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Olaparib In Metastatic Breast Cancer

Primary Purpose

Metastatic Breast Cancer, Invasive Breast Cancer, Somatic Mutation Breast Cancer (BRCA1)

Status
Recruiting
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Olaparib
Sponsored by
Beth Israel Deaconess Medical Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Metastatic Breast Cancer focused on measuring Metastatic Breast Cancer, Invasive Breast Cancer, Somatic Mutation Breast Cancer (BRCA1), Somatic Mutation Breast Cancer (BRCA2)

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Patients must have histologically confirmed invasive breast cancer with stage IV disease, either biopsy proven or with unequivocal evidence of metastatic disease by physical examination or radiological study.
  • Cohorts 1 and 2: Documented germline (Cohort 1) or somatic mutation or homozygous deletion (Cohort 2) in one of the DNA repair genes listed below that is deleterious or suspected to be deleterious, and no germline BRCA1 or BRCA2 mutation. The mutation may be identified through any CLIA approved NGS panel.

    • ATM, ATR, BARD1, BRIP1 (FANCJ), CHEK2 , FANCA, FANCC, FANCD2, FANCE, FANCF, FANCM, MRE11A, NBN, PALB2, RAD50, RAD51C, RAD51D, plus other HR-related genes at the discretion of Dr. Tung with the key study collaborators (see details below in italics). (Cohorts 1 or 2)

      --- OR

    • Documented somatic mutation (deleterious or suspected deleterious) in BRCA1 or BRCA2 through any CLIA approved lab only if in addition to the lack of a germline BRCA1/2 mutation is demonstrated through a CLIA approved lab. Patients with germline mutations in BRCA1/2 are NOT eligible for this study. (Cohort 2 only)
  • Cohort 1a: germline PALB2 mutation

    -- The mutation must be identified through a CLIA-approved NGS panel. Mutations must be reviewed and confirmed by Dr. Tung to meet eligibility prior to registration.

  • Cohort 2a: somatic mutation of BRCA 1 or BRCA 2

    -- The mutation must be identified through a CLIA-approved NGS panel. Mutations must be reviewed and confirmed by Dr. Tung to meet eligibility prior to registration. Documentation of absence of germline mutation in BRCA 1/2 is required.

  • All deep (homozygous) deletions, frameshift mutations and truncating mutations in the genes listed above are eligible as well as missense variants in these genes that have previously been reported as pathogenic or likely pathogenic. If there is a discrepancy between two labs regarding the pathogenicity of a particular variant, the final decision regarding eligibility will be determined by the study steering committee.
  • At least one measurable lesion that can be accurately assessed at baseline by CT (MRI where CT is contraindicated) and is suitable for repeated assessment as per RECIST 1.1.

    -- NOTE: If the only site of measurable of disease has been previously irradiated, there must be evidence of post-radiation progression. For a lesion to be considered as measurable, it must be one 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) and which is suitable for accurate repeated measurements

  • Patients may not have progressed on more than two chemotherapy regimens in the metastatic setting.
  • The following will NOT be counted as a prior line of cytotoxic chemotherapy:

    • If a patient discontinued a cytotoxic regimen due to toxicity (e.g., hypersensitivity or neuropathy) but had not progressed on that regimen, or if a prior chemotherapy regimen was discontinued after response achieved, it will not be counted in the number of prior chemotherapy regimens allowed.
    • Prior hormonal therapy and non-hormonal targeted therapy; including the combination of an aromatase inhibitor and everolimus.
    • Targeted and biologic therapies.
    • The patient can receive a stable dose of bisphosphonates or denosumab for bone metastases, before and during the study as long as this was started at least 5 days prior to study treatment.
  • The most recent cytotoxic, biologic or targeted therapy received must have been completed at least 21 days prior to study treatment; hormonal therapy must have been completed at least 7 days prior, unless otherwise noted.
  • Prior therapy is allowed as follows:

