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
Overview
- Phase
- Phase 1
- Intervention
- Olaparib
- Conditions
- Breast Cancer
- Sponsor
- Colette Shen
- Enrollment
- 41
- Locations
- 7
- Primary Endpoint
- Frequency and severity of adverse events
- Status
- Recruiting
- Last Updated
- 4 months ago
Overview
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.
Investigators
Colette Shen
Sponsor-Investigator
Hoosier Cancer Research Network
Eligibility Criteria
Inclusion Criteria
- •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.
Exclusion Criteria
- •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.
Arms & Interventions
Study Treatment Arm
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.
Intervention: Olaparib
Study Treatment Arm
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.
Intervention: Stereotactic Radiosurgery
Study Treatment Arm
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.
Intervention: Durvalumab
Study Treatment Arm
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.
Intervention: Physicians Choice systemic chemotherapy
Outcomes
Primary Outcomes
Frequency and severity of adverse events
Time Frame: 4 weeks
Phase I: frequency and severity of adverse events will be measured using common toxicity criteria for adverse events version 5.
Intracranial Disease control rate
Time Frame: 6 months
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.
Secondary Outcomes
- Overall survival(2 years)
- Extracranial response rate per RECIST 1.1(2 years)
- Intracranial disease progression free survival per iRANO(2 years)
- Intracranial disease progression free survival per RANO-BM(2 years)
- Intracranial response rate(2 years)
- Extracranial disease progression free survival per iRECIST(2 years)
- Extracranial response rate per iRECIST criteria.(2 years)
- Intracranial response rate per iRANO criteria.(2 years)
- Extracranial disease progression free survival per RECIST(2 years)