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Clinical trial information and results are updated daily from ClinicalTrials.gov. The latest data update was conducted on 01/22/2021.

Olaparib+Trastuzumab in HER2[+],Breast Cancer Susceptibility Gene (BRCA) Mutated or Homologous Recombination Deficient (HRD) Advanced Breast Cancer

Clinicaltrials.gov identifier NCT03931551

Recruitment Status Recruiting

First Posted April 30, 2019

Last update posted August 26, 2019

Study Description

Brief summary:

This multicenter, single-arm, two-cohort, Simon's two-stage minimax design, phase II trial will evaluate the efficacy and safety of olaparib plus trastuzumab in patients with HER2[+], BRCA-mutated or wild-type BRCA/HRD advanced breast cancer

  • Condition or Disease:Advanced Breast Cancer
  • Intervention/Treatment: Drug: Olaparib [Lynparza®] plus Trastuzumab [Herceptin®]
  • Phase: Phase 2
Detailed Description

This open-label, multicenter, single arm, two cohorts, Simon's Two-Stage minimax design, phase II clinical trial will assess the efficacy of olaparib in combination with trastuzumab in patients with HER2-positive ABC with gene alterations in HRR DNA pathway. To be included in the cohort A of the study, patients must exhibit germinal deleterious mutations in BRCA1 or BRCA2 genes. In the second stage of the study, patients must show wild-type germinal BRCA1/2 genes with HRD positive status based on HRDetect test, in order to be included in the exploratory cohort B. Eligible patients will have histologically proven diagnosis of adenocarcinoma of the breast with evidence of advanced disease, and at least one measurable disease as per RECIST v.1.1. Patients will have a documented history of progression on HER2-directed therapy for the treatment of HER2-positive breast cancer with not more than three prior regimens of chemotherapy and/or trastuzumab-lapatinib in advanced scenario, and at least one regimen of chemotherapy including trastuzumab. Patients will be accrued in a Simon's Two-Stage minimax design. The accrual goal will be a total of 20 patients: 7 patients in the first stage and 13 patients in the second stage. Additionally, in the second stage, the investigators will accrual 13 patients on the exploratory cohort B.