    • Platinum chemotherapy in the adjuvant setting is allowed, if the last platinum dose was > 12 months before identification of metastatic disease. Platinum-based chemotherapy in the metastatic setting is not permitted.
    • History of prior anthracycline (e.g. doxorubicin, epirubicin) and taxane-based (e.g. paclitaxel, docetaxel) chemotherapy in the neo-adjuvant / adjuvant or metastatic setting is preferred, but not required.
    • Patients with hormone receptor-positive (estrogen and/or progesterone receptor-positive) disease must have received and progressed on at least one endocrine therapy (adjuvant or metastatic), or have disease that the treating physician believes to be inappropriate for endocrine therapy. Endocrine therapy must have been completed at least 7 days before study treatment.
    • Prior radiation is allowed; radiation therapy must have been completed at least 21 days before study treatment.
    • Prior treatment with FDA approved or investigational biologics (other than PARP inhibitors) and novel molecularly targeted therapies, including oral or IV formulations, shall not exclude patients from participation.
    • For agents with ambiguous categorization, final determination of patient eligibility will be made by the Protocol Chair prior to enrollment.
    • Prior PARP inhibitor use is not allowed for this study
  • Age ≥ 18 years.
  • ECOG performance status 0-1 (Karnofsky ≥60%, see Appendix A) Life expectancy ≥16 weeks
  • Participants must have normal organ and bone marrow function measured within 28 days prior to registration as defined below:

    • absolute neutrophil count ≥1,500/mcL
    • white blood cells > 3,000/mcL
    • platelets ≥100,000/mcL
    • hemoglobin ≥ 10.0 g/dL with no blood transfusions (packed red blood cells in the past 28 days is permitted)
    • total bilirubin ≤ 1.5 x institutional upper limit of normal
    • AST(SGOT)/ALT(SGPT) ≤2.5 × institutional upper limit of normal
    • Serum or plasma creatinine ≤ 1.5 x institutional upper limit of normal (ULN)

      --- OR

    • creatinine clearance ≥51 mL/min/1.73 m2 for participants
    • 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.
  • Willingness to undergo biopsy.
  • Patients with a history of treated CNS metastases are eligible, provided they meet all of the following criteria: Disease outside the CNS is present; no clinical evidence of progression since completion of CNS-directed therapy; minimum of 2 weeks between completion of radiotherapy and Cycle 1 Day 1 and recovery from significant (Grade ≥3) acute toxicity with no ongoing requirement for > 10mg of prednisone per day or an equivalent dose of other corticosteroid. NOTE: 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.
  • Both men and women are eligible for this study
  • Postmenopausal or evidence of non-childbearing status for women of childbearing potential. For women who are not post-menopausal, a negative urine or serum pregnancy test is required within 28 days of study treatment and confirmed prior to treatment on day 1.
  • Post-menopausal is defined as one of the following:

    • > 60 years old
    • Amenorrheic for 1 year or more following cessation of exogenous hormonal treatments
    • Luteinizing hormone (LH) and Follicle stimulating hormone (FSH) levels in the post menopausal range for women under 50
    • radiation-induced oophorectomy with last menses >1 year ago
    • surgical sterilisation (bilateral oophorectomy or hysterectomy)
  • Men and women of reproductive potential need to employ two highly effective and acceptable forms of contraception throughout their participation in the study and for 30 days (for women) or 90 days (for men) after the last dose of study medication because the effects of olaparib on the developing human fetus are unknown. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately.
  • Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations.
  • Ability to understand and the willingness to sign a written informed consent document. Informed consent must be provided prior to any study specific procedures

Exclusion Criteria:

  • Any previous treatment with a PARP inhibitor, including olaparib.
  • Germline BRCA1 or BRCA2 mutation
  • Patients with myelodysplastic syndrome/acute myeloid leukemia or with features suggestive of MDS/AML.
  • Patients with symptomatic uncontrolled brain metastases. A scan to confirm the absence of brain metastases is not required. Patients with spinal cord compression unless considered to have received definitive treatment for this and evidence of clinically stable disease for 28 days.
  • Major surgery within 2 weeks of starting study treatment and patients must have recovered from any effects of any major surgery.
  • Concomitant use of known strong CYP3A inhibitors (e.g., itraconazole, telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) and grapefruit, grapefruit juice or any product containing grapefruit,or moderate CYP3A inhibitors (e.g., ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil). The required washout period prior to starting olaparib is 2 weeks.
  • 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 olaparib is 5 weeks for enzalutamide or phenobarbital and 3 weeks for other agents.
  • Patients considered a poor medical risk due to a serious, uncontrolled medical disorder, non-malignant systemic disease or active, uncontrolled infection. 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, extensive interstitial bilateral lung disease on High Resolution Computed Tomography (HRCT) scan or any psychiatric disorder that prohibits obtaining informed consent
  • Persistent toxicities (≥CTCAE grade 2) caused by previous cancer therapy, excluding alopecia
  • Immunocompromised patients, e.g., patients who are known to be serologically positive for human immunodeficiency virus (HIV).
  • Patients with prior myelodysplastic syndrome or acute myeloid leukemia.
  • Other malignancy within the last 5 years except: adequately treated non-melanoma skin cancer; curatively treated in situ cancer of the cervix; ductal carcinoma in situ (DCIS); 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
  • Resting EKG with QTc > 470 msec or family history of long QT syndrome. If EKG demonstrates QTc >470 msec, patient will be eligible only if repeat EKG demonstrates QTc ≤470 msec.
  • Pregnant or breast feeding women.
  • Patients with a known hypersensitivity to olaparib or any of the excipients of the product.
  • Major surgery within 2 weeks of starting study treatment: patients must have recovered from any effects of any major surgery.
  • Patients with known active hepatitis (i.e., Hepatitis B or C)
  • Previous allogenic bone marrow transplant or double umbilical cord blood transplantation (dUCBT)
  • Whole blood transfusions in the last 120 days prior to entry to the study (packed red blood cells and platelet transfusions are acceptable).
  • Patients unable to swallow orally administered medication and patients with gastrointestinal disorders likely to interfere with absorption of the study medication

