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
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).
• 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
‣ Chemotherapy-induced menopause with \> 1-year interval since last menses
‣ Surgical sterilisation (bilateral oophorectomy or hysterectomy)
⁃ Female patients of childbearing potential must be willing to abstain from heterosexual activity or to use 2 highly effective methods of contraception as described in the protocol from the time of informed consent until 3 months after treatment discontinuation.
⁃ Male patients must be willing to abstain from heterosexual activity or use a condom during treatment and for 3 months after treatment discontinuation. See the protocol for additional information.
⁃ As determined by the enrolling physician or protocol designee, ability of the subject to understand and comply with study procedures for the entire length of the study.
⁃ Other inclusion criteria as specified by drug manufacturer for specific investigational drug(s), and/or required to specify disease status etc.
• Subjects planned for surgical resection of their brain metastasis must meet the following criteria:
• Subject is planned for surgical resection of their brain metastasis. NOTE: subjects with acutely symptomatic brain metastasis requiring surgical resection within 1 week are not eligible for the sub-study.
• Subject meets inclusion criteria #1, 2, 4, 6, 8-16 above.1 Female patients of child-bearing potential and male patients must be willing to abstain from heterosexual intercourse or use contraception as described in protocol.