Phase I/II Study of Stereotactic Radiosurgery With Concurrent Administration of DNA Damage Response (DDR) Inhibitor (OLAparib) Followed by Adjuvant Combination of DuRvalumab (MEDI4736) and Physician's Choice Systemic Therapy in Subjects With BreAst Cancer Brain Metastases

Summary

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.

Eligibility

Age range

18+ years

Sex

All

Healthy volunteers

No

Interventions

• Drug
  Olaparib

  Olaparib 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.

• Radiation
  Stereotactic Radiosurgery

  SRS 1-5 fractions will be given per institutional standards

• Drug
  Durvalumab

  Durvalumab 1120 mg IV over 60 minutes Day 1 of each cycle 21 day cycle.

• Drug
  Physicians Choice systemic chemotherapy

  Olaparib: 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

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