Sites / Locations

  • University of Alabama at BirminghamRecruiting
  • University of California, San Francisco
  • University of ChicagoRecruiting
  • Indiana University
  • Johns Hopkins UniversityRecruiting
  • Beth Israel Deaconess Medical CenterRecruiting
  • Brigham and Women's HospitalRecruiting
  • Dana-Farber Cancer InstituteRecruiting
  • Memorial Sloan Kettering Cancer Center Basking RidgeRecruiting
  • Memorial Sloan Kettering Cancer Center MonmouthRecruiting
  • Memorial Sloan Kettering Cancer Center BergenRecruiting
  • Memorial Sloan Kettering Cancer Center CommackRecruiting
  • Memorial Sloan Kettering Cancer Center WestchesterRecruiting
  • Memorial Sloan Kettering Cancer CenterRecruiting
  • Memorial Sloan Kettering Cancer Center NassauRecruiting
  • Duke UniversityRecruiting
  • UPMC Hillman Cancer Center - ErieRecruiting
  • University of PennsylvaniaRecruiting
  • University of Pittsburgh
  • University of Washington Fred Hutchinson Cancer CareRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Experimental

Experimental

Experimental

Arm Label

OLAPARIB QD GERMLINE MUTATION

OLAPARIB QD GERMLINE MUTATION - EXPANSION

OLAPARIB QD SOMATIC MUTATION

OLAPARIB QD SOMATIC MUTATION - EXPANSION

Arm Description

After the screening procedures confirm eligibility to participate in the research study: Olaparib: Each study treatment cycle lasts 21 days (3 weeks), taking 2 times per day, 12 hours apart. Tumor measurement q6 weeks x 24 weeks, then q 12 weeks

After the screening procedures confirm eligibility to participate in the research study: Olaparib: Each study treatment cycle lasts 21 days (3 weeks), taking 2 times per day, 12 hours apart. Tumor measurement q6 weeks x 24 weeks, then q 12 weeks

After the screening procedures confirm eligibility to participate in the research study: Olaparib: Each study treatment cycle lasts 21 days (3 weeks), taking 2 times per day, 12 hours apart. Tumor measurements q6 weeks x 24 weeks, then q 12 weeks

After the screening procedures confirm eligibility to participate in the research study: Olaparib: Each study treatment cycle lasts 21 days (3 weeks), taking 2 times per day, 12 hours apart. Tumor measurements q6 weeks x 24 weeks, then q 12 weeks

Outcomes

Primary Outcome Measures

Objective Response Rate
RECIST 1.1 criteria will be reported with a two-sided 90% confidence interval using the method from Atkinson and Brown to account for the two-stage design

Secondary Outcome Measures

Clinical Benefit Rate
Reported with 90% binomial exact confidence intervals.
Progression Free Survival
Kaplan-Meier
Stable Disease
Kaplan-Meier
Number of Participants with Severe Adverse Events
Treatment-related toxicities will be summarized within and across Cohorts by maximum grade and by term using CTCAE v4.0 and reported with 90% binomial exact confidence intervals.
Mutant Allele Frequency
Two-sample t-test with 10% Type-I error level

Full Information

First Posted
October 31, 2017
Last Updated
June 16, 2023
Sponsor
Beth Israel Deaconess Medical Center
Collaborators
Johns Hopkins University, AstraZeneca, Dana-Farber Cancer Institute
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1. Study Identification