Study Design
  • Study Type: Interventional
  • Estimated Enrollment: 33 participants
  • Intervention Model: Single Group Assignment
  • Masking: None (Open Label) ()
  • Primary Purpose: Treatment
  • Official Title: Effectiveness of Olaparib Plus Trastuzumab in HER2[+], BRCA-mutated or Homologous Recombination Deficient (HRD) Advanced Breast Cancer Patients (The OPHELIA Study)
  • Actual Study Start Date: April 2019
  • Estimated Primary Completion Date: September 2022
  • Estimated Study Completion Date: September 2022
Arms and interventions
Arm Intervention/treatment
Experimental: Interventional Arm
Olaparib tablet 300mg bd po + Herceptin (IV 4 mg/kg body followed by weekly doses of 2 mg/kg, or SC 600 mg every 3 weeks) until progression or unacceptable toxicity.
Drug: Olaparib [Lynparza®] plus Trastuzumab [Herceptin®]
Participants will receive olaparib (300 mg tablets, orally twice daily during 21-day cycles) in combination with herceptin (intravenous dose of 4 mg/kg body weight with subsequent weekly doses of 2 mg/kg or subcutaneous dose of 600 mg every 3 weeks) until progression or unacceptable toxicity.
Outcome Measures
  • Primary Outcome Measures: 1. Overall response rate (ORR) in cohort A [ Time Frame: Baseline up to 30 months. ]
    ORR -defined as the number of patients with complete response (CR) and partial response (PR) divided by the number of patients in the analysis set- in patients with germinal BRCA-mutated [cohort A] based on local investigator's assessment according to Response Evaluation Criteria In Solid Tumors (RECIST) criteria guidelines v.1.1.
  • 2. Progression-free survival (PFS) in cohort A [ Time Frame: Baseline up to 30 months. ]
    PFS -defined as the period of time from treatment initiation to the first occurrence of disease progression or death from any cause, whichever occurs first- in patients with germinal BRCA-mutated tumors [cohort A] based on local investigator's assessment according to RECIST criteria guidelines v.1.1.
  • Secondary Outcome Measures: 1. ORR in cohort B [ Time Frame: Baseline up to 30 months. ]
    ORR -defined as the number of patients with CR and PR divided by the number of patients in the analysis set- in patients with wild-type germinal BRCA/HRD-positive tumors [cohort B] based on local investigator's assessment according to RECIST criteria guidelines v.1.1.
  • 2. PFS in cohort B [ Time Frame: Baseline up to 30 months. ]
    PFS -defined as the period of time from treatment initiation to the first occurrence of disease progression or death from any cause, whichever occurs first- in patients with wild-type germinal BRCA/HRD-positive tumors [cohort B] based on local investigator's assessment according to RECIST criteria guidelines v.1.1.
  • 3. Clinical benefit rate (CBR) in cohorts A and B [ Time Frame: Baseline up to 30 months. ]
    CBR -defined as the number of patients with CR, PR or stable disease (SD) divided by the number of patients in the analysis set- both in patients with germinal BRCA-mutated [cohort A] and wild-type germinal BRCA/HRD-positive [cohort B] tumors based on local investigator's assessment according to RECIST criteria guidelines v.1.1.
  • 4. Duration of response (DoR) in cohorts A and B [ Time Frame: From documented objective response up to 30 months. ]
    DoR -defined as the time from the first occurrence of a documented objective response to disease progression or death from any cause, whichever occurs first- both in patients with germinal BRCA-mutated [cohort A] and wild-type germinal BRCA/HRD-positive [cohort B] tumors based on local investigator's assessment according to RECIST criteria guidelines v.1.1.
  • 5. Maximum Tumor Shrinkage in cohorts A and B [ Time Frame: Baseline up to 30 months. ]
    Maximum Tumor Shrinkage -defined as the percentage of tumor shrinkage from baseline [obtained from the sum of the largest diameters of the target lesions]- both in patients with germinal BRCA-mutated [cohort A] and wild-type germinal BRCA/HRD-positive [cohort B] tumors based on local investigator's assessment according to RECIST criteria guidelines v.1.1.
  • 6. Overall survival (OS) in cohorts A and B [ Time Frame: Baseline up to 30 months. ]
    OS -defined as the period of time from treatment initiation to death from any cause- both in patients with germinal BRCA-mutated [cohort A] and wild-type germinal BRCA/HRD-positive [cohort B] tumors based on local investigator's assessment according to RECIST criteria guidelines v.1.1.
  • 7. Health-Related Quality of Life (HRQoL) in cohorts A and B [ Time Frame: Baseline up to 30 months. ]
    Change from baseline in scores using the European Organisation for Research and Treatment of Cancer QoL Questionnaire Core 30 (QLQ-C30) [with 5 functional and 3 symptom scales, a Global Health Status (GHS)/QoL scale, and 6 single items], QLQ-BR23 [with 4 functional and 4 symptom scales], and EQ-5D [with 5 dimensions and a health status rating scales] modules at baseline, Day 1 of cycles 2-4, then on Day 1 of each subsequent cycle starting with cycle 6, and at the end-of-treatment. Responses to all items are converted to a 0-100 scale using a standard scoring algorithm. For functional scales, higher score represents a better level of functioning; for symptom scales, a higher score represents a higher severity of symptoms.
  • 8. Safety adverse events (AEs) in cohorts A and B [ Time Frame: Baseline up to 30 months. ]
    Number of patients with treatment-related AEs (Grade 3 and 4 AEs and serious adverse events [SAEs]) by using the National Cancer Institute (NCI)-Common Terminology Criteria for Adverse Events (CTCAE) v.5.0.
  • Other Outcome Measures: 1. Exploratory Objective (prevalence of BRCA alterations) [ Time Frame: Baseline up to 30 months. ]
    The number of patients with HER2[+], germinal BRCA1/2 mutated advanced breast cancer divided by the number of patients in the analysis set.
  • 2. Exploratory Objective (prevalence of HRD alterations) [ Time Frame: Baseline up to 30 months. ]
    The number of patients with HER2[+], germinal wild type BRCA1/2, HRD[+] advanced breast cancer divided by the number of patients in the analysis set.
  • 3. Exploratory Objective (predictive value of BRCA alterations) [ Time Frame: Baseline up to 30 months. ]
    The number of patients with HER2[+], germinal BRCA1/2 mutated ABC who obtain best response, in terms of CR, PR, SD, or progressive disease (PD) divided by the number of patients in the analysis set.
  • 4. Exploratory Objective (predictive value of HRD alterations) [ Time Frame: Baseline up to 30 months. ]
    The number of patients with HER2[+], germinal wild type BRCA1/2, HRD[+] ABC who obtain best response, in terms of CR, PR, SD, or progressive disease (PD) divided by the number of patients in the analysis set.
Eligibility Criteria
  • Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
  • Sexes Eligible for Study: All
  • Accepts Healthy Volunteers: No
Criteria

