Olaparib in Treating Patients with Metastatic Breast Cancer with DNA Repair Gene Mutations
- 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 mutation or somatic mutation (or homozygous deletion) in one of the DNA repair genes listed below that is deleterious or suspected to be deleterious; the mutation must be identified through a Clinical Laboratory Improvement Act (CLIA)-approved next generation sequencing (NGS) panel. All mutations (both cohorts) must be reviewed and confirmed by Dr. Tung to meet eligibility prior to registration * Cohort 1: Germline mutation in one of the DNA repair genes listed below OR * Cohort 2: Somatic mutation or homozygous deletion in one of the DNA repair genes listed below or a somatic mutation of BRCA1 or BRCA2 (without germline BRCA 1 /2 mutation) * DNA Repair Gene List: ATM, ATR, BARD1, BLM, BRIP1 (FANCJ), CHEK1, CHEK2 , CDK12, FANCA, FANCC, FANCD2, FANCE, FANCF, FANCM, MRE11A, NBN (NBS1), PALB2, RAD50, RAD51C, RAD51D, plus other hormone receptor (HR)-related genes at the discretion of Dr. Tung with the key study collaborators
- COHORT 1A: Germline PALB2 mutation * The mutation must be identified through a Clinical Laboratory Improvement Act (CLIA)-approved next-generation sequencing (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
- At least one measurable lesion that can be accurately assessed at baseline by computed tomography (CT) (magnetic resonance imaging [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 non-hormonal targeted therapy received must have been completed at least 21 days prior to study treatment
- 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. Patients who received platinum-based chemotherapy in the metastatic setting for breast cancer (cisplatin or carboplatin, either as monotherapy or in combination) are eligible provided there has been no evidence of disease progression during the platinum chemotherapy * Patients who received prior platinum- based chemotherapy as treatment for a prior non-breast cancer (e.g. ovarian cancer) are eligible provided that there has been no evidence of disease for >= 5 years prior to study entry * 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 14 days before study treatment * Prior treatment with Food and Drug Administration (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
- Eastern Cooperative Oncology Group (ECOG) performance status 0-1 (Karnofsky >= 60%)
- Life expectancy >= 16 weeks
- Absolute neutrophil count >= 1,500/mcL (measured within 28 days prior to registration)
- White blood cells > 3,000/mcL (measured within 28 days prior to registration)
- Platelets >= 100,000/mcL (measured within 28 days prior to registration)
- Hemoglobin >= 10.0 g/dL with no blood transfusions (packed red blood cells in the past 28 days is permitted) (measured within 28 days prior to registration)
- Total bilirubin =< 1.5 x institutional upper limit of normal (ULN). In the case of known Gilbert’s syndrome, a higher serum total bilirubin (< 2 x ULN) is allowed (measured within 28 days prior to registration)
- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) =< 2.5 x institutional upper limit of normal or =< 5 x ULN if patient has liver metastases (measured within 28 days prior to registration)
- Alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal or =< 5 x ULN if patient has liver metastases (measured within 28 days prior to registration)
- Serum or plasma creatinine =< 1.5 x institutional upper limit of normal (ULN) OR creatinine clearance >= 51 mL/min/1.73 m^2 for participants (measured within 28 days prior to registration)
- Willingness to undergo biopsy; if biopsy is not felt to be possible or safe, permission must be received from Dr. Tung to forgo a biopsy; in that event, formalin fixed, paraffin embedded (FFPE) tumor sample from a prior metastatic biopsy (preferable) or from the primary tumor tissue will be collected, unless none is available or a biopsy would create unacceptable risk for the patient, and Dr. Tung provides approval; if paraffin blocks are unable to be sent for analysis due to institutional policy, 15 unstained paraffin slides may be sent instead; a formal eligibility exception is not needed as long as approval is granted and documented by Dr. Tung
- Patients with a history of treated central nervous system (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 > 10 mg 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
- Post-menopausal 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 sterilization (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; 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
- Any previous treatment with a PARP inhibitor, including olaparib
- Germline BRCA1 or BRCA2 mutation
- Patients with myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) 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 (>= Common Terminology Criteria for Adverse Events [CTCAE] grade 2) caused by previous cancer therapy, excluding alopecia
- 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 * Malignancy within the last 5 years that is low risk for recurrence and was treated curatively without systemic therapy. These cases should be reviewed and approved by Dr. Tung prior to enrollment (eligibility exception will not be required)
- Pregnant or breast-feeding women
- Patients with a known hypersensitivity to olaparib or any of the excipients of the product
- Patients with known active hepatitis (i.e., hepatitis B or C) or human immunodeficiency virus (HIV) with detectable viral load (history of HIV with undetectable viral load is allowed)
- 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
I. To determine the objective response rate (ORR) (complete response [CR] and partial response [PR] by Response Evaluation Criteria in Solid Tumors [RECIST]) in patients with metastatic breast cancer and germline mutations in deoxyribonucleic acid (DNA) repair genes other than BRCA1/2 (Cohort 1) treated with olaparib monotherapy.
II. To determine the objective response rate (ORR) (complete response [CR] and partial response [PR] by RECIST) in patients with metastatic breast cancer and somatic mutations in DNA repair genes (somatic pathogenic BRCA1 or BRCA2 mutations are permitted in patients who lack a germline mutation in BRCA1 or BRCA2) (Cohort 2) treated with olaparib monotherapy.
III. To determine the objective response rate (ORR) (complete response [CR] and partial response [PR] by RECIST) in patients with metastatic breast cancer and germline PALB2 mutation (Cohort 1a) in patients treated with olaparib monotherapy.
IV. To determine the objective response rate (ORR) (complete response [CR] and partial response [PR] by RECIST) in patients with metastatic breast cancer and somatic pathogenic BRCA1 or BRCA2 mutations (Cohort 2a) in patients treated with olaparib monotherapy.
I. To determine the progression free survival (PFS), clinical benefit rate (CBR), (CR + PR + stable disease [SD] >= 18 weeks), and duration of response or stable disease with olaparib monotherapy in all cohorts.
II. To assess the safety and toxicity of olaparib in all cohorts.
III. To determine if the mutant allele frequency (MAF) is significantly higher in responders than in non-responders among patients with sBRCA1 or sBRCA2 mutations (from Cohorts 2 and 2a combined).
I. Assessment of germline and somatic mutations in DNA repair genes in blood and tumor samples from patients in both cohorts.
II. Biomarkers of DNA repair defects or homologous recombination repair deficiency in tumor tissue (e.g., RAD51 nuclear foci; tumor mutational signatures; loss of heterozygosity [LOH] and other measures of tumor genomic loss and instability).
III. Clinical factors (e.g., prior chemotherapy; estrogen receptor status of tumor).
IV. Other novel biomarkers of PARP inhibitor sensitivity (e.g., PARP expression or function).
V. Metabolic consequences of PARP inhibition.
Patients receive olaparib orally (PO) twice daily (BID) on days 1-21. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up for 30 days, then every 3 months.
Trial Phase Phase II
Trial Type Treatment
Dana-Farber Harvard Cancer Center
Nadine Muskatel Tung
- Primary ID 17-428
- Secondary IDs NCI-2018-00778
- Clinicaltrials.gov ID NCT03344965