Unique Protocol Identification Number
NCT03344965
Brief Title
Olaparib In Metastatic Breast Cancer
Official Title
A Phase 2 Study of Olaparib Monotherapy in Metastatic Breast Cancer Patients With Germline or Somatic Mutations in DNA Repair Genes (Olaparib Expanded)
Study Type
Interventional

2. Study Status

Record Verification Date
June 2023
Overall Recruitment Status
Recruiting
Study Start Date
April 1, 2018 (Actual)
Primary Completion Date
December 30, 2023 (Anticipated)
Study Completion Date
December 30, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Beth Israel Deaconess Medical Center
Collaborators
Johns Hopkins University, AstraZeneca, Dana-Farber Cancer Institute

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
Yes
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This research study is for patients with metastatic breast cancer. Metastatic means that the cancer has spread beyond the breast. In addition, through genetic testing of the blood or tumor, an altered gene has been found that suggests the tumor may not be able to repair its genetic material (DNA) when it becomes damaged. This aspect of the cancer may cause it to be more sensitive - that is, more effectively killed by certain types of drugs such as the study agent being evaluated in this trial, Olaparib. Olaparib is a type of drug known as a PARP inhibitor. Some types of breast cancer and ovarian cancer share some basic features that make them sensitive to similar treatments. Information from those other research studies suggests that this drug may help to treat metastatic breast cancer. This study will evaluate whether olaparib is effective in breast cancer patients whose tumor has a mutation in one of the other genes that function with BRCA1 and BRCA2 to repair damaged DNA .This mutation may have been inherited from a parent, or may have developed only in the tumor. This study will also evaluate whether olaparib is effective in breast cancer patients whose tumor has a mutation in BRCA1 or BRCA2 that was acquired by the tumor, but not inherited.
Detailed Description
This research study is a Phase II clinical trial. Phase II clinical trials test the safety and effectiveness of an investigational drug to learn whether the drug works in treating a specific cancer. "Investigational" means that the study drug, Olaparib, is being studied for use in this setting and the research doctors are trying to learn more about it-the side effects it may cause and if the drug is effective in treating this type of cancer. What is a DNA repair gene mutation? -- In order to survive, all cells, even cancer cells, must be able to repair their genetic material (DNA) when it gets damaged. A mutation is an alteration or change in a gene- either inherited from a parent or acquired over time- that prevents the gene from working properly. Faulty genes (or genes that carry a mutation) have been linked to increased risk of hereditary breast and ovarian cancer. What is Olaparib? Olaparib is a drug that may stop cancer cells from growing. Olaparib is a PARP inhibitor which means that it blocks an enzyme (proteins that help chemical reactions in the body occur) in cells called PARP. PARP helps repair DNA when it becomes damaged. It has been shown that the tumors in individuals who have inherited or acquired a mutation in the BRCA1 or BRCA2 genes are often sensitive to killing by PARP inhibitors. In normal cells and many other tumors, repair of damage to the DNA requires pathways of genes that work with BRCA1 and BRCA2. Therefore, when a drug that inhibits PARP from working is given to people with a BRCA mutation, or a defect in another gene that works with BRCA1 and BRCA2, both ways of repairing damaged DNA no longer work. The combined effect of knocking out both DNA repair mechanisms is so severe that the cancer cells could die. This might stop the growth of type of breast cancer, but this is not known. The FDA (U.S. Food and Drug Administration) has approved Olaparib for use in advanced ovarian cancer with a BRCA1 or BRCA2 mutation. Olaparib is not approved for breast cancer.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Metastatic Breast Cancer, Invasive Breast Cancer, Somatic Mutation Breast Cancer (BRCA1), Somatic Mutation Breast Cancer (BRCA2), CHEK2 Gene Mutation, ATM Gene Mutation, PALB2 Gene Mutation, RAD51 Gene Mutation, BRIP1 Gene Mutation, NBN Gene Mutation
Keywords
Metastatic Breast Cancer, Invasive Breast Cancer, Somatic Mutation Breast Cancer (BRCA1), Somatic Mutation Breast Cancer (BRCA2)