Inclusion Criteria:

1. Provision of informed consent prior to any study specific procedures.

2. Male or female ≥18 years of age at the time of signing the ICF.

3. Histologically and/or cytologically confirmed breast cancer with evidence of advanced
disease (locoregionally recurrent or metastatic) not amenable to resection or
radiation therapy with curative intent.

4. Patients with histologically and/or cytologically locally confirmed diagnosis of
HER2-positive breast cancer according to the ASCO/CAP 2013 criteria.

Note: tissue (slides or blocks) must be available for HER2 confirmation by local
laboratory.

5. [Cohort A]: Patients with documented germinal mutation in BRCA1 or BRCA2 genes that is
predicted to be deleterious or suspected deleterious (known or predicted to be
detrimental/lead to loss of function). Patients with germinal BRCA1/2 mutations that
are considered to be non-detrimental (e.g., "Variants of uncertain clinical
significance" or "Variant of unknown significance" or "Variant, favor polymorphism" or
"benign polymorphism," etc.) will not be eligible for the study. Patients with known
germinal BRCA status prior to enrollment are considered eligible to participate.

[Exploratory cohort B]: Patients with wild-type germinal BRCA1/2 genes with
HRD-positive status based on HRDetect test.

6. History of progression on HER2-directed therapy for the treatment of HER2-positive
breast cancer with not more than three prior regimens of chemotherapy and/or
trastuzumab-lapatinib in advanced scenario, and at least one regimen of chemotherapy
including trastuzumab.

7. Eastern Cooperative Oncology Group (ECOG) performance status score ≤ 1.

8. Life expectancy greater or equal to 16 weeks.

9. Patients must have evaluable or measurable disease by Computed Tomography (CT) scan or
Magnetic resonance imaging (MRI), according to RECIST 1.1 criteria.

10. Patients must have normal organ and bone marrow function within 35 days prior to
administration of study treatment as defined below:

- Hematological: White blood cell (WBC) count >3.0 x 109/L, absolute neutrophil
count (ANC) ≥1.5 x 109/L, platelet count ≥100.0 x109/L, and hemoglobin ≥ 10 g/dL
with no blood transfusions (packed red blood cells and platelet transfusions in
the past 35 days are permitted).

- Hepatic: bilirubin ≤ 1.5 times the upper limit of normal (x ULN) (≤2.0 in
patients with known Gilberts syndrome) or direct bilirubin ≤ 1 x ULN; alkaline
phosphatase (ALP), Aspartate aminotransferase (AST) / Serum Glutamic Oxaloacetic
Transaminase (SGOT), and Alanine aminotransferase (ALT) / Serum Glutamic Pyruvate
Transaminase (SGPT) ≤ 2.5 x institutional ULN unless liver metastases are
present, in which case they must be ≤ 5 x ULN.

- Renal: Serum creatinine ≤ 1.5 x ULN or based on a 24-hour urine test or estimated
creatinine clearance ≥ 51 mL/min using the Cockcroft-Gault equation:

Estimated creatinine clearance = (140-age [years]) x weight (kg) (x F)a serum
creatinine (mg/dL) x 72 a where F=0.85 for females and F=1 for males.

11. Patients have been informed about the nature of study, including the exploratory
studies and has agreed to participate and signed the Informed Consent Form (ICF) prior
to participation in any study-related activities.

