This is a phase I, dose escalating study evaluating the safety of combining talazoparib and low dose consolidative thoracic radiotherapy for small cell lung cancer patients. This study will also determine the maximum tolerated dose (MTD) of talazoparib in combination with low dose thoracic radiotherapy.

Patients will start on talazoparib on day 1 of study intervention, and will continue to orally take talazoparib until the last day of radiation therapy. Up to 24 patients will be enrolled to the study, where the first 3 patients will start with a starting dose level of talazoparib is 0.5 mg PO once daily. This will increase to 1mg daily with each new cohort.

This is a phase I, dose escalating study evaluating the safety of combination talazoparib and low dose consolidative thoracic radiotherapy for extensive-stage small cell lung cancer patients with at least stable disease after standard of care 4 - 6 cycles of chemotherapy (a platinum agent and etoposide). This study will also determine the maximum tolerated dose (MTD) of talazoparib in combination with low dose thoracic radiotherapy. Secondary objectives will be to examine clinical outcomes, including locoregional recurrence within the radiation field, progression-free survival, overall survival and acute/chronic toxicities up to 1 year.

Patients will start on talazoparib on day 1 of study intervention, and will continue to orally take talazoparib until the last day of RT. Patient will start low dose RT on day 6-9, and will continue for 10 fractions throughout 2 weeks. Up to 24 patients will be enrolled to the study, where the first 3 patients will start with a starting dose level of talazoparib is 0.5 mg PO once daily. This will increase to 1mg daily with each new cohort. Patients will be monitored weekly during study treatment, and followed up at 3 weeks, and every 3 months after for 1 year.

Inclusion Criteria:

• Histological documented diagnosis of SCLC confirmed by a UHN pathologist.
• Documented extensive disease
• Completion of induction chemotherapy, 4-6 cycles of a platinum agent and etoposide.
• No disease progression (i.e.SD or better response by RECIST 1.1) at the completion of chemotherapy.
• Eastern Cooperative Oncology Group (ECOG) performance status 0-2 (Karnosfsky Performance Score (KPS) ≥50; see Appendix B).
• Adequate organ and marrow function,
• 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.

Exclusion Criteria:

• Untreated brain metastases.
• Previous radiotherapy to thorax (prior breast RT is permitted).
• Patients receiving any systemic chemotherapy, radiotherapy or immunotherapy (except for standard of care treatments or palliative reasons) within 3 weeks prior to study treatment.
• Exposure to an investigational product within 30 days or 5 half-lives (whichever is longer) prior to start of the current study drug.
• Any previous treatment with PARP inhibitor, including talazoparib.
• Concomitant use of strong P-gp inhibitors
• Concomitant use of other known P-gp inhibitors, P-gp inducers, or BCRP inhibitors
• Persistent toxicities (>Common Terminology Criteria for Adverse Event (CTCAE) grade 2) caused by previous cancer therapy, excluding alopecia.
• Patients with myelodysplastic syndrome/acute leukaemia or with features suggestive thereof.
• Major surgery within 2 weeks of study treatment initiation and patients must have recovered from any effects of any major surgery.
• Patients considered a poor medical risk due to a serious, uncontrolled medical disorder, non-malignant systemic disease or active/uncontrolled infection. Examples include, but are not limited to, uncontrolled ventricular arrhythmia, recent (within 3 months) myocardial infarction, uncontrolled major seizure disorder, unstable spinal cord compression, superior vena cava syndrome, extensive interstitial bilateral lung disease on High Resolution Computed Tomography (HRCT) scan or any psychiatric disorder that prohibits obtaining informed consent
• Patients unable to swallow orally administered medication and patients with gastrointestinal disorders likely to interfere with absorption of the study medication.
• Immunocompromised patients,
• Previous allogenic bone marrow transplant or double umbilical cord blood transplantation (dUCBT).
• Whole blood transfusions in the last 120 days prior to entry to the study
• Other malignancy within the last 5 years
• Patients with spinal cord compression