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
114 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
OLAPARIB QD GERMLINE MUTATION
Arm Type
Experimental
Arm Description
After the screening procedures confirm eligibility to participate in the research study: Olaparib: Each study treatment cycle lasts 21 days (3 weeks), taking 2 times per day, 12 hours apart. Tumor measurement q6 weeks x 24 weeks, then q 12 weeks
Arm Title
OLAPARIB QD GERMLINE MUTATION - EXPANSION
Arm Type
Experimental
Arm Description
After the screening procedures confirm eligibility to participate in the research study: Olaparib: Each study treatment cycle lasts 21 days (3 weeks), taking 2 times per day, 12 hours apart. Tumor measurement q6 weeks x 24 weeks, then q 12 weeks
Arm Title
OLAPARIB QD SOMATIC MUTATION
Arm Type
Experimental
Arm Description
After the screening procedures confirm eligibility to participate in the research study: Olaparib: Each study treatment cycle lasts 21 days (3 weeks), taking 2 times per day, 12 hours apart. Tumor measurements q6 weeks x 24 weeks, then q 12 weeks
Arm Title
OLAPARIB QD SOMATIC MUTATION - EXPANSION
Arm Type
Experimental
Arm Description
After the screening procedures confirm eligibility to participate in the research study: Olaparib: Each study treatment cycle lasts 21 days (3 weeks), taking 2 times per day, 12 hours apart. Tumor measurements q6 weeks x 24 weeks, then q 12 weeks
Intervention Type
Drug
Intervention Name(s)
Olaparib
Other Intervention Name(s)
AZD2281, KU-0059436
Intervention Description
olaparib tablets bid daily continuously on a 21 day cycle until progression, intolerable toxicity, consent withdrawn, patient noncompliance or death.
Primary Outcome Measure Information:
Title
Objective Response Rate
Description
RECIST 1.1 criteria will be reported with a two-sided 90% confidence interval using the method from Atkinson and Brown to account for the two-stage design
Time Frame
21 Days
Secondary Outcome Measure Information:
Title
Clinical Benefit Rate
Description
Reported with 90% binomial exact confidence intervals.
Time Frame
16 weeks
Title
Progression Free Survival
Description
Kaplan-Meier
Time Frame
36 Months
Title
Stable Disease
Description
Kaplan-Meier
Time Frame
36 Months
Title
Number of Participants with Severe Adverse Events
Description
Treatment-related toxicities will be summarized within and across Cohorts by maximum grade and by term using CTCAE v4.0 and reported with 90% binomial exact confidence intervals.
Time Frame
after the first dose of study treatment and ends 30 days following the last administration of study treatment or study discontinuation/termination,
Title
Mutant Allele Frequency
Description
Two-sample t-test with 10% Type-I error level
Time Frame
36 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Patients must have histologically confirmed invasive breast cancer with stage IV disease, either biopsy proven or with unequivocal evidence of metastatic disease by physical examination or radiological study. Cohorts 1 and 2: Documented germline (Cohort 1) or somatic mutation or homozygous deletion (Cohort 2) in one of the DNA repair genes listed below that is deleterious or suspected to be deleterious, and no germline BRCA1 or BRCA2 mutation. The mutation may be identified through any CLIA approved NGS panel. ATM, ATR, BARD1, BRIP1 (FANCJ), CHEK2 , FANCA, FANCC, FANCD2, FANCE, FANCF, FANCM, MRE11A, NBN, PALB2, RAD50, RAD51C, RAD51D, plus other HR-related genes at the discretion of Dr. Tung with the key study collaborators (see details below in italics). (Cohorts 1 or 2) --- OR Documented somatic mutation (deleterious or suspected deleterious) in BRCA1 or BRCA2 through any CLIA approved lab only if in addition to the lack of a germline BRCA1/2 mutation is demonstrated through a CLIA approved lab. Patients with germline mutations in BRCA1/2 are NOT eligible for this study. (Cohort 2 only) Cohort 1a: germline PALB2 mutation -- The mutation must be identified through a CLIA-approved NGS panel. Mutations must be reviewed and confirmed by Dr. Tung to meet eligibility prior to registration. Cohort 2a: somatic mutation of BRCA 1 or BRCA 2 -- The mutation must be identified through a CLIA-approved NGS panel. Mutations must be reviewed and confirmed by Dr. Tung to meet eligibility prior to registration. Documentation of absence of germline mutation in BRCA 1/2 is required. All deep (homozygous) deletions, frameshift mutations and truncating mutations in the genes listed above are eligible as well as missense variants in these genes that have previously been reported as pathogenic or likely pathogenic. If there is a discrepancy between two labs regarding the pathogenicity of a particular variant, the final decision regarding eligibility will be determined by the study steering committee. At least one measurable lesion that can be accurately assessed