12. Males, postmenopausal and premenopausal women. Premenopausal women of childbearing
potential (not undergoing to tubal ligation or hysterectomy) must have a negative
blood or urine pregnancy test within 28 days prior to the start of study treatment and
confirmed on Day 1 prior to commencing treatment

- Postmenopausal status is defined as either:

f) Prior bilateral oophorectomy; Or g) Age > 60 years; Or h) Age < 60 years and amenorrhoeic for 12 months in the absence of chemotherapy, tamoxifen, toremifene or ovarian suppression, and Folliclestimulating hormone (FSH) and estradiol in postmenopausal range; Or i) Age 1-year interval since last menses.

- Premenopausal status is defined as all those women who do not meet any of above
criteria.

Note: Documented hysterectomy must be confirmed with medical records of the actual
procedure or confirmed by an ultrasound. Tubal ligation must be confirmed with medical
records of the actual procedure, otherwise the patient must be willing to use 2 highly
effective forms of contraception in combination male condom plus an acceptable
hormonal or non-hormonal method) throughout the study. Information must be captured
appropriately within the site's source documents. Correct forms of contraception for
males and females are detailed in Appendix 5: Acceptable birth control methods.

13. Patients is willing and able to comply with the protocol for the duration of the study
including undergoing treatment and scheduled visits and examinations.

14. [Cohort A] Snap frozen or formalin fixed paraffin-embedded (FFPE) tumor sample is
mandatory for exploratory central testing.

[Exploratory cohort B] For inclusion in the exploratory cohort B, snap frozen or FFPE
metastatic tissue since the last progression is mandatory for testing HRD status. As
alternative, an archived tumor sample will be used.

15. Patients of both cohorts must fulfil the relative field on the informed consent for
donating blood samples and serial biopsies at baseline and on disease progression for
the exploratory biomarker studies.

Exclusion Criteria:

1. Patients that have previously received any PARPi for any reason, including olaparib.

2. Previous treatment with carboplatin or other platinum containing compounds in the last
12 months prior to entry to the study.

3. Patients who have not received any previous chemotherapy in the advanced setting.

4. Involvement in the planning and/or conduct of the study (applies to both Sponsor's
staff and/or staff at the study site).

5. Previous enrolment in the present study.

6. Patients simultaneously enrolled in any interventional clinical trial.

7. Patients who have received any systemic chemotherapy during the last 3 weeks prior
initiating protocol therapy.

8. Patients who have had radiation therapy encompassing >20% of the bone marrow within 3
weeks prior to start of treatment, excepting for palliative radiation therapy to a
small field >1 week prior to Day 1 of study.

9. Resting electrocardiogram (ECG) indicating uncontrolled, potentially reversible
cardiac conditions, as judged by the investigator (e.g., unstable ischemia,
uncontrolled symptomatic arrhythmia, congestive heart failure, QTcF prolongation >500
ms, electrolyte disturbances, etc.), or patients with congenital long QT syndrome.

10. Patients with symptomatic visceral disease are not eligible.

11. Concomitant use of known strong CYP3A inhibitors (e.g., itraconazole, telithromycin,
clarithromycin, boosted protease inhibitors, indinavir, saquinavir, nelfinavir,
boceprevir, telaprevir) or moderate CYP3A inhibitors (ciprofloxacin, erythromycin,
diltiazem, fluconazole, verapamil). The required washout period prior to starting
olaparib is 2 weeks.

12. Concomitant use of known strong (e.g. phenobarbital, enzalutamide, phenytoin,
rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John's Wort) or
moderate CYP3A inducers (e.g. bosentan, efavirenz, modafinil). The required washout
period prior to starting study treatment is 5 weeks for enzalutamide or phenobarbital
and 3 weeks for other agents.

13. Persistent toxicities (CTCAE grade 2) caused by previous cancer therapy, excluding
alopecia.

14. Patients with MDS / AML or with features suggestive of MDS/AML.

15. Patients having diagnosis, detection, or treatment of another type of cancer during
the last 5 years prior to initiating protocol therapy (except adequately treated
non-melanoma skin cancer, curatively treated in situ cancer of the cervix,
definitively treated ductal carcinoma in situ, stage 1, grade 1 endometrial
carcinoma), or other solid tumors including lymphomas (without bone marrow
involvement) curatively treated with no evidence of disease for ≤5 years).

