Study of Stereotactic Radiosurgery With Olaparib Followed by Durvalumab and Physician's Choice Systemic Therapy in Subjects With Breast Cancer Brain Metastases

Running, not enrolling · Phase 1/Phase 2

Conditions studied: Breast Cancer, Brain Metastases, Adult

In brief

This study is a Phase I/II study evaluating the safety and effectiveness of focused radiation therapy (radiosurgery) together with olaparib, followed by immunotherapy, for patients with brain metastases from triple negative or BRCA-mutated breast cancers. This study will have a Phase I portion in which subjects will be enrolled based on 3+3 dose escalation rules. Three dose levels of olaparib will be studied. Cycle 1 of study treatment will consist of Olaparib given twice daily concurrently with stereotactic radiosurgery (SRS). Olaparib will start one week prior to SRS and continue during and following SRS (1-5 fractions) for up to 28 days total. The number of doses of Olaparib will be dependent on how long it takes a subject to recover from SRS (ideally the subject will be off steroids, if they are required, at the start of Cycle 2, with exceptions outlined later in this section). Once the subject has recovered from SRS (based on investigator discretion) that will be considered the DLT period. Cycle 2 will be initiated with physician's choice systemic therapy and durvalumab. Cycle 2+ will equal 21 days. During Cycles 2 and 3, physician's choice systemic monotherapy will be given along with durvalumab per protocol. Each cycle will last 21 days. Imaging to evaluate intracranial and extracranial disease will be performed after Cycle 3, and subjects with response will continue with the systemic therapy and durvalumab until progression (intracranial or extracranial), unacceptable toxicity or death.

Key facts

Study ID

NCT04711824

Run by

Colette Shen

People needed

41

Starts

2022-03-09

Expected to finish

2026-11-01

Last updated by the study team

2026-07-10

Who can join

Age: 18 and older. Sex: any. Healthy volunteers: not accepted.

You may qualify if…

• Able and willing to provide written informed consent and HIPAA authorization for release of personal health information prior to registration. NOTE: HIPAA authorization may be included in the informed consent or obtained separately.
• Subject has histologically confirmed diagnosis of breast cancer per AJCC 8th edition meeting any of the following criteria: 1) triple negative, defined as ER/PR expression <10% and HER2-negative, with any BRCA status; or 2) HER2-negative (with ER/PR expression >=10% with germline or somatic BRCA mutation.
• Subject has diagnosis of new brain metastasis by MRI, with a plan to undergo stereotactic radiosurgery (SRS) (up to 15 untreated metastases and at least 1 metastasis with maximum dimension > 5mm). Patients are permitted to have undergone recent craniotomy and resection of metastasis/metastases if at least 1 other intact metastasis or gross residual tumor planned for definitive SRS is present. Patients may have had prior SRS as long as the previously treated brain metastases are stable and not planned for additional therapy. Re-irradiation of a lesion previously treated with SRS is not allowed. Discrete dural lesions are allowed.
• Subject may have other sites of extracranial metastatic disease (does not need to be stable, as long as no signs of impending visceral crisis).
• Subjects may have had prior systemic therapy other than combination DDR inhibitor (PARP inhibitor) and immune checkpoint inhibitor (i.e., prior PARP inhibitor without concurrent immune checkpoint inhibitor, or prior immune checkpoint inhibitor without concurrent PARP inhibitor, are allowed).
• Subject has Eastern Cooperative Oncology Group (ECOG) performance status 0-2 within 28 days prior to registration.
• Body weight >30 kg (for durvalumab monotherapy or durvalumab combination).
• Subject has life expectancy > 16 weeks.
• Age ≥ 18 years at the time of consent.
• Prior systemic cancer treatment must be completed at least 7 days prior to treatment and the subject must have recovered from all reversible acute toxic effects of the regimen (other than alopecia) to Grade ≤ 1 or baseline.
• Subject is willing and able to provide blood and tissue samples for correlative research activities, if applicable.
• Patients must have normal organ and bone marrow function measured within 28 days prior to administration of study treatment as defined in the table below:
• Platelets ≥100 x 109/L
• Absolute Neutrophil Count (ANC) ≥ 1.5 x 109/L
• Hemoglobin (Hgb) ≥ 10 g/dL with no blood transfusion in the past 28 days
• Calculated creatinine clearance ≥ 51 mL/min
• Bilirubin ≤ 1.5 × institutional upper limit of normal (ULN)
• Aspartate aminotransferase (AST) (Serum Glutamic Oxaloacetic Transaminase (SGOT)) ≤ 2.5 × ULN unless liver metastases are present in which case they must be ≤ 5x ULN
• Alanine aminotransferase (ALT) (Serum Glutamic Pyruvate Transaminase (SGPT)) Alanine aminotransferase (ALT) ≤ 2.5 × ULN unless liver metastases are present in which case, they must be ≤ 5x ULN
• International Normalized Ratio (INR) or Prothrombin Time (PT)
• Activated Partial Thromboplastin Time (aPTT) ≤ 1.5 × ULN; Patients taking warfarin may participate in this study; however, it is recommended that INR be monitored carefully at least once per week for the first month, then monthly if the INR is stable.
• 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 is defined as:
• 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