at baseline by CT (MRI where CT is contraindicated) and is suitable for repeated assessment as per RECIST 1.1. -- NOTE: If the only site of measurable of disease has been previously irradiated, there must be evidence of post-radiation progression. For a lesion to be considered as measurable, it must be one 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) and which is suitable for accurate repeated measurements Patients may not have progressed on more than two chemotherapy regimens in the metastatic setting. The following will NOT be counted as a prior line of cytotoxic chemotherapy: If a patient discontinued a cytotoxic regimen due to toxicity (e.g., hypersensitivity or neuropathy) but had not progressed on that regimen, or if a prior chemotherapy regimen was discontinued after response achieved, it will not be counted in the number of prior chemotherapy regimens allowed. Prior hormonal therapy and non-hormonal targeted therapy; including the combination of an aromatase inhibitor and everolimus. Targeted and biologic therapies. The patient can receive a stable dose of bisphosphonates or denosumab for bone metastases, before and during the study as long as this was started at least 5 days prior to study treatment. The most recent cytotoxic, biologic or targeted therapy received must have been completed at least 21 days prior to study treatment; hormonal therapy must have been completed at least 7 days prior, unless otherwise noted. Prior therapy is allowed as follows: Platinum chemotherapy in the adjuvant setting is allowed, if the last platinum dose was > 12 months before identification of metastatic disease. Platinum-based chemotherapy in the metastatic setting is not permitted. History of prior anthracycline (e.g. doxorubicin, epirubicin) and taxane-based (e.g. paclitaxel, docetaxel) chemotherapy in the neo-adjuvant / adjuvant or metastatic setting is preferred, but not required. Patients with hormone receptor-positive (estrogen and/or progesterone receptor-positive) disease must have received and progressed on at least one endocrine therapy (adjuvant or metastatic), or have disease that the treating physician believes to be inappropriate for endocrine therapy. Endocrine therapy must have been completed at least 7 days before study treatment. Prior radiation is allowed; radiation therapy must have been completed at least 21 days before study treatment. Prior treatment with FDA approved or investigational biologics (other than PARP inhibitors) and novel molecularly targeted therapies, including oral or IV formulations, shall not exclude patients from participation. For agents with ambiguous categorization, final determination of patient eligibility will be made by the Protocol Chair prior to enrollment. Prior PARP inhibitor use is not allowed for this study Age ≥ 18 years. ECOG performance status 0-1 (Karnofsky ≥60%, see Appendix A) Life expectancy ≥16 weeks Participants must have normal organ and bone marrow function measured within 28 days prior to registration as defined below: absolute neutrophil count ≥1,500/mcL white blood cells > 3,000/mcL platelets ≥100,000/mcL hemoglobin ≥ 10.0 g/dL with no blood transfusions (packed red blood cells in the past 28 days is permitted) total bilirubin ≤ 1.5 x institutional upper limit of normal AST(SGOT)/ALT(SGPT) ≤2.5 × institutional upper limit of normal Serum or plasma creatinine ≤ 1.5 x institutional upper limit of normal (ULN) --- OR creatinine clearance ≥51 mL/min/1.73 m2 for participants 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. Willingness to undergo biopsy. Patients with a history of treated CNS metastases are eligible, provided they meet all of the following criteria: Disease outside the CNS is present; no clinical evidence of progression since completion of CNS-directed therapy; minimum of 2 weeks between completion of radiotherapy and Cycle 1 Day 1 and recovery from significant (Grade ≥3) acute toxicity with no ongoing requirement for > 10mg of prednisone per day or an equivalent dose of other corticosteroid. NOTE: 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. Both men and women are eligible for this study Postmenopausal or evidence of non-childbearing status for women of childbearing potential. For women who are not post-menopausal, a negative urine or serum pregnancy test is required within 28 days of study treatment and confirmed prior to treatment on day 1. Post-menopausal is defined as one of the following: > 60 years old Amenorrheic for 1 year or more following cessation of exogenous hormonal treatments Luteinizing hormone (LH) and Follicle stimulating hormone (FSH) levels in the post menopausal range for women under 50 radiation-induced oophorectomy with last menses >1 year ago surgical sterilisation (bilateral oophorectomy or hysterectomy) Men and women of reproductive potential need to employ two highly effective and acceptable forms of contraception throughout their participation in the study and for 30 days (for women) or 90 days (for men) after the last dose of study medication because the effects of olaparib on the developing human fetus are unknown. