Biomarker Directed trial of Temozolomide and PARP inhibition in relapsed SCLC

Background: Lung Cancer is the leading cause of cancer death in Veterans, with Small Cell Lung Cancer (SCLC) being an aggressive form of this disease. While initially responsive to platinum-based chemotherapy, recurrence is almost universal in SCLC patients with limited options available for second line therapy. The combination of PARP inhibition (PARPi) with Temozolomide (TMZ) has response rates ~35-40% in unselected SCLC patients, which is not an improvement from currently approved treatments. Attempts to develop biomarkers to predict patients with greater clinical benefit have focused on alterations of two genes directly mediating sensitivity to these agents: O6-Methylguaninemethyltransferase (MGMT) and Schlafen 11 (SLFN11) but have been limited by availability of tissue samples and have previously used diagnostic samples, and not samples at relapse. Both MGMT and SLFN11 are altered in SCLC by promoter region DNA methylation leading to gene silencing. We have adapted sensitive methods for detection of cell free DNA (cfDNA) from plasma to detect DNA methylation of these two genes. We hypothesize that MGMT methylation and lack of SLFN11 methylation will predict sensitivity in SCLC patients to Niraparib and TMZ. Specific aim 1: We will conduct a multicenter Phase II clinical trial at Lung Precision Oncology Program Sites to assess the efficacy of Temozolomide with Niraparib in biomarker selected relapsed SCLC patients. We will employ a novel cfDNA methylation detection in plasma of MGMT (predicting sensitivity to TMZ) and SLFN11 (predicting resistance to PARPi). Patients with MGMT methylation and lack of SLFN11 methylation will be randomized in a 2:1 fashion to Niraparib with TMZ or Lurbinectedin. Veterans without predicted sensitivity with MGMT unmethylation and SLFN11 methylation will be treated with standard of care lurbinectedin. We will enroll a total number of 152 subjects, with 67 biomarker positive patients receiving TMZ+niraparib, 34 biomarker positive and 51 biomarker negative patients receiving Lurbinectedin on 2 separate arms. The primary endpoint of the study is progression free Survival, with secondary end points of overall Response Rate, overall Survival, and toxicities. Specific aim 2: Determining whether changes of ctDNA, MGMT and SLFN11 methylation in SCLC patients on trial are measures of response and mechanisms of resistance, and whether differentially methylated ctDNA according to SCLC transcriptional subtypes impact response to Niraparib and Temozolomide. We will determine whether changes in level of MGMT or SLFN11 change with treatment, whether circulating tumor DNA levels reflect clinical response and whether certain SCLC subtypes are more sensitive to TMZ/Niraparib combination. Successful completion of this study will provide a new approach in precision oncology for selection of treatment for patients with refractory SCLC. It will demonstrate a blood assay can be used to determine biomarker status in SCLC overcoming all the challenges of tumor sample limitations in SCLC. It will pave the way for personalizing the use of DNA damaging agents in SCLC. This work is critical for Veterans who continue to suffer from SCLC. Project Number: 1I01CX002801-01A1 | Fiscal Year: 2026 | NIH Institute/Center: Veterans Affairs (VA) | Principal Investigator: Shadia Jalal (+1 co-PI) | Institution: RLR VA MEDICAL CENTER, INDIANAPOLIS, IN | Activity Code: I01 | Study Section: Special Emphasis Panel[ZRD1 SPLP-Y (01)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11053925