Radiation Combined With BIspecific T-Cell Engager in DLL3 Expressing Tumors

This is a Phase I, Open label, Single Arm, Multi-center Study, with nested Phase II to examine safety of standard palliative and consolidative RT regimens in a main cohort of patients with tumor histologies with high prevalence of DLL3 (N=20-24) with an extracranial site (primary or metastatic) amenable to radiation (not allowing for re-irradiation of the same lesion, with a minimum of 10 thoracic sites. Given the potential toxicity of ICANS with tarlatamab, once deemed safe in the main cohort, we will allow for expansion for treatment of cranial sites amenable to radiation (excluding lesion re-irradiation except for stereotactic radiosurgery / fractionated stereotactic radiosurgery \[SRS/fSRS\] after prior whole brain RT or prophylactic cranial irradiation \[PCI\]) with continued enrollment in the main cohort. Given the need to determine safety of administration of tarlatamb with RT, if safety is not met for concurrent administration in the main cohort, we would discontinue concurrent treatment, and assess safety in a sequential RT and tarlatamab cohort, as temporal de-escalation. If safety is not met in the sequential cohort, treatment with RT will be discontinued and enrollment will continue with tarlatamab monotherapy, not requiring patients having a site amenable to RT and enriching for patients without SCLC. In the nested phase II, we will assess efficacy of radiation and tarlatamab amongst patients with tumors with high prevalence of DLL3 or those who have positive DLL3 (≥1% per IHC), including but not exclusive to SCLC. This would allow for potential evaluation of safety and response for tumors beyond the DeLLPhi 300/301 studies. The study population will include patients ≥18 years of age with primary/metastatic sites amenable to external beam radiation treatment refractory solid tumors of: 1. small cell histology 2. high grade / poorly differentiated neuroendocrine histology 3. tumor histologies with high prevalence of DLL3 (≥ 50% prevalence), including but not limited to: melanoma, medullary thyroid cancer, sinonasal undifferentiated carcinoma, esthesioneuroblastoma, bladder cancer, testicular cancer, glioblastoma multiforme, cervical cancer; large cell neuroendocrine tumor of lung, non-small cell lung cancers with mixed neuroendocrine features, and Merkel cell carcinoma OR 4. Patients with DLL3+ tumors (≥1% IHC) Up to 30 patients will be enrolled.