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations. Ability to understand and the willingness to sign a written informed consent document. Informed consent must be provided prior to any study specific procedures Exclusion Criteria: Any previous treatment with a PARP inhibitor, including olaparib. Germline BRCA1 or BRCA2 mutation Patients with myelodysplastic syndrome/acute myeloid leukemia or with features suggestive of MDS/AML. Patients with symptomatic uncontrolled brain metastases. A scan to confirm the absence of brain metastases is not required. Patients with spinal cord compression unless considered to have received definitive treatment for this and evidence of clinically stable disease for 28 days. Major surgery within 2 weeks of starting study treatment and patients must have recovered from any effects of any major surgery. Concomitant use of known strong CYP3A inhibitors (e.g., itraconazole, telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) and grapefruit, grapefruit juice or any product containing grapefruit,or moderate CYP3A inhibitors (e.g., ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil). The required washout period prior to starting olaparib is 2 weeks. 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 olaparib is 5 weeks for enzalutamide or phenobarbital and 3 weeks for other agents. Patients considered a poor medical risk due to a serious, uncontrolled medical disorder, non-malignant systemic disease or active, uncontrolled infection. 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, extensive interstitial bilateral lung disease on High Resolution Computed Tomography (HRCT) scan or any psychiatric disorder that prohibits obtaining informed consent Persistent toxicities (≥CTCAE grade 2) caused by previous cancer therapy, excluding alopecia Immunocompromised patients, e.g., patients who are known to be serologically positive for human immunodeficiency virus (HIV). Patients with prior myelodysplastic syndrome or acute myeloid leukemia. Other malignancy within the last 5 years except: adequately treated non-melanoma skin cancer; curatively treated in situ cancer of the cervix; ductal carcinoma in situ (DCIS); 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 Resting EKG with QTc > 470 msec or family history of long QT syndrome. If EKG demonstrates QTc >470 msec, patient will be eligible only if repeat EKG demonstrates QTc ≤470 msec. Pregnant or breast feeding women. Patients with a known hypersensitivity to olaparib or any of the excipients of the product. Major surgery within 2 weeks of starting study treatment: patients must have recovered from any effects of any major surgery. Patients with known active hepatitis (i.e., Hepatitis B or C) Previous allogenic bone marrow transplant or double umbilical cord blood transplantation (dUCBT) Whole blood transfusions in the last 120 days prior to entry to the study (packed red blood cells and platelet transfusions are acceptable). Patients unable to swallow orally administered medication and patients with gastrointestinal disorders likely to interfere with absorption of the study medication
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Nadine Tung, MD
Phone
617-667-1962
Email
ntung@bidmc.harvard.edu
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Nadine Tung, MD
Organizational Affiliation
Beth Israel Deaconess Medical Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of Alabama at Birmingham
City
Birmingham
State/Province
Alabama
ZIP/Postal Code
35294
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Nuzhat Siddiqui
Phone
205-975-2618
Email
Nuzhat@uab.edu
First Name & Middle Initial & Last Name & Degree
Eddy Shih-Hsin Yang, MD
Facility Name
University of California, San Francisco
City
San Francisco
State/Province
California
ZIP/Postal Code
94143
Country
United States
Individual Site Status
Active, not recruiting
Facility Name
University of Chicago
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60637
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Nanda Rita, MD
Email
rnanda@medicine.bsd.uchicago.edu
First Name & Middle Initial & Last Name & Degree
Jerrica Hill
Email
jhill1@bsd.uchicago.edu
First Name & Middle Initial & Last Name & Degree
Rita Nanda, MD
Facility Name
Indiana University
City
Indianapolis
State/Province
Indiana
ZIP/Postal Code
46202
Country
United States
Individual Site Status
Active, not recruiting
Facility Name
Johns Hopkins University
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21218
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Cesar Santa-Maria, MD
Email
cesar.santa-maria@northwestern.edu