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

17. Patients considered a high medical risk due to a serious, uncontrolled medical
disorder, nonmalignant systemic disease or active, uncontrolled infection. Examples
include, but are not limited to, uncontrolled ventricular arrhythmia, recent (within 6
months) myocardial infarction, uncontrolled major seizure disorder, unstable spinal
cord compression, superior vena cava syndrome, extensive interstitial bilateral lung
disease on High Resolution CT scan or any psychiatric disorder that prohibits
obtaining informed consent.

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

19. Immunocompromised patients (e.g., patients who are known to be serologically positive
for human immunodeficiency virus and those with undetectable viral load).

20. Patients with a known hypersensitivity to olaparib or trastuzumab or any of the
excipients of the products.

21. Clinically significant cardiovascular disease [stroke, unstable angina pectoris, or
documented myocardial infarction) within 6 months prior to study entry; history of
documented congestive heart failure (New York Heart Association II-III-IV);
symptomatic pericarditis; documented cardiomyopathy; ventricular arrhythmias with the
exception of benign premature ventricular contractions; conduction abnormality
requiring a pacemaker; other arrhythmias not controlled with medication].

22. Left ventricular ejection fraction below 55% as determined by multiple-gated
acquisition (MUGA) scan or echocardiography (ECHO).

23. Uncontrolled hypertension (systolic > 150 mm Hg and/or diastolic > 100 mm Hg) despite
adequate antihypertensive treatment.

24. Patients currently receiving anti-coagulant therapy (low molecular weight heparin, and
warfarin with careful monitoring of patients are permitted), or another
immunosuppressive agent (standard premedication for chemotherapy and local
applications are allowed).

25. Patients with pulmonary disease requiring continuous oxygen therapy.

26. Previous history of bleeding diathesis.

27. Patients with known active hepatitis (i.e. Hepatitis B or C).

28. Patients with moderate or severe hepatic impairment.

29. Chronic daily treatment with corticosteroids with a dose of ≥ 10 mg/day
methylprednisolone equivalent (excluding inhaled steroids), except for prophylaxis
use.

30. Previous allogenic bone marrow transplant or double umbilical cord blood
transplantation.

31. Whole blood transfusions in the last 120 days prior to entry to the study (packed red
blood cells and platelet transfusions are acceptable, if received in the past 35 days
prior to starting study treatment).

32. Patients with symptomatic uncontrolled brain metastases. A scan to confirm the absence
of brain metastases is not required. 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 and in a dose < 10 mg/day methylprednisolone equivalent. Patients with spinal cord compression unless considered to have received definitive treatment for this and evidence of clinically stable disease for 28 days. 33. Female patients who are pregnant or breastfeeding, or adults of reproductive potential who are not using effective birth control methods. 34. Patients unwilling to or unable to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations.

Contacts and Locations
Contacts

Contact: Cristina Masferrer +34657463102 cristina.masferrer@medsir.org

Contact: Alicia Garcia +34611261467 alicia.garcia@medsir.org

Locations
Show 17 Study Locations
Sponsors and Collaborators

MedSIR

Investigators

Principal Investigator: Jose Enrique Alés-Martínez Complejo Hospitalario de Ávila

More Information
  • Responsible Party: MedSIR
  • ClinicalTrials.gov Identifier: NCT03931551 History of Changes
  • Other Study ID Numbers: MedOPP168
  • First Posted: April 30, 2019 Key Record Dates
  • Last Update Posted: August 26, 2019
  • Last Verified: May 2019
  • Individual Participant
    Data (IPD) Sharing
    Statement:
  • Plan to Share IPD: No
  • Plan Description: It is not planned
  • Studies a U.S. FDA-regulated Drug Product: No
  • Studies a U.S. FDA-regulated Device Product: No
  • Product Manufactured in and Exported from the U.S.: Yes
  • Additional relevant MeSH terms: Breast Neoplasms