NANETS2022 15th Annual Multidisciplinary NET Medical Symposium NANETS 2022 Trials In Progress (10 abstracts)
Phase Ia/Ib Study of BAY1895344 Plus Topoisomerase I Inhibitors with a Focus on Poorly Differentiated Neuroendocrine Carcinomas and Pancreatic Adenocarcinoma
Shannon Stockton 1 , G. Dan Ayers 1 , Michael Cecchini 2 , Raid Ajumaily 3 , Jennifer Whisenant 1 , Steven Gore 4 , Percy Ivy 4 , Patricia LoRusso 2 , Jordan Berlin 1 & Satya Das 1
1Vanderbilt University Medical Center, Ingram Cancer Center, Nashville, TN; 2Yale University Cancer Center, New Haven, CT; 3Oklahoma University Health Stephenson Cancer Center, Oklahoma City, OK; 4National Cancer Institute, Cancer Therapeutics Evaluation Program, Bethesda, MD.
Background: Advanced small cell lung cancer (SCLC), extra-pulmonary neuroendocrine carcinoma (EP-NEC) and pancreatic adenocarcinoma (PDA) are rapidly progressive cancers characterized by unbridled replication stress. Patients with these malignancies possess dismal prognoses with limited options after initial first-line chemotherapy. These tumors rely on the integrity of DNA damage repair pathways to ensure genomic stability. The ataxia telangiectasia and Rad3-related (ATR) protein kinase is a potential therapeutic target in these cancers and is activated by replication stress. The ATR inhibitor BAY 1895344 has demonstrated cytotoxic potential in SCLC and gastrointestinal cancer xenografts in combination with the topoisomerase I(TopI) inhibitors topotecan and irinotecan. We developed a phase I study combining BAY 1895344 with irinotecan or topotecan.
Methods: NCT04514497 is a phase Ia/Ib study with 3 dose escalation cohorts (irinotecan IV D1 plus BAY 1895344 PO BID D1, D2 Q14 days; irinotecan IV D1,8,15 plus BAY 1895344 QD D1-D3, D8-10 and D15-17 Q21 days; topotecan IV D1-D5 plus BAY 1895344 PO QD D2, D5 Q21 days) and 3 dose expansion cohorts. Primary objectives are to assess safety and tolerability and estimate the maximum tolerated dose and recommended phase 2 dose of the combinations. Secondary objectives include estimating pharmacokinetic profiles and assessing anti-tumor activity of the combinations. In dose escalation, patients with refractory advanced solid tumors for whom TopI inhibitors are considered SOC are eligible. In dose expansion, patients must have SCLC, EP-NEC (large cell or small cell histology mandated) or PDA. Dose escalation will utilize a 3+3 design. Biopsies for pharmacodynamic DNA damage biomarker assessment are required in dose expansion. The tissue-based correlative studies are outlined in Table 1.
Results: The trial is currently enrolling patients.
| Biomarker | Phase of Study | Time of Collection | Purpose | Mandatory (M)/Optional (O) |
| &unix263;H2AX, pNBS1 | Dose Expansion | D-7 C1D3 | Measure DNA damage biomarkers | M |
| Whole Exome Sequencing, RNA Sequencing | Dose Expansion, Escalation | Archival | Determine if certain mutations or expression of DNA damage repair genes predict treatment sensitivity | O |
| ATM | Dose Expansion, Escalation | Archival | Identify pts with tumors responsive to ATR inhibition | O |
Conclusion: Anti-tumor activity has been observed with the ATR inhibitor berzosertib in combination with topotecan in patients with SCLC and EP-NEC. Based upon the potential best-in-class cytoreductive capacity of BAY 1895344 preclinically compared with other ATR inhibitors, we are hopeful that TopI inhbitors plus BAY 1895344 will represent safe and meaningful treatment options for patients with SCLC and EP-NEC which can be carried forward to more definitive efficacy-assessing studies.
Abstract ID 21375
Volume 89
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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