Talazoparib and Thoracic RT for ES-SCLC

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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A Phase I Study of Talazoparib and Consolidative Thoracic Radiotherapy for Extensive Stage Small Cell Lung Cancer

Conditions
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Lung Cancer, Small-Cell Lung Cancer

Intervention / Treatment
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* Other: Talazoparib in Combination with Low Dose Radiotherapy (RT)


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Sequential Assignment
Interventional Model Description: Dose escalation based on the maximum tolerated dose from each previous cohort within the study.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Talazoparib in Combination with Low Dose RT<br>Patients will start on talazoparib on day 1 of study intervention, and will continue to orally take talazoparib until the last day of RT (until day 20-23). Patient will start low dose RT on day 6-9, and will continue for 10 fractions throughout 2 weeks. Talazoparib dose levels will start at 0.5mg daily and increase to 1mg if dose limiting toxicites are not observed. Toxicities include renal impairment and other treatment related toxicities Grade ≥3. Patients will be monitored weekly during study treatment, and followed up at 3 weeks, and every 3 months after for 1 year. | Other: Talazoparib in Combination with Low Dose Radiotherapy (RT)<br>* Dose escalation model to determine the safety and MTD of talazoparib in combination with low dose RT.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety of Talazoparib in Combination with Low Dose Thoracic Radiotherapy | Safety will be measured by assessing all adverse events as determined by the investigator using CTCAE v.5.0. | Up to 3 years upon enrollment | 
| Maximum Tolerated Dose (MTD) of Talazoparib in Combination with Low Dose Thoracic Radiotherapy | MTD will be defined as the maximum dose by a standard 3+3 design | Up to 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Loco-regional Recurrence | Loco-regional recurrence will be assessed by using RECIST v1.1 criteria | 6 months and 1 year | 
| Progression-Free Survival (PFS) | PFS will be defined as the time of start of radiotherapy to first local/loco-regional or distance recurrence event, or death. | 6 months and 1 year | 
| Overall Survival (OS) | OS will be defined as the time from the start of radiotherapy to death from any cause. | 6 months and 1 year | 
| Acute Toxicities | Acute toxicities will be assessed by physician-graded CTCAE. | Up to 1 year | 
| Chronic Toxicities | Chronic toxicities will be assessed by physician-graded CTCAE. | Up to 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Talazoparib, Thoracic Radiotherapy, Chemotherapy