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.
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).
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.
Single group
Olaparib
DrugOlaparib 100-300 mg twice daily up to 28 days concurrently with stereotactic radiosurgery. Three dose levels of olaparib will be explored in the Phase I portion. Olaparib will start one week prior to SRS and continue during and following SRS for up to 28 days total. One cycle will be given.
Stereotactic Radiosurgery
RadiationSRS 1-5 fractions will be given per institutional standards
Durvalumab
DrugDurvalumab 1120 mg IV over 60 minutes Day 1 of each cycle 21 day cycle.
Physicians Choice systemic chemotherapy
DrugOlaparib: 300mg PO BID; Days 1-21 Paclitaxel: 80 mg/m2 IV over 60 min; Day 1 and 8 Nab-paclitaxel:100 mg/m2 IV over 30 min; Day 1 and 8 Eribulin: 1.4 mg/m2 IV over 2-5 min; Day 1 and 8 Carboplatin: AUC 2 mg/ml/min IV over 30-60 min; Day 1 and 8 Cisplatin: 75 mg/m2 IV over 30-60 min; Day 1 Capecitabine: 1000 mg/m2 PO BID; Days 1-14 Gemcitabine: 1000 mg/m2 IV over 30 min; Day 1 and 8 Gemcitabine + Carboplatin: 1000mg/m2 IV over 30-60 min; Day 1 and 8
Frequency and severity of adverse events
Phase I: frequency and severity of adverse events will be measured using common toxicity criteria for adverse events version 5.
Intracranial Disease control rate
Phase II: Intracranial disease control rate will be defined as the percentage of subjects with \[complete response (CR) + partial response (PR) + stable disease\] per RANO-BM criteria at 6 months after study treatment initiation.
Intracranial disease progression free survival per RANO-BM
Intracranial progression free survival (PFS) is defined as time from the day of study treatment initiation until evidence of disease progression per RANO-BM or death from any cause.
Overall survival
Overall survival (OS) will be calculated starting from the day of study treatment initiation until death from any cause.
Intracranial response rate
Intracranial response rate will be measured by RANO-BM criteria.
Extracranial response rate per RECIST 1.1
Extracranial response rate will be measured by RECIST 1.1 criteria.
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Colette Shen
Lead sponsor
Hoosier Cancer Research Network
Sponsor institution
AstraZeneca
Collaborator
University of North Carolina, Chapel Hill
Collaborator
