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

NCT04711824 | Recruiting Phase 1 DMC FDA Drug

• 1 other identifier: HCRN BRE18-360
• Study Type: interventional
• Target: 41
• Locations: 1 country
• Sites: 7

Brief 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.

Conditions

Breast Cancer; Brain Metastases, Adult

Outcome Measures

Primary Outcomes (2)

• 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.

  4 weeks

• 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.

  6 months

Secondary Outcomes (9)

• Intracranial disease progression free survival per RANO-BM

  2 years

• Overall survival

  2 years

• Intracranial response rate

  2 years

• Extracranial response rate per RECIST 1.1

  2 years

• Intracranial disease progression free survival per iRANO

  2 years

Study Arms (1)

Study Treatment Arm

EXPERIMENTAL

Cycle 1 of study treatment will consist of Olaparib 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. Once the subject has recovered from SRS, 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. 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.

Drug: Olaparib; Radiation: Stereotactic Radiosurgery; Drug: Durvalumab; Drug: Physicians Choice systemic chemotherapy

Interventions

Olaparib DRUG

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.

Also known as: Lynparza

Study Treatment Arm

Stereotactic Radiosurgery RADIATION

SRS 1-5 fractions will be given per institutional standards

Also known as: SRS

Study Treatment Arm

Durvalumab DRUG

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

Also known as: Imfinzi

Study Treatment Arm

Physicians Choice systemic chemotherapy DRUG

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

Also known as: Olaparib, Paclitaxel, Nab-paclitaxel, Eribulin, Carboplatin, Cisplatin, Capecitabine, Gemcitabine

Study Treatment Arm

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

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

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).

Sponsors & Collaborators

• Colette Shen: lead
• AstraZeneca: collaborator
• University of North Carolina, Chapel Hill: collaborator

Study Sites (7)

University of Alabama at Birmingham

Birmingham, Alabama, 35294, United States

RECRUITING

Memorial Healthcare System

Hollywood, Florida, 33028, United States

RECRUITING

Indiana University Melvin and Bren Simon Comprehensive Cancer Center

Indianapolis, Indiana, 46202, United States

RECRUITING

Memorial Sloan Kettering Cancer Center

New York, New York, 10065, United States

RECRUITING

University of North Carolina at Chapel Hill

Chapel Hill, North Carolina, 27899, United States

RECRUITING

Duke Cancer Institute

Durham, North Carolina, 27710, United States

RECRUITING

Cleveland Clinic

Cleveland, Ohio, 44195, United States

RECRUITING

MeSH Terms

Conditions

Breast Neoplasms; Brain Neoplasms

Interventions

olaparib; Radiosurgery; durvalumab; Paclitaxel; 130-nm albumin-bound paclitaxel; eribulin; Carboplatin; Cisplatin; Capecitabine; Gemcitabine

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases; Central Nervous System Neoplasms; Nervous System Neoplasms; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases

Intervention Hierarchy (Ancestors)

Radiotherapy; Therapeutics; Stereotaxic Techniques; Neurosurgical Procedures; Surgical Procedures, Operative; Investigative Techniques; Taxoids; Cyclodecanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Diterpenes; Terpenes; Coordination Complexes; Chlorine Compounds; Inorganic Chemicals; Nitrogen Compounds; Platinum Compounds; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Fluorouracil; Uracil; Pyrimidinones; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides

Study Officials

• Colette Shen, M.D., Ph.D

  University of North Carolina, Chapel Hill

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Colette Shen, M.D., Ph.D.

CONTACT

984-974-8429; colette_shen@med.unc.edu

Allison Lipps

CONTACT

317-634-5842; alipps@hoosiercancer.org

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Sponsor-Investigator

Study Record Dates

• First Submitted: January 12, 2021
• First Posted: January 15, 2021
• Study Start: March 9, 2022
• Primary Completion: February 1, 2026
• Study Completion (Estimated): November 1, 2026
• Last Updated: December 23, 2025

Record last verified: 2025-12

Data Sharing

• IPD Sharing: Will not share

Locations

US (7)