First Name & Middle Initial & Last Name & Degree
Ashley Carpenter
Email
acarpen7@jhmi.edu
First Name & Middle Initial & Last Name & Degree
Cesar Santa-Maria, MD
Facility Name
Beth Israel Deaconess Medical Center
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02115
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Nadine Tung, MD
Email
ntung@bidmc.harvard.edu
First Name & Middle Initial & Last Name & Degree
Nadine Tung, MD
Facility Name
Brigham and Women's Hospital
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02115
Country
United States
Individual Site Status
Recruiting
Facility Name
Dana-Farber Cancer Institute
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02215
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Judy Garber, MD, MPH
Phone
617-632-2282
Email
jegarber@partners.org
Facility Name
Memorial Sloan Kettering Cancer Center Basking Ridge
City
Basking Ridge
State/Province
New Jersey
ZIP/Postal Code
07920
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Nicole Barbier
Email
barbiern@mskcc.org
First Name & Middle Initial & Last Name & Degree
Mark Robson, MD
Facility Name
Memorial Sloan Kettering Cancer Center Monmouth
City
Middletown
State/Province
New Jersey
ZIP/Postal Code
07748
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Nicole Barbier
Email
barbiern@mskcc.org
First Name & Middle Initial & Last Name & Degree
Mark Robson, MD
Facility Name
Memorial Sloan Kettering Cancer Center Bergen
City
Montvale
State/Province
New Jersey
ZIP/Postal Code
07645
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Nicole Barbier
Email
barbiern@mskcc.org
First Name & Middle Initial & Last Name & Degree
Mark Robson, MD
Facility Name
Memorial Sloan Kettering Cancer Center Commack
City
Commack
State/Province
New York
ZIP/Postal Code
11725
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Nicole Barbier
Email
barbiern@mskcc.org
First Name & Middle Initial & Last Name & Degree
Mark Robson, MD
Facility Name
Memorial Sloan Kettering Cancer Center Westchester
City
Harrison
State/Province
New York
ZIP/Postal Code
10604
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Nicole Barbier
Email
barbiern@mskcc.org
First Name & Middle Initial & Last Name & Degree
Mark Robson, MD
Facility Name
Memorial Sloan Kettering Cancer Center
City
New York
State/Province
New York
ZIP/Postal Code
10065
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Nicole Barbier
Email
barbiern@mskcc.org
First Name & Middle Initial & Last Name & Degree
Mark Robson, MD
Facility Name
Memorial Sloan Kettering Cancer Center Nassau
City
Uniondale
State/Province
New York
ZIP/Postal Code
11553
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Nicole Barbier
Email
barbiern@mskcc.org
First Name & Middle Initial & Last Name & Degree
Mark Robson, MD
Facility Name
Duke University
City
Durham
State/Province
North Carolina
ZIP/Postal Code
27708
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Gretchen Kimmick, MD
Email
gretchen.kimmick@duke.edu
First Name & Middle Initial & Last Name & Degree
Michelle Parks
Email
michelle.parks@duke.edu
First Name & Middle Initial & Last Name & Degree
Gretchen Kimmick, MD
Facility Name
UPMC Hillman Cancer Center - Erie
City
Erie
State/Province
Pennsylvania
ZIP/Postal Code
16505
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Joshua Plassmeyer
Phone
412-648-6417
Email
plassmeyerjm@upmc.edu
First Name & Middle Initial & Last Name & Degree
Leisha Emens, MD
Facility Name
University of Pennsylvania
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19104
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Catherine Rudloff, BSN
Email
Catherine.rudloff@pennmedicine.upenn.edu
First Name & Middle Initial & Last Name & Degree
Payal Shah, MD
Facility Name
University of Pittsburgh
City
Pittsburgh
State/Province
Pennsylvania
ZIP/Postal Code
15260
Country
United States
Individual Site Status
Active, not recruiting
Facility Name
University of Washington Fred Hutchinson Cancer Care
City
Seattle
State/Province
Washington
ZIP/Postal Code
98109
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Shaveta Vinayak, MD
Email
shaveta@uw.edu
First Name & Middle Initial & Last Name & Degree
Shaveta Vinayak, MD

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
33119476
Citation
Tung NM, Robson ME, Ventz S, Santa-Maria CA, Nanda R, Marcom PK, Shah PD, Ballinger TJ, Yang ES, Vinayak S, Melisko M, Brufsky A, DeMeo M, Jenkins C, Domchek S, D'Andrea A, Lin NU, Hughes ME, Carey LA, Wagle N, Wulf GM, Krop IE, Wolff AC, Winer EP, Garber JE. TBCRC 048: Phase II Study of Olaparib for Metastatic Breast Cancer and Mutations in Homologous Recombination-Related Genes. J Clin Oncol. 2020 Dec 20;38(36):4274-4282. doi: 10.1200/JCO.20.02151. Epub 2020 Oct 29.
Results Reference
derived

Learn more about this trial

Olaparib In Metastatic Breast Cancer

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