Testing the Safety of M6620 (VX-970) When Given With Standard Whole Brain Radiation Therapy for the Treatment of Brain Metastases From Non-small Cell Lung Cancer, Small Cell Lung Cancer, or Neuroendocrine Tumors

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PRIMARY OBJECTIVE: I. To conduct a phase 1 dose escalation trial in patients with brain metastases from non-small cell lung cancer (NSCLC) to determine the recommended phase 2 dose (RP2D) of twice weekly intravenous (i.v.) M6620 (VX-970) administered concurrent with conventionally fractionated whole...

PRIMARY OBJECTIVE: I. To conduct a phase 1 dose escalation trial in patients with brain metastases from non-small cell lung cancer (NSCLC) to determine the recommended phase 2 dose (RP2D) of twice weekly intravenous (i.v.) M6620 (VX-970) administered concurrent with conventionally fractionated whole brain radiotherapy (WBRT), with M6620 (VX-970) starting 18-30 hours after the first dose of radiation (but prior to the second fraction of radiation). SECONDARY OBJECTIVES: I. To estimate the incidence of >= grade 3 delayed neurological toxicity at 2, 4 and 6-months post-completion of whole-brain radiotherapy (for patients without intracranial progression). II. To observe and record anti-tumor activity. IIa. To estimate the radiological response rates (RR) at 6 months including bi-directional and volumetric measurements of lesion size. IIb. To estimate the intracranial 6-month progression-free survival (PFS). EXPLORATORY/HYPOTHESIS GENERATING OBJECTIVES: I. Changes in dynamic susceptibility contrast enhancement (DSC-magnetic resonance imaging [MRI]) perfusion and mean apparent diffusion coefficient (ADC) measurements in diffusion-weighted magnetic resonance imaging (DWI). (Group I) II. To measure cerebrospinal fluid (CSF) M6620 (VX-970) levels, tumor M6620 (VX-970) levels, and pATR T1989, pCHK1 S345 and RAD51 multiplex foci. (Group II) III. Changes in DSC-MRI perfusion and mean ADC measurements in DWI. (Group II) OUTLINE: This is a dose-escalation study of berzosertib. Patients are assigned to 1 of 2 treatment groups. GROUP I: Patients undergo whole-brain radiation therapy once daily (QD), 5 days a week for 15 fractions. Patients also receive berzosertib intravenously (IV) over 60-90 minutes twice a week, 18-30 hours after first radiation therapy. Treatment continues for 3 weeks in the absence of disease progression or unacceptable toxicity. GROUP II: Patients receive berzosertib IV over 60-90 minutes 2-4 hours prior to surgery. After surgery, patients undergo whole-brain radiation therapy and receive berzosertib as in Group I. After completion of study treatment, patients are followed up every 2 months for 6 months, every 3-4 months for 6 months, then every 6 months for 1 year.

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