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
Condition: Metastatic Lung Neuroendocrine Neoplasm; Metastatic Lung Non-Small Cell Carcinoma; Metastatic Lung Small Cell Carcinoma; Metastatic Malignant Neoplasm in the Brain; Stage IV Lung Cancer AJCC v8; Stage IVA Lung Cancer AJCC v8; Stage IVB Lung Cancer AJCC v8
MeSH terms: Carcinoma; Lung Neoplasms; Neoplasms; Brain Neoplasms; Carcinoma, Non-Small-Cell Lung; Neuroendocrine Tumors; Carcinoma, Small Cell; Small Cell Lung Carcinoma
Intervention: Berzosertib; Quality-of-Life Assessment; Therapeutic Conventional Surgery; Whole-Brain Radiotherapy
Intervention description: Given IV; Ancillary studies; Undergo surgery; Undergo whole-brain radiation therapy
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 15.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      This phase I trial studies the side effects and best dose of berzosertib (M6620 [VX-970])
      when given together with whole brain radiation therapy in treating patients with non-small
      cell lung cancer, small cell lung cancer, or neuroendocrine tumors that have spread from the
      original (primary) tumor to the brain (brain metastases). Berzosertib may stop the growth of
      tumor cells by blocking some of the enzymes needed for cell growth. Radiation therapy uses
      high energy x-rays to kill tumor cells and shrink tumors. Giving berzosertib together with
      radiation therapy may work better compared to standard of care treatment, including brain
      surgery and radiation therapy, in treating patients with non-small cell lung cancer, small
      cell lung cancer, or neuroendocrine tumors.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Patients with a histologically confirmed diagnosis of non-small cell lung cancer
             (NSCLC), including neuroendocrine tumors or small cell lung cancer (SCLC) who are
             being evaluated for palliative WBRT (with or without neurosurgical resection or
             stereotactic radiosurgery [SRS]) for radiologically or histologically diagnosed brain
             metastases presumed to be from the lung cancer are eligible for this Phase I study.
             Group 2 will only include NSCLC patients.

          -  Life expectance of greater than two months to allow completion of study treatment and
             assessment of dose-limiting toxicity

          -  Group 2 patients should have archived or fresh tumor tissue available from the
             non-craniotomy site and will have fresh tumor tissue available from the planned
             craniotomy

          -  Age >= 18 years. Because no dosing or adverse event data are currently available on
             the use of M6620 (VX-970, berzosertib) in patients < 18 years of age, children are
             excluded from this study, but will be eligible for future pediatric trials.

          -  Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)

               -  Note: though patients with ECOG performance status of 3 due to neurological
                  deficits who are otherwise fit to receive systemic therapy per clinician
                  assessments will be allowed

          -  Leukocytes >= 3,000/mcL

          -  Absolute neutrophil count (ANC) >= 1,500/mcL

          -  Platelets >= 100,000/mcL

          -  If no known liver metastases: total bilirubin < 1.5 x institutional upper limit of
             normal (ULN); if known liver metastases, then: total bilirubin < 2.5 x ULN

          -  If no known liver metastases: aspartate aminotransferase (AST)/serum glutamic
             oxaloacetic transaminase (SGOT) or alanine aminotransferase (ALT)/serum glutamic
             pyruvic transaminase (SGPT) < 2 x ULN; if known liver metastases, then: AST/SGOT of
             ALT/SGPT < 5 x ULN

          -  Creatinine within normal institutional limits for age OR creatinine clearance >= 45
             mL/min/1.73 m^2 for patients with creatinine levels above ULN

          -  Negative serum or urine pregnancy test result for females of child bearing potential

               -  The effects of M6620 (VX-970, berzosertib) on the developing human fetus are
                  unknown. For this reason and because radiation therapy is known to have
                  teratogenic potential, women of child-bearing potential and men must agree to use
                  adequate contraception (hormonal or barrier method of birth control; abstinence)
                  prior to study entry and for the duration of study participation. Should a woman
                  become pregnant or suspect she is pregnant while she or her partner is
                  participating in this study, she should inform her treating physician
                  immediately. Men treated or enrolled on this protocol must also agree to use
                  adequate contraception prior to the study, for the duration of study
                  participation, and 6 months after completion of M6620 (VX-970, berzosertib)
                  administration.

          -  Ability to understand and the willingness to sign a written informed consent document

        Exclusion Criteria:

          -  Patients with 1-3 brain metastases, each < 3 cm by contrast MRI, with stable systemic
             disease and ECOG score of 0-2, who would otherwise be eligible for SRS/stereotactic
             radiation therapy (SRT) alone should not be enrolled into this study unless WBRT is
             recommended due to any medical reasons or logistic limitations as determined by the
             treating physician. Patients who develop recurrence post-SRS/SRT or surgery alone and
             are recommended WBRT will be eligible for the protocol.

          -  Greater than 1 cm mid-line shift, severe uncal herniation or significant
             hemorrhage/hydrocephalus (intra-lesional hemorrhage is acceptable). Patients with
             seizure at presentation who have been started on levetiracetam and have been stable
             for 48 hours prior to study registration are eligible at the discretion of treating
             physician

          -  Patients who have received systemic cytotoxic chemotherapy and/or, immunotherapy or
             other intravenous standard therapy for 2 weeks before initiation of planned WBRT, for
             oral targeted agents 3-7 days per clinician discretion or patients who have not
             recovered to Common Terminology Criteria for Adverse Events (CTCAE) grade 2 or less
             from serious (CTCAE grade 3 or more) adverse events form the previously received
             agents. For any other investigational agents, at least 4 half-lives of the agent (6
             weeks for nitrosoureas or mitomycin C) should have elapsed prior to starting study
             treatment

          -  Patients must not have received prior WBRT (previous SRS/SRT done at least 2 weeks
             from the planned start of WBRT is acceptable). Patients planned upfront to undergo
             SRS/SRT/fractionated boosts or neurosurgery after WBRT are not eligible; however,
             these treatments/procedures can be performed once the dose limiting toxicity (DLT)
             assessment has been completed, if felt clinically necessary

          -  Pregnant women are excluded from this study because M6620 (VX-970, berzosertib) as a
             deoxyribonucleic acid (DNA)-damage response (DDR) inhibitor may have the potential for
             teratogenic or abortifacient effects. Further, radiation therapy is known to have the
             potential for teratogenic or abortifacient effects. Because there is an unknown but
             potential risk for adverse events in nursing infants secondary to treatment of the
             mother with M6620 (VX-970, berzosertib), breastfeeding should be discontinued if the
             mother is treated with M6620 (VX-970, berzosertib).

          -  History of allergic reactions attributed to compounds of similar chemical or biologic
             composition to M6620 (VX-970, berzosertib).

          -  M6620 (VX-970, berzosertib) is primarily metabolized by cytochrome P450, family 3,
             subfamily A, polypeptide 4 (CYP3A4); therefore, concomitant administration with strong
             inhibitors or inducers of CYP3A4 should be avoided. Because the lists of these agents
             are constantly changing, it is important to regularly consult a frequently-updated
             medical reference for a list of drugs to avoid or minimize use of. As part of the
             enrollment/informed consent procedures, the patient will be counseled on the risk of
             interactions with other agents, and what to do if new medications need to be
             prescribed or if the patient is considering a new over-the-counter medicine or herbal
             product. Ongoing phenytoin should be either discontinued if clinically safe or
             transitioned to non-enzyme-inducing antiepileptics like levetiracetam with a 8-day
             washout period (half-life 18-22 hours, time to steady-state 4-8 days) prior to first
             dose of M6620 (VX-970, berzosertib) (7-days prior to WBRT).

          -  Patients needing more than 8 mg dexamethasone per day at the time of start of WBRT
             will not be eligible to participate in the study. However, patients will be allowed
             entry into the study if it is medically safe to reduce the daily dose of dexamethasone
             to 8 mg or less from the day of the start of WBRT. The dexamethasone dose for such
             patients may be increased beyond 8 mg per day during the course of treatment if
             medically necessary. This increased need for dose should be communicated to the
             study's principal investigator, Dr Mohindra at the University of Maryland.

          -  Uncontrolled intercurrent illness that would increase the risk of toxicity or limit
             compliance with study requirements. This includes but is not limited to, ongoing
             uncontrolled serious infection requiring i.v. antibiotics at the time of registration,
             or psychiatric illness/social situations that would limit compliance with study
             requirements

          -  Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral
             therapy are ineligible because of the potential for pharmacokinetic interactions with
             M6620 (VX-970, berzosertib) and the uncertainties of any impact thereof on the
             radiation toxicities. In addition, these patients are at increased risk of lethal
             infections when treated with marrow-suppressive therapy. Appropriate studies will be
             undertaken in patients receiving combination antiretroviral therapy when indicated.

          -  Patients with known diagnoses that are associated with germline DDR defects such as Li
             Fraumeni syndrome and ataxia telangiectasia are excluded from the study as M6620
             (VX-970, berzosertib) is a DDR inhibitor.