The efficacy population will be the primary population for the efficacy analysis. It will be performed a sensitivity analysis using the intend to treat population.
Measure:Overall Survival (OS) defined as the time from the date of study enrolment to the date of death from any cause.
Time Frame:Estimated median of 12 months
Safety Issue:
Description:The efficacy population will be the primary population for the efficacy analysis. It will be performed a sensitivity analysis using the intend to treat population.
Measure:Percentage of participants with Adverse Events as Assessed by CTCAE v4.0 out of the total of patients of the efficacy population
Time Frame:Estimated median of 6 months (until disease progression is confirmed)
Safety Issue:
Description:Safety population will include all patients enrolled in the study who received at least one dose of treatment.
Measure:Correlation value of BRCA1 and 2 methylation status measured in DNA from blood cells pre-and post olaparib treatment
Time Frame:Estimated median time frame of 7 months
Safety Issue:
Description:The methylation status of the BRCA1 and 2 promoters will be measured in germline DNA from blood cells at the beginning of the study and after disease progression or at the end of study treatment for other cause to analyse changes of germline methylation pre and post-treatment. Methylation status will be provided as a continuous (the methylation value will be obtained from the average of the CpG dinucleotides included in the sequence analysed) and also as a binomial variable (status methylated or not methylated).
Measure:Correlation value between germline methylation status and efficacy outcome data;
Time Frame:Estimated median time frame of 13 months
Safety Issue:
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.
Measure:Correlation value between BRCA1 and BRCA2 methylation data observed in DNA from blood cells (germline) and DNA from tumor cells (somatic)
Time Frame:Estimated median time frame of 1 month
Safety Issue:
Description:To compare the continuous values of germline and somatic DNA methylation, the difference of these values will be used and it will be used statistical t (student-Fisher) or Wilcoxon test depending if it must be used a parametric or non-parametric test.
Measure:Correlation value between primary and metastatic lesions (if enough samples are available)
Time Frame:Estimated median time frame of 7 months
Safety Issue:
Description:The methylation status of the BRCA1 and 2 promoters in available paired primary and metastatic lesions. Methylation status will be provided as a continuous (the methylation value will be obtained from the average of the CpG dinucleotides included in the sequence analysed) and also as a binomial variable (status methylated or not methylated). If methylation status is a continuous variable, to compare the value of methylation between prior and after treatment, the difference of these values will be used and will be used statistical t (student-Fisher) or Wilcoxon test depending if it must be used a parametric or non-parametric test. If methylation status is a binomial variable, to compare the value of methylation between prior and after treatment it will be used the McNemar test or exact binomial test.
Measure:BRCA1 and BRCA2 expression data will be correlated with promoter methylation status
Time Frame:Estimated median time frame of 7 months
Safety Issue:
Description:BRCA1/2 expression by quantitative Polymerase chain reaction (PCR) and BRCA1/2 promoter methylation will be correlated as categorical or continues values. If methylation status and expression data are given as continuous variables, they will be compared using statistical t (student-Fisher) or Wilcoxon test depending if it must be used a parametric or non-parametric test.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Spanish Breast Cancer Research Group

Trial Keywords

  • Advanced Breast Cancer
  • Triple Negative
  • olaparib
  • lynparza
  • BRCA
  • Methylation

Last Updated

January 20, 2021