You may not qualify if…

• Subject has evidence of diffuse symptomatic leptomeningeal carcinomatosis.
• Subject has symptomatic brain metastases requiring immediate surgical resection within 1 week.
• Subject has evidence of intracranial hemorrhage or signs of impending herniation.
• Subject has had prior whole brain radiation therapy. Prior SRS to brain metastases is allowed as long as previously treated lesions are stable and not planned for further therapy.
• Subject has had prior extracranial radiation therapy within 3 weeks of study initiation unless palliative.
• Subject has signs of impending visceral crisis.
• Subject has a history of severe brain injury.
• Receipt of the last dose of anticancer therapy (chemotherapy, immunotherapy, endocrine therapy, targeted therapy, biologic therapy, tumor embolization, monoclonal antibodies) ≤ 7 days prior to the first dose of study drug. If sufficient wash-out time has not occurred (defined as 5 half-lives for the prior anti-cancer therapy), a longer wash-out period will be required, as agreed by sponsor-investigator and the site investigator. Concurrent use of hormonal therapy for non-cancer-related conditions is acceptable.
• Subject with myelodysplastic syndrome/acute myeloid leukemia or with features suggestive of MDS/AML
• Resting ECG indicating uncontrolled, potentially reversible cardiac conditions, as judged by the investigator (eg., unstable ischemia, uncontrolled symptomatic arrhythmia, congestive heart failure, QTcF prolongation > 470 ms, electrolyte disturbances, etc.), or patients with congenital long QT syndrome.
• Subject has had any known Grade 3 or 4 anemia, neutropenia or thrombocytopenia due to prior chemotherapy that persisted > 4 weeks and was related to the most recent treatment.
• Subject has a history of interstitial lung disease.
• Subject has a diagnosis of primary immunodeficiency.
• Subject must not have received colony stimulating factors (e.g., granulocyte colony-stimulating factor, granulocyte macrophage colony stimulating factor, or recombinant erythropoietin) within 4 weeks prior initiating study therapy.
• Immunocompromised patients, e.g., patients who are known to be serologically positive for human immunodeficiency virus (HIV).
• Subject is pregnant or breastfeeding (NOTE: breast milk cannot be stored for future use while the mother is being treated on study).
• Subject is not eligible for sequential MRI or CT evaluations.
• Subject with spinal cord compression unless considered to have received definitive treatment for this and evidence of clinically stable disease for 28 days.
• Subject unable to swallow orally administered medication and patients with gastrointestinal disorders likely to interfere with absorption of the study medication.
• Concomitant use of known strong CYP3A inhibitors (eg. itraconazole, telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) or moderate CYP3A inhibitors (eg. ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil). The required washout period prior to starting olaparib is 2 weeks.
• Concomitant use of known strong (eg. 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.
• Previous allogenic bone marrow transplant or double umbilical cord blood transplantation (dUCBT).
• Participation in another clinical study with an investigational product during the last 4 weeks. NOTE: Subjects that consented to the sub-study may enroll in the primary therapeutic study if they meet all eligibility criteria outlined in Section 3.1.
• Concurrent enrollment in another clinical study, unless it is an observational (non-interventional) clinical study or during the follow-up period of an interventional study. NOTE: Subjects that consented to the sub-study may enroll in the primary therapeutic study if they meet all eligibility criteria outlined in Section 3.1.
• Any unresolved toxicity NCI CTCAE Grade ≥ 2 from previous anticancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria.

Where it is running

• University of Alabama at Birmingham — Birmingham, Alabama, United States
• Memorial Healthcare System — Hollywood, Florida, United States
• Indiana University Melvin and Bren Simon Comprehensive Cancer Center — Indianapolis, Indiana, United States
• Memorial Sloan Kettering Cancer Center — New York, New York, United States
• University of North Carolina at Chapel Hill — Chapel Hill, North Carolina, United States
• Duke Cancer Institute — Durham, North Carolina, United States
• Cleveland Clinic — Cleveland, Ohio, United States

Full record on ClinicalTrials.gov

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