Title
A Phase II Trial of Durvalumab and Ablative Radiation in Extensive-Stage Small Cell Lung Cancer (DARES)

Description
This this study is for individuals who have treatment-naïve extensive-stage small cell lung cancer (small cell lung cancer that wont respond to treatment). Doctors leading this study hope to learn if combining durvalumab, carboplatin and etoposide with hyofractionated ablative radiation therapy (radiation focused on certain parts of the body) will help treat your cancer and improve how long you can live with extensive-stage small cell cancer without it getting worse (progression-free survival). Your participation in this research will last about 48 months.

Durvalumab along with chemotherapy has been approved by the Food and Drug Administration (FDA) for the treatment of small cell lung cancer along with chemotherapy. This study is testing the addition of radiation to durvalumab and chemotherapy.

Objective
Primary Objectives:
To estimate the progression-free survival (PFS) of subjects treated with durvalumab, carboplatin and etoposide with hypofractionated ablative radiation therapy in subjects with treatment-naïve extensive stage small cell lung cancer
Secondary Objective(s):
1. To estimate the rates of ? grade 3-4 adverse events, by organ system, by Common Terminology Criteria for Adverse Events (CTCAE) v5.0 that occur within 3 months from the start of radiation.
2. To estimate the progression-free survival at 12 months.
3. To estimate the response rate of chemotherapy, durvalumab, and hypofractionated ablative radiotherapy.
4. To estimate the overall survival after treatment with chemotherapy, durvalumab, and hypofractionated ablative radiotherapy.
5. To estimate time to second-line therapy
6. To estimate time to new, distant lesions(s)
Exploratory Objective(s):
(1) To determine how pre-treatment radiomic features, as well as post-treatment radiomic features, may help predict for favorable response to durvalumab, chemotherapy, and hypofractionated ablative radiotherapy (RT)
(2) To explore peripheral blood T cell receptor deep sequencing quantification of T cell receptor (TCR) repertoire changes throughout the study course and how TCR repertoire may correlate with progression free survival and overall survival. These will be collected at four time points:
1) baseline 2) after completion of radiation 3) at progression or immune toxicity 4) if immune toxicity resolves.
(3) To investigate the microbiome using nasal, buccal, and stool samples. These will be collected at four time points: 1) baseline 2) after completion of radiation 3) at progression or immune toxicity
4) if immune toxicity resolves.

Treatment Radiation: Ablative Radiation
Drug: Durvalumab
Drug: Etoposide
Drug: Carboplatin

Key Eligibility For inclusion in the study patients must fulfill all of the following criteria:

Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in the study protocol.

Age > 18 years at time of study entry.

Have a histologic/clinically confirmed diagnosis of small cell lung cancer with known metastatic disease.

Patient is suitable to receive a platinum-based chemotherapy regimen as first line treatment for extensive stage small cell lung cancer.

Brain metastases must be asymptomatic or treated and stable off steroids and anti-convulsant for at least 2 weeks prior to study treatment.

Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2

Life expectancy of at least 12 weeks

Body weight >30 kg

Adequate normal organ and marrow function as defined by lab values the study doctor will review.

Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up.

Have measurable disease based on Response Evaluation Criteria in Solid Tumor (RECIST 1.1) including at least ONE lesion that meets criteria for ablative radiation, including 0.25 cc to 65 cc of viable tumor (i.e. primary disease or metastases) approximately 5cm in maximal dimension. Tumors larger than 65 cc can be partially treated.

Female subject of childbearing potential should have a negative urine or serum pregnancy within 24 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.

Female subjects of childbearing potential should be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication. Subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year.

Male subjects should agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of study therapy.

Applicable Disease Sites
Lung

Participating Institutions
UW Health Eastpark Medical Center; UW